Synthesis of Functionalized Organic Molecules Using Copper Catalyzed

Duquesne University Duquesne Scholarship Collection

Electronic Theses and Dissertations

Fall 2011 Synthesis of Functionalized Organic Molecules Using Copper Catalyzed Cyclopropanation, Atom Transfer Radical Reactions and Sequential Azide- Alkyne Cycloaddition Carolynne Lacar Ricardo

Follow this and additional works at: https://dsc.duq.edu/etd

Recommended Citation Ricardo, C. (2011). Synthesis of Functionalized Organic Molecules Using Copper Catalyzed Cyclopropanation, Atom Transfer Radical Reactions and Sequential Azide-Alkyne Cycloaddition (Doctoral dissertation, Duquesne University). Retrieved from https://dsc.duq.edu/etd/1099

This Immediate Access is brought to you for free and open access by Duquesne Scholarship Collection. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of Duquesne Scholarship Collection. For more information, please contact [email protected].

SYNTHESIS OF FUNCTIONALIZED ORGANIC MOLECULES USING COPPER

CATALYZED CYCLOPROPANATION, ATOM TRANSFER RADICAL

REACTIONS AND SEQUENTIAL AZIDE-ALKYNE CYCLOADDITION

A Dissertation

Submitted to the Bayer School of Natural and Environmental Sciences

Duquesne University

In partial fulfillment of the requirements for

the degree of Doctor of Philosophy

Carolynne Lacar Ricardo

December 2011

Carolynne Lacar Ricardo

2011

SYNTHESIS OF FUNCTIONALIZED ORGANIC MOLECULES USING COPPER

CATALYZED CYCLOPROPANATION, ATOM TRANSFER RADICAL

REACTIONS AND SEQUENTIAL AZIDE-ALKYNE CYCLOADDITION

Carolynne Lacar Ricardo

Approved November 16, 2011

______Dr. Tomislav Pintauer Dr. Partha Basu Associate Professor of Chemistry and Professor of Chemistry and Biochemistry Biochemistry Committee Member Committee Chair

______Dr. Jeffrey D. Evanseck Dr. Nicolay V. Tsarevsky Professor of Chemistry and Biochemistry Assistant Professor Committee Member Southern Methodist University External Reviewer

______David W. Seybert Dr. Ralph A. Wheeler Dean, Bayer School of Natural and Chair, Department of Chemistry and Environmental Sciences Biochemistry Professor of Chemistry and Professor of Chemistry and Biochemistry Biochemistry

iii ABSTRACT

SYNTHESIS OF FUNCTIONALIZED ORGANIC MOLECULES USING COPPER

CATALYZED CYCLOPROPANATION, ATOM TRANSFER RADICAL

REACTIONS AND SEQUENTIAL AZIDE-ALKYNE CYCLOADDITION

Carolynne Lacar Ricardo

December 2011

Dissertation supervised by Dr. Tomislav Pintauer

Copper-catalyzed regeneration in atom transfer radical addition (ATRA) utilizes reducing agents, which continuously regenerate the activator (CuI) from the deactivator

(CuII) species. This technique was originally found for mechanistically similar atom transfer radical polymerization (ATRP) and its application in ATRA and ATRC has allowed significant reduction of catalyst loadings to ppm amounts. In order to broaden the synthetic utility of in situ catalyst regeneration technique, this was applied in copper- catalyzed atom transfer radical cascade reaction in the presence of free radical diazo initiators such as 2,2‘-azobis(isobutyronitrile) (AIBN) and (2,2‘-azobis(4-methoxy-2,4- dimethyl valeronitrile) (V-70), which is the first part of this dissertation. This methodology can be translated to sequential ATRA/ATRC reaction, in which the addition

iv of CCl4 to 1,6-dienes results in the formation 5-hexenyl radical intermediate, which undergoes expedient 1,5-ring closure in the exo- mode to form 1,2-disubstituted cyclopentanes. When [CuII(TPMA)Cl][Cl] complex was used in conjunction with AIBN

0 at 60 C, cyclic products derived from the addition of CCl4 to 16-heptadiene, diallyl ether and N,N-diallyl-2,2,2-trifluoroacetamide were synthesized in nearly quantitative yields using as low as 0.02 mol% of the catalyst (relative to 1,6-diene). Even more impressive were the results obtained utilizing tert-butyl-N,N-diallylcarbamate and diallyl malonate using only 0.01 mol% of the catalyst. Cyclization was also found to be efficient at ambient temperature when V-70 was used as the radical initiator. High product yields

(>80%) were obtained for mixtures having catalyst concentrations between 0.02 and 0.1 mol%. Similar strategy was also conducted utilizing unsymmetrical 1,6-diene esters. It was found out that dialkyl substituted substrates (dimethyl-2-propenyl acrylate and ethylmethyl-2-propenyl acrylate) underwent 5-exocyclization producing halogenated -

II lactones after the addition of CCl4 in the presence of 0.2 mol% of [Cu (TPMA)Cl][Cl].

Based on calculations using density functional theory (DFT) and natural bond order

(NBO) analysis, cyclization of 1,6-diene esters was governed by streoelectronic factors.

As a part of broadening the synthetic usefulness of in situ copper(I) regeneration, scope was further extended to sequential organic transformations. Based on previous studies, copper(I) catalyzed [3+2] azide-alkyne cycloaddition is commonly conducted via in situ reduction of CuII to CuI species by sodium ascorbate or ascorbic acid. At the same time, ATRA reactions have been reported to proceed efficiently via in situ reduction of

CuII complex to the activator species or CuI complex has been fulfilled in the presence of ascorbic acid. Since the aforementioned reactions share similar catalyst in the form of

v copper(I), a logical step was taken in performing these reactions in one-pot sequential manner. Reactions involving azidopropyl methacrylate and 1-(azidomethyl)-4- vinylbenzene in the presence of a variety of alkynes and alkyl halides, catalyzed by as low as 0.5 mol-% of [CuII(TPMA)X][X] (X=Br-, Cl-) complex, proceeded efficiently to yield highly functionalized (poly)halogenated esters and aryl compounds containing triazolyl group in almost quantitative yields (>90%). Additional reactions that were carried out utilizing tri-, di- and monohalogenated alkyl halides in the ATRA step provided reasonable yields of functionalized trriazoles. A slightly different approach involving a ligand-free catalytic system (CuSO4 and ascorbic acid) in the first step followed by addition of the TPMA ligand in the second step was applied in the synthesis of polyhalogened polytriazoles. Sequential reactions involving vinylbenzyl azide, tripropargylamine and polyhalogenated methane (CCl4 and CBr4) provided the desired products in quantitative yield in the presence of 10 mol% of the catalyst. Modest yields of functionalized polytriazoles were obtained from the addition of less active tri- and dihalogenated alkyl halides utilizing the same catalyst loading.

The last part focuses on copper(I) complexes, which were used catalysts in cyclopropanation reaction. One class represented cationic copper(I)/2,2-bipyridine

I - complexes with -coordinated styrene [Cu (bpy)(-CH2CHC6H5)][A] (A = CF3SO3 (1)

- - and PF6 (2) and ClO4 (3). Structural data suggested that the axial coordination of the counterion in these complexes observed in the solid state weak to non-coordinating

(2.4297(11) Å 1, 2.9846(12) Å 2, and 2.591(4) Å 3). When utilized in cyclopropanation, complexes 1-3 provided similar product distribution suggesting that counterions have negligible effect on catalytic activity. Furthermore, the rate of decomposition of EDA in

vi -3 -1 the presence of styrene catalyzed by 3 (kobs=(7.7±0.32)10 min ) was slower than the

-2 -1 -2 -1 rate observed for 1 (kobs=(1.4±0.041)10 min ) or 2 (kobs=(1.0±0.025)10 min ). On the other hand, tetrahedral copper(I) complexes with bipyridine and phenanthroline based ligands have been reported to have strongly coordinated tetraphenylborate anions.

I I I Cu (bpy)(BPh4), Cu (phen)(BPh4) and Cu (3,4,7,8-Me4phen)(BPh4) complexes are the

- first examples in which BPh4 counterion chelates a transition metal center in bidentate fashion through 2 -interactions with two of its phenyl rings. The product distribution revealed that the mole percent of trans and cis cyclopropanes were very similar. The observed rate constants (kobs) shown in for decomposition of EDA in the presence of

-3 -1 externally added styrene were determined to be kobs=(1.5±0.12)10 min ,

(6.8±0.30)10-3 min-1 and (5.1±0.19)10-3 min-1.

vii DEDICATION

To my late Lolo Miguel

viii ACKNOWLEDGEMENT

I owe my deepest gratitude to my advisor, Dr. Tomislav Pintauer for his excellent mentorship and constant encouragement throughout my Ph.D pursuit. He has always believed in my abilities and trusted me with several projects, which at first I thought were elusive. Although they have been very challenging, they served as stepping-stones for intellectual and professional advancement. It has been a great opportunity performing research under his tutelage for he taught me consciously and unconsciously to be highly motivated and meticulous in everything that I undertake. Overall, he always made sure that good science and hard work were never put in vain.

The members of my dissertation committee, Dr. Partha Basu and Dr. Jeffrey D.

Evanseck are greatly acknowledged for without whose knowledge, constructive criticisms and insightful comments, this dissertation would have been unsuccessful.

I am very much indebted to Dr. Nicolay Tsarevsky, who agreed to be my external reader, despite the limited time and busy schedule. The comments and suggestions he provided significantly contributed to the improvement of the whole dissertation.

One of the top reasons for being so productive in research because I was so fortunate to work with Dr. Marielle Balili and Dr. William Eckenhoff, whose intellect and enthusiasm in research have been very contagious. Their ideas during group discussions have supplemented me with a broader understanding of my research. In addition to the pleasant working atmosphere, I am also thankful for fostering a good friendship, which is very reminiscent from all the pictures we had in the lab, conferences and group gatherings.

ix Before Matthew Taylor, Ashley Biernesser and Sean Noonan joined the group, the lab was so quiet. Thanks to them for creating a fun environment by bringing humor, entertainment and friendship. It has been a wonderful experience to work with the most brilliant undergraduate students for I turned to them for answers to my questions and clarifications to concepts that I often fail to remember.

Special mention is also extended to my groupmates Rajbhupinder Kaur and Dr.

Kayode Oshin for the worthy advice during group presentations and taking part in lab duties. I am also grateful to work with the current undergraduate students, Tom Ribelli and Matthew Holtz, who know how to value research.

The career grant endowed by the National Science Foundation is greatly acknowledged as it enabled me to realize all the different projects entrusted to me.

Some of the pages of this dissertation would have not been printed without turning to some people at the department. Venkatta S. Pakkala willingly accepted the collaboration on the computational studies. Dr. Stephanie Wetzel spared her time for interpreting the data and Rebecca Wagner helped me on mass spectroscopic analyses.

I would also like to convey thanks to the staff at Duquesne University, whose services have been very crucial for my progress. Dan Bodnar, Lance Crosby and Dave

Hardesty, have always been around maintaining and fixing the equipment I broke, especially the NMR. Amy Stroyne and Sandy Russell, have cheerfully assisted me in most of the paperworks, setting schedules, reserving conference rooms and sending out important documents. Dr. Ian Welsh, has always been reliable in purchasing the right reagents and glasswares and even chose high-quality orders at cheaper prices. Heather

x Costello is very much appreciated for her running things smoothly for graduate students and always ready to entertain queries.

Pursuing graduate school has its rough times but I have been surrounded with friends who kept me stay sane. Dr. Anna K. Javier, has always been on the end of the line ready to lend an ear to all my sentiments and frustrations. Iyad Batal deserves special mention for helping me to stay focused and giving me access to all the journals I needed.

Tita Luz Teodoro became so close to me as if she is my second mother. Linh Nguyen, I am very fortunate to have her as a roommate who is very sincere and understanding. To the members of the Pinoy Graduate Asssociation in Pittsburgh, I cherish the times singing the karaoke and hanging out. Mabuhay mga taga-UP, mabuhay mga gwapo at gwapa!

My heartfelt gratitude goes to my relatives (Lacar and Agas families) and family friends for all the moral support and prayers. They taught me that the keys towards success are striving hard without the expense of others and humility.

I am very grateful to my siblings, Dr. Mary Janice L. Ricardo and Engr. Jelwyn

Jerome L. Ricardo for their concern and unflagging support. I have missed many important events but they always understood absence. I am so delighted to have Kaye R.

Ricardo as my sister-in-law for being patient with our family. To my cousin, Kimberly L.

Velota, talking to her once in a while takes away my worries.

No words can express how indebted I am to my amazing mama, Dr. Luz L.

Ricardo for her nurturing love and prayers. She is very effective in instilling the value of education and fulfilling chosen endeavor.

To God, Almighty Father, I owe my success from Him for he never ceased to listen to my prayers.

xi TABLE OF CONTENTS

ABSTRACT ...... iv

DEDICATION ...... viii

ACKNOWLEDGEMENT ...... ix

LIST OF SCHEMES ...... xix

LIST OF FIGURES ...... xxii

LIST OF TABLES ...... xxxi

Chapter 1 ...... 1

1.1 Atom Transfer Radical Addition and Cyclization ...... 2

1.1.1 Origins of Transition Metal Catalyzed Atom Transfer Radical Addition (TMC ATRA) ...... 2

1.1.2 Proposed Catalytic Cycle of Transition Metal Catalyzed Atom Transfer Radical Addition and Cyclization (TMC ATRA and ATRC)...... 3

1.1.3 Basic Components of TMC ATRA and ATRC ...... 6

1.1.4 Synthetic Applications of TMC ATRA and ATRC ...... 10

1.1.5 Copper Catalyzed Atom Transfer Radical Cascade or Domino Reactions ... 16

1.1.6 Towards a ―Greener‖ TMC ATRA and ATRC Strategy ...... 18

1.1.4.1 Solid Supported Catalysts ...... 19

1.1.4.2 Biphasic System ...... 20

1.1.4.3 Development of Highly Active Ligands for ATRA and ATRC ...... 21

1.1.4.4 Catalyst Regeneration Technique ...... 22

1.1.7 Highly Efficient TMC ATRA Reactions in the Presence of Reducing Agents 23

1.1.8 Atom Transfer Radical Cyclizations in the Presence of Reducing Agents ... 30

xii 1.1.9 Catalyst Regeneration Technique in Sequential Organic Transformations .. 32

1.1.10 Section Summary and Project Overview...... 41

1.2 Click Chemistry ...... 42

1.2.1 Click Chemistry as a Guiding Principle ...... 42

1.2.2 Copper-Catalyzed Azide-Alkyne Cycloadditon (CuAAC): The Center Stage of Click Chemistry ...... 43

1.2.3 Mechanism of Copper(I)-Catalyzed Azide-Alkyne [3+2] Cycloaddition..... 46

1.2.4 Applications of CuI Catalyzed Azide-Alkyne Cycloaddition ...... 48

1.2.4.1 Bioconjugation ...... 48

1.2.4.2 Drug Discovery ...... 48

1.2.4.3 Material Science and Polymer Chemistry ...... 49

1.2.5 Sequential and Simultaneous Click Chemistry and ATRP ...... 53

1.2.6 Section Summary and Project Objective ...... 62

1.3 Cyclopropanation Reaction ...... 63

1.3.1 Historical Perspective of Copper-Catalyzed Cyclopropanation ...... 65

1.3.2 Mechanism of Copper-Mediated Cyclopropanation Reaction ...... 66

1.3.3 Aspects of Reaction ...... 69

1.3.3.1 Role of Olefin Coordination ...... 69

1.3.3.2 Role of Counterion ...... 70

1.3.4 Asymmetric Cyclopropanation ...... 72

1.3.4.1 Origin of Trans/Cis Selectivity ...... 72

1.3.4.2 Enantioselectivity ...... 73

1.3.4.3 Chiral Ligands in Achieving Enantioselectivity ...... 74

1.3.5 Section Summary and Project Overview...... 81

1.3 References ...... 82

xiii Chapter 2 ...... 119

2.1 Introduction ...... 119

2.2 Atom Transfer Radical Addition to 1,5-Hexadiene ...... 123

2.3 Atom Transfer Radical Cascade Reactions Involving 1,6-Dienes ...... 130

2.4 Summary and Conclusions ...... 134

2.5 Experimental ...... 135

2.5.1 General Procedures ...... 135

2.5.2 Copper Catalyzed Atom Transfer Radical Reactions Involving 1,5- Hexadiene ...... 136

2.5.3 Product Characterization ...... 138

2.5.4 Copper Catalyzed Atom Transfer Radical Reactions Involving 1,6- Dienes 139

2.6 References ...... 141

Chapter 3 ...... 146

3.1 Introduction ...... 147

3.2 Copper-Catalyzed Addition of Carbon Tetrachloride in the Presence of Reducing Agents ...... 150

3.3 Density Functional Theory Calculations...... 158

3.4 Summary and Conclusions ...... 166

3.5 Experimental ...... 167

3.5.1 General Procedures ...... 167

3.5.2 Synthesis of 1,6-Diene Esters ...... 167

3.5.3 General Procedure for [CuII(TPMA)Cl][Cl] and AIBN Catalyzed Atom Transfer Radical Addition of CCl4 to Unsymmetrical Diene Esters...... 168

3.5.4 Product Characterization ...... 169

3.5.5 Computational Methods ...... 170

3.6 References ...... 172

xiv Chapter 4 ...... 180

4.1 Introduction ...... 181

4.2 Copper-Catalyzed [3+2] Azide-Alkyne Cycloaddition ...... 186

4.3 Copper-Catalyzed [3+2] Azide-Alkyne Cycloaddition ...... 187

4.4 Sequential Azide-Alkyne [3+2] Cycloaddtion and Atom TransferRadical Addition (ATRA) ...... 189

4.5 Summary and Conclusions ...... 196

4.6 Experimental ...... 196

4.6.1 General Procedures ...... 196

4.6.2 Stock Solutions ...... 197

4.6.3 General Procedure for Azide-Alkyne [3+2] Cycloaddition Catalyzed by [CuII(TPMA)Cl][Cl] in the Presence of Ascorbic Acid...... 197

4.6.4 General Procedure for Sequential Azide-Alkyne [3+2] Cycloaddition-Atom Transfer Radical Addition Catalyzed by [CuII(TPMA)Cl][Cl] in the Presence of Ascorbic Acid ...... 198

4.6.5 X-ray Crystal Structure Determination ...... 198

4.6.6 Product Characterization ...... 199

4.7 References ...... 208

Chapter 5 ...... 215

5.1 Introduction ...... 216

5.2 Results and Discussion ...... 220

5.3 Summary and Conclusions ...... 229

5.4 Experimental ...... 230

5.4.1 General Procedures ...... 230

5.4.2 Stock Solutions ...... 231

5.4.3 Copper-Catalyzed [3+2] Azide-Alkyne Cycloaddition between 4- Vinylbenzyl Azide and Tripropargylamine ...... 231

xv 5.4.4 General Procedure for the ATRA of Alkyl Halides to TVBTA Catalyzed by [CuII(TPMA)X][X] (X= Cl- or Br-) and Ascorbic Acid ...... 231

5.4.5 General Procedure for Sequential Copper Catalyzed [3+2] Cycloaddition and Atom Transfer Radical Addition in the Presence of Ascorbic Acid ...... 232

5.4.6 Product Characterization ...... 233

5.7 References ...... 235

Chapter 6 ...... 243

6.1 Introduction ...... 244

6.2 Results and Discussion ...... 247

6.2.1 X-ray crystallography ...... 247

6.2.2 1H NMR and FT-IR Characterization ...... 252

6.2.3 Cyclopropanation Studies ...... 254

6.3 Summary and Conclusion ...... 257

6.4 Experimental ...... 257

6.4.1 General ...... 257

I 6.4.2 [Cu (bpy)(-CH2=CHC6H5)][CF3SO3] (1) ...... 259

I 6.4.3 [Cu (bpy)(-CH2=CHC6H5)][PF6]*1/2CH2=CHC6H5 (2) ...... 259

I 6.4.4 [Cu (bpy)(-CH2=CHC6H5)][ClO4] (3)...... 260

6.4.5 General procedure for cyclopropanation of styrene ...... 260

6.4.6 Kinetic studies ...... 261

6.4.7 X-ray Crystallography ...... 261

6.5 References ...... 262

Chapter 7 ...... 267

7.1 Introduction ...... 267

7.2 Results and Discussion ...... 269

7.3 Summary and Conclusions ...... 278

xvi 7.4 Experimental ...... 278

7.4.1 General Procedures ...... 278

I 7.4.2 Synthesis of Cu (BPh4)(CH3CN) ...... 279

I 7.4.3 Synthesis of Cu (BPh4)(3,4,7,8-Me4phen) (1) ...... 280

I 7.4.4 Synthesis of Cu (BPh4)(bpy) (2) ...... 280

I 7.4.5 Synthesis of Cu (BPh4)(phen) (3) ...... 281

7.4.6 General Procedure for Cyclopropanation of Styrene ...... 281

7.4.7 Kinetic Studies...... 282

7.4.8 X-ray Crystal Structure Determination...... 282

7.4.9 DFT Calculations ...... 283

7.5 References ...... 283

AppendixA ...... 286

Spectroscopic Data for Products Obtained from Copper-Catalyzed Atom Transfer Radical Cascade Reactions in the Presence of Diazo Radical Initiators as Reducing Agents...... 286

Appendix B ...... 300

B.1 Spectroscopic Data ...... 300

Appendix C ...... 308

C.1 Spectroscopic Data of Products Obtained from One-Pot Sequential Azide-Alkyne [3+2] Cycloaddition and Atom Transfer Radical Addition (ATRA) ...... 308

C.2 Crystallographic Information ...... 349

Appendix D ...... 355

D.1 1H and 13C Spectroscopic Data of Functionalized Polytriazoles...... 355

D.2 High Resolution Mass Spectroscopic Data of Functionalized Polytriazoles ..... 367

Appendix E ...... 373

Crystallographic Information ...... 373

xvii Appendix F ...... 374

Data for Copper(I) Bipyridine and Phenanthroline Based Complexes and their Effect on Catalytic Activity in Cyclopropanation of Styrene ...... 374

xviii LIST OF SCHEMES

Scheme 1.1. Kharasch Addition of Halogenated Compound to Alkene...... 2

Scheme 1.2. Iron-Catalyzed ATRA of CCl4 to Acrylonitrile...... 3

Scheme 1.3. Proposed Catalytic Cycle for TMC ATRA...... 5

Scheme 1.4. Proposed Catalytic Cycle for Transition Metal Catalyzed Atom Transfer Radical Cyclization...... 6

Scheme 1.5. Tributylstannane (Bu3SnH) and Iodine Halogen Atom Transfer...... 10

Scheme 1.6. Synthesis of Quercus Lactone via Copper-Catalyzed ATRC...... 13

Scheme 1.7. Copper Catalyzed ATRC of -Chloroglycine Derivatives to 3-(1- Chloroalkyl)-Substituted Proline...... 14

Scheme 1.8. Copper Catalyzed Domino or Cascade Reactions in the Synthesis of Bicyclic Compounds...... 17

Scheme 1.9. Formation of Spiro-Indole via Sequential Radical Cyclization...... 18

Scheme 1.10. Transition Metal Catalyzed ATRA in the Presence of Reducing Agents. . 23

Scheme 1.11. Proposed Reduction of CuII Complex to CuI Complex in the Presence of Ascorbic Acid.128...... 29

Scheme 1.12. Sequential ATRA/Reductive Dehalogenation in the Formation of Cyclopropane...... 35

Scheme 1.13. Synthesis of 1,5-Dichlorides via One-Pot Consecutive ATRA Reactions Catalyzed by RuIII Complex in the Presence of Mg.175 ...... 36

Scheme 1.14. Synthesis of 1,5- Cyclopentane via Sequential ATRA and ATRC Reactions Catalyzed by RuIII Complex in the Presence of Mg.175 ...... 37

Scheme 1.15. Copper-Catalyzed ATRA of CCl4 to 1,6-Dienes in the Presence of Reducing Agents...... 39

Scheme 1.17. Thermal- and Copper(I)-Catalyzed Huisgen 1,3-Dipolar Cycloaddtion. ... 44

Scheme 1.18. Proposed Catalytic Cycle of Copper-Catalyzed Azide-Alkyne Cycloaddition...... 47

xix Scheme 1.19. First Examples of Sequential ATRP and Click Chemistry.241,242,255 ...... 56

Scheme 1.20. Functional Macrocyclic (a)277 and ABC Block Copolymers (b)278 Synthesized via Sequential ATRP and Click Reactions...... 57

Scheme 1.21. Reactions Performed via One-Pot Sequential ATRP and Click Chemistry.281-283 ...... 60

Scheme 1.22. One-Pot, Simultaneous ATRP and Click Chemistry.261,284,285 ...... 61

Scheme 1.23. Synthetic Methodologies Involved in Cyclopropane Formation...... 64

Scheme 1.24. Proposed Catalytic Cycle for Copper-Catalyzed Cyclopropanation ...... 68

Scheme 1.25. Origin of Trans/Cis Selectivity ...... 72

Scheme 1.26. Origin of Enantioselectivity331 ...... 74

Scheme 2.1 Example of copper-Catalyzed Atom Transfer Radical Cascade Reaction. . 120

Scheme 2.2. Transition Metal Catalyzed Atom Transfer Radical Addition in the Presence of Reducing Agents...... 122

Scheme 2.3. Observed Products in the Addition of Polyhalogenated Methanes to 1,5- Hexadiene...... 123

Scheme 2.4. Ring-closure Pathways of 5-Pentenyl Radical...... 125

Scheme 2.5. Proposed Pathways for the Cyclization of Compound A Resulting in the Formation of Cyclic Products B and C...... 126

Scheme 2.6. ATRC Pathways in the Addition of Polyhalogenated Compounds to 1,6- Hexadiene Catalyzed by Copper Complexes...... 131

Scheme 3.1. Catalyst regeneration in ATRA in the presence of reducing agents...... 148

Scheme 3.2. Open-chain adducts as a result of radical trapping via halide transfer from CuII complex...... 151

Scheme 3.3. Conformations of the ester derived radical...... 155

Scheme 3.4. 5-Exocyclization of allyl ester radical leading to the formation of -lactone...... 158

Scheme 4.1 Proposed Mechanism for Copper-Catalyzed [3+2] Azide-Alkyne Cycloaddition.7,8 ...... 182

Scheme 4.2. Proposed Mechanism for Copper-Catalyzed Atom Transfer Radical Addition (ATRA) in the Presecence of Reducing Agents...... 184

xx Scheme 4.3. Copper-catalyzed azide-alkyne cycloaddition and atom transfer radical addition...... 186

Scheme 4.4. Structures of alkynes used in azide-alkyne [3+2] cycloaddition and atom transfer radical addition...... 187

Scheme 5.1. Proposed Mechanism for Copper Catalyzed Azide-Alkyne [3+2] Cycloaddition...... 217

Scheme 5.2. Proposed Mechanism for Copper Catalyzed Atom Transfer Radical Addition (ATRA) in the Presence of Reducing Agents...... 219

Scheme 5.3. Sequential Copper-Catalyzed Azide-Alkyne Cycloaddition and ATRA. .. 222

Scheme 6.1. Proposed mechanism for copper(I)/2,2‘-bipyridine catalyzed cyclopropanation of olefins...... 245

Scheme 6.2 Structures of cationic copper(I)/alkene complexes with bidentate nitrogen based ligands...... 246

Scheme 7.1. Proposed mechanism for copper(I) catalyzed cyclopropanation of alkenes...... 268

Scheme 7.2. Synthesis of copper(I) complexes 1-3...... 272

xxi LIST OF FIGURES

Figure 1.1. Alkyl halides and alkenes commonly used in ATRA...... 6

Figure 1.2. Halogenated Olefinic and Propargylic Substrates for ATRC...... 7

Figure 1.3. Nitrogen-Based Ligands Utilized in Copper-Mediated Atom Transfer Radical Reactions...... 9

Figure 1.4. Examples Solid Supported Catalysts ...... 20

Figure 1.5. Perfluorinated Ligands for Copper-Catalyzed ATRC...... 21

Figure 1.6. Selected Reactions Fulfilling Click Chemistry Criteria...... 43

Figure 1.7. N-Based Ligands Used to Promote Cu(I)-Catalyzed Triazole Formation...... 46

Figure 1.8. Functional Initiator (a), Monomers (b), Post-Polymerization Modification (c) and Clickable Macromonomers (d-f) Utilized in Combined ATRP and Azide-Alkyne Cycloaddition...... 51

Figure 1.9. Representative Macromolecular Structures Constructed via ATRP and Click Chemistry...... 52

Figure 1.10. First examples of copper complexes employed in asymmetric cyclopropanation...... 66

Figure 1.11. Copper(I)-carbene complex ...... 69

Figure 1.12. Copper(I)-olefin Complexes as Catalysts in Cyclopropanation ...... 70

Figure 1.13. Preferred Conformations of trans- and cis- Transition States (Tc and Tt) .... 72

Figure 1.14. Chiral Ligands utilized in Copper-Mediated Cyclopropanation Reactions. . 77

Figure 2.1. Resemblance of 7-Heptenyl and 5-Heptenyl Radicals to Dichloromethyl and Ispopropyl Radicals...... 127

Figure 2.2. Monitoring the Formation of Cyclic Products (B and C) at Timed Intervals in the Addition of Carbon Tetrachloride (CCl4) to 1,5-Hexadiene...... 129

Figure 2.3. Monitoring Formation of Cyclic Products (B and C) as a Result of ATRC of Monoadduct (A) at Timed Intervals...... 130

Figure 2.4. Transition States Involved in the Cyclization of 5-Hexenyl Radical...... 134

xxii Figure 3.1. Representative commercial and synthesized 1,6-diene esters...... 151

Figure 3.2. Conformations of esters and amides as a result of electron delocalization. . 154

Figure 3.3. Different transition structures of 1 for the interconversion of Z and E conformations...... 160

Figure 3.4. Stabilizing σ(C-H)  σ*(O-C) hyperconjugation interactions in the Z to E transition structure of (3)...... 161

Figure 3.5. Stabilizing σ(C-H) σ*(C-C) hyperconjugation interactions in the 5-exo cyclization transitions structure of 3...... 163

Figure 3.6. Z and E conformations of allyl acrylate along with the corresponding transition states and final γ-lactone involved in the reaction path...... 165

Figure 3.7. Reaction path for the formation of -lactone...... 166

1 13 Figure 4.1. H (a) and C NMR (CDCl3, 298 K) (b) spectra of 6a...... 191

Figure 4.2. Molecular structure of (S)-monoadduct (12a) formed by the sequential azide- alkyne [3+2] cycloaddition between azidopropyl methacylate and methyl propiolate followed by ATRA of CBr4 at 296 K, shown with 30% probability displacement ellipsoids. H-atoms have been omitted for clarity...... 194

Figure 5.1. 1H NMR (a) and HRMS (b) spectra of tris((1-(4-vinylbenzyl)-1H-1,2,3- triazol-4-yl)methyl)amine (TVBTA)...... 223

Figure 5.2. 1H NMR (a) and experimental (b) and simulated (c) mass spectra of tris((1-(4- (1,3,3,3-tetrachloropropyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl)amine...... 227

I Figure 6.1. Molecular structure of [Cu (bpy)(-CH2=CHC6H5][CF3SO3] (1), shown with 50% probability displacement ellipsoids. H atoms have been omitted for clarity...... 250

I Figure 6.2. Molecular structure of [Cu (bpy)(-CH2=CHC6H5][PF6]•1/2Sty (2), shown with 50% probability displacement ellipsoids. H atoms have been omitted for clarity. . 252

Figure 6.3. Plots of ln([EDA]0/[EDA]t) vs. time for the cyclopropanation of styrene with 0 -2 -1 EDA in CH2Cl2 at 25 C catalyzed by 1 (, kobs = (1.4  0.041) x 10 min ), 2 (, kob s= -2 -1 -3 -1 (1.0  0.025) x 10 min ) and 3 (, kobs = (7.7  0.032) x 10 min ). -3 [Cu]0:[EDA]0/[Styrene]0 =1:250:2500, [Cu]0 = 1.71 x 10 M. Errors are given at 95% confidence limits...... 256

Figure 6.4. 1H NMR labeling scheme...... 258

Figure 7.1. Axial coordination of counterion in [CuI(bpy)(π-M)]+ (M = methyl acrylate, styrene) complexes...... 270

xxiii I Figure 7.2. Molecular structures of [Cu (3,4,7,8-Me4phen)(BPh4)]*3CH2Cl2 (1), I I Cu (bpy)(BPh4) (2) and Cu (phen)(BPh4) (3) shown with thermal ellipsoids at 50% probability. H atoms and solvent molecules have been omitted for clarity...... 271

I Figure 7.3. Partial packing diagram of [Cu (2,9-Me2phen)(CH3CN)][BPh4] showing weak - C-HC interactions of coordinated CH3CN (a) and 2,9-Me2phen (b) with BPh4 anion and - stacking interactions between 2,9-Me2phen ligands (c)...... 273

Figure 7.4. NBO orbital interactions between C-C p-bonds (a) and B-C s bonds (b) of the - * BPh4 counterion and n orbital of copper (>99% s character); and between filled d orbitals of copper ((c) LP(4) and (d) LP(5)) and empty C-C p* orbitals of phenyl rings...... 275

Figure 7.5. Plots of ln([EDA]0/[EDA]t) vs. time for cyclopropanation of styrene with o -3 -1 EDA in CH2Cl2 at 25 C catalyzed by 1 (, kobs=(1.5±0.12)10 min ), 2 (, -3 -1 -3 -1 kobs=(6.8±0.30)10 min ) and 3 (, kobs=(5.1±0.19)10 min ). I I -3 [Cu ]0:[EDA]0:[Styrene]0=1:250:2500, [Cu ]0=1.7110 M, kobs and relative errors were calculated from two independent kinetic runs ...... 277

Figure A.1. 1H NMR of 5,7,7,7-Tetrachloro-1-heptene (A)...... 287

Figure A.2. 13C NMR of 5,7,7,7-Tetrachloro-1-heptene (A)...... 288

Figure A.3. 1H NMR of 1,1,5-Trichloro-2-chloromethylcyclohexane (B)...... 288

Figure A.4. 1H-1H COSY of 1,1,5-Trichloro-2-chloromethylcyclohexane (B)...... 289

Figure A.5. 1H NMR of 1-Chloro-3-(2,2,2,-trichloroethyl)cyclopentane (C)...... 290

Figure A.6 13C NMR of 1-Chloro-3-(2,2,2,-trichloroethyl)cyclopentane (C)...... 291

Figure A.7. 1H NMR of 1,1,1,3,6,8,8,8-Octachlorooctane (D)...... 292

Figure A.8.1H NMR of 5,7,7,7-Tetrabromo-1-heptene (A2)...... 293

Figure A.9. 1H NMR of 1,1,5-Tribromo-2-bromomethylcyclohexane (B2)...... 294

Figure A.10. 13C NMR of 1,1,5-Tribromo-2-bromomethylcyclohexane (B2)...... 295

Figure A.11. 13C NMR of 1,1,5-Tribromo-2-bromomethylcyclohexane (B2)...... 296

Figure A.12. DEPT NMR of 1,1,5-Tribromo-2-bromomethylcyclohexane (B2)...... 297

Figure A.12. 1H NMR of 1-Bromo-3-(2,2,2,-tribromoethyl)cyclopentane (C2)...... 298

1 Figure A.13. H NMR (CD3Cl, RT, 400 MHz) spectrum of a mixture of cis and trans 1- (3-(Chloromethyl)-4-(2,2,2-trichloroethyl)pyrrolidin-1-yl)-2,2,2-trifluoroethanone. .... 299

xxiv Figure B.1. 1H NMR of methyl allyl acrylate (3)...... 301

Figure B.2. 1H NMR of phenylallyl acrylate (4)...... 302

Figure B.3. 1H NMR of dimethylallyl acrylate (5)...... 303

Figure B.4. 1H NMR of ethylmethylallyl acrylate (6)...... 304

Figure B.5. 1H NMR of dimethylallyl methacrylate (7)...... 305

Figure B.6. 1H NMR of -lactone...... 306

Figure B.7. 13C NMR of -lactone...... 307

Figure C.1.1H-1H COSY spectrum of 3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propyl 2,4,4,4-tetrachloro-2-methylbutanoate (3a)...... 308

Figure C.2. 13C-1H HETCOR spectrum of 3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propyl 2,4,4,4-tetrachloro-2-methylbutanoate (3a)...... 309

Figure C.3. 13H NMR spectrum of 3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl methacrylate (1)...... 310

Figure C.4. 13C NMR spectrum of 3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl methacrylate (1)...... 311

Figure C.5. 1H NMR spectrum of 3-(4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)propyl methacrylate (2)...... 312

Figure C.6. 1H NMR spectrum of 3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propyl methacrylate (3)...... 313

Figure C.7. 13C NMR spectrum of 3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propyl methacrylate (3)...... 314

Figure C.8. 1H NMR spectrum of methyl 1-(3-(methacryloyloxy)propyl)-1H-1,2,3- triazole-4-carboxylate (5)...... 315

Figure C.9. 13C NMR spectrum of methyl 1-(3-(methacryloyloxy)propyl)-1H-1,2,3- triazole-4-carboxylate (5)...... 316

Figure C.10. 1H NMR spectrum of ethyl 1-(3-(methacryloyloxy)propyl)-1H-1,2,3- triazole-4-carboxylate (6)...... 317

Figure C.11. 13C NMR spectrum of ethyl 1-(3-(methacryloyloxy)propyl)-1H-1,2,3- triazole-4-carboxylate (6)...... 318

Figure C.12. 1H NMR spectrum of 3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl 2,4,4,4- tetrachloro-2-methylbutanoate (1a)...... 319

xxv Figure C.13. 13C NMR spectrum of 3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl 2,4,4,4- tetrachloro-2-methylbutanoate (1a)...... 320

Figure C.14.1H NMR spectrum of 3-(4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1- yl)propyl-2,4,4,4-tetrachloro-2-methylbutanoate (2a)...... 321

Figure C.15. 13C NMR spectrum of 3-(4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1- yl)propyl-2,4,4,4-tetrachloro-2-methylbutanoate (2a)...... 322

Figure C.16. 1H NMR spectrum of 3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propyl- 2,4,4,4-tetrachloro-2-methylbutanoate (3a)...... 323

Figure C.17. 13C NMR spectrum of 3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propyl- 2,4,4,4-tetrachloro-2-methylbutanoate (3a)...... 324

Figure C.18. 1H NMR spectrum of methyl-1-(3-(2,4,4,4-tetrachloro-2- methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (5a)...... 325

Figure C.19. 13C NMR spectrum of methyl-1-(3-(2,4,4,4-tetrachloro-2- methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (5a)...... 326

Figure C.20. 1H NMR spectrum of of ethyl-1-(3-(2,4,4,4-tetrachloro-2- methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (6a)...... 327

Figure C.21. 13C NMR spectrum of ethyl-1-(3-(2,4,4,4-tetrachloro-2- methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (6a)...... 328

Figure C.22. 1H NMR spectrum of methyl-1-(3-(2,4,4,4-tetrabromo-2- methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (12a)...... 329

Figure C.23. 13C NMR spectrum of methyl-1-(3-(2,4,4,4-tetrachloro-2- methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (12a)...... 330

Figure C.24. 13C NMR of 1-ethyl 5-(3-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1- yl)propyl) 2,2,4-trichloro-4-methylpentanedioate (13a)...... 331

Figure C.25. 13C NMR of 1-ethyl 5-(3-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1- yl)propyl) 2,2,4-trichloro-4-methylpentanedioate (13a)...... 332

Figure C.26. 1H NMR of 1-ethyl 5-(3-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1- yl)propyl) 2,4-dichloro-4-methylpentanedioate (15a)...... 333

Figure C.27. 13C NMR of 1-ethyl 5-(3-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1- yl)propyl) 2,4-dichloro-4-methylpentanedioate (15a)...... 334

Figure C.28. 1H NMR of 1-(3-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)propyl) 5- methyl 2,4-dichloro-2-methylpentanedioate (16a)...... 335

xxvi Figure C.29. 1H NMR of methyl 1-(3-(2,4-dichloro-4-cyano-2- methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (17a)...... 336

Figure C.30. 13C NMR of methyl 1-(3-(2,4-dichloro-4-cyano-2- methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (17a)...... 337

Figure C.31. 1H NMR spectrum of 4-phenyl-1-(4-(1,3,3,3-tetrachloropropyl)benzyl)-1H- 1,2,3-triazole (19a)...... 338

Figure C.32. 13C NMR spectrum of 4-phenyl-1-(4-(1,3,3,3-tetrachloropropyl)benzyl)-1H- 1,2,3-triazole (19a)...... 339

Figure C.33. 1H NMR spectrum of methyl 1-(4-vinylbe)nzyl)-1H-1,2,3-triazole-4- carboxylate (22)...... 340

Figure C.34. 13C NMR of spectrum of methyl 1-(4-vinylbenzyl)-1H-1,2,3-triazole-4- carboxylate (22)...... 341

Figure C.35. 1H NMR spectrum of methyl 1-(4-(1,3,3,3-tetrachloropropyl)benzyl)-1H- 1,2,3-triazole-4-carboxylate (22a)...... 342

Figure C.36. 13C NMR spectrum of methyl 1-(4-(1,3,3,3-tetrachloropropyl)benzyl)-1H- 1,2,3-triazole-4-carboxylate (22a)...... 343

Figure C.37. 13C NMR spectrum of methyl 1-(4-(1,3,3-trichloropropyl)benzyl)-1H-1,2,3- triazole-4-carboxylate (28a)...... 344

Figure C.38. 1H NMR spectrum of methyl 1-(4-(1,3,3-trichloro-4-ethoxy-4- oxobutyl)benzyl)-1H-1,2,3-triazole-4-carboxylate (23a)...... 345

Figure C.39. 13C NMR spectrum of methyl 1-(4-(1,3,3-trichloro-4-ethoxy-4- oxobutyl)benzyl)-1H-1,2,3-triazole-4-carboxylate (23a)...... 346

Figure C.40. 1H NMR spectrum of methyl 1-(4-(1,3,3-trichloro-4-methoxy-4- oxobutyl)benzyl)-1H-1,2,3-triazole-4-carboxylate (24a)...... 347

Figure C.41. 13C NMR spectrum of methyl 1-(4-(1,3,3-trichloro-4-methoxy-4- oxobutyl)benzyl)-1H-1,2,3-triazole-4-carboxylate (24a)...... 348

Figure D.1. 1H NMR of Tris((1-(4-vinylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)amine (TVBTA)...... 355

Figure D.2. 13C NMR of Tris((1-(4-vinylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)amine (TVBTA)...... 356

Figure D.3. 1H NMR of Tris((1-(4-(1,3,3,3-tetrachloropropyl)benzyl)-1H-1,2,3-triazol-4- yl)methyl)amine (TBTA(CCl4)3)...... 357

xxvii Figure D.4. 13C NMR of Tris((1-(4-(1,3,3,3-tetrachloropropyl)benzyl)-1H-1,2,3-triazol-4- yl)methyl)amine (TBTA(CCl4)3)...... 358

Figure D.5. 1H NMR of Tris((1-(4-(1,3,3,3-tetrabromopropyl)benzyl)-1H-1,2,3-triazol-4- yl)methyl)amine (TBTA(CBr4)3)...... 359

Figure D.6. 13C NMR of Tris((1-(4-(1,3,3,3-tetrabromopropyl)benzyl)-1H-1,2,3-triazol-4- yl)methyl)amine (TBTA(CBr4)3)...... 360

Figure D.7. 1H NMR of trimethyl 4,4',4''-(((4,4',4''-(nitrilotris(methylene))tris(1H-1,2,3- triazole-4,1-diyl))tris(methylene))tris(benzene-4,1-diyl))tris(2,2,4-trichlorobutanoate) (TBTA(Cl3CCO2Me)3)...... 361

Figure D.8. 13C NMR of trimethyl 4,4',4''-(((4,4',4''-(nitrilotris(methylene))tris(1H-1,2,3- triazole-4,1-diyl))tris(methylene))tris(benzene-4,1-diyl))tris(2,2,4-trichlorobutanoate) (TBTA(Cl3CCO2Me)3)...... 362

Figure D.9. 1H NMR of 4,4',4''-(((4,4',4''-(nitrilotris(methylene))tris(1H-1,2,3-triazole- 4,1-diyl))tris(methylene))tris(benzene-4,1-diyl))tris(2,4-dichlorobutanenitrile)) (TBTA(CHCl2CN)3)...... 363

Figure D.10. 13C NMR of 4,4',4''-(((4,4',4''-(nitrilotris(methylene))tris(1H-1,2,3-triazole- 4,1-diyl))tris(methylene))tris(benzene-4,1-diyl))tris(2,4-dichlorobutanenitrile)) (TBTA(CHCl2CN)3)...... 364

Figure D.11. 1H NMR of trimethyl 4,4',4''-(((4,4',4''-(nitrilotris(methylene))tris(1H-1,2,3- triazole-4,1-diyl))tris(methylene))tris(benzene-4,1-diyl))tris(2,4-dichlorobutanoate) (TBTA(Cl2HCCO2Me)3)...... 365

Figure D.12. 13C NMR of trimethyl 4,4',4''-(((4,4',4''-(nitrilotris(methylene))tris(1H-1,2,3- triazole-4,1-diyl))tris(methylene))tris(benzene-4,1-diyl))tris(2,4-dichlorobutanoate) (TBTA(Cl2HCCO2Me)3)...... 366

Figure D.13. HRMS of Tris((1-(4-vinylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)amine (TVBTA)...... 367

Figure D.14. HRMS of Tris((1-(4-(1,3,3,3-tetrachloropropyl)benzyl)-1H-1,2,3-triazol-4- yl)methyl)amine (TBTA(CCl4)3)...... 368

Figure D.15. HRMS of Tris((1-(4-(1,3,3,3-tetrabromopropyl)benzyl)-1H-1,2,3-triazol-4- yl)methyl)amine (TBTA(CBr4)3)...... 369

Figure D.16. HRMS of Dimethyl 4,4'-(((4,4'-((((3-(4-(1,3,3-trichloro-4-methoxy-4- oxobutyl)benzyl)-3H-pyrazol-5-yl)methyl)azanediyl)bis(methylene))bis(1H-1,2,3- triazole-4,1-diyl))bis(methylene))bis(4,1-phenylene))bis(2,2,4-trichlorobutanoate) (TBTA(Cl3CCO2Me)3)...... 370

xxviii Figure D.17. HRMS of 4,4',4''-(((4,4',4''-(nitrilotris(methylene))tris(1H-1,2,3-triazole-4,1- diyl))tris(methylene))tris(benzene-4,1-diyl))tris(2,4-dichlorobutanenitrile)) (TBTA(CHCl2CN)3)...... 371

Figure D.18. HRMS of Dimethyl 4,4'-(((4,4'-((((3-(4-(1,3-dihloro-4-methoxy-4- oxobutyl)benzyl)-3H-pyrazol-5-yl)methyl)azanediyl)bis(methylene))bis(1H-1,2,3- triazole-4,1-diyl))bis(methylene))bis(4,1-phenylene))bis(2,2,4-trichlorobutanoate (TBTA(Cl2HCCO2Me)3)...... 372

Figure E.1. Crystal packing diagram of [CuI(bpy)(-CH2=CHC6H5)][PF6]*1/2Sty (2)...... 373

I Figure F.1. Packing diagram of [Cu (BPh4)(3,4,7,8-Me4phen)]*3CH2Cl2 (1), shown with 50% probability displacement ellipsoids...... 376

I Figure F.2. Packing diagram of Cu (BPh4)(bpy) (2), shown with 50% probability displacement ellipsoids...... 377

I Figure F.3. Packing diagram of Cu (BPh4)(phen) (3), shown with 50% probability displacement ellipsoids...... 378

I Figure F.4. Partial packing diagram of [Cu (BPh4)(3,4,7,8-Me4phen)]*3CH2Cl2 showing weak C-HF interactions (dashed lines)...... 379

Figure F.5. Typical 6- and 2-coordination modes of tetraphenylborate anion to transition metal complexes, (a) Rh(BPh4)(diphos) and (b) Cu(BPh4)(CO)(en)...... 379

I Figure F.6. Molecular structure of [Cu (2,9-Me2phen)(CH3CN)][BPh4] (4), shown with 30% probability displacement ellipsoids. H atoms have been omitted for clarity...... 380

I Figure F.7. Partial packing diagram of [Cu (2,9-Me2phen)(CH3CN)][BPh4] (4) showing - weak C-HC interactions of coordinated CH3CN (a) and 2,9-Me2phen (b) with BPh4 anion and - stacking interactions between 2,9-Me2phen ligands (c)...... 381

I Figure F.8. Molecular structure of [Cu (2,9-Me2phen)(CH3CN)][PF6] (5), shown with 30% probability displacement ellipsoids. H atoms have been omitted for clarity...... 382

1 I Figure F.9. H HMR spectrum (300 MHz, CD2Cl2, RT) of [Cu (3,4,7,8-Me4phen)][BPh4]...... 383

I Figure F.10. Solid state FT-IR Spectrum of [Cu (3,4,7,8-Me4phen)][BPh4]...... 384

I Figure F.11. Solid State FT-IR Spectrum of [Cu (CH3CN)][BPh4]...... 385

Figure F.12. Overlay of crystal structure (shown in orange) and B3LYP/6-31G(d) optimized structure (shown in blue) of 2...... 387

xxix Figure F.13. Overlay of crystal structure (shown in orange) and MP2/6-31G(d) optimized structure (shown in blue) of 2...... 388

Figure F.14. Overlay of crystal structure (shown in orange) and B3LYP/6-31G(d) optimized structure (shown in blue) of 2...... 389

xxx LIST OF TABLES

Table 1.1. Copper-Catalyzed ATRC of Unsaturated Trichloroesters...... 12

Table 1.3. Synthesis of -lactams using copper catalyzed ATRC.64 ...... 13

Table 1.4. Synthesis of Medium-Sized and Macrocyclic Lactones via Copper-Catalyzed ATRC...... 15

Table 1.5. Photoinitiated Cu-Catalyzed ATRA of CCl4 and CBr4 to Highly Active Alkenes at Ambient Temperaturea ...... 27

Table 1.6. Photoinitiated Cu-Catalyzed ATRA of CHBr3, CHCl3, Cl3CO2Et, BzBr and BzCl to Highly Active Alkenes at Ambient Temperaturea ...... 28

Table 1.7. ATRC of Bromoacetamides Catalyzed by Copper Complexes with TPMA Ligand in the Presence of AIBN.a ...... 31

Table 1.8. Sequential ATRA or ATRC and Dechlorination Reactions Catalyzed by * a b [Cp RuCl2(PPh3)] in the Presence of Mg or Mn...... 33

* Table 1.9. Sequential ATRA Reactions Catalyzed [Cp RuCl2(PPh3)] and Mg...... 35

Table 1.10. ATRA of CCl4 to 1,6-Dienes Followed by Sequential ATRC Catalyzed by CuITpX and [CuII(TPMA)Cl][Cl] Complexes in the Presence of Reducing Agents...... 40

Table 1.12. Enantioselective Cycopropanation of Styrene with Ethyl Diazoacetate Catalyzed by Complexes of Copper in Conjunction with Chiral Ligands...... 78

II Table 2.1. [Cu (TPMA)Cl][Cl] Mediated Addition of CCl4 to 1,5-Hexadiene in the Presence of AIBN...... 124

Table 2.2. ATRC of Monoadduct A Catalyzed by [CuII(TPMA)Cl][Cl] and AIBN ...... 126

Table 2.3. Kinetics of the Addition of CCl4 to 1,5-Hexadiene Catalyzed by [CuII(TPMA)Cl][Cl] and AIBN...... 128

Table 2.4. Kinetics of the Atom Transfer Radical Cyclization of Monoadduct (A) Catalyzed by [CuII(TPMA)Cl][Cl] and AIBN...... 129

Table 2.5. ATRA of CCl4 to 1,6-dienes Followed by Sequential ATRC Catalyzed by [CuII(TPMA)Cl][Cl] in the Presence of Free-Radical Initiators as Reducing Agents.a .. 132

Table 3.1. Addition of Carbon Tetrachloride to 1,6-Diene Esters Catalyzed by [CuII(TPMA)Cl][Cl] and AIBN or V-70...... 152

xxxi Table 3.2. Addition of Carbon Tetrachloride to 1,6-Diene Estes Catalyzed by [CuII(TPMA)Cl][Cl] and AIBN...... 156

Table 3.3. Effect of Various Catalyst Loadings on the Addition of Carbon Tetrachloride to Dimethylallyl Acrylate...... 157

Table 3.4. Energy differences (kcal/mol) between Z and E allyl ester radicals at M062X/aug-cc-pVDZ level of theory, ∆E = EZ – EE...... 158

‡ Table 3.5. Activation energies (kcal/mol) for Z to E rotational barrier (∆E = ETS – EZ)...... 159

Table 3.6. Strength of the σ(C-C/H)  σ*(O-C) hyperconjugation interactions pushing electron density into O-C bond in kcal/mol and the corresponding bond lengths...... 162

 Table 3.7. Activation energies (kcal/mol) for 5-exocyclization( E  ETS  EE )...... 162

Table 3.8. Strength of the σ(C-C/H)  σ*(C-C) hyperconjugation interactions pushing electron density into C-C bond in kcal/mol and the corresponding bond lengths...... 164  Table 4.1. [CuII(TPMA)Cl][Cl] catalyzed azide-alkyne [3+2] cycloaddition in the presence of ascorbic acid as a reducing agent...... 188

Table 4.2. Sequential azide-alkyne [3+2] cycloaddition and atom transfer radical addition (ATRA) of carbon tetrachloride catalyzed by [CuII(TPMA)Cl][Cl] in the presence of ascorbic acid as a reducing agent...... 190

Table 4.3. Sequential azide-alkyne [3+2] cycloaddition and atom transfer radical addition (ATRA) of various alkyl halides catalyzed by [CuII(TPMA)X][X] (X=Br- or Cl-) in the presence of ascorbic acid as reducing agent...... 192

Table 4.4. Sequential azide-alkyne [3+2] cycloaddition and atom transfer radical addition (ATRA) of various alkyl halides catalyzed by [CuII(TPMA)X][X] (X=Br- or Cl-) in the presence of ascorbic acid as reducing agent...... 193

Table 4.5. Crystal structure analysis data for methyl-1-(3-(2,4,4,4-tetrabromo-2- methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (12a)...... 195

Table 5.1. Copper Catalyzed ATRA of Alkyl Halides to TVBTA in the Presence of Ascorbic Acid...... 225

Table 5.2 One-Pot Sequential Copper-Catalyzed [3+2] Azide-Alkyne Cycloaddition and ATRA in the Presence of Ascorbic Acid...... 226

Table 6.1. Crystallographic data and experimental details for 1 and 2...... 248

Table 6.2. Selected bond distances (Å) and angles (o) for 1 and 2...... 249

xxxii 1 Table 6.3. H NMR chemical shifts (300 MHz, CD2Cl2, 180 K) of olefinic protons and C=C stretching frequency (cm-1) for 1-3...... 253

Table 6.4. Cyclopropanation of styrene in the presence of EDA catalyzed by 1-3.a ...... 255

Table 7.1. Cyclopropanation of styrene in the presence of EDA catalyzed by 1-3.a ...... 276

Table C.1. Crystal data and structure refinement for 12a...... 349

Table C.2. Atomic coordinates ( x 10^4) and equivalent isotropic displacement ...... 349

Table C.3. Bond lengths [A] and angles [deg] for 12a...... 351

Table C.4. Anisotropic displacement parameters (A^2 x 10^3) for 12a. The anisotropic displacement factor exponent takes the form: -2 pi^2 [ h^2 a*^2 U11 + ... + 2 h k a* b* U12 ] ...... 353

Table C.5. Hydrogen coordinates ( x 10^4) and isotropic displacement parameters (A^2 x 10^3) for 12a...... 354

Table F.2. Selected bond distances (Å) and angles (o) for 1-3...... 375

Table F.3. Selected bond distances (Å) and angles (o) for [CuI(2,9- I Me2phen)(CH3CN)][BPh4] (4) and [Cu (2,9-Me2phen)(CH3CN)][PF6] (5)...... 380

- a Table F.6. Significant  donation from BPh4 anion to copper(I) complexes 1 and 2. .. 389

- Table F.7. -Backbonding interactions between copper(I) complexes 1 and 2 and BPh4 anion.a ...... 391

xxxiii Chapter 1

Introduction

In recent years, organic reactions catalyzed by transition metal complexes have become a popular tool for the synthesis of simple and even complex molecules.1-7 Among the transition metals, copper has played a major role in the development of several synthetic techniques and this can be attributed to the following features: attainable oxidation states (0-3),8 ability to mediate two electron and one-electron transfer processes8 and high binding affinity to polar functional groups and π-bonds.8-10 The relatively low cost of copper also makes it a very attractive reagent for organic synthesis.

A broadening synthetic utility of copper has been reflected in C-C and C-heteroatom (C-

O, C-N, C-S) bond formations leading to linear as well as carbocyclic and heterocyclic compounds.8,9,11 Organic transformations mediated by copper include transition-metal catalyzed intermolecular and intramolecular atom transfer radical reactions (TMC ATRA and TMC ATRC).6,7,12-14 Numerous contributions have also been made in [2+1] cycloaddition, particularly carbene transfer to olefins to form cyclopropanes.15-17

Furthermore, copper has been the most successful transition metal to mediate C-N bond formation to form a triazole via the Huisgen [3+2] azide- alkyne cycloaddition or ―click chemistry‖.18-20 Systematic studies performed in understanding actual mechanisms and intermediates involved in these reactions have led to catalytic design involving copper complexes to further fine-tune their reactivity, selectivity and efficiency.13,15-17,20-25 This chapter provides a discussion on the increasing significance of copper in mediating atom transfer radical reaction, azide-alkyne cycloaddition and cyclopropanation reactions.

1 1.1 Atom Transfer Radical Addition and Cyclization

1.1.1 Origins of Transition Metal Catalyzed Atom Transfer Radical Addition (TMC ATRA)

Carbon-carbon bond formation resulting from the addition of polyhalogenated methanes (CX4 and CHX3, X= Br, Cl) to olefins in the presence of light or conventional radical initiators (e.g. organic peroxides) was first discovered by Kharasch in 1937

(Scheme 1.1).26-30 Although this reaction involving -olefins such as 1-hexene, 1-octene and 1-decene was successful, monoadduct formation was hampered for highly active olefins such as styrene, methyl acrylate and methyl methacrylate. Decreased product selectivity for the highly active monomers was attributed to radical-radical coupling and disproportionation (radical termination) reactions and the repeating addition of monomer units forming oligomers or polymers.

or h X CX4 + X3C R R Scheme 1.1. Kharasch Addition of Halogenated Compound to Alkene.

In 1956, when Minisci and co-workers attempted to polymerize acrylonitrile with

CCl4 and CHCl3 using a steel autoclave, they observed the formation of the monoadducts

31 instead. This was rather surprising since the transfer rate constants (ktr) for CCl4 and

CHCl3 were low enough to compete with the propagation rate constant (kp) of the acrylonitrile. Similar observations in another experiment conducted in 1961 led to the proposition that iron(III) chlorides (FeCl3) generated from the corrosion of the steel autoclave acted as a halogen transfer agents (Scheme 1.2).32-36 This marked the beginning of transition metal catalyzed Kharasch addition reactions. Over the years, it has become

2 more popularly known as transition metal catalyzed atom transfer radical addition. (TMC

ATRA).

Cl3C Cl3C Cl + CCl4 CN CN CN II III II Fe Cl-FeIII Cl-Fe Fe

Scheme 1.2. Iron-Catalyzed ATRA of CCl4 to Acrylonitrile.

Since the initial discovery of transition metals acting as better halogen transfer agents, complexes incorporating copper (Cu), iron (Fe), ruthenium (Ru) and nickel (Ni) as well as zero-valent metals (Cu and Fe) have been found to catalyze ATRA reactions.7,37-45 Great progress has been made in the use of transition metals as catalysts in controlling product selectivity for highly active alkenes such as styrene, alkyl acrylates and acrylonitrile in addition to simple -olefins (1-hexene, 1-octene and 1-decene)

(Figure 1.1). Furthermore, a variety of functionalized adducts has been synthesized via

ATRA utilizing different halogenated compounds shown in Figure 1.1 (alkyl and aryl chlorides,36,46,47 N-chloroamines,36 alkylsulfonyl halides,48-53 -halonitrile,54 - haloacetates,55,56 -haloaldehydes42,57 and polyhalogenated compounds48,51,58,59).

Subsquently, TMC ATRA has emerged as a powerful tool in organic synthesis.37,40,41,60-62

1.1.2 Proposed Catalytic Cycle of Transition Metal Catalyzed Atom Transfer Radical Addition and Cyclization (TMC ATRA and ATRC)

It is generally accepted that the mechanism of TMC ATRA involves free-radical intermediates and makes use of the redox properties of the transition metal complex in order to activate the alkyl-halogen bond.36,41,48,63 As shown in Scheme 1.3, the proposed catalytic cycle starts with a homolytic cleavage of the carbon-halogen bond (C-X) by the

3 n • transition metal in the lower oxidation state (Mt Lm). This generates an alkyl radical (R )

n+1 and the transition metal in the higher oxidation state (Mt LmX). The radical can add to the double bond of the olefin, terminates by radical-radical coupling or disproportionation, or abstracts the halogen from the transition metal complex in the

n+1 higher oxidation state (Mt LmX). If the abstraction of halogen occurs after the addition of R• to alkene, the desired monoadduct is formed. This regenerates the transition metal

n in the lower oxidation state (Mt Lm), thus completing the catalytic cycle. The key to increasing the chemoselectivity towards the monoadduct lies in the radical generating step, which is governed by a set of guidelines. Firstly, radical concentration must be low in order to suppress radical termination reactions (rate constants of activation [ka,1 and ka,2] << rate constants of deactivation [kd,1 and kd,2]). Secondly, further activation of monoadduct should be avoided (ka,1 >> ka,2, ideally, ka,1 ≈ 0). Lastly, formation of oligomers or polymers should be suppressed by having a much larger rate of deactivation

n+1 than the rate of propagation (kd,2[Mt LmX] >> kp[alkene]).

Scheme 1.3. Proposed Catalytic Cycle for TMC ATRA.

When both alkene and carbon-halogen moieties are present in the substrate, addition can occur in an intramolecular fashion. Such mechanism, which results in a radical ring closure, is called transition metal catalyzed atom transfer radical cyclization

(TMC ATRC).41 In the proposed catalytic cycle shown in Scheme 1.4, the reaction starts with a reversible abstraction of the halide from the C-X end of the substrate by the

n transition metal complex in the lower oxidation state (Mt Lm) to yield an electrophilic

n+1 radical and the complex in its oxidized form (Mt LmX). Subsequent intramolecular addition of the radical to one of the olefinic carbons (C=C) generates a nucleophilic cyclic radical species, which, promptly and irreversibly deactivated via halogen transfer

n+1 from the Mt LmX, furnishing the halogen-functionalized carbocycle and the complex in

n n its reduced form (Mt Lm). Consequently, the regenerated Mt Lm species begins a new reaction cycle.

5 X

n n

n n+1 Mt Lm Mt LmX

n n

X = Cl, Br Scheme 1.4. Proposed Catalytic Cycle for Transition Metal Catalyzed Atom Transfer Radical Cyclization.

1.1.3 Basic Components of TMC ATRA and ATRC

Alkyl Halides Alkenes

CX4 CX3H CX2H2 CX3Y CX2Y2 n = 1: hexene O X n n = 3: octene n = 5: decene CHX2 S X O O O O O O CH CH CN O 3 O 3 X X X O O H2N

O O X X X NC X X O R O O X CN CN X

X,Y = Cl or Br R = H, CH3, OCH3, F or Cl Figure 1.1. Alkyl halides and alkenes commonly used in ATRA.

6 Substrates having C=C bonds (alkenes or olefins) and alkyl halides are the main reactants in TMC ATRA and ATRC reactions. Alkenes commonly used include simple

-olefins (1-hexene, 1-octene, 1-decene), methyl acrylate, methyl methacrylate, styrene, vinyl acetate, and acrylonitrile (Figure 1.1).48,51,58,59,64 Halogenated compounds that have been utilized include alkyl and aryl chlorides,36,46,47 N-chloroamines,36 alkylsulfonyl halides,48-53 -halonitrile,54 -haloacetates,55,56 -haloaldehydes42,57 and polyhalogenated compounds Figure 1.1).48,51,58,59 A variety of substrates such as tri- di- and monounsaturated alkenes,65 ketones,65 amides41,66-68 and esters69-76 as well as propargylic acetamides77,78 containing halogen functional groups been very useful in intramolecular addition (ATRC) studies (Figure 1.2).

O O X X X n O n n Y2 Y2 Y2

O O N X X O n N N X R Y2 R Y2

O X N

R Y2 X, Y = Cl, Br R = Bn, Ts Figure 1.2. Halogenated Olefinic and Propargylic Substrates for ATRC.

The role of the transition metal is the most indispensable in ATRA as it regulates the dynamic equilibrium (KATRA = ka,1/kd,1) between the dormant (alkyl halide) and the

7 active species (alkyl radical). Catalytic systems based on copper(I) are usually prepared from stoichiometric amounts (1:1) of the copper(I) salt, CuX (X= I, Br, Cl) and the ligand, with the exception of some bidentate ligands such as 2,2‘-bipyridine and its derivatives. Ligand coordination accelerates the reaction by enhancing the solubility of the copper salt and by altering the redox potential of the CuI/CuII system, which correlates with the rate of activation in ATRA.79 In order to enhance the catalytic activity in copper-mediated atom transfer radical reactions, complexes with N-based ligands have been utilized (Figure 1.7). Treatment of halogenated amides and esters with catalytic amounts of copper(I) complexes with bipyridine (bpy) ligand provided efficient cyclization to desired lactams and lactones; respectively.41,67,80 The ability of N-alkyl-2- pyridylmethanimines (NAlkPMI)41,77,81-86 to solubilize copper(I) halides and their relatively facile synthesis from commercially available amines have also been reported to mediate ATRC. Ligands with better chelating ability or higher denticity have been found to fine-tune the efficiency of the catalytic system. In particular, copper(I) complexes with tridentate (N, N, N’, N”, N”-pentamethyldiethylenetriamine (PMDETA)),87-89 tetradentate

(tris(2-pyridinyl)methylamine (TPMA),61,90 N, N, N’, N”,N”, N”- hexamethyltriethylenetriamine (HMTETA),61 1,4,8,11-tetraaza-1,4,8,11-

91 tetramethylcyclotetradecane (Me4Cyclam), dimethylated 1,8-ethylene cross-bridged

1,4,8,11-tetramethylcyclotetradecane (DMCBCy)92 and tris[2-

66,77,82 (dimethyl)aminoethyl]amine (Me6TREN) )) and multidentate ((5,5‘-(N,N,N’,N’- tetrakis(2-pyridylmethyl))dimethyl-2,2‘-bipyridine (TPDMBpy),61 N,N,N’,N’- tetrakis(2- pyridylmethyl)ethylenediamine (TPEDA)61,90) ligands provided higher product yields and distributions. Furthermore, copper complexes with multidentate N-based ligands have

8 N

N N N N R N N

bpy NAlkPMI PMDETA

N N N N N N N N N N N Me6TREN HMTETA N

TPMA

N N N N N N N N N N N N N N

TPDMBpy TPEDA

H R1 R R1 N N N HN B 1 N N N R R2 2 R3 N N N N N NH N R3 R3 R3

DMCBCy Tpx Me4Cyclam Figure 1.3. Nitrogen-Based Ligands Utilized in Copper-Mediated Atom Transfer Radical Reactions. been proven superior activity over bidentate bipyridine-based complexes in the synthesis of macrolactones and macrocyclic ethers.41,61 Copper(I) tris(pyrazolyl)borate (TpxCuI) complexes have demonstrated efficient ATRA of polyhalogenated methanes to olefins.62,93 An attractive feature of this type of CuI complexes is that catalytic activity

9 can be altered by incorporating substituents on the pyrazoles that exert distinct steric and electronic effects to the metal center.

1.1.4 Synthetic Applications of TMC ATRA and ATRC

At present, the use of radicals is an important tool for the construction of complex molecules and natural products.7,94-98 In particular, construction of ring systems via free- radical means has become a powerful method for the efficient synthesis of carbocyclic and heterocyclic compounds, ranging from small-sized to macrocycles.99-102 A number of groups have reported successful radical cyclization of polyhalogenated unsaturated esters and amides, leading to the formation of lactones, lactams, and indoles. These can serve as core structures in the synthesis of biologically active natural products and pharmaceutical compounds.41,66-73,103-107

Br Br Bu3SnH, AIBN  major product

I O O Bu3Sn-SnBu3 o O O 80 C, h

major product

Scheme 1.5. Tributylstannane (Bu3SnH) and Iodine Halogen Atom Transfer.

Early reports on successful radical cyclization include the pioneering work of

Giese (tin hydride mediated radical addition to olefins),95 and Curran (iodine atom transfer radical reactions) (Scheme 1.5).108 Despite their importance in organic synthesis, the major drawback of these reactions is the utilization of organotin and organosilane

10 reagents. This can be a disadvantage given the following reasons: a) the reduction of the cyclized radicals via hydrogen transfer greatly limits the synthetic use of the cyclic products due to the loss of functional groups, which are essential for further organic transformations and b) the presence of toxic organotin complexes in the reaction mixture requires additional purification procedures to remove the highly toxic tin byprodducts, often leading to a decreased product yield.

The quest for safer and more environmentally friendly techniques as alternatives to radical ring closure shifted the attention to TMC ATRC reaction.41 Transition metal complexes of Cu, Ru and Fe41,61,81,82,87,109-112 as catalysts in ATRC have provided a useful alternative to the more widely used tin hydride variants. Compared to other radical cyclization methods, the attractive features of ATRC include the conservation of the C-X bonds in the resulting product, environmentally friendly catalysts, ease of use, high selectivity and high productivity. Furthermore, the significance of this methodology lies in the versatility of the C-X functionality in the resulting product as it can be easily reduced, eliminated, displaced, converted to a Grignard reagent, or can serve as a radical precursor.

Copper-mediated ATRC has become an increasingly popular synthetic tool due to the low cost of copper and ease-of work-up. Successful studies utilizing this protocol include the synthesis of trichlorinated 5- and 6-membered lactones from readily accessible alkenyl trichloroacetates (Error! Not a valid bookmark self-reference.).72,113

Reactions catalyzed by CuCl were selective, however, elevated temperatures (110-130

0C) and high catalyst loadings (20-30 mol%) were required (Table 1.1). Some improvements have been achieved by utilizing CuCl in conjunction with tetradentate N-

11 based ligand such as tris(2-pyridyl)methylamine (TPMA) and N,N,N’,N’- tetrakis(2- pyridylmethyl)ethylenediamine TPEDA. This allowed reactions to be conducted at a lower catalyst loading (3-10 mol% relative to substrate) and reaction temperature (80 0C)

(Table 1.1).61,74-76

Table 1.1. Copper-Catalyzed ATRC of Unsaturated Trichloroesters. Cl Cl CCl3 Cl n O O n O O Catalyst (mol %) n Solvent T (oC) Time (h) Yield (%) CuCl (20) 1 MeCN 110 16 59 CuCl (30) 1 MeCN 110 16 95 CuCl/PMDETA (10) 1 DCE 80 12-48 48 CuCl/TPEDA (10) 2 DCE 80 12-48 99 CuCl/TPMA (3) 2 DCE 80 12-48 90 CuCl/bpy (30) 3 DCE 80 18 60 CuCl/bpy (30) 3 DCE 80 2.5 58 CuCl/TPEDA (10) 3 DCE 80 12-48 53 CuCl/TPMA (10) 3 DCE 80 12-48 53

CH3CN = acetonitrile, DCE = 1,-dichloroethane. Refer to Figure 1.3 for ligand structures.

Synthetic usefulness of ATRC has been demonstrated in the formation of Quercus lactones, which are known to be present in different types of wood and are responsible for giving aroma to whiskey and cognac alcohols.80 As represented in Scheme 1.6, copper-catalyzed ATRC of the dichlorinated esters derived from secondary allylic alcohols provided the halogen-functionalized -butyrolactones. Subsequent reductive dehalogenation transformed the dichlorinated lactones to the target compounds in high yield.

12 Cl Cl H Cl CuCl/bpy Cl 2 Bu3SnH, AIBN 145oC, CH CN 80oC, toluene O O 3 O O O O 72% 86% Scheme 1.6. Synthesis of Quercus Lactone via Copper-Catalyzed ATRC.

Synthesis of nitrogen heterocycles has also been reported using copper-mediated

ATRC. Typical cyclization of unsaturated amides to produce -lactams were carried out utilizing only CuCl ats higher temperatures (80-140 oC). Treatment of the substrates with

10-30 mol% CuCl/bpy complex allowed reactions to be conducted even at room temperature (Table 1.2).64,68,77,114 Additional advantage of this synthetic methodology is that reactions can be conducted in either polar (CH3CN) or nonpolar (CH2Cl2) medium without further drying of the solvents.

Table 1.2. Synthesis of -lactams using copper catalyzed ATRC.64 Cl Cl Cl Cl Cl Cl

O N O N R R R = Benzyl (Bn), Tosyl (Ts), tert-butyloxycarbonyl (BOC) Catalyst (mol %) R Solvent T (oC) Time (h) Yield (%) CuCl (30) Bn CH3CN 80 18 68 CuCl/bpy (30) Bn CH2Cl2 RT 1 98 CuCl (30) Ts CH3CN RT 24 97 CuCl/bpy (5) Ts CH2Cl2 RT 0.2 91 CuCl (30) Boc CH3CN 80 4 80 CuCl/bpy (30) Boc CH2Cl2 RT 2 78

13 Copper(I) chloride in conjunction with 2,2‘-bipyridine was also found to efficiently catalyze the ATRC of several -chloroglycine derivatives containing 3- alkenyl substituent on the nitrogen atom (Scheme 1.7).115 Reactions proceeded via 2-aza-

5-alken-1-yl radicals as intermediates, resulting in the predominant formation of 5- exocyclic products upon ring closure. The resulting ring structure in the product resembles proline, an important amino acid utilized in the production of collagen and cartilage.

R2 R2 R2 Cl R R1 R1 1 R R3 3 R CuCl/bpy 3 Cl N N N CO2Me CO2Me CO2Me O O OMe O OMe OMe

Scheme 1.7. Copper Catalyzed ATRC of -Chloroglycine Derivatives to 3-(1- Chloroalkyl)-Substituted Proline.

Further synthetic application of copper-catalyzed ATRC has emerged in the construction of medium-sized rings in the form of 8-, 9- and 10-membered lactones.61,116

Reactions performed at 80 0C in the presence of CuICl and bpy ligand (Table 1.3 provided good yields of 8-membered lactones. As the ring size becomes larger (9- and

10-membered), the combination of CuCl and tetradentate N-based ligand (TPMA or

TBDMBpy) proved to be more effective than the bidentate bpy. It is also apparent that cyclization of the 6-heptenyl trichloroacetate to form the 10-membered lactone becomes challenging, resulting in decreased product yields (Table 1.3). Impressively, copper- catalyzed ATRC has demonstrated its potential in the synthesis of polyoxocyclic heterocycle, which is a structural component of antimicrobial compunds.61

14 Table 1.3. Synthesis of Medium-Sized and Macrocyclic Lactones via Copper-Catalyzed ATRC.

Substrate Product Catalyst (mol %) Solvent T(oC) Yield (%) Cl O O CuCl/bpy (30) 1,2-DCE 80 75 O CHCl2 O Cl

Me Me O Me Cl Cl CuCl/bpy (30) Benzene 180 81 Me O O Me Cl O Cl

Me O Cl CuCl/bpy (30) 1,2-DCE 120 57 O CCl3 O Me O Cl Cl

O Cl CuCl/bpy (30) 1,2-DCE 80 75 O CCl3 O CuCl/ TPDMBpy (10) 1,2-DCE 80 99 CuCl/TPMA (3) 1,2-DCE 80 90 O Cl Cl

O Cl CuCl/ TPDMBpy (10) 1,2-DCE 80 53 O CCl3 O Cl CuCl/TPMA (10) 1,2-DCE 80 53 O Cl

Cl O CuCl/ TPDMBpy (10) 1,2-DCE 80 51 O CCl Cl 3 O CuCl/TPMA (10) 1,2-DCE 80 34 Cl O O O O O O O CuCl/TPMA (10) 1,2-DCE 80 70

O O Cl Cl O CCl O 3 Cl O O

Refer to Figure 1.3 for ligand structures.

15 1.1.5 Copper Catalyzed Atom Transfer Radical Cascade or Domino Reactions

The ability of copper(I) complexes to mediate both intermolecular radical addition and cyclization (ATRA and ATRC) has been exploited as a way to initiate cascade reactions or domino reactions. Increasing significance of these strategies can be attributed to the formation of several bonds in one sequence without the isolation of intermediates, changes in the reaction conditions or addition of external reagents and catalysts.117,118

First examples of successful cascade or domino transition-mediated ATRC include the bicyclic formation from N-allyl trichloracetamide and methylene cyclohexane in the presence of 10 mol% CuCl/bipyridine (a, Scheme 1.8).67 In this process, 5-exocyclization of the N-allyl trichloracetamide proceeded to form -dichlorolactam, which was further reactivated by the CuI complex to generate a new cyclic radical. Subsequently, radical underwent an intermolecular addition to the C=C bond of methylenecyclohexane and the resulting radical was finally trapped by chlorine transfer from the CuCl2/bpy generated in the second initiation step. This approach has also been used to facilitate the synthesis of bicyclic lactam from dienyl trichloracetamides (N-tosyl-N-geranyl trichloroacetamide and

N-benzyl-N-geranyl trichloroacetamide) catalyzed by 10-30 mol% of CuCl/bipyridine (b,

Scheme 1.8).67 When heated to 40 0C, the substrate underwent cyclization in the exo- mode, which led to the formation of -dichlorolactam. Reactivation of the C-Cl bond of this monocyclic intermediate followed by 6-endocyclization gave the 6-membered carbocycle. The cascade reaction utilizing unsaturated -chloro -chloroester, which was efficiently catalyzed by copper(I) chloride in conjunction with bipyridine or bis(oxazoline) ligand under mild reaction conditions has also been reported (c, Scheme

16 1.8).119 In this tandem reaction, first cyclization afforded the 6-endocyclic radical, which was trapped by the remaining double bond product to form additional cyclic structure.

CCl3 Cl (a) + CuCl/bpy Cl O N o Cl Ts CH2Cl2, 83 C O N Ts

Cl Cl CuCl/bpy (b) o CCl3 CH2Cl2, 40 C O O N N Z Z Z= tosyl, benzyl O O O CO2Et (c) OEt Cl Cl Cl CuCl/bpy H DCE, 80oC

Scheme 1.8. Copper Catalyzed Domino or Cascade Reactions in the Synthesis of Bicyclic Compounds.

Recently, copper-mediated atom transfer radical cascade or domino reactions have demonstrated its potential in the synthesis of natural products and pharmaceutical drugs. Indeed, it has been shown to be very effective in the synthesis of polycyclic spiro- indoles, which is described as 5-exo-6-endo domino product utilizing copper complex with TMEDA ligand (Scheme 1.9).94 In this example, the precursor bearing homo allyl substituent on the N-indole underwent ATRC to form the 5-membered ring. Sequential activation of the functionalized moiety (C-Cl) and 6-endocyclization via electrophilic attack of the radical center to a double bond led to the formation of the benzospiroindole.

17 R R N O N Cl CCl3 I O Cu Cl Cl N N TMEDA Cl

1 2 (40%)

R R O N O N Cl Cl Cl Cl N N

B A

Scheme 1.9. Formation of Spiro-Indole via Sequential Radical Cyclization.

1.1.6 Towards a “Greener” TMC ATRA and ATRC Strategy TMC ATRA and ATRC reactions are still not fully utilized in organic synthesis and far less represented in the literature as compared to the standard tributyltin hydride- mediated radical addition to olefin95,120 and iodine atom transfer radical addition reaction.120,121 The principal problem remained the large amount of the catalyst, which typically ranges between 5 and 30 mol% in order to achieve high product selectivity.12-

14,122 In order to understand the necessity for the high catalyst loadings, it is important to take into account the first step in ATRA, which involves an equilibrium between the activation and deactivation of the alkyl halide (KATRA = ka,1/kd,1). Although, a highly active catalyst can be utilized at low concentration, the transition metal in the lower oxidation state (activator) is constantly converted to the higher oxidation state

(deactivator). This increases the concentration of alkyl radical relative to the activator

18 species. Since radical concentration increases, so does the rate of unavoidable radical

9 -1 -1 termination reactions, which are nearly diffusion controlled (kd ≈ 2.0 x 10 M s ). As the reaction progresses, equilibrium is further shifted towards the deactivator until it becomes the only species remaining in the reaction mixture. Consequently, lower alkene conversions and monoadduct yields are achieved since the activator needed to homolytically cleave the C-X bond is no longer present.

Although several reports have appeared on the synthetic use of TMC ATRA and

ATRC,12,40,41,60,120,122-124 the high metal concentration in the reaction mixtures requires lengthy procedures for catalyst removal and purification of the final product, thus making it unsuitable for large scale syntheses and industrial applications. In addition, the relatively large excess of alkyl halide is considered to be non-atom-economic, environmentally unfriendly and expensive. In order to overcome these limitations and problems, various techniques have been developed, such as a) use of solid-supported transition metal catalysts,13,41,125,126 b) use of biphasic fluorous system,75,76,90 c) tuning catalytic efficiency by ligand design63,127 and d) catalyst regeneration in the presence of reducing agents.12-14,122,128-132

1.1.4.1 Solid Supported Catalysts

An advantage of using solid supported catalyst is the recovery of the catalyst from the reaction mixture and recycling in subsequent reactions. Examples of solid- supported metal catalysts that have been successfully used in ATRA and ATRC processes include a silica-tethered Cu catalyst 1,125,126 a carbosilane-supported arylnickel catalyst 2133,134 and an amphilic resin-supported Ru complex 3135 (Figure

1.4).

19 NMe2 O Ph N Si CS Ni Cl PS O O HN C P Ru N Cu n Cl NCMe Ph Cl X NMe2 1 2 3

Figure 1.4. Examples Solid Supported Catalysts

In particular, the first successful ATRC reactions that were conducted on a solid-support involved a copper(I) species ligated to N-propyl-2- pyridynylmethanamine anchored to silica.41,126 When applied to a range of activated and unactivated haloacetamides, excellent yields of 5-exocyclic products were achieved after refluxing in 1,2-dichloroethane (DCE) for 18-48 hours. Results achieved utilizing this particular heteregenous catalytic system were comparable to previously reported copper-mediated ATRC utilizing N-butyl-2-pyridylmethanamine ligand performed under homogenous condition.81 Heteregenous catalytic system based on a solid support can be beneficial in catalyst recycling, although the catalytic activity is diminished. Decreased catalytic efficency is due to the inevitable accumulation of the deactivator species (CuII) as observed in the color change from brown to green, a strong indication of the oxidation of CuI to CuII.

1.1.4.2 Biphasic System

TMC ATRC has been conducted under fluorous biphasic systems, which consist of a mixture of aqueous (usually water or fluorous) and organic solvents. In particular, perfluorinated analogues of PMDETA and ME6TREN (Figure 1.5) have been utilized as ligands in copper-mediated ATRC reactions of pent-4-enyl trichloroacetate to yield an eight-membered lactone.90 The reactions were performed

20 in a mixture of perfluoroheptane and DCE at 80 0C. High yields of the lactone were achieved at optimum conditions, in which reactions are heated for 20 hours in the presence of 5 mol% of the catalyst. Catalytic activity was enhanced in the presence of iron metal, which served as a reducing agent, thus inhibiting the accumulation of the deactivator species (CuII).

The main lure of biphasic solvent systems is that they become homogenous at elevated temperatures, enabling the reaction to be conducted under single phase condition. After the reaction concludes, product separation can then performed at lower temperatures under biphasic condition. Additional benefit is the potential for catalyst recycling. For instance, perfluorinated ligands (Figure 1.5) complexed with copper and the presence of iron enabled four consecutive ATRC reactions to be carried out.

C8F17 C8F17 C8F17 C8F17

N N N N N N

C8F17 C8F17 C8F17 N C8F17 C8F17 C F C F 8 17 8 17 Figure 1.5. Perfluorinated Ligands for Copper-Catalyzed ATRC.

1.1.4.3 Development of Highly Active Ligands for ATRA and ATRC

As mentioned earlier, the complexing ligand is important because it regulates the dynamic equilibrium for atom transfer radical reactions (KATRA = ka,1/kd,1 and KATRP

127,136-140 = ka,1/kd,1). The presence of the ligand enhances catalytic activity by increasing the solubility of the copper complex. At the same time, it alters the redox

21 I II potential of the Cu /Cu system, which correlates to the activation rate constant (ka)

63,141 and overall equilibrium (KATRA). Thus for complexes, having similar

―halidophilicities‖ or equilibrium constants for coordination of the halide to the copper(II) center, the redox potential can be used to measure catalytic activity. A study conducted by Matyjaszewski and coworkers revealed the linear correlation

142-145 between the equilibrium constant for ATRP (KATRP) and redox potential (E1/2).

Based on this study, the more reducing catalysts include complexes bearing neutral tetradentate and multidentate N-based ligands listed in Figure 1.3, such as

66,77,79,82,146,147 61,79,90,132,146,148,149 61,90,127 91 Me6TREN, TPMA, TPEDA Me4Cyclam and

DMCBCy.92

1.1.4.4 Catalyst Regeneration Technique

The most promising technique for harnessing TMC atom transfer radical reactions towards a ―greener‖ methodology is catalyst regeneration in the presence of reducing agents (Scheme 1.10). Originally, this methodology has been found for copper catalyzed atom transfer radical polymerization (ATRP).12,129,130,150-154 ATRP is mechanistically similar to ATRA, with the exception that the structure of the alkyl halide is modified in such a way that more than one activation/deactivation can occur. Subsequently, this was applied first to ruthenium-131 and then copper-102,132,155 catalyzed ATRA reactions. In this methodology, the transition metal in the lower oxidation state (activator) is continuously regenerated from the transition metal in the higher oxidation state (deactivator), provided that reducing agents such as phenols, glucose, ascorbic acid, hydrazine, tin(II)-ethyl hexanoate and free radical initiators 2,2‘-azobis(isobutyronitrile), (AIBN) and 2,2‘-

22 azobis(4-methoxy-2,3-dimethylvaleronitrile), (V-70) listed in Scheme 1.10 are present in the system.

Scheme 1.10. Transition Metal Catalyzed ATRA in the Presence of Reducing Agents.

1.1.7 Highly Efficient TMC ATRA Reactions in the Presence of Reducing Agents

Successful catalyst regeneration in ATRA was first reported utilizing

III 131,156,157 [Ru Cl2Cp*PPh3] in conjunction with AIBN or Mg as reducing agent. In the

23 ATRA of CCl4 to styrene, yields as high as 89% were obtained with an impressive turnover number (TON) of 44,500.131 This was a significant improvement over previous

II methodology, which used 0.3 mol% loading of [Ru ClCp*(PPh3)2] as catalyst without

158,159 AIBN in order to achieve the same yields. Similarly, Ru-catalyzed ATRA of CCl4 to styrene but in the presence of Mg as reducing agent resulted in nearly quantitative yields of the monoadduct at an alkene to catalyst ratio of 5000:1.157 Although the use of

Mg increases the overall metal concentration, it decreases the concentration of free radicals, thus suppressing competing free radical polymerization, resulting in higher product distributions and yields. In addition, reactions can be conducted at ambient conditions, unless using AIBN, which typically requires heating to generate free-radicals.

Highly efficient ATRA reactions of polyhalogenated methanes to alkenes have been reported using catalytic amounts of [CuI(TPMA)X] (X = Cl, Br) in conjunction with

AIBN.132,149 Turnover numbers ranging between 4900-7200 (1-hexene) and 4350-6700

132 (1-octene) were obtained in the addition of CCl4. In the case of styrene and methyl acrylate, lower yields (42-85% for styrene, 60% for methyl acrylate) were observed due to the competing free radical polymerization of these highly active alkenes.132 Even more impressive is the ATRA of CBr4 to styrene and methyl acrylate in the presence of

[CuI(TPMA)Br] and AIBN, allowing reactions to be conducted using as low as 5 ppm of

Cu catalyst to provide nearly quantitative yields. This is by far the lowest catalyst loading reported in transition metal-mediated ATRA.149

Decomposition of AIBN to generate isobutyronitrile radicals is induced thermally and therefore proceeds faster at elevated temperatures. However, this is problematic for

2 -1 -1 alkenes such as methyl methacrylate (kp,60 = 8.2 x 10 M s ), vinyl acetate (kp,60 = 7.9 x

24 3 -1 -1 2 -1 -1 10 M s ) and acrylonitrile (kp,60 = 1.9 x 10 M s ) that are very active towards free- radical polymerization because high temperature increases their propagation rate constants. As a consequence, the target monoadducts are often contaminated with oligomers or polymers.160,161 As an alternative solution, copper-mediated ATRA reactions can be conducted in the presence of 2,2‘-azobis(4-methoxy-2,4- dimethylvaleronitrile or (V-70), which actively decomposes at ambient temperature.155

Although results were inferior to CuII/AIBN catalytic system, greater control over competing free radical polymerization for highly active alkenes was obtaines as a result

2 of the decrease in the propagation rate constants of methyl methacrylate (kp,25 = 3.2 x 10

-1 -1 3 -1 -1 2 -1 -1 M s ), vinyl acetate (kp,25 = 3.4 x 10 M s ) and acrylonitrile (kp,25 = 9.3 x 10 M s ).

Such values are significantly lower compared to the halide transfer from the copper(II)

II 5 -1 complex (kd,2 = [Cu LmX2] < 1.8 x 10 s ), thus allowing for radical trapping to form the desired monoadducts.160

Although the use of V-70 was a proof-of-concept that lowering reaction temperature could control competing free radical polymerization, it is an expensive and unstable reagent. Another way of performing reactions effectively at ambient conditions utilizing cheaper and readily available free-radical diazo initiator such as AIBN is through ultraviolet (UV) irradiation since the photoinitiated decomposition rate constant of AIBN at 25 0C (k = 1.2 x 10-5 s-1)162 is similar to the thermal-initiated process at 60 0C (k = 1.5 x

-5 -1 23 10 s ). In the experiment conducted in the addition of CCl4 in presence of 1 mol% of

[CuII(TPMA)Cl][Cl], total conversion of methyl acrylate to the desired monoadduct was observed (entry 2, Table 1.4. Furthermore, quantitative yields of monoadduct were also achieved in the addition of CCl4 to methyl acrylate and methyl methacrylate at even

25 lower catalyst loading (0.05 mol%) (entries 5 and 12, Table 1.4).163 Even more impressive results were the excellent yields obtained in the ATRA of CBr4 to methyl acrylate and methyl methacrylate catalyzed by 0.01 mol% of [CuII(TPMA)Br][Br].

ATRA experiments utilizing acrylonitrile, vinyl acetate and styrene showed high product selectivity as indicated by the percent product, however, higher catalyst loadings were required (Table 1.4).

The scope of the photoinitiated copper catalyzed ATRA in the presence of AIBN was also expanded to less active alkyl halides such as CHCl3, CHBr3, ethyl trichloracetate (CCl3CO2Et), benzyl chloride (BzCl) and benzyl bromide (BzBr) (Table

1.5). Such ATRA reactions often require elevated temperatures, high catalyst loadings and/or large excesses of alkyl halides in order to achieve reasonable yields of the monoadduct. The addition of trihalogenated compounds such as CHCl3, CHBr3 and

CCl3CO2Et to methyl acrylate utilizing 1 mol% of the catalyst resulted in reasonable yields of the corresponding monoadducts (entries 1-3).163 For the case of methyl methacrylate (entries 6-8), acrylonitrile (entries 11-13) and vinyl acetate (entries 16-18), significantly lower yields of the monoadducts were obtained as compared to methyl acrylate. ATRA reactions conducted utilizing monohalogenated benzyl halides (BzBr and

BzCl), lower yields of the monoadducts were observed due to incomplete alkene conversion, AIBN initiated free-radical polymerization and monoadduct reactivation

(entries 4, 5, 9, 10, 22 and 23). Despite unfavorable results, these are the first ATRA reactions of BzCl and BzBr to be reported and thus, offer an opportunity for further optimizations.

26 Table 1.4. Photoinitiated Cu-Catalyzed ATRA of CCl4 and CBr4 to Highly Active Alkenes at Ambient Temperaturea II d Entry Alkene RX [Alk]0:[Cu ]0 %Conv %Product %Yield b 1 CCl4 1000:1 100 47 47 2 O CCl4 100:1 100 100 100 3 CCl4 500:1 100 99 99 O 4 CCl4 1000:1 100 94 94 methyl 5 CCl4 2000:1 100 85 85 acrylate c 6 CBr4 500:1 100 100 100 c 7 CBr4 10000:1 100 79 79 b 8 CCl4 1000:1 100 46 46 9 O CCl4 100:1 100 100 100 10 O CCl4 500:1 100 99 99 11 CCl4 1000:1 95 96 91 12 methyl CCl4 2000:1 90 90 81 c 13 methacrylate CBr4 500:1 100 100 100 c 14 CBr4 10000:1 100 73 73 b 15 CCl4 1000:1 100 48 48 16 CCl4 100:1 100 98 98 17 CCl4 500:1 100 84 84 18 CN CCl 1000:1 100 75 75 acrylonitrile 4 19 CCl4 2000:1 96 68 65 c 20 CBr4 500:1 100 96 96 c 21 CBr4 1000:1 95 92 87 b 22 CCl4 1000:1 99 90 88 23 CCl4 100:1 99 100 99 O 24 CCl4 500:1 98 100 98 25 O CCl4 1000:1 96 99 95 26 vinyl acetate CCl4 2000:1 95 97 92 c 27 CBr4 500:1 99 100 99 c 28 CBr4 5000:1 78 95 74 b 29 CCl4 1000:1 65 58 38 30 CCl4 100:1 99 97 96 31 CCl4 500:1 50 92 46 32 CCl4 1000:1 32 90 29 33 CCl4 2000:1 27 82 22 c 34 styrene CBr4 500:1 77 98 75 c 35 CBr4 2000:1 60 85 51 a All reactions were performed in CH3CN in the presence of light for 24 h. Reaction temperature was maintained at 23  2 ºC using a water bath. [alkene]0:[AIBN]0=1:0.05, II b [alkene]0=0.75M, catalyst = [Cu (TPMA)Cl][Cl]. AIBN decomposition by heating at 60ºC; ccatalyst = [CuII(TPMA)Br][Br]. dYield is based on the formation of monoadduct and was determined by 1H NMR spectroscopy (relative errors are  10%).

27 Table 1.5. Photoinitiated Cu-Catalyzed ATRA of CHBr3, CHCl3, Cl3CO2Et, BzBr and BzCl to Highly Active Alkenes at Ambient Temperaturea

Alkyl Entry Alkene [Alk] :[RX] %Conv %Prod %Yieldb Halide 0 0

1 CHBr3 1:1.25 70 90 63 2 O CHCl3 1:1.25 51 90 46 3 Cl3CO2Et 1:1.25 55 89 49 4 O BzBr 1:4 42 78 33 5 BzCl 1:4 35 74 26

6 CHBr3 1:1.25 98 32 31 7 O CHCl3 1:1.25 80 25 20 8 O Cl3CO2Et 1:1.25 86 33 28 9 BzBr 1:4 70 17 12 10 BzCl 1:4 59 12 7

11 CHBr3 1:1.25 69 70 48 12 CHCl3 1:1.25 55 64 35 13 CN Cl3CO2Et 1:1.25 50 80 40 14 BzBr 1:4 49 42 21 15 BzCl 1:4 47 35 16

16 O CHBr3 1:1.25 10 95 9 17 CHCl3 1:1.25 5 95 5 O 18 Cl3CO2Et 1:1.25 10 99 10

19 CHBr3 1:1.25 89 88 78 20 CHCl3 1:1.25 61 80 49 21 Cl3CO2Et 1:1.25 68 90 61 22 BzBr 1:4 40 84 34

23 BzCl 1:4 29 79 23 a All reactions were performed in CH3CN in the presence of light for 24 h. Reaction II temperature was maintained at 23  2 ºC using a water bath. [alkene]0:[Cu ]0:[AIBN]0 = II 100:1:5, [alkene]0=0.75M, catalyst=[Cu (TPMA)Cl][Cl] for alkyl chlorides, [CuII(TPMA)Br][Br] for alkyl bromides. bYield is based on the formation of monoadduct and was determined by 1H NMR spectroscopy (relative errors are  10%).

Very recently, a ―greener‖ methodology of conducting copper-catalyzed ATRA and ATRC has been reported using a more environmentally benign reducing agent, ascorbic acid commonly known as vitamin C.128 Aside from its reduced environmental impact, ascorbic acid decomposition proceeds via non-radical means (Scheme 1.11). This feature can be synthetically useful as it avoids unwanted polymerization that could be

28 attributed to free-radical polymerization usually observed in the ATRA of alkyl halides to alkenes having high propagation rate constants when performed in the presence of AIBN.

Consequently, product selectivity towards the desired monoadduct is increased. In addition, the system is proven to be oxygen-tolerant allowing for bench-top preparation of reaction mixtures and isolation of the products in high purity can be achieved by simple liquid-liquid extractions.

When applied to copper-catalyzed addition of CBr4 to 1-octene, excellent yields

(90%) were obtained in the presence of 0.02 mol% of catalyst. Decreasing the catalyst loadings to 0.01 and 0.005 mol% still afforded the formation of 85% and 76% of the monoadducts; respectively. Furthermore, TONs of 15000 were reported employing this technique. Alkenes that are highly susceptible to free-radical polymerization such as methyl methacrylate, acylonitrile and methyl acrylate required higher catalyst loadings in order to achieve quantitative yields of the desired monoadducts. However, yields higher than 80% were obtained using as low as 0.02 mol% of the copper(II) complex in the presence of ascorbic acid. Interestingly, the values for product conversions and yields were very similar, indicating the absence of interfering side reactions and exceptional product selectivity.

OH OH OHOH O O k O OH reduction O OH II + 2[Cu (TPMA)Cl][Cl] + 2CuI(TPMA)Cl + 2HCl koxidation HO OH O O

Scheme 1.11. Proposed Reduction of CuII Complex to CuI Complex in the Presence of Ascorbic Acid.128

29 1.1.8 Atom Transfer Radical Cyclizations in the Presence of Reducing Agents

Radical annulation mediated by various transition metal complexes has created a vast array of medium-sized-41,64,68,72,74,76,78,80,110,113,116,119,164-166 and macrocyclic compounds.41,61 This process also known as atom transfer radical cyclization (ATRC) is synthetically attractive as it enables the synthesis of functionalized ring systems that can be used as starting materials in the preparation of complex organic molecules. Traditional

ATRC reactions were conducted in the presence of the transition metal complex in the lower oxidation state to activate homolytic cleavage of the C-X bond.41

Ruthenium157,167 and copper110,168,169 mediated cyclization reactions in the presence of reducing agents have been successfully applied in the formation of 5-exo- trig- and 5-exo-dig- products. Copper(I) regeneration in ATRC reactions of N-allyl bromoacetamides catalyzed by 0.1-1.0 mol% of CuI(TPMA)Br or [CuII(TPMA)Br][Br] complexes proceeded efficiently (Table 1.6).110 The presence of AIBN as a reducing agent resulted in a 30- to 300-fold reduction in catalyst loading when compared to previously reported cyclizations. Furthermore, this catalytic system has been effective in the cyclization of olefinic amides, esters and ethers producing lactams, lactones and cyclic ethers; respectively.157,167 In addition to the reduction in the amount of catalyst, other interesting features of catalyst regeneration is the ability of the reactions to be conducted starting with the relatively air- and moisture- stable transition complex in the higher oxidation state and even at ambient conditions. This was demonstrated in the successful ATRC of N-allyl-N-tosyldichloroacetamide utilizing as low as 5 mol% of

* III [Cp Ru Cl2(PPh3)] in conjunction with metallic Mg, achieving yield as high as 94% after 4h at room temperature.

30 Table 1.6. ATRC of Bromoacetamides Catalyzed by Copper Complexes with TPMA Ligand in the Presence of AIBN.a Substrate Product Solvent T (oC) Yield (%) Br Br CH2Cl2 50 84 b CH2Cl2 50 97 O N O N toluene 110 87 Bn Bn Br Br CH2Cl2 50 95

O N O N Ts Ts Br Br CH2Cl2 50 100

O N O N Ts Ts Ph Ph CH2Cl2 50 99 Br Br

O N O N Ts Ts Br Br CH2Cl2 50 99

O N O N Ts Ts b Br CH2Cl2 50 13 toluene 110 88b (1:2)

O N O N O N Bn Bn Bn Br Br CH2Cl2 50 30 (3:2) toluene 110 67 (1:1) O N Bn O N O N Bn Bn Br Br CH2Cl2 50 33 (1:2) toluene 110 67 (1:1) O N Ts O N O N Ts Ts Br Br Br toluene 110 90 (4:1)

O N O N O N Ts Ts Ts a I II Reactions were performed with [substrate]0:[Cu or Cu ]0:[AIBN]0 = 1:0.01:0.10 for 24 b h. CuBr2/TPMA complex was used.

1.1.9 Catalyst Regeneration Technique in Sequential Organic Transformations

What has made radical reactions increasingly significant in carbon-carbon formations is that they can be conducted using a wide spectrum of solvents ranging from aprotic to protic polar and even nonpolar media.41,170-172 An additional benefit is the high functional group tolerance of unprotected side chains. Compared to any radical reaction,

TMC ATRA preserves the carbon-halogen bond in the resulting product, thus making it synthetically useful for further organic transformations. The aforementioned attractive features of both TMC intermolecular and intramolecular radical additions can be very conducive in performing one-pot sequential reactions.

The versatility of the C-X bond as a subsequent precursor has been explored for reductive ring closure leading to the formation of cyclopropanes173,174 as shown in

Scheme 1.12. Interestingly, the entire procedure was performed in one-pot via sequential

* III 173 ATRA and dechlorination processes in the presence of [Cp Ru Cl2PPh3] and Mg. In this transformation, Mg not only regenerates the catalytically active RuII complex, but also acts as dechlorinating agent. As shown in Scheme 1.12, the first step involves ruthenium-catalyzed addition of 1,1-dichlorides to olefinic substrates. The resulting 1,3- dichlorides are then directly converted to cylopropanes by reductive dehalogenation with

Mg (Table 1.7). A shortcoming of this methodology, however, is the requirement of two different solvents for both reactions. Ruthenium-catalyzed ATRA requires a nonpolar solvent such as toluene, while dechlorination is made possible after the external addition of tetrahydrofuran (THF), a polar solvent. Optimizations were then conducted utilizing metallic Mn instead of Mg.174 Sequential ATRA and dechlorination reactions were first

32 performed at room temperature, however, heating the mixtures to 60 0C reactions were found out to proceed more efficiently using THF as a solvent (Table 1.7) possible after the external addition of THF, a polar solvent. An alternative solution was sought, in which metallic Mn was utilized instead of Mg.174 Initially, sequential ATRA and dechlorination reactions were performed at room temperature using THF as solvent.

Further optimization such as heating the mixtures to 60 0C reactions were found to proceed more efficiently (Table 1.7).

Table 1.7. Sequential ATRA or ATRC and Dechlorination Reactions Catalyzed by * a b [Cp RuCl2(PPh3)] in the Presence of Mg or Mn. c d Substrate(s) Product Reducing t1 t2 Yield cis:trans Agent (h) (h) ATRA CO2Et Ph Ph Mg 6 1 74 1:3.0 Cl2HCCO2Et CN Ph Ph Mg 24 2 70 1:2.8 Cl2HCCN Cl Ph Ph Mg 24 2 71 1:2.3 CHCl3 O CO2Et O Mg 8 3 60 1:2.9 MeO2C Cl2HCCO2Et

MeO C 2 Mg 48 0.5 51 1:12.6 Cl2HCCO2Et Ph CO2Et Cl e Ph Ph Mn 3 / 64 6:1 Cl3CCO2Et CO2Et F f F Cl Mn 3 / 49 7:1 Cl3CCO2Et CO2Et MeO f MeO Cl Mn 3 / 49 2:1 Cl3CCO2Et CN CN g Ph Ph Mn 19 / 64 / Cl2C(CN)2

33 CN F g F CN Mn 19 / 83 / Cl2C(CN)2 CN MeO MeO CN Mng 19 / 51 /

Cl2C(CN)2 CN Ph Ph CN Mng 19 / 53 /

Cl2C(CN)2 CN CN Mng 19 / 73 / Cl2C(CN)2 COOEt COOEt g Ph Ph Mn 2 / 66 / Cl2C(COOEt)2 ATRC Ph Ph

CCl3 Cl Mg 3 1 67 1:11.7 O O Cl Cl Mg 4 0.5 65 / O N O N Ph Ph Cl ClCl PhN O Mg 2 24 61 / O N O NPh Ph a ATRA reactions were performed in toluene with [alkene]0 = 0.33 M, [Cl2CHR]0 = 0.33 M and [alkene]0/[Mg]0 = 1/40 with 1 mol% of Ru catalyst.ATRC reactions were performed in toluene with [alkene]0 = 0.16 M and [alkene]0/[Mg]0 = 1/40 with 1 or 2 0 mol% of Ru catalyst. After the time t1 at 60 C, the reaction mixture was diluted 2.5 times 0 0 b the volume of THF and stirred at t2 at either 0 C or 25 C. ATRA and dechlorination reactions were performed in THF over a single period of time (t1) with [alkene]0 = 0.10 M, [Cl3CCOOEt, Cl2C(CN)2]0 = 0.40 M, [Cl2C(COOEt)2]0 = 0.25 M, and e f g 0 c [alkene]0/[Mn]0 = 1/5 with 1, 2 or 5 mol% of Ru catalyst at 60 C. Isolated yields. dCis:trans ratio was determined by 1HNMR analysis.

Scheme 1.12. Sequential ATRA/Reductive Dehalogenation in the Formation of Cyclopropane.

* Table 1.8. Sequential ATRA Reactions Catalyzed [Cp RuCl2(PPh3)] and Mg. a,b Olefin(s) /Cl2CRR’ Product t1 (h) t2 (h) %Yield Cl CN Cl

Cl2CHCN 48 / 91

Cl CN Cl

Cl2CHCN 48 / 90 Cl Cl Cl Cl CN Cl Cl CHCN F 2 48 / 92 F F Cl CN Cl 24 / 88 CN Cl2C(CN)2

Cl CN Cl Cl2C(CN)2 24 / 90 CN

Cl CN Cl 24 / 90 CO Et Cl2C(CO2Et)CN 2

O OEt Cl Cl 48 / 70 Cl2C(CO2Et)2 O OEt Cl Cl CN 24 24 75 Cl2C(CN)2 CN Cl CN Cl Ph 24 24 76 CN Cl2C(CN)2

Cl CN Cl Cl2C(CN)2 24 48 70 F CN F

35 Cl CN Cl Cl2C(CN)2 24 48 70 Cl CN Cl a 0 ATRA reactions were performed in toluene at 60 C with [alkene]0 = 1.50 M, [Cl2CRR‘]0 = 0.50 M or [2-vinylnaphthalene]0 = 0.90 M, [Cl2CRR‘]0 = 0.3 M and b [Cl2CRR‘]0/[Mg]0 = 1/30 with 1 mol% of Ru catalyst relative to Cl2CRR‘. ATRA 0 reactions with two different olefins were performed in toluene at 60 C with [olefin 1]0 = 0.55 M, [olefin 2]0 = 1.0 M, [Cl2CRR‘]0 = 0.50 M or [2-vinylnaphthalene]0 = 0.44 M, [styrene]0 = 0.80 M [Cl2CRR‘]0 = 0.40 M and [Cl2CRR‘]0/[Mg]0 = 1/30 with 1 mol% of c Ru catalyst relative to Cl2CRR‘. Isolated yields relative to Cl2CRR‘.

3 * Cl R Cl R2 Cl [Cp RuCl2(PPh3)], Mg 0 1 2 3 toluene, 60 C 1 4 1 4 R + Cl2CR R R Cl + R R R R2 R3

Scheme 1.13. Synthesis of 1,5-Dichlorides via One-Pot Consecutive ATRA Reactions Catalyzed by RuIII Complex in the Presence of Mg.175

* III Recently, two consecutive ATRA reactions catalyzed by [Cp Ru Cl2(PPh3)] in combination with Mg have been reported. In this methodology, first step involves the addition of alkyl halide to an olefin to form a 1,3-dihalide. Further activation by homolytic cleavage of the C-X bond in the monoadduct generates an organic radical, which subsequently adds to another molecule of olefin to produce 1,5-dichloride (Scheme

1.13).175 Such reaction demonstrated the synthetic attractiveness of ATRA in controlling product selectivity in two ways. First, ATRA was successfully terminated after the second step to form the 1,5-dihalides without contamination of oligomers/polymers.

Second, reactivation of two 1,3-dichlorides (generated after the first ATRA) followed radical-radical coupling to form a diadduct was successfully prevented. Results for the one-pot, sequential ATRA reactions involving 1,1-dihalides to similar or different olefins are presented in Table 1.8.

36 It has been reported that cyclopropanes can be synthesized via Mg- or Mn- induced dechlorination of 1,3-dichloride obtained from ATRA reaction.173,174 In a similar fashion, synthesis of cyclopentanes has been achieved from one-pot, three-component reaction involving two successive ruthenium-catalyzed ATRA and reductive cyclization.175 In this methodology, the 1,3-dihalide generated in the first ATRA step was subsequently activated, and added across the C=C bond of another alkene to form the 1,5- dihalide. Reductive dehalogenation of the resulting monoadduct induced by LiCl provided the cyclopentane in modest yield (Scheme 1.14).

* CN [Cp RuCl2(PPh3)], Mg LiCl 60 0C, toluene THF, RT Ph + Cl2CHCN 3 : 1 one-pot reaction Ph Ph 42%

Scheme 1.14. Synthesis of 1,5- Cyclopentane via Sequential ATRA and ATRC Reactions Catalyzed by RuIII Complex in the Presence of Mg.175

The scope of catalyst regeneration has also been expanded in intermolecular and intramolecular ATRA resulting in the regioselective formation of cyclic compounds

(Scheme 1.15).128,163,168,169 The principal advantage of this methodology is that the presence of reducing agents enables the significant reduction of catalyst loading. Such reduction is very beneficial as it enhances the radical annulation efficiency by decreasing the rate of radical trapping by the deactivator (kd) compared to rate of radical ring closure

(kc). Additionally, the rate constant for deactivation can be further controlled through ligand design.

37 1,6-Dienes are excellent candidates to further expand the methodology of catalyst regeneration because the addition of alkyl radicals results in the formation of 5-hexenyl radicals, which are known to undergo very fast regioselective 5-exocyclization.98,176 The results for ATRA followed by sequential ATRC of reaction mixtures of 1,6-dienes and

163,168 168 CCl4 in the presence of free radical initiators such as AIBN or V70, and reducing agents such as Mg169 and ascorbic acid128 are summarized in Table 1.9. When

[CuII(TPMA)Cl][Cl] was used in combination with a free-radical initiator, truly remarkable results were obtained. In the presence of AIBN and running reactions at 600C, cyclic products derived from the addition of CCl4 to 1,6-heptadiene, diallyl ether and

N,N-diallyl-2,2,2-trifluoroacetamide were synthesized in nearly quantitative yields using as low as 0.02 mol% of catalyst (relative to diene). Excellent results with N,N-diallyl carbamate and diethyl diallylmalonate were also achieved using even smaller amounts of the catalyst (0.01 mol%).168 Photoinitiated decomposition of AIBN with the aid of a ultraviolet (UV) lamp enabled reactions to be conducted at room temperature.163 Utilizing

0.05 mol% of the copper(II) complex, cyclization of diallyl ether, N,N-diallyl carbamate, diethyl diallylmalonate and N,N-diallyl-2,2,2-trifluoroacetamide proceeded efficiently after the addition of CCl4 furnishing 5-exocyclic compounds in yields higher than 90%.

More outstanding results were achieved with the use of ascorbic acid as a reducing

128 agent. Formation of the cyclic products derived from N,N-diallyl carbamate and CCl4 was obtained in 99% yield with catalyst loading of 0.01 mol%. Cyclizations were also very efficient at ambient temperature using V-70 as a reducing agent, although slightly higher catalyst loadings were required (0.04-0.1mol%).168

38 Similarly, neutral copper(I) homoscorpionate complexes also required higher catalyst loadings of 1 mol% at 30 0C.169 However, these complexes have been shown to be quite promising in ATRA reactions in the absence of any reducing agents. The catalytic mechanism is not presently understood, however, it appears that an equilibrium between copper(I) and copper(II) species in these systems is controlled through the addition of an ancillary ligand such as acetonitrile, which in turn suppresses radical termination reactions. The data presented in Table 1.9 also indicate that regardless of the choice of the 1,6-diene, catalyst, reaction temperature or reducing agent, 1,2-disubstituted cyclopentanes showed a strong preference for the formation of the cis product, which was also observed in similar free radical cyclizations that do not utilize transition metal complexes as halogen transfer agents.176-178

CuITpX or [CuII(TPMA)Cl][Cl] + CCl4 Cl CCl reducing agents 3 1-5 1a-5a

O O F3C tBu O O O O O O N N

1 2 3 4 5

O O F3C tBu O O O O O O N N

Cl3C Cl Cl3C Cl Cl3C Cl Cl3C Cl Cl3C Cl 1a 2a 3a 4a 5a

Scheme 1.15. Copper-Catalyzed ATRA of CCl4 to 1,6-Dienes in the Presence of Reducing Agents.

Table 1.9. ATRA of CCl4 to 1,6-Dienes Followed by Sequential ATRC Catalyzed by CuITpX and [CuII(TPMA)Cl][Cl] Complexes in the Presence of Reducing Agents. a 0 II Product Ligand T [ C] Reducing Agent [Cu ]0 (mol%) Yield (%) Cis:Trans 1a TptBu,Me 30 / 1.0b 59 87:13 TpCy,4Br 30 / 1.0 62 84:16 TPMA 60 AIBN 0.02 95(83)c 84:16 TPMA 30 V-70 0.04 92 85:15 TPMA RTd V-70 0.04 87 86:14 2a TptBu,Me 30 Mg 1.0 >99 86:14 TpCy,4Br 30 Mg 1.0 >99 82:18 TPMA 60 AIBN 0.05 89(70)c 80:20 TPMA 30 V-70 0.1 91 79:21 TPMA RT V-70 0.1 80 82:18 TPMA RTe AIBN 0.05 96 80:20 TPMA 60 ascorbic acid 0.1 86 76:24 TPMA 60 ascorbic acid 0.05 74 79:21 3a TptBu,Me 30 Mg 1.0 95 87:13 TpCy,4Br 30 Mg 1.0 90 83:17 TPMA 60 AIBN 0.02 96 74:26 TPMA 60 AIBN 0.01 91(75)c 66:34 TPMA 30 V-70 0.02 87 64:36 TPMA RT V-70 0.02 77 56:44 TPMA RTe AIBN 0.05 97 79:21 TPMA 60 ascorbic acid 0.01 99 73:27 4a TptBu,Me 30 Mg 1.0 >99 93:7 TpCy,4Br 30 Mg 1.0 >99 90:10 TPMA 60 AIBN 0.02 >99 86:14 TPMA 60 AIBN 0.01 89(80)c 84:16 TPMA 30 V-70 0.02 90 91:9 TPMA RT V-70 0.02 81 86:14

40 TPMA RTe AIBN 0.05 93 83:17 TPMA 60 ascorbic acid 0.02 93 81:19 TPMA 60 ascorbic acid 0.01 82 82:18 5a TPMA 60 AIBN 0.02 90(77)c 81:19 TPMA 60 AIBN 0.01 73 84:16 TPMA 30 V-70 0.02 95 73:27 TPMA RT V-70 0.02 87 73:27 TPMA RTe AIBN 0.05 90 85:15 a II Reactions with [Cu (TPMA)Cl][Cl] were performed in CH3OH for 24 h with [CCl4]0:[1,6-Diene]0:[AIBN or V-70]0= 1.25:1:0.05, [1,6-Diene]0= 1.0 M or [CCl4]0:[1,6- I X Diene]0:[ascorbic acid]0= 1.25:1:0.07, [1,6-Diene]0= 1.34 M. Reactions with Cu Tp were performed in [D6]benzene for 24 h with [CCl4]0:[1,6-Diene]0= 400:100. The yield is based on the formation of cis and trans cyclopentanes and was determined by 1H NMR using anisole or 1,4-dimethoxybenzene as internal standard (relative errors ± 15%). bMol percent of catalyst relative to 1,6-diene. cIsolated yield after column chromatography. dRoom temp. = 22 ± 2 0C. ePhotoinitiated reactions using UV lamp. 1.1.10 Section Summary and Project Overview

Traditional transition metal atom transfer radical reactions (ATRA, ATRC and

ATRP) have been conducted in high catalyst loadings in order to achieve high product selectivity. However, high amount of catalysts limited their synthetic usefulness because it resulted problems during product separation, catalyst recycling and most of all, it is environmentally unfriendly due to the large concentration of transition metal involved.

The catalyst regeneration technique originally developed for ATRP circumvented the problems through the use of free-radical initiators and reducing agents, which prevent the accumulation of the deactivator by continuously regenerating the activator species. As a consequence, reactions can now be conducted in much lower catalyst loadings, thus making the overall process ―greener‖. Recently, this technique has become widely adopted in organic transformations such as TMC ATRC and sequential organic transformations. In an effort to further expand the scope of catalyst regeneration technique for synthetic utility, experiments have been initiated on the copper-catalyzed intermolecular and intramolecular ATRA via the cascade mechanism to form

41 functionalized rings. Details will be elaborated in succeeding chapters for the addition of polyhalogenated alkyl halides to symmetrical 1,6-dienes (Chapter 2) and unsymmetrical

1,6-dienes or 1,6-diene esters (Chapter 3). Computational studies validating experimental observations will also be presented in Chapter 3 particularly for the cyclization of the 1,6- diene esters.

1.2 Click Chemistry

1.2.1 Click Chemistry as a Guiding Principle

The ―click chemistry‖ concept coined in 2001 by Sharpless, Kolb and Finn serves as a guiding principle in the quest for function and it can be summarized as: ―searches must be restricted to molecules that are easy to make.‖18 With its enormous and expanding arrays of applications in various disciplines such as chemistry,18,19,179 biology,180,181 material science182-184 and drug discovery,185-188 it is undeniably the most eminent synthetic strategy of the century. A reaction under the ―click chemistry‖ classification is defined by a set of stringent criteria: modular, wide in scope, high yielding, stereospecific and generates safe by-products. Ideally, the synthesis utilizes readily available starting materials and proceeds under simple reaction conditions, either in neat or using environmentally benign and easily removable solvents. Purification involves non-chromatographic methods, preferably crystallization or distillation. Selected reactions shown in Figure 1.6 that have fulfilled the requirements include cycloadditions

(1,3-dipolar cycloaddition and Diels-Alder reaction); nucleophilic substitution chemistry,

42 particularly ring-opening reactions of highly strained elctrophiles (epoxides, aziridines, aziridinium ions and episulfonium ions); carbonyl chemistry of the non-aldol type

(formation of ureas, thioureas, aromatic heterocycles, oxime ethers, hydrazones and amides); and addition to carbon-carbon multiple bonds (oxidative and Michael additions).18,185,187

Figure 1.6. Selected Reactions Fulfilling Click Chemistry Criteria.

1.2.2 Copper-Catalyzed Azide-Alkyne Cycloadditon (CuAAC): The Center Stage of Click Chemistry

Among the myriad of reactions that have met the ―click chemistry‖ requirements, the Huisgen azide-alkyne cycloaddition to yield 1,2,3-triazole is the premier example.189,190 The ease of azide synthesis and commercial availability of alkynes, along with their high kinetic stability and high tolerance to different functional groups and various solvents, have made them excellent coupling partners. Classical Huisgen 1,3- dipolar cycloaddition was originally carried out by heating reaction mixtures. However,

43 this procedure was characterized by inherently low reaction rate and poor regioselectivity as demonstrated in the formation of stoiochiometric ratio of 1,4- and 1,5-triazoles

(Scheme 1.16).189,191 Copper(I) catalysis reported independently by the groups of

Meldal192 and Sharpless193 drastically changed the mechanism by accelerating the rate by a factor of 107, allowing the reaction to proceed at lower temperature with the exclusive formation of the 1,4-triazole. Furthermore, the reaction is described to be ―near perfect‖ since it does not require any protecting groups, proceeds to completion and provides quantitative yield with no need for lengthy purification method. Possessing all these characteristics, copper(I)-catalyzed [3+2] azide-alkyne cycloaddition (CuAAC) has accelerated progress in many areas of science, becoming the center of attention and almost synonymous to the term ―click chemistry‖.

Scheme 1.16. Thermal- and Copper(I)-Catalyzed Huisgen 1,3-Dipolar Cycloaddtion.

Copper(I) mediated [3+2] cycloaddition of azides and alkynes stands out to be the most efficient methodology for the synthesis of a variety of functionalized 1,4- triazoles.19,20,179,187 To date, various catalytic systems have been developed, all of which relies on the maintenance of high amounts of CuI species at all times during the reaction.19,20 Catalysts include copper(I) salts such as CuI, CuBr, CuCl and CuOAc and

19,192 coordination complexes [Cu(CH3CN)4][PF6] and [Cu(CH3CN)4][OTf]. In situ

44 reduction of CuII salts to CuI by sodium ascorbate or ascorbic acid has allowed reactions to be performed in aqueous conditions.19,193 A convenient procedure designed for substrates that are intolerant to ascorbate or its oxidation products is the comproportionation of Cu0 and CuII. This is performed by utilizing copper metal in the form of wire, turnings powder or nanoparticles with or without a CuII source.193-197

Recent reports suggest that ligand coordination can stabilize the copper(I) complex under aerobic aqueous conditions and facilitates the desired transformation.

Effective ligands are typically N-based (Figure 1.7), particularly PMDETA,198-206

204,207-209 204 204 204 bipyridine derivatives, terpyridine derivatives, Me6TREN, TPMA, tris-

(benzyltriazolylmethyl)amine (TBTA)210-215 and bathophenanthroline (batho).209,216-219

TBTA and bathophenanthroline are commonly used in organic synthesis. In the synthesis of click-functionalized polymers, PMDETA is predominantly used over Me6TREN and

TPMA. Several CuI complexes with N-heterocyclic carbene ligands have been utilized as catalysts in organic solvents, under heterogeneous conditions and in neat or solvent-free conditions.220,221 Phosphorus-based (P-based) ligands such as triphenyl phosphine

222,223 224 225 (PPh3), trimethoxyphosphine (P(OMe3)) and monodentate phosphoramidite are often used in organic solvents, in which CuI salts have limited solubility.

The robustness of the reaction has been demonstrated by its ability to tolerate a wide spectrum of solvents.19 Most frequently, reactions utilizing CuI salts are performed in

THF, CH3CN, DMSO, DMF, acetone or pyridine. Aqueous media particularly water/alcohol (t-BuOH, EtOH, MeOH) mixtures have been highly suitable for reactions utilizing CuSO4 in conjunction with a reducing agent (sodium ascorbate or ascorbic acid).

KO2C

N N N N N N N N N N N N N N N N N KO2C N N N N N N N N N N

CO2K

N N N N

R R N N

R = H, OMe, Me NaO3S SO3Na

O O N N N N N N N N N NH HN N

NH N N HN N N N NH N N N

Figure 1.7. N-Based Ligands Used to Promote Cu(I)-Catalyzed Triazole Formation.

1.2.3 Mechanism of Copper(I)-Catalyzed Azide-Alkyne [3+2] Cycloaddition

A large body of mechanistic insight emanated from computational194,226,227 and experimental24,25,193 investigations. Regardless of the starting copper salt or complex, it has been identified that CuI is the active catalytic species in the coupling of the

46 dipolarophile (organic azide) and alkyne. The mechanism begins with the coordination of the alkyne to form a -complex, which lowers the pKa of the alkynyl proton by approximately 10 units. This allows efficient deprotonation, converting the -complex to

-acetylide copper intermediate. Kinetic investigations25 revealed that the reaction rate is second-order with respect to the metal suggesting the possible formation of CuI aggregates.226,227 The coordination of the organic azide follows, which consequently activates the N-terminus for nucleophilic attack to the acetylide. This results in the formation of vinylidine-like structure, which subsequently turn to a more stable copper(I) triazolide.228 Lastly, protonolysis yields the 1,2,3-triazole and the copper(I) species back to the catalytic cycle.24

Scheme 1.17. Proposed Catalytic Cycle of Copper-Catalyzed Azide-Alkyne Cycloaddition.

1.2.4 Applications of CuI Catalyzed Azide-Alkyne Cycloaddition

1.2.4.1 Bioconjugation

Owing to its broad chemical orthogonality and versatility, ―click chemistry‖ has been widely exploited in all aspects of bioconjugation, drug discovery and material science. In biomedical research, CuAAC has had a major impact in polypeptide/protein oligonucleotide and carbohydrate chemistry. It has become a powerful tool for successful covalent linking of biomolecules even under physiological conditions, thus allowing in vivo and in vitro studies to be performed. One useful application is the tagging of proteins and live organisms, in which a fluorescent dye is incorporated to the azide- and alkyne- modified proteins followed by copper-mediated [3+2] cycloadditon. Success in this area has been reported in the tagging of the cowpea mosaic virus (CPMV),212 surface proteins of Escherichia coli (E. coli)229 and proteins in Sacharomyces cerevisiae (S. cerevisiae).230

Bioconjugation technique has also benefited oligonuceotide chemistry particularly in

DNA labeling and sequencing.231,232 Modification of carbohydrates has been accessed through the easy introduction of azide groups and high reliability of click chemistry.

Since 1,2,3-triazoles are capable of interacting with biological targets through hydrogen bonding and dipole interactions, carbohydrate modification has been performed by incorporating azido functional groups or azidocoumarin dye on the surface of cellulose and mixing it with low-molecular weight alkynes.233

1.2.4.2 Drug Discovery

Click chemistry was originally launched to meet the demands of medicinal chemistry.18,185 It does not necessarily replace traditional drug discovery techniques,

48 rather, complements and extends them. It has worked well in conjunction with structure- based design and combinatorial library. As a powerful lead discovery, click chemistry has significantly contributed in developing novel approaches for screening libraries for potential pharmacophores, drugs and natural products. Furthermore, the synthesis of each library compound proceeds efficiently with high purity in short reaction sequences.

Consequently, much compound diversity has been achieved and large-scale preparations are feasible utilizing commercially available building blocks.

In recent years, novel means of lead discovery have been demonstrated in the synthesis of neoglycoconjugates,234 enzyme inhibitors and HIV inhibitors. Copper(I)- catalyzed 1,3-dipolar cycloaddition simplified and accelerated the discovery of high- affinity carbohydrate mimetics, an example of which is the synthesis of neoglycoconjugates starting from carbohydrate-derived azides and acetylenes.234 The reported discovery of selective inhibitors to fucosyltransferase, an enzyme responsible for the final glycosylation steps in the biosynthesis and expression of saccharides235 has been significant in cancer therapy. Recently, several elegant and thorough experiments have demonstrated the efficacy of copper(I)-catalyzed [3+2] azide-alkyne cycloaddition in the in situ target-directed synthesis of acetylcholinesterase (AcHE), an enzyme involved in neurotransmitter hydrolysis in the central and peripheral nervous systems and active target of Alzheimer‘s dementia drugs.236 Scope of in situ copper(I)-catalyzed [3+2] azide- alkyne cycloaddition has been expanded to include carbonic anhydrase (CA) fragments237 and HIV-protease targets.238

1.2.4.3 Material Science and Polymer Chemistry

49 Although click chemistry was initially developed as a drug discovery tool, most successful applications thus far have been in the field of material science/polymer chemistry.19,179,182-184,203,239-242 The union between ―click chemistry‖ and controlled radical polymerization (CRP) techniques such as atom transfer radical polymerization

(ATRP),170,243,244 Nitroxide-Mediated Polymerization (NMP)245 and Reversible Addition-

Fragmentation Polymerization (RAFT).246,247 Among the CRP methods, ATRP dominates the large body and even represents the first intensely exploited examples of combined azide-alkyne cycloaddition and living polymerization.182,184,239,240 Strategies (Figure 1.8) developed for the combination of the two reactions include the use of functional initiators

(a), monomers bearing azido or acetylenic moieties (b) and post-polymerization modification, typically, the conversion of the halogen into azido groups (c) creating azido telechelic macromonomers (d), alkyne telechelic macromonomers (e) and pendant azido or acetylenic moieties within the side chains (f). In recent years, an extensive range of new polymeric materials (Figure 1.9) for macromolecular engineering and biological applications have been developed in conjunction with click chemistry; particularly multiblock copolymers,248-250 multisegmented block copolymers,204,205,242,251,252 micelles213,253,254 and polymers with complex structures such as star polymers,199,255-263 brush and graft copolymers,203,256,264-266 dendrimers,267 hydrogels,268,269 model networks206 and functionalized nanotubes.270

High solvent and functional group tolerance of copper-catalyzed Huisgen 1,3- dipolar cycloaddition have been very significant in developing strategies for biomaterial synthesis. At the same time, several polymeric techniques have been widely utilized in the preparation of water-soluble and biocompatible polymers. These are otherwise known

50 as polymer therapeutics enumerating polymer-drug conjugates,271 polymer-protein conjugates,181,200,272 glycopolymers/carbohydrate-polymer conjugates,273,274 polymeric

O O O NH2 O N3 O N3 O Br (a) (b)

NaN3 X N3 (c)

N3 (d) (e)

N 3 N3

N3 (f)

Figure 1.8. Functional Initiator (a), Monomers (b), Post-Polymerization Modification (c) and Clickable Macromonomers (d-f) Utilized in Combined ATRP and Azide-Alkyne Cycloaddition.

51 block copolymers model networks star polymers

graft polymers micelles nanotubes Figure 1.9. Representative Macromolecular Structures Constructed via ATRP and Click Chemistry. micelles213,253,254,275 to which a drug is covalently-bound, and multi-component polyplexes that are being developed for non-viral vectors.212,273 They are either active ingredients (bioactive) or inert functional components of materials or conjugates for improved drug, protein or gene delivery, thus enabling them to treat numerous diseases.

Another appealing attribute of CuI azide-alkyne cycloaddition is its high reactivity in heterogenous systems, thus enabling chemoselective derivatization of exposed functional groups attached on various surfaces. This approach has been demonstrated in surface derivatization of bionanoparticles via ATRP and click chemistry.213,217

Several reasons for the compatibility of these two reactions can be inferred from mechanisms. Firstly, both require the presence of the copper(I) species, however, in different contexts. The CuI species in ATRP serve as an activator for the homolytic cleavage of the C-X bond and at the same time, they are in dynamic equilibrium with their oxidized partners (CuII) to maintain low levels of propagating chain radicals.170,243,244 Copper(I)-catalyzed Huisgen [3+2] cycloaddition on the other hand,

52 requires high levels of CuI at all times during the course of the reaction.19,24 Secondly, both require the presence of nitrogen-based complexing ligands. In ATRP, the presence of complexing ligands influence the redox potential, which is directly correlated with catalyst activity and equilibrium constant for atom transfer (KATRP). Mechanistic investigations revealed that the copper catalyzed azide-alkyne cycloaddition proceeds faster in the presence of aliphatic amine-based compared to the pyridine-based ligands, due to the high basicity and enhanced lability of the former. Additionally, faster rates were observed with tridentate versus tetradentate ligands. It is believed that the saturation of the CuI center by the tetradentate ligands blocks the coordination of the incoming alkyne and azide. Finally, click chemistry like ATRP, is highly tolerant to a wide range of reaction solvents.

1.2.5 Sequential and Simultaneous Click Chemistry and ATRP

As previously mentioned, ATRP represents the first example of living polymerization to be combined with click chemistry. This was demonstrated in the preparation of copolymers with 5-tetrazole units starting from homopolymers and copolymers (both random and block including polymers of polystyrene on silica support) of acrylonitrile obtained from ATRP.241 Nitrile functional groups were subsequently functionalized by the reaction with NaN3 in the presence of Lewis acid (ZnCl2) to yield polymer derivatives of tetrazole (a, Scheme 1.18). The same research group also reported the synthesis of side-chain modified polymers from the ATRP of 3-azidopropyl methacrylate as the monomer (b, Scheme 1.18).203 Copper-catalyzed click coupling of the azide moieties with various alkynes to form 1,2,3-triazoles proceeded efficiently at room temperature. Linear polystyrene bearing azido chain-ends coupled with multiple

53 functional alkyne-containing agents represented the first synthetic strategy to form three- arm and four-arm star polymers via the sequential ATRP and azide-alkyne cycloaddition protocol (c, Scheme 1.19).255 Post-polymerization modification using the coupling procedure to generate the triazole groups was found to be fast and efficient under mild reaction conditions. The successful click functionalization of polymers generated from

ATRP has attracted considerable interest in developing strategies for the construction of other macromolecular architectures. In particular, quantitative yields of macrocyclic polymers have been achieved through the ATRP of styrene utilizing an alkyne- functionalized initiator followed by nucleophilic displacement of the terminal halogen in the polymer and intramolecular click coupling protocol.276 In a similar manner, cyclic polymer was also synthesized starting from N-isopropylacrylamide (NIPAM) serving as the monomer and the propargyl 2-chloropropionate as the functional initator (a, Scheme

1.19).277 As one of the most efficient ways to combine different molecular structures together that are often found to be very challenging, click chemistry has played a major role in linking homopolymers to form block copolymers. Utilizing a modular approach, an initiator bearing a trisopropylsilyl (TIPS) protected acetylene, homopolymers of polystyrene (PS), poly(tert-butyl acrylate) (PtBA) and poly(methyl acrylate) (PMA) were synthesized by means of ATRP.278 Terminal bromides were displaced by azides, followed by cleavage of the protecting group. Resulting homopolymers were linked together via copper(I)-catalyzed azide-alkyne cycloaddition forming an ABC type of block copolymer (b, Scheme 1.19). Employing the same strategy, polymers with azide as well as alkyne functionalities were first prepared from ATRP. Subsequent click coupling provided amphiphilic block copolymers.279 Thermoresponsive microcapsules have also

54 been fabricated based on covalent layer-by-layer (LbL) assembly via 1,3-dipolar cycloaddition using clickable azido- and acetylene-functionalized poly(N- isporopylacrylamide) (PNIPAm) copolymers, which were synthesized by ATRP.280In essence, modular processes that sequentially combine ATRP and CuAAC have been proven to be powerful synthetic routes to functional polymers with complex macromolecular architectures. These reactions were originally performed in separate mixtures, in which the polymers obtained via ATRP were isolated and utilized for click derivatization in the second step.

55 ATRP + CN

styrene acrylonitrile NaN3, ZnCl2,  Click Chemistry (a)

N N N N

O CuBr/bpy, 50 0C + R Br O O (b) O O CuBr, RT n + ATRP n Click Chemistry O N3 N n N O 3 N N R

O O O O

1) CuBr/PMDETA, 25 0C N3 ATRP n n + 0 2) NaN3, 25 C O O

(c)

CuBr/PMDETA, Cu0, 25 0C Click Chemistry

O N N O N n

Scheme 1.18. First Examples of Sequential ATRP and Click Chemistry.241,242,255

56 O O Cl O 0 N3 1) CuCl/Me6TREN, 25 C O n ATRP + O NH 0 O 2) NaN3, 45 C n N 0 H CuBr/bpy, 120 C Click Chemistry

(a)

O N N N O n O N

O N N Br O O N m N O O 3 n O O O n H TIPS

0 1) CuBr/Me6TREN, 25 C + + Click Chemistry O O 2) TBAF N3 Br O p O m TIPS O O H O O (b)

0 CuBr/Me6TREN, 50 C Click Chemistry

N N O N N Br TIPS O N O O N n n O p O O O O CH3

Scheme 1.19. Functional Macrocyclic (a)277 and ABC Block Copolymers (b)278 Synthesized via Sequential ATRP and Click Reactions.

57 In recent reports, a one-pot, two-step protocol has been developed for the combination of ATRP and CuAAC reactions.184 This has been demonstrated in the synthesis of functional linear homopolymers such as poly(methyl methacrylate) with triazole terminus (a, Scheme 1.20)281 and triazole-derived hydrophilic methacrylic macromonomers (b, Scheme 1.20).282 Another example includes the work of Dubois and co-workers, in which well-defined amphiphilic diblock copolymer, poly(-caprolactone)- block-poly(N,N-dimethylamino-2-ethyl methacrylate (PCL-b-PDMAEMA) was synthesized from the ATRP of N,N-dimethylamino-2-ethyl methacrylate (DMAEMA) with azide-functionalized initiator (2-(2-azidoethoxy)ethyl bromisobutyrate) followed by in situ click coupling with -isopropoxy--4-pentynoate-poly(-caprolactone)(PCL-

CCH) macromonomer (c, Scheme 1.20).283

Recent reports also revealed that both organic transformations occur simultaneously. Haddleton and co-workers reported the preparation of methacrylic polymer with triazole in one-pot using an ATRP initiator, CuBr/N- ethylpyridineimine/triethylamine, alkyne-containing monomer (propargyl methacrylate) and an organic azide all at once in the reaction mixture (a, Scheme 1.21).284

Drockenmuller‘s group described the elaborate preparation of random copolymers using two complementary tandem strategies based on the one-pot combination of click chemistry and ATRP.285 In the first strategy, functionalized random copolymers were obtained from the simultaneous copolymerization of methyl methacrylate and propargyl acrylate and click coupling of a monofunctional azide. In another approach, copolymerization of methyl methacrylate and 11-azidoundecanoyl methacrylate and triazole formation utilizing monofunctional alkyne occurred simultaneously. In another

58 approach, copolymerization of methyl methacrylate and 11-azidoundecanoyl methacrylate occurred simultaneously to triazole formation utilizing monofunctional alkyne (b, Scheme 1.21).285 Facile one-pot synthesis of miktoarm star terpolymers has been achieved by simultaneously conducting ATRP, ROMP and click chemistry using

CuBr/PMDETA catalytic system, starting from trifunctional core molecule alkynyl(-

261 OH)-Br and azide-terminated polystyrene (PS-N3) (c, Scheme 1.21). Simultaneous interpenetrating polymer networks (sIPNs) has also been synthesized via concurrent

ATRP and click chemistry utilizing semi-(poly(polyethylene glycol)/poly(2-hydroxyethyl

268 methacrylate) PEG/PHEMA-sIPN and poly(ethylene glycol)-diazide (N3-PEG-N3).

Functional microspheres, also referred to as therapeutics because of their potential applications as drug delivery vesicles and protecting shields for biomacromolecules, have also been prepared. As a proof of concept, simultaneous [3+2] azide-alkyne cycloaddition and dispersion ATRP was conducted in the reaction of ethynyl pyrene, azide- functionalized initiator and methyl methacrylate catalyzed by CuIBr ligated to perfluorinated amine-based macroligand using a supercritical fluid provided functional microsphere.286

59 O

O N3 CuBr/ O Br N-alkyl-2-pyridylmethanimine, Br 0 O N3 + 70 C n O OMe O ATRP (a) n O R Click Chemistry

O Br N O N n N O OMe R

O O O N3 CuBr/bpy, 20 0C Br Br O N3 + n O OCH CH NH O ATRP 2 2 2 NH n O 2 O (b) O , 20 0C

Click Chemistry

O Br N O N n N

O OCH2CH2NH2 O

O O O O O + O + N n N3 O m O O Br

0 1) CuBr/3bpy, 25 C (c) ATRP 2) 60 0C Click Chemistry

O O O Br O N O O O n N N m N O O

Scheme 1.20. Reactions Performed via One-Pot Sequential ATRP and Click Chemistry.281-283

60 O O O Br Br O 0 n CuBr/N-ethylpyridineimine/NEt3, 60 C + O O (a) O ATRP, Click Chemistry N N O N R +

RN3

O x y 0 + ToSCl/CuBr/bpy, 90 C O O O O (b) O (H2C)11 ATRP, Click Chemistry N N N O N3 11 R +

RN3

N O 3 O O n O O O O + O Br + N + O OH O

A alkynyl(-OH)-Br B C trifunctional core

A C Scheme 1.21. One-Pot, Simultaneous ATRP and Click Chemistry.261,284,285

61 1.2.6 Section Summary and Project Objective

Sequential reactions involving copper-catalyzed ATRP and azide-alkyne [3+2] cycloaddition have attracted considerable interest. This methodology provided means to rapid development of a plethora of functionalized molecules with complex macromolecular architectures chemistry.19,179,182-184,203,239-242 Despite the success in various applications, the synthesis of small molecules seems to be somewhat neglected.

Thus, we initiated a study on sequential reactions that would yield compounds bearing triazole and halide functionalities. The presence of the C-X bond in the resulting molecule is synthetically attractive because it offers versatility towards further organic transformations involving reduction, elimination, conversion to a Grignard reagent or free radical.287 Our motivation for this study was primarily to demonstrate the synthetic usefulness of catalyst regeneration technique in mediating sequential organic reactions in one-pot. The pioneering work on copper-catalyzed ATRA in the presence of diazo compounds radical initiators showed significant reduction of the required catalyst loading with high turnover numbers (TONs).132,149 Improved selectivity on very reactive alkenes prone to polymerization was demonstrated in the use of radical initiator that decomposes at ambient condition155 and photinitiated copper(I)-mediated ATRA performed at room temperature.163 Very recently, we have successfully reported ATRA reactions mediated by copper(II) complexes in conjunction with a more environmentally benign reducing agent. Thus, the use of ascorbic acid in ATRA and ATRC gave high product yields and

TONs and even superior selectivity toward the monoadduct formation.128

Based on literature reports, triazole formation via copper(I) catalyzed [3+2] azide- alkyne cycloaddition is commonly conducted via in situ reduction of CuII to CuI species

62 by sodium ascorbate or ascorbic acid.19,193 At the same time, ATRA reactions have been reported to proceed efficiently via in situ reduction of CuII complex to the activator species or CuI complex has been fulfilled in the presence of ascorbic acid.128 Since the aforementioned reactions share similar catalyst in the form of copper(I), a logical step was taken in performing these reactions in one-pot sequential manner which will be discussed in Chapters 4 and 5.

1.3 Cyclopropanation Reaction

Cyclopropane and cyclopropane derivatives are the simplest among the carbocycles to perform a key structural role in a wide array of bioactive natural and synthetic products.299,300 In organic synthesis, the cyclopropyl group plays a significant role as starting material and reaction intermediate, particularly in ring opening reactions, ring expansions and contractions.301 The importance of these compounds has recently drawn considerable attention and efforts have been invested in the development of catalytic methods in asymmetric synthesis of the target compounds.300,301

63 IZn I H2 R2 R4 2 C 4 2 C 4 + IZnCH2I R R R R + ZnI2 (1) R1 R3 1 3 R1 R3 R R

Transition metal (TM) + N2CHR' + N2 (2) R R R' catalyst trans/cis

R R'CH-LG EWG R EWG R EWG LG (3) R' R' R R' R'CH2 R' EWG (4) EWG R EWG LG R

Scheme 1.22. Synthetic Methodologies Involved in Cyclopropane Formation.

There are three synthetic methodologies that have been developed to generate cyclopropanes (Scheme 1.22). One of them includes the halomethyl mediated cylopropanation, commonly known as the classical Simmons-Smith reaction (eq.1).301,302

Its mechanism involves the reaction of a carbenoid, in the form of iodomethylzinc iodide

(IZnCH2I) to alkenes. Transition metal-catalyzed decomposition of diazo compounds represents most effective and efficient cyclopropanation procedure (eq. 2).15-17,301

Formation of three-membered rings via nucleophilic addition to alkenes to form an enolate, followed by cyclization is described as Michael-initiated ring closure reaction

(MIRC), which can be classified into two types (eqs. 3 and 4).17,303 Methylene transfer from ylides of sulfur, phosphorous, arsenium and telluronium to electrophilic alkenes, constitutes the first type (eq. 3).303-305 Alternatively, cyclopropanation reaction can be carried out by the addition of nucleophiles (alkoxides, thiolates, Grignard reagents,

64 hydrides, phosphates and phosphonites) to substrates containing a leaving group (eq 4).

306

Stereoselective addition of a carbene into an olefin to form optically active cyclopropanes is a very significant reaction (eq. 2) and represents the earliest form of asymmetric synthesis and thus, most extensive studies have been devoted on the development of transition metal catalysts. From a mechanistic point of view, the transition metal plays a significant role in facilitating the extrusion of dinitrogen gas (N2), and in the formation of a stable reaction intermediate.15,16,301,307 Effective catalysts for diazo decomposition include a variety of ruthenium, rhodium, palladium, copper, gold and silver complexes.15,17,308

1.3.1 Historical Perspective of Copper-Catalyzed Cyclopropanation

Copper catalysis in cyclopropanation has been known for over a century.309

Bronze, copper(II) sulfate and copper(II) oxide are among the first known catalysts for diazo decomposition.16,307,309 Nozaki and Noyori reported copper-catalyzed cyclopropanation as the first successful asymmetric homogenous transition metal catalysis in 1966.310 The reaction between ethyl diazoacetate and styrene in the presence of a chiral nitrogen-based ligand shown in Figure 1.10 (bis(acetylacetonato) copper (II) complex, structure A) gave the corresponding mixture of trans- and cis- isomers of 2- phenylcyclopropanecarboxylate in a 1:2.3 ratio. Although enantioselectivity was modest, this served as a guide for further ligand modification. Subsequently, Aratani reported improvement in enantioselectivity after designing and evaluating the activity of salicylaldimine ligands (Figure 1.10, structure B) ligated to copper.311,312 Nozaki and

Noyori confirmed the importance of carbene coordination to copper based on their

65 investigation, in which the desired products were not achieved in the absence of a copper- chelate.313 Moser reported the use of CuICl in conjunction with trialkyl and triaryl phosphite ligands and explained the steric effects of the ligands.314 Basic understanding of copper catalysis was first elaborated in the seminal report by Salomon and Kochi.315

During the course of their investigation, they discovered that copper(I) triflate, CuOTf

(OTf = CF3SO2Ph) was very active in the cyclopropanation of various olefins with diazo compounds. This drew attention to the CuI as the active form of the catalyst rather than

CuII species for diazo decomposition. Additionally, copper(II) triflate and other CuII salts could be utilized as catalysts after in situ reduction to CuI.

R CHPhMe 1 H R3O N R2 O Cu R Cu O 2 R2 = O O N 2 tBu CHPhMe R1 = CH3, CH2Ph A B Figure 1.10. First examples of copper complexes employed in asymmetric cyclopropanation.

1.3.2 Mechanism of Copper-Mediated Cyclopropanation Reaction

Copper reacts with the diazo compound to generate a transient electrophilic copper-carbene through a σ-donation and π-backbonding.316,317 The carbene contains a non-bonding pair of electrons located in the sp2 orbital, which are donated to the metal to form a σ-bond. The copper donates an electron to the empty p orbital of the carbene forming a  bond. In the absence of an olefin, the carbene dimerizes, forming the cis- and trans- coupled products. In the presence of an olefin, the carbene dissociates from the

66 complex and selectively adds to the double bond, forming the three-membered cyclic compound.

In recent years, CuI-mediated cyclopropanation reaction has been the subject of kinetic and mechanistic investigations.15,16,315,318-321 Perez and co-workers presented catalytic cycle based on collective kinetic data on the BpCuI-catalyzed (Bp= dihydrobis(pyrazolyl)borate) decomposition of ethyl diazoacetate (EDA) in the absence and presence of olefin.319,321 In the absence of an olefin, the coordinatively unsaturated,

14 e- BpCuI complex, facilitated the decomposition of ethyl diazoacetate (EDA) to form a copper-carbene complex. However, the addition of an olefin resulted in a rate-retarding effect on the BpCuI-carbene complex formation and this could be attributed to the BpCuI- olefin complex formation. Addition of other coordinating ligands showed a similar effect on the rate of diazocarbene decomposition. Mechanistic interpretations as shown in

Scheme 1.23 account for the dissociative ligand exchange and the existence of two pre- equilibria (KL and Ko) prior to the interaction of EDA to the copper center. This led to a proposition that the active catalytic species could be the coordinatively unsaturated, 14 e- species and the CuI-carbene is the reaction intermediate.319,321

Details of the catalytic cycle have been studied using density functional level of theory (DFT).317,322 According to Straub and co-workers, the copper(I)-olefin complex is the resting state of the catalytic cycle, which is in agreement with kinetic investigations.317 The existence of pre-equilibrium can be attributed to the copper(I)- diazoalkane complex, copper(I)-olefin complex, free diazoalkane and free alkene. The first step involves the complexation of the diazo compound through the displacement of the olefin or excess ligands present, which is also found to be rate-determining. All

67 theoretical studies agree on the central role to the copper(I)-carbene as the reactive species, which is formed after N2 extrusion.

Scheme 1.23. Proposed Catalytic Cycle for Copper-Catalyzed Cyclopropanation

Until 2000, the existence of the reactive copper(I)-carbene intermediate remained undetected. For this reason, Straub and Hofmann synthesized copper(I) alkene iminophosphanamide complexes, which allowed feasible isolation of a sterically stabilized copper diazoalkane complex. Conversion of the resulting complex to copper(I)- carbene species was monitored through in situ low-temperature spectroscopic characterization was the first to document the existence of a carbene intermediate, which is the active catalytic species in cyclopropanation.323

68 SiMe3 COOMe tBu N Cu P tBu N SiMe3

Figure 1.11. Copper(I)-carbene complex

1.3.3 Aspects of Reaction

1.3.3.1 Role of Olefin Coordination

Salomon and Kochi have extensively studied the role of the olefin in copper- catalyzed cyclopropanation.315 Generally, relative reactivity of olefins correlate to the stability of resulting CuI-olefin complexes.314,315 Experimental observations revealed that the copper center presents a high affinity for the olefin, promoting the coordination and therefore inhibiting the diazo decomposition.15,307,315 As a consequence, reaction selectivity and product distributions change towards the formation of the desired cyclopropanes and decreased amounts of the undesired products in the form of coupled carbenes.

The observed increased product selectivity in the presence of excess olefin has led to the preparation of olefin-copper(I) complexes and used as catalysts for the conversion

323,324 of olefins to cyclopropanes. The copper(I) complex Tp‘Cu(C2H4) (complex 1 of

Figure 1.12, Tp‘ = hydrotris(3,5-dimethyl-1-pyrazolylborate) was found to be an efficient catalyst under mild conditions for the diazo decomposition followed by carbene transfer to various alkenes (styrene, cis-cyclooctene and 1-hexene).324 Styrene and cis- cyclooctene displayed similar reactivities, with yields greater than 90% were achieved, while 1-hexene gave the corresponding cyclopropane in 76% yield. Straub and Hofmann synthesized a novel copper(I) ethylene complex, (tBu2P(NSiMe3)2N)Cu(C2H2) (complex

69 2 of Figure 1.12), which can catalyze the cyclopropanation of styrene with - carbonyldiazoalkane at room temperature.323

H B SiMe3 N N N tBu H N N N N P Cu tBu N SiMe3 Cu

1 2

Figure 1.12. Copper(I)-olefin Complexes as Catalysts in Cyclopropanation

1.3.3.2 Role of Counterion

It has been suggested that significant ionic interactions can occur during catalysis and influence reaction selectivity. Binary copper(I) and copper(II) salts with weakly

- - coordinating anions such as triflate (OTf ) and perchlorate (ClO4 ) are strongly ionized in solutions.315 This enabled accessible coordination of the olefin to the metal center and consequently, the preferential cyclopropanation of olefins with diazo compound. In accordance with this, there is emerging evidence that noncoordinating and weakly coordinating ions can have dramatic influence on enantioselectivity. This was demonstrated in the reactions catalyzed by neutral bis(oxazoline) complexes of CuI and

CuII complexes with triflate counterion, in which superior enantioselectivity was achieved.325,326 It has also been reported that cationic copper(I) complexes with triflate 325

- 327 and hexafluorophosphate (PF6 ) counterions are efficient catalysts. On the other hand,

- - - - counteranions such as chloride (Cl ), cyanide (CN ), acetate (OAc ) and ClO4 showed little or no catalytic activity and the observed enantioselectivity was inferior to those of

70 triflate-ligand complexes.325 In particular, when the counterion was changed from OTf- to

Cl- in the bis(oxazoline)-copper(I) complex, the cyclopropanation of styrene with ethyl diazoacetate resulted in decreased enantiomeric excess (ee): from 94 to 3% for trans- cyclopropanes, and from 92 to 8% for cis-cyclopropanes.328 The origin of this behavior, however, still remains unclear and mechanistic interpretation is not available.

A theoretical investigation dealing with the effect of the counterion of the catalytic complex and on the mechanism of the cyclopropanation reaction and its effect on enantioselectivity has been conducted.329 Theoretical calculations were carried out on a simple nonchiral diimine-copper(I) and chiral bis(oxazoline)-copper(I) complexes with a coordinating chloride anion. The Cl- had important consequences on the geometries of the reaction intermediates and transition structures but not on the overall reaction mechanism. The main effect was manifested in the reduced chemoselectivity toward cylopropanation and increased carbene dimerization. Such occurrence was attributed to the high activation energy barrier for alkene insertion and the propensity of the Cl- containing complex to exist as a dimer. Theoretical calculations on a chiral bis(oxazoline)-copper(I) complex in the presence of Cl- agreed with the decreased enantioselectivity observed experimentally, which has been explained by the Pfaltz model. According to this model, the main steric interaction between the carbonyl oxygen of the carbene ester group and the substituent on one of the stereogenic centers of the ligand is crucial for asymmetric induction. In the presence of Cl-, the distance calculated between the two groups was longer. As a consequence, the diastereomeric transition structures for the carbene insertion lack any clear steric interaction that is able to discriminate the two prochiral faces of the carbene-carbon atom.

71 1.3.4 Asymmetric Cyclopropanation

1.3.4.1 Origin of Trans/Cis Selectivity

R H H H H H H R H H H H L M n LnM LnM LnM Z Z Z Z H H H R R H H H C1 C2 C3 C4

Figure 1.13. Preferred Conformations of trans- and cis- Transition States (Tc and Tt)

C1 H H H R -MLn R H LnM C LnM Z H Z H H Z C2 + Tt C3 H H H H H -MLn H H LnM H R H Z R R Z C4 Tc Scheme 1.24. Origin of Trans/Cis Selectivity

It is generally accepted that effective carbene transfer leading to cyclopropanation occurs by the association of the olefin to the metal-carbene complex, giving rise to four orientations, representing the basis set of stable conformations (C1, C2, C3 and C4) as shown in Figure 1.13.307,330 During the course of the reaction, the olefin rotates around the electrophilic center to an orientation that places the carbon-carbon bond of the olefin parallel to the metal-carbon bond so that the more substituted carbon of the olefin is anti-

330 to the transition metal (Scheme 1.24). In this operation C1 and C2 are both transformed to the trans transition state (Tt), while C3 and C4 are give rise to the cis transition state

(Tc). In the absence of steric interaction between the R group of the olefin and the Z substituent of the carbene in Tc, the more kinetically favored cis cyclopropane is formed.

As steric interactions become significant, Tt is favored and thus trans cyclopropane

72 predominates.307,330

1.3.4.2 Enantioselectivity

Nozaki and co-workers first realized that the formation of different enantiomers could be attributed to the ligand with pronounced chirality.310,313 Enantioselectivity in cyclopropanation reactions has been explained by the Pfaltz model (Scheme 1.25).331

Accordingly, the more nucleophilic end of the olefin approaches the carbene in two ways: the Si attack (pathway A) and Re attack (pathway B) with concomitant pyramidalization of the involved centers. Pathway B leads to the formation of cyclopropanes with configurations of 1R, 2R and 1R, 2S. In this approach, the carbenoid ester group is directed towards the alkyl substituent (R) of the ligand, which is positioned above the plane bisecting the carbenoid ester group, causing repulsive interaction as the reaction proceeds. Pathway A is more favorable than B since olefin attacks the carbene in two possible ways: transoid and cisoid to the ester group of the carbenoid affording cyclopropanes having 1S, 2S and 1S, 2R stereochemical configurations. This approach is more favorable since the substituents between the carbene ester and ligand are too remote to experience repulsion, as shown in the transition state (Scheme 1.25. In addition, this model outlines the trans- and cis- diasteroselectivity. In a prototypical cyclopropanation of styrene with a diazoester, considerable steric interaction builds up between the ester group of the carbene and the olefinic substituents (R1 and R2) in the cisoid attack. If pathway A is followed, there is a strong stereochemical preference towards the trans- isomer and can be explained in two reasons. First, olefinic bonds are too remote to experience steric repulsion from the ligand. Second, the orientation of alkyl (R) group of

73 the olefin being transoid to the carbene minimizes steric interaction between the R group of the olefin and the ester group of the carbene.

H H R1 R R1 R3OOC S S R2 R2 R2 N trans major NC Cu H 2 1 H R R R N COOR3 3 A COOR 3 S R 1 N A H R OOC R NC Cu R cis major N H R H 3 1 B R2 R R OOC R B 3 N COOR R S 2 H H R R1 NC Cu N R3OOC R2 R2 1 R R H R 1 R H R

Scheme 1.25. Origin of Enantioselectivity331

1.3.4.3 Chiral Ligands in Achieving Enantioselectivity

After the seminal report of Nozaki and Noyori in the first effective asymmetric induction in cyclopropanation catalyzed by the simple chiral copper salicylaldimine complex, giving modest enantioselectivity,310 Aratani developed and designed a more effective salicylaldimine ligand.311,312 The resulting copper complex demonstrated effectiveness in mediating intermolecular cyclopropanation especially the 2,5-dimethyl-

2,4-hexadiene and isobutylene. Until, the mid 1980s, Aratani‘s catalyst emerged to be the most effective and has been employed by other research groups in both intermolecular and intramolecular cyclopropanations.311,312,332,333 In recent years, extensive studies have been focused on the design and development of chiral copper complexes for enantioselective cyclopropanation reactions that could give results beyond the salicyclaldimine-copper complex. To date, over a hundred chiral ligands have been synthesized and tested in copper-mediated enantioselective cyclopropanation

74 reactions.2,14,17,325,331,334-345 Figure 1.14 and Table 1.10 summarize the chiral ligands that have contributed modest to superior enantioselectivity in the cyclopropanation of styrene with diazoacetates (ethyl, tert-butyl- d-menthyl, l-menthyl, and 2,6-di-tert-butyl-4- methylphenyl (BHT)).

In the late 1980‘s the major advance in catalytic design and development was spearheaded by Pfaltz and coworkers who first introduced copper(II) complexes that could be reduced to copper(I) complexes bearing the semicorrin ligands by diazo reagents.331 The potential of the semicorrin ligands when tested in cyclopropanation reactions gave excellent enantioselectivities (99%), however, low yields were obtained.331

Following the success of the semicorrin, led to the construction of alternative 5- azasemicorrin ligands, which were readily assembled from corresponding butyrolactam

335 derivatives. In recognition of the enantioselective control promoted by these C2- symmetric ligands, structural analogues such as bis(oxazolines) and methylenebis(oxazolines), were synthesized from commercially available amino alcohols by the groups of Masamune,336,346 Evans,325,326 Corey347 and Pfaltz.337 After the pioneering work of Evans involving the direct preparation CuIOTf and bis(oxazoline) as catalysts, further cyclopropanation reactions were conducted by several groups utilizing copper(I) complexes in conjunction with chiral ligands, which displayed high enantioselectivities. Ito and Katsuki prepared chiral ligands with pyridine moieties, such as bipyridines, which have proven to be effective for enantiocontrol in select cyclopropanation reactions.348-350 Phenanthroline-based ligands351 with pronounced chirality when utilized in cycloropanation gave poor results when compared to the bipyridines. The copper(I) complexes of simple diamines showed promising results in

75 controlling diastereoselectivity towards the trans- cyclopropane.342,343 Kwong carried out cyclopropanation of styrene with terpyridine complexes of copper(II), giving excellent yields (87-98%) and enantiomeric excess of 86%.352 Surprisingly, diastereoslectivity towards the cis-cyclopropane was achieved in the presence C3-symmetric tris(pyrazolyl)borate ligands, also called homoscorpionate copper(I) complexes.21,353

Copper(I) complexes of tris(pyrazolyl)pyridines have also been found to catalyze cyclopropanation reactions providing moderate yields and low enantioselectivities.345

76 semicorrin 5-azasemicorrin bis(oxazoline) methylenebis(oxazoline)

CN CH3 N H3C CH3 O O O O O O N N N N N N H N N N N R R R R R R R R R R 1a: R = CH OSiMe tBu 2a: R = CMe OSiMe 2 2 2 3 3a: R = CHMe2 4a: R = CHMe2 5a: R = CHMe2 2b: R = CH OSiMe tBu 1b: R = CMe2OH 2 2 4b: R = CMe3 5b: R = CMe3 4c: R = CH(CH3)2 4d: R = CH2Ph 4e: R = Ph 4f: R = CH2OH 4g: R = CH2CH3 4h: R = CMe2OH bipyridine

R1 R1 N N N N N N N N tBu R R' MeO R2 R2 OMe MeO OMe 6a: R = R' = Me 7a: R = Me, R = iPr 1 2 8a 6b: R = R' = Et 7b: R = H, R = TMS 9a tBu 1 2 tBu

phenanthroline terpyridine

N N N N N N N R R 10a: R = CH R R 3 11a: R = CH3 10b: R = CH Ph 12a: R = CH3 2 11b: R = CH2Ph 12b: R = Bu 12c: R = iPr 12d: R = CH2Ph

diamine tris(pyrazolyl)borate tris(pyrazolyl)pyridine Ph Ph H H R Me NH NH Me B R1 B R1 1 N N N R N N N N N N R R R2 R2 R Me Me N N N N N N 2 N N R R R R 3 R3 R Me 13a Me 3 16a: R1, R2 = H; R3 = Ph 17a 16b: R , R = H; R = -naphthyl HO Ph 15a: R,R = 1 2 3 N 16c: R1 = H, R2 = CH3, R3 = Ph Ph Ph 16d: R1, R2 = H, R3 = Mesityl N Ph OH 14a

Figure 1.14. Chiral Ligands utilized in Copper-Mediated Cyclopropanation Reactions.

Table 1.10. Enantioselective Cycopropanation of Styrene with Ethyl Diazoacetate Catalyzed by Complexes of Copper in Conjunction with Chiral Ligands.

+ N2 CHCOOR catalyst Ph Ph R Ph R trans cis A: R = Et, B: R =tBu, C: R = d-menthyl, D: R = l-menthyl E: R = BHT (BHT =2,6-di-tert-butyl-4-methylphenyl)

% Enantiomeric Entry Diazoacetate CuI/CuII salt Ligand % Yield Trans:Cis Ratio Ref excess (trans/cis) 1 A Cu(OtBu)2 1a 65 73:27 92/80, 85/68 331,334

2 C Cu(OtBu)2 1b 60-70 82:18 97/95 331

78 3 A CuOTf 2a 80 75:25 94/68 335 4 C CuOTf 2a 89 84:16 98/99 335 5 A CuOTf 2b 45 77:23 95/90 335 6 A CuOTf 3a ND 66:34 3/8 335 7 A CuOTf 4a ND 64:36 64/48 326 336 8 D CuCl2 4b 71 86:14 98/96 9 A CuOTf 4b ND 77:23 98/93 337 336 10 A CuCl2 4b 80 75:25 90/77 336 11 D CuCl2 4b 71 86:14 98/96 336 12 A CuCl2 4c 72 71:29 46/31 336 13 A CuCl2 4d 76 71:29 36/15 14 4e 81 70:30 60/52 336 A CuCl2 15 4f 88 75:25 48/36 336 A CuCl2

16 4g 78 72:28 19/31 336 A CuCl2 17 C CutBuO 4h ND 83:17 90/90 337 18 A CuOTf 5a ND 69:31 49/45 326 326 19 A CuOTf 5b 77 73:27 99/97 20 E CuOTf 5b 85 94:6 99 326 21 A CuOTf 6a 93 62:38 79/78 338 22 A CuOTf 6b 94 73:27 84/83 338 23 A CuOTf 7a 85 72:28 72/70 339 24 B CuOTf 7b 75 86:14 92 348 25 A CuOTf 8a 50 80:20 89/74 340 26 A CuOTf 9a 89 86:14 80 341 27 A Cu(OTf)2 9a 95 86:14 86 341 79 28 A CuOTf 10a 63 68:32 24/19 351 29 A CuOTf 10b 67 60:40 47/37 351 30 B CuOTf 10b 61 70:30 65/64 351 31 A CuOTf 11a 57 64:36 30/22 351 32 A CuOTf 11b 51 60:40 32/12 351 33 B CuOTf 11b 58 78:22 66/38 351 34 A 12a 87 64:36 75/84 352 Cu(OTf)2 35 A 12b 98 68:32 86/90 352 Cu(OTf)2 36 12b 91 77:23 85/90 352 B Cu(OTf)2 37 89 91:9 83/58 352 C Cu(OTf)2 12b 38 90 75:25 76:83 352 D Cu(OTf)2 12b 39 12c 98 59:41 40/51 352 A Cu(OTf)2

40 12d 97 61:39 72/75 352 A Cu(OTf)2 331 41 A Cu(OTf)2 13a 88 74:26 86/58 342 42 C Cu(OTf)2 13a 50 93:7 96/6 43 A CuOTf 14a 82 ND 60/52 343 343 44 A Cu(OAc)2 15a 68 76:24 40/57 45 A CuI 15a 48 68:32 36/54 353 46 A CuOTf 15a 53 76:24 40/62 353 47 A CuI 16a 80 20:80 ND 344 48 A CuI 16b 87 18:82 ND 344 49 A CuI 16c 86 18:82 ND 344 50 A CuI 16d >98 2:98 ND 344 51 A CuOTf 17a 73 63:37 40/41 345 80

1.3.5 Section Summary and Project Overview

In recent years, efforts have been directed on the development of asymmetric cyclopropanation reactions via copper-catalyzed decomposition of diazo compounds followed by carbene insertion to olefins. Successful diastereo- and enantiocontrol have been achieved through empirical catalyst development, in particular, the design and synthesis of various copper complexes bearing ligands with renowned chirality. In addition, kinetic and theoretical investigations have contributed to the elucidation of the reaction mechanism. Two points of the mechanistic detail are widely accepted: that the actual catalyst is a CuI species even if CuII is used and that a short-lived electrophilic copper(I)-carbene is the reactive intermediate. Albeit great progress, one mechanistic aspect of this very important organic transformation seems to be neglected, particularly the role of the counterion. Experiments have shown that weakly-coordinating counterion affects the cis/trans selectivity as well as the catalytic activity. Theoretical investigation on the effect of strongly coordinating counterion revealed that changes occurring in the transition structures affect the rate and catalytic activity. Mechanistic and kinetic studies to further complement these findings, however, are lacking. Thus, in Chapters 6 and 7 will present cyclopropanation studies utilizing copper(I) complexes with bidentate N- based ligands. The main focus will be on the role of the counterion in the olefin coordination, diazo decomposition and cycloropanation of styrene.

1.3 References

1. Colquhoun, H. M.; Holton, J.; Thompson, D. J.; Twigg, M. V., New Pathways for Organic Synthesis. Practical Applications of Transition Metals. 1984; p Medium: X; Size: Pages: 454.

2. Beller, M.; Bolm, C., Transition Metals for Organic Synthesis: Building Blocks and Fine Chemicals. Wiley-VCH: Weinheim, 2004.

3. Lautens, M.; Klute, W.; Tam, W., Transition Metal-Mediated Cycloaddition Reactions. Chem. Rev. 1996, 96 (1), 49-92.

4. Yet, L., Metal-Mediated Synthesis of Medium-Sized Rings. Chem. Rev. 2000, 100 (8), 2963-3007.

5. Nakamura, I.; Yamamoto, Y., Transition-Metal-Catalyzed Reactions in Heterocyclic Synthesis. Chem. Rev. 2004, 104 (5), 2127-2198.

6. Jasperse, C. P.; Curran, D. P.; Fevig, T. L., Radical Reactions in Natural Product Synthesis. Chem. Rev. 1991, 91 (6), 1237-1286.

7. Iqbal, J.; Bhatia, B.; Nayyar, N. K., Transition Metal Promoted Free Radical Reactions in Organic Synthesis: The Formation of Carbon-Carbon Bonds. Chem. Rev. 1994, 94 (2), 519-564.

8. Krause, N., Modern Organocopper Chemistry. Wiley-VCH: 2002.

9. Chemler, S. R.; Fuller, P. H., Heterocycle Synthesis by Copper Facilitated Addition of Heteroatoms to Alkenes, Alkynes and Arenes. Chem. Soc. Rev. 2007, 36, 1153-1160.

10. Munakata, M.; Kitagawa, S.; Kosome, S.; Asahara, A., Studies of Copper(I) Olefin Complexes. Formation Constants of Copper Olefin Complexes with 2,2'- Bipyridine, 1,10-Phenanthroline, and their Derivatives. Inorg. Chem. 1986, 25 (15), 2622-2627.

11. Ley, S. V.; Thomas, A. W., Modern Synthetic Methods for Copper-Mediated C(aryl)-O, C(aryl)-N, and C(aryl)-S Bond Formation. Angew. Chem. Int. Ed. 2003, 42 (44), 5400-5449.

12. Pintauer, T.; Matyjaszewski, K., Atom Transfer Radical Addition and Polymerization Reactions Catalyzed by ppm Amounts of Copper Complexes. Chem. Soc. Rev. 2008, 37 (6), 1087-1097.

13. Eckenhoff, W. T.; Pintauer, T., Copper Catalyzed Atom Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions in the Presence of Reducing Agents. Cat. Rev. Sci. Eng. 2010, 51, 1-59.

14. Pintauer, T., Catalyst Regeneration in Transition-Metal-Mediated Atom-Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions. Eur. J. Inorg. Chem. 2010, (17), 2449-2460.

15. Doyle, M. P.; Forbes, D. C., Recent Advances in Asymmetric Catalytic Metal Carbene Transformations. Chem. Rev. 1998, 98 (2), 911-936.

16. Kirmse, W., Copper Carbene Complexes: Advanced Catalysts, New Insights. Angew. Chem. Int. Ed. 2003, 42 (10), 1088-1093.

17. Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B., Stereoselective Cyclopropanation Reactions. Chem. Rev. 2003, 103 (4), 977-1050.

18. Kolb, H. C.; Finn, M. G.; Sharpless, K. B., Click Chemistry: Diverse Chemical Function from a Few Good Reactions. Angew. Chem. Int. Ed. 2001, 40 (11), 2004-2021.

19. Meldal, M.; Tornoe, C. W., Cu-Catalyzed Azide-Alkyne Cycloaddition. Chem. Rev. 2008, 108 (8), 2952-3015.

20. Hein, J. E.; Fokin, V. V., Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) and Beyond: New Reactivity of Copper(I) Acetylides. Chem. Soc. Rev. 2010, 39 (4), 1302-1315.

21. Diaz-Requejo, M. M.; Caballero, A.; Belderrain, T. R.; Nicasio, M. C.; Trofimenko, S.; Perez, P. J., Copper(I)-Homoscorpionate Catalysts for the

Preferential, Kinetically Controlled Cis Cyclopropanation of α-Olefins with Ethyl Diazoacetate J. Am. Chem. Soc. 2002, 124 (6), 978-983.

22. Balili, M. N. C.; Pintauer, T., Persistent Radical Effect in Action: Kinetic Studies of Copper-Catalyzed Atom Transfer Radical Addition in the Presence of Free- Radical Diazo Initiators as Reducing Agents. Inorg. Chem. 2009, 48 (18), 9018- 9026.

23. Balili, M. N. C.; Pintauer, T., Kinetic Studies of the Initiation Step in Copper Catalyzed Atom Transfer Radical Addition (ATRA) in the Presence of Free Radical Diazo Initiators as Reducing Agents. Inorg. Chem. 2010, 49 (12), 5642- 5649.

24. Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H., CuI-Catalyzed Alkyne–Azide ―Click‖ Cycloadditions from a Mechanistic and Synthetic Perspective. Eur. J. Org. Chem 2006, 2006 (1), 51-68.

25. Rodionov, V. O.; Fokin, V. V.; Finn, M. G., Mechanism of the Ligand-Free CuI- Catalyzed Azide–Alkyne Cycloaddition Reaction. Angew. Chem. Int. Ed. 2005, 44 (15), 2210-2215.

26. Kharasch, M. S.; Jensen, E. V.; Urry, W. H., Addition of Carbon Tetrabromide and Bromoform to Olefins. J. Am. Chem. Soc. 1946, 68 (1), 154-155.

27. Kharasch, M. S.; Mayo, F. R., The Peroxide Effect in the Addition of Reagents to Unsaturated Compounds. I. The Addition of Hydrogen Bromide to Allyl Bromide. J. Am. Chem. Soc. 1933, 55 (6), 2468-2496.

28. Kharasch, M. S.; Engelmann, H.; Mayo, F. R., The Peroxide Effect in the Addition of Reagents to Unsaturated Compounds. XV. The Addition of Hydrogen Bromide to 1- and 2-Bromo- and Chloropropenes. J. Org. Chem. 1937, 02 (3), 288-302.

29. Kharasch, M. S.; Jensen, E. V.; Urry, W. H., Addition of Carbon Tetrachloride and Chloroform to Olefins. Science 1945, 102 (2640), 128.

30. Kharasch, M. S.; Jensen, E. V.; Urry, W. H., Addition of Derivatives of Chlorinated Acetic Acid to Olefins. J. Am. Chem. Soc. 1945, 67 (9), 1626.

31. De Malde, M.; Minisci, F.; Pallini, U.; Volterra, E.; Quilico, A., Reactions between acrylonitriles and aliphatic halogen derivatives. Chim. Ind. (Milan) 1956, 38, 371-382.

32. Minisci, F., Radical Reactions in Solution. Dipolar Character of Free Radicals from Decomposition of Organic Peroxides. Gazz. Chim. Ital. 1961, 91, 386-389.

33. Minisci, F.; Pallini, U., Radical Reactions in Solution. Haloalkylation of Acrylic Acid Derivatives. Gazz. Chim. Ital. 1961, 91, 1030-1036.

34. Minisci, F.; Galli, R., Influence of the Electrophilic Character on the Reactivity of Free Radicals in Solution. Reactivity of Alkoxy, Hydroxy, Alkyl, and Azido Radicals in the Presence of Olefins. Tetrahedron Lett. 1962, 12, 533-538.

35. Minisci, F.; Galli, R., Addition of N-Chloroamines to Styrene and Butadiene, Catalyzed by Iron and Copper Salts. Chim. Ind. (Milan) 1963, 45 (11), 1400- 1401.

36. Minisci, F., Free-Radical Additions to Olefins in the Presence of Redox Systems. Acc. Chem. Res. 1975, 8 (5), 165-171.

37. Gossage, R. A.; Van De Kuil, L. A.; Van Koten, G., Diaminoarylnickel(II) "Pincer" Complexes: Mechanistic Considerations in the Kharasch Addition Reaction, Controlled polymerization, and Dendrimeric Transition Metal Catalysts. Acc. Chem. Res. 1998, 31 (7), 423-431.

38. Nagashima, H., Ruthenium in Organic Synthesis. In Ruthenium in Organic Synthesis, Murahashi, S.-I., Ed. Wiley-VCH: Weinheim, 2004; pp 333-343.

39. Delaude, L.; Demonceau, A.; Noels, A. F., Topics in Organometallic Chemistry. In Topics in Organometallic Chemistry, Bruneau, C.; Dixneuf, P. H., Eds. Springer: Berlin, 2004; Vol. 11, pp 155-171.

40. Severin, K., Ruthenium Catalysts for the Kharasch Reaction. Curr. Org. Chem. 2006, 10, 217-224.

41. Clark, A. J., Atom Transfer Radical Cyclisation Reactions Mediated by Copper Complexes. Chem. Soc. Rev. 2002, 31 (1), 1-11.

42. Steiner, E.; Martin, P.; Bellius, D., Metal-Catalyzed Radical Addition of Polyhalogenated Compounds to Olefins. Part 2. A New Simple Synthesis of 2,3,5-Trichloropyridine. Helv. Chim. Acta. 1982, 65, 983-985.

43. Metzger, J. O.; Mahler, R., Radical Additions of Activated Haloalkanes to Alkenes Initiated by Electron Transfer from Copper in Solvent-Free Systems. Angew. Chem. Int. Ed. 1995, 34 (8), 902-904.

44. Forti, L.; Ghelfi, F.; Pagnoni, U. M., Fe0 Initiated Halogen Atom Transfer Radical Addition of Methyl 2-Br-2-Cl-Carboxylates to Olefins. Tetrahedron Lett. 1996, 37 (12), 2077-2078.

45. Forti, L.; Ghelfi, F.; Libertini, E.; Pagnoni, U. M.; Soragni, E., Halogen Atom Transfer Radical Addition of -Polychloro Esters to Olefins Promoted by Fe0 Filings. Tetrahedron 1997, 53 (52), 17761-17768.

46. Caronna, T.; Citterio, A.; Ghirardini, M.; Minisci, F., Nucleophilic Character of Alkyl Radicals−XIII: Absolute Rate Constants for the Addition of Alkyl Radicals to Acrylonitrile and Methyl Acrylate. Tetrahedron 1977, 33 (7), 793-796.

47. Baban, J. A.; Roberts, B. P., An Electron Spin Resonance Study of Alkyl Radical Addition to Diethyl Vinylphosphonate. J. Chem. Soc. Perkin Trans. 2. 1981, 1, 161-166.

48. Asscher, M.; Vosfsi, D., Chlorine Activation by Redox-Transfer. Part I. The Reaction Between Aliphatic Amines and Carbon Tetrachloride. J. Chem. Soc. 1961, 2261-2264.

49. Sinnreich, J.; Asscher, M., Redox-Transfer. Part VII. Addition of Ethylene and Butadiene to Functionally Substituted Aromatic Sulphonyl Chlorides. J. Chem. Soc., Perkin Trans. 1. 1972, 1, 1543-1545.

50. Kamigata, N.; Sawada, H.; Kobayashi, M., Reactions of Arenesulfonyl Chlorides with Olefins Catalyzed by Ruthenium(II) Complex. J. Org. Chem. 1983, 48 (21), 3793-3796.

51. Truce, W. E.; Wolf, G. C., Adducts of Sulfonyl Iodides with Acetylenes. J. Org. Chem. 1971, 36 (13), 1727-1732.

52. Block, E.; Aslam, M.; Eswarakrishman, V.; Gebreyes, K.; Hutchinson, J.; Iyer, R. S.; Laffitte, J. A., α-Haloalkanesulfonyl Bromides in Organic Synthesis. 5. Versatile Reagents for the Synthesis of Conjugated Polyenes, Enones, and 1,3- Oxathiole 1,1-Dioxides. J. Am. Chem. Soc. 1986, 108 (15), 4568-4580.

53. Amiel, Y., The Thermal and the Copper-Catalyzed Addition of Sulfonyl Bromides to Phenylacetylene J. Org. Chem. 1974, 39, 3867-3870.

54. Miniotte, H. G.; Hubert, A. J.; Teyssie, P., The Role of Copper(I) Complexes in the Selective Formation of Oxazoles from Unsaturated Nitriles and Diazoesters. J. Organomet. Chem. 1975, 88 (1), 115-120.

55. Murai, S.; Sonoda, N.; Tsutsumi, S., Copper Salts Induced Addition of Ethyl Trichloroacetate to Olefins. J. Org. Chem. 1964, 31, 3000-3003.

56. Fernandez-Zumel, M. A.; Thommes, K.; Kiefer, G.; Sienkiewicz, A.; Pierzchala, K.; Severin, K., Atom-Transfer Radical Addition Reactions Catalyzed by RuCp* Complexes: A Mechanistic Study. . Chem. Eur. J. 2009, 15 (43), 11601-11607.

57. Bellius, D., Copper-Catalyzed Addition of Polyhalides to Olefins: a Versatile Synthetic Tool. Pure Appl. Chem. 1985, 57, 1827-1838.

58. Freidlina, R. K.; Velichko, F. K., Synthetic Applications of Homolytic Addition and Telomerization Reactions of Bromine-Containing Addends with Unsaturated Compounds Containing Electron-Withdrawing Substituents. Synthesis 1977, 3, 145-154.

59. Julia, M.; Sasussine, L.; Thuillier, G. I., Addition du chloracetate de methyle sur les olefines. J. Organomet. Chem. 1979, 174, 359-366.

60. Curran, D. P., Comprehensive Organic Synthesis. Pergamon: New York, 1992; p 715.

61. De Campo, F.; Lastecoueres, D.; Verlhac, J. B., New Copper(I) and Iron(II) Complexes for Atom Transfer Radical Addition. J. Chem. Soc. Perkin Trans. 1 2000, 4, 575-580.

62. Muñoz-Molina, J. M.; Caballero, A.; Diaz-Requejo, M. M.; Trofimenko, S.; Belderrain, T. R.; Perez, P. J., Copper−Homoscorpionate Complexes as Active

Catalysts for Atom Transfer Radical Addition to Olefins. Inorg. Chem. 2007, 46 (19), 7725-7730.

63. Pintauer, T.; Matyjaszewski, K., Structural Aspects of Copper Catalyzed Atom Transfer Radical Polymerization. Coord. Chem. Rev. 2005, 249 ((11-12)), 1155- 1184.

64. Nagashima, H.; Ozaki, N.; Ishii, M.; Seki, K.; Washiyama, M.; Itoh, K., Transition Metal Catalyzed Radical Cyclizations: A Low Temperature Process for the Cyclization of N-Protected N-Allyltrichloroacetamides to Trichlorinated γ- Lactams and Application to the Stereoselective Preparation of β,γ-Disubstituted γ- Lactams. J. Org. Chem. 1993, 58 (2), 464-470.

65. Fernandez-Zumel, M. A.; Thommes, K.; Kiefer, G.; Sienkiewicz, A.; Pierzchala, K.; Severin, K., Atom-Transfer Radical Addition Reactions Catalyzed by RuCp* Complexes: A Mechanistic Study. . Chem. Eur. J. 2009, 15 (43), 11601-11607.

66. Lee, G. M.; Weinreb, S. M., Transition Metal Catalyzed Intramolecular Cyclizations of (Trichloromethyl)alkenes. J. Org. Chem. 1990, 55 (4), 1281-1285.

67. Clark, A. J.; Dell, C. P.; Ellard, J. M.; Hunt, N. A.; McDonagh, J. P., Efficient Room Temperature Copper(I) Mediated 5-endo Radical Cyclisation. Tetrahedron Lett. 1999, 40 (49), 8619-8623.

68. Iwamatsu, S.; Kondo, H.; Matsubara, K.; Nagashima, H., Copper-Catalyzed Facile Carbon-Carbon Bond Forming Reactions at the α-Position of α,α,γ- Trichlorinated γ-Lactams. Tetrahedron 1999, 55 (6), 1687-1706.

69. Nagashima, H.; Wakamatsu, H.; Itoh, K., A Novel Preparative Method for γ- Butyrolactams via Carbon-Carbon Bond Formation: Copper or Ruthenium Catalyzed Cyclization of N-Allyl Trichloroacetimides. J. Chem. Soc. 1984, (10), 652-653.

70. Hayes, T. K., R.;; Villani, R.; Weinreb, S. M., Exploratory Studies of the Transition Metal Catalyzed Intramolecular Cyclization of Unsaturated α,α- Dichloro Esters, Acids and Nitriles. J. Am. Chem. Soc. 1988, 110 (16), 5533- 5543.

71. Lee, G. M.; Parvez, M.; Weinreb, S. M., Intramolecular Metal Catalyzed Kharasch Cyclizations of Olefinic, α-Halo Esters and Acids. Tetrahedron 1988, 44 (15), 4671-4678.

72. Iritani, K.; Yanagihara, N.; Utimoto, K., Transition Metal Promoted Intramolecular Cyclizations of α,α-Dichloro Esters and Acids. J. Org. Chem. 1986, 51 (26), 5501-5503.

73. Nagashima, H.; Seki, K.; Ozaki, N.; Wakamatsu, H.; Itoh, K.; Tomo, Y.; Tsuji, J., Transition Metal Catalyzed Radical Cyclization: Copper Catalyzed Cyclization of Allyl Trichloroacetate to Trichlorinated γ-Lactones. J. Org. Chem. 1990, 55 (3), 985-990.

74. de Campo, F.; Lastecoueres, D.; Verlhac, J. B., New and Improved Catalysts for Transition Metal Catalysed Radical Reactions. Chem. Commun. 1998, 19, 2117- 2118.

75. Pirrung, F.; Hiemstra, H.; Speckamp, N., Synthesis of Medium-Sized Lactones by the Copper(I)Chloride/2,2'-Bipyridine-Catalyzed Cyclization of Di- and Trichloroacetates. Tetrahedron 1994, 50 (43), 12415-12442.

76. Pirrung, F. O. H.; Hiemstra, H.; Kaptein, B.; Sobrino, M. E. M.; Petra, D. G. I.; Schoemaker, H. E.; Speckamp, W. N., Diastereoselective Synthesis of Medium- Sized Lactones by Cu(bpy)Cl Catalyzed Cyclization of Trichloroacetates. Synlett 1993, 10, 739-740.

77. Pirrung, F. O. H.; Hiemstra, H.; Speckamp, W. N.; Kaptein, B.; Schoemaker, H. E., Synthesis of Enantiometrically Pure Eight- and Nine- Membered Lactones by Copper(I) Chloride/2,2'-Bipyridine-Catalyzed Cyclization. Synthesis 1995, 4, 458-472.

78. Clark, A. J.; De Campo, F.; Deeth, R. J.; Filik, R. P.; Gatard, S.; Hunt, N. A.; Lastecoueres, D.; Thomas, G. H.; Verlhac, J.-B.; Wongtap, H., Atom Transfer Radical Cyclizations of Activated and Unactivated N-Allylhaloacetamides and N- Homoallylhaloacetamides Using Chiral and Non-Chiral Copper Complexes. J. Chem. Soc. Perkin Trans.1 2000, (5), 671-680.

79. Clark, A. J.; Battle, G. M.; Bridge, A., 5-exo Atom Transfer Cyclisation onto Alkynes Mediated by Copper(I) Complexes. Tetrahedron Lett. 2001, 42 (10), 1999-2001.

80. Xia, J.; Zhang, X.; Matyjaszewski, K., The Effect of Ligands on Copper-Mediated Atom Transfer Radical Polymerization. ACS Symp. Ser. 2000, 760 (Transition Metal Catalysis in Macromolecular Design), 207-223.

81. Felluga, F.; Forzato, C.; Ghelfi, F.; Nitti, P.; Pitacco, G.; Pagnonib, U. M.; Roncaglia, F., Atom Transfer Radical Cyclization (ATRC) Applied to a Chemoenzymatic Synthesis of Quercus Lactones Tetrahedron: Asym. 2007, 18, 527-536.

82. Clark, A. J.; Duncalf, D. J.; Filik, R. P.; Haddleton, D. M.; Thomas, G. H.; Wongtap, H., N-Alkyl-2-pyridylmethanimines as Tuneable Alternatives to Bipyridine Ligands in Copper Mediated Atom Transfer Radical Cyclization. Tetrahedron Lett. 1999, 40 (19), 3807-3810.

83. Clark, A. J.; Battle, G. M.; Heming, A. M.; Haddleton, D. M.; Bridge, A., Ligand Electronic Effects on Rates of Copper Mediated Atom Transfer Radical Cyclisation and Polymerisation. Tetrahedron Lett. 2001, 42 (10), 2003-2005.

84. Haddleton, D. M.; Crossman, M. C.; Hunt, K. H., Reactivity Ratios in MMA Copolymerizations. Macromolecules 1997, 30, 3992-3995.

85. Haddleton, D. M.; Duncalf, D. J.; Kukulj, D.; Crossman, M. C.; Jackson, S. G.; Bon, S. A. F.; Clark, A. J.; Schooter, A. J., N-Alkyl-Pyridylmethanimine Copper(I) Complexes. Eur. J. Inorg. Chem. 1998, 1799-1806.

86. Haddleton, D. M.; Jasieczek, C. B.; Hannon, M. J.; Shooter, A. J.; Transfer, A., Radical Polymerization of Methyl Methacrylate Initiated by Alkyl Bromide and 2-Pyridinecarbaldehyde Imine Copper(I) Complexes. Macromolecules 1997, 30 (7), 2190- 2193.

87. Lad, J.; Harrisson, S.; Mantovani, G.; Haddleton, D. M., Copper Mediated Living Radical Polymerisation: Interactions Between Monomer and Catalyst. Dalton Trans. 2003, (21), 4175-4180.

88. Benedetti, M.; Forti, L.; Ghelfi, F.; Pagnoni, U. M.; Ronzoni, R., Halogen Atom Transfer Radical Cyclization of N-Allyl-N-Benzyl-2,2-Dihaloamides to 2- Pyrrolidinones, Promoted by Fe0-FeCl3 or CuCl-TMEDA. Tetrahedron 1997, 53 (41), 14031-14042.

89. Ghelfi, F.; Bellesia, F.; Forti, L.; Ghirardini, G.; Grandi, R.; Libertini, E.; Montemaggi, M. C.; Pagnoni, U. M.; Pinetti, A., The Influence of Benzylic Protection and Allylic Substituents on the CuCl-TMEDA Catalyzed Rearrangement of N-Allyl-N-Benzyl-2,2-Dihaloamides to γ-Lactams. Applications to the Stereoselective Synthesis of Pilolactam. Tetrahedron 1999, 55 (18), 5839-5852.

90. Ghelfi, F., N,N-(Dimethylamino)-2-Pyrrolidinones from the Rearrangement of N- Allyl-N,N-Dimethyl-2,2-dichlorohydrazides Promoted by CuCl-N,N,N,N- Tetramethylethylenediamine. J. Org. Chem. 2000, 65 (19), 6249-6253.

91. De Campo, F., Lastecoueres, D., Vincent, J., Verlhac, J., Copper(I) Complexes Mediated Cyclization Reaction of Unsaturated Ester under Fluoro Biphasic Procedure. J. Org. Chem. 1999, 64 (13), 4969-4971.

92. Konak, C.; Ganchev, B.; Teodorescu, M.; Matyjaszewski, K.; Kopeckov·, P.; Kopecek, J., Poly[N-(2-hydroxypropyl)methacrylamide-block-n-butyl acrylate] Micelles in Water/DMF Mixed Solvents. Polymer 2002, 43 (13), 3735-3741.

93. Kamigaito, M.; Ando, T.; Sawamoto, M., Metal-Catalyzed Living Radical Polymerization. Chem. Rev. 2001, 101 (12), 3689-3745.

94. Clark, A. J.; Battle, G. M.; Heming, A. M.; Haddleton, D. M.; Bridge, A., Ligand Electronic Effects on Rates of Copper Mediated Atom Transfer Radical Cyclisation and Polymerisation. Tetrahedron Lett. 2001, 42 (10), 2003-2005.

95. Muñoz-Molina, J. M.; Belderrain, T. R.; Perez, P. J., An Efficient, Selective, and Reducing Agent-Free Copper Catalyst for the Atom-Transfer Radical Addition of Halo Compounds to Activated Olefins Inorg. Chem. 2010, 49 (2), 642-645.

96. Stevens, C. V.; Van Meenen, E.; Masschelein, K. G. R.; Eeckhout, Y.; Hooghe, W.; D‘hondt, B.; Nemykin, V. N.; Zhandkin, V. V., A Copper-Catalyzed Domino Radical Cyclization Route to Benzospiro-Indolizidinepyrrolidinones. Tetrahedron Lett. 2007, 48, 7108-7111.

97. Giese, B., Syntheses with Radicals. C-C Bond Formation via Organotin and Organomercury Compounds. Angew. Chem. Int. Ed. 1985, 97 (7), 555-567.

98. Iqbal, J.; Bhatia, B.; Nayyar, N. K., Transition Metal Promoted Free Radical Reactions in Organic Synthesis: The Formation of Carbon-Carbon Bonds. Chem. Rev. 1994, 94 (2), 519-564.

99. Renaud, P.; Sibi, M. P., Radicals in organic synthesis. Wiley-VCH: Weinheim, New York, 2001.

100. Matyjaszewski, K.; Davis, T. P., Handbook of Radical Polymerization. Wiley: Hoboken, 2002.

101. Togo, H., Advanced Free Radical Reactions for Organic Synthesis. Elsevier: Amsterdam, 2004.

102. Lee, E.; Choi, S. J., Radical Cyclization of β-Alkoxymethacrylates: Expedient Synthesis of (+)-Methyl Nonactate. Org. Lett. 1999, 1 (7), 127-1128.

103. Stork, G.; Sher, P. M.; Chen, H. L., Radical Cyclization-Trapping in the Synthesis of Natural Products. A Simple, Stereocontrolled Route to Prostaglandin F2α. J. Am. Chem. Soc. 1986, 108, 6384-6385.

104. Snider, B. B., Manganese(III)-Based Oxidative Free-Radical Cyclizations. Chem. Rev. 1996, 96, , 339-363.

105. Parsons, P. J.; Penkett, C. S.; Shell, A. J., Tandem Reactions in Organic Synthesis: Novel Strategies for Natural Product Elaboration and the Development of New Synthetic Methodology. Chem. Rev. 1996, 96, 195-206.

106. Ghelfi, F.; Roncaglia, F.; Pattarozzi, M.; Giangiordano, V.; Petrillo, G.; Sancassan, F.; Parsons, A. F., Atom Transfer Radical Cyclization of O-Allyl-2,2- Dichlorohemiacetal Acetates: An Expedient Method to Dichloro-γ-Lactones. Tetrahedron 2009, 65, 10323-10333.

107. Wetter, C.; Studer, A., Microwave-Assisted Free Radical Chemistry Using the Persistent Radical Effect. Chem. Commun. 2004, 174-175.

108. Iwamatsu, S. I.; Matsubara, K.; Nagashima, H., Synthetic Studies of cis-3α- Aryloctahydroindole Derivatives by Copper-Catalyzed Cyclization of N- Allyltrichloroacetamides: Facile Construction of Benzylic Quaternary Carbons by Carbon-Carbon Bond-Forming Reactions. J. Org. Chem. 1999, 64, 9625-9631.

109. Yoshimitsu, T.; Nakajima, H.; Nagaoka, H., Synthesis of the CD Ring System of Paclitaxel by Atom-Transfer Radical Annulation Reaction. Tetrahedron Lett. 2002, 43, 8587-8590.

110. Yanada, R.; Koh, Y.; Nishimori, N.; Matsumara, A.; Obika, S.; Mitsuya, H.; Fujii, N.; Takemoto, Y., Indium-Mediated Atom-Transfer and Reductive Radical Cyclizations of Iodoalkynes: Synthesis and Biological Evaluation of HIV- Protease Inhibitors. J. Org. Chem. 2004, 69, 2417-2422.

111. Curran, D. P.; Chen, M.-H.; Dooseop, K., Atom-Transfer Cyclization. A Novel Isomerization of Hex-5-ynyl Iodides to Iodomethylene Cyclopentanes. . J. Am. Chem. Soc. 1986, 108, 2489-2490.

112. Bull, J. A.; Hutchings, M. G.; Lujan, C.; Quayle, P., New Reactivity Patterns of Copper(I) and Other Transition Metal NHC Complexes: Application to ATRC and Related Reactions. Tetrahedron Lett. 2008, 49, 1352-1356.

113. Clark, A. J.; Wilson, P., Copper mediated atom transfer radical cyclisations with AIBN. Tetrahedron Lett. 2008, 49, 4848-4850.

114. Clark, A. J.; Filik, R. P.; Thomas, G. H., Ligand Geometry Effects in Copper Mediated Atom Transfer Radical Cyclisations. Tetrahedron Lett. 1999, 40 (26), 4885-4888.

115. Clark, A. J.; Battle, G. M.; Heming, A. M.; Haddleton, D. M.; Bridge, A., Ligand Electronic Effects on Rates of Copper Mediated Atom Transfer Radical Cyclisation and Polymerisation. Tetrahedron Lett. 2001, 42 (10), 2003-2005.

116. Schmidt, B.; Pohler, M., Ruthenium-Catalyzed Tandem Ring Closing Metathesis (RCM) − Atom Transfer Radical Cyclization (ATRC) Sequences. J. Organomet. Chem. 2005, 690, 5552-5555.

117. Nagashima, H.; Wakamatsu, H.; Itoh, K.; Tomo, Y.; Tsuji, J., New Regio- and Stereoselective Preparation of Trichlorinated γ-Butyrolactones by Copper Catalyzed Cyclization of Allyl Trichloroacetates. Tetrahedron Lett. 1983, 24 (23), 2395-2398.

118. Nagashima, H.; Ara, K.; Wakamatsu, H.; Itoh, K., Stereoselective Preparation of Bicyclic Lactams by Copper or Ruthenium Catalyzed Cyclization of N-

Allyltricholoacetamides: A Novel Entry to Pyrrolidine Alkaloid Skeletons. Chem. Comm. 1985, (8), 518-519.

119. Udding, J. H.; Tuijp, K.; Hiemstra, H.; Speckamp, W., Transition Metal Catalyzed Chlorine Transfer Cyclizations of Carbon-Carbon Glycine Radicals; A Novel Synthetic Route to Cyclic α-Amino Acids. Tetrahedron 1994, 50 (6), 1907- 1918.

120. Pirrung, F.; Hiemstra, H.; Speckamp, N., Synthesis of Medium-sized Lactones by the Copper(I)Chloride/ 2,2'-Bipyridine-Catalyzed Cyclization of Di- and Trichloroacetates. Tetrahedron 1994, 50 (43), 12415-12442.

121. Tietze, L. F., Domino Reactions in Organic Synthesis. Chem. Rev. 1996, 96, 115- 136.

122. Tietze, L. F. R., N. , Domino Reactions in the Synthesis of Heterocyclic Natural Products and Analogs. Pure Appl. Chem. 2004, 76 (11), 1967-1983.

123. Yang, D.; Yan, Y.; Zheng, B. F.; Gao, Q.; Zhu, N. Y., Copper(I)-Catalyzed Chlorine Atom Transfer Radical Cyclization Reactions of Unsaturated α-Chloro β-Keto Esters. Org. Lett. 2006, 8 (25), 5757-5760.

124. Curran, D. P., The Design and Application of Free Radical Chain Reactions in Organic Synthesis. Part 1. Synthesis 1988, (6), 417-439.

125. Curran, D. P.; Chen, M. H.; Kim, D., Atom-Transfer Cyclization. A Novel Isomerization of Hex-5-ynyl Iodides to Iodomethylene Cyclopentanes. J. Am. Chem. Soc. 1986, 108 (9), 2489-2490.

126. Pintauer, T., "Greening" of Copper Catalyzed Atom Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions. ACS Symp. Ser. 2009, 1023, 63-84.

127. Curran, D. P., The Design and Application of Free Radical Chain Reactions in Organic Synthesis. Part 2. Synthesis 1988, (7), 489-513.

128. Pintauer, T., Catalyst Regeneration in Transition-Metal-Mediated Atom-Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions. Eur. J. Inorg. Chem. 2010, 2010 (17), 2449-2460.

129. Clark, A. J.; Filik, R. P.; Haddleton, D. M.; Radigue, A.; Sanders, C. J., Solid Supported Catalysts for Atom Transfer Radical Cyclization of 2-Haloacetamides. J. Org. Chem. 1999, 64 (24), 8954-8957.

130. Clark, A. J.; Geden, J. V.; Thom, S., Solid-Supported Copper Catalysts for Atom- Transfer Radical Cyclizations: Assessment of Support Type and Ligand Structure on Catalyst Performance in the Synthesis of Nitrogen Heterocycles. J. Org. Chem. 2006, 71 (4), 1471-1479.

131. Tang, H.; Arulsamy, N.; Radosz, M.; Shen, Y.; Tsarevsky, N. V.; Braunecker, W. A.; Tang, W.; Matyjaszewski, K., Highly Active Copper-Based Catalyst for Atom Transfer Radical Polymerization. J. Am. Chem. Soc. 2006, 128 (50), 16277- 16285.

132. Taylor, M. J. W.; Eckenhoff, W. T.; Pintauer, T., Copper-Catalyzed Atom Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions in the Presence of Environmentally Benign Ascorbic Acid as a Reducing Agent. Dalton Trans. 2010, 39 (47), 11475-11482.

133. Jakubowski, W.; Matyjaszewski, K., Activators Regenerated by Electron Transfer for Atom-Transfer Radical Polymerization of (Meth)acrylates and Related Block Copolymers. Angew. Chem. Int. Ed. 2006, 45 (27), 4482-4486.

134. Jakubowski, W.; Min, K.; Matyjaszewski, K., Activators Regenerated by Electron Transfer for Atom Transfer Radical Polymerization of Styrene. Macromolecules 2006, 39 (1), 39-45.

135. Quebatte, L.; Thommes, K.; Severin, K., Highly Efficient Atom Transfer Radical Addition Reactions with a RuIII Complex as a Catalyst Precursor. J. Am. Chem. Soc. 2006, 128 (23), 7440-7441.

136. Eckenhoff, W. T.; Pintauer, T., Atom Transfer Radical Addition in the Presence of Catalytic Amounts of Copper(I/II) Complexes with Tris(2- pyridylmethyl)amine Inorg. Chem. 2007, 46 (15), 5844-5846.

137. Kleij, A. W.; Gossage, R. A.; Klein Gebbink, R. J. M.; Brinkmann, N.; Reijerse, E. J.; Kragl, U.; Lutz, M.; Spek, A. L.; van Koten, G., A "Dendritic Effect" in Homogeneous Catalysis with Carbosilane-Supported Arylnickel(II) Catalysts: Observation of Active-Site Proximity Effects in Atom-Transfer Radical Addition. J. Am. Chem. Soc. 2000, 122 (49), 12112-12124.

138. Kleij, A. W.; Gossage, R. A.; Jastrzebski, J. T. B. H.; Boersma, J.; van Koten, G., The ―Dendritic Effect‖ in Homogeneous Catalysis with Carbosilane-Supported Arylnickel(II) Catalysts: Observation of Active-Site Proximity Effects in Atom- Transfer Radical Addition. Angew. Chem. Int. Ed. 2000, 39 (1), 176-178.

139. Oe, Y.; Uozumia, Y., Highly Efficient Heterogeneous Aqueous Kharasch Reaction with an Amphiphilic Resin-Supported Ruthenium Catalyst Adv. Synth. Catal. 2008, 350, 1771-1775.

140. Braunecker, W.; Matyjaszewski, K., Controlled/living radical polymerization: Features, developments, and perspectives. Prog. Poly. Sci. 2007, 32, 93-146.

141. Tsarevsky, N. V.; Braunecker, W. A.; Tang, W.; Brooks, S. J.; Matyjaszewski, K.; Weisman, G. R.; Wong, E. H., Copper-Based ATRP Catalysts of Very High Activity Derived from Dimethyl Cross-Bridged Cyclam. J. Mol. Catal. A: Chem. 2006, 257 (1-2), 132-140.

142. Tang, W.; Matyjaszewski, K., Effect of Ligand Structure on Activation Rate Constants in ATRP. Macromolecules 2006, 39 (15), 4953-4959.

143. Tsarevsky, N.; Braunecker, W. A.; Matyjaszewski, K., Electron Transfer Reactions Relevant to Atom Transfer Radical Polymerization. J. Organomet. Chem. 2007, 692 (15), 3212-3222.

144. Pintauer, T.; Zhou, P.; Matyjaszewski, K., General Method for Determination of the Activation, Deactivation, and Initiation Rate Constants in Transition Metal Catalyzed Atom Transfer Radical Processes. J. Am. Chem. Soc. 2002, 124, 8196- 8197.

145. Pintauer, T.; McKenzie, B.; Matyjaszewski, K., Toward Structural and Mechanistic Understanding of Transition Metal-Catalyzed Atom Transfer Radical Processes. ACS Symp. Ser. 2003, 854, 130-147.

146. Tang, W.; Tsarevsky, N. V.; Matyjaszewski, K., Determination of Equilibrium Constants for Atom Transfer Radical Polymerization. J. Am. Chem. Soc. 2006, 128 (5), 1598-1604.

147. Matyjaszewski, K.; Gobelt, B.; Paik, H. J.; Horwitz, C. P., Tridentate Nitrogen- Based Ligands in Cu-Based ATRP: A Structure-Activity Study. Macromolecules 2001, 34 (3), 430-440.

148. Qiu, J.; Matyjaszewski, K.; Thouin, L.; Amatore, C., Cyclic Voltammetric Studies of Copper Complexes Catalyzing Atom Transfer Radical Polymerization Macromol. Chem. Phys. 2000, 201, 1625-1631.

149. Matyjaszewski, K., From Atom Transfer Radical Addition to Atom Transfer Radical Polymerization. Curr. Org. Chem. 2002, 6 (2), 67.

150. Xia, J.; Zhang, X.; Matyjaszewski, K., The Effect of Ligands on Copper-Mediated Atom Transfer Radical Polymerization. In Transition Metal Catalysis in Macromolecular Design, American Chemical Society: 2000; Vol. 760, pp 207- 223.

151. Xia, J.; Gaynor, S. G.; Matyjaszewski, K., Controlled/"Living" Radical Polymerization. Atom Transfer Radical Polymerization of Acrylates at Ambient Temperature. Macromolecules 1998, 31 (17), 5958-5959.

152. Xia, J.; Matyjaszewski, K., Controlled/"Living" Radical Polymerization. Atom Transfer Radical Polymerization Catalyzed by Copper(I) and Picolylamine Complexes. Macromolecules 1999, 32 (8), 2434-2437.

153. Eckenhoff, W. T.; Garrity, S. T.; Pintauer, T., Highly Efficient Copper-Mediated Atom Transfer Radical Addition (ATRA) in the Presence of a Reducing Agent. Eur. J. Inorg. Chem. 2008, (4), 563-571.

154. Kamigaito, M.; Ando, T.; Sawamoto, M., Metal-Catalyzed Living Radical Polymerization. Chem. Rev. 2001, 101 (12), 3689-3745.

155. Matyjaszewski, K.; Jakubowski, W.; Min, K.; Tang, W.; Huang, J.; Braunecker, W.; Tsarevsky, N., Diminishing Catalyst Concentration in Atom Transfer Radical Polymerization with Reducing Agents. Proc. Nat. Acad. Sci. 2006, 103 (42), 15309-15314.

156. Jakubowski, W.; Matyjaszewski, K., Activator Generated by Electron Transfer for Atom Transfer Radical Polymerization. Macromolecules 2005, 38 (10), 4139- 4146.

157. Matyjaszewski, K.; Dong, H.; Jakubowski, W.; Pietrasik, J.; Kusumo, A., Grafting from Surfaces for "Everyone": ARGET ATRP in the Presence of Air. Langmuir 2007, 23 (8), 4528-4531.

158. Min, K.; Gao, H.; Matyjaszewski, K., Preparation of Homopolymers and Block Copolymers in Miniemulsion by ATRP Using Activators Generated by Electron Transfer (AGET). J. Am. Chem. Soc. 2005, 127 (11), 3825-3830.

159. Min, K.; Gao, H.; Matyjaszewski, K., Use of Ascorbic Acid as Reducing Agent for Synthesis of Well-Defined Polymers by ARGET ATRP. Macromolecules 2007, 40 (6), 1789-1791.

160. Pintauer, T.; Eckenhoff, W. T.; Ricardo, C.; Balili, M. N. C.; Biernesser, A. B.; Noonan, S. T.; Taylor, M. T., Highly Efficient Ambient-Temperature Copper- Catalyzed Atom-Transfer Radical Addition (ATRA) in the Presence of Free- Radical Initiator (V-70) as a Reducing Agent Chem. Eur. J. 2009, 15 (1), 38-41.

161. Fernandez-Zumel, M. A.; Thommes, K.; Kiefer, G.; Sienkiewicz, A.; Pierzchala, K.; Severin, K., Atom-Transfer Radical Addition Reactions Catalyzed by RuCp* Complexes: A Mechanistic Study. Chem. Eur. J. 2009, 15 (43), 11601-11607.

162. Thommes, K.; Icli, B.; Scopelliti, R.; Severin, K., Atom Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions Catalyzed by a Mixture of [RuCl2Cp*(PPh3)] and Magnesium. Chem. Eur. J. 2007, 13 (24), 6899-6907.

163. Quebatte, L.; Thommes, K.; Severin, K., Highly Efficient Atom Transfer Radical Addition Reactions with a RuIII Complex as a Catalyst Precursor. J. Am. Chem. Soc. 2006, 128 (23), 7440-7441.

164. Quebatte, L.; Thommes, K.; Severin, K., Highly Efficient Atom Transfer Radical Addition Reactions with a RuIII Complex as a Catalyst Precursor. J. Am. Chem. Soc. 2006, 128 (23), 7440-7441.

165. Bland, W. J.; Davis, R.; Durrant, J. L. A., The Mechanism of the Addition of Haloalkanes to Alkenes in the Presence of Dichlorotris(triphenylphosphine)ruthenium(II), [RuCl2(PPh3)3]. J. Organomet. Chem. 1985, 280 (3), 397-406.

166. Quebatte, L.; Haas, M.; Solari, E.; Scopelliti, R.; Nguyen, Q. T.; Severin, K., Combinatorial Catalysis with Bimetallic Complexes: Robust and Efficient Catalysts for Atom-Transfer Radical Additions. Angew. Chem. Int. Ed. 2004, 43 (12), 1520-1524.

167. Odian, G., Principles of Polymerization. 4th ed.; John Wiley & Sons: Hoboken, NJ, 2004.

168. Beuermann, S.; Buback, M., Rate Coefficients of Free-Radical Polymerization Deduced from Pulsed Laser Experiments. Prog. Polym. Sci. 2002, 27 (2), 191- 254.

169. Gruber, H. F., Photoinitiators for Free Radical Polymerization. Prog. Polym. Sci. 1992, 17 (6), 953-1044.

170. Balili, M. N. C.; Pintauer, T., Photoinitiated Ambient Temperature Copper- Catalyzed Atom Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions in the Presence of Free-Radical Diazo Initiator (AIBN). Dalton Trans. 2011, 40 (12), 3060-3066.

171. Clark, A. J.; Battle, G. M.; Bridge, A., Efficient B-Lactam Synthesis via 4-exo Atom Transfer Radical Cyclisation Using CuBr(tripyridylamine) Complex. Tetrahedron Lett. 2001, 42 (26), 4409-4412.

172. Pattarozzi, M.; Roncaglia, F.; Accorsi, L.; Parsons, A. F.; Ghelfi, F., Functional Rearrangement of 3-Cl or 3,3-diCl-γ-lactams Bearing a Secondary 1-Chloroalkyl Substituent at C-4. Tetrahedron 2010, 66 (6), 1357-1364.

173. Nagashima, H.; Ara, K.; Wakamatsu, H.; Itoh, K., Stereoselective Preparation of Bicyclic Lactams by Copper or Ruthenium Catalyzed Cyclization of N- Allyltricholoacetamides: A Novel Entry to Pyrrolidine Alkaloid Skeletons. Chem. Commun. 1985, (8), 518-519.

174. Pirrung, F.; Hiemstra, H.; Speckamp, N., Synthesis of Medium-sized Lactones by the Copper(I)Chloride/ 2,2'-Bipyridine-Catalyzed Cyclization of Di- and Trichloroacetates. Tetrahedron 1994, 50 (43), 12415-12442.

175. Clark, A. J.; Wilson, P., Copper mediated atom transfer radical cyclisations with AIBN. Tetrahedron Lett. 2008, 49, 4848-4850.

176. Wolf, J.; Thommes, K.; Briel, O.; Scopelliti, R.; Severin, K., Dinuclear Ruthenium Ethylene Complexes: Syntheses, Structures, and Catalytic Applications in ATRA and ATRC Reactions. Organometallics 2008, 27 (17), 4464-4474.

177. Ricardo, C.; Pintauer, T., Copper Catalyzed AtomTransfer Radical Cascade Reactions in the Presence of Free-Radical Diazo Initiators as Reducing Agents. J. Chem. Soc. Chem. Commun. 2009, (21), 3029-3031.

178. Clark, A. J.; Wilson, P., Copper mediated atom transfer radical cyclisations with AIBN. Tetrahedron Lett. 2008, 49, 4848-4850.

179. Muñoz-Molina, J. M.; Belderrain, T. R.; Perez, P. J., Copper-Catalyzed Synthesis of 1,2-Disubstituted Cyclopentanes from 1,6-Dienes by Ring-Closing Kharasch Addition of Carbon Tetrachloride Adv. Synth. Catal. 2008, 350, 2365-2372.

180. Clark, A. J.; Wilson, P., Copper mediated atom transfer radical cyclisations with AIBN. Tetrahedron Lett. 2008, 49, 4848-4850.

181. Matyjaszewski, K.; Xia, J., Atom Transfer Radical Polymerization. Chem. Rev. 2001, 101 (9), 2921-2990.

182. Julia, M., Free Radical Cyclizations. J. Am. Chem. Soc. 1970, 4, 386-392.

183. Julia, M., Free Radical Cyclizations, XVII. Mechanistic Studies. Pure Appl. Chem. 1974, 40, 553.

184. Thommes, K.; Kiefer, G.; Scopelliti, R.; Severin, K., Olefin Cyclopropanation by a Sequential Atom-Transfer Radical Addition and Dechlorination in the Presence of a Ruthenium Catalyst. Angew. Chem. Int. Ed. 2009, 48 (43), 8115-8119.

185. Fernández-Zúmel, M. A.; Buron, C.; Severin, K., Sequential ATRA/Reductive Cyclopropanation Reactions with a Ruthenium Catalyst in the Presence of Manganese. Eur. J. Org. Chem. 2011, (12), 2272-2277.

186. Thommes, K.; Fernández-Zúmel, M. A.; Buron, C.; Godinat, A.; Scopelliti, R.; Severin, K., Ruthenium-Catalyzed Synthesis of 1,5-Dichlorides by Sequential Intermolecular Kharasch Reactions. Eur. J. Org. Chem. 2011, (2), 249-255.

187. Beckwith, A. L. J., Regio-Selectivity and Stereo-Selectivity in Radical Reactions. Tetrahedron 1981, 37 (18), 3073-3100.

100

188. Brace, N. O., Cyclization Reactions of 6-Hepten-2-yl Radicals, 1- Trichloromethyl-6-hepten-2-yl Radicals and Related Compounds. J. Org. Chem. 1967, 32 (9), 2711-2718.

189. Spellmeyer, D. C.; Houk, K. N., Force-Field Model for Intramolecular Radical Additions. J. Org. Chem. 1987, 52 (6), 959-974.

190. Moses, J. E.; Moorhouse, A. D., The Growing Applications of Click Chemistry. Chem. Soc. Rev. 2007, 36 (8), 1249-1262.

191. Agard, N. J.; Prescher, J. A.; Bertozzi, C. R., A Strain-Promoted [3 + 2] Azide- Alkyne Cycloaddition for Covalent Modification of Biomolecules in Living Systems. J. Am. Chem. Soc. 2004, 126 (46), 15046-15047.

192. Dirks, A. J.; van Berkel, S. S.; Hatzakis, N. S.; Opsteen, J. A.; van Delft, F. L.; Cornelissen, J. J. L. M.; Rowan, A. E.; van Hest, J. C. M.; Rutjes, F. P. J. T.; Nolte, R. J. M., Preparation of biohybrid amphiphiles via the copper catalysed Huisgen [3 + 2] dipolar cycloaddition reaction. Chem. Commun. 2005, (33), 4172-4174.

193. Binder, W. H.; Kluger, C., Azide/Alkyne-"Click" Reactions: Applications in Material Science and Organic Synthesis. Curr. Org. Chem. 2006, 10 (14), 1791- 1815.

194. Nandivada, H.; Jiang, X.; Lahann, J., Click Chemistry: Versatility and Control in the Hands of Materials Scientists. Adv. Mater. 2007, 19 (17), 2197-2208.

195. Binder, W. H.; Sachsenhofer, R., ‗Click‘ Chemistry in Polymer and Materials Science. Macromol. Rapid Commun. 2007, 28 (1), 15-54.

196. Kolb, H. C.; Sharpless, K. B., The Growing Impact of Click Chemistry on Drug Discovery. Drug Discov. Today 2003, 8 (24), 1128-1137.

197. Amblard, F.; Cho, J. H.; Schinazi, R. F., Cu(I)-Catalyzed Huisgen Azide-Alkyne 1,3-Dipolar Cycloaddition Reaction in Nucleoside, Nucleotide, and Oligonucleotide Chemistry. Chem. Rev. 2009, 109 (9), 4207-4220.

198. Hein, C.; Liu, X.-M.; Wang, D., Click Chemistry, A Powerful Tool for Pharmaceutical Sciences. Pharm. Res. 2008, 25 (10), 2216-2230.

101

199. Najera, C.; Sansano, J. M., 1,3-Dipolar cycloadditions: Applications to the Synthesis of Antiviral Agents. Org. Biomol. Chem. 2009, 7 (22), 4567-4581.

200. Huisgen, R.; Szeimies, G.; Möbius, L., 1.3-Dipolare Cycloadditionen, XXXII. Kinetik der Additionen Organischer Azide an CC-Mehrfachbindungen. Chemische Berichte 1967, 100 (8), 2494-2507.

201. Huisgen, R., Kinetics and Reaction Mechanisms: Selected Examples from the Experience of Forty Years. Pure. Appl. Chem. 1989, 61 (4), 613.

202. Padwa, A., 1,3-Dipolar Cycloaddition Chemistry. Wiley: New York, 1984.

203. Tornoe, C. W.; Christensen, C.; Meldal, M., Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides. J. Org. Chem. 2002, 67 (9), 3057- 3064.

204. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B., A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective ―Ligation‖ of Azides and Terminal Alkynes. Angew. Chem. Int. Ed. 2002, 41 (14), 2596- 2599.

205. Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V., Copper(I)-Catalyzed Synthesis of Azoles. DFT Study Predicts Unprecedented Reactivity and Intermediates. J. Am. Chem. Soc. 2005, 127 (1), 210-216.

206. Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der Eycken, E., A Microwave- Assisted Click Chemistry Synthesis of 1,4-Disubstituted 1,2,3-Triazoles via a Copper(I)-Catalyzed Three-Component Reaction. Org. Lett. 2004, 6 (23), 4223- 4225.

207. Molteni, G.; Bianchi, C. L.; Marinoni, G.; Santo, N.; Ponti, A., Cu/Cu-oxide Nanoparticles as Catalyst in the "Click" Azide-Alkyne Cycloaddition. New J. Chem. 2006, 30 (8), 1137-1139.

208. Lipshutz, B. H.; Taft, B. R., Heterogeneous Copper-in-Charcoal-Catalyzed Click Chemistry. Angew. Chem. Int. Ed. 2006, 45 (48), 8235-8238.

102

209. Altintas, O.; Yankul, B.; Hizal, G.; Tunca, U., A3-Type Star Polymers via Click Chemistry. J. Polym. Sci A: Polym. Chem 2006, 44 (21), 6458-6465.

210. Altintas, O.; Hizal, G.; Tunca, U., ABC-Type Hetero-Arm Star Terpolymers Through ―Click‖ Chemistry. J. Polym. Sci A: Polym. Chem 2006, 44 (19), 5699- 5707.

211. Lutz, J.-F.; Borner, H. G.; Weichenhan, K., Combining ATRP and ―Click‖ Chemistry: a Promising Platform toward Functional Biocompatible Polymers and Polymer Bioconjugates. Macromolecules 2006, 39 (19), 6376-6383.

212. Gao, H.; Louche, G.; Sumerlin, B. S.; Jahed, N.; Golas, P.; Matyjaszewski, K., Gradient Polymer Elution Chromatographic Analysis of α,ω- Dihydroxypolystyrene Synthesized via ATRP and Click Chemistry. Macromolecules 2005, 38 (22), 8979-8982.

213. Gondi, S. R.; Vogt, A. P.; Sumerlin, B. S., Versatile Pathway to Functional Telechelics via RAFT Polymerization and Click Chemistry. Macromolecules 2007, 40 (3), 474-481.

214. Sumerlin, B. S.; Tsarevsky, N. V.; Louche, G.; Lee, R. Y.; Matyjaszewski, K., Highly Efficient "Click" Functionalization of Poly(3-azidopropyl methacrylate) Prepared by ATRP. Macromolecules 2005, 38 (18), 7540-7545.

215. Golas, P. L.; Tsarevsky, N. V.; Sumerlin, B. S.; Matyjaszewski, K., Catalyst Performance in Click Coupling Reactions of Polymers Prepared by ATRP: Ligand and Metal Effects. Macromolecules 2006, 39 (19), 6451-6457.

216. Golas, P. L.; Tsarevsky, N. V.; Sumerlin, B. S.; Walker, L. M.; Matyjaszewski, K., Multisegmented Block Copolymers by 'Click' Coupling of Polymers Prepared by ATRP. Aust. J. Chem. 2007, 60 (6), 400-404.

217. Johnson, J. A.; Lewis, D. R.; Diaz, D. D.; Finn, M. G.; Koberstein, J. T.; Turro, N. J., Synthesis of Degradable Model Networks via ATRP and Click Chemistry. J. Am. Chem. Soc. 2006, 128 (20), 6564-6565.

218. Punna, S.; Kaltgrad, E.; Finn, M. G., "Clickable" Agarose for Affinity Chromatography. Bioconjugate Chem. 2005, 16 (6), 1536-1541.

103

219. Cristiano, R.; de Oliveira Santos, D. M. P.; Conte, G.; Gallardo, H., 1,4-Diaryl and Schiff's base [1,2,3]-Triazole Derivative Liquid Crystalline Compounds. Liq. Cryst. 2006, 33 (9), 997-1003.

220. Lewis, W. G.; Magallon, F. G.; Fokin, V. V.; Finn, M. G., Discovery and Characterization of Catalysts for Azide‚àíAlkyne Cycloaddition by Fluorescence Quenching. J. Am. Chem. Soc. 2004, 126 (30), 9152-9153.

221. Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V., Polytriazoles as Copper(I)-Stabilizing Ligands in Catalysis. Org. Lett. 2004, 6 (17), 2853-2855.

222. Oyelere, A. K.; Chen, P. C.; Yao, L. P.; Boguslavsky, N., Heterogeneous Diazo- Transfer Reaction: A Facile Unmasking of Azide Groups on Amine- Functionalized Insoluble Supports for Solid-Phase Synthesis. J. Org. Chem. 2006, 71 (26), 9791-9796.

223. Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K. B.; Finn, M. G., Bioconjugation by Copper(I)-Catalyzed Azide-Alkyne [3 + 2] Cycloaddition. J. Am. Chem. Soc. 2003, 125 (11), 3192-3193.

224. Opsteen, J. A.; Brinkhuis, R. P.; Teeuwen, R. L. M.; Lowik, D. W. P. M.; van Hest, J. C. M., "Clickable" Polymersomes. Chem. Commun. 2007, (30), 3136- 3138.

225. Hosoya, T.; Hiramatsu, T.; Ikemoto, T.; Aoyama, H.; Ohmae, T.; Endo, M.; Suzuki, M., Design of Dantrolene-Derived Probes for Radioisotope-Free Photoaffinity Labeling of Proteins Involved in the Physiological Ca2+ Release from Sarcoplasmic Reticulum of Skeletal Muscle. Bioorg. Med. Chem. Lett. 2005, 15 (5), 1289-1294.

226. Xie, J.; Seto, C. T., A Two Stage Click-Based Library of Protein Tyrosine Phosphatase Inhibitors. Bioorg. Med. Chem. Lett. 2007, 15 (1), 458-473.

227. Said Hassane, F.; Frisch, B.; Schuber, F., Targeted Liposomes: Convenient Coupling of Ligands to Preformed Vesicles Using "Click Chemistry". Bioconjugate Chem. 2006, 17 (3), 849-854.

228. Zeng, Q.; Li, T.; Cash, B.; Li, S.; Xie, F.; Wang, Q., Chemoselective Derivatization of a Bionanoparticle by Click Reaction and ATRP Reaction. Chem. Commun. 2007, (14), 1453-1455.

104

229. Gupta, S. S.; Kuzelka, J.; Singh, P.; Lewis, W. G.; Manchester, M.; Finn, M. G., Accelerated Bioorthogonal Conjugation: A Practical Method for the Ligation of Diverse Functional Molecules to a Polyvalent Virus Scaffold. Bioconjugate Chem. 2005, 16 (6), 1572-1579.

230. Devaraj, N. K.; Dinolfo, P. H.; Chidsey, C. E. D.; Collman, J. P., Selective Functionalization of Independently Addressed Microelectrodes by Electrochemical Activation and Deactivation of a Coupling Catalyst. J. Am. Chem. Soc. 2006, 128 (6), 1794-1795.

231. Díez-González, S.; Correa, A.; Cavallo, L.; Nolan, S. P., (NHC)Copper(I)- Catalyzed [3+2] Cycloaddition of Azides and Mono- or Disubstituted Alkynes. Chem. Eur. J. 2006, 12 (29), 7558-7564.

232. Díez-González, S.; Nolan, S. P., [(NHC)2Cu]X Complexes as Efficient Catalysts for Azide–Alkyne Click Chemistry at Low Catalyst Loadings. Angew. Chem. 2008, 120 (46), 9013-9016.

233. Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel, A.; Voit, B.; Pyun, J.; Fréchet, J. M. J.; Sharpless, K. B.; Fokin, V. V., Efficiency and Fidelity in a Click-Chemistry Route to Triazole Dendrimers by the Copper(I)-Catalyzed Ligation of Azides and Alkynes. Angew. Chem. Int. Ed. 2004, 43 (30), 3928- 3932.

234. Gonda, Z.; Novak, Z., Highly Active Copper-Catalysts for Azide-Alkyne Cycloaddition. Dalton Trans. 2009, 39 (3), 726-729.

235. Perez-Balderas, F.; Ortega-Munoz, M.; Morales-Sanfrutos, J.; Hernandez-Mateo, F.; Calvo-Flores, F. G.; Calvo-Asin, J. A.; Isac-Garcia, J. n.; Santoyo-Gonzalez, F., Multivalent Neoglycoconjugates by Regiospecific Cycloaddition of Alkynes and Azides Using Organic-Soluble Copper Catalysts. Org. Lett. 2003, 5 (11), 1951-1954.

236. Campbell-Verduyn, L. S.; Mirfeizi, L.; Dierckx, R. A.; Elsinga, P. H.; Feringa, B. L., Phosphoramidite Accelerated Copper(I)-Catalyzed [3 + 2] Cycloadditions of Azides and Alkynes. Chem. Commun. 2009, (16), 2139-2141.

237. Ahlquist, M.; Fokin, V. V., Enhanced Reactivity of Dinuclear Copper(I) Acetylides in Dipolar Cycloadditions. Organometallics 2007, 26 (18), 4389-4391.

105

238. Straub, B. F., μ-Acetylide and μ-Alkenylidene Ligands in "Click" Triazole Syntheses. Chem. Commun. 2007, (37), 3868-3870.

239. Nolte, C.; Mayer, P.; Straub, B. F., Isolation of a Copper(I) Triazolide: A ―Click‖ Intermediate. Angew. Chem. Int. Ed. 2007, 46 (12), 2101-2103.

240. Link, A. J.; Tirrell, D. A., Cell Surface Labeling of Escherichia coli via Copper(I)-Catalyzed [3+2] Cycloaddition. J. Am. Chem. Soc. 2003, 125 (37), 11164-11165.

241. Deiters, A.; Cropp, T. A.; Mukherji, M.; Chin, J. W.; Anderson, J. C.; Schultz, P. G., Adding Amino Acids with Novel Reactivity to the Genetic Code of Saccharomyces Cerevisiae. J. Am. Chem. Soc. 2003, 125 (39), 11782-11783.

242. Seo, T. S.; Li, Z.; Ruparel, H.; Ju, J., Click Chemistry to Construct Fluorescent Oligonucleotides for DNA Sequencing. J. Org. Chem. 2002, 68 (2), 609-612.

243. Sirivolu, V. R.; Chittepu, P.; Seela, F., DNA with Branched Internal Side Chains: Synthesis of 5-Tripropargylamine-dU and Conjugation by an Azide-Alkyne Double Click Reaction. ChemBioChem 2008, 9 (14), 2305-2316.

244. Liebert, T.; Hänsch, C.; Heinze, T., Click Chemistry with Polysaccharides. Macromol. Rapid Commun. 2006, 27 (3), 208-213.

245. Wong, C. H., Carbohydrate-Based Drug Discovery. Wiley-VCH: Weinheim [Cambridge], 2003.

246. Lee, L. V.; Mitchell, M. L.; Huang, S.-J.; Fokin, V. V.; Sharpless, K. B.; Wong, C.-H., A Potent and Highly Selective Inhibitor of Human α-1,3- Fucosyltransferase via Click Chemistry. J. Am. Chem. Soc. 2003, 125 (32), 9588- 9589.

247. Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radić, Z.; Carlier, P. R.; Taylor, P.; Finn, M. G.; Sharpless, K. B., Click Chemistry In Situ: Acetylcholinesterase as a Reaction Vessel for the Selective Assembly of a Femtomolar Inhibitor from an Array of Building Blocks. Angew. Chem. Int. Ed. 2002, 41 (6), 1053-1057.

106

248. Mocharla, V. P.; Colasson, B.; Lee, L. V.; Röper, S.; Sharpless, K. B.; Wong, C.- H.; Kolb, H. C., In Situ Click Chemistry: Enzyme-Generated Inhibitors of Carbonic Anhydrase II. Angew. Chem. Int. Ed. 2005, 44 (1), 116-120.

249. Brik, A.; Muldoon, J.; Lin, Y.-C.; Elder, J. H.; Goodsell, D. S.; Olson, A. J.; Fokin, V. V.; Sharpless, K. B.; Wong, C.-H., Rapid Diversity-Oriented Synthesis in Microtiter Plates for In Situ Screening of HIV Protease Inhibitors. ChemBioChem 2003, 4 (11), 1246-1248.

250. Golas, P. L.; Matyjaszewski, K., Click Chemistry and ATRP: A Beneficial Union for the Preparation of Functional Materials. QSAR Comb. Sci. 2007, 26 (11-12), 1116-1134.

251. Golas, P. L.; Matyjaszewski, K., Marrying Click Chemistry with Polymerization: Expanding the Scope of Polymeric Materials. Chem. Soc. Rev. 2010, 39 (4), 1338- 1354.

252. Tsarevsky, N. V.; Bernaerts, K. V.; Dufour, B.; Du Prez, F. E.; Matyjaszewski, K., Well-Defined (Co)polymers with 5-Vinyltetrazole Units via Combination of Atom Transfer Radical (Co)polymerization of Acrylonitrile and "Click Chemistry"-Type Postpolymerization Modification. Macromolecules 2004, 37 (25), 9308-9313.

253. Tsarevsky, N. V.; Sumerlin, B. S.; Matyjaszewski, K., Step-Growth "Click" Coupling of Telechelic Polymers Prepared by Atom Transfer Radical Polymerization. Macromolecules 2005, 38 (9), 3558-3561.

254. Kamigaito, M.; Ando, T.; Sawamoto, M., Metal-Catalyzed Living Radical Polymerization. Chem. Rev. 2001, 101 (12), 3689-3746.

255. Tsarevsky, N. V.; Matyjaszewski, K., "Green" Atom Transfer Radical Polymerization: From Process Design to Preparation of Well-Defined Environmentally Friendly Polymeric Materials. Chem. Rev. 2007, 107 (6), 2270- 2299.

256. Hawker, C. J.; Bosman, A. W.; Harth, E., New Polymer Synthesis by Nitroxide Mediated Living Radical Polymerizations. Chem. Rev. 2001, 101 (12), 3661- 3688.

107

257. Moad, G.; Chiefari, J.; Chong, Y. K.; Krstina, J.; Mayadunne, R. T. A.; Postma, A.; Rizzardo, E.; Thang, S. H., Living Free Radical Polymerization with Reversible Addition – Fragmentation Chain tTansfer (the Life of RAFT). Polym. Int. 2000, 49 (9), 993-1001.

258. Rizzardo, E.; Chiefari, J.; Mayadunne, R.; Moad, G.; Thang, S., Tailored Polymer Architectures by Reversible Addition-Fragmentation Chain Transfer. Macromol. Symp. 2001, 174 (1), 209-212.

259. Opsteen, J. A.; van Hest, J. C. M., Modular Synthesis of Block Copolymers via Cycloaddition of Terminal Azide and Alkyne Functionalized Polymers. Chem. Commun. 2005, (1), 57-59.

260. Durmaz, H.; Dag, A.; Altintas, O.; Erdogan, T.; Hizal, G.; Tunca, U., One-Pot Synthesis of ABC Type Triblock Copolymers via in situ Click [3 + 2] and Diels- Alder [4 + 2] Reactions. Macromolecules 2006, 40 (2), 191-198.

261. Kyeremateng, S. O.; Amado, E.; Blume, A.; Kressler, J., Synthesis of ABC and CABAC Triphilic Block Copolymers by ATRP Combined with ‗Click‘ Chemistry. Macromol. Rapid Commun. 2008, 29 (12-13), 1140-1146.

262. Wang, W.; Li, T.; Yu, T.; Zhu, F., Synthesis of Multiblock Copolymers by Coupling Reaction Based on Self-Assembly and Click Chemistry. Macromolecules 2008, 41 (24), 9750-9754.

263. Grieshaber, S. E.; Farran, A. J. E.; Lin-Gibson, S.; Kiick, K. L.; Jia, X., Synthesis and Characterization of Elastin-Mimetic Hybrid Polymers with Multiblock, Alternating Molecular Architecture and Elastomeric Properties. Macromolecules 2009, 42 (7), 2532-2541.

264. Jiang, X.; Zhang, G.; Narain, R.; Liu, S., Fabrication of Two Types of Shell- Cross-Linked Micelles with "Inverted" Structures in Aqueous Solution from Schizophrenic Water-Soluble ABC Triblock Copolymer via Click Chemistry. Langmuir 2009, 25 (4), 2046-2054.

265. Yuan, W.; Li, X.; Gu, S.; Cao, A.; Ren, J., Amphiphilic Chitosan Graft Copolymer via Combination of ROP, ATRP and Click Chemistry: Synthesis, Self-Assembly, Thermosensitivity, Fluorescence, and Controlled Drug Release. Polymer 2011, 52 (3), 658-666.

108

266. Gao, H.; Matyjaszewski, K., Synthesis of Star Polymers by a Combination of ATRP and the "Click"Coupling Method. Macromolecules 2006, 39 (15), 4960- 4965.

267. Gao, H.; Matyjaszewski, K., Synthesis of 3-Arm Star Block Copolymers by Combination of ‗‗Core-First‘‘ and ‗‗Coupling-Onto‘‘ Methods Using ATRP and Click Reactions. J. Am. Chem. Soc. 2007, 129 (20), 6633-6639.

268. Altintas, O.; Yankul, B.; Hizal, G.; Tunca, U., One-Pot Preparation of 3- Miktoarm Star Terpolymers via Click [3 + 2] Reaction. J. Polym. Sci A: Polym. Chem 2007, 45 (16), 3588-3598.

269. Deng, G.; Ma, D.; Xu, Z., Synthesis of ABC-type Miktoarm Star Polymers by "Click" Chemistry, ATRP and ROP. Eur. Polym. J. 2007, 43 (4), 1179-1187.

270. Whittaker, M. R.; Urbani, C. N.; Monteiro, M. J., Synthesis of 3-Miktoarm Stars and 1st Generation Mikto Dendritic Copolymers by "Living" Radical Polymerization and "Click" Chemistry. J. Am. Chem. Soc. 2006, 128 (35), 11360- 11361.

271. Liu, H.; Li, C.; Liu, H.; Liu, S., pH-Responsive Supramolecular Self-Assembly of Well-Defined Zwitterionic ABC Miktoarm Star Terpolymers. Langmuir 2009, 25 (8), 4724-4734.

272. Zhang, Y.; Li, C.; Liu, S., One-Pot Synthesis of ABC Miktoarm Star Terpolymers by Coupling ATRP, ROP, and Click Chemistry Techniques. J. Polym. Sci A: Polym. Chem 2009, 47 (12), 3066-3077.

273. Li, C.; Ge, Z.; Liu, H.; Liu, S., Synthesis of Amphiphilic and Thermoresponsive ABC Miktoarm Star Terpolymer via a Combination of Consecutive Click Reactions and Atom Transfer Radical Polymerization. J. Polym. Sci A: Polym. Chem 2009, 47 (16), 4001-4013.

274. Zhang, Y.; Liu, H.; Hu, J.; Li, C.; Liu, S., Synthesis and Aggregation Behavior of Multi-Responsive Double Hydrophilic ABC Miktoarm Star Terpolymer. Macromol. Rapid Commun. 2009, 30 (11), 941-947.

275. Tsarevsky, N. V.; Bencherif, S. A.; Matyjaszewski, K., Graft Copolymers by a Combination of ATRP and Two Different Consecutive Click Reactions. Macromolecules 2007, 40 (13), 4439-4445.

109

276. Li, C.; Ge, Z.; Fang, J.; Liu, S., Synthesis and Self-Assembly of Coil-Rod Double Hydrophilic Diblock Copolymer with Dually Responsive Asymmetric Centipede- Shaped Polymer Brush as the Rod Segment. Macromolecules 2009, 42 (8), 2916- 2924.

277. Gao, H.; Matyjaszewski, K., Synthesis of Molecular Brushes by ―Grafting onto‖ Method: Combination of ATRP and Click Reactions. J. Am. Chem. Soc. 2007, 129 (20), 6633-6639.

278. Urbani, C. N.; Lonsdale, D. E.; Bell, C. A.; Whittaker, M. R.; Monteiro, M. J., Divergent synthesis and self-assembly of amphiphilic polymeric dendrons with selective degradable linkages. J. Polym. Sci A: Polym. Chem 2008, 46 (5), 1533- 1547.

279. Xu, L. Q.; Yao, F.; Fu, G. D.; Kang, E. T., Interpenetrating Network Hydrogels via Simultaneous "Click Chemistry" and Atom Transfer Radical Polymerization. Biomacromolecules 2010, 11 (7), 1810-1817.

280. Pan, T.-T.; He, W.-D.; Li, L.-Y.; Jiang, W.-X.; He, C.; Tao, J., Dual Thermo- and pH-Sensitive Network-Grafted Hydrogels Formed by Macrocrosslinker as Drug Delivery System. J. Polym. Sci A: Polym. Chem 2011, 49 (10), 2155-2164.

281. Li, H.; Cheng, F.; Duft, A. M.; Adronov, A., Functionalization of Single-Walled Carbon Nanotubes with Well-Defined Polystyrene by "Click" Coupling. J. Am. Chem. Soc. 2005, 127 (41), 14518-14524.

282. Chen, X.; McRae, S.; Parelkar, S.; Emrick, T., Polymeric Phosphorylcholine- Camptothecin Conjugates Prepared by Controlled Free Radical Polymerization and Click Chemistry. Bioconjugate Chem. 2009, 20 (12), 2331-2341.

283. Agut, W.; Taton, D.; Lecommandoux, S. b., A Versatile Synthetic Approach to Polypeptide Based Rod-Coil Block Copolymers by Click Chemistry. Macromolecules 2007, 40 (16), 5653-5661.

284. Gupta, S. S.; Raja, K. S.; Kaltgrad, E.; Strable, E.; Finn, M. G., Virus- Glycopolymer Conjugates by Copper(I) Catalysis of Atom Transfer Radical Polymerization and Azide-Alkyne Cycloaddition. Chem. Commun. 2005, (34), 4315-4317.

110

285. Ladmiral, V.; Mantovani, G.; Clarkson, G. J.; Cauet, S.; Irwin, J. L.; Haddleton, D. M., Synthesis of Neoglycopolymers by a Combination of ―Click Chemistry‖ and Living Radical Polymerization. J. Am. Chem. Soc. 2006, 128 (14), 4823- 4830.

286. Wan, X.; Liu, T.; Liu, S., Synthesis of Amphiphilic Tadpole-Shaped Linear- Cyclic Diblock Copolymers via Ring-Opening Polymerization Directly Initiating from Cyclic Precursors and Their Application as Drug Nanocarriers. Biomacromolecules 2011, 12 (4), 1146-1154.

287. Laurent, B. A.; Grayson, S. M., An Efficient Route to Well-Defined Macrocyclic Polymers via Click Cyclization. J. Am. Chem. Soc. 2006, 128 (13), 4238-4239.

288. Xu, J.; Ye, J.; Liu, S., Synthesis of Well-Defined Cyclic Poly(N- isopropylacrylamide) via Click Chemistry and Its Unique Thermal Phase Transition Behavior. Macromolecules 2007, 40 (25), 9103-9110.

289. Opsteen, J. A.; van Hest, J. C. M., Modular Synthesis of ABC Type Block Copolymers by ―Click‖ Chemistry. J. Polym. Sci A: Polym. Chem 2007, 45 (14), 2913-2924.

290. Van Camp, W.; Germonpre, V.; Mespouille, L.; Dubois, P.; Goethals, E. J.; Du Prez, F. E., New Poly(acrylic acid) Containing Segmented Copolymer Structures by Combination of "Click" Chemistry and Atom Transfer Radical Polymerization. React. Func. Polym. 2007, 67 (11), 1168-1180.

291. Huang, C.-J.; Chang, F.-C., Using Click Chemistry To Fabricate Ultrathin Thermoresponsive Microcapsules through Direct Covalent Layer-by-Layer Assembly. Macromolecules 2009, 42 (14), 5155-5166.

292. Mantovani, G.; Ladmiral, V.; Tao, L.; Haddleton, D. M., One-Pot Tandem Lving Radical Polymerisation-Huisgens Cycloaddition Process ("Click") Catalysed by N-alkyl-2-pyridylmethanimine/Cu(I)Br Complexes. Chem. Commun. 2005, (16), 2089-2091.

293. Topham, P. D.; Sandon, N.; Read, E. S.; Madsen, J.; Ryan, A. J.; Armes, S. P., Facile Synthesis of Well-Defined Hydrophilic Methacrylic Macromonomers Using ATRP and Click Chemistry. Macromolecules 2008, 41 (24), 9542-9547.

111

294. Mespouille, L.; Vachaudez, M.; Suriano, F.; Gerbaux, P.; Coulembier, O.; Degee, P.; Flammang, R.; Dubois, R., One-Pot Synthesis of Well-Defined Amphiphilic and Adoptive Block copolymers. Macromol. Rapid Commun. 2007, 28, 2151- 2158.

295. Geng, J.; Lindqvist, J.; Mantovani, G.; Haddleton, D. M., Simultaneous Copper(I)-Catalyzed Azide–Alkyne Cycloaddition (CuAAC) and Living Radical Polymerization. Angew. Chem. Int. Ed. 2008, 47 (22), 4180-4183.

296. Damiron, D.; Desorme, M.; Ostaci, R.-V.; Al Akhrass, S.; Hamaide, T.; Drockenmuller, E., Functionalized Random Copolymers from Versatile One-Pot Click Chemistry/ATRP Tandems Approaches. J. Polym. Sci A: Polym. Chem 2009, 47 (15), 3803-3813.

297. Grignard, B.; Calberg, C.; Jerome, C.; Detrembleur, C., "One-Pot" Dispersion ATRP and Alkyne-Azide Huisgen's 1,3-DipolarCycloaddition in Supercritical Carbon Dioxide: Towards the Formation of Functional Microspheres. J. Supercrit. Fluids 2010, 53 (1-3), 151-155.

298. Ricardo, C. L.; Pintauer, T., One-Pot Sequential Azide–Alkyne [3+2] Cycloaddition and Atom Transfer Radical Addition (ATRA): Expanding the Scope of In Situ Copper(I) Regeneration in the Presence of Environmentally Benign Reducing Agent. Eur. J. Inorg. Chem. 2011, (8), 1292-1301.

299. Reichelt, A.; Martin, S. F., Synthesis and Properties of Cyclopropane-Derived Peptidomimetics. Acc. Chem. Res. 2006, 39 (7), 433-442.

300. Salaun, J.; Baird, M. S., Biologically-active cyclopropanes and cyclopropenes. Curr. Med. Chem. 1995, 2 (1), 511-542.

301. Salaun, J., Optically Active Cyclopropanes. Chem. Rev. 1989, 89 (5), 1247-1270.

302. Simmons, H. E.; Cairns, T. L.; Vladuchick, S. A.; Hoiness, C. M., Cyclopropanes from Unsaturated Compounds, Methylene Iodide, and Zinc-Copper Couple. In Organic Reactions, John Wiley & Sons, Inc.: 2004.

303. Li, A.-H.; Dai, L.-X.; Aggarwal, V. K., Asymmetric Ylide Reactions: Epoxidation, Cyclopropanation, Aziridination, Olefination, and Rearrangement. Chem. Rev. 1997, 97 (6), 2341-2372.

112

304. Tang, Y.; Ye, S.; Sun, X.-L., Telluronium and Sulfonium Ylides for Organic Transformation. Synlett 2005, 2005 (EFirst), 2720-2730.

305. Sun, X.-L.; Tang, Y., Ylide-Initiated Michael Addition-Cyclization Reactions beyond Cyclopropanes. Accounts of Chemical Research 2008, 41 (8), 937-948.

306. Drury, C., Reactions of Conjugated Haloenoates with Nucleophilic Reagents. Tetrahedron 2001, 57 (14), 2643-2684.

307. Doyle, M. P., Catalytic Methods for Metal Carbene Transformations. Chem. Rev. 1986, 86 (5), 919-939.

308. Diaz-Requejo, M. M.; Perez, P. J., Copper, Silver and Gold-Based Catalysts for Carbene Addition or Insertion Reactions. J. Organomet. Chem. 2005, 690 (24- 25), 5441-5450.

309. Silberrad, O.; Roy, C. S., XXIV.-Gradual Decomposition of Ethyl Diazoacetate. J. Chem. Soc. Trans 1906, 89, 179-182.

310. Nozaki, H.; Moriuti, S.; Takaya, H.; Noyori, R., Asymmetric Induction in Carbenoid Reaction by Means of a Dissymmetric Copper Chelate. Tetrahedron Lett. 1966, 7 (43), 5239-5244.

311. Aratani, T.; Yoneyoshi, Y.; Nagase, T., Asymmetric Synthesis of Chrysanthemic Acid. An application of Copper Carbenoid Reaction. Tetrahedron Lett. 1977, 18 (30), 2599-2602.

312. Aratani, T., Catalytic Asymmetric Synthesis of Cyclopropanecarboxylic Acids: An Application of Chiral Copper Carbenoid Reaction. Pure Appl. Chem. 1985, 57 (12), 1839-1844.

313. Nozaki, H.; Takaya, H.; Moriuti, S.; Noyori, R., Homogeneous Catalysis in the Decomposition of Diazo Compounds by Copper Chelates : Asymmetric Carbenoid Reactions. Tetrahedron 1968, 24 (9), 3655-3669.

314. Moser, W. R., Mechanism of the Copper-Catalyzed Addition of Diazoalkanes to Olefins. I. Steric Effects. J. Am. Chem. Soc. 1969, 91 (5), 1135-1140.

113

315. Salomon, R. G.; Kochi, J. K., Copper(I) Catalysis in Cyclopropanations with Diazo Compounds. Role of Olefin Coordination. J. Am. Chem. Soc. 1973, 95 (10), 3300-3310.

316. Crabtree, R. H., Physical Methods in Organometallic Chemistry. In The Organometallic Chemistry of the Transition Metals, 4 ed.; John Wiley & Sons Inc.: Hoboken, NJ, 2005; pp 275-296.

317. Straub, B. F.; Gruber, I.; Rominger, F.; Hofmann, P., Mechanism of Copper(I)- Catalyzed Cyclopropanation: A DFT Study Calibrated with Copper(I) Alkene Complexes. J. Organomet. Chem. 2003, 684 (1-2), 124-143.

318. Diaz-Requejo, M. M.; Perez, P. J.; Brookhart, M.; Templeton, J. L., Substituent Effects on the Reaction Rates of Copper-Catalyzed Cyclopropanation and Aziridination of para-Substituted Styrenes. Organometallics 1997, 16 (20), 4399- 4402.

319. Diaz-Requejo, M. M.; Belderrain, T. R.; Nicasio, M. C.; Prieto, F.; Perez, P. J., Kinetics of the BpCu-Catalyzed Carbene Transfer Reaction (Bp = Dihydridobis(1-pyrazolyl)borate). Is a 14-Electron Species the Real Catalyst for the General Copper-Mediated Olefin Cyclopropanation? Organometallics 1999, 18 (14), 2601-2609.

320. Rasmussen, T.; Jensen, J. F.; Ostergaard, N.; Tanner, D.; Ziegler, T.; Norrby, P.- O., On the Mechanism of the Copper-Catalyzed Cyclopropanation Reaction. Chem. Eur. J. 2002, 8 (1), 177-184.

321. Diaz-Requejo, M. M.; Nicasio, M. C.; Perez, P. J., BpCu-Catalyzed Cyclopropanation of Olefins: (A Simple System That Operates under Homogeneous and Heterogeneous Conditions (Bp = Dihydridobis(pyrazolyl)borate). Organometallics 1998, 17 (14), 3051-3057.

322. Fraile, J. M.; Garcia, J. I.; Martinez-Merino, V.; Mayoral, J. A.; Salvatella, L., Theoretical (DFT) Insights into the Mechanism of Copper-Catalyzed Cyclopropanation Reactions. Implications for Enantioselective Catalysis. J. Am. Chem. Soc. 2001, 123 (31), 7616-7625.

323. Straub, B. F.; Hofmann, P., Copper(I) Carbenes: The Synthesis of Active Intermediates in Copper-Catalyzed Cyclopropanation. Angew. Chem. Int. Ed. 2001, 113 (7), 1328-1330.

114

324. Perez, P. J.; Brookhart, M.; Templeton, J. L., A Copper(I) Catalyst for Carbene and Nitrene Transfer to Form Cyclopropanes, Cyclopropenes, and Aziridines. Organometallics 1993, 12 (2), 261-262.

325. Evans, D. A.; Woerpel, K. A.; Hinman, M.; Faul, M. M., Bis(oxazolines) as Chiral Ligands in Metal-Catalyzed Asymmetric Reactions. Catalytic, Asymmetric Cyclopropanation of Olefins. J. Am. Chem. Soc. 1991, 113 (2), 726-728.

326. Evans, D. A.; Woerpel, K. A.; Scott, M. J., ‗Bis(oxazolines)‘ as Ligands for Self- Assembling Chiral Coordination Polymers— Structure of a Copper(I) Catalyst for the Enantioselective Cyclopropanation of Olefins. Angew. Chem. Int. Ed. 1992, 31 (4), 430-432.

327. Doyle, M. P., Formation of Macrocyclic Lactones by Enantioselective Intramolecular Cyclopropanation of Diazoacetates Catalyzed by Chiral CuI and RhII Compounds. Angew. Chem. Int. Ed. 1996, 35 (12), 1334-1336.

328. Fraile, J. M.; GarcIa, J. I.; Mayoral, J. A.; Tarnai, T.; Harmer, M. A., Bis(oxazoline)-Copper Complexes, Supported by Electrostatic Interactions, as Heterogeneous Catalysts for Enantioselective Cyclopropanation Reactions: Influence of the Anionic Support. Journal of Catalysis 1999, 186 (1), 214-221.

329. Fraile, J. M.; García, J. I.; Gil, M. J.; Martínez-Merino, V.; Mayoral, J. A.; Salvatella, L., Theoretical Insights into the Role of a Counterion in Copper- Catalyzed Enantioselective Cyclopropanation Reactions. Chem. Eur. J. 2004, 10 (3), 758-765.

330. Doyle, M. P.; Griffin, J. H.; Bagheri, V.; Dorow, R. L., Correlations Between Catalytic Reactions of Diazo Compounds and Stoichiometric Reactions of Transition-Metal Carbenes with Alkenes. Mechanism of the Cyclopropanation Reaction. Organometallics 1984, 3 (1), 53-61.

331. Fritschi, H.; Leutenegger, U.; Pfaltz, A., Semicorrin Metal Complexes as Enantioselective Catalysts. Part 2. Enantioselective Cyclopropane Formation From Olefins with Diazo Compounds Catalyzed by Chiral (Semicorrinato)copper Complexes. Helv. Chim. Acta 1988, 71 (6), 1553–1565.

332. Aratani, T.; Yoneyoshi, Y.; Nagase, T., Asymmetric Synthesis of Chrysanthemic Acid. An application of Copper Carbenoid Reaction. Tetrahedron Lett. 1975, 16 (21), 1707-1710.

115

333. Aratani, T.; Yoneyoshi, Y.; Nagase, T., Asymmetric Synthesis of Permethric Acid. Stereochemistry of Chiral Copper Carbenoid Reaction. Tetrahedron Lett. 1982, 23 (6), 685-688.

334. Pfaltz, A., Chiral Semicorrins and Related Nitrogen Heterocycles as Ligands in Asymmetric Catalysis. Acc. Chem. Res. 1993, 26 (6), 339-345.

335. Leutenegger, U.; Umbricht, G.; Fahrni, C.; von Matt, P.; Pfaltz, A., 5-Aza- semicorrins: A New Class of Bidentate Nitrogen Ligands for Enantioselective Catalysis. Tetrahedron 1992, 48 (11), 2143-2156.

336. Lowenthal, R. E.; Abiko, A.; Masamune, S., Asymmetric Catalytic Cyclopropanation of Olefins: Bis-oxazoline Copper Complexes. Tetrahedron Lett. 1990, 31 (42), 6005-6008.

337. Muller, D.; Umbricht, G.; Weber, B.; Pfaltz, A., C2-Symmetric 4,4′,5,5′- Tetrahydrobi(oxazoles) and 4,4′,5,5′-Tetrahydro-2,2′-methylenebis[oxazoles] as Chiral Ligands for Enantioselective Catalysis Preliminary Communication. Helv. Chim. Acta 1991, 74 (1), 232-240.

338. Lotscher, D.; Rupprecht, S.; Stoeckli-Evans, H.; von Zelewsky, A., Enantioselective Catalytic Cyclopropanation of Styrenes by Copper Complexes with Chiral Pinene-[5,6]-Bipyridine Ligands. Tetrahedron: Asym. 2000, 11 (21), 4341-4357.

339. Malkov, A. V.; Baxendale, I. R.; Bella, M.; Langer, V.; Fawcett, J.; Russell, D. R.; Mansfield, D. J.; Valko, M.; Kocovsky, P., Synthesis of New Chiral 2,2'- Bipyridyl-Type Ligands, Their Coordination to Molybdenum(0), Copper(II), and Palladium(II), and Application in Asymmetric Allylic Substitution, Allylic Oxidation, and Cyclopropanation. Organometallics 2001, 20 (4), 673-690.

340. Kwong, H.-L.; Lee, W.-S.; Ng, H.-F.; Chiu, W.-H.; Wong, W.-T., Chiral Bipyridine-Copper(II) Complex. Crystal Structure and Catalytic Activity in Asymmetric Cyclopropanation. Dalton Trans. 1998, (6), 1043-1046.

341. Wong, H. L.; Tian, Y.; Chan, K. S., Electronically Controlled Asymmetric Cyclopropanation Catalyzed by a New Type of Chiral 2,2'-Bipyridine. Tetrahedron Lett. 2000, 41 (40), 7723-7726.

116

342. Kanemasa, S.; Hamura, S.; Harada, E.; Yamamoto, H., C2-Symmetric 1,2- Diamine/Copper(II) Trifluoromethanesulfonate Complexes as Chiral Catalysts. Asymmetric Cyclopropanations of Styrene with Diazo Esters. Tetrahedron Lett. 1994, 35 (43), 7985-7988.

343. Tanner, D.; Andersson, P. G.; Harden, A.; Somfai, P., C2-Symmetric Bis(aziridines): A New Class of Chiral Ligands for Transition Metal-Mediated Asymmetric Synthesis. Tetrahedron Lett. 1994, 35 (26), 4631-4634.

344. Diaz-Requejo, M. M.; Belderrain, T. R.; Nicasio, M. C.; Perez, P. J., From Homogeneous to Heterogeneous Catalysis: Novel Anchoring of Polypyrazolylborate Copper(I) Complexes on Silica Gel through Classical and Nonclassical Hydrogen Bonds. Use as Catalysts of the Olefin Cyclopropanation Reaction. Organometallics 2000, 19 (3), 285-289.

345. Christenson, D. L.; Tokar, C. J.; Tolman, W. B., New Copper and Rhodium Cyclopropanation Catalysts Supported by Chiral Bis(pyrazolyl)pyridines. A Metal-Dependent Enantioselectivity Switch. Organometallics 1995, 14 (5), 2148- 2150.

346. Lowenthal, R. E.; Masamune, S., Asymmetric Copper-Catalyzed Cyclopropanation of Trisubstituted and Unsymmetrical Cis-1,2-Disubstituted Olefins: Modified Bis-oxazoline Ligands. Tetrahedron Lett. 1991, 32 (50), 7373- 7376.

347. Corey, E. J.; Myers, A. G., Efficient Synthesis and Intramolecular Cyclopropanation of Unsaturated Diazoacetic Esters. Tetrahedron Lett. 1984, 25 (33), 3559-3562.

348. Ito, K.; Tabuchi, S.; Katsuki, T., Synthesis of New Chiral Bipyridine Ligands and Their Application to Asymmetric Cyclopropanation. Synlett 1992, 1992 (7), 575- 576.

349. Ito, K.; Katsuki, T., Asymmetric Cyclopropanation of E-Olefins Using a Copper Complex of an Optically Active Bipyridine as a Catalyst. Synlett 1993, 1993 (9), 638-640.

350. Ito, K.; Katsuki, T., Catalytic Asymmetric Cyclopropanation Using Copper Complex of Optically Active Bipyridine as a Catalyst. Tetrahedron Lett. 1993, 34 (16), 2661-2664.

117

351. Chelucci, G.; Gladiali, S.; Sanna, M. G.; Brunner, H., Chiral Ligands with Pyridine Donors in Transition Metal Catalyzed Enantioselective Cyclopropanation and Hydrosilylation Reactions. Tetrahedron: Asym. 2000, 11 (16), 3419-3426.

352. Kwong, H.-L.; Lee, W.-S., First Enantioselective Catalyst Based on a Chiral Terpyridine: Synthesis of New C2-symmetric 2,2':6',2''-Terpyridine Ligands and Copper-Catalyzed Enantioselective Cyclopropanation of Alkenes. Tetrahedron: Asym 2000, 11 (11), 2299-2308.

353. Brunner, H.; Singh, U. P.; Boeck, T.; Altmann, S.; Scheck, T.; Wrackmeyer, B., Asymmetric Catalysis : LXXX. An Optically-Active Tetrakispyrazolylborate: Synthesis and Use in Cu-Catalysed Enantioselective Cyclopropanation. J. Organomet. Chem. 1993, 443 (1), C16-C18.

118

Chapter 2

Copper-Catalyzed Atom Transfer Radical Cascade Reactions in the Presence of Diazo Radical Initiators as Reducing Agents

Reproduced in part with permission from Ricardo, C., Pintauer, T. J. Chem. Soc. Chem. Commun. 2009, 21, 3029-303. Royal Society of Chemistry

2.1 Introduction

The formation of carbon-carbon bonds using atom transfer radical addition

(ATRA) is becoming an increasingly popular synthetic tool.1-3 Transition metal complexes of Cu, Ru, Fe, and Ni are typically used as catalysts for such transformations.1,4-6 Copper-catalyzed ATRA and ATRC reactions have been utilized in cascade or sequential additions in the synthesis of natural products and pharmaceutical drugs (Scheme 2.1).7 These strategies are becoming increasingly popular because they allow the formation of several bonds in one sequence without the isolation of the intermediates, changes in the reaction conditions or the addition of external reagents and catalysts.8,9

Until recently, the major drawback of this useful synthetic method remained the large amount of catalyst required to achieve high selectivity towards the desired target compound (as high as 30 mol% relative to alkene).1 This obstacle caused serious problems in product separation and catalyst regeneration, making the process

119

environmentally unfriendly and expensive. Originally, the solution to this problem was found for copper catalyzed atom transfer radical polymerization (ATRP)1,10-13 and was

R R N O N Cl CCl3 I O Cu Cl Cl N N TMEDA Cl

1 2 (40%)

R R O N O N Cl Cl Cl Cl N N

B A Scheme 2.1 Example of copper-Catalyzed Atom Transfer Radical Cascade Reaction.

subsequently applied first to ruthenium14 and then copper15,16 catalyzed ATRA reactions. In all of these processes, the activator (transition metal complex in the lower oxidation state) is continuously regenerated from the deactivator (transition metal complex in the higher oxidation state) in the presence of reducing agents such as phenols, glucose, ascorbic acid, hydrazine, tin(II) 2-ethylhexanoate, magnesium, and free radical diazo initiators (Scheme 2.2).1 Such regeneration compensates for unavoidable radical- radical coupling reactions, enabling a significant reduction in the amount of metal catalyst needed. When applied to the ATRA of CCl4 to alkenes catalyzed by

* III Cp Ru Cl2(PPh3) complex in the presence of AIBN, turnover numbers (TONs) as high

120

as 44500 were obtained.14 Even more impressive TONs (as high as 160000) were

II achieved with CBr4 and [Cu (TPMA)Br][Br] (TPMA=tris(2-pyridylmethyl)amine) complex, enabling efficient ATRA reactions in the presence of as little as 5 ppm of copper.16 Previous TONs for copper catalyzed ATRA ranged between 0.1 and 10. Since the seminal reports by our,15 and the research group of Severin,14 this method of catalyst regeneration in ATRA has attracted considerable academic interest,1,17-24 and was successfully applied to intramolecular ATRA or atom transfer radical cyclization (ATRC) reactions.23-25 The principal advantages of this methodology for catalyst regeneration in

ATRC are two fold. On one hand, the presence of reducing agents enables a significant reduction in the amount of metal catalyst. Such reduction is very beneficial because it increases the radical annulation efficiency by decreasing the rate of radical trapping by the deactivator, compared to the rate of radical ring closure. On the other hand, the rate constant of deactivation can be further controlled through ligand design.

121

Scheme 2.2. Transition Metal Catalyzed Atom Transfer Radical Addition in the Presence of Reducing Agents.

Catalyst regeneration in the presence of reducing agents has transformed Cu and

Ru catalyzed ATRC reactions into more synthetically useful and ―greener‖ processes. In order to broaden the scope of this technique, its further application in intermolecular

ATRA followed by sequential ATRC to ,-dienes is very appealing. It is expected that the addition of the polyhalogenated methane to one of the C=C bonds would result in the formation of alkenyl radical, which undergoes radical ring closure to generate a cyclic radical and finally trapped via halogen transfer. In this chapter, the addition of polyhalogenated methanes to symmetrical 1,5-dienes and 1,6-dienes catalyzed by a copper(II) complex with a tris(2-pyridylmethyl)amine ligand in the presence of free- radical diazo initiators such as 2,2′-azobis(2-methylpropionitrile) and 2,2'- azobis(4- methoxy-2,4-dimethyl valeronitrile (AIBN and V-70) will be discussed.

122

2.2 Atom Transfer Radical Addition to 1,5-Hexadiene

Scheme 2.3 shows that in the ATRA of CBr4 and CCl4 to 1,5-hexadiene, several products were formed, which included the monoaddduct (A), double addition product (D)

6-membered (B) and 5-membered (C) halogen functionalized rings. The formation of these compounds has been confirmed via spectroscopic methods such as 1H NMR, 1H

COSY, 13C NMR and 13C DEPT (see spectra in Appendix A) and gas chromatography after product separation. These results prompted us to vary the catalyst concentration and temperature in the addition of CCl4 to 1,5-hexadiene in order to achieve the formation of the desired product. CCl4 as the alkyl halide was chosen since the addition of CBr4 to 1,5- hexadiene proceeded efficiently with high 1,5-hexadiene conversion in the presence of

AIBN only.

CX3 X A

X X X

X CulI/TPMA B + CX4 AIBN, 

X = Cl, Br CX3

X C

X3C CX3 X D

Scheme 2.3. Observed Products in the Addition of Polyhalogenated Methanes to 1,5- Hexadiene.

123

II Two sets of reactions, each with varied [1,5-diene]0 to [Cu ]0 ratios ranging from

100: 1 to 5000:1 and constant amount of AIBN (10 mol% relative to the diene) were

o o carried out at 60 C and 80 C. ATRA of CCl4 to 1,5-hexadiene resulted in very low conversion in the presence of AIBN only for both reaction temperatures. In the presence of CuII complex, negligible difference in conversion was observed whether the reaction was conducted at 60 0C or 80 0C (Table 2.1). However, varied catalyst loadings gave an impact on the conversion of 1,5-hexadiene. Taking into account the product distribution, it is apparent that reactions carried out at 60 oC resulted in lower percent composition of

A, when compared to those carried out at 80 oC (Table 2.1). The cyclic compounds, B and C, however, seemed to be present in higher percentages for reactions having of 0.5 to

1 mol% of [CuII(TPMA)Cl][Cl] when carried out at 60 oC.

II Table 2.1. [Cu (TPMA)Cl][Cl] Mediated Addition of CCl4 to 1,5-Hexadiene in the Presence of AIBN. II [1,5-Diene]0:[Cu ]0 Temperature % % Product Distribution (0C) Conversion A B C D blank 60 18 100 0 0 0 80 7 100 0 0 0 100:1 60 84 0 45 37 18 80 80 3 44 35 18 250:1 60 83 0 47 39 14 80 77 11 33 29 24 500:1 60 82 9 34 29 26 80 76 35 20 19 23 2000:1 60 79 54 3 4 33 80 70 82 0 0 18 5000:1 60 79 66 0 0 34 80 50 92 0 0 8 All reactions were performed in 1,2-DCE solvent at 60 0C for 48 h in the presence of 10 mol% of AIBN (relative to 1,5-Diene). [1,5-Diene]0 = 0.25 M. Product distribution was obtained via GC based on anisole as internal standard.

124

Formation of the functionalized cyclopentane (compound C) is rather surprising.

One possible mechanism for its formation is shown in Scheme 2.4 in which, the electrophilic radical that is formed after the first addition undergoes subsequent cyclization to form an endocyclic radical, which is then trapped by abstraction of the halogen from the copper(II) complex. However, according to Baldwin‘s ring closure of 4- pentenyl radical, 5-endocyclization is a disfavored process due to thermodynamic reasons.26 Alternatively, compound C could be formed from the reactivation of compound A. For this case, the internal -carbon is homolytically cleaved by the copper(I) complex, which subsequently undergoes ATRC in the endo- mode (Scheme

2.5).

CX3 X CX3 CX3

r1 r2 exo

CulI/TPMA

+ CX4 AIBN, 

CX CX 3 CX3 3 X X r2 endo r1

Scheme 2.4. Ring-closure Pathways of 5-Pentenyl Radical.

In addition to the 5-exocyclization, 5,7,7,7-tetrachloroheptene (A) can also be subsequently activated by CuII/TPMA in the presence of AIBN and undergo ATRC via the endo-mode, which affords the formation of 1,1,5-trichloro-2-

125

chloromethylcyclohexane (B) (Scheme 2.5). The 6-endo closure of 5,7,7,7- tetrachloroheptene (A) is similar to the previously reported cyclization behavior of 1,1,1- trichloro-6-heptene.27 In order to prove such claims, compound A was isolated and utilized for cyclization studies (Table 2.2).

Table 2.2. ATRC of Monoadduct A Catalyzed by [CuII(TPMA)Cl][Cl] and AIBN II [A]0:[Cu ]0 % Product Distribution % Yield Conversion [B]:[C] [B]:[C] 100:1a 95 57:43 54:41 500:1b 91 56:44 51:40 500:1c 96 53:47 52:45 1000:1b 66 55:45 36:30 1000:1c 39 56:44 22:17 All reactions were performed in 1,2-DCE solvent at 60 0C in the presence of 10 mol% of AIBN (relative to A). a[A] = 0.1 M, 24 h; b[A] = 0.25 M, 24 h; d[A] = 0.1 M, 48 h. Product distribution and yields were obtained via GC based on anisole as internal standard.

Scheme 2.5. Proposed Pathways for the Cyclization of Compound A Resulting in the Formation of Cyclic Products B and C.

Results confirmed that both cyclic products are formed as a result of the reactivation of the monoadduct followed by subsequent copper-catalyzed ATRC. While it

126

has been shown that Compound C is indeed formed from the reactivation of the monoadduct A, another surprising finding is the product distribution, which is 60:40 for products [B] and [C] regardless of any [CuII(TPMA)Cl][Cl] concentration. As shown in

Scheme 2.5, homolytic cleavage of the C-Cl bond occurs at the terminal carbon for the 6- exo and at the internal -Carbon for the 5-endo product. Comparing these radicals to dihloromethyl (dcm) and isopropyl (ipr) radicals (Figure 2.1); respectively, one would expect different reactivity and consequently, the yields. In previous study,28 calculated

o bond dissociation energy (BDE), bond dissociation enthalpy (H 298) and the equilibrium constant (KATRP), for dcm radical is higher compared to ipr. The equilibrium constant

6 (KATRP), which is 10 higher for the dcm radical suggests that ATRC via 6-endo mode would be way more selective, however, it was not manifested in the product distribution for B and C.

CCl2 CCl3 Cl

Cl Cl H3C CH3 dcm ipr

Figure 2.1. Resemblance of 7-Heptenyl and 5-Heptenyl Radicals to Dichloromethyl and Ispopropyl Radicals.

Perhaps, the best way to explain the regioselectivity of the cyclization of

Compound A as well as the product distribution of Compounds B and C is by taking into account the activation parameters. It has been revealed based on calculation that the 5- endocyclization of 4-pentenyl radical has an activation energy of Ea= 18.3 kcal/mol,29,30 while the preferred 6-exocyclization of 6-heptenyl radical is approximately Ea= 8

127

kcal/mol. On the assumption that the frequency factors are the same for both pathways,

31,32 then relative rate ratio of 6-exo- and 5-endo- ring closure (k6-exo/k5-endo) is 1.5.

Kinetic experiments were conducted for further verification. In one set of experiment, formation of 5-membered (C) and 6-membered (B) cyclic compounds was monitored starting from 1,5-hexadiene. Table 2.3 and Error! Reference source not found. show that the cyclic products were not observed until after 4 hours. This is acceptable since they are formed from the activation of the monoadduct. The product distributions of compounds B and C were observed to be 70:30 and 67:33 (after 4 and 5 h), afterwhich, an average ratio of 60:40 was obtained. In another experiment, monoadduct (compound A) was utilized as starting material (Table 2.4). Unlike with hexadiene, the cyclic products were formed after one hour, though lower yields were obtained (Table 2.4 and Error! Reference source not found.). However, as the reaction progressed, consumption of A increased giving products B and C with constant 60:40 product distribution. This is in good agreement with the ratio of the relative rates (k6- exo/k5-endo= 1.5).

Table 2.3. Kinetics of the Addition of CCl4 to 1,5-Hexadiene Catalyzed by [CuII(TPMA)Cl][Cl] and AIBN. Time (h) % Product Distribution (%) Conversion B:C 1 24 0:0 2 40 0:0 3 48 0:0 4 53 70:30 5 58 67:33 7 59 61:39 9 60 65:35 10 60 62:38 All reactions were performed in 1,2-DCE solvent at 60 0C catalyzed by 0.4 mol% [CuII(TPMA)Cl][Cl] and 10 mol% of AIBN (relative to 1,5-Diene). [1,5-

128

II Hexadiene]0:[[Cu (TPMA)Cl][Cl]]0:[AIBN]0 = 0.25:0.001:0.025. Percent conversion and product distribution were obtained via1H NMR based on p-dimethoxybenzene as the internal standard.

Table 2.4. Kinetics of the Atom Transfer Radical Cyclization of Monoadduct (A) Catalyzed by [CuII(TPMA)Cl][Cl] and AIBN. Time (h) % Product Distribution (%) Conversion of A B:C 1 14 59:41 2 31 59:41 3 45 59:41 4 55 55:45 5 65 56:44 All reactions were performed in 1,2-DCE solvent at 60 0C catalyzed by 0.5 mol% [CuII(TPMA)Cl][Cl] and 10 mol% of AIBN (relative to 1,5-Diene). [1,5- II Hexadiene]0:[CCl4]0:[[Cu (TPMA)Cl][Cl]]0:[AIBN]0 = 0.25:0.25:0.00125:0.025. Percent conversion and product distribution were obtained via GC based on anisole as the internal standard.

70 70 % B 67

% C 65

62 61 60

50 39

40 38

35 33 30 30

Product Distribution of B and C (%) C and B of Distribution Product 10

0 1 2 3 4 5 7 9 10 Time (h) Figure 2.2. Monitoring the Formation of Cyclic Products (B and C) at Timed Intervals in the Addition of Carbon Tetrachloride (CCl4) to 1,5-Hexadiene.

129

100 70

% Conversion % B % C

60 Distribution %Product 80 50

60 40

30 40

% Conversion % 20 20 10

0 0 1 2 3 4 5 Time (h) Figure 2.3. Monitoring Formation of Cyclic Products (B and C) as a Result of ATRC of Monoadduct (A) at Timed Intervals. 2.3 Atom Transfer Radical Cascade Reactions Involving 1,6-Dienes

As discussed in the previous section, the cyclic products that were formed from as a result of subsequent copper-catalyzed ATRC of the monoadduct. Such findings prompted us to screen other substrates that would satisfy the sequential ATRA/ATRC via cascade mechanism. Very recently, copper homoscorpionate complexes33 have been

34 utilized in the addition of CCl4 to 1,6-dienes to yield 1,2-disubstituted cyclopentanes.

Quantitative yields of the products were obtained using 1 mol % of the catalyst in the presence of Mg as a reducing agent.

1,6-Dienes are excellent candidates to further expand the methodology for catalyst regeneration originally developed for ATRA35,36 because the addition of radicals generated from alkyl halides results in the formation of 5-hexenyl radicals, which are

5 -1 known to undergo very fast and selective 5-exo-trig mode of cyclization (kexo-trig≈10 s ,

37 kexo-trig/kendo-trig≈100) (Scheme 2.6). Assuming that the rate constant of deactivation for

130

copper(II) complexes with highly active TPMA ligand in ATRA is on the order of 108 M-

1s-1,35,36,38 the rate of radical ring closure (resulting in 5-exo-trig cyclic product) will approach the rate of radical trapping (resulting in halogen terminated open chain monoadduct and diadduct) at copper(II) concentrations on the order of 1.010-3 M (0.1 mol% relative to diene when [diene]0=1.0 M). Therefore, in theory, the selective formation of 5-exo-trig cyclic product could be obtained using much lower copper(II) concentrations, provided that a reducing agent is present in the system. The reducing agent continuously regenerates copper(I) from the copper(II) complex, which accumulates in the system as a result of unavoidable radical-radical termination reactions

(Scheme 2.2).35,36

II Cu LmX2

kexo X R I Cu LmX R + RX 5-exo-trig

R II kendo Cu LmX2 X=Br-, Cl- R R X R=CCl , CBr CuIIL X 3 3 m 2 6-endo-trig

I X II X X X Cu LmX Cu LmX2

R R R R R monoadduct diadduct

Scheme 2.6. ATRC Pathways in the Addition of Polyhalogenated Compounds to 1,6- Hexadiene Catalyzed by Copper Complexes.

AIBN (2,2′-azobis(2-methylpropionitrile)) or V-70 (2,2'- azobis(4-methoxy-2,4- dimethyl valeronitrile)) initiated ATRA of CCl4 to 1,6-heptadiene in the absence of a

131

catalyst resulted in ~20% yield of the 5-exo-trig cyclic product. For all other dienes investigated, no cyclic products were observed. However, when [CuII(TPMA)Cl][Cl] complex was used in conjunction with the free-radical diazo initiator, truly remarkable results were obtained (Table 2.5). In the presence of AIBN at 60 oC, cyclic products derived from the addition of CCl4 to 1,6-heptadiene (entry 1), diallyl ether (entry 4) and

N,N-diallyl-2,2,2-trifluoroacetamide (entry 15) were synthesized in nearly quantitative yields using as low as 0.02 mol% of the catalyst (relative to diene). On the other hand, excellent results with tert-butyl-N,N-diallylcarbamate (entry 8) and diethyl diallylmalonate (entry 12) were also achieved using even smaller amounts of the catalyst

(0.01 mol%). These results indicate nearly a 100 times improvement in catalyst loading over the methodology that utilizes copper homoscorpionate complexes and Mg as the reducing agent.39

Table 2.5. ATRA of CCl4 to 1,6-dienes Followed by Sequential ATRC Catalyzed by [CuII(TPMA)Cl][Cl] in the Presence of Free-Radical Initiators as Reducing Agents.a o II b Entry 1,6-Diene Product T/ C Initiator [Diene]0:[Cu ]0 % Yield cis:trans 1 60 AIBN 5000:1 (0.02) 95(83)d 84:16

Cl 2 Cl3C 30 V-70 2500:1 (0.04) 92 85:15 3 RTc V-70 2500:1 (0.04) 87 86:14 4 O O 60 AIBN 2000:1 (0.05) 89(70)d 80:20

5 Cl C Cl 30 V-70 1000:1 (0.1) 91 79:21 3 6 RT V-70 1000:1 (0.1) 80 87:13 7 60 AIBN 5000:1 (0.02) 96 74:26 O O d 8 O O 60 AIBN 10000:1 (0.01) 91(75) 66:34 9 N N 30 V-70 5000:1 (0.02) 87 64:36

10 Cl C Cl RT V-70 5000:1 (0.02) 77 56:44 3 11 O O O O 60 AIBN 5000:1 (0.02) 100 86:14 12 O O O O 60 AIBN 10000:1 (0.01) 89(80)d 84:16

13 Cl C Cl 30 V-70 5000:1 (0.02) 90 91:9 3 14 RT V-70 5000:1 (0.02) 81 86:14

132

F3C F3C d 15 O O 60 AIBN 5000:1 (0.02) 90(77) 81:19 16 N N 60 AIBN 10000:1 (0.01) 73 84:16

17 Cl 30 V-70 1000:1 (0.1) 95 73:27 Cl3C 18 RT V-70 1000:1 (0.1) 87 73:27 a All reactions were performed in MeOH for 24 h with [CCl4]0:[Diene]0:[AIBN or V-70]0 = 1.25:1:0.05, :[Diene]0 = 1.0 M. The yield is based on the formation 5-exo-trig product (cis and trans) and was determined by 1H NMR using 1,4-dimethoxybenzene as internal standard (relative errors are 15%). bMol percent of catalyst relative to diene. cRT = 222 0C. dIsolated yield after column chromatography for the large scale reaction.

Additional experiments were performed using low temperature free-radical initiator V-70 as a reducing agent. In our previous report, V-70 enabled selective formation of the monoadduct in ATRA of polyhalogenated compounds to alkenes at ambient temperatures using as low as 0.002 mol% of the copper catalyst.40 For 1,6- heptadiene (entry 2), diallyl ether (entry 5), and N,N-diallyl-2,2,2-trifluoroacetamide

(entry 17), very high yields of the cyclic products were obtained at 30 oC when the catalyst concentration was 1.010-3 M (0.1 mol% relative to diene). Slightly lower yields were observed for reactions conducted at 22 oC (entries 3, 6 and 18) Such finding can be attributed to the slower rate of decomposition of the radical initiator at lower temperature, hence affecting reduction of the CuII to CuI species. Slower rate of reduction results in lower concentration of the catalytically active species, which homolytically cleaves the

C-Cl bond and consequently, incomplete 1,6-diene conversions. Furthermore, V-70 was a more effective reducing agent in atom transfer radical cascade reactions of CCl4 to tert- butyl-N,N-diallylcarbamate (entries 9 and 10) and diethyl diallylmalonate (entries 13 and

14), resulting in greater than 80% yield of the cyclic products when the

II [Cu (TPMA)Cl][Cl]0 to [diene]0 ratio was 1:5000 (0.02 mol%). Regardless of the choice of the 1,6-diene, reaction temperature or free-radical reducing agent, 1,2-disubstituted

133

cyclopentanes showed a strong preference for the formation of the cis-product. As presented in Table 2.5, the average cis:trans distributions are 85:15, 83:17, 70:30, 87:13 and 69:31 for 1,6-heptadiene (entries 1-3), diallyl ether (entries 4-6), tert-butyl N,N- diallyl carbamate (entries 7-10) diethyldiallylmalonate (entries 11-14) and N,N-diallyl-

2,2,2-trifluoroacetamide (entries 15-18); respectively. Similar observations have also been reported for free radical cyclizations that do not utilize transition metal complexes as halogen transfer agents.31,32,41 Diastereoselectivity can be accounted to the transition states of the organic radical involved in cyclization (Figure 2.4).39,42 Transition states II and III afford the formation of the trans-5-exocyclic radical, however due to steric repulsions, these are less stabilized. The most stable conformation is that of I, which upon cyclization leads to the formation of the cis- diastereomer.

R H R X R X H H X CCl3 R CCl3 R H R H CCl3 I II III

X= C, O or N; R= CO2Et, CO2tBu or COCF3

Figure 2.4. Transition States Involved in the Cyclization of 5-Hexenyl Radical.

2.4 Summary and Conclusions

In summary, The ability of [CuII(TPMA)X][X] (X=Br- and Cl-) complexes in the presence of a reducing agent AIBN to mediate cascade ATRA reactions involving alkyl halides and ,-dienes (1,5-diene and 1,6-dienes) was investigated. The addition of CCl4 to the 1,5-diene proceeded to yield several products, which include the tetrahalo monoadduct, the diadduct, the six-membered ring and the five-membered ring. Cyclic

134

compounds were formed after the reactivation and subsequent ATRC of the monoadduct

[CuII(TPMA)Cl][Cl] (X=Br- and Cl-) and AIBN.

On the other hand, exceptional activity of [CuII(TPMA)Cl][Cl] complex in ATRA of CCl4 to 1,6-dienes followed by sequential ATRC in the presence of free radical diazo initiators as reducing agents was reported. Selective formation of the 1,2-disubstituted cyclopentanes in these cascade type reactions was achieved using as low as 100 ppm of the catalyst, which is by far the smallest number reported for such transformations. It is envisioned that these results could have profound implications on the synthesis of small cyclic molecules using transition metal mediated ATRA and ATRC.

2.5 Experimental

2.5.1 General Procedures

All reagents were obtained from commercial sources and were used as received.

2,2-azobisisobutyronitrile (AIBN) was recrystallized from cold methanol and dried at room temperature under vacuum. Tris(2-pyridylmethyl)amine (TPMA) and

[CuII(TPMA)Cl][Cl] were synthesized according to published procedures.43 1H NMR and

13C NMR spectra were obtained at room temperature on a Bruker Avance Spectrometer operating at 400 MHz and 100 MHz; respectively. Chemical shifts are given in ppm

1 13 relative to residual CDCl3 peak (7.26 ppm for H and 77 ppm for C). IR spectra were recorded in the solid state or solution using Nicolet Smart Orbit 380 FT-IR spectrometer

(Thermo Electron Corporation). Gas chromatography was performed on a Shimadzu GC-

135

14A instrument equipped with a flame ionization detector (FID) using a cross-linked

(6%-cyanopropyl-phenyl)-methylpolysiloxane column (30 m x 0.53 mm x 1 m).

2.5.2 Copper Catalyzed Atom Transfer Radical Reactions Involving 1,5-Hexadiene

Catalyst Solutions. 0.025 M [CuII(TPMA)Cl][Cl] were prepared using volumetric flasks to accommodate various catalyst loadings.

General Procedure for the ATRA of CBr4 and CCl4 to dienes. A stock solution containing CBr4 or CCl4, diene, AIBN, internal standard (anisole) and 1,2-dichloroethane

(DCE) solvent was prepared ([CBr4 or CCl4]0/[diene]0/[AIBN]0 = 1:1:0.05). Into each 5- ml Schlenk flask was then added 1.0 mL of the stock solution, followed by

[CuII(TPMA)(Br)][Br] or [CuII(TPMA)(Cl)][Cl]. The flasks were then tightly sealed under argon and stirred in an oil bath at 60 or 80 C for 24 h. A small amount was taken from each reaction mixture, passed through a basic alumina column to remove CuII and diluted with DCE. The percent conversion of 1,5-hexadiene was determined from the diluted reaction mixture using GC based on anisole as internal standard with an oven temperature of 35 0C for 1 min, then 10 0C/min to 205 0C.

Kinetic Studies on the Addition of CCl4 to 1,5-Hexadiene. A stock solution containing

1,5-hexadiene (2.1 mmol 250 L) AIBN (0.21 mmol, 0.0346 g) anisole (40.15 L) and

1,2-DCE (550 L) was prepared to make a concentration of 2.5 M in 1,5-hexadiene. A

100 L aliquot of the stock solution (0.25 mmol) was transferred into a vial containing

II CCl4 (0.25 mmol, 24.1 L), [Cu (TPMA)Cl][Cl] (0.00125 mmol, 50 L) and 1,2-DCE

(826 L). The resulting 0.25 M solution in 1,5-hexadiene was distributed into 5-ml

Schlenk flasks, which were sealed with a Teflon cap and immersed into an oil bath set at

60 0C. A sample was taken every hour, exposed to air, diluted with DCE and passed

136

through a basic alumina column. Percent conversion and product distribution were determined using GC with an oven temperature of 35 0C for 1 min, then 10 0C/min to 205

0C.

ATRC of 5,7,7,7-Tetrachloro-1-heptene (Compound A). In a typical experiment, 5,7,7,7- tetrachloro-1-heptene (0.213 mmol, 0.0502 g), AIBN (0.021 mmol, 0.0034 g), anisole (10

L) and 1,2-DCE (400 L) were mixed to make a stock solution of 0.5 M in 5,7,7,7- tetrachloro-1-heptene. Aliquots of 100 L each were transferred into 5 mm NMR tubes.

The corresponding amounts [CuII(TPMA)Cl][Cl] were added to the NMR tubes and 1,2-

DCE was added to make a constant volume and concentration of 0.25 M in 5,7,7,7- tetrachloro-1-heptene. The NMR tubes were then flushed with argon for 30 seconds, sealed with a plastic cap and Teflon tape, followed by electrical tape and heated in an oil bath thermostated at 60 oC for 24h. The conversion of 5,7,7,7-tetrachloro-1-heptene and the percent yield of the products were obtained using 1H NMR spectroscopy.

Kinetics of ATRC of 5,7,7,7-Tetrachloro-1-heptene. A stock solution containing 5,7,7,7- tetrachloro-1-heptene (0.407 mmol, 0.0960 g), AIBN (0.041 mmol, 0.0067 g) p- dimethpoxybenzene (0.1 eq relative to substrate), 1,2-DCE (540 L) and

[CuII(TPMA)(Cl)][Cl] (0.00164 mmol, 130 L from 0.0125 M catalyst solution) was prepared to make a concentration of 0.5 M in 5,7,7,7-tetrachloro-1-heptene. The resulting

0.5 M solution was distributed into 5-ml Schlenk flasks and afterwhich, corresponding amounts of DCE were added to make a constant volume and a total concentration of 0.25

M in 5,7,7,7-tetrachloro-1-heptene. Schlenk flasks were sealed with a Teflon cap and immersed into an oil bath set at 60 0C. A sample was taken every hour, exposed to air and

137

percent conversion and product distribution were determined using 1H NMR and GC

(oven temperature of 35 0C for 1 min, then 10 0C/min to 205 0C).

2.5.3 Product Characterization

1 5,7,7,7-tetrachloro-1-heptene (A). H NMR (400 MHz; CDCl3): δ 5.81 (d, J = 6.3 Hz,

1H), 5.15-5.05 (m, 2H), 4.31-4.28 (m, 1H), 3.31 (dd, J = 15.7, 5.7 Hz, 1H), 3.15 (dd, J =

15.7, 4.4 Hz, 1H), 2.36-2.29 (m, 2H), 2.06 (dddd, J = 14.2, 8.8, 6.8, 4.1 Hz, 1H), 1.94

13 (dtd, J = 14.3, 8.9, 5.4 Hz, 1H). ). C NMR (100 MHz; CDCl3): δ 136.43, 116.19, 96.83,

62.31, 57.02, 38.10, 30.19.

1 1,1,5-trichloro-2-chloromethylcyclohexane (B). H NMR (400 MHz; CDCl3): δ 4.21

(dd, J = 11.0, 2.6 Hz, 1H), 4.10 (tt, J = 11.8, 4.1 Hz, 1H), 3.39 (dd, J = 11.0, 10.1 Hz,

1H), 3.12 (ddd, J = 13.8, 4.0, 2.2 Hz, 1H), 2.48 (dd, J = 13.8, 11.7 Hz, 1H), 2.40-2.31 (m,

2H), 2.24 (dddd, J = 11.8, 10.0, 3.7, 2.7 Hz, 1H), 1.72-1.61 (m, 1H), 1.52-1.43 (m, 1H).

13 C NMR (100 MHz; CDCl3): δ 55.71, 53.64, 44.68, 35.31, 27.86, 26.59, 17.54.

1 1-chloro-3-(2,2,2,-trichloroethyl)cyclopentane (C). H NMR (400 MHz; CDCl3): δ

4.32-4.25 (m, 1H), 4.17-4.14 (m, 1H), 3.56-3.50 (m, 1H), 2.87 (ddt, J = 14.7, 4.4, 1.2 Hz,

1H), 2.64-2.58 (m, 1H), 2.56-2.50 (m, 1H), 2.19-2.14 (m, 2H), 2.10-2.02 (m, 1H), 1.91-

13 1.81 (m, 1H). C NMR (100 MHz; CDCl3): δ 90.19, 54.24, 32.05, 51.0, 43.12, 30.64,

22.91.

1 1,1,1,3,6,8,8,8-octachlorooctane (D). H NMR (400 MHz; CDCl3): δ 4.38-4.29 (m, 2H),

3.38-3.30 (m, 2H), 3.20-3.13 (m, 2H), 2.41-2.35 (m, 1H), 2.27-2.11 (m, 2H), 2.03-1.96

(m, 1H).

1 5,7,7,7-tetrabromo-1-heptene (A2). H NMR (400 MHz; CDCl3): δ 5.83 (dddd, J =

17.2, 10.2, 7.1, 6.1 Hz, 1H), 5.17-5.07 (m, 1H), 4.23 (td, J = 9.1, 4.3 Hz, 1H), 3.88 (dd, J

138

= 16.1, 4.4 Hz, 1H), 3.58 (dd, J = 16.2, 5.0 Hz, 1H), 2.45-2.37 (m, 1H), 2.35-2.27 (m,

1H), 2.22 (dddd, J = 14.4, 8.8, 6.8, 3.7 Hz, 1H), 2.12-2.04 (m, 1H).

1 1,1,5-tribromo-2-bromomethylcyclohexane (B2). H NMR (400 MHz; CDCl3): δ 4.23

(tt, J = 12.0, 4.1 Hz, 1H), 4.08 (dd, J = 10.2, 2.4 Hz, 1H), 3.43-3.36 (m, 1H), 3.22 (t, J =

10.1 Hz, 1H), 2.90 (dd, J = 14.1, 11.7 Hz, 1H), 2.48-2.43 (m, 1H), 2.27 (dq, J = 10.7, 3.6

Hz, 1H), 2.18-2.11 (m, 1H), 1.85 (qd, J = 12.9, 4.1 Hz, 1H), 1.45 (tdd, J = 14.1, 11.3, 3.1

13 Hz, 1H). C NMR (100 MHz; CDCl3): δ 71.32, 58.96, 55.17, 44.56, 36.34, 35.67, 29.02.

1 1-bromo-3-(2,2,2,-tribromoethyl)cyclopentane (C2). H NMR (400 MHz; CDCl3): δ

4.41-4.31 (m, 1H), 4.17-4.12 (m, 1H), 3.53-3.48 (m, 1H), 3.46-3.39 (m, 1H), 3.19-3.13

(m, 1H), 3.13-3.04 (m, 1H), 2.89-2.79 (m, 1H), 2.74-2.65 (m, 1H), 2.37-2.27 (m, 2H),

2.26-2.19 (m, 2H).

2.5.4 Copper Catalyzed Atom Transfer Radical Reactions Involving 1,6- Dienes

Catalyst Solutions. 0.01M and 0.005M solutions of [CuII(TPMA)Cl][Cl] were prepared by dissolving the copper(II) complex in MeOH using volumetric flasks to accommodate various catalyst loadings.

General Procedure for Addition of Carbon Tetrachloride to 1,6-Heptadiene Catalyzed by

[CuII(TPMA)Cl][Cl] in the Presence of AIBN. All reactions were performed in disposable 5.0mm NMR tubes equipped with a plastic cap. In a typical experiment, 1,6- heptadiene (2.0 mmol, 269 µL), CCl4 (2.5 mmol, 241 µL), AIBN (0.1 mmol, 0.0164 g) and internal standard (1,4-dimethoxybenzene or toluene, 10 mol% relative to 1,6-diene) were dissolved in 510 µL of methanol in order to make the final solution 2.0 M in 1,6- heptadiene. 200 µL of the stock solution (0.4 mmol 1,6-heptadiene, 0.5 mmol CCl4 and

0.02 mmol AIBN) were then added to the NMR tube, followed by the desired amount of

139

the copper(II) complex (from 0.01 M [CuII(TPMA)Cl][Cl] and for [1,6-

II heptadiene]0:[Cu ]0 ratios of 1000:1 (V = 40 µL) and 2000:1 (V = 20 µL), from 0.05 M

II II [Cu (TPMA)Cl][Cl] and for [1,6-heptadiene]0:[Cu ]0 ratio of 5000:1 (V = 16 µL) and

10000:1 (V = 8 µL)) and the total volume adjusted by adding methanol in order to maintain the concentration of 1,6-heptadiene at 1.0 M. The NMR tube was then flushed with argon for 30 seconds, sealed with a plastic cap and teflon tape, followed by electrical tape and heated in an oil bath thermostated at 60 oC for 24h. The conversion of

1,6-heptadiene and the percent yield of the products were obtained using 1H NMR spectroscopy. The trans- and cis- ratios were determined by 1H NMR after solvent evaporation.

General Procedure for Addition of Carbon Tetrachloride to 1,6-Dienes Catalyzed by

[CuII(TPMA)Cl][Cl] and AIBN/V-70. Same procedures described above were followed except that the following volumes of 1,6-diene in the stock solution were used: V(diallyl ether) = 244 µL, V(diethyldiallylmalonate) = 484 µL, V(tert-butyl-N,N-diallylcarbamate)

= 216 µL) and V(N,N-diallyl-2,2,2-trifluoroacetamide) = 342 µL). After adding CCl4

(2.5 mmol, 241 µL), reducing agent (0.1 mmol, AIBN = 0.0164 g or V-70 = 0.0308 g) and internal standard (1,4-dimethoxybenzene or toluene, 10 mol% relative to 1,6-diene), methanol was added to maintain the concentration of 1,6-diene at 2.0 M (for diallyl ether

= 515 µL, diethyldiallylmalonate=275 µL, tert-butyl-N,N-diallylcarbamate = 543 µL) and N,N-diallyl-2,2,2-trifluoroacetamide = 417 µL).

Product Characterization. 1H and 13C NMR spectra for all 5-exo-trig cyclic products have been reported elsewhere,34 except for 1-(3-(chloromethyl)-4-(2,2,2- trichloroethyl)pyrrolidin-1-yl)-2,2,2-trifluoroethanone. 1-(3-(Chloromethyl)-4-(2,2,2-

140

1 trichloroethyl)pyrrolidin-1-yl)-2,2,2-trifluoroethanone. H (CDCl3, 400 MHz, RT): mixture of cis and trans, 3.95-4.10 (m, 1H), 3.65-3.90 (m, 3H), 3.40-3.55 (m, 2H),

13 3.00-3.10 (m, 2H), 2.80-2.85 (m, 2H). C (CDCl3, 100 MHz, RT): mixture of cis and trans, 156.0, 155.5, 117.6, 114.7, 97.9, 53.2, 52.8, 51.1, 50.3, 49.3, 42.7, 42.0, 41.2,

39.0, 37.2.

2.6 References

1. Pintauer, T.; Matyjaszewski, K., Atom Transfer Radical Addition and Polymerization Reactions Catalyzed by ppm Amounts of Copper Complexes. Chem. Soc. Rev. 2008, 37 (6), 1087-1097.

2. Curran, D. P., Comprehensive Organic Synthesis. Pergamon: New York, 1992; p 715.

3. Clark, A. J., Atom Transfer Radical Cyclisation Reactions Mediated by Copper Complexes. Chem. Soc. Rev. 2002, 31 (1), 1-11.

4. Gossage, R. A.; Van De Kuil, L. A.; Van Koten, G., Diaminoarylnickel(II) "Pincer" Complexes: Mechanistic Considerations in the Kharasch Addition Reaction, Controlled polymerization, and Dendrimeric Transition Metal Catalysts. Acc. Chem. Res. 1998, 31 (7), 423-431.

5. Iqbal, J.; Bhatia, B.; Nayyar, N. K., Transition Metal Promoted Free Radical Reactions in Organic Synthesis: The Formation of Carbon-Carbon Bonds. Chem. Rev. 1994, 94 (2), 519-564.

141

6. Severin, K., Ruthenium Catalysts for the Kharasch Reaction. Curr. Org. Chem. 2006, 10, 217-224.

7. Stevens, C. V.; Van Meenen, E.; Masschelein, K. G. R.; Eeckhout, Y.; Hooghe, W.; D‘hondt, B.; Nemykin, V. N.; Zhandkin, V. V., A Copper-Catalyzed Domino Radical Cyclization Route to Benzospiro-Indolizidinepyrrolidinones. Tetrahedron Lett. 2007, 48, 7108-7111.

8. Tietze, L. F., Domino Reactions in Organic Synthesis. Chem. Rev. 1996, 96, 115- 136.

9. Tietze, L. F.; Rackelmann, N., Domino Reactions in the Synthesis of Heterocyclic Natural Products and Analogs. Pure Appl. Chem. 2004, 76 (11), 1967-1983.

10. Matyjaszewski, K.; Jakubowski, W.; Min, K.; Tang, W.; Huang, J.; Braunecker, W.; Tsarevsky, N., Diminishing Catalyst Concentration in Atom Transfer Radical Polymerization with Reducing Agents. Proc. Nat. Acad. Sci. 2006, 103 (42), 15309-15314.

11. Wang, J. S.; Matyjaszewski, K., Controlled/"Living" Radical Polymerization. Atom Transfer Radical Polymerization in the Presence of Transition-Metal Complexes. J. Am. Chem. Soc. 1995, 117 (20), 5614-5615.

12. Jakubowski, W.; Matyjaszewski, K., Activators Regenerated by Electron Transfer for Atom-Transfer Radical Polymerization of (Meth)acrylates and Related Block Copolymers. Angew. Chem. Int. Ed. 2006, 45 (27), 4482-4486.

13. Jakubowski, W.; Min, K.; Matyjaszewski, K., Activators Regenerated by Electron Transfer for Atom Transfer Radical Polymerization of Styrene. Macromolecules 2006, 39 (1), 39-45.

14. Quebatte, L.; Thommes, K.; Severin, K., Highly Efficient Atom Transfer Radical Addition Reactions with a RuIII Complex as a Catalyst Precursor. J. Am. Chem. Soc. 2006, 128 (23), 7440-7441.

15. Eckenhoff, W. T.; Pintauer, T., Atom Transfer Radical Addition in the Presence of Catalytic Amounts of Copper(I/II) Complexes with Tris(2- pyridylmethyl)amine Inorg. Chem. 2007, 46 (15), 5844-5846.

142

16. Eckenhoff, W. T.; Garrity, S. T.; Pintauer, T., Highly Efficient Copper-Mediated Atom Transfer Radical Addition (ATRA) in the Presence of a Reducing Agent. Eur. J. Inorg. Chem. 2008, 2008 (4), 563-571.

17. Blackman, A., Tripodal Tetraamine Ligands Containing Three Pyridine Units: The other Polypyridyl Ligands Eur. J. Inorg. Chem. 2008, 17, 2633-2647.

18. Diaz-Alvarez, A. E.; Crochet, P.; Zablocka, M.; Duhayon, C.; Cadierno, V.; Majoral, J. P., Developing the Kharasch Reaction in Aqueous Media: Dinuclear Group 8 and 9 Catalysts Containing the Bridging Cage Ligand tris(1,2- Dimethylhydrazino)diphosphane. Eur. J. Inorg. Chem. 2008, (5), 786-794.

19. Iizuka, Y.; Li, Z.; Satoh, K.; Kamigaito, M.; Okamoto, Y.; Ito, J.-i.; Nishiyama, H., Chiral (–)-DIOP Ruthenium Complexes for Asymmetric Radical Addition and Living Radical Polymerization Reactions. Eur. J. Org. Chem. 2007, 2007 (5), 782-791.

20. Lundgren, R. J.; Rankin, M. A.; McDonald, R.; Stradiotto, M., Neutral, Cationic, and Zwitterionic Ruthenium(II) Atom Transfer Radical Addition Catalysts Supported by P,N-Substituted Indene or Indenide Ligands. Organometallics 2008, 27 (2), 254-258.

21. Maiti, D.; Narducci Sarjeant, A. A.; Itoh, S.; Karlin, K. D., Suggestion of an Organometallic Intermediate in an Intramolecular Dechlorination Reaction Involving Copper(I) and a ArCH2Cl Moiety. J. Am. Chem. Soc. 2008, 130 (17), 5644-5645.

22. Oe, Y.; Uozumia, Y., Highly Efficient Heterogeneous Aqueous Kharasch Reaction with an Amphiphilic Resin-Supported Ruthenium Catalyst Adv. Synth. Catal. 2008, 350, 1771-1775.

23. Thommes, K.; Icli, B.; Scopelliti, R.; Severin, K., Atom Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions Catalyzed by a Mixture of [RuCl2Cp*(PPh3)] and Magnesium. Chem. Eur. J. 2007, 13 (24), 6899-6907.

24. Wolf, J.; Thommes, K.; Briel, O.; Scopelliti, R.; Severin, K., Dinuclear Ruthenium Ethylene Complexes: Syntheses, Structures, and Catalytic Applications in ATRA and ATRC Reactions. Organometallics 2008, 27 (17), 4464-4474.

143

25. Clark, A. J.; Wilson, P., Copper Mediated Atom Transfer Radical Cyclisations with AIBN. Tet. Lett. 2008, 49 (33), 4848-4850.

26. Baldwin, J. E., Rules for ring closure. J. Chem. Soc. Chem. Commun. 1976, (18), 734-736.

27. Lee, G. M.; Weinreb, S. M., Transition Metal Catalyzed Intramolecular Cyclizations of (Trichloromethyl)alkenes. J. Org. Chem. 1990, 55 (4), 1281-1285.

28. Gillies, M. B.; Matyjaszewski, K.; Norrby, P.-O.; Pintauer, T.; Poli, R.; Richard, P., A DFT Study of Bond Dissociation Enthalpies of Relevance to the Initiation Process of Atom Transfer Radical Polymerization. Macromolecules 2003, 36 (22), 8551-8559.

29. Watkins, K. W.; Olsen, D. K., Cyclization and Decomposition of 4-Penten-1-yl Radicals in the Gas Phase. J. Phys. Chem. 2002, 76 (8), 1089-1092.

30. Yamamoto, Y.; Ohno, M.; Eguchi, S., Study of 5-Endo Cyclization of 5- Oxapenta-2,4-dienoyl Radical and Related Radicals by ab Initio Calculations. Unusual Nonradical Cyclization Mechanism. J. Org. Chem. 1996, 61 (26), 9264- 9271.

31. Beckwith, A. L. J.; Schiesser, C. H., Regio- and Stereo-Selectivity of Alkenyl Radical Ring Closure: A Theoretical Study. Tetrahedron 1985, 41 (19), 3925- 3941.

32. Spellmeyer, D. C.; Houk, K. N., Force-Field Model for Intramolecular Radical Additions. J. Org. Chem. 1987, 52 (6), 959-974.

33. Munoz-Molina, J. M.; Caballero, A.; Diaz-Requejo, M. M.; Trofimenko, S.; Belderrain, T. R.; Perez, P. J., Copper-Homoscorpionate Complexes as Active Catalysts for Atom Transfer Radical Addition to Olefins. Inorg. Chem. 2007, 46, 7725-7730.

34. Munoz-Molina, J. M.; Belderrain, T. R.; Perez, P. J., Copper-Catalyzed Synthesis of 1,2-Disubstituted Cyclopentanes from 1,6-Dienes by Ring-Closing Kharasch Addition of Carbon Tetrachloride. Adv. Synth. Catal. 2008, 350, 2365-2372.

144

35. Eckenhoff, W. T.; Garrity, S. T.; Pintauer, T., Highly Efficient Copper Mediated Atom Transfer Radical Addition (ATRA) in the Presence of Reducing Agent. Eur. J. Inorg. Chem. 2008, 563-571.

36. Eckenhoff, W. T.; Pintauer, T., Atom Transfer Radical Addition in the Presence of Catalytic Amounts of Copper(I/II) Complexes with Tris(2- pyridylmethyl)amine. Inorg. Chem. 2007, 46 (15), 5844-5846.

37. Togo, H., Advanced Free Radical Reactions for Organic Synthesis. Elsevier: Amsterdam, 2004.

38. Pintauer, T.; Matyjaszewski, K., Atom Transfer Radical Addition and Polymerization Reactions Catalyzed by ppm Amounts of Copper Complexes. Chem. Soc. Rev. 2008, 37, 1087-1097.

39. Munoz-Molina, J. M.; Belderrain, T. R.; Perez, P. J., Copper-Catalyzed Synthesis of 1,2-Disubstituted Cyclopentanes from 1,6-Dienes by Ring-Closing Kharasch Addition of Carbon Tetrachloride Adv. Synth. Catal. 2008, 350, 2365-2372.

40. Pintauer, T.; Eckenhoff, W. T.; Ricardo, C.; Balili, M. N. C.; Biernesser, A. B.; Noonan, S. T.; Taylor, M. T., Highly Efficient Ambient-Temperature Copper- Catalyzed Atom-Transfer Radical Addition (ATRA) in the Presence of Free- Radical Initiator (V-70) as a Reducing Agent Chem. Eur. J. 2009, 15 (1), 38-41.

41. Brace, N. O., Cyclization Reactions of 6-Hepten-2-yl Radicals, 1- Trichloromethyl-6-hepten-2-yl Radicals and Related Compounds. J. Org. Chem. 1967, 32 (9), 2711-2718.

42. Beckwith, A. L. J., Regio-Selectivity and Stereo-Selectivity in Radical Reactions. Tetrahedron 1981, 37 (18), 3073-3100.

43. Tyeklar, Z.; Jacobson, R. R.; Wei, N.; Murthy, N. N.; Zubieta, J.; Karlin, K. D., Reversible Reaction of Dioxygen (and Carbon Monoxide) with a Copper(I) Complex. X-ray Structures of Relevant Mononuclear Cu(I) Precursor Adducts and the Trans-(μ-1,2-Peroxo)dicopper(II) Product. J. Am. Chem. Soc. 1993, 115 (7), 2677-2689.

145

Chapter 3

Sigma C-H and C-C Hyperconjugative Control of Copper Catalyzed Atom Transfer Radical Addition and Cyclization of 1,6-Diene Esters in the Presence of a Reducing Agent

The technique of catalyst regeneration in the presence of 2,2‘- azobis(isobutyronitrile) (AIBN) was applied in atom transfer radical domino reactions of carbon tetratchloride (CCl4) and 1,6-diene esters allyl acrylate (1), allyl methacrylate (2), methyl-2-propenyl acrylate (3), phenyl-2-propenyl acrylate (4), dimethyl-2-propenyl acrylate (5), ethylmethyl-2-propenyl acrylate (6) and dimethyl-2-propenyl methacrylate

(7) to yield functionalized -lactones in a one-step synthesis. The addition of CCl4 in the presence of 0.2 mol% of copper (II) complex with tris(2-pyridmethyl)amine (TPMA) ligand and 10 mol% of 2,2‘-azobis(isobutyronitrile) to substrates with dialkyl substitutions 5 and 6 furnished the formation of the desired -lactones in 46 and 51% yields; respectively, while open-chain halogenated allylic ester were observed for substrates 1, 2, 3, 4 and 7. The M06-2x density functional with Dunning‘s aug-cc-pVDZ basis set was used to compute the stationary points along the stepwise reaction path involving Z to E interconversion after ester radical formation followed by 5- exocyclization to -lactone product. Natural bond orbital (NBO) analysis was employed to gain deeper insight into the dialkyl substituent requirement showing -lactone formation of 5 and 6. NBO computations reveal that the presence of dialkyl groups in 5 and 6 lowers the activation barrier of Z to E interconversion by weakening and elongating

146

the rotating C-O bond at the transition structure through specific σ(C-C/H)  σ*(O-C) hyperconjugations. Similarly, the dialkyl groups in 5 and 6 facilitate 5-exocyclization by relieving ring-strain in the transition structure by lengthening the C-C bond within the forming ring adjacent to the double bond involved in radical addition by σ(C-C/H) 

σ*(C-C) hyperconjugations. This work signifies the importance of C-C and C-H sigma bond hyperconjugation in intermolecular atom transfer radical addition, followed by sequential cyclization reactions.

3.1 Introduction

Domino-type reactions employing copper-catalyzed atom transfer radical addition

(ATRA) and cyclization (ATRC) have found great deal of application in the synthesis of natural products and pharmaceutical drugs.1,2 This methodology is quite attractive since it allows formation of several bonds in one sequence without the isolation of intermediates, changes in the reaction conditions or the addition of external reagents. Additionally, it allows the synthesis of functionalized cyclic compounds, which can be useful as precursors for the preparation of more complex molecules.3

Copper-catalyzed ATRA, ATRC and domino reactions have been traditionally conducted in the presence of as much as 30 mol% of the catalyst (relative to the substrate), which caused problems in product separation and catalyst recycling.4,5 A new methodology for catalyst regeneration in ATRA has been developed, following its success in the mechanistically similar atom transfer radical polymerization (ATRP).6-8 In this technique as shown in Scheme 3.1, transition metal complex in the higher oxidation state commonly referred to as deactivator is continuously reduced to the lower oxidation

147

state or activator in the presence of reducing agents such as ascorbic acid, magnesium and free-radical initiators (2,2‘-azobisisobutyronitrile (AIBN) and 2,2‘-azobis(4- methoxy-2,4-dimethyl valeronitrile) (V-70)).4,5,9 As a result, ATRA reactions can now be conducted using ppm amounts of the catalyst.7,8,10,11

Scheme 3.1. Catalyst regeneration in ATRA in the presence of reducing agents.

Since the seminal reports by our group7 and the research group of Severin,10 this method of catalyst regeneration in ATRA has attracted considerable academic interest9,11-

17 and was successfully applied to intramolecular ATRA or atom transfer radical cyclization (ATRC).18-21 Furthermore, this technique has been utilized in domino or tandem radical annulation processes. Recently, copper(I) homoscorpionate complexes

148

have been utilized in the addition of CCl4 to 1,6-dienes to yield 1,2-disubstituted cyclopentanes.20 Quantitative yields of the products were obtained using 1 mol% of the catalyst in the presence of Mg as a reducing agent. In a similar work performed by our laboratory employing the [CuII(TPMA)Cl][Cl] in conjunction with free-diazo radical initiators (AIBN and 2,2‘-azobis-4-methoxy-2,4-dimethyl valeronitrile (V-70)) catalytic system, selective formation of the cyclic products were achieved in the presence of as low as 100 ppm of the catalyst.21

Symmetrical 1,6-dienes are excellent candidates to further expand the methodology for catalyst regeneration originally developed for ATRA because the addition of radicals generated from alkyl halides results in the formation of 5-hexenyl radicals, which are known to undergo very fast and selective 5-exo-trig mode of

5 -1 22 cyclization (kexo-trig10 s , kexo-trig/kendo-trig<100). Aside from symmetrical 1,6-dienes, substrates having the same chain length, in particular the 1,6-diene esters can be a good choice for expanding the scope of catalyst regeneration technique. If the cyclization proceeds via the 5-exo mode, this results in the formation of the -lactone. Synthesis of this class of heterocyclic compounds has become ubiquitous because these serve as analogs and often; they constitute the structural component of natural products and pharmaceutical drugs.23-25 Furthermore, functionalized lactones are important intermediates in the synthesis of stereo-defined acyclic and other natural products.23

Cyclization of these substrates, particularly the unsaturated acrylates, appeared in earlier publications, in the free-radical photostimulated addition of alkylmercury halides26 and toluenesulfonyl bromides27 producing organomercurial and sulfonylated -lactones; respectively. However, product selectivity was rather low, as manifested in the reported

149

yields and the inevitable occurrence of competing telomerization and acyclic monoadduct formation.

Another synthetic route to the one-pot formation of -lactones that has not been explored is via the intermolecular addition followed by atom transfer radical cyclization cascade mechanism involving 1,6-diene esters and alkyl halides mediated by copper(II) complexes and reducing agents. Since highly efficient 5-exocyclization has been achieved with [CuII(TPMA)Cl][Cl] in the presence of free-diazo radical initiators21 (AIBN and

2,2‘-azobis-4-methoxy-2,4-dimethyl valeronitrile (V-70)) and ascorbic acid28 systems, it is envisioned that catalyst regeneration technique could potentially cyclize unsymmetrical

1,6-dienes. This chapter reports on the attempted cyclization of various unsymmetrical diene esters utilizing copper-catalyzed ATRA followed by sequential ATRC.

Experimental findings were verified by density functional theory and natural bond orbital analysis. To our knowledge, these are the first computational investigations ever been performed for the radical ring closure of unsaturated acrylates. Furthermore, the factors governing the selective formation of the desired -lactones are presented.

3.2 Copper-Catalyzed Addition of Carbon Tetrachloride in the Presence of Reducing Agents

Initial attempts were focused on the addition of CCl4 to commercially available allyl acrylate (1) and allyl methacrylate (2) (Figure 3.1). As shown in Scheme 3.2, the addition can occur in two possibilities: to the acrylic site resulting in the formation of radical A, or to the allylic site forming radical B. Preliminary results revealed that the generated trichloromethyl radicals (CCl3) attack the more polar acrylic side, which are in agreement with previously reported experiments.26,29-32 Such observation can be

150

Figure 3.1. Representative commercial and synthesized 1,6-diene esters.

attributed to the electrophilic nature of the alkyl radicals. Considering the neighboring neighboring atoms or functional groups of the terminal double bonds, one could easily speculate that the addition of the alkyl radicals would be much favored on the more electron-rich acrylic site. Furthermore, formation of A gives a tertiary radical for the case of alllyl methacrylate, which is relatively more stable than the secondary radical B. The disappearance of the resonance signals corresponding to the acrylic protons after 1H

NMR analysis of the crude reaction mixtures proved that the monoadduct was formed as a result of radical trapping of A after halide transfer by the CuII complex giving product E and CuI complex.

O O O O O R'X R'X R' O R' R R CulI/TPMA R CulI/TPMA (A) AIBN,  AIBN,  (B) CulICl/TPMA CulICl/TPMA

l Cul/TPMA Cu /TPMA O O

R' O O R' R X R X (E) (F) R= H, CH 3

Scheme 3.2. Open-chain adducts as a result of radical trapping via halide transfer from CuII complex.

151

Table 3.1 summarizes the results of the addition of CCl4 to allyl acrylate (1) and allyl methacrylate (2) catalyzed by [CuII(TPMA)(Cl)][Cl] complex in conjunction with free-radical diazo initiators (AIBN or V-70). Only polymers were observed for reactions performed in the presence of reducing agent only (Entries 2 and 6). Reactions carried out in the presence of [CuII(TPMA)(Cl)][Cl] complex afforded the formation of the open- chain monoadduct. Two sets of reactions were performed wherein the amount of AIBN was varied. For reaction mixtures with [2] to [CuII] ratios ranging from 100:1 to 500:1 and 10 mol% of AIBN, the monoadduct yields were found to be higher as opposed to the mixtures containing 5 mol% of AIBN. It is evident from Table 3.1 that higher product yields were obtained when the reducing agent was V-70 as opposed to AIBN for reactions having [2] to [CuII] ratios ranging from 250:1 to 500:1. Additionally, the selectivity towards the formation of the monoadduct decreased at lower catalyst concentrations.

Table 3.1. Addition of Carbon Tetrachloride to 1,6-Diene Esters Catalyzed by [CuII(TPMA)Cl][Cl] and AIBN or V-70. Entry [1,6-Diene]:[CuII] Substrate Reducing agent % Conversion/ % Yield 1 500:1 1 5 mol% AIBN 100/100b 2 blank 100/100b 3 100:1 2 5 mol% AIBN 100/29a 4 250:1 100/28a 5 500:1 100/19a 6 blank 100/100b 7 100:1 2 10 mol % AIBN 100/43a 8 250:1 100/40a 9 500:1 100/30a 10 250:1 2 5 mol% V-70 100/72a 11 500:1 100/67a Conditions: Reactions were performed in the presence of AIBN or V-70 at 60 0C or RT; respectively in MeOH as solvent for a period of 24h. % Conversions and yields were determined via 1H NMR using 1,4-dimethoxybenzene as internal standard (relative error = 15%). aYield of monoadduct, bpolymers.

152

It is generally accepted that the addition of alkyl radicals to symmetrical 1,6- dienes generates a 5-hexenyl radical, which is known to undergo expedient formation of

5 -1 33,34 5-exocyclic compounds (k1,5-cyclization= 10 s ). This is 100 times faster when compared

3 -1 to the cyclization pathway in the 6-endo mode (k1,6-cyclization= 10 s ). It is expected that the

 addition of the CCl3 to allyl acrylate (1) and allyl methacrylate (2) results in the formation of 5-hexenyl ester type of radical. Based on experimental findings 1,5-ring closure, however, failed to proceed suggesting rate of cyclization of these radicals is very slow. Cyclization of ester- and amide-derived radicals is subject to streoelectronic and thermodynamic factors.35 It has been reported that the s-trans (Z) and s-cis (E) conformations are both present in these radicals, which can be attributed to the partial double bond character of the C-O and C-N as a result of electron delocalization (Figure

3.2).36 In order to have an efficient cyclization, the barrier for the interconversion between the Z and E conformers must be overcome (Scheme 3.3). However, due to the incipient delocalization between the radical center and the acyl carbon, Z is typically 7.01 kcal/mol more stable than E conformer.32,35 Moreover, the activation barrier to rotation to the preferred geometry is 11.56 kcal/mol. This value is even higher when compared to the

5-exocyclization of the s-cis (E) -ester radical, which is 8.61 kcal/mol.35 In order to overcome this, reactions at elevated temperatures are normally carried out to increase the rotamer population of the less stable conformation (E).37,38 Screening various solvents revealed that polarity contribute to the rotation about the C-O bond of the more stable Z to the higher energy E conformer. An explanation for this is that E has higher net dipole moment compared to Z and consequently, the polar transition state involved during the cyclization process.35 Hence, polar effects can promote overall cyclization reactions

153

because the molecule with a larger dipole moment is more stabilized in a more polar solvent.

Figure 3.2. Conformations of esters and amides as a result of electron delocalization.

In an effort to selectively form the cyclic compounds, reaction conditions were optimized. Changing solvent polarity and incorporation of Lewis acid in the reaction mixture were then performed. In one set of experiments, addition of CCl4 to diene esters was carried out in the 3:1 ratio of MeOH to water. Unfortunately, the use of water only promoted the formation of more polymers and the open-chain monoadducts. The role of

Lewis acids has been reported to enhance sluggish atom transfer radical addition and cyclization.39-42 In addition, mild reaction times and short reaction times are possible.

Based on these findings, Lewis acid was also utilized, however instead of forming the cyclic compounds, the monoadduct and even polymers were obtained. One problem seen has been the solvent choice. Reactions were carried out in MeOH solvent; however, the coordination of the Lewis acid to the solvent might have prevented the reaction to proceed since low conversions were obtained. When a nonpolar dichloroethane was utilized, conversion was improved; however, no cyclization products were observed.

Optimization of the reaction conditions for the addition of alkyl halides to allyl acrylate (1) and allyl methacrylate (2) indicate that the desired E rotamers were not stable

154

O O O Cl C O 3 Cl3C

s-trans (Z) s-cis (E)

kdeactivation kcyclization

O O O Cl C Cl3C O 3 Cl Cl

Scheme 3.3. Conformations of the ester derived radical.

enough and as a consequence, s-trans to s-cis (Z to E) tautomerism could not be easily achieved. In order to enhance the cyclization of ester radicals, previous studies have demonstrated one key factor is attributable to the alkyl substitution on the methylene carbon on the allylic side.26 Bulky substituents tend to occupy more space than hydrogens causing a compression of the internal angle, thus, bringing the reactive centers closer to one another. Such phenomenon is known as Thorpe-Ingold effect and is largely affected by gem-dialkyl substitution.43 Furthermore, dialkyl substitution reduces the energy barrier for the s-trans to s-cis (Z to E) interconversion. Consequently, a higher population of the reactive rotamer is achieved, allowing cyclization to occur. Besides physical reasons, energetic basis of this effect could be the lowering of the enthalpy of activation (H‡) and consequently, the decrease in free energy of activation (G‡).43 In light with this argument, substrates bearing alkyl or aryl substituents on the carbon adjacent to the oxygen atom were synthesized from commercially available secondary and tertiary alcohols and acryloyl chloride or methacryloyl chloride. Representative 1,6- diene esters that have been utilized include methyl-2-propenyl acrylate (3), phenyl-2-

155

propenyl acrylate (4), dimethyl-2-propenyl acrylate (5), ethylmethyl-2-propenyl acrylate

(6) and dimethyl-2-propenyl methacrylate (7).

Table 3.2. Addition of Carbon Tetrachloride to 1,6-Diene Estes Catalyzed by [CuII(TPMA)Cl][Cl] and AIBN. Substrate [Substrate]:[CuII] % Yield Product 3 500:1 54 Open-chain adduct 4 500:1 20 Open-chain adduct 5 500:1 46 5-membered lactone 6 500:1 51 5-membered lactone 7 500:1 45 Open-chain adduct II Reaction conditions: [Substrate]:[CCl4]:[Cu ]:[AIBN] ratios: 500:625:1:10. All reactions were performed in acetonitrile as the solvent and heated to 80 0C for a period of 24h. %Yields were based on 1H NMR using 1,4-dimethoxybenzene as the internal standard (relative errors are 15%).

Table 3.2 presents the results on the addition of alkyl halides to the substituted allyl acrylates. Similarly to substrates 1 and 2, addition of CCl4 to 3 furnished the formation of the open-chain halogenated allylic ester in 54% yield. The presence of the bulky phenyl substituent on substrate 4 was expected to yield the cyclized products; however, it afforded the formation of lower amount of the monoadduct (20%). The results indicate that single methyl or phenyl substitution on the alkoxy carbon was insufficient to facilitate the rotation of the C-O bond from s-trans- to s-cis conformer (Z to E). Dramatic improvement was observed in the addition of CCl4 to dimethyl-2- propenyl acrylate (5) and ethylmethyl-2-propenyl acrylate (6) as these underwent 5- exocyclization to yield the desired -lactone. Cyclization of diene esters 5 and 6 revealed the significance of dialkyl substitution in achieving the desired s-cis (E) geometry.

Substrate 6 having ethyl and methyl substituents gave the highest yield of the lactone

(51%) followed by the dimethyl substituted 1,6-diene ester (5), in which 46% yield was

156

Table 3.3. Effect of Various Catalyst Loadings on the Addition of Carbon Tetrachloride to Dimethylallyl Acrylate. Entry [Substrate]:[CuII] % Yieldc 1 blank 100d 2 100:1a 35c 3 250:1a 34c 4 500:1a 32c 5 1000:1a 30c 6 blank 100d 7 100:1b 49c 8 500:1b 47c 9 1000:1b 42c Reaction conditions: All reactions were performed in acetonitrile as the solvent and heated to 80 0C for a period of 24h in the presenece of a5 mol% AIBN and b10 mol% AIBN (relative to substrate). cYields of 5-membered lactone and dpolymers were based on 1H NMR (relative errors are 15%) using 1,4-dimethoxybenzene as the internal standard.

achieved. Although substrate 7 was dimethyl substituted, the desired 5-exocyclic product was not observed.

Extent of catalyst loading in the presence of 5 and 10 mol% AIBN was additionally examined in the cyclization of substrate 5. For reaction mixtures having

[substrate]:[CuII] ranging from 100:1 to 1000:1 and in the presence of 5 mol% of AIBN provided -lactones in 30-35% yield. Increasing the amount of AIBN to 10 mol% afforded the formation of 47% and 42% of the cyclic product for reaction mixtures having [substrate]:[CuII] ratio of 500:1 and 1000:1, repectively. The yields are higher by

15% and 12% when compared to reaction mixtures having the same catalyst loading but in the presence of lower amount of AIBN. Based on the results presented on Table 3.3, it is apparent that the amount of AIBN affects product yield, while catalyst loading has negligible effect. Table 3.3 also shows that the presence of the copper(II) complex controls the selectivity towards the 5-exocyclization. In the absence of the

157

[CuII(TPMA)Cl][Cl], which are represented by the blank reaction runs (Entries 1 and 6,

Table 3.3) only polymers were obtained.

3.3 Density Functional Theory Calculations

Scheme 3.4. 5-Exocyclization of allyl ester radical leading to the formation of -lactone.

In order to provide further explanation on the cyclization behavior of the unsymmetrical 1,6-diene esters utilized in this study, we turned to theoretical investigations. For comparison purposes, we focused on substrates with no substituent

(1), methyl group on the acrylic bond (2), methyl group on the allylic bond (3), dialkyl substituents on the allylic bond (5 and 6) (Scheme 3.4). DFT computations were carried out to determine the Z and E ground states, corresponding interconversion barriers, the 5- exocyclization activation energies and the γ-lactones of acrylates (1, 2, 3, 5 and 6).

Although stereoisomers are possible for 3 and 6, only the most stable isomers are included for discussion.

Table 3.4. Energy differences (kcal/mol) between Z and E allyl ester radicals at M062X/aug-cc-pVDZ level of theory, ∆E = EZ – EE.

Substrates ∆Eelec ∆EZPE ∆H298 ∆G298

158

1 -4.0 -4.1 -4.1 -3.8 2 -9.8 -9.7 -9.8 -9.3 3 -3.9 -4.0 -4.0 -3.8 5 -3.7 -3.7 -3.7 -3.7

6 -3.7 -3.8 -3.7 -3.8

In agreement with previously reported energy differences between Z and E isomers of esters, Z is more stable than E in all the cases due to the Columbic (dipole- dipole) interactions, which are minimized in Z and maximized in E.44-46 In addition, it has been noted that an increase in conjugation between the ether oxygen π-type lone pair electrons and the π electrons of the carbonyl (CO) bond is achieved in Z conformation.47-

50 Our computations predict that the enthalpy difference of -9.8 kcal/mol between Z and E is an anomaly for 2, whereas the other structures have energy differences between -3.7 to

-4.1 kcal/mol that are with in the range of previous experimental and theoretical results on different ester systems.44-51

‡ Table 3.5. Activation energies (kcal/mol) for Z to E rotational barrier (∆E = ETS – EZ).

‡ ‡ ‡ ‡ Substrates ∆E elec ∆E ZPE ∆H 298 ∆G 298 1 10.7 10.3 9.9 10.8 2 10.8 10.2 9.9 10.7 3 10.3 9.9 9.5 10.2 5 7.9 7.6 7.1 7.6 6 7.0 6.7 6.2 7.2

159

Figure 3.3. Different transition structures of 1 for the interconversion of Z and E conformations.

There are two different pathways for Z to E conversion for each of the acrylates considered, except for 2. The difference in the pathways depends on clockwise or anticlockwise rotation of the OCOC dihedral angle (α), as shown in Figure 3.3. Only

TS2 could be located for 2. Steric repulsion between the methyl group on the radical center with the ethylene group in 2 prevents the Z to E conversion via transition structure

TS1 along the reaction path. Therefore, we have included only the energetically favorable

TS1 for the discussion of 1, 3, 5, and 6 and TS2 for 2. It has been observed that alkyl substitutions leads to the lowering of the Z to E interconversion barriers in 3, 5, and 6, compared to unsubstituted esters 1 and 2. We find from the NBO computations that the reduction in interconversion barriers are due to the stabilizing σ(C-C/H)  σ*(O-C) hyperconjugation interactions in 3, 5 and 6, which are absent in 2 and 1. For example, the specific hyperconjugations are shown below for 3 in Figure 3.4.

160

Figure 3.4. Stabilizing σ(C-H)  σ*(O-C) hyperconjugation interactions in the Z to E transition structure of (3).

Energy values of the Z rotamer (Ez) of the second-order perturbation theory analysis obtained from NBO analysis were used to estimate the magnitudes of these interactions and are given in Table 3.6. The σ(C-C/H)σ*(O-C) hyperconjugation interaction leads to a weakening and lengthening of the O-C bond (~0.01 Å), thus lowering the barrier of interconversion.

The computed activation energies for 5-exocyclization of the radicals are given in

Table 3.7. Experimental observations suggest that 1, 2, and 3 do not cyclize to form the desired product. However, it has been observed that 5 and 6, which have dialkyl substituents on the geminal position, formed the final five-membered γ-lactones.

Computed activation energies presented in Table 3.7 give light to the experimental findings. Substrates without alkyl substituents on the methylene carbon on the allylic site gave the highest activation energies. The influence of single alkyl substitution on activation energy for γ-lactone formation was very negligible. Apparently, substrates 5 and 6 gave the lowest activation barriers and highest yields.

161

Table 3.6. Strength of the σ(C-C/H)  σ*(O-C) hyperconjugation interactions pushing electron density into O-C bond in kcal/mol and the corresponding bond lengths. Substrates Hyperconjugationa O-Cb 1 0.0 1.434 2 0.0 1.435 3 -3.0 1.449 5 -6.9 1.462 6 -7.2 1.461 aHypercojugation(kcal/mol) interactions pushing electron density into O-C bond. bBond length in Å.

 Table 3.7. Activation energies (kcal/mol) for 5-exocyclization( E  ETS  EE ). ‡ ‡ ‡ ‡ Substrates E elec E ZPE H 298 G 298 1 10.7 10.1 9.6 11.6 2 9.0 8.8  8.1 11.1 3 9.9 9.4 8.8 10.9 5 8.6 7.7 7.2 9.0 6 7.7 7.2 6.7 8.6 aKey transition state distance involved in the bond formation (Å).

A plausible hypothesis that explains the selective decrease in activation barriers is the Thorpe-Ingold effect involving gem-dialkyl compression of the internal angle that brings the reactive centers (5-exocyclization) closer to one another.52 In order to understand the Thorpe-Ingold effect, the bond angles involved with gem-dimethyl effect in the E conformation of radical esters were considered, as shown in Figure 3.3. It is computed that alkyl substitution (R1 and/or R2) compresses the internal angle associated with ring closure, where 1 (113.4°) and 2 (114.0°) are both larger than 6 (111.5°), 5

(111.8°) and 3 (112.0°). Although these changes in angles seem to be minor, they are significant.52 Anomaly in 2 can be attributed to the steric congestion between the methyl group on the radical carbon and the allyl group leading to the opening of the bond angles.

It is inferred that the alkyl substituents on the radical carbon leads to the relaxation of the

162

internal angles involved in ring closure, thus disfavoring the cyclization process compared to unsubstituted radical carbon systems.

Figure 3.5. Stabilizing σ(C-H) σ*(C-C) hyperconjugation interactions in the 5-exo cyclization transitions structure of 3.

Figure 3.5 shows the formation of γ-lactone from the E conformation that involves the rotation about the C-O bond. Apart from promoting Thorpe-Ingold effect, alkyl substitution also provide σ(C-C/H)  σ*(C-C) hyperconjugation interactions that decrease the C-C bond strength and increase the C-C bond length thereby lowering the barrier of rotation about this bond. The magnitude of the hyperconjugation interactions

σ(C-C/H)  σ*(C-C) are quantified by the E(2) energy values of the second-order perturbation theory analysis obtained from NBO analysis and are given in Table 3.5.

These hyperconjugation interactions are illustrated in Figure 3.5 for 3, which are absent in 1 and 2. Single methyl substitution in 3 results in a stabilizing hyperconjugation interaction (2.3 kcal/mol) that is not strong enough to lower the activation energy of cyclization considerably. Dialkyl substitution in 5 and 6 leads to two different stabilizing hyperconjugations with total magnitude of 5.1 kcal/mol and 5.3 kcal/mol, respectively, leading to increased C-C bond length and lowering of activation barriers.

163

Table 3.8. Strength of the σ(C-C/H)  σ*(C-C) hyperconjugation interactions pushing electron density into C-C bond in kcal/mol and the corresponding bond lengths. Substrates Hyperconjugationa C-Cb 1 0.0 1.517 2 0.0 1.516 3 -2.3 1.521 5 -5.1 1.532 6 -5.3 1.532 aHypercojugation(kcal/mol) representing sum of the terms involving anomeric effects pushing electron density into C-C bond. bBond length in Å.

Finally, the reaction path for the formation of five membered γ-lactone rings from each of the acrylates was computed as shown Figure 3.6. The energetics of the reaction path are given in Figure 3.7. DFT predicts that the activation barriers for both Z to E conversion and 5-exocyclization are low for 6, followed by 5. Experimentally, it has been determined that 6 bearing the ethyl and methyl group at the germinal carbon gave the highest yield of the lactone, followed by 5 with dimethyl substitution. Predicted DFT activation barriers are in accord with the experiments, as 6 has the lowest barrier height followed by 5. Highest activation barriers were predicted for 2, which was unable to form lactones experimentally, followed by 1. Steric interactions between the methyl group on the radical carbon and the allyclic group leads to the increase in the activation barrier for

5-exocyclization in 2.

164

Figure 3.6. Z and E conformations of allyl acrylate along with the corresponding transition states and final γ-lactone involved in the reaction path.

165

Figure 3.7. Reaction path for the formation of -lactone.

3.4 Summary and Conclusions

Copper-catalyzed atom transfer radical addition (ATRA) followed by cyclization

(ATRC) of CCl4 and 1,6-diene esters (allyl acrylate (1), allyl methacrylate (2), methyl-2- propenyl acrylate (3), phenyl-2-propenyl acrylate (4), dimethyl-2-propenyl acrylate (5), ethylmethyl-2-propenyl acrylate (6) and dimethyl-2-propenyl methacrylate (7)) leading to the formation of functionalized -lactones was investigated. The reaction involves a sequence of intermolecular addition of CCl4 to the of acrylic C=C bond generating a 5- hexenyl type radical followed by intramolecular trapping of the ester radical by the remaining allylic C=C bond. Experimental observations revealed that substrates 5 and 6 yielded the desired 5-exocyclic products, while other substrates afforded the formation of open-chain adducts and polymers. Experimental findings and computational investigations both agreed that the cyclization of the allylic ester radicals is promoted by the dialkyl substitution on the methylene carbon of the allylic side. Dialkyl substitution

166

facilitates hyperconjugation interactions that are responsible for the lowering of Z to E interconversion barrier and the barrier for 5-exo cyclizations. However, consistent with the Hammond Postulate,67 anomeric hyperconjugations at the transition structures are responsible for the activation energy lowering that allows 5 and 6 to cyclize. This study emphasizes the significance of streoelectronics in governing the selectivity towards cyclization of 1,6-diene esters.

3.5 Experimental

3.5.1 General Procedures

All alcohols (3-buten-2-ol, 1-phenyl-2-propen-1-ol, 2-methyl-3-buten-2-ol and3- methyl-1-penten-3-ol), allyl acrylate, allyl methacrylate, acryloyl chloride and triethylamine were purchased from commercial sources and used as received.

Acetonitrile and methylene chloride were degassed and deoxygenated using Innovative

Technology solvent purifier. 2,2-Azobisisobutyronitrile was recrystallized from cold methanol and dried under vacuum. Tris(2-pyridylmethyl)amine (TPMA) was synthesized according to literature procedure.53 [CuII(TPMA)Cl]Cl] was prepared according to published procedure.7 1H NMR and 13C spectra were obtained using Bruker Avance 400

MHz and 100 MHz; respectively. All chemical shifts are given in ppm relative to residual

1 13 solvent peaks ( H =CDCl3, 7.26 ppm, C= 77.2 ppm).

3.5.2 Synthesis of 1,6-Diene Esters

Into a Schlenk flask were added 50-mL CH2Cl2, corresponding alcohol (3-buten-

2-ol (10 mmols, 870 L), 1-phenyl-2-propen-1-ol (10 mmols, 1314 L), 2- methyl-3-buten-2-ol (10 mmols, 1050 L) and 3-methyl-1penten-3-ol (10 mmols, 1195

167

L)) and triethylamine (30 mmols 4.2 mL), afterwards, the resulting mixture was kept stirring at 00C. Acryloyl choride (890 L, 11 mmols) or methacryloyl chloride (1075 L,

11 mmols) was then added, dropwise to the mixture. After the addition, the resulting mixture was allowed to warm up to room temperature and stirred overnight. Work-up with 10% v/v HCl (3 x 20 ml) solution followed, extracting the organic layer each time.

Collected organic layer was washed with brine solution and dried over anhydrous magnesium sulfate and solvent removed in vacuo. Flash column chromatography on a silica gel with hexane:ethyl acetate (40:1) as the eluent provided the 1,6-diene ester.

3.5.3 General Procedure for [CuII(TPMA)Cl][Cl] and AIBN Catalyzed Atom Transfer Radical Addition of CCl4 to Unsymmetrical Diene Esters.

All reactions were performed in disposable 5.0mm NMR tubes equipped with a plastic cap. In a typical experiment, a stock solution containing diene ester, CCl4, AIBN and p-dimethoxybenzene internal standard was prepared in a 1:1.25:0.05:0.1 ratio and

MeOH was added to maintain a concentration of 1.0M. Aliquots of the solution (0.2 mmol, 200L) were distributed to NMR tubes, followed by the desired amount of the copper(II) complex and total volume was adjusted by to maintain a concentration of

0.5M. Each reaction mixture flushed with argon for at least 30 seconds, secured with standard polyethylene NMR tube cap and sealed with a Teflon tape followed by electrical tape. The reaction mixture was then immersed in an oil bath thermostated at 800C for a period of 24h. The percent conversion and yield were obtained using 1H NMR spectroscopy relative to the internal standard. The -lactones were isolated by preperative

TLC on silica gel with hexane:ethyl acetate (80:20) as the mobile phase.

168

3.5.4 Product Characterization

Spectral data for 1,6-diene esters methyl-2-propenyl acrylate (3) and dimethyl-2- propenyl acrylate (5) were consistent with previously reported publication.26

Phenyl-2-propenyl acrylate (4) O O Ph

1 H NMR (400 MHz; CDCl3):  7.26-7.18 (m. 5H), 6.33 (d, J = 17.3 Hz, 1H), 6.21 (d, J =

5.9 Hz, 1H), 6.06 (dd, J = 17.3, 10.4 Hz 1H), 5.91 (ddd, J = 16.9, 10.4, 6.2 Hz 1H), 5.73

(d, J = 10.4, Hz 1H), 5.16 (dd, J = 22.2, 13.8 Hz, 2H).

13 C NMR (100 MHz; CDCl3):  165.2, 138.8, 136.2, 131.2, 128.3, 127.7, 127.2, 126.4,

117.1, 75.3.

Ethylmethyl-2-propenyl acrylate (6) O O

1 H NMR (400 MHz; CDCl3):  6.20 (dd, J = 17.3, 1.6 Hz 1H), 5.90 (ddd, J = 39.2, 17.3,

10.7 Hz 2H), 5.62 (dd, J = 10.3, 1.6 Hz 1H), 5.04 (dd, J = 14.2, 1.0 Hz, 1H), (dd, J = 7.8,

1.0 Hz, 1H), 1.68-1.80 (m, 2H), 1.43 (s, 3H), 0.74 (t, J = 7.5, 1.0 Hz, 2H).

13 C NMR (100 MHz; CDCl3):  165.1, 141.5, 129.9, 113.4, 83.6, 32.6, 23.1, 7.9.

Dimethyl-2-propenyl methacrylate (7) O O

1 H NMR (400 MHz; CDCl3):  5.96 (dd, J = 17.4, 11.2 Hz 1H), 5.90 (s, 1H), 5.36 (s,

1H), 5.06(d, J = 17.6 Hz 1H), 4.95(d, J = 11.2 Hz 1H), 1.77 (s, 3H), 1.42 (s, 6H).

13 C NMR (100 MHz; CDCl3):  165.2, 142.6, 137.7, 124.7, 112.6, 80.8, 26.5, 18.4.

169

3-(Chloromethyl)-5,5-dimethyl-4-(2,2,2-trichloroethyl)dihydrofuran-2(3H)-one O

Cl O

Cl3C 1 H NMR (400 MHz; CDCl3):  4.05 (dd, J = 12.0, 4.0 Hz 1H), 3.63 (dd, J = 12.0, 4.0 Hz

1H), 3.53 (dd, J = 15.3, 4.7 Hz 1H), 2.94 (dd, J = 15.4, 4.1 Hz, 1H), 2.83 (dd, J = 12.2,

4.6 Hz 1H), 2.62-2.55 (m, 1H), 1.67 (s, 3H), 1.50 (s, 1H).

13 C NMR (100 MHz; CDCl3):  174.0, 97.7, 84.7, 54.4, 52.7, 42.8, 41.7, 29.6, 21.6.

3-(Chloromethyl)-5-ethyl-5-methyl-4-(2,2,2-trichloroethyl)dihydrofuran-2(3H)-one O

Cl O

Cl3C

1 H NMR (400 MHz; CDCl3): (cis isomer) 4.03 (dd, J = 12.0, 4.0 Hz, 1H), 3.65 (dd, J =

12.0, 10.2 Hz, 1H), 3.52 (dd, J = 15.2, 4.8 Hz, 1H), 2.97 (dd, J = 15.4, 4.2 Hz, 1H), 2.86-

2.82 (m, 1H), 2.70-2.63 (m, 1H), 1.90-1.77 (m, 1H), 1.47 (s, 3H), 0.74 (t, J = 7.4 Hz,

3H). (trans isomer)  4.04 (dd, J = 12.0, 4.4 Hz, 1H), 3.68 (dd, J = 12.0, 10.4 Hz, 1H),

3.53 (dd, J = 15.2, 4.0 Hz, 1H), 2.90 (dd, J = 14.2, 4.2 Hz, 1H), 2.65-2.59 (m, 1H), 2.09-

2.0 (m, 1H), (1.90-1.77 (m, 1H), 1.61 (s, 3H), 0.75 (t, J = 7.4 Hz, 3H).

13 C NMR (100 MHz; CDCl3):  174.2, 97.7, 86.9, 54.4, 53.9, 42.7, 34.3 26.0, 19.7, 7.8.

3.5.5 Computational Methods

Computer resources were acquired from the Center for Computational Sciences

(CCS) at Duquesne University.54 The Gaussian 09 program55 has been used for all the electronic structure calculations. Truhlar‘s hybrid meta-generalized gradient exchange correlation functional M06-2X56,57 combined with Dunning‘s augmented correlation- consistent polarized-valence double-zeta basis set (aug-cc-pVDZ)58 has been used to

170

investigate the atom transfer radical cascade reactions involving 1,6-diene esters of interest. Tomasi‘s polarized continuum model (PCM)59,60 was utilized to include the effects of solvent. Full ground-state and transition-state optimizations were carried out on different using dielectric constant of 35.69 (acetonitrile). Frequency calculations were carried out to confirm all stationary points as minima or first-order saddle points on the potential energy surface.

Natural bond orbital (NBO) analysis was performed using the NBO 5.9 program,61 embedded within the Gaussian 09 suite. NBO transforms the non-orthogonal atomic orbitals from the HF wave function into orthonormal natural atomic orbitals

(NAO),62 natural hybrid orbitals (NHO),63 natural bond orbitals (NBO)64 and natural localized molecular orbitals (NLMO).65 This allows electron density to be treated in a more intuitive manner, i.e. localized onto bonds, atoms, and lone pairs, leading to a description of the molecule as a localized Lewis structure. NBO estimates the energy involved in specific hyperconjugations between donor and acceptor orbital interactions.

In this study, NBO was used to estimate the σ(C-H)→ σ*(O—C) and σ (C-H)→ σ*(C—

C) interaction energies. All NBO computations were performed at M062X/aug-cc-pVDZ level of theory as Goodman suggested the use of Dunning‘s basis set for the accurate prediction of orbital interactions when using NBO.66

171

3.6 References

1. Stevens, C. V.; Van Meenen, E.; Masschelein, K. G. R.; Eeckhout, Y.; Hooghe, W.; D‘hondt, B.; Nemykin, V. N.; Zhandkin, V. V., A Copper-Catalyzed Domino Radical Cyclization Route to Benzospiro-Indolizidinepyrrolidinones. Tet. Lett. 2007, 48, 7108-7111.

2. Yang, D.; Yan, Y.; Zheng, B. F.; Gao, Q.; Zhu, N. Y., Copper(I)-Catalyzed Chlorine Atom Transfer Radical Cyclization Reactions of Unsaturated α-Chloro β-Keto Esters. Org. Lett. 2006, 8 (25), 5757-5760.

3. Tietze, L. F., Domino Reactions in Organic Synthesis. Chem. Rev. 1996, 96, 115- 136.

4. Eckenhoff, W. T.; Pintauer, T., Copper Catalyzed Atom Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions in the Presence of Reducing Agents. Cat. Rev. Sci. Eng. 2010, 51, 1-59.

5. Pintauer, T., Catalyst Regeneration in Transition-Metal-Mediated Atom-Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions. Eur. J. Inorg. Chem. 2010, 2010 (17), 2449-2460.

6. Quebatte, L.; Haas, M.; Solari, E.; Scopelliti, R.; Nguyen, Q. T.; Severin, K., Combinatorial Catalysis with Bimetallic Complexes: Robust and Efficient Catalysts for Atom-Transfer Radical Additions. Angew. Chem., Int. Ed. 2004, 43 (12), 1520-1524.

7. Eckenhoff, W. T.; Pintauer, T., Atom Transfer Radical Addition in the Presence of Catalytic Amounts of Copper(I/II) Complexes with Tris(2- pyridylmethyl)amine Inorg. Chem. 2007, 46 (15), 5844-5846.

8. Eckenhoff, W. T.; Garrity, S. T.; Pintauer, T., Highly Efficient Copper-Mediated Atom Transfer Radical Addition (ATRA) in the Presence of a Reducing Agent. Eur. J. Inorg. Chem. 2008, (4), 563-571.

172

9. Pintauer, T.; Matyjaszewski, K., Atom transfer radical addition and polymerization reactions catalyzed by ppm amounts of copper complexes. Chem. Soc. Rev. 2008, 37 (6), 1087-1097.

10. Quebatte, L.; Thommes, K.; Severin, K., Highly Efficient Atom Transfer Radical Addition Reactions with a RuIII Complex as a Catalyst Precursor. J. Am. Chem. Soc. 2006, 128 (23), 7440-7441.

11. Thommes, K.; Icli, B.; Scopelliti, R.; Severin, K., Atom Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions Catalyzed by a Mixture of [RuCl2Cp*(PPh3)] and Magnesium. Chem. Eur. J. 2007, 13 (24), 6899-6907.

12. Maiti, D.; Narducci Sarjeant, A. A.; Itoh, S.; Karlin, K. D., Suggestion of an Organometallic Intermediate in an Intramolecular Dechlorination Reaction Involving Copper(I) and a ArCH2Cl Moiety. J. Am. Chem. Soc. 2008, 130 (17), 5644-5645.

13. Blackman, A., Tripodal Tetraamine Ligands Containing Three Pyridine Units: The other Polypyridyl Ligands Eur. J. Inorg. Chem. 2008, 17, 2633-2647.

14. Iizuka, Y.; Li, Z.; Satoh, K.; Kamigaito, M.; Okamoto, Y.; Ito, J.-i.; Nishiyama, H., Chiral (–)-DIOP Ruthenium Complexes for Asymmetric Radical Addition and Living Radical Polymerization Reactions. Eur. J. Org. Chem. 2007, (5), 782-791.

15. Lundgren, R. J.; Rankin, M. A.; McDonald, R.; Stradiotto, M., Neutral, Cationic, and Zwitterionic Ruthenium(II) Atom Transfer Radical Addition Catalysts Supported by P,N-Substituted Indene or Indenide Ligands. Organometallics 2008, 27 (2), 254-258.

16. Oe, Y.; Uozumia, Y., Highly Efficient Heterogeneous Aqueous Kharasch Reaction with an Amphiphilic Resin-Supported Ruthenium Catalyst Adv. Synth. Catal. 2008, 350, 1771-1775.

17. Diaz-Alvarez, A. E.; Crochet, P.; Zablocka, M.; Duhayon, C.; Cadierno, V.; Majoral, J. P., Developing the Kharasch reaction in aqueous media: Dinuclear group 8 and 9 catalysts containing the bridging cage ligand tris(1,2- dimethylhydrazino)diphosphane. Eur. J. Inorg. Chem. 2008, (5), 786-794.

18. Wolf, J.; Thommes, K.; Briel, O.; Scopelliti, R.; Severin, K., Dinuclear Ruthenium Ethylene Complexes: Syntheses, Structures, and Catalytic

173

Applications in ATRA and ATRC Reactions. Organometallics 2008, 27 (17), 4464-4474.

19. Clark, A. J.; Wilson, P., Copper Mediated Atom Transfer Radical Cyclisations with AIBN. Tetrahedron Lett. 2008, 49, 4848-4850.

20. Muñoz-Molina, J. M.; Belderrain, T. R.; Perez, P. J., Copper-Catalyzed Synthesis of 1,2-Disubstituted Cyclopentanes from 1,6-Dienes by Ring-Closing Kharasch Addition of Carbon Tetrachloride Adv. Synth. Catal. 2008, 350, 2365-2372.

21. Ricardo, C.; Pintauer, T., Copper Catalyzed AtomTransfer Radical Cascade Reactions in the Presence of Free-Radical Diazo Initiators as Reducing Agents. J. Chem. Soc. Chem. Commun. 2009, 3029-3031.

22. Togo, H., Advanced Free Radical Reactions for Organic Synthesis. Elsevier: Amsterdam, 2004.

23. ApSimon, J., The Total Synthesis of Natural Products. Wiley-Interscience: New York, 1973.

24. Ogliaruso, M. A.; Wolfe, J. F.; Patai, S.; Rappoport, Z., Synthesis of Lactones and Lactams. Wiley: Chichester New York, 1993.

25. Hanessian, S., Total synthesis of natural products, the "Chiron" approach. Pergamon Press: Oxford [Oxfordshire] New York, 1983.

26. Russell, G. A.; Li, C.; Chen, P., Cyclizations in the Addition of Alkylmercury Halides to Dienes and Enynes. J. Am. Chem. Soc. 1996, 118 (41), 9831-9840.

27. Wang, C.; Russell, G. A., γ-Lactone Formation in the Addition of Benzenesulfonyl Bromide to Diene and Enyne Esters. J. Org. Chem. 1999, 64 (6), 2066-2069.

28. Taylor, M. J. W.; Eckenhoff, W. T.; Pintauer, T., Copper-Catalyzed Atom Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions in the Presence of Environmentally Benign Ascorbic Acid as a Reducing Agent. Dalton Trans. 2010, 39 (47), 11475-11482.

174

29. Zytowski, T.; Fischer, H., Absolute Rate Constants for the Addition of Methyl Radicals to Alkenes in Solution: New Evidence for Polar Interactions. J. Am. Chem. Soc. 1996, 118 (2), 437-439.

30. Zytowski, T.; Fischer, H., Absolute Rate Constants and Arrhenius Parameters for the Addition of the Methyl Radical to Unsaturated Compounds: The Methyl Affinities Revisited. J. Am. Chem. Soc. 1997, 119 (52), 12869-12878.

31. Russell, G. A.; Li, C., Cyclization of α-Carbonyl Radicals via Condensation of Electron- Deficient Alkenes with t-BuHgI and Ph2S2. Synlett 1996, 7, 699-700.

32. Serra, A. C.; da Silva Correa, C. M. M.; do Vale, M. L. C., The Effect of the Carbonyl Cyclization of 1-Hexenyl Group in the Radicals Tetrahedron 1991, 47 (45), 9463-9488.

33. Beckwith, A. L. J., Regio-Selectivity and Stereo-Selectivity in Radical Reactions. Tetrahedron 1981, 37 (18), 3073-3100.

34. Julia, M., Free Radical Cyclizations. J. Am. Chem. Soc. 1970, 4, 386-392.

35. Yorimitsu, H.; Nakamura, T.; Shinokubo, H.; Oshima, K.; Omoto, K.; Fujimoto, H., Powerful Solvent Effect of Water in Radical Reaction: Triethylborane- Induced Atom-Transfer Radical Cyclization in Water. J. Am. Chem. Soc. 2000, 122 (45), 11041-11047.

36. Oki, M.; Nakanishi, H., Conformations of the Ester Group. Bull. Chem. Soc. Jpn. 1970, 43 (8), 2558-2566.

37. Curran, D. P.; Tamine, J., Effects of temperature on atom transfer cyclization reactions of allylic α-iodo esters and amides J. Org. Chem. 1991, 56 (8), 2746- 2750.

38. Clark, A. J., Atom Transfer Radical Cyclisation Reactions Mediated by Copper Complexes. Chem. Soc. Rev. 2002, 31 (1), 1-11.

39. Mero, C. L.; Porter, N. A., Lewis-Acid Promoted Free Radical Additions. J. Am. Chem. Soc. 1999, 121 (22), 5155-5160.

175

40. Feng, H.; Kavrakoka, I.; Pratt, D. A.; Tellinghuisen, J.; Porter, N. A., Lewis Acid- Promoted Kharasch-Curran Additions: A Competition Kinetics Study of Bromine Atom Transfer Addition of N-α-Bromoacetyl-oxazolidinone to 1-Hexene. J. Am. Chem. Soc. 2002, 67 (17), 6050-6054.

41. Yang, D.; Gu, S.; Yan, Y.; Zhu, N.; Cheung, K., Highly Enantioselective Atom- Transfer Radical Cyclization Reactions Catalyzed by Chiral Lewis Acids. J. Am. Chem. Soc. 2001, 123 (35), 8612-8613.

42. Yoshioka, E.; Kohtani, S.; Miyabe, H., Enantioselective Radical Cyclization for the Synthesis of Cyclic Compounds. Heterocycles 2009, 79, 229-242.

43. Jung, M. E.; Gervay, J., gem-Dialkyl Effect in the Intramolecular Diels-Alder Reaction of 2-Furfuryl Methyl Fumarates: The Reactive Rotamer Effect, the Enthalpic Basis for Acceleration, and Evidence for a Polar Transition State. J. Am. Chem. Soc. 1971, 113 (1), 224-232.

44. Eucken, A.; Meyer, L., Die elektrischen Momenteder aliphatischen Lactame und die Konfiguration der Siiureamidgrupp. Physik. Z 1929, 30.

45. Curl, J. R. F., Microwave Spectrum, Barrier to Internal Rotation, and Structure of Methyl Formate. J. Chem. Phys. 1959, 30 (6), 1529-1536.

46. Blom, C. E.; G¸nthard, H. H., Rotational isomerism in methyl formate and methyl acetate; a low-temperature matrix infrared study using thermal molecular beams. Chem. Phys. Lett 1981, 84 (2), 267-271.

47. Wennerstrom, H.; Forsen, S.; Roos, B., Ester group. I. Ab Initio Calculations on Methyl Formate. J. Chem. Phys. 1972, 76 (17), 2430-2436.

48. Jones, G. I. L.; Owen, N. L., Molecular structure and conformation of carboxylic esters. J. Mol. Struct. 1973, 18 (1), 1-32.

49. John, I. G.; Radom, L., Molecular conformations of methyl formate and methyl vinyl ether from ab initio molecular orbital calculations. J. Mol. Struct. 1977, 36 (1), 133-147.

176

50. Evanseck, J. D.; Houk, K. N.; Briggs, J. M.; Jorgensen, W. L., Quantification of Solvent Effects on the Acidities of Z and E Esters from Fluid Simulations. J. Am. Chem. Soc 1994, 116 (23), 10630-10638.

51. Wiberg, K. B.; Laidig, K. E., Barriers to Rotation Adjacent to Double Bonds. 3. The Carbon-Oxygen Barrier in Formic Acid, Methyl Formate, Acetic Acid, and Methyl Acetate. The Origin of Ester and Amide Resonance. J. Am. Chem. Soc 1987, 109 (20), 5935-5943.

52. Beesley, R. M.; Ingold, C. K.; Thorpe, J. F., CXIX.-The formation and stability of spiro-compounds. Part I. spiro-Compounds from cyclohexane. J. Chem. Soc., Trans 1915, 107, 1080-1106.

53. Tyeklar, Z.; Jacobson, R. R.; Wei, N.; Murthy, N. N.; Zubieta, J.; Karlin, K. D., Reversible Reaction of Dioxygen (and Carbon Monoxide) with a Copper(I) Complex. X-ray Structures of Relevant Mononuclear Cu(I) Precursor Adducts and the Trans-(μ-1,2-Peroxo)dicopper(II) Product. J. Am. Chem. Soc. 1993, 115 (7), 2677-2689.

54. Evanseck, J. D.; Madura, J., In National Science Foundation: CHE-0723109 and CHE-0321147 and United States Department of Education: P116Z080180, P116Z050331, and P116Z040100.

55. Gaussian 09, R. A., M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, and D. J. Fox, Gaussian, Inc., Wallingford CT, 2009.

56. Zhao, Y.; Schultz, N. E.; Truhlar, D. G., Design of Density Functionals by Combining the Method of Constraint Satisfaction with Parametrization for Thermochemistry, Thermochemical Kinetics, and Noncovalent Interactions. J.

177

Chem. Theory Comput. FIELD Full Journal Title:Journal of Chemical Theory and Computation 2006, 2 (2), 364-382.

57. Zhao, Y.; Truhlar, D. G., The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-Class Functionals and 12 Other Functionals. Theor. Chem. Acc. FIELD Full Journal Title:Theoretical Chemistry Accounts 2008, 120 (1-3), 215-241.

58. Dunning, T. H., Jr., Gaussian Basis Sets for Use in Correlated Molecular Calculations. I. The Atoms Boron Through Neon and Hydrogen. J. Chem. Phys. 1989, 90 (2), 1007-23.

59. Miertus, S.; Scrocco, E.; Tomasi, J., Electrostatic Interaction of a Solute with a Continuum. A Direct Utilizaion of AB Initio Molecular Potentials for the Prevision of Solvent Effects. Chem. Phys. 1981, 55 (1), 117-129.

60. Miertus, S.; Tomasi, J., Approximate Evaluations of the Electrostatic Free Energy and Internal Energy Changes in Solution pProcesses. Chem. Phys. 1982, 65 (2), 239-245.

61. Glendening, E. D.; Badenhoop, J. K.; Reed, A. E.; Carpenter, J. E.; Bohmann, J. A.; Morales, C. M.; Weinhold, F. NBO 5.9, (Theoretical Chemistry Institute, University of Wisconsin, Madison, WI, 2009); http://www.chem.wisc.edu/~nbo5.

62. Reed, A. E.; Weinhold, F., Natural Localized Molecular Orbitals. J. Chem. Phys. 1985, 83 (4), 1736-1740.

63. Foster, J. P.; Weinhold, F., Natural Hybrid Orbitals. J. Am. Chem. Soc 1980, 102 (24), 7211-7218.

64. Reed, A. E.; Curtiss, L. A.; Weinhold, F., Intermolecular interactions from a natural bond orbital, donor-acceptor viewpoint. Chem. Rev. 1988, 88 (6), 899- 926.

65. Reed, A. E.; Weinstock, R. B.; Weinhold, F., Natural Population Analysis. J. Chem. Phys. 1985, 83 (2), 735-746.

178

66. Goodman, L.; Sauers, R. R., Diffuse Functions in Natural Bond Orbital Analysis. J. Comput. Chem. FIELD Full Journal Title:Journal of Computational Chemistry 2007, 28 (1), 269-275.

67. Hammond, G. S., A Correlation of Reaction Rates. J. Am. Chem. Soc 1955, 77 (2), 334-338.

179

Chapter 4

One-Pot Sequential Azide-Alkyne [3+2] Cycloaddition and Atom Transfer Radical Addition (ATRA): Expanding the Scope of In Situ Copper(I) Regeneration in the Presence of Environmentally Benign Reducing Agent

One-pot sequential reactions involving azide-alkyne [3+2] cycloaddition and atom transfer radical addition (ATRA) catalyzed by [CuII(TPMA)X][X] (X=Br- or Cl-, TPMA= tris(2-pyridylmethyl)amine) in the presence of ascorbic acid as a reducing agent were reported. Reactions with azidopropyl methacrylate and 1-(azidomethyl)-4-vinylbenzene in the presence of a variety of alkynes (phenylacetylene, 3,4-difluorophenylacetylene, propargyl alcohol, 2-methyl-3-butyn-2-ol, methyl propiolate and ethyl propiolate) and alkyl halides (carbon tetrachloride, carbon tetrabromide, ethyl trichloroacetate, methyl trichloroacetate, ethyl dichloroacetate, methyl dichloroacetate, dichloroacetonitrile and 2- bromopropionitrile) proceeded efficiently to yield highly functionalized

(poly)halogenated esters and aryls containing triazolyl group in the presence of as low as

0.5 mol-% of the catalyst. It is envisioned that the presented methodology could have further implications in organic synthesis of functionalized triazoles, which have recently been identified as the lead targets for the screening of potential pharmaceutical drugs.

180

4.1 Introduction

In 2001, reinvigoration of old style of organic synthesis was defined in response to the demands of modern chemistry.1 This was coined as ―click chemistry‖ describing faster and modular style of synthesis. Among the reactions that met the stringent criteria, copper-catalyzed Huisgen [3+2] cycloaddition popularized by the Meldal2 and Sharpless3 laboratories was the first to achieve the ―click status‖. To date, this reaction has emerged as the best example of click chemistry due to its reliability, robustness, functional group tolerance, ability to withstand wide spectrum of solvents, and desirable properties of the triazole.1,2,4 Numerous applications of this type of chemistry have been found in all aspects of bioconjugation, drug discovery, and material science.4-6

181

Scheme 4.1 Proposed Mechanism for Copper-Catalyzed [3+2] Azide-Alkyne Cycloaddition.7,8 Mechanistically, the first step in copper catalyzed [3+2] cycloaddition involves the formation of copper(I) acetylides, which are formed from copper(I) (typically regenerated from copper(II) in the presence of sodium ascorbate), terminal alkynes, and a base (Scheme 4.1). The generated copper(I) acetylide species have a strong tendency to form -coordinate bridged aggregates, the formation of which is strongly dependent on the nature and type of complexing ligand.7 The second step in the catalytic cycle is the reaction of copper(I) acetylides with organic azides to from triazolyl-copper intermediates,9 which upon protonolysis yield the desired 1,2,3-triazole. This last step also regenerates the copper(I) catalyst.

Another C-C forming reactions that are becoming more synthetically useful are the transition-metal catalyzed atom transfer radical addition (ATRA) and the

182

intramolecular counterpart, atom transfer radical cyclization (ATRC).10-15 Traditionally, both were conducted in the presence of high catalyst loadings, therefore facing issues in product separation and catalyst recycling. Solution to these problems was found for the mechanistically similar atom transfer radical polymerization (ATRP),16,17 in which reducing agents were utilized to continuously regenerate the activator or copper(I) complex.18-21 Catalyst regeneration technique has also been shown to be highly efficient in ruthenium22 and copper13,23-26 catalyzed ATRA and ATRC reactions. The presence of the reducing agents (free-radical diazo initiators, magnesium or ascorbic acid) successfully allowed the reduction in the amount of transition metal complex, and as a result, these reactions can now be conducted using very low amounts of the catalyst.27-39

Additionally, the methodology was also extended to include sequential organic transformations involving ATRA/ATRC.30,40,41

183

Scheme 4.2. Proposed Mechanism for Copper-Catalyzed Atom Transfer Radical Addition (ATRA) in the Presecence of Reducing Agents.

The proposed mechanism for copper catalyzed ATRA in the presence of reducing agents is shown in Scheme 4.2. To role of the reducing agent is to continuously regenerate copper(I) from the copper(II) complex that accumulates in the reaction mixture as a result of unavoidable and often diffusion controlled radical-radical termination reactions. The copper(I) complex starts a catalytic cycle by homolytically cleaving an alkyl halide bond to produce an alkyl radical that adds across a carbon-carbon double bond of an alkene. The generated secondary radical then irreversibly abstracts halogen atom from the copper(II) complex to form a desired monoadduct. This step regenerates the activator or copper(I) complex, completing the catalytic cycle. As

184

indicated in Scheme 4.2, the competing side reactions in this process besides radical terminations by either coupling or disproportionation include repeating radical additions to alkene to form oligomers/polymers.

Since azide-alkyne [3+2] cycloaddition (Scheme 4.1)1,3,4 and ATRA (Scheme

4.2)13,25,26 are both catalyzed by copper(I) complexes, our attention has focused on the possibility for mediating these reactions in a one-pot sequential manner (Scheme 4.3).

Such sequence would lead to the formation of compounds with both triazole and halogen functionalities. The latter one is particularly attractive because it opens up the possibilities for numerous organic transformations such as elimination, displacement, conversion to a Grignard reagent, etc. Also, on the other hand, the halogen functionality could serve as further radical precursor. A combination of copper catalyzed azide-alkyne

[3+2] cycloaddition and mechanistically similar ATRP was first explored by the group of

Matyjaszewski in a two-pot two-step manner consisting of converting the halogen end- groups in well-defined polymers to azides and then subsequently triazoles.42,43 The methodology was also successfully extended to one-pot simultaneous reaction in which propargyl methacrylate and alkyl azides were reacted to yield highly functionalized and well-defined polymeric materials.44,45 However, to the best of our knowledge, the two reactions were never applied to small molecule synthesis.

In this chapter, we report on one-pot sequential reactions involving azide-alkyne

[3+2] cycloaddition and atom transfer radical addition (ATRA) catalyzed by

[CuII(TPMA)X][X] (X=Br- or Cl-, TPMA=tris(2-pyridylmethyl)amine) in the presence of ascorbic acid as a reducing agent.

185

Scheme 4.3. Copper-catalyzed azide-alkyne cycloaddition and atom transfer radical addition.

4.2 Copper-Catalyzed [3+2] Azide-Alkyne Cycloaddition

In our previous reports we demonstrated that copper(II) complexes with TPMA ligand ([CuII(TPMA)X][X], X= Br- or Cl-) in the presence of reducing agents such as free radical diazo initiators or ascorbic acid were highly active in ATRA, ATRC, and domino or cascade type reactions.23,24,29,39,40 The next logical step was to determine whether the same complexes could also catalyze azide-alkyne [3+2] cycloaddition, particularly taking into account that tetradentate nature of TPMA46 ligand could block the coordination of alkyne to the copper(I) center, which is an important step in the reaction mechanism

(Scheme 4.1).6,47,48 Series of reactions involving azidopropyl methacrylate (AzPM) and various alkynes (Scheme 4.4 and Table 4.1) were performed in the presence of

[CuII(TPMA)][Cl][Cl] and ascorbic acid as a reducing agent.

186

Scheme 4.4. Structures of alkynes used in azide-alkyne [3+2] cycloaddition and atom transfer radical addition.

4.3 Copper-Catalyzed [3+2] Azide-Alkyne Cycloaddition

Although sodium ascorbate is widely used for in situ regeneration of CuI from

CuII salts in azide- alkyne cycloaddition,6 its insolubility in MeOH shifted our choice towards ascorbic acid. As indicated in Table 4.1, cycloaddition reactions between AzPM and alkynes: phenylacetylene (PhA), 3,4-difluorophenylacetylene (DFPhA), propargyl alcohol (PrOH) 2-methyl-3-butyn-2-ol (MBOH), methyl propiolate (MPr) and ethyl propiolate (EPr) (entries 1, 6, 11, 14, 17, and 21) in the presence of 1.0 mol% of

[CuII(TPMA)Cl][Cl] and 10-25 equiv. of ascorbic acid (relative to CuII complex) afforded the formation of the corresponding triazoles in nearly quantitative yields. Encouraged by these results, the extent of catalyst loading was further examined. In previous reports, azide-alkyne [3+2] cycloaddition reactions catalyzed by copper(I) in conjunction with

TPMA ligand required at least 10 mol% of the complex relative to azide.42,47

187

Table 4.1. [CuII(TPMA)Cl][Cl] catalyzed azide-alkyne [3+2] cycloaddition in the presence of ascorbic acid as a reducing agent.

Entry[a] Alkyne Product [CuII][b] t (h) Yield (%)[c] 1 PhA 1 1.0 1 ~100 2 0.25 1 93 3 0.25 6 96 4 0.2 6 90 5 0.1 24 83 6 DFPhA 2 1.0 1 ~100 7 0.5 2 92 8 0.5 3 ~100 9 0.25 18 92 10 0.20 18 93 11 PrOH 3 1.0 3 ~100 12 0.50 3 90 13 0.25 6 76 14 MBOH 4 1.0 3 ~100 15 0.50 24 91 16 0.25 24 56 17 MPr 5 1.0 1 ~100 18 0.50 1 95 19 0.25 3 90 20 0.20 3 81 21 EPr 6 1.0 3 ~100 22 0.50 3 97 23 0.25 3 93 24 0.20 3 86 [a] All reactions were performed in CH3OH at 60oC using [AzPM]0:[Alkyne]0 = 1:1, [AzPM]0=0.50M. The amount of ascorbic acid in each system ranged between 20 and 25 eq. relative to copper(II) complex. For alkyne structures refer to Scheme 4.4. [b] Mole percent relative to AzPM. [c] The yield is based on the formation of the triazole and was determined by 1H NMR spectroscopy using p-dimethoxybenzene as internal standard (relative errors are ±15%).

188

Surprisingly, with DFPhA, MPr, and EPr triazoles were synthesized in 93%, 81%, and 86% yields (Table 4.1, entries 10, 20 and 24), respectively, using as low as 0.2 mol% of copper. Even lower catalyst loading (0.1 mol%) was required for the reaction between

AzPM and PhA (entry 5). To the best of our knowledge, these are one of the lowest amounts of copper(II) complexes required to efficiently catalyze azide-alkyne [3+2] cycloaddition.

4.4 Sequential Azide-Alkyne [3+2] Cycloaddtion and Atom TransferRadical Addition (ATRA)

Having demonstrated the efficiency of [CuII(TPMA)Cl][Cl] to catalyze azide- alkyne [3+2] cycloaddition in the presence of ascorbic acid as a reducing agent, optimization studies were conducted to maximize the yield of the monoadduct in the second sequential step involving ATRA of CCl4. The results are summarized in Table

4.2. For all alkynes, nearly quantitative yields of the triazolyl haloalkyl esters were obtained using 1.0 mol% of the copper catalyst (entries 1, 5, 8, 12, 16, and 20). A typical

1H and 13C NMR spectra of the reaction product (6a) are shown in Figure 4.1. Further decrease in catalyst loading to 0.5 mol% still resulted in very high yields of the desired monoadduct (entries 2, 6, 9, 13, 17, and 21). It is particularly important to notice that the reaction mixtures containing as low as 0.25 mol% of [CuII(TPMA)Cl][Cl] still proceeded efficiently to afford the final product in yields greater than 80% (entries 7, 10, 18 and 22).

189

Entry[a] Alkyne Product [CuII][b] t (h)[c] Yield (%)[d] 1 PhA 1a 1.0 2 ~100(91)[e] 2 0.50 3 90 3 0.25 3 78 4 0.20 3 70 5 DFPhA 2a 1.0 3 96 6 0.50 4 90 7 0.25 6 83 8 PrOH 3a 1.0 3 95(86)[e] 9 0.50 3 86 10 0.25 3 83 11 0.20 3 73 12 MBOH 4a 1.0 3 ~100 13 0.50 3 86 14 0.25 3 74 15 0.20 3 72 16 MPr 5a 1.0 1 98 17 0.50 1 91 18 0.25 1 86 19 0.20 1 72 20 EPr 6a 1.0 3 ~100(89)[e] 21 0.50 3 ~100 22 0.25 3 85 23 0.20 3 65 o [a] All reactions were performed in CH3OH at 60 C using [AzPM]0:[Alkyne]0 = 1:1, [AzPM]0=0.50M. The amount of ascorbic acid in each system ranged between 20 and 25 eq. relative to copper(II) complex. For alkyne structures refer to Scheme 4.4. [b] Mole percent relative to alkyne. [c] Reaction time for azide-alkyne cycloaddition (time for ATRA reaction was 8 h for all substrates with [AzPM]0:[CCl4]0=1:1.25). [d] The yield is based on the formation of the product and was determined by 1H NMR spectroscopy using p-dimethoxybenzene as internal standard (relative errors are ±15%). [e] Isolated yield for the large scale reaction.

190

1 13 Figure 4.1. H (a) and C NMR (CDCl3, 298 K) (b) spectra of 6a.

191

[a] II [b] [c] [d] Entry Alk. RX [Cu ] t1(h)/t2(h) Product Yield (%)

O N3

[e] 1 CBr4 1.0 2/8 7a 99(90) 2 0.50 2/8 96 3 0.25 6/8 80 4 CCl3CO2Et 1.0 2/24 8a 82 5 PhA 0.50 2/24 72 6 CCl2HCO2Et 1.0 2/24 9a 80 7 0.50 2/24 65 8 CCl2HCN 1.0 2/24 10a 85 9 0.50 2/24 70 10 CHBr(CH3)CN 1.0 2/24 11a 35 11 1.0 2/8 100(86)[e] 12 CBr4 0.50 2/8 12a 94 13 0.25 6/8 78 14 1.0 1/24 81 15 CCl3CO2Et 0.50 1/24 13a 75 16 1.0 2/24 91 17 CCl3CO2Me 0.50 2/24 14a 81 18 1.0 2/24 80(73)[e] 19 MPr CCl2HCO2Et 0.50 2/24 15a 75 20 0.25 2/24 64 21 1.0 2/24 83 22 CCl2HCO2Me 0.50 2/24 16a 70 23 1.0 2/24 83 24 CCl2HCN 0.50 2/24 17a 78 25 1.0 2/24 75 26 CHBr(CH3)CN 0.50 2/24 18a 74 o [a] All reactions were performed in CH3OH at 60 C using [AzPM]0:[Alkyne]0 = 1:1, [AzPM]0 = 0.50M. The amount of ascorbic acid in each system ranged between 20 and 25 eq. relative to CuII complex. For alkyne structures refer to Scheme 4.4. [b] Mole percent relative to alkyne. [c] t1= reaction time for azide-alkyne cycloaddition, t2= reaction time for ATRA. For all alkyl halides 2 eq. were used relative to AzPM, except for CCl4 where only 1 eq. was utilized. [e] Yield was based on product formation and was determined by 1H NMR spectroscopy using p-dimethoxybenzene as internal standard (relative errors are ±15%). [e] Isolated yield for the large-scale reaction.

192

[a] II [b] [c] [d] Entry Alk. RX [Cu ] t1(h)/t2(h) Product Yield (%)

[e] 1 CCl4 1.0 3/8 19a 85(86) 2 0.50 3/8 83 3 PhA 0.25 6/8 32 4 CCl3CO2Et 1.0 6/24 20a 45 5 CCl3CO2Me 1.0 6/24 21a 57 [e] 6 CCl4 1.0 2/8 22a 92(90) 7 0.50 2/8 73 8 0.25 2/8 47 9 CCl3CO2Et 1.0 2/24 23a 87 10 0.50 2/24 83 [e] 11 CCl3CO2Me 1.0 2/24 24a 82(84) 12 MPr 0.50 2/24 78 13 CCl2HCO2Et 1.0 2/24 25a 43 14 CCl2HCO2Me 1.0 2/24 26a 48 15 CCl2HCN 1.0 2/24 27a 46 16 CHCl3 1.0 1/24 28a 42 17 CHBr(CH3)CN 1.0 2/24 29a 26 o [a] All reactions were performed in CH3OH at 60 C using [AzMVB]0:[Alkyne]0 = 1:1, [VBAz]0 = 0.50M. The amount of ascorbic acid in each system ranged between 20 and 25 eq. relative to CuII complex. For alkyne structures refer to Scheme 4.4. [b] Mole percent relative to alkyne. [c] t1= reaction time for azide-alkyne cycloaddition, t2= reaction time for ATRA. For all alkyl halides 2 eq. were used relative to AzMVB, except for CCl4 where only 1 eq. was utilized. [e] Yield was based on product formation and was determined by 1H NMR spectroscopy using p-dimethoxybenzene as internal standard (relative errors are ±15%). [e] Isolated yield for the large-scale reaction.

The results presented in Table 4.1 and Table 4.2 clearly indicate that copper(II)

complexes with TPMA ligand, in conjunction with ascorbic acid, are very efficient

catalysts for both azide-alkyne [3+2] cycloaddition and ATRA. In order to further

demonstrate the synthetic usefulness of this sequential sequence of reactions, additional

experiments were performed using a variety of alkyl halides including carbon

193

tetrabromide (CBr4), ethyl trichloroacetate (CCl3CO2Et), methyl trichloroacetate

(CCl3CO2Me), ethyl dichloroacetate (CCl2HCO2Et), methyl dichloroacetate

(CCl2HCO2Me), dichloroacetonitrile (CCl2HCN), and 2-bromopropionitrile

(CHBr(CH3)CN). The results for azidopropyl methacrylate (AzPM) and 1-

(azidomethyl)-4-vinylbenzene (AzMVB) are summarized in Table 4.3 and Table 4.4. As expected, for AzPM excellent yields of the final monoadduct were obtained using CBr4 and catalyst loadings as low as 0.50 mol% (entries 2 and 12). The corresponding molecular structure of the product in the case of methyl propiolate is shown in Figure 4.2.

Sequential azide-alkyne [3+2] cycloaddition and ATRA also worked reasonably well for tri- and di-halogenated substrates using 1.0 mol% of the catalyst. Monohalogenated alkyl halide, 2-bromopropionitrile, yielded only 35 and 75% of the monoadduct in the case of phenylacetylene (entry 10) and methyl propiolate (entry 25), respectively. The decreased

194

Table 4.5. Crystal structure analysis data for methyl-1-(3-(2,4,4,4-tetrabromo-2- methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (12a). Empirical formula C12H15Br4N3O4

Formula weight 584.91 Temperature 296(2) K Wavelength 0.71073 Å Crystal system, space group monoclinic, P 21/n Unit cell dimensions a=11.6637(4) Å, =90o b=6.0493(2) Å, =98.406(2)o c=26.2815(9) Å, =90o Volume 1834.43(11) Å3 Z, Calculated density 4, 2.118 mg/m3 Absorption coefficient 8.795 mm-1 F(000) 1120 Crystal size 0.320.090.05 mm  range for data collection 1.57 to 26.19o Limiting indices -14h14, -7k7, -32l32 Reflections collected / unique 21440/3654 [R(int)=0.0426] Completeness to  99.0% Absorption correction semi-empirical from equivalents Max. and min. transmission 0.6930 and 0.1676 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 3654/0/210 Goodness of fit on F2 1.363 Final R indices [I>2(I)] R1=0.0587, wR2=0.1796 R indices (all data) R1=0.0785, wR2=0.1947 Largest diff. peak and hole 2.685 and -1.162 eÅ-3

yield can be attributed to monoadduct reactivation resulting in the formation of oligomers/polymers. Furthermore, as indicated in Table 4.4, the results for AzMVB were similar to AzPM. Generally, with 1.0 mol% of the catalyst relative to azide, yields greater than 80% were obtained using CCl4 (entries 1 and 6). Respectable yields of the monoadduct were still observed using trihalogenated alkyl halides (entries 4, 5, 9 and 10), but significantly decreased for dihalogenated ones (entries 13, 14 and 15). Lastly, the monoadduct formed from the azide-alkyne [3+2] cycloaddition of methyl propiolate to

AzMVB followed by sequential ATRA of 2-bromopropionitrile was attained in only 26% yield. Certainly, from the point of view of further synthetic modifications of the resulting

195

sequential product such as conversion to a Grignard reagent, monohalogenated alkyl halides are of particular interest. Future efforts in our laboratories are directed towards optimizing reaction conditions for such substrates and utilizing more active copper complexes.

4.5 Summary and Conclusions

In conclusion, we have reported the first examples of one-pot sequential reactions involving azide-alkyne [3+2] cycloaddition and atom transfer radical addition (ATRA).

Both transformations were catalyzed by [CuII(TPMA)X][X] (X=Br- or Cl-) complexes in conjunction with ascorbic acid as the reducing agent. Reactions with azidopropyl methacrylate and 1-(azidomethyl)-4-vinylbenzene in the presence of a variety of alkynes and alkyl halides proceeded efficiently to yield highly functionalized (poly)halogenated esters and aryls containing triazolyl group in the presence of as low as 0.5 mol% of the catalyst. It is envisioned that the presented methodology could have further implications in organic synthesis of functionalized triazoles. Such compounds have recently been identified as the lead targets for the screening of potential pharmaceutical drugs.

Additionally, our methodology incorporates highly desirable halogen functionality, which is very versatile towards further organic transformations.

4.6 Experimental

4.6.1 General Procedures

All alkynes (phenylacetylene, 3,4-difluorophenylacetylene, propargyl alcohol, 2- methyl-3-butyn-2-ol, methyl propiolate and ethyl propiolate), 3-bromopropanol, methacryloyl chloride, and solvents (methanol, methylene chloride and pentane) were

196

purchased from commercial sources and used as received. Tris(2-pyridylmethyl)amine,49 azidopropyl methacrylate,43 1-(azidomethyl)-4-vinylbenzene,50 and [CuII(TPMA)X][X]

(X=Br- or Cl-)23,24 were synthesized according to literature procedures. 1H NMR and 13C spectra were obtained using Bruker Avance 400 MHz and 500 MHz spectrometers. All

1 chemical shifts are given in ppm relative to residual solvent peaks ( H =CDCl3, 7.26

13 ppm; CD2Cl2, 5.32 ppm; C= CDCl3, 77.2 ppm; CD2Cl2, 54.0 ppm).

4.6.2 Stock Solutions

[CuII(TPMA)Cl][Cl] solutions (0.04M, 0.02M and 0.01M) were prepared by dissolving the corresponding copper(II) complex in methanol using volumetric flasks to accommodate various catalyst loadings. Azidopropyl methacrylate (320 µL, 2.0 mmol) was mixed with equimolar amount of the alkyne (2.0 mmol, V(phenylacetylene)=220 µL,

V(3,4-difluorophenylacetylene)=240 µL, V(propargyl alcohol)=117 µL, V(2-methyl-3- butyn-2-ol)=194 µL, V(methyl propopiolate)=179 µL) and V(ethyl propopiolate)=203

µL)) and p-dimethoxybenzene added as internal standard (approximately 0.1 mol-% relative to azidopropyl methacrylate). Methanol was then added in order to make each stock solution 3.3M in azidopropyl methacrylate.

4.6.3 General Procedure for Azide-Alkyne [3+2] Cycloaddition Catalyzed by [CuII(TPMA)Cl][Cl] in the Presence of Ascorbic Acid

All reactions were performed in disposable 5.0 mm NMR tubes equipped with a plastic cap and Teflon tape. In a typical experiment, 60 µL of the stock solution (0.2 mmol azidopropyl methacrylate (AzPM) and 0.2 mmol alkyne) was added to the NMR tube, followed by the desired amount of the copper(II) catalyst (from 0.04M

II II [Cu (TPMA)Cl][Cl] and for [AzPM]0:[Cu ]0 =100:1 (V=50 µL), from 0.02M

II II [Cu (TPMA)Cl][Cl] and for [AzPM]0:[Cu ]0 = 200:1 (V= 50 µL), from 0.01M

197

II II [Cu (TPMA)Cl][Cl] and for [AzPM]0:[Cu ]0 = 400:1 and 500:1 (V= 50 µL and 40 µL, respectively)) and 20-25 equivalents of 0.25 M ascorbic acid in methanol (relative to

[CuII(TPMA)Cl][Cl]). Methanol was then added in order to maintain constant volume and total concentration of 0.50M in azidopropyl methacrylate. Each reaction mixture was immediately flushed with argon for at least 30 seconds and immersed in an oil bath thermostated at 60 oC. The percent yield of the expected triazole was obtained using 1H

NMR spectroscopy relative to the internal standard. If necessary, solvent was partially evaporated prior to 1H NMR analysis.

4.6.4 General Procedure for Sequential Azide-Alkyne [3+2] Cycloaddition-Atom Transfer Radical Addition Catalyzed by [CuII(TPMA)Cl][Cl] in the Presence of Ascorbic Acid

The first step was performed as explained above. After the completion of azide- alkyne [3+2] cycloaddition, the reaction mixture was taken into the dry box (<1.0 ppm O2 and <0.5 ppm H2O) and carbon tetrachloride (24 µL, 2.5 mmol, 1.25 eq relative to

AzPM) or (poly)halogenated alkyl halide (4.0 mmol, 2.0 eq. relative to AzPM) added.

The NMR tube was then capped and sealed with Teflon tape and immersed in an oil bath thermostated at 60 oC. The percent yield of the expected triazolyl halogenated alkyl ester was obtained using 1H NMR spectroscopy relative to the internal standard. If necessary, solvent was partially evaporated prior to 1H NMR analysis.

4.6.5 X-ray Crystal Structure Determination

The X-ray intensity data were collected at 150K using graphite-monochromated

Mo-K radiation (0.71073 Å) with a Bruker Smart Apex II CCD diffractometer. Data reduction included absorption corrections by the multi-scan method using SADABS.51

Structures were solved by direct methods and refined by full matrix least squares using

198

SHELXTL 6.1 bundled software package.52 The H-atoms were positioned geometrically

(aromatic C-H 0.93, methylene C-H 0.97, and methyl C-H 0.96) and treated as riding atoms during subsequent refinement, with Uiso(H) = 1.2Ueq(C) or 1.5Ueq(methyl C). The methyl groups were allowed to rotate about their local threefold axes. ORTEP-3 for windows53 and Crystal Maker 7.2 were used to generate molecular graphics.

4.6.6 Product Characterization

3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl methacrylate (1). 1H NMR (500 MHz,

o CDCl3, 25 C): δ7.82-7.80 (m, 2H,), δ7.77 (s, 1H), δ7.41 (t, J = 7.5 Hz, 2H,), δ7.32 (t, J=

7.5 Hz, 1H), δ6.10 (s, 1H), δ5.60(s, 1H,) δ4.53 (t, J = 7.0 Hz, 2H), δ4.24 (t, J = 7.0 Hz,

2H), δ4.02 (d, J = 15 Hz, 1H), δ3.50 (d, J = 15 Hz, 1H), δ2.36 (quintet, J = 6.0 Hz, 2H),

13 o 1.94 (s, 3H). C NMR (100 MHz, CDCl3, 25 C): δ 167.19, 147.94, 135.95, 130.52,

128.87, 128.23, 126.10, 125.75, 119.79, 61.25, 47.39, 29.58, 18.33.

3-(4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)propyl methacrylate (2). 1H NMR

o (500 MHz, CDCl3, 25 C): δ7.75(s, 1H), δ7.67-7.62 (m, 1H), δ7.52-7.49 (m, 1H), δ7.19

(q, J = 10 Hz, 1H), δ6.10 (s, 1H), δ5.60 (s, 1H), δ4.51 (t, J = 7.0 Hz, 2H), δ4.23 (t, J = 6.0

13 o Hz, 1H), δ2.38-2.30 (m, 2H), δ1.93 (s, 3H). C NMR (100 MHz, CDCl3, 25 C):

δ167.18, 151.74, 149.27, 146.08, 135.92, 126.13, 121.78, 119.98, 117.79, 114.48, 61.16,

47.5, 29.34, 18.32.

3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propyl methacrylate (3). 1H NMR (500

MHz; CDCl3): δ7.58 (s, 1H), δ6.13 (s, 1H), δ5.63 (s, 1H), δ4.83 (s, 2H), δ4.50 (t, J = 7.0

Hz, 2H), δ4.20 (t, J = 6.0 Hz, 2H), δ2.38-2.32 (m, 2H), δ1.97 (s, 3H). 13C NMR (100

o MHz, CDCl3, 25 C): δ161.13, 140.23, 136.00, 127.79, 126.21, 60.85, 52.39, 47.63,

29.10, 18.26.

199

3-(4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)propyl methacrylate (4). 1H NMR

o (400 MHz, CDCl3, 25 C): δ7.49 (s, 1H), δ6.11 (s, 1H), δ5.60

(s, 1H), δ4.46 (t, J = 7.0 Hz, 2H), δ4.20 (t, J = 6.0 Hz, 2H), δ2.35-2.29 (m, 2H), δ1.95 (s,

13 o 3H) δ1.64 (s, 6H). C NMR (100 MHz, CDCl3, 25 C): δ167.32, 15.79, 135.95, 127.79,

126.03, 119.59, 68.38, 61.41, 47.19, 30.57, 29.50, 18.23. methyl 1-(3-(methacryloyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (5). 1H NMR

o (500 MHz, CDCl3, 25 C): δ8.11 (s, 1H), δ6.08 (s, 1H), δ5.60 (s, 1H), δ4.52 (t, J = 7.0

Hz, 2H), δ4.20 (t, J = 6.0 Hz, 2H), δ3.95 (s, 3H), δ2.37-2.31 (m, 2H), δ1.93 (s, 3H). 13C

o NMR (100 MHz, CDCl3, 25 C): δ173.03, 167.22, 147.64, 136.26, 126.21, 121.97, 61.38,

56.62, 47.36, 29.63, 18.26. ethyl 1-(3-(methacryloyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (6). 1H NMR

o (400 MHz, CDCl3, 25 C): δ8.11 (s, 1H), δ6.07 (s, 1H), δ5.59 (s, 1H), δ4.52 (t, J = 7.0

Hz, 2H), δ4.41 (q, J = 7.1 Hz, 3H), δ4.20 (t, J = 6.0 Hz, 2H), δ2.37-2.31 (m, 2H), δ1.92

13 o (s, 3H) ,δ1.39 (t, J= 7.1 Hz, 2H). C NMR (100 MHz, CDCl3, 25 C): δ167.01 160.68,

140.36, 135.84, 127.65, 126.17, 61.35, 60.96, 47.71, 29.42, 18.29, 14.32.

3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl 2,4,4,4-tetrachloro-2-methylbutanoate (1a).

1 o Isolated yield=620 mg (91%). H NMR (500 MHz, CDCl3, 25 C): δ7.82-7.80 (m, 2H),

δ7.77 (s, 1H), δ7.43-7.40 (m, 2H), δ7.34-7.31 (m, 1H), δ4.53 (t, J = 7.0 Hz, 2H), δ4.36-

4.32 (m, 1H), δ4.27-4.22 (m, 1H), δ4.02 (d, J = 15 Hz, 1H), δ3.50 (d, J = 15 Hz, 1H),

13 o δ2.36 (quintet, J = 6.5 Hz, 2H), δ1.94 (s, 3H). C NMR (100 MHz, CDCl3, 25 C): δ

169.33, 130.44, 128.92, 128.32, 125.81, 119.99, 94.59, 64.76, 63.10, 62.18, 46.90, 29.17,

26.13.

200

3-(4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)propyl-2,4,4,4-tetrachloro-2-

1 o methylbutanoate (2a). H NMR (500 MHz, CD2Cl2, 25 C): δ7.80 (s, 1H), δ7.69 (ddd, J

= 11.5 Hz, 7.7 Hz, 2.1 Hz, 1H), δ7.56-7.53 (m, 1H,), δ7.25 (dt, J = 10.3 Hz, 8.4 Hz, 1H),

δ4.53 (t, J = 6.9 Hz, 2H), δ4.30 (m, 1H), δ4.24 (m, 1H), δ3.99 (d, J = 15.4 Hz, 1H), δ3.53

(d, J = 15.4 Hz, 1H), δ2.39 (quintuplet, J = 6.5 Hz, 2H), δ2.02 (s, 3H). 13C NMR (100

o MHz, CD2Cl2, 25 C): δ169.33, 121.83, 121.76, 121.71, 117.82, 117.63, 114.66, 114.47,

94.67, 64.82, 63.24, 61.91, 47.10, 26.10, 26.19.

3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propyl-2,4,4,4-tetrachloro-2-

1 methylbutanoate (3a). Isolated yield=550 mg (86%). H NMR (500 MHz, CDCl3, 25 oC): δ7.59 (s, 1H), δ4.82 (s, 2H), δ4.50 (t, J = 7.0 Hz, 2H), δ4.32 (dt, J = 11.6 Hz, 5.9 Hz,

1H), δ4.23 (dt, J = 11.6 Hz, 5.8 Hz, 1H), δ4.34-4.3(m, 1H), δ4.25-4.2(m, 1H), δ4.02 (d, J

= 15.4 Hz, 1H), δ3.52 (d, J = 15.4 Hz, 1H), δ2.39 (quintet, J = 6.4 Hz, 2H), δ2.05 (s, 3H).

13 o C NMR (100 MHz, CDCl3, 25 C): δ169.60, 148.17, 121.20, 94.72, 64.82, 62.97, 47.10,

29.37, 26.46.

3-(4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)propyl 2,4,4,4-tetrachloro-2-

1 o methylbutanoate (4a). H NMR (500 MHz, CDCl3, 25 C): δ8.11 (s, 1H), δ4.56 (t, J =

7.0 Hz, 2H), δ4.35-4.31(m, 1H), δ4.26-4.22(m, 1H), δ4.02 (d, J = 15.4 Hz, 1H), δ3.12 (d,

J = 15.4 Hz, 1H), δ2.72 (s, 3H), δ2.41 (quintet, J = 6.4 Hz, 2H), δ2.05 (s, 3H). 13C NMR

o (100 MHz, CDCl3, 25 C): δ169.47, 148.29, 125.76, 94.39, 64.62, 62.75, 62.75, 47.20,

28.96, 27.35, 26.28. methyl-1-(3-(2,4,4,4-tetrachloro-2-methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-

1 o carboxylate (5a). H NMR (500 MHz, CDCl3, 25 C): δ8.15 (s, 1H), δ4.57 (t, J = 7.0

Hz, 2H), δ4.36-4.3(m, 1H), δ4.26-4.20 (m, 1H), δ4.01 (d, J = 15.4 Hz, 1H), δ3.98 (s, 3H),

201

δ3.52 (d, J = 15.4 Hz, 1H), δ2.43 (quintet, J = 6.4 Hz, 2H), δ2.05 (s, 3H). 13C NMR (100

o MHz, CDCl3, 25 C): δ169.33, 161.13, 140.23, 94.19, 64.56, 62.71, 62.13, 52.39, 47.36,

29.10, 26.19. ethyl-1-(3-(2,4,4,4-tetrachloro-2-methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-

1 o carboxylate (6a). Isolated yield=610 mg (89%). H NMR (400 MHz, CDCl3, 25 C):

δ8.11 (s, 1H), δ4.55 (t, J = 6.9 Hz, 2H), δ4.43 (q, J = 7.1 Hz, 3H), δ4.33-4.3 (m, 1H),

δ4.26-4.17 (m, 1H), δ3.99 (d, J = 15.4 Hz, 1H), δ3.49 (d, J = 15.4 Hz , 1H), δ2.43-2.37

13 o (m, 2H), δ2.02 (s, 3H), δ1.41 (t, J = 7.1 Hz, 2H). C NMR (100 MHz, CDCl3, 25 C): δ

169.38, 160.63, 140.46, 127.77, 94.48, 64.70, 62.74, 62.14, 61.41, 47.28, 29.01, 26.19,

14.34.

3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl 2,4,4,4-tetrabromo-2-methylbutanoate (7a).

1 o Isolated yield=870 mg (90%). H NMR (400 MHz, CDCl3, 25 C): δ7.85 (d, J = 8.2 Hz,

2H), δ7.84 (s, 1H), δ7.45 (t, J = 7.4 Hz, 3H), δ7.36 (t, J = 7.4 Hz, 1H), δ4.73 (d, J = 15.6

Hz, 1H), δ4.59 (t, J = 6.8 Hz, 3H), δ4.42-4.36 (m, 1H), δ4.30-4.24 (s, 1H), δ3.99 (d, J =

15.6 Hz, 1H), δ2.45 (quintuplet, J = 6.4 Hz, 3H), δ2.33 (s, 3H). 13C NMR (100 MHz,

o CDCl3, 25 C): δ 169.8, 147.9, 130.4, 128.9, 128.3, 125.8, 65.8, 62.9, 57.8, 47.0, 31.2,

29.1, 26.0.

1-ethyl 5-(3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl) 2,2,4-trichloro-4-

1 o methylpentanedioate (8a). H NMR (400 MHz, CDCl3, 25 C): δ7.85 (d, J = 8.2 Hz,

2H), δ7.84 (s, 1H), ), δ7.45 (t, J = 7.4 Hz, 3H), δ7.36 (t, J = 7.4 Hz, 1H), δ4.56 (t, J = 7

Hz, 2H), δ4.36 (q, J = 7 Hz, 2H), δ4.29-4.23 (m, 2H), δ3.61 (d, J = 15.2 Hz, 1H), δ3.47

(d, J = 15.2 Hz, 1H), δ2.45-2.35 (m, 2H), 1.86 (s, 3H), δ1.41 (t, J = 15.2 Hz, 1H). 13C

202

o NMR (100 MHz, CDCl3, 25 C): δ170.0, 165.3, 147.8, 130.5, 128.9, 128.2, 125.7, 120.2

80.9, 65.3, 64.4, 63.3, 53.8, 53.3, 48.0, 29.1, 27.8, 13.7.

5-ethyl 1-(3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl) 2,4-dichloro-2-

1 o methylpentanedioate (9a). H NMR (400 MHz, CDCl3, 25 C , approx. 50/50 mixture of diastereomers): δ7.85 (d, J = 8.2 Hz, 2H), δ7.84 (s, 1H), ), δ7.42 (t, J = 7.4 Hz, 3H),

δ7.33 (t, J = 7.4 Hz, 1H), δ4.57-4.51 (m, 1H), δ4.54 (t, J = 7 Hz, 2H), δ4.33 (q, J = 7.2

Hz, 2H), δ4.26-4.19 (m, 2H), δ3.01-2.96 (m, 1H), δ2.85-2.74 (m, 1H), δ2.68-2.63 (m,

1H), δ2.40-2.33 (m, 2H), δ1.84 (s, 3H), δ1.82 (s, 3H), δ1.30 (t, J = 15.2 Hz, 2H). 13C

o NMR (101 MHz, CDCl3, 25 C): δ169.9, 169.3, 147.7, 130.5, 128.8, 128.2, 125.7, 120.1,

66.7, 63.5, 53.3, 52.5, 48.0, 45.8, 29.3, 29.1, 13.9.

3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl 2,4-dichloro-4-cyano-2-methylbutanoate

1 o (10a). H NMR (400 MHz, CDCl3, 25 C , approx. 50/50 mixture of diastereomers):

δ7.84 (d, J = 6.0 Hz, 2H), δ7.82 (s, 1H), δ7.47-7.43 (m, 2H), δ7.39-7.34 (m, 1H), δ4.86-

4.79 (m, 1H), δ4.62-4.55 (m, 1H), δ4.38-4.28 (m, 1H), δ3.04 (ddd, J = 14.8 Hz, 8.8 Hz,

0.6 Hz, ), δ2.95-2.89 (m, 1H), δ2.83-2.78 (m, 1H), δ2.68-2.63 (m, 1H), δ2.46-2.39 (m,

13 o 2H), δ1.90 (s, 3H) δ1.89 (s, 3H). C NMR (101 MHz, CDCl3, 25 C): δ 169.5, 148,

130.4, 128.9, 128.3, 125.7, 120, 116.6, 65.9, 63.8, 47.6, 38.7, 29, 28.8. methyl 1-(3-(2-bromo-4-cyano-2-methylpentanoyloxy)propyl)-1H-1,2,3-triazole-4-

1 o carboxylate (11a). H NMR (400 MHz, CDCl3, 25 C , approx. 50/50 mixture of diastereomers): δ8.12 (s, 1H), δ8.19 (s, 1H), δ4.6 (t, J = 7.0 Hz, 2H), δ4.34-4.21 (m, 2H),

δ3.97 (s, 3H), δ3.83 (s, 3H), δ2.95-2.88 (m, 1H), δ2.65-2.55 (m, 1H), δ2.59-2.55 (m, 1H),

δ2.70-2.63 (m, 1H), δ2.45-2.39 (m, 1H), δ2.36-2.61 (m, 1H), δ2.07 (s, 3H), δ2.04 (s, 3H),

203

13 δ1.46 (d, J = 7.1 Hz, 3H), δ 1.43 (d, J = 7.1 Hz, 3H). C NMR (101 MHz, CDCl3, 25 oC): δ170.3, 161.3, 140.0, 128.1, 114.7, 63.0, 55.8, 46.5, 45.3, 29.7, 27.2, 21.0, 19.5. methyl 1-(3-(2,4,4,4-tetrabromo-2-methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-

1 o carboxylate (12a). Isolated yield=850 mg (86%). H NMR (400 MHz, CDCl3, 25 C):

δ8.18 (s, 1H), δ4.68 (d, J = 15.5 Hz, 1H), δ4.59 (t, J = 6.9 Hz, 2H), δ4.37-4.31 (m, 1H),

δ4.25-4.19 (m, 1H), δ3.97 (d, J = 15.6 Hz, 1H), δ3.96 (s, 3H), δ2.43 (quintet, J = 6.4 Hz,

13 o 2H), δ2.30 (s, 3H). C-NMR (101 MHz, CDCl3, 25 C): δ 25.99, 29.00, 31.06, 47.40,

52.33, 57.69, 62.59, 65.79, 127.92, 161.06, 169.84.

1-ethyl 5-(3-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)propyl) 2,2,4-trichloro-4-

1 o methylpentanedioate (13a). H NMR (400 MHz, CDCl3, 25 C): δ8.18 (s, 1H), δ4.58 (t,

J = 6.9 Hz, 2H), δ4.38 (q, J = 7.1 Hz, 2H), δ4.29-4.21 (m, 2H), δ3.97 (s, 3H), δ3.61 (d, J

= 15.2 Hz, 1H), δ3.47 (d, J = 15.2 Hz, 1H), δ2.45-2.38 (quintuplet, J = 6.2 Hz, 2H), δ1.86

13 o (s, 3H), δ1.39 (t, J = 15.2 Hz, 1H). C NMR (101 MHz, CDCl3, 25 C): δ170.1, 165.3,

161.2, 140.12, 127.8, 80.7, 65.4, 64.3, 62.6, 53.3, 52.3, 47.3, 29.1, 27.6, 13.3.

5-(3-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)propyl) 1-methyl 2,2,4-trichloro-4-

1 o methylpentanedioate (14a). H NMR (400 MHz, CDCl3, 25 C): δ8.20 (s, 1H), δ 4.57

(t, J = 6.9 Hz, 2H), δ4.28-4.22 (m, 2H), δ3.95 (s, 3H), δ3.56 (d, J = 15.0 Hz, 1H) δ3.44

(d, J = 15.0 Hz, 1H), δ2.39 (quintuplet, J = 6.2 Hz, 2H), 1.82 (s, 3H).

5-ethyl 1-(3-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)propyl) 2,4-dichloro-2-

1 methylpentanedioate (15a). Isolated yield=670 mg (73%). H NMR (500 MHz, CDCl3,

25 oC , approx. 50/50 mixture of diastereomers): δ8.02 (s, 1H), δ8.16 (s, 1H), δ4.86-4.79

(m, 1H), δ4.57-4.54 (m, 1H), δ4.58 (t, J = 7.0 Hz, 2H), δ4.27-4.16 (m, 2H), δ3.95 (s,

3H), δ2.96 (dd, J = 15.1 Hz, 6.9 Hz, 1H), δ2.78 (qd, J = 16.4 Hz, 6.6 Hz, 1H), δ2.65 (dd,

204

J = 15.1 Hz, 6.2 Hz, 1H), δ2.41-2.35 (m, 2H), δ1.84 (s, 1H), δ1.81 (s, 1H), δ1.31 (t, , J =

13 o 7.2 Hz, 3H). C NMR (101 MHz, CDCl3, 25 C): δ170.0, 168.9, 161.1, 140.0, 128.0,

66.7, 66.1, 62.6, 52.6, 52.3, 47.3, 45.8, 29.0, 27.7, 13.9.

1-(3-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)propyl) 5-methyl 2,4-dichloro-2-

1 o methylpentanedioate (16a). H NMR (500 MHz, CDCl3, 25 C, approx. 50/50 mixture of diastereomers): δ8.20 (s, 1H), δ8.19 (s, 1H), δ4.54-4.61 (m, 2H), δ4.25-4.18 (m, 1H),

δ4.27-4.16 (m, 2H), δ3.95 (s, 3H), δ3.82 (s, 3H), δ3.81 (s, 3H), δ2.99 (dd, J = 15.1 Hz,

7.0 Hz, 1H), δ2.80 (qd, J = 13.8 Hz, 6.6 Hz, 2H), δ2.65 (dd, J = 15.1 Hz, 6.1 Hz, 1H),

13 o δ2.43-2.36 (m, 2H), δ1.85 (s, 1H), δ1.83 (s, 1H). C NMR (101 MHz, CDCl3, 25 C):

δ169.9, 169.4, 161.1, 140.0 128.1, 66.7, 66.1, 62.8, 62.7, 53.4, 52.9, 52.3, 47.3, 46.2,

46.0, 29.4, 28.9, 27.8. methyl 1-(3-(2,4-dichloro-4-cyano-2-methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-

1 o carboxylate (17a). H NMR (400 MHz; CDCl3, 25 C , approx. 50/50 mixture of diastereomers): δ8.18 (s, 1H), δ8.16 (s, 1H), δ4.87-4.79 (m, 1H), δ4.58 (t, J = 7.0 Hz,

2H), δ4.30-4.23 (m, 2H), δ3.97 (s, 3H), δ3.83 (s, 3H), δ3.07-3.01 (m, 1H), δ2.94-2.88 (m,

1H), δ2.83-2.78 (m, 1H), δ2.70-2.63 (m, 1H), δ2.48-2.39 (m, 2H), δ 1.90 (s, 3H), δ1.89

13 o (s, 3H). C NMR (101 MHz, CDCl3, 25 C): δ169.5, 140.2, 127.6, 116.1, 66.0, 63.7,

58.6, 52.2, 47.2, 38.3, 32.3, 29.3, 28.9. methyl 1-(3-(2-bromo-4-cyano-2-methylpentanoyloxy)propyl)-1H-1,2,3-triazole-4-

1 o carboxylate (18a). H NMR (400 MHz, CDCl3, 25 C, approx. 50/50 mixture of diastereomers): δ8.12 (s, 1H), δ8.19 (s, 1H), δ4.60 (t, J = 7.0 Hz, 2H), δ4.34-4.21 (m,

2H), δ3.97 (s, 3H), δ3.83 (s, 3H), δ2.95-2.88 (m, 1H), δ2.65-2.55 (m, 1H), δ2.59-2.55 (m,

1H), δ2.70-2.63 (m, 1H), δ2.45-2.39 (m, 1H), δ2.35-2.61 (m, 1H), δ2.07 (s, 3H), δ2.04 (s,

205

13 3H), δ1.46 (d, J = 7.1 Hz, 3H), δ1.43 (d, J = 7.1 Hz, 3H). C NMR (101 MHz, CDCl3,

25 oC): δ170.3, 161.3, 140.0, 128.1, 114.7, 63.0, 55.8, 46.5, 45.3, 29.7, 27.2, 21.0, 19.5.

4-phenyl-1-(4-(1,3,3,3-tetrachloropropyl)benzyl)-1H-1,2,3-triazole (19a). Isolated

1 o yield=600 mg (86%). H NMR (400 MHz, CDCl3, 25 C): δ7.83 (d J = 7.2 Hz, 2H), δ7.47

(d, J = 8.0 Hz, 2H), δ7.44-7.41 (m, 2H), δ7.36-7.32 (m, 1H), δ7.33 (d J = 8.0 Hz, 2H),

δ5.59 (s, 2H), δ5.31 (dd, J = 6.3 Hz, 5.6 Hz, 1H), δ3.63 (dd, J = 15.3 Hz, 5.3 Hz, 1H),

13 o δ3.52 (dd, J = 15.3 Hz, 6.5 Hz, 1H). C NMR (101 MHz, CDCl3, 25 C): δ148.3, 140.9,

135.6, 130.5, 128.9, 128.50, 128.31, 128.25, 125.7, 119.8, 96.1, 62.5, 57.7, 53.6. ethyl 2,2,4-trichloro-4-(4-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)butanoate

1 o (20a). H NMR (400 MHz, CDCl3, 25 C): δ8.05 (s, 1H), δ7.46 (d, J = 8.2 Hz, 2H),

δ7.32 (d, J = 8.2 Hz, 2H), δ5.60 (d, J = 4.2 Hz, 2H), δ5.26-5.22 (m, 1H), δ4.35 (q, J = 7.2

Hz, 2H), δ3.44 (dd, J = 15.0 Hz, 7.2 Hz, 1H), δ3.20 (dd, J = 15.0 Hz, 6.0 Hz, 1H), δ1.27

13 o (t, J = 7.2 Hz, 3H). C NMR (101 MHz, CDCl3, 25 C): δ165.5, 148.3, 140.2, 135.7,

130.4, 128.9, 128.7, 128.4, 128.2, 125.6, 81.9, 64.1, 57.8, 54.5, 53.7, 13.8. methyl 2,2,4-trichloro-4-(4-((4-phenyl-1H-1,2,3-triazol-1-

1 o yl)methyl)phenyl)butanoate (21a). H NMR (400 MHz, CDCl3, 25 C): δ7.81 (d, J =

7.2, 2H), δ7.79 (s, 1H), δ7.42-7.38 (m, 4H), δ7.35-7.28 (m, 3H), δ5.55 (s, 2H), δ5.22 (dd,

J = 7.5 Hz, 6.0 Hz, 1H), δ3.87 (s, 3H), δ3.42 (dd, J = 15.0 Hz, 7.6 Hz, 1H), δ3.17 (dd, J =

13 o 15.0 Hz, 5.9 Hz, 1H). C NMR (101 MHz, CDCl3, 25 C): δ165.5, 148.3, 140.2, 135.7,

130.4, 128.4, 128.3, 128.2, 125.7, 81.9, 57.8, 54.5, 53.9, 53.8. methyl 1-(4-(1,3,3,3-tetrachloropropyl)benzyl)-1H-1,2,3-triazole-4-carboxylate (22a).

1 o Isolated yield=570 mg (90%). H NMR (400 MHz, CDCl3, 25 C): δ8.04 (s, 1H), δ7.49-

7.45 (m, 2H), δ7.31 (d, J = 8.2 Hz, 2H), δ5.60 (s, 2H), δ5.30-5.27 (m, 1H), δ3.93 (s, 3H),

206

δ3.60 (dd, J = 15.3 Hz, 5.3 Hz, 1H), δ3.50 (dd, J = 15.3, 6.6 Hz, 1H). 13C NMR (101

o MHz, CDCl3, 25 C): δ161.0, 141.4, 134.6, 128.7, 128.4, 127.5, 96.0, 62.5, 57.5, 53.9,

52.3. methyl 1-(4-(1,3,3-trichloro-4-ethoxy-4-oxobutyl)benzyl)-1H-1,2,3-triazole-4-

1 o carboxylate (23a). H NMR (400 MHz, CDCl3, 25 C): δ8.05 (s, 1H), δ7.46 (d, J = 8.2

Hz, 2H), δ7.32 (d, J = 8.2 Hz, 2H), δ5.60 (d, J = 4.2 Hz, 2H), δ5.26-5.22 (m, 1H), δ4.19-

4.07 (m, 2H), δ3.95-3.94 (m, 3H), δ3.43 (dd, J = 15.0 Hz, 7.6 Hz, 1H), δ3.17 (dd, J =

13 o 15.0 Hz, 5.8 Hz, 1H), δ1.30 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, CDCl3, 25 C):

δ165.5, 161.0, 140.8, 140.4, 134.5, 128.6, 128.4, 127.5, 81.8, 57.7, 54.5, 53.95, 53.80,

52.3, 13.7. methyl 1-(4-(1,3,3-trichloro-4-methoxy-4-oxobutyl)benzyl)-1H-1,2,3-triazole-4-

1 o carboxylate (24a). Isolated yield=610 mg (84%). H NMR (400 MHz, CDCl3, 25 C):

δ8.04 (s, 1H), δ 7.45 (d, J = 8.2 Hz, 2H), δ7.31 (d, J = 8.2 Hz, 2H), δ5.60 (s, 2H), δ5.23

(dd, J = 7.6 Hz, 5.8 Hz, 1H), δ3.94 (s, 3H), δ3.72 (s, 3H), δ3.43 (dd, J = 15.0, Hz 7.7 Hz,

13 o 1H), δ3.17 (dd, J = 15.0 Hz, 5.8 Hz, 1H). C NMR (101 MHz, CDCl3, 25 C): δ165.5,

161.0, 134.5, 128.7, 128.4, 127.5, 81.8, 57.7, 54.5, 53.8, 52.3. methyl 1-(4-(1,3-dichloro-4-ethoxy-4-oxobutyl)benzyl)-1H-1,2,3-triazole-4-

1 o carboxylate (25a). H NMR (400 MHz, CDCl3, 25 C, approx. 50/50 mixture of diastereomers): δ8.04 (s, 1H), δ8.01 (s, 1H), δ7.44 (d, J = 8.2 Hz, 2H), δ7.23 (d, J = 8.2

Hz, 2H), δ5.61 (s, 2H), δ4.68 (dd, J = 17.0 Hz, 3.7 Hz, 1H), δ4.33 (q, J = 7.2 Hz, 2H),

δ4.28-4.2 (m, 1H), δ4.14 (dd, J = 17.0, 6.0 Hz, 1H), δ3.93 (s, 3H), δ3.90 (s, 3H), δ2.79-

2.67 (m, 2H), δ1.36 (t, J = 7.4 Hz, 3H). methyl 1-(4-(1,3-dichloro-4-methoxy-4-oxobutyl)benzyl)-1H-1,2,3-triazole-4-

207

1 o carboxylate (26a). H NMR (400 MHz, CDCl3, 25 C, approx. 50/50 mixture of diastereomers): δ8.06 (s, 1H), δ8.03 (s, 1H), δ7.37 (d, J = 8.2 Hz, 2H), δ7.25 (d, J = 8.2

Hz, 2H), δ5.53 (s, 2H), δ4.68 (dd, J = 17.0 Hz, 3.7 Hz, 1H), δ4.33 (q, J = 7.2 Hz, 2H),

δ4.28-4.20 (m, 1H), δ4.14 (dd, J = 17.0 Hz, 6.0 Hz, 1H), δ3.93 (s, 3H), δ3.90 (s, 3H),

δ2.79-2.67 (m, 2H), δ1.36 (t, J = 7.4 Hz, 3H). methyl 1-(4-(1,3-dichloro-3-cyanopropyl)benzyl)-1H-1,2,3-triazole-4-carboxylate

1 o (27a). H NMR (400 MHz, CDCl3, 25 C, approx. 50/50 mixture of diastereomers): δ8.05

(s, 1H), δ8.04 (s, 1H), δ7.41 (d, J = 8.2 Hz, 2H), δ7.31 (d, J = 8.2 Hz, 2H), δ5.58 (s, 2H),

δ4.75 (dd, J = 10.0 Hz, 4.4 Hz, 1H), δ4.54-4.50 (m, 1H), δ3.86 (s, 3H), δ2.81-2.73 (m,

1H), δ2.69-2.63 (m, 1H), δ2.60-2.52 (m, 1H). methyl 1-(4-(1,3,3-trichloropropyl)benzyl)-1H-1,2,3-triazole-4-carboxylate (28a). 1H

o NMR (400 MHz, CDCl3, 25 C, approx. 50/50 mixture of enantiomers): δ8.04 (s, 1H),

δ8.00 (s, 1H), δ7.46 (d, J = 8.2 Hz, 2H), δ7.33 (d, J = 8.2 Hz, 2H), δ6.72 (dd, J = 17.6

Hz, 10.9 Hz, 1H), δ5.84-5.81 (m, 1H), δ5.61 (s, 2H), δ5.58 (s, 2H), δ5.09 (dd, J = 9.6 Hz,

4.8 Hz, 1H), δ3.95 (s, 3H), δ3.94 (s, 3H), δ2.96 (ddd, J = 14.6 Hz, 9.7 Hz, 4.8 Hz, 1H),

13 o δ2.76 (ddd, J = 14.7 Hz, 8.5 Hz, 4.8 Hz, 1H). C NMR (101 MHz, CDCl3, 25 C):

δ161.2, 140.5, 135.8, 134.7, 128.9, 128, 127.1, 70.1, 58.6, 57, 54.3, 52.3.

4.7 References

1. Kolb, H. C.; Finn, M. G.; Sharpless, K. B., Click Chemistry: Diverse Chemical Function from a Few Good Reactions. Angew. Chem. Int. Ed. 2001, 40 (11), 2004-2021.

2. Tornoe, C. W.; Christensen, C.; Meldal, M., Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides. J. Org. Chem. 2002, 67 (9), 3057- 3064.

208

3. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B., A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective ―Ligation‖ of Azides and Terminal Alkynes. Angew. Chem. Int. Ed. 2002, 41 (14), 2596- 2599.

4. Kolb, H. C.; Sharpless, K. B., The Growing Impact of Click Chemistry on Drug Discovery. Drug Discov. Today 2003, 8 (24), 1128-1137.

5. Binder, W. H.; Kluger, C., Azide/Alkyne-"Click" Reactions: Applications in Material Science and Organic Synthesis. Curr. Org. Chem. 2006, 10 (14), 1791- 1815.

6. Meldal, M.; Tornoe, C. W., Cu-Catalyzed Azide-Alkyne Cycloaddition. Chem. Rev. 2008, 108 (8), 2952-3015.

7. Rodionov, V. O.; Fokin, V. V.; Finn, M. G., Mechanism of the Ligand-Free CuI- Catalyzed Azide–Alkyne Cycloaddition Reaction. Angew. Chem. Int. Ed. 2005, 44 (15), 2210-2215.

8. Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V., Copper(I)-Catalyzed Synthesis of Azoles. DFT Study Predicts Unprecedented Reactivity and Intermediates. J. Am. Chem. Soc. 2005, 127 (1), 210-216.

9. Nolte, C.; Mayer, P.; Straub, B. F., Isolation of a Copper(I) Triazolide: A ―Click‖ Intermediate. Angew. Chem. Int. Ed 2007, 46, 2101-2103.

10. Curran, D. P., The Design and Application of Free Radical Chain Reactions in Organic Synthesis. Part 2. Synthesis 1988, 7, 489-513.

11. Curran, D. P., The Design and Application of Free Radical Chain Reactions in Organic Synthesis. Part 1. Synthesis 1988, 6, 417-439.

12. Curran, D. P., Comprehensive Organic Synthesis. Pergamon: New York, 1992; p 715.

13. Eckenhoff, W. T.; Pintauer, T., Copper Catalyzed Atom Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions in the Presence of Reducing Agents. Cat. Rev. Sci. Eng. 2010, 52, 1-59.

209

14. Iqbal, J.; Bhatia, B.; Nayyar, N. K., Transition Metal-Promoted Free-Radical Reactions in Organic Synthesis: The Formation of Carbon-Carbon Bonds Chem. Rev. 1994, 94 (2), 519-564.

15. Severin, K., Ruthenium Catalysts for the Kharasch Reaction. Curr. Org. Chem. 2006, 10 (2), 217-224.

16. Matyjaszewski, K.; Xia, J., Atom Transfer Radical Polymerization. Chem. Rev. 2001, 101 (9), 2921-2990.

17. Wang, J.-S.; Matyjaszewski, K., Controlled/"Living" Radical Polymerization. Atom Transfer Radical Polymerization in the Presence of Transition-Metal Complexes. J. Am. Chem. Soc. 1995, 117 (20), 5614-5615.

18. Jakubowski, W.; Matyjaszewski, K., Activators Regenerated by Electron Transfer for Atom-Transfer Radical Polymerization of (Meth)acrylates and Related Block Copolymers. Angew. Chem. Int. Ed. 2006, 45 (27), 4482-4486.

19. Jakubowski, W.; Min, K.; Matyjaszewski, K., Activators Regenerated by Electron Transfer for Atom Transfer Radical Polymerization of Styrene Macromolecules 2006, 39 (1), 39-45.

20. Matyjaszewski, K.; Jakubowski, W.; Min, K.; Tang, W.; Huang, J.; Braunecker, W. A.; Tsarevsky, N. V., Diminishing Catalyst Concentration in Atom Transfer Radical Polymerization with Reducing Agents. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 15309-15314.

21. Pintauer, T.; Matyjaszewski, K., Atom Transfer Radical Addition and Polymerization Reactions Catalyzed by ppm Amounts of Copper Complexes. Chem. Soc. Rev. 2008, 37, 1087-1097.

22. Quebatte, L.; Thommes, K.; Severin, K., Highly Efficient Atom Transfer Radical Addition Reactions with a RuIII Complex as a Catalyst Precursor. J. Am. Chem. Soc. 2006, 128 (23), 7440-7441.

23. Eckenhoff, W. T.; Garrity, S. T.; Pintauer, T., Highly Efficient Copper Mediated Atom Transfer Radical Addition (ATRA) in the Presence of Reducing Agent. Eur. J. Inorg. Chem. 2008, 563-571.

210

24. Eckenhoff, W. T.; Pintauer, T., Atom Transfer Radical Addition in the Presence of Catalytic Amounts of Copper(I/II) Complexes with Tris(2- pyridylmethyl)amine. Inorg. Chem. 2007, 46 (15), 5844-5846.

25. Pintauer, T., "Greening" of Copper Catalyzed Atom Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions. ACS Symp. Ser. 2009, 1023, 63-84.

26. Pintauer, T., Catalyst Regeneration in Transition-Metal-Mediated Atom-Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions. Eur. J. Inorg. Chem. 2010, 2449-2460.

27. Balili, M. N. C.; Pintauer, T., Persistent Radical Effect in Action: Kinetic Studies of Copper-Catalyzed Atom Transfer Radical Addition in the Presence of Free- Radical Diazo Initiators as Reducing Agents. Inorg. Chem. 2009, 48, 9018-9026.

28. Balili, M. N. C.; Pintauer, T., Kinetic Studies of the Initiation Step in Copper Catalyzed Atom Transfer Radical Addition (ATRA) in the Presence of Free Radical Diazo Initiators as Reducing Agents. Inorg. Chem. 2010, 49 (12), 5642- 5649.

29. Pintauer, T.; Eckenhoff, W. T.; Ricardo, C.; Balili, M. N. C.; Biernesser, A. B.; Noonan, S. J.; Taylor, M. J. W., Highly Efficient, Ambient-Temperature Copper- Catalyzed Atom-Transfer Radical Addition (ATRA) in the Presence of Free- Radical Initiator (V-70) as a Reducing Agent. Chem. Eur. J. 2009, 15, 38-41.

30. Thommes, K.; Icli, B.; Scopelliti, R.; Severin, K., Atom Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions Catalyzed by a Mixture of [RuCl2Cp*(PPh3)] and Magnesium. Chem. Eur. J. 2007, 13 (24), 6899-6907.

31. Wolf, J.; Thommes, K.; Brie, O.; Scopelliti, R.; Severin, K., Dinuclear Ruthenium Ethylene Complexes: Synthesis, Structures, and Catalytic Applications in ATRA and ATRC Reactions. Organometallics 2008, 27, 4464-4474.

32. Muñoz-Molina, J. M.; Belderraín, T. R.; Pérez, P. J., An Efficient, Selective, and Reducing Agent-Free Copper Catalyst for the Atom-Transfer Radical Addition of Halo Compounds to Activated Olefins. Inorg. Chem. 2010, 49 (2), 642-645.

33. Muñoz-Molina, J. M.; Caballero, A.; Díaz-Requejo, M. M.; Trofimenko, S.; Belderraín, T. R.; Pérez, P. J., Copper-Homoscorpionate Complexes as Active

211

Catalysts for Atom Transfer Radical Addition to Olefins. Inorg. Chem. 2007, 46, 7725-7730.

34. Clark, A. J.; Wilson, P., Copper Mediated Atom Transfer Radical Cyclizations with AIBN. Tetrahedron Lett. 2008, 49, 4848-4850.

35. Fernández-Zúmel, M. A.; Thommes, K.; Kiefer, G.; Sienkiewicz, A.; Pierzchala, K.; Severin, K., Atom-Transfer Radical Addition Reactions Catalyzed by RuCp* Complexes: A Mechanistic Study. Chem. Eur. J. 2009, 15 (43), 11601-11607.

36. Lundgren, R. J.; Rankin, M. A.; McDonald, R.; Stradiotto, M., Neutral, Cationic, and Zwitterionic Ruthenium(II) Atom Transfer Radical Addition Catalysts Supported by P,N-Substituted Indene or Indenide Ligands Organometallics 2008, 27 (2), 254-258.

37. Thommes, K.; Severin, K., Olefin Cyclopropanations via Sequential Atom Transfer Radical Addition-Dechlorination Reactions. CHIMIA International Journal for Chemistry 2010, 64 (3), 188-190.

38. Nair, R. P.; Kim, T. H.; Frost, B. J., Atom Transfer Radical Addition Reactions of CCl4, CHCl3, and p-Tosyl Chloride Catalyzed by Cp*Ru(PPh3)(PR3)Cl Complexes. Organometallics 2009, 28 (16), 4681-4688.

39. Taylor, M. J. W.; Eckenhoff, W. T.; Pintauer, T., Copper Catalyzed Atom Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions in the Presence of Environmentally Benign Ascorbic Acid as a Reducing Agent. Dalton. Trans. 2010, 39, 11475-11482.

40. Ricardo, C.; Pintauer, T., Copper Catalyzed Atom Transfer Radical Cascade Reactions in the Presence of Free-Radical Diazo Initiators as Reducing Agents. Chem. Commun. 2009, 3029-3031.

41. Muñoz-Molina, J. M.; Belderraín, T. R.; Pérez, P. J., Copper-Catalyzed Synthesis of 1,2-Disubstituted Cyclopentanes from 1,6-Dienes by Ring-Closing Kharasch Addition of Carbon Tetrachloride. Adv. Synth. Catal. 2008, 350, 2365-2372.

42. Sumerlin, B. S.; Tsarevsky, N. V.; Louche, G.; Lee, R. Y.; Matyjaszewski, K., Highly Efficient "Click" Functionalization of Poly(3-Azidopropyl Methacrylate) Prepared by ATRP. Macromolecules 2005, 38 (18), 7540-7545.

212

43. Tsarevsky, N. V.; Bernaerts, K. V.; Dufour, B.; Du Prez, F. E.; Matyjaszewski, K., Well-Defined (Co)polymers with 5-Vinyltetrazole Units via Combination of Atom Transfer Radical (Co)polymerization of Acrylonitrile and "Click Chemistry"-Type Postpolymerization Modification. Macromolecules 2004, 37 (25), 9308-9313.

44. Geng, J.; Lindqvist, J.; Mantovani, G.; Haddleton, D. M., Simultaneous Copper(I)-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) and Living Radical Polymerization. Angew. Chem. Int. Ed 2008, 47, 4180-4183.

45. Grignard, B.; Calberg, C.; Jerome, C.; Detrembleur, C., "One-Pot" Dispersion ATRP and Alkyne-Azide Huisgen's 1,3-Dipolar Cycloaddition in Supercritical Carbon Dioxide: Towards the Formation of Functional Microspheres. J. Supercrit. Fluids 2010, 53 (1-3), 151-155.

46. Eckenhoff, W. T.; Pintauer, T., Structural Comparision of Copper(I) and Copper(II) Complexes with Tris(2-pyridylmethyl)amine Ligand. Inorg. Chem. 2010, 49, 10617-10626.

47. Golas, P. L.; Tsarevsky, N. V.; Sumerlin, B. S.; Matyjaszewski, K., Catalyst Performance in Click Coupling Reactions of Polymers Prepared by ATRP: Ligand and Metal Effects. Macromolecules 2006, 39 (19), 6451-6457.

48. Straub, B. F., μ-Acetylide and μ-Alkenylidene Ligands in "Click" Triazole Syntheses. Chem. Commun. 2007, (37), 3868-3870.

49. Tyeklar, Z.; Jacobson, R. R.; Wei, N.; Murthy, N. N.; Zubieta, J.; Karlin, K. D., Reversible Reaction of Dioxygen (and Carbon Monoxide) with a Copper(I) Complex. X-ray Structures of Relevant Mononuclear Cu(I) Precursor Adducts and the Trans-(μ-1,2-Peroxo)dicopper(II) Product. J. Am. Chem. Soc. 1993, 115 (7), 2677-2689.

50. Xu, L. Q.; Yao, F.; Fu, G. D., Simultaneous ―Click Chemistry‖ and Atom Transfer Radical Emulsion Polymerization and Prepared Well-Defined Cross- Linked Nanoparticles. Macromolecules 2009, 42, 6385-6392.

51. Sheldrick, G. M., SADABS Version 2.03. University of Gottingen: Germany, 2002.

213

52. Sheldrick, G. M., SHELXTL 6.1,Crystallographic Computing System. Bruker Analytical X-Ray System: Madison, WI, 2000.

53. Faruggia, L. J., ORTEP-3 for Windows. J. Appl. Cryst. 1997, 30 (5, Pt. 1), 565.

214

Chapter 5

Synthesis of Functionalized Polytriazoles via Single-Pot Sequential Copper-Catalyzed [3+2] Azide-Alkyne Cycloaddition and Atom Transfer Radical Addition (ATRA) in the Presence of Ascorbic Acid as a Reducing Agent

Reproduced in part with permission from Ricardo, C. L.; Pintauer, T. Israel J. Chem. 2011, accepted.

As a continuing effort of expanding the scope of catalyst regeneration in the presence of environmentally benign reducing agents, one-pot sequential azide-alkyne

[3+2] cycloaddition and atom transfer radical addition (ATRA) reactions were performed via in situ reduction of copper(II) by ascorbic acid. The formation of functionalized triazoles was achieved utilizing a ligand-free catalytic system for the cycloaddition between tripropargylamine and vinylbenzyl azide and subsequent addition of tris(2- pyridyl)methylamine (TPMA) ligand in the ATRA step. With this strategy, reactions with carbon tetrachloride and carbon tetrabromide proceeded efficiently providing the desired triazoles in nearly quantitative yields (>90%) using 10 mol-% of copper.

Sequential azide-alkyne [3+2] cycloaddition and ATRA reactions were also extended to less active alkyl halides such as methyl trichloroacetate, methyl dichloroacetate and dichloroacetonitrile. The corresponding products were obtained in modest yields (50-

80%). The presented methodology enables efficient synthesis of functionalized

215

polytriazoles, which could have a potential use as chelating agents for a variety of transition metals.

5.1 Introduction

The term, ―click chemistry‖ coined in 2001 serves as a guiding principle in the synthesis of compounds with desired functionality using ―near perfect‖ reaction conditions.1 Typically, reactions classified under the click chemistry umbrella are defined by stringent set of criteria and among them, copper-catalyzed Huisgen [3+2] cycloaddition popularized by the Meldal2 and Sharpless3 groups was the first to achieve the ―click status‖. To date, this reaction has dominated this area of research and even became synonymous with ―click chemistry‖, mainly due to its reliability, robustness, functional group tolerance, ability to withstand wide spectrum of solvents, and desirable properties of the resulting triazoles. Immense contributions have been made and wide arrays of applications found in various disciplines such as biology,4,5 chemistry,1,6-8 bioconjugation,7,9 dug discovery9-12 and materials/polymer science.8,13-16

The mechanism of copper catalyzed azide-alkyne [3+2] cycloaddition has been widely investigated using computational17-19 and experimental3,20,21 techniques.

Regardless of the starting copper salt or complex (either CuI or CuII), it has been established that CuI is the active catalytic species in the coupling of azide and alkyne.6

The catalytic cycle begins with the coordination of the alkyne to the copper(I) center, resulting in the formation of a -complex (Scheme 5.1). This step lowers the pKa of terminal alkyne proton by approximately 10 units, enabling the conversion of the - complex to a -acetylide copper(I) intermediate. Kinetic investigation20 has revealed that the reaction rate is second-order with respect to the metal, suggesting the strong tendency

216

of copper(I) acetylide species to form -coordinate bridged aggregates,18,19 the formation of which is highly dependent on the nature of the complexing ligand. The next step in the catalytic cycle is the coordination of the organic azide, which consequently activates the

N-terminus for nucleophilic attack to the acetylide. This results in the formation of vinylidene-like structure, which subsequently converts to a more stable copper(I) triazolide. Lastly the catalytic cycle is completed by protonolysis, which yields the desired 1,2,3-triazole and regenerates the active copper(I) species.

Scheme 5.1. Proposed Mechanism for Copper Catalyzed Azide-Alkyne [3+2] Cycloaddition.

Another C-C forming reactions that are becoming more synthetically useful are the transition-metal catalyzed atom transfer radical addition (ATRA) and the intramolecular counterpart, atom transfer radical cyclization (ATRC).22-27 Traditionally,

217

both were conducted in the presence of high catalyst loadings, therefore facing issues in product separation and catalyst recycling. Solution to these problems was found for the mechanistically similar atom transfer radical polymerization (ATRP)28,29 in which reducing agents were utilized to continuously regenerate the activator or copper(I) complex (Scheme 5.2). Catalyst regeneration technique has also been shown to be highly efficient in ruthenium30 and copper catalyzed ATRA and ATRC reactions.26,31-34 The presence of the reducing agents (free-radical diazo initiators, magnesium or ascorbic acid) successfully allowed the reduction in the amount of transition metal complex, and as a result, these reactions can now be conducted using very low amounts of the catalyst.35-46 Synthetic usefulness of the methodology has also been demonstrated in sequential organic transformations involving ATRA/ATRC.47-49

The proposed mechanism26,34 for copper catalyzed ATRA in the presence of reducing agents is shown in Scheme 5.2. The role of the reducing agent is to continuously regenerate copper(I) from the copper(II) complex that accumulates in the reaction mixture as a result of unavoidable and often diffusion controlled radical-radical termination reactions. Catalytic cycle starts with a homolytic cleavage of the alkyl halide bond by the copper(I) complex to produce an alkyl radical, which subsequently adds across a carbon-carbon double bond of an alkene. The generated secondary radical is then trapped by irreversible abstraction of halogen atom from the copper(II) complex to form the desired monoadduct. This step regenerates the activator or copper(I) complex, completing the catalytic cycle. As indicated in Scheme 5.2, the competing side reactions in this process besides radical terminations by either coupling or disproportionation include repeating radical additions to alkene to form oligomers/polymers.

218

Scheme 5.2. Proposed Mechanism for Copper Catalyzed Atom Transfer Radical Addition (ATRA) in the Presence of Reducing Agents.

A combination of copper catalyzed azide-alkyne [3+2] cycloaddition and mechanistically similar ATRP was first explored by the group of Matyjaszewski in a two- pot two-step manner consisting of converting the halogen end-groups in well-defined polymers to azides and then subsequently triazoles.50,51 The methodology was also successfully extended to one-pot simultaneous reaction, in which propargyl methacrylate and alkyl azides were reacted to yield highly functionalized and well-defined polymeric

219

materials.52,53 Furthermore, our laboratory also initiated the study on sequential reactions involving copper(I)-catalyzed azide-alkyne [3+2] cycloaddition and mechanistically similar ATRA.54 A wide variety of small organic molecules bearing triazole and halide functionalities have been synthesized.

Since we have demonstrated the efficiency of our catalytic system to mediate both organic transformations in one-pot two-step process, our focus has shifted towards functionalized polytriazoles. Such compounds are very effective chelating agents and have found use in many different areas of catalysis.55 Recent study has shown that the incorporation of polytriazole ligands enhanced the photophysical and electron-transfer

56 properties of tripodal zinc porphyrins (TPZn3). In DNA and RNA chemistry, multiple alkynylation of nucleosides and oligonucleotides followed by functionalization via the copper(I) catalyzed Huisgen cycloaddition with fluorophore-decorated organic azides resulted in the formation of modified DNA and RNA molecules that are highly fluorescent.57

In this chapter, we report on the synthesis of halogenated polytriazole derivatives employing sequential copper catalyzed azide-alkyne [3+2] cycloaddition and atom transfer radical addition (ATRA). The presence of the halide functionality in the resulting molecule offers versatility towards further organic transformations involving reduction, elimination, conversion to a Grignard reagent, and/or free radical chemistry.

5.2 Results and Discussion

The motivation for the study of one-pot sequential reactions involving azide- alkyne [3+2] cycloaddition and atom transfer radical addition54 catalyzed by

[CuII(TPMA)X][X] (TPMA=tris(2-pyridylmethyl)amine, X= Cl-, Br-) complexes in the

220

presence of ascorbic acid as a reducing agent was primarily to demonstrate the synthetic usefulness of catalyst regeneration technique originally developed for mechanistically similar ATRP. The pioneering work in our laboratory on copper-catalyzed ATRA in the presence of free-radical diazo initiator AIBN showed a significant reduction in the required catalyst loading with high turnover numbers (TONs).31,32 Improved selectivity towards the desired monoadduct formation for alkenes that are prone to free-radical polymerization was demonstrated through the use of radical initiator that decomposes at ambient temperature (such as V-70)37 or photoinitiated ATRA.58 Very recently, copper- catalyzed ATRA and ATRC reactions have also been conducted in the presence of a more environmentally benign reducing agent such as ascorbic acid.46 This reducing agent enabled not only high product yields and TON‘s, but also more superior selectivity towards the monoadduct formation (particularly in the case of highly active acrylonitrile).

Based on literature reports, triazole formation via copper(I) catalyzed [3+2] azide- alkyne cycloaddition is commonly conducted via in situ reduction of CuII to CuI complex by either sodium ascorbate or ascorbic acid.3,6,20,21 Similarly, ATRA,46 ATRC46 and

ATRP59,60 reactions also utilize the same reducing agent to regenerate the copper(I) complex, which is needed to start the catalytic cycle by homolytically cleaving the carbon-halogen bond. Therefore, a logical step was taken in combining the two reactions in a one-pot sequential manner. Indeed, reactions with azidopropyl methacrylate and 1-

(azidomethyl)-4-vinylbenzene in the presence of a variety of alkynes and alkyl halides, catalyzed by as low as 0.5 mol-% of [CuII(TPMA)X][X] (X=Br-, Cl-) complex, proceeded efficiently to yield highly functionalized (poly)halogenated esters and aryl compounds containing triazolyl group in almost quantitative yields (>90%, Scheme 5.3).

221

Encouraged by these results, we then applied the same methodology to azide- alkyne [3+2] cycloaddition between tripropargylamine and vinyl benzyl azide (VBA), followed by sequential ATRA of carbon tetrachloride. Surprisingly, reactions conducted in the presence of 1 mol% of [CuII(TPMA)Cl][Cl] complex and 20 mol% of ascorbic acid

(relative to CuII) for 24 h at 60 oC yielded less than 10% of the desired product.

Conducting reactions at elevated temperatures (80 oC) for longer reaction times (48 h) did

Scheme 5.3. Sequential Copper-Catalyzed Azide-Alkyne Cycloaddition and ATRA.

222

Figure 5.1. 1H NMR (a) and HRMS (b) spectra of tris((1-(4-vinylbenzyl)-1H-1,2,3- triazol-4-yl)methyl)amine (TVBTA).

223

not result in significant improvements. At the present time, it is unclear why the same catalytic system does not work efficiently for tripropargylamine. On one hand, this substrate could inherently be less active in azide-alkyne cycloaddition. On the other, if the reaction requires multiple coordinations to the copper(I) center, such interactions will be efficiently blocked because of the tetradentate nature of TPMA ligand. We are presently exploring both possibilities.

Since one-pot sequential reactions catalyzed by [CuII(TPMA)Cl][Cl] complex were not successful, we reverted to carrying out two-step, two-pot reactions. The first step involved the reaction between vinylbenzyl azide (VBA) and tripropargylamine at 60 o II C in the presence of 10 mol% of Cu SO4 and sodium ascorbate (1:10 molar ratio) in methylene chloride/water (50/50 by volume). After heating for 24 hours, the desired tris(2-vinylbenzyl)triazole was isolated in 74% yield. Even better results were obtained when the solvent was changed to methanol and ascorbic acid utilized as a reducing agent

(91% isolated yield). The resulting triazole was characterized using 1H NMR and high resolution mass spectroscopy (HRMS). The corresponding spectra are shown in Figure

5.1. Positive ion mass spectrum indicates the presence of two molecular ion peaks, namely the protonated triazole (MH+) and sodium ion (MNa+).

For the second step, ATRA reactions of various alkyl halides were conducted in the presence of [CuII(TPMA)X][X] (X=Br- or Cl-) and ascorbic acid. The results are summarized in Table 5.1. The addition of polyhalogenated methanes such as CCl4 and

224

Table 5.1. Copper Catalyzed ATRA of Alkyl Halides to TVBTA in the Presence of Ascorbic Acid.

R-X[a] [CuII][b] T [oC] Time [h] Yield [%][c] CCl4 1.0 60 24 95 [d] CCl4 0.40 60 24 60(64) CCl4 0.20 60 24 62 [d] CBr4 1.0 60 24 98(92) CBr4 0.40 60 24 86 CBr4 0.20 60 24 84 [d] CCl3CO2Me 2.0 80 27 78(77) CCl3CO2Me 1.0 80 27 76 [d] CCl2HCN 2.0 80 27 70(67) [d] CCl2HCO2Me 2.0 80 27 70(55) CCl2HCO2Me 1.0 80 27 64

[a] All reactions were performed in MeOH using [TVBTA]0 /[CCl4 or CBr4]0=1:3.75, or TVBTA]0 /[CCl3CO2Me, CHCl2CN, or CCl2HCO2Me]0=1:6, [TVBTA]0 = 0.08 M. The amount of ascorbic acid in each system ranged between 20 and 25 equiv. relative to the copper(II) complex. [b] mol-% relative to [TVBTA]. [c] The yield is based on the formation of the triazole and was determined by 1H NMR spectroscopy using p- dimethoxybenzene as internal standard (relative errors are ±15%). [d] Isolated yield after column chromatography.

225

Table 5.2 One-Pot Sequential Copper-Catalyzed [3+2] Azide-Alkyne Cycloaddition and ATRA in the Presence of Ascorbic Acid.

N3 + 1/3 N

CuIISO 1 4 Ascorbic Acid

RX 2 TPMA

R X

N N N

X R R N N N X N N N N

X=Br- or Cl- [a] II [b] [c] [d] Entry R-X [Cu ] t1 [h]/t2[h] Yield [%] [e] 1 CCl4 10 1/8 91(80) 2 CCl4 10 1/19 90 3 CCl4 1.0 1/19 56 [e] 4 CBr4 10 1/8 92(86) 5 CBr4 10 1/19 99 6 CBr4 1.0 1/19 60 [e] 7 CCl3CO2Me 10 1/24 75(78) 8 CCl3CO2Me 1.0 1/24 43 [e] 9 CCl2HCO2Me 10 1/24 66(43) 10 CCl2HCO2Me 1.0 1/24 50

[a] All reactions were performed at 60 0C in MeOH using [VBA]0:[tripropargylamine]0=3:1, [VBA]0=0.1 M. The amount of ascorbic acid was 20 II II equiv. relative to Cu SO4. In the second step, 1.0 equiv. of TPMA relative to Cu SO4 and RX (CCl4 or CBr4=3.75 equiv., CCl3CO2Me or CCl2HCO2Me=6.0 equiv. relative to II VBA) were added. [b] Mol % of Cu SO4 relative to VBA. [c] t1=time for click reaction, t2=time for ATRA. [d] The yield is based on the formation of the triazole and was determined by 1H NMR spectroscopy using p-dimethoxybenzene as internal standard (relative errors are ±15%). [e] Isolated yield after column chromatography.

226

Figure 5.2. 1H NMR (a) and experimental (b) and simulated (c) mass spectra of tris((1- (4-(1,3,3,3-tetrachloropropyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl)amine.

227

CBr4 provided nearly quantitative yields of TBTA(CCl4)3 (95%) and TBTA(CBr4)3

(98%) in the presence of as low as 1.0 mol-% of the catalyst. Decreasing catalyst loadings to 0.4 and 0.2 mol-% still resulted in reasonably high yields of the desired polytriazole monoadducts. The scope of ATRA was also extended to include trihalogenated (methyl trichloroacetate) and dihalogenated (methyl dichloroacetate and dichloroacetonitrile) alkyl halides. Since they are generally less active compared to CCl4 and CBr4, reactions were performed utilizing excess of alkyl halides (6.0 equivalents relative to TVBTA), elevated temperatures (80 oC), prolonged reaction times (27 h), and higher catalyst loadings (1.0-2.0 mol-%). As indicated in Table 1, the results were clearly inferior to those of CCl4 and CBr4. Modest yield (78%) was obtained in the

II addition of CCl3CO2Me in the presence of 2.0 mol-% of [Cu (TPMA)Cl][Cl] and ascorbic acid. For the case of CCl2HCN and CCl2HCO2Me, the yields of the halogenated polytriazoles were approximately 70% using the same catalyst loading (2.0 mol-%).

Further decrease in the amount of copper catalyst resulted in a decrease in the yield of the desired monoadduct.

We have already demonstrated that copper-catalyzed [3+2] azide-alkyne cycloaddition between vinylbenzyl azide and tripropargylamine in the presence of TPMA ligand can be problematic. However, TPMA is necessary for the ATRA step, and it is currently among the most active nitrogen based ligands for such copper catalyzed organic transformation.26,33,34 With a strong determination to fulfill one-pot synthesis of halogenated polytriazoles, a new strategy was devised. In the first step, [3+2] azide- alkyne cycloaddition between vinylbenzyl azide and tripropargylamine was conducted in a ligand-free catalytic system containing ascorbic acid. After completion of the reaction,

228

free TPMA and alkyl halide were then added to the same reaction mixture and ATRA allowed to proceed. Indeed, with this protocol, the monoadduct in the case of CCl4 was obtained in 91% yield using 10 mol-% of copper (Table 5.2, entry 1). Increasing the reaction time for ATRA from 8 to 19 hours did not result in significant increase in the product yield (90%, entry 2). Furthermore, decreasing catalyst loading to 1.0 mol-% resulted in a significant decrease in the yield of the monoadduct (entry 3). The same trend was also observed in the case of CBr4 (entries 4-6). As indicated in Table 5.2, sequential [3+2] azide-alkyne cycloaddition and ATRA proceeded reasonably well with less active methyl trichloroacetate (entry 7 and 8) and methyl dichloroacetate (entry 9 and

10). For both reactions, a large excess of alkyl halide was used (6.0 equivalents relative to vinyl benzyl azide).

Product characterization via spectroscopic techniques (1H and 13C NMR) and high resolution mass spectroscopy (HRMS) were carried out for all substrates to verify the formation of the monoadducts. Shown in Figure 5.2 are the 1H NMR and HRMS spectra of the addition product involving CCl4. In the HRMS spectrum, there are two observable molecular ion peaks corresponding to the protonated triazole (MH+) and sodium ion

(MNa+).

5.3 Summary and Conclusions

In summary, we reported efficient synthesis of functionalized polytriazoles via one-pot sequential reactions involving copper-catalyzed [3+2] azide-alkyne cycloaddition and atom transfer radical addition (ATRA). In the first step, reactions were performed in

II a ligand-free catalytic system, comprising of anhydrous Cu SO4 and ascorbic acid. After

229

completion of the click reaction, free TPMA and alkyl halide were then added to the same reaction mixture and ATRA allowed to proceed. It was observed that the reaction between vinyl benzyl azide, tripropargylamine and tetrahalogenated methanes (CCl4 and

CBr4), proceeded efficiently in the presence of as low as 10.0 mol-% of copper.

Reactions with trihalogenated (methyl trichloroacetate) and dihalogenated (methyl dichloroacetate and dichloroacetonitrile) substrates were also successful, although the products were isolated in modest yields (50-80%). The presented methodology enables efficient synthesis of functionalized polytriazoles, which could have a potential use as chelating agents for a variety of transition metals.

5.4 Experimental

5.4.1 General Procedures

Copper(II) sulfate (anhydrous), CuSO45H2O, ascorbic acid, tripropargylamine, alkyl halides (carbon tetrachloride, carbon tetrabromide, methyl trichloroacetate, methyl dichloroacetate and dichloroacetonitrile) and methanol were purchased from commercial sources and used without further purification. Tris(2-pyridylmethyl)amine (TPMA)61 and

4-vinylbenzyl azide (VBA)62 were synthesized according to literature procedures. 1H

NMR and 13C spectra were obtained using Bruker Avance 400 MHz operating at room temperature. All chemical shifts are given in ppm relative to residual solvent peaks

1 13 (CDCl3, H:  = 7.26 ppm and C:  = 77.2 ppm). Mass spectroscopic analyses were performed using electrospray ionization time of flight mass spectrometry on a Bruker microTOF instrument. Simulated data for the molecular ion peaks and isotopic distributions were obtained using an Isotopic Distribution Simulator (IsoPro) v. 3.0.

230

5.4.2 Stock Solutions

II - - II 0.01M [Cu (TPMA)X][X] (X = Cl or Br ) and anhydrous Cu SO4 solutions were prepared in methanol. Ascorbic acid solution (0.25M) was prepared in methanol immediately before use.

5.4.3 Copper-Catalyzed [3+2] Azide-Alkyne Cycloaddition between 4-Vinylbenzyl Azide and Tripropargylamine

Into a 100 mL Schlenk flask equipped with a stirring bar were added 4- vinylbenzyl azide (VBA) (12.0 mmol, 1.8 mL), tripropargylamine (4.0 mmol, 564 L),

CH2Cl2/H2O (50 mL, 1:1 mixture by volume), CuSO45H2O (0.30 g, 1.2 mmol) and sodium ascorbate (12.0 mmol, 2.377 g). Reaction flask was then capped with a rubber septum and stirred overnight at room temperature. Reaction was quenched by adding

H2O and ethylenediamine tetraacetic acid sodium salt dihydrate (Na4EDTA2H2O, 1.2 mmol, 0.499 g), stirred for approximately 1 h and poured into a separatory funnel.

Product was extracted with CH2Cl2 (2 x 10 mL). Collected organic extract was dried over MgSO4 and solvent was removed in vacuo to give yellow solid in 74% yield (2.98 mmol, 1.813 g). In another reaction flask, VBA (3.0 mmol, 450 L), tripropargylamine

(1.0 mmol, 141 L), anhydrous CuSO4 (0.3 mmol, 0.0479 g) and ascorbic acid (6.0 mmol, 1.0578 g dissolved in 24 mL MeOH) were mixed together. Aforementioned procedure was followed and after aqueous work-up and solvent removal, product was isolated in 91% yield (0.0913 mmol, 0.556 g).

5.4.4 General Procedure for the ATRA of Alkyl Halides to TVBTA Catalyzed by [CuII(TPMA)X][X] (X= Cl- or Br-) and Ascorbic Acid

TVBTA (0.1 mmol, 0.0609 g), alkyl halide (CCl4 = 0.375 mmol, 36 µL; CBr4 =

0.375 mmol, 0.1244 g; Cl3CO2Me = 0.6 mmol, 72 µL; Cl2HCO2Me = 0.6 mmol, 62 µL

231

and CHCl2CN = 0.6 mmol, 48 µL), p-dimethoxybenzene, and corresponding amount of

[CuII(TPMA)X][X] were added into a 5 mL Schlenk flask equipped with micro stirring bar. Methanol was then added in order to maintain constant volume and concentration of

0.08 M for TVBTA. Ascorbic acid solution was then added and immediately each reaction flask was secured with an airtight Teflon cap. The resulting reaction mixtures were immersed in an oil bath thermostated at 60 0C/80 0C for 24/27 h. The percent yield

1 of the expected functionalized polytriazole (TBTA(RX)3) was obtained using H NMR spectroscopy relative to the internal standard. If necessary, solvent was partially evaporated prior to 1H NMR analysis.

5.4.5 General Procedure for Sequential Copper Catalyzed [3+2] Cycloaddition and Atom Transfer Radical Addition in the Presence of Ascorbic Acid

In a typical experiment, a stock solution containing VBA (3.0 mmol, 450 µL), tripropargylamine (1.0 mmol, 141 µL), p-dimethoxybenzene and 2.4 mL MeOH was prepared to give a 1.0 M solution in VBA. Aliquots of the solution (0.5 mmol in VBA,

500 µL) were distributed into 5 mL Schlenk flasks containing a micro stirring bar. For

II II each reaction mixture with [VBA]0:[Cu ]0 ratio of 10:1, anhydrous Cu SO4 (0.05 mmol,

0.0080 g) and ascorbic acid solution (1.0 mmol, 4.0 mL from 0.25M solution) were

II II added. For reactions utilizing [VBA]0:[Cu ]0 ratio of 100:1, anhydrous Cu SO4 (0.005 mmol, 500 µL from 0.01 M CuSO4 solution) and ascorbic acid solution (0.1 mmol, 400

µL) were added. The volume of each reaction mixture was adjusted by adding MeOH in order to maintain constant concentration of VBA (0.10 M). Schlenk flasks were secured with an airtight Teflon cap and immersed in an oil bath thermostated at 60 0C for 1h (10.0

II II mol-% of Cu SO4) or 20h (1.0 mol-% of Cu SO4). Upon completion, each reaction mixture was taken inside the glovebox and uncapped. The corresponding amounts of

232

II TPMA (1.0 equiv. relative to Cu SO4) and alkyl halide (CCl4 = 1.875 mmol, 181 µL;

CBr4 = 1.875 mmol, 0.622 g; Cl3CO2Me = 3.0 mmol, 360 µL; Cl2HCO2Me = 3.0 mmol,

310 µL or CHCl2CN = 3.0 mmol, 240 µL) were added. The resulting mixtures were then

o II heated in an oil bath at 60 C for 8 h (10.0 mol-% of Cu SO4) or 24 h (1.0 mol-% of

II Cu SO4). The percent yield of the expected functionalized polytriazole (TBTA(RX)3) was obtained using 1H NMR spectroscopy relative to the internal standard. If necessary, solvent was partially evaporated prior to 1H NMR analysis.

5.4.6 Product Characterization

Tris((1-(4-vinylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)amine (TVBTA). 1H NMR (400

MHz; CDCl3): 7.69 (s, 3H), 7.41(d, J = 8.4 Hz, 6H), 7.24 (d, J = 8 Hz, 6H), 6.71

(dd, J = 17.6, 10.9 Hz, 3H), 5.77 (d, J = 17.6 Hz, 3H), 5.50 (s, 6H), 5.30 (d, J = 10.9

13 Hz, 3H), 3.73 (s, 6H). C NMR (100 MHz; CDCl3): 144.5, 138.0, 136.0, 134.1,

+ 128.3, 126.8, 124.0, 114.9, 53.9, 47.1. HR-ESI-TOF for C36H37N10 [M+H ]: simulated:

+ 609.3202, experimental: 609.3952. HR-ESI-TOF for C36H36N10Na [M+Na ]: simulated:

631.3022, experimental: 631.3791.

Tris((1-(4-(1,3,3,3-tetrachloropropyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl)amine

1 (TBTA(CCl4)3). H NMR (400 MHz; CDCl3): 7.76 (s, 3H), 7.46 (d, J = 8.4 Hz, 6H),

7.29 (d, J = 8.4 Hz, 6H), 5.54 (s, 6H), 5.32-5.29 (m, 3H), 3.74 (s, 6H), 3.59 (dd, J =

13 15.4, 5.4 Hz, 3H), 3.49 (dd, J = 15.4, 6.4 Hz, 3H). C NMR (100 MHz; CDCl3):

149.40, 141.24, 135.79, 128.53, 128.19, 124.68, 96.02, 62.57, 57.61, 53.68, 46 96.02,

+ 62.57, 57.61, 53.68, 46.81. HR-ESI-TOF for C36H37Cl12N10 [M+H ]: simulated:

+ 1070.9358, experimental: 1071.0706. HR-ESI-TOF for C36H36Cl12N10Na [M+Na ]: simulated: 1092.9186, experimental: 1093.0548.

233

Tris((1-(4-(1,3,3,3-tetrabromopropyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl)amine

1 (TBTA(CBr4)3). H NMR (400 MHz; CDCl3): δ7.78 (s, 3H), δ7.51 (d, J = 8.4 Hz, 6H),

δ7.27 (d, J = 8.4 Hz, 6H), δ5.53 (s, 6H), δ5.32 (dd, J = 7.6, 4.0 Hz, 3H), δ4.12 (dd, J =

15.4, 4.0 Hz, 3H), δ4.03 (dd, J = 15.4, 7.8 Hz, 3H), δ3.75 (s, 6H). 13C NMR (100 MHz;

CDCl3): δ143.35, 141.36, 135.48, 128.94, 128.45, 124.47, 82.90, 66.27, 56.90, 53.65,

+ 49.14, 46.89. HR-ESI-TOF for C36H37Br12N10 [M+H ]: simulated: 1604.3242,

+ experimental: 1604.5386. HR-ESI-TOF for C36H36Br12N10Na [M+Na ]: simulated:

1626.3115, experimental: 1626.5079.

Trimethyl 4,4',4''-(((4,4',4''-(nitrilotris(methylene))tris(1H-1,2,3-triazole-4,1- diyl))tris(methylene))tris(benzene-4,1-diyl))tris(2,2,4-trichlorobutanoate)

1 (TBTA(Cl3CCO2Me)3). H NMR (400 MHz; CDCl3): δ8.10 (s, 3H), δ7.44 (d, J = 8.4 Hz,

6H), δ7.00 (d, J = 8.4 Hz, 6H), δ5.56 (s, 6H), δ5.24 (dd, J = 7.6, 5.8 Hz, 3H), δ3.93 (s,

9H), δ3.71 (s, 6H), δ3.42 (dd, J = 15.0, 7.6 Hz, 3H), δ3.18 (dd, J = 15.0, 5.8 Hz, 3H). 13C

NMR (101 MHz; CDCl3): δ165.6, 143.8, 140.3, 135.6, 128.4, 128.1, 124.2, 81.9, 57.8,

54.5, 53.9, 53.6, 46.8, 43.613C NMR: 165.6, 143.67, 135.8, 128.5, 128.2, 124.2, 82.0,

+ 57.9, 54.5, 53.8, 47.0, 43.6. HR-ESI-TOF for C46H50N10Cl12O6 [M+H ]: simulated:

1157.1051, experimental: 1160.9780.

4,4',4''-(((4,4',4''-(nitrilotris(methylene))tris(1H-1,2,3-triazole-4,1- diyl))tris(methylene))tris(benzene-4,1-diyl))tris(2,4-dichlorobutanenitrile))

1 (TBTA(CHCl2CN)3). H-NMR (400 MHz; CDCl3): mixture of diastereomers δ7.76 (s,

3H), δ7.75 (s, 3H), δ7.42 (d, J = 8.4 Hz, 6H), δ7.31 (d, J = 8.4 Hz, 6H), δ5.54 (s, 6H),

δ5.13-5.05 (m, 3H), δ4.79-4.75 (m, 3H), δ4.55-4.51 (m, 3H), δ3.72 (s, 6H), δ2.85-2.77

13 (m, 3H), δ2.73-2.66 (m, 3H), 2.66-2.56 (m, 3H). C NMR (100 MHz; CDCl3): 144.15,

234

144.06; 139.40, 139.10; 136.09, 135.98; 128.79, 128.75; 127.77, 127.75; 124.10, 124.05;

116.29, 116.04; 57.85, 57.70; 53.54; 46.98, 46.96; 45.73, 45.40; 40.20, 39.91. HR-ESI-

+ TOF for C42H40Cl6N13 [M+H ]: simulated: 938.16275, experimental: 938.2882. HR-ESI-

+ TOF for C42H39Cl6N13Na [M+Na ]: simulated: 960.1459, experimental: 960.2722.

Trimethyl 4,4',4''-(((4,4',4''-(nitrilotris(methylene))tris(1H-1,2,3-triazole-4,1- diyl))tris(methylene))tris(benzene-4,1-diyl))tris(2,4-dichlorobutanoate).

1 (TBTA(Cl2HCCO2Me)3). H NMR (400 MHz; CDCl3): mixture of diastereomers δ7.73 (s,

3H), δ 7.72 (s, 3H), δ7.39 (d, J = 8.0 Hz, 6H), δ7.29 (d, J = 8.4 Hz, 6H), δ5.49 (s, 6H),

δ5.14 (dd, J = 5.9, 2.9 Hz, 3H), δ5.12-5.02 (m, 3H), δ4.71-4.62 (m, 6H), δ3.77 (s, 9H),

δ3.67 (s, 6H), δ3.66 (s, 6H), δ2.76-2.61 (m, 6H), δ2.43-2.31(m, 6H). 13C NMR (100

MHz; CDCl3): 169.28, 168.99, 144.11, 144.03, 140.79, 135.45, 128.57, 127.84, 124.03,

124.0, 59.11, 57.1, 56.94, 54.84, 53.31, 46.97, 44.1. HR-ESI-TOF for C46H53N10Cl6O6

[M+H+]: simulated: 1053.2217, experimental: 1053.2524.

5.7 References

1. Kolb, H. C.; Finn, M. G.; Sharpless, K. B., Click Chemistry: Diverse Chemical Function from a Few Good Reactions. Angew. Chem. Int. Ed. 2001, 40 (11), 2004-2021.

235

4. Agard, N. J.; Prescher, J. A.; Bertozzi, C. R., A Strain-Promoted [3 + 2] Azide- Alkyne Cycloaddition for Covalent Modification of Biomolecules in Living Systems. J. Am. Chem. Soc. 2004, 126 (46), 15046-15047.

5. Dirks, A. J.; van Berkel, S. S.; Hatzakis, N. S.; Opsteen, J. A.; van Delft, F. L.; Cornelissen, J. J. L. M.; Rowan, A. E.; van Hest, J. C. M.; Rutjes, F. P. J. T.; Nolte, R. J. M., Preparation of biohybrid amphiphiles via the copper catalysed Huisgen [3 + 2] dipolar cycloaddition reaction. Chem. Commun. 2005, (33), 4172-4174.

6. Meldal, M.; Tornoe, C. W., Cu-Catalyzed Azide-Alkyne Cycloaddition. Chem. Rev. 2008, 108 (8), 2952-3015.

7. Moses, J. E.; Moorhouse, A. D., The Growing Applications of Click Chemistry. Chem. Soc. Rev. 2007, 36 (8), 1249-1262.

8. Binder, W. H.; Kluger, C., Azide/Alkyne-"Click" Reactions: Applications in Material Science and Organic Synthesis. Curr. Org. Chem. 2006, 10 (14), 1791- 1815.

9. Kolb, H. C.; Sharpless, K. B., The Growing Impact of Click Chemistry on Drug Discovery. Drug Discov. Today 2003, 8 (24), 1128-1137.

10. Amblard, F.; Cho, J. H.; Schinazi, R. F., Cu(I)-Catalyzed Huisgen Azide-Alkyne 1,3-Dipolar Cycloaddition Reaction in Nucleoside, Nucleotide, and Oligonucleotide Chemistry. Chem. Rev. 2009, 109 (9), 4207-4220.

11. Hein, C.; Liu, X.-M.; Wang, D., Click Chemistry, A Powerful Tool for Pharmaceutical Sciences. Pharm. Res. 2008, 25 (10), 2216-2230.

12. Najera, C.; Sansano, J. M., 1,3-Dipolar cycloadditions: applications to the synthesis of antiviral agents. Org. Biomol. Chem. 2009, 7 (22), 4567-4581.

13. Binder, W. H.; Sachsenhofer, R., ‗Click‘ Chemistry in Polymer and Materials Science. Macromol. Rapid Commun. 2007, 28 (1), 15-54.

14. Nandivada, H.; Jiang, X.; Lahann, J., Click Chemistry: Versatility and Control in the Hands of Materials Scientists. Adv. Mater. 2007, 19 (17), 2197-2208.

236

15. Golas, P. L.; Matyjaszewski, K., Click Chemistry and ATRP: A Beneficial Union for the Preparation of Functional Materials. QSAR Comb. Sci. 2007, 26 (11-12), 1116-1134.

16. Golas, P. L.; Matyjaszewski, K., Marrying click chemistry with polymerization: expanding the scope of polymeric materials. Chem. Soc. Rev. 2010, 39 (4), 1338- 1354.

17. Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V., Copper(I)-Catalyzed Synthesis of Azoles. DFT Study Predicts Unprecedented Reactivity and Intermediates. J. Am. Chem. Soc. 2005, 127 (1), 210-216.

18. Ahlquist, M.; Fokin, V. V., Enhanced Reactivity of Dinuclear Copper(I) Acetylides in Dipolar Cycloadditions. Organometallics 2007, 26 (18), 4389-4391.

19. Straub, B. F., μ-Acetylide and μ-Alkenylidene Ligands in "Click" Triazole Syntheses. Chem. Commun. 2007, (37), 3868-3870.

20. Rodionov, V. O.; Fokin, V. V.; Finn, M. G., Mechanism of the Ligand-Free CuI- Catalyzed Azide–Alkyne Cycloaddition Reaction. Angew. Chem. Int. Ed. 2005, 44 (15), 2210-2215.

21. Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H., CuI-Catalyzed Alkyne–Azide ―Click‖ Cycloadditions from a Mechanistic and Synthetic Perspective. Eur. J. Org. Chem 2006, 2006 (1), 51-68.

22. Curran, D. P., The Design and Application of Free Radical Chain Reactions in Organic Synthesis. Part 2. Synthesis 1988, (7), 489-513.

23. Curran, D. P., The Design and Application of Free Radical Chain Reactions in Organic Synthesis. Part 1. Synthesis 1988, (6), 417-439.

24. Curran, D. P., Comprehensive Organic Synthesis. Pergamon: New York, 1992; p 715.

25. Iqbal, J.; Bhatia, B.; Nayyar, N. K., Transition Metal Promoted Free Radical Reactions in Organic Synthesis: The Formation of Carbon-Carbon Bonds. Chem. Rev. 1994, 94 (2), 519-564.

237

26. Eckenhoff, W. T.; Pintauer, T., Copper Catalyzed Atom Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions in the Presence of Reducing Agents. Cat. Rev. Sci. Eng. 2010, 51, 1-59.

27. Severin, K., Ruthenium Catalysts for the Kharasch Reaction. Curr. Org. Chem. 2006, 10, 217-224.

28. Wang, J.-S.; Matyjaszewski, K., Controlled/"living" radical polymerization. atom transfer radical polymerization in the presence of transition-metal complexes. J. Am. Chem. Soc. 1995, 117 (20), 5614-5615.

29. Matyjaszewski, K.; Xia, J., Atom Transfer Radical Polymerization. Chem. Rev. 2001, 101 (9), 2921-2990.

30. Quebatte, L.; Thommes, K.; Severin, K., Highly Efficient Atom Transfer Radical Addition Reactions with a RuIII Complex as a Catalyst Precursor. J. Am. Chem. Soc. 2006, 128 (23), 7440-7441.

31. Eckenhoff, W. T.; Pintauer, T., Atom Transfer Radical Addition in the Presence of Catalytic Amounts of Copper(I/II) Complexes with Tris(2- pyridylmethyl)amine Inorg. Chem. 2007, 46 (15), 5844-5846.

32. Eckenhoff, W. T.; Garrity, S. T.; Pintauer, T., Highly Efficient Copper-Mediated Atom Transfer Radical Addition (ATRA) in the Presence of a Reducing Agent. Eur. J. Inorg. Chem. 2008, 2008 (4), 563-571.

33. Pintauer, T., "Greening" of Copper Catalyzed Atom Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions. ACS Symposium Series 2009, 1023, 63-84.

34. Pintauer, T., Catalyst Regeneration in Transition-Metal-Mediated Atom-Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions. Eur. J. Inorg. Chem. 2010, 2010 (17), 2449-2460.

35. Balili, M. N. C.; Pintauer, T., Persistent Radical Effect in Action: Kinetic Studies of Copper-Catalyzed Atom Transfer Radical Addition in the Presence of Free- Radical Diazo Initiators as Reducing Agents. Inorg. Chem. 2009, 48 (18), 9018- 9026.

238

36. Balili, M. N. C.; Pintauer, T., Kinetic Studies of the Initiation Step in Copper Catalyzed Atom Transfer Radical Addition (ATRA) in the Presence of Free Radical Diazo Initiators as Reducing Agents. Inorg. Chem. 2010, 49 (12), 5642- 5649.

37. Pintauer, T.; Eckenhoff, W. T.; Ricardo, C.; Balili, M. N. C.; Biernesser, A. B.; Noonan, S. T.; Taylor, M. T., Highly Efficient Ambient-Temperature Copper- Catalyzed Atom-Transfer Radical Addition (ATRA) in the Presence of Free- Radical Initiator (V-70) as a Reducing Agent Chem. Eur. J. 2009, 15 (1), 38-41.

38. Thommes, K.; Icli, B.; Scopelliti, R.; Severin, K., Atom Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions Catalyzed by a Mixture of [RuCl2Cp*(PPh3)] and Magnesium. Chem. Eur. J. 2007, 13 (24), 6899-6907.

39. Wolf, J.; Thommes, K.; Briel, O.; Scopelliti, R.; Severin, K., Dinuclear Ruthenium Ethylene Complexes: Syntheses, Structures, and Catalytic Applications in ATRA and ATRC Reactions. Organometallics 2008, 27 (17), 4464-4474.

40. Munoz-Molina, J. M.; Caballero, A.; Diaz-Requejo, M. M.; Trofimenko, S.; Belderrain, T. R.; Perez, P. J., Copper−Homoscorpionate Complexes as Active Catalysts for Atom Transfer Radical Addition to Olefins. Inorg. Chem. 2007, 46 (19), 7725-7730.

41. Munoz-Molina, J. M.; Belderrain, T. R.; Perez, P. J., An Efficient, Selective, and Reducing Agent-Free Copper Catalyst for the Atom-Transfer Radical Addition of Halo Compounds to Activated Olefins Inorg. Chem. 2010, 49 (2), 642-645.

42. Clark, A. J.; Wilson, P., Copper mediated atom transfer radical cyclisations with AIBN. Tet. Lett. 2008, 49 (33), 4848-4850.

43. Fernandez-Zumel, M. A.; Thommes, K.; Kiefer, G.; Sienkiewicz, A.; Pierzchala, K.; Severin, K., Atom-Transfer Radical Addition Reactions Catalyzed by RuCp* Complexes: A Mechanistic Study Chem. Eur. J. 2009, 15 (43), 11601-11607.

44. Lundgren, R. J.; Rankin, M. A.; McDonald, R.; Stradiotto, M., Neutral, Cationic, and Zwitterionic Ruthenium(II) Atom Transfer Radical Addition Catalysts Supported by P,N-Substituted Indene or Indenide Ligands. Organometallics 2008, 27 (2), 254-258.

239

45. Nair, R. P.; Kim, T. H.; Frost, B. J., Atom Transfer Radical Addition Reactions of CCl4, CHCl3, and p-Tosyl Chloride Catalyzed by Cp'Ru(PPh3)(PR3)Cl Complexes. Organometallics 2009, 28 (16), 4681-4688.

46. Taylor, M. J. W.; Eckenhoff, W. T.; Pintauer, T., Copper-Catalyzed Atom Transfer Radical Addition (ATRA) and Cyclization (ATRC) Reactions in the Presence of Environmentally Benign Ascorbic Acid as a Reducing Agent. Dalton Trans. 2010, 39 (47), 11475-11482.

47. Ricardo, C.; Pintauer, T., Copper Catalyzed AtomTransfer Radical Cascade Reactions in the Presence of Free-Radical Diazo Initiators as Reducing Agents. J. Chem. Soc. Chem. Commun. 2009, 2009 (21), 3029-3031.

48. Thommes, K.; Kiefer, G.; Scopelliti, R.; Severin, K., Olefin Cyclopropanation by a Sequential Atom-Transfer Radical Addition and Dechlorination in the Presence of a Ruthenium Catalyst. Angew. Chem. Int. Ed. 2009, 48 (43), 8115-8119.

49. Munoz-Molina, J. M.; Belderrain, T. R.; Perez, P. J., Copper-Catalyzed Synthesis of 1,2-Disubstituted Cyclopentanes from 1,6-Dienes by Ring-Closing Kharasch Addition of Carbon Tetrachloride Adv. Synth. Catal. 2008, 350, 2365-2372.

50. Sumerlin, B. S.; Tsarevsky, N. V.; Louche, G.; Lee, R. Y.; Matyjaszewski, K., Highly Efficient "Click" Functionalization of Poly(3-Azidopropyl Methacrylate) Prepared by ATRP. Macromolecules 2005, 38 (18), 7540-7545.

51. Tsarevsky, N. V.; Bernaerts, K. V.; Dufour, B.; Du Prez, F. E.; Matyjaszewski, K., Well-Defined (Co)polymers with 5-Vinyltetrazole Units via Combination of Atom Transfer Radical (Co)polymerization of Acrylonitrile and "Click Chemistry"-Type Postpolymerization Modification. Macromolecules 2004, 37 (25), 9308-9313.

52. Geng, J.; Lindqvist, J.; Mantovani, G.; Haddleton, D. M., Simultaneous Copper(I)-Catalyzed Azide–Alkyne Cycloaddition (CuAAC) and Living Radical Polymerization. Angew. Chem. Int. Ed. 2008, 47 (22), 4180-4183.

53. Grignard, B.; Calberg, C.; Jerome, C.; Detrembleur, C., "One-Pot" Dispersion ATRP and Alkyne-Azide Huisgen's 1,3-Dipolar Cycloaddition in Supercritical Carbon Dioxide: Towards the Formation of Functional Microspheres. J. Supercrit. Fluids 2010, 53 (1-3), 151-155.

240

54. Ricardo, C. L.; Pintauer, T., One-Pot Sequential Azide–Alkyne [3+2] Cycloaddition and Atom Transfer Radical Addition (ATRA): Expanding the Scope of In Situ Copper(I) Regeneration in the Presence of Environmentally Benign Reducing Agent. Eur. J. Inorg. Chem. 2011, 2011 (8), 1292-1301.

55. Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V., Polytriazoles as Copper(I)-Stabilizing Ligands in Catalysis. Org. Lett. 2004, 6 (17), 2853-2855.

56. Takai, A.; Chkounda, M.; Eggenspiller, A.; Gros, C. P.; Lachkar, M.; Barbe, J. M.; Fukuzumi, S., Efficient Photoinduced Electron Transfer in a Porphyrin Tripod−Fullerene Supramolecular Complex via π−π Interactions in Nonpolar Media. J. Am. Chem. Soc. 2010, 132 (12), 4477-4489.

57. Seela, F.; Ingale, S. A., ―Double Click‖ Reaction on 7-Deazaguanine DNA: Synthesis and Excimer Fluorescence of Nucleosides and Oligonucleotides with Branched Side Chains Decorated with Proximal Pyrenes. J. Org. Chem. 2010, 75 (2), 284-295.

58. Balili, M. N. C.; Pintauer, T., Photoinitiated ambient temperature copper- catalyzed atom transfer radical addition (ATRA) and cyclization (ATRC) reactions in the presence of free-radical diazo initiator (AIBN). Dalton Trans. 2011, 40 (12), 3060-3066.

59. Min, K.; Gao, H.; Matyjaszewski, K., Preparation of Homopolymers and Block Copolymers in Miniemulsion by ATRP Using Activators Generated by Electron Transfer (AGET). J. Am. Chem. Soc. 2005, 127 (11), 3825-3830.

60. Min, K.; Gao, H.; Matyjaszewski, K., Use of Ascorbic Acid as Reducing Agent for Synthesis of Well-Defined Polymers by ARGET ATRP. Macromolecules 2007, 40 (6), 1789-1791.

61. Tyeklar, Z.; Jacobson, R. R.; Wei, N.; Murthy, N. N.; Zubieta, J.; Karlin, K. D., Reversible reaction of dioxygen (and carbon monoxide) with a copper(I) complex. X-ray structures of relevant mononuclear Cu(I) precursor adducts and the trans-(.mu.-1,2-peroxo)dicopper(II) product. J. Am. Chem. Soc. 1993, 115 (7), 2677-2689.

62. Xu, L. Q.; Yao, F.; Fu, G.-D.; Shen, L., Simultaneous "Click Chemistry" and Atom Transfer Radical Emulsion Polymerization and Prepared Well-Defined Cross-Linked Nanoparticles. Macromolecules 2009, 42 (17), 6385-6392.

241

242

Chapter 6

Synthesis, Characterization, and the Role of Counterion in Cyclopropanation of Styrene Catalyzed by [CuI(2,2’- - - - bpy)(-CH2=CHC6H5)][A] (A=ClO4 , PF6 and CF3SO3 ) Complexes

I Copper(I)/2,2‘-bipyridine complexes, [Cu (bpy)(-CH2CHC6H5)][A] (A =

- - CF3SO3 (1) and PF6 (2) have been synthesized and characterized. The equilibrium constants for the coordination of styrene to [CuI(bpy)]+ cations at 300 K were determined

3 3 3 -1 - to be 4.3x10 (1), 4.4x10 (2) and 3.8x10 M (A=ClO4 , 3). These data suggested that the axial coordination of the counterion in these complexes observed in the solid state

(2.4297(11) Å 1, 2.9846(12) Å 2, and 2.591(4) Å 3) did not significantly affect the binding constant of styrene to [CuI(bpy)]+ cations in solution. In cyclopropanation reactions catalyzed by 1-3, similar product distribution was obtained. The rate of decomposition of EDA in the presence of styrene at room temperature catalyzed by 3

-3 -1 (kobs=(7.7±0.32)10 min ) was slower than the rate observed for 1

-2 -1 -2 -1 (kobs=(1.4±0.041)10 min ) or 2 (kobs=(1.0±0.025)10 min ).

243

6.1 Introduction

In recent years, a considerable effort has been devoted to the development of transition metal catalysts for diastereo- and enantioselective cyclopropanation1-4 and aziridination5,6 of olefins. Effective catalytic system for the cyclopropanation of alkenes with diazo reagents requires the use of a transition metal complex, which facilitates the loss of N2 from the diazo reagent, as well as stabilizes intermediate carbene species against competing carbene dimerization.7-10 A variety of transition metal complexes have been found to be active in cyclopropanation reactions and they include the complexes of

Fe,11 Rh,12 Ru13,14 and Cu.4 Copper appears to be particularly attractive because of its low cost relative to other transition metal complexes. So far, cationic copper(I) complexes in

15 16 conjunction with a C2-symmetric ligand, such as bis(oxazoline), 2,2‘-bipyridine (bpy),

2,2′:6′,2′′ terpyridine16-18 and 1,10-phenanthroline (phen),16,19 and neutral copper(I) complexes with semicorrin,20 polypyrazolylborates,21-23 iminophosphanamidates24,25 and

-diketiminates26 have been successfully used in cyclopropanation reactions. However, despite a tremendous effort directed towards empirical catalyst development, mechanism of these very important synthetic reactions is still not fully understood. It is generally accepted that the copper catalyzed cyclopropanation reactions proceed via a copper- carbene complex, as indicated in Scheme 6.1 for cyclopropanation catalyzed by copper(I)/2,2‘-bipyridine complex.1,2,15 However, the details of this process are not well- known.

Only, very recently, copper-carbene complexes have been detected as reaction intermediates in cyclopropanation reactions utilizing low temperature NMR measurements24,25 and X-ray diffraction.26 Another key mechanistic feature of these

244

Scheme 6.1. Proposed mechanism for copper(I)/2,2‘-bipyridine catalyzed cyclopropanation of olefins.

reactions includes the role of monomer and counterion, both of which are poorly understood. Mechanistic15,27 and computational28,29 studies have indicated that copper(I)/olefin complexes in these systems might act as either catalytically active species or resting states. Furthermore, the reactivity of cationic copper(I) complexes is strongly influenced by the counterion. Triflates and hexafluorophosphates15,30 were found to be highly effective catalysts whereas halides, cyanides, acetates and perchlorate showed little or no catalytic activity.

Cationic copper(I)/alkene complexes with bidentate nitrogen based ligands are very rare and so far only two complexes with nonpolar olefins such as styrene31 and cyclohexene32 have been isolated (Scheme

6.2). In both complexes, the geometry around

245

Scheme 6.2 Structures of cationic copper(I)/alkene complexes with bidentate nitrogen based ligands.

copper(I) atom was found to be trigonal pyramidal, due to the weak interaction with the counterion. Recently, we have successfully isolated and structurally characterized

I - - - [Cu (bpy)(-CH2CHCOOCH3)][A] (A=CF3SO3 , ClO4 and PF6 ) complexes (Scheme

6.2). These complexes represented the first class of trigonal pyramidal copper(I) complexes with -coordinated electron poor olefins. Weak coordination of the

- - counterion was observed in the case of CF3SO3 (Cu-O=2.388(4) Å) and PF6 (Cu-

- F=2.609(2) Å) complexes. The counterion ClO4 , on the other hand, was noncoordinating and the corresponding copper(I) complex was dimeric in the solid state

246

with oxygen atoms of the carbonyl moieties in methyl acrylate bridging two copper(I) centers (Cu-O=2.434(4) Å).

In this chapter, we report the synthesis and characterization of copper(I)/bpy

I - - complexes [Cu (bpy)(-CH2=CHC6H5)][A] (A = CF3SO3 (1), and PF6 (2)).

Furthermore, the role of counterion in cyclopropanation of styrene with ethyldiazoacetate

I (EDA) catalyzed by these complexes and [Cu (bpy)(-CH2=CHC6H5)][ClO4] (3) is also discussed.

6.2 Results and Discussion

6.2.1 X-ray crystallography

I - - - [Cu (bpy)(-CH2=CHC6H5)][A] (A=CF3SO3 (1), PF6 (2) and ClO4 (3)) were

I I synthesized by reacting [Cu (CF3SO3)]2*C6H5CH3, [Cu (CH3CN)4][PF6] and

I [Cu (CH3CN)4][ClO4], respectively, with the stoichiometric amounts of 2,2‘-bipyridine

(bpy) and large excess of styrene (typically 30 equivalents). Slow crystallization from methanol at -35 oC afforded colorless crystals of 1-3 in reasonable yields. Shown in

Figure 6.1 is the molecular structure of complex 1. Selected bond distances and angles are listed in

Table 6.2. Complex 1 is distorted trigonal pyramidal in geometry and copper(I) atom is coordinated by two nitrogen atoms of bpy ligand, two olefinic carbon atoms of

- styrene at the equatorial position, and an oxygen atom of CF3SO3 anion at the axial

247

position. The dihedral angle between the planes defined by the copper and two nitrogen atoms of the bpy molecule and by the copper and two carbon atoms of styrene is

19.63(4)o. The CuI-N bond distances (Cu(1)-N(1) = 1.9998(12) Å, Cu(1)-N(2) =

1.9978(12) Å) are in the range generally found for copper(I) complexes with bpy

Table 6.1. Crystallographic data and experimental details for 1 and 2. [CuI(bpy) [CuI(bpy)(- Compound (-CH2=CHC6H5)][CF3SO3] CH2=CHC6H5)][PF6]*1/2Sty (1) (2) formula C19H16CuF3N2O3S C44H40Cu2F12N4P2 color/shape colorless/needles colorless/needles formula weight 472.94 1041.82 cryst sys monoclinic monoclinic space group P2(1)/c P2(1)/c temp, K 150(2) 150(2) cell constants a, Å 8.36140(10) 22.3107(7) b, Å 15.6925(2) 12.2893(4) c, Å 14.8425(2) 16.5493(5) , deg 90. 90. , deg 98.4940(10) 107.63(4) , deg 90. 90. V, Å3 1926.14(4) 4324.5(2) Formula units/unit cell 4 4 -3 Dcalcd, gcm 1.631 1.600 , mm-1 1.294 1.148 F(000) 960 2112 diffractometer Bruker Smart Apext II Bruker Smart Apex II radiation, graphite Mo K (=0.71073 Å) Mo K (=0.71073 Å) crystalmonochr. size, mm 0.25 x 0.14 x 0.08 0.49 x 0.29 x 0.17  range, deg 1.90<  < 30.97 0.96<  < 32.47 range of h,k,l ±12, ±22, ±21 ±32, ±18, ±24 reflections 33538/6103 53954/14828

collected/uniqueRint 0.0280 0.0476 refinement method full-matrix least-squares on F2 full-matrix least-squares on F2 data/restraints/parameters 6103/0/265 14828/0/577 GOF on F2 1.023 0.745 final R indices [I>2(I)] R1=0.0288, wR2=0.0716 R1=0.0325, wR2=0.0975 R indices (all data) R1=0.0391, wR2=0.0764 R1=0.0503, wR2=0.1104

248

max. resid. peaks (e•Å-3) 0.426 and -0.304 0.668 and -0.461

Table 6.2. Selected bond distances (Å) and angles (o) for 1 and 2. I [Cu (bpy)(-CH2=CHC6H5)][CF3SO3] (1) Distances Angles Cu(1)-N(1) 1.9998(12) N(2)-Cu(1)-N(1) 82.88(5) Cu(1)-N(2) 1.9978(12) N(2)-Cu(1)-C(1) 156.03(6) Cu(1)-C(1) 2.0033(14) N(1)-Cu(1)-C(1) 119.27(6) Cu(1)-C(2) 2.0304(14) N(2)-Cu(1)-C(2) 115.92(6) Cu(1)-O(1) 2.4297(11) N(1)-Cu(1)-C(2) 153.24(5) C(1)-C(2) 1.383(2) C(1)-Cu(1)-C(2) 40.11(6) N(2)-Cu(1)-O(1) 91.31(4) N(1)-Cu(1)-O(1) 94.77(4) C(1)-Cu(1)-O(1) 95.49(5) C(1)-C(2)-C(3) 125.04(13) I [Cu (bpy)(-CH2=CHC6H5)][PF6]*1/2Sty (2) Distances Angles Cu(1)-N(1) 1.9779(13) N(1)-Cu(1)-N(2) 83.40(5) Cu(1)-N(2) 1.9964(13) N(1)-Cu(1)-C(1) 117.64(6) Cu(1)-C(1) 2.0144(15) N(2)-Cu(1)-C(1) 158.31(6) Cu(1)-C(2) 2.0167(14) N(1)-Cu(1)-C(2) 156.27(6) C(1)-C(2) 1.378(2) N(2)-Cu(1)-C(2) 118.37(6) Cu(2)-N(3) 1.9713(12) C(1)-Cu(1)-C(2) 39.99(6) Cu(2)-N(4) 1.9621(12) C(1)-C(2)-C(3) 124.80(14) Cu(2)-C(19) 1.9706(15) N(4)-Cu(2)-C(19) 115.05(6) Cu(2)-C(20) 2.0131(14) N(4)-Cu(2)-N(3) 84.01(5) Cu(2)-F(9) 2.9846(12) C(19)-Cu(2)-N(3) 159.80(6) C(19)-C(20) 1.388(2) N(4)-Cu(2)-C(20) 155.71(6) C(19)-Cu(2)-C(20) 40.76(6) N(3)-Cu(2)-C(20) 119.75(6) C(19)-C(20)-C(21) 125.19(14)

33 I containing ligands (1.93-2.16 Å). The Cu -O(SO2CF3) distance (2.4297(11) Å) is longer than the sum of ionic radii for CuI (0.96 Å) and O- (1.40 Å), and is also longer than

249

2.388(4) Å observed in structurally related -methyl acrylate complex, [CuI(bpy)(-

34 CH2=CHCOOCH3][CF3SO3]. The two Cu-C bond distances (Cu(1)-C(1) =

2.0033(14)Å, Cu(1)-C(2) = 2.0304(14) Å) are slightly shorter than those found in

I tetrahedral Cu (PMDETA)(-CH2=CHC6H5)][BPh4] (PMDETA = N,N,N’,N”,N”- pentamethyldiethylenetriamine) complex (CuI-C=2.052(2) and 2.108(2) Å).35

Furthermore, the C=C double bond distance of the coordinated styrene (1.383(2) Å) is slightly longer than those reported for other free olefin molecules (1.355±0.005 Å).35,36

The crystal structure of 1 is stabilized by - stacking interactions between bpy units

(perpendicular separation between least-squares planes = 3.304(6) Å). Such interactions are very common in copper(I) complexes with bipyridine based ligands and are typically in the range 3.30-3.60 Å.37,38

250

I Figure 6.1. Molecular structure of [Cu (bpy)(-CH2=CHC6H5][CF3SO3] (1), shown with 50% probability displacement ellipsoids. H atoms have been omitted for clarity.

The crystals of complex 2 contain two crystallographically independent

I I molecules, [Cu (bpy)(-CH2=CHC6H5)(PF6)] and [Cu (bpy)(-CH2=CHC6H5)][PF6]

(Figure 3) and styrene solvate (Figure 6.2). The structure of [CuI(bpy)(-

CH2=CHC6H5)(PF6)] is very similar to 1. The copper(I) atom is coordinated by two nitrogen atoms from bpy ligand (Cu(2)-N(3) = 1.9713(12) Å, Cu(2)-N(4) = 1.9621(12)

Å), two carbon atoms from styrene in equatorial position (Cu(2)-C(19) = 1.9706(15) Å,

- Cu(2)-C(20) = 2.0131(14) Å), and a fluorine atom from PF6 anion (Cu(2)-F(9) =

I 2.9846(12) Å) in the axial position. Relatively long Cu -F(PF5) distance (2.9846(12) Å)

251

indicates that counterion in this complex is weakly coordinated to the copper(I) center.

The C=C bond length of coordinated styrene is 1.388(2) Å. The dihedral angle between

Cu(2)-C(19)-C(20) and Cu(2)-N(3)-N(4) planes in 2 is 6.34(3)o, which is much smaller

o o I 31 than 19.63(4) and 12.60(5) observed in 1 and [Cu (bpy)(-CH2=CHC6H5)][ClO4] (3),

I + respectively. This result indicates that Cu (bpy)(-CH2=CHC6H5) moiety in 2 is more

I + trigonal planar in geometry than in 1 and 3. The [Cu (bpy)(-CH2=CHC6H5)] cations in

2 form - stacking interactions between bpy planes (perpendicular separation between least-squares planes=3.303(5) Å).

In the molecular structure of complex 3, which has been published previously

(Scheme 6.2),31 the copper(I) center is distorted trigonal pyramidal in geometry.

Bipyridine ligand coordinates to the copper(I) atom in a bidentate fashion (Cu-N =

1.985(4) and 2.014(5) Å). Additionally, two coordination sites are occupied by olefinic carbon atoms from styrene in equatorial position (Cu-C=2.014(5) and 1.985(6) Å) and an

- oxygen atom from ClO4 anion (Cu-O=2.591(4) Å) in the axial position. The dihedral angle between the planes defined by the copper and two nitrogen atoms of the bpy molecule and by the copper and two carbon atoms of styrene is 12.60(5)o. Similarly to the structures of 1 and 2, the structure of 3 is stabilized by - stacking interactions between bpy planes (3.37 Å).

252

I Figure 6.2. Molecular structure of [Cu (bpy)(-CH2=CHC6H5][PF6]•1/2Sty (2), shown with 50% probability displacement ellipsoids. H atoms have been omitted for clarity.

6.2.2 1H NMR and FT-IR Characterization

Complexes 1-3 are very stable in the solid state even in the presence of air.

However, they disproportionate in CD3OD, (CD3)2CO and CD2Cl2 within 10 minutes at room temperature, unless excess free styrene is present. The spectra of 1 and 2 in CD2Cl2

(experimental section) indicated 1:1 ratio between 2,2‘-bipyridine and styrene. However, only four resonances for bpy ligand were observed at temperatures as low as 180 K, which is not consistent with solid state structures. This is most likely induced by the fast rotation about the alkene-copper(I) bond on the NMR time scale.

253

1 Table 6.3. H NMR chemical shifts (300 MHz, CD2Cl2, 180 K) of olefinic protons and C=C stretching frequency (cm-1) for 1-3. 1 2 3 a H(H) 6.22(0.52) 6.31(0.43) 6.26(0.48) trans trans H (H ) 5.01(0.77) 5.19(0.59) 5.12(0.66) cis cis H (H ) 4.65(0.60) 4.74(0.51) 4.68(0.57) (C=C)()b 1529(101) 1527(103) 1525(105) a trans cis H = H(free Sty) - H(observed), ppm (R-CH=CH CH ). b = (free Sty) - (observed), cm-1.

Chemical shifts of complexed styrene are summarized in Table 6.3 and compared to those of free styrene. For 1-3, strong shielding of vinyl protons was observed which indicates -backbonding donation from CuI, although with different magnitudes.39,40 The shielding effect is the weakest with -carbon, which is also further away from CuI than is the -carbon (Table 2). The -nature of C=C of styrene is further supported by a decrease in the IR stretching frequency of C=C by approximately 102 cm-1 upon coordination.

Because complexes 1-3 undergo fast styrene exchange on the NMR time scale at room temperature, the average signals for the free and complexed styrene were observed.

Methods for the determination of the equilibrium constant for styrene coordination to the copper(I) center for such a reaction from solution NMR data are well-known. Using previously described methodology,41,42 the equilibrium constants for the coordination of styrene to [CuI(bpy)]+ cations at 300 K were determined to be 4.3x103 (1), 4.4x103 (2) and 3.7x103 M-1 (3). These data suggest that the axial coordination of the counterion in these complexes observed in the solid state (2.4297(11) Å 1, 2.9846(12) Å 2, and

254

2.591(4) Å 3) does not significantly affect the binding constant of styrene to [CuI(bpy)]+ cations in solution.

6.2.3 Cyclopropanation Studies

In order to further investigate the role of counterion in 1-3, cyclopropanation of styrene in the presence of ethyldiazoacetate (EDA) was conducted. The reactions were performed in CH2Cl2 at room temperature using standard conditions

I 23,43 1 [Cu ]0:[Styrene]0:[EDA]0=1:500:50. The product distribution was determined by H

NMR and the results are summarized in Table 4. For all three complexes, the relative amounts of EDA decomposition products, diethyl fumarate and diethyl maleate, ranged between 16.0 and 18.0 mol%. Furthermore, the mole percent of trans and cis cyclopropane were very similar for complexes 1 and 2. In the case of complex 3, there was a slight increase in the amount of trans cyclopropane formed (66.9 mol%), accompanied by a decrease in the amount of cis product (14.7 mol%). However, surprisingly, the diethyl fumarate to diethyl maleate ratio does not follow the same trend.

Cyclopropanation of styrene catalyze by complex 3 leads to a 36:64 mol% ratio, favoring the formation of diethyl maleate, whereas the same ratio for complexes 1 and 2 was determined to be 53:47 mol% and 62:38 mol%, respectively. We are presently conducting kinetic measurements in the absence of styrene to gain further information on the effect of counterion on the ratio of EDA decomposition products. Overall, based on the results presented in this article, it appears that 1-3 showed similar trans:cis cyclopropane selectivity.

The effect of counterion in 1-3 on the cyclopropanation of styrene in the presence of EDA was additionally examined by monitoring the rate of decomposition of EDA. The

255

decomposition of EDA in the presence of 1-3 was very fast and quantitative conversions were achieved within 2 minutes at room temperature. However, the presence of externally added styrene dramatically slowed down the reaction rate. This result was expected due to the known fact that the coordination of olefin to the copper(I) center inhibits the diazocarbene decomposition (Scheme 6.1) 43,44. Shown in Figure 6.3 are the plots for the pseudo-first order decomposition of EDA in the presence of styrene and 1-3.

Table 6.4. Cyclopropanation of styrene in the presence of EDA catalyzed by 1-3.a Ph H H H EtO2C H H H Catalyst H CO2Et Ph CO2Et H CO2Et EtO2C CO2Et 1 58.0 27.0 8.0 7.0 2 58.7 25.3 9.9 6.1 3 66.9 14.7 6.7 11.7 a I solvent=CH2Cl2, reaction time=2h, [Cu ]0:[2,2‘-bpy]0:[EDA]0:[Styrene]0=1:1:50:500, I -3 1 [Cu ]0=1.7x10 M, % yield based on H NMR.

Linearity was observed for all three complexes (Figure 6.3), enabling the determination of the observed rate constant (kobs). The observed rate constant (kobs), as pointed out by detailed kinetic studies with anionic poly(pyrazolyl) borate ligands,43 is a complex function of the total copper(I) and styrene concentration, equilibrium constant for styrene coordination to the copper(I) center (Ko, Scheme 1), and the rate constant for the formation of copper(I) carbene complex (k1, Scheme 6.1). The rate of decomposition

256

-3 -1 of EDA catalyzed by 3 (kobs=(7.7±0.32)10 min ) is slower than the rate observed for 1

-2 -1 -2 -1 (kobs=(1.4±0.041)10 min ) or 2 (kobs=(1.0±0.025)10 min ). This result is consistent with the cyclopropanation of styrene catalyzed by copper(I) complexes with

- bis(oxazolines) in which the presence of ClO4 counterion resulted in a decrease in the catalytic activity.15,30 Furthermore, the decrease in the observed rate constant for EDA

- decomposition in the case of ClO4 counterion cannot be explained in terms of equilibrium constant for styrene coordination to the copper(I) center because variable temperature 1H NMR measurements have indicated similar binding constant of styrene to

257

1 (4.3x103 M-1), 2 (4.4x103 M-1) and 3 (3.8x103 M-1). We believe that the counterion in

I + 1-3 can also have an effect on the formation of tetrahedral [Cu (2,2‘-bpy)2] cations,33,37,39,45,46 which are commonly present in these systems (Scheme 6.1), and would additionally slow down the rate of decomposition of EDA. This possibility is currently under investigation.

6.3 Summary and Conclusion

In summary, novel copper(I)/2,2-bipyridine complexes with -coordinated styrene have been synthesized and characterized. These complexes are used as catalysts in copper(I) mediated cyclopropanation of styrene. The equilibrium constants for the coordination of styrene to [CuI(bpy)]+ cations at 300 K were determined to be 4.3x103,

4.4x103 and 3.8x103 M-1 for 1,2 and 3, respectively. These data suggested that the axial coordination of the counterion in these complexes observed in the solid state (2.4297(11)

Å 1, 2.9846(12) Å 2, and 2.591(4) Å 3) did not significantly affect the binding constant of styrene to [CuI(bpy)]+ cations in solution. In cyclopropanation reactions catalyzed by

1-3, similar product distribution was obtained. Furthermore, the rate of decomposition of

-3 -1 EDA in the presence of styrene catalyzed by 3 (kobs=(7.7±0.32)10 min ) was slower

-2 -1 -2 than the rate observed for 1 (kobs=(1.4±0.041)10 min ) or 2 (kobs=(1.0±0.025)10 .

6.4 Experimental

6.4.1 General

I I [Cu (CF3SO3)]2*C6H5CH3 (99.99%, Aldrich), [Cu (CH3CN)4][PF6] (98+%,

I Strem) and 2,2‘-bipyridine (99+%, Acros) were used as received. [Cu (CH3CN)4][ClO4]

258

was synthesized according to the literature procedure.39 Styrene (99%, Acros) was stirred over CaH2 for 24 hours and distilled under argon. Solvents (methylene chloride, pentane, acetonitrile and methanol) were degassed and deoxygenated using Innovative

Technology solvent purifier. Ethyl diazoacetate (EDA, 99% Aldrich) was degassed prior to use. All manipulations were performed under argon atmosphere in a dry box (<1.0

1 ppm of O2 and <0.5 ppm of H2O) or using standard Schlenk line techniques. H NMR spectra were obtained using Bruker Avance 300 and 400 MHz spectrometers and chemical shifts are given in ppm relative to residual solvent peaks ((CD2Cl2) = 5.32 and

(CDCl3) = 7.26). IR spectra were recorded in the solid state or solution using Nicolet

Smart Orbit 380 FT-IR spectrometer (Thermo Electron Corporation). Elemental analyses for C, H and N were obtained from Midwest Microlab, LLC. CAUTION: Perchlorate metal salts are potentially explosive and were handled in small quantities under argon atmosphere.

Figure 6.4. 1H NMR labeling scheme.

259

I 6.4.2 [Cu (bpy)(-CH2=CHC6H5)][CF3SO3] (1)

I -4 [Cu (CF3SO3)]2*C6H5CH3 (0.100 g, 1.93  10 mol) and styrene (1.33 mL, 1.16 

10-2 mol) were dissolved in 2.0 ml of dry and degassed methanol and the solution stirred at room temperature for 20 minutes. 2,2‘-bipyridine (0.0604 g, 3.86  10-4 mol) was then added and the solution stirred for additional 30 minutes. Pentane (2.0 mL) was layered on top of methanol and the solution placed inside dry box refrigerator at -35 oC. After 24 hours, colorless crystals were formed, which were washed with 10 mL of pentane and

I dried under vacuum to yield 0.120 g (68%) of [Cu (bpy)(-CH2=CH-C6H5)][CF3SO3].

1 H NMR (300 MHz, CD2Cl2, 250K): 8.39 (d, J=5.0 Hz, 2H, H6+H6‘), 8.24 (d, J=8.1

Hz, 2H, H3+H3‘), 8.11 (t, J=7.7 Hz, H4+H4‘), 7.60 (m, 2H, H5+H5‘), 7.51 (d, J=7.5

 Hz, 2H, Sty), 7.27-7.36 (m, 3H, Sty), 6.32 (dd, Jtrans=16 Hz, Jcis=10 Hz, 1H, H ), 5.06

  (d, Jtrans=16 Hz, 1H, H trans), 4.73 (d, Jcis=10 Hz, 1H, H cis). FT IR (solid):

-1 (C=C)=1529 cm . Anal. Calcd. for C19H16CuF3N2O3S: C, 48.25; H, 3.41; N, 5.92.

Found: C, 48.36; H, 3.42; N, 5.87.

I 6.4.3 [Cu (bpy)(-CH2=CHC6H5)][PF6]*1/2CH2=CHC6H5 (2)

I The complex was prepared using the procedure for [Cu (bpy)(-CH2=CH-

I -4 C6H5)][CF3SO3] except that [Cu (CH3CN)4][PF6] (0.100 g, 2.68  10 mol) was used

I 1 instead of [Cu (CF3SO3)]2*C6H5CH3. Yield = 0.105 g (75%). H NMR (300 MHz,

CD2Cl2, 180K): 8.55 (ddd, J1=5.0 Hz, J2=1.5 Hz, J3=0.90 Hz, 2H, H6+H6‘), 8.41 (dt,

J1=8.0 Hz, J2=1.0 Hz, 2H, H3+H3‘), 8.32 (dt, J1=8.0 Hz, J2= 1.7Hz, 2H H4+H4‘), 7.80

 (m, 2H, H5+H5‘), 7.5-7.6 (m, 7.5H, Sty), 6.31 (dd, Jtrans=16 Hz, Jcis=10 Hz, 1.5H, H ),

  5.23 (d, Jtrans=16 Hz, 1.5H, H trans), 4.74 (d, Jcis=10 Hz, 1.5H, H cis). FT IR (solid):

260

-1 (C=C)=1527 cm . Anal. Calcd. for C44H40Cu2F12N4P2: C, 50.72; H, 3.87; N, 5.38.

Found: C, 50.57; H, 3.88; N, 5.18.

I 6.4.4 [Cu (bpy)(-CH2=CHC6H5)][ClO4] (3)

The complex was synthesized according to the modified literature procedure,

I 31 starting from [Cu (CH3CN)4][ClO4], 2,2‘-bipyridine and excess styrene . The complex

1 was obtained in 83% yield. H NMR (300 MHz, CD2Cl2, 220K): 8.40 (d, J=4.5 Hz,

2H, H6+H6‘), 8.25 (d, J=8.1 Hz, 2H, H3+H3‘), 8.15 (dt, J1=7.8 Hz, J2= 1.7 Hz, 2H

H4+H4‘), 7.64 (m, 2H, H5+H5‘), 7.51 (d, J=6.9 Hz, 2H, Sty), 7.30-7.40 (m, 3H, Sty),

  6.33 (dd, Jtrans=16 Hz, Jcis=10 Hz, 1H, H ), 5.17 (d, Jtrans=16 Hz, 1H, H trans), 4.75 (d,

 -1 Jcis=10 Hz, 1H, H cis). FT-IR (solid): (C=C)=1525 cm .

6.4.5 General procedure for cyclopropanation of styrene

In a 20-mL Schlenk flask, catalyst precursor (0.0250 mmol, 1 equiv.), 2, 2‘- bipyridine (0.00380 g, 0.0250 mmol, 1 equiv.) and styrene (1.40 mL, 12.2 mmol, 500 equiv.) were suspended in CH2Cl2 (1.4 mL) and stirred at room temperature for 10 min.

To the homogenous solution, EDA (130 L, 1.24 mmol, 50 equiv.) was added in one portion and stirred for 2 hours. Completeness of the reaction was determined by IR spectroscopy, as indicated by the disappearance of the absorption of the diazo group (-

N=N-) at 2112 cm-1. The reaction mixture was then exposed to air and the remaining copper(II) complex was removed by passing through a basic alumina column. The solvent was removed by vacuum evaporation and the product distribution determined by

1 H NMR in CDCl3.

261

6.4.6 Kinetic studies

A solution at time zero was prepared separately by mixing EDA (260 L, 2.47 mmol), styrene (2.8 mL, 24.4 mmol) and CH2Cl2 (2.8 mL) and the IR spectrum was

-1 recorded (νN=N = 2112 cm ). In a 20-mL Schlenk flask, the solution was prepared by dissolving the catalyst precursor (0.0100 mmol, 1.0 equiv.) and 2, 2‘-bipyridine (0.00160 g, 0.0100 mmol, 1.0 equiv.) in styrene (2.80 mL, 24.7 mmol, 2500 equiv.) and CH2Cl2

(2.80 mL). The solution was stirred at room temperature until it became homogeneous

(10 minutes). EDA (260 L, 2.47 mmol, 250 equiv.) was then added in one portion. The consumption of EDA was monitored by collecting 0.2 mL of the reaction solution every

15 minutes and recording the IR spectrum for a period of 3 hours.

6.4.7 X-ray Crystallography

The X-ray intensity data were collected at room temperature using graphite- monochromated Mo K radiation (=0.71073 Å) on a Bruker Smart Apex II CCD diffractometer. Data reduction included absorption corrections by the multiscan method using SADABS.47 Crystal data and experimental conditions are given in Table 1.

Structures were solved by direct methods and refined by full-matrix least squares using

SHELXTL 6.1 bundled software package.48 The H atoms were positioned geometrically

(aromatic C-H=0.93 Å, methylene C-H=0.97 Å and methyl C-H=0.96 Å) and treated as riding atoms during subsequent refinement, with Uiso(H)=1.2Ueq(C) or 1.5Ueq(methyl C).

Crystal maker 7.2 was used to generate molecular graphics

262

6.5 References

1. Doyle, M. P.; McKervey, M. A.; Ye, T., Modern Catalytic Methods for Organic Synthesis. Wiley: New York, 1998.

2. Pfaltz, A., Transition Metals for Organic Synthesis. Wiley-VCH: Weinheim, 1998.

3. Pfaltz, A., Comprehensive Asymmetric Catalysis. Springer: Berlin, 1999; Vol. 2.

4. Kirmse, W., Copper Carbene Complexes: Advanced Catalysts, New Insights. Angew. Chem. Int. Ed. 2003, 42 (10), 1088-1093.

5. Evans, D. A.; Bilodeau, M. T.; Faul, M. M., Development of the Copper- Catalyzed Olefin Aziridination Reaction. J. Am. Chem. Soc. 1994, 116 (7), 2742- 2753.

6. Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.; Barnes, D. M., Bis(oxazoline)-Copper Complexes as Chiral Catalysts for the Enantioselective Aziridination of Olefins. J. Am. Chem. Soc. 1993, 115 (12), 5328-5329.

7. Doyle, M. P.; Griffin, J. H.; Bagheri, V.; Dorow, R. L., Correlations Between Catalytic Reactions of Diazo Compounds and Stoichiometric Reactions of Transition Metal Carbenes With Alkenes. Mechanism of the Cyclopropanation Reaction. Organometallics 1984, 3 (1), 53-61.

8. Doyle, M. P., Electrophilic Metal Carbenes as Reaction Intermediates in Catalytic Reactions. Acc. Chem. Res. 1986, 19 (11), 348-356.

9. Brookhart, M.; Studabaker, W. B., Cyclopropanes from Reactions of Transition Metal Carbene Complexes With Olefins. Chem. Rev. 1987, 87 (2), 411-432.

10. Bartley, D. W.; Kodadek, T., Identification of the Active Catalyst in the Rhodium Porphyrin-Mediated Cyclopropanation of Alkenes. J. Am. Chem. Soc. 1993, 115 (5), 1656-1660.

11. Hamaker, C. G.; Mirafzal, G. A.; Woo, L. K., Catalytic Cyclopropanation with Iron(II) Complexes. Organometallics 2001, 20 (24), 5171-5176.

263

12. Maxwell, J. L.; Brown, K. C.; Bartley, D. W.; Kodadek, T., Mechanism of the Rhodium Porphyrin-Catalyzed Cyclopropanation of Alkenes. Science 1992, 256 (5063), 1544-1547.

13. Collman, J. P.; Rose, E.; Venburg, G. D., Reactivity of Ruthenium 5,10,15,20- Tetramesitylporphyrin Towards Diazoesters: Formation of Olefins. J. Chem. Soc. Chem. Commun. 1993, (11), 934-935.

14. Galardon, E.; Maux, P. L.; Toupet, L.; Simonneaux, G. r., Synthesis, Crystal Structure, and Reactivity of (5,10,15,20-Tetraphenylporphyrinato)ruthenium(II) (Diethoxycarbonyl)carbene Methanol. Organometallics 1998, 17 (4), 565-569.

15. Evans, D. A.; Woerpel, K. A.; Hinman, M.; Faul, M. M., Bis(oxazolines) as Chiral Ligands in Metal-Catalyzed Asymmetric Reactions. Catalytic, Asymmetric Cyclopropanation of Olefins. J. Am. Chem. Soc. 1991, 113 (2), 726-728.

16. Chelucci, G.; Thummel, R. P., Chiral 2,2'-Bipyridines, 1,10-Phenanthrolines, and 2,2':6',2"-Terpyridines: Syntheses and Applications in Asymmetric Homogeneous Catalysis. Chem. Rev. 2002, 102 (9), 3129-3170.

17. Kwong, H.-L.; Lee, W.-S., First Enantioselective Catalyst Based on a Chiral Terpyridine: Synthesis of New C2-symmetric 2,2':6',2''-Terpyridine Ligands and Copper-Catalyzed Enantioselective Cyclopropanation of Alkenes. Tetrahedron: Asym. 2000, 11 (11), 2299-2308.

18. Kwong, H.-L.; Wong, W.-L.; Lee, W.-S.; Cheng, L.-S.; Wong, W.-T., New Chiral 2,2′:6′,2′′-Terpyridine Ligands from the Chiral Pool: Synthesis, Crystal Structure of a Rhodium Complex and Uses in Copper- and Rhodium-Catalyzed Enantioselective Cyclopropanation of Styrene. Tetrahedron: Asym. 2001, 12 (19), 2683-2694.

19. Chelucci, G.; Gladiali, S.; Sanna, M. G.; Brunner, H., Chiral Ligands with Pyridine Donors in Transition Metal Catalyzed Enantioselective Cyclopropanation and Hydrosilylation Reactions. Tetrahedron: Asym. 2000, 11 (16), 3419-3426.

20. Fritschi, H.; Leutenegger, U.; Pfaltz, A., Semicorrin Metal Complexes as Enantioselective Catalysts. Part 2. Enantioselective Cyclopropane Formation From Olefins with Diazo Compounds Catalyzed by Chiral (Semicorrinato)copper Complexes. Helv. Chim. Acta 1988, 71 (6), 1553–1565.

264

21. Perez, P. J.; Brookhart, M.; Templeton, J. L., A Copper(I) Catalyst for Carbene and Nitrene Transfer to Form Cyclopropanes, Cyclopropenes, and Aziridines. Organometallics 1993, 12 (2), 261-262.

22. Diaz-Requejo, M.; Perez, P. J., The Use of Polypyrazolylborate Copper(I) Complexes as Catalysts in the Conversion of Olefins Into Cyclopropanes, Aziridines and Epoxides and Alkynes into Cyclopropenes. J. Organomet. Chem. 2001, 617-618, 110-118.

23. Diaz-Requejo, M. M.; Caballero, A.; Belderrain, T. R.; Nicasio, M. C.; Trofimenko, S.; Perez, P. J., Copper(I)-Homoscorpionate Catalysts for the Preferential, Kinetically Controlled Cis Cyclopropanation of α-Olefins with Ethyl Diazoacetate J. Am. Chem. Soc. 2002, 124 (6), 978-983.

24. Straub, B. F.; Hofmann, P., Copper(I) Carbenes: The Synthesis of Active Intermediates in Copper-Catalyzed Cyclopropanation. Angew. Chem. Int. Ed. 2001, 40 (7), 1288-1290.

25. Straub, B. F.; Hofmann, P., Copper(I) Carbenes: The Synthesis of Active Intermediates in Copper-Catalyzed Cyclopropanation. Angew. Chem. Int. Ed. 2001, 113 (7), 1328-1330.

26. Dai, X.; Warren, T. H., Discrete Bridging and Terminal Copper Carbenes in Copper-Catalyzed Cyclopropanation. J. Am. Chem. Soc. 2004, 126 (32), 10085- 10094.

27. Fraile, J. M.; Garcia, J. I.; Mayoral, J. A.; Tarnai, T., Solvent and Counterion Effects in the Asymmetric Cyclopropanation Catalysed by Bis(oxazoline)-Copper Complexes. J. Mol. Catal. A Chem. 1999, 144 (1), 85-89.

28. Fraile, J. M.; Garcia, J. I.; Martinez-Merino, V.; Mayoral, J. A.; Salvatella, L., Theoretical (DFT) Insights Into the Mechanism of Copper-Catalyzed Cyclopropanation Reactions. Implications for Enantioselective Catalysis. J. Am. Chem. Soc. 2001, 123 (31), 7616-7625.

29. Fraile, J. M.; García, J. I.; Gil, M. J.; Martínez-Merino, V.; Mayoral, J. A.; Salvatella, L., Theoretical Insights into the Role of a Counterion in Copper- Catalyzed Enantioselective Cyclopropanation Reactions. Chem. Eur. J. 2004, 10 (3), 758-765.

265

30. Evans, D. A.; Woerpel, K. A.; Scott, M. J., Bis(oxazoline)‖als Liganden für sich selbst organisierende, chirale Koordinationspolymere; Struktur eines Kupfer(I)- Katalysators für die enantioselektive Cyclopropanierung von Olefinen. Angew. Chem. 1992, 104 (4), 439-441.

31. Masuda, H.; Machida, K.; Munakata, M.; Kitagawa, S.; Shimono, H., Synthesis and Structural Study of (2,2'-Bipyridine)perchlorato(styrene)-copper(I). J. Chem. Soc. Dalton Trans. 1988, 1907-1910.

32. Stamp, L.; Dieck, T., Copper(I) Complexes with Unsaturated Nitrogen Ligands. Part III. Copper(I) Diazadiene Complexes with Carbon Monoxide, Olefins and Acetylenes. Inorg. Chim. Acta 1987, 129, 107-114.

33. Pintauer, T.; Matyjaszewski, K., Structural Aspects of Copper Catalyzed Atom Transfer Radical Polymerization. Coord. Chem. Rev. 2005, 249 ((11-12)), 1155- 1184.

34. Pintauer, T., Synthesis, Characterization, and the Role of Counterion in Stabilizing Trigonal Pyramidal Copper(I)/2,2'-Bipyridine Complexes Containing Electron-Poor Methyl Acrylate. J. Organomet. Chem. 2006, 691, 3948-3953.

35. Braunecker, W. A.; Pintauer, T.; Tsarevsky, N. V.; Kickelbick, G.; Matyjaszewski, K., Crystal Strucutres of [Cu(PMDETA)(p-MA)][BPh4]. J. Organomet. Chem. 2005, 690, 916-924.

36. Sutton, L. E., Tables of Interatomic Distances and Configurations in Molecules and Ions. The Chemical Society: London, 1965.

37. Pintauer, T., Crystal Strucutre of [Cu(bpy)2][CF3SO3]. Acta Cryst. Sect. E 2006, E62, m620-m622.

38. Cunningham, C. T.; Moore, J. J.; Cunningham, K. L. H.; Fanwick, P. E.; McMillin, D. R., Structural and Photophysical Studies of Cu(NN)2+ Systems in the Solid State. Emission at Last from Complexes with Simple 1,10- Phenanthroline Ligands. Inorg. Chem. 2000, 39 (16), 3638-3644.

39. Munakata, M., Crystal Structure of Bis(2,2'-bipyridine)copper(I) Perchlorate. Bull. Chem. Soc. Jpn. 1987, 60 (5), 1927-1929.

266

40. Munakata, M.; Kitagawa, S.; Kosome, S.; Asahara, A., Studies of Copper(I) Olefin Complex. Formation Constants of Copper Olefin Complexes with 2,2'- Bipyridine, 1,10-Phenantroline and Their Derivatives. Inorg. Chem. 1986, 25, 2622-2627.

41. Fielding, L., Determination of Association Constants (Ka) from Solution NMR Data. Tetrahedron 2000, 56 (34), 6151-6170.

42. Hartley, F. R.; Burgess, C.; Alcock, R. M., Solution Equilibria. Ellis Horwood Limited: Chichester, 1980.

43. Diaz-Requejo, M. M.; Belderrain, T. R.; Nicasio, M. C.; Prieto, F.; Perez, P. J., Kinetics of the BpCu-Catalyzed Carbene Transfer Reaction (Bp = Dihydridobis(1-pyrazolyl)borate). Is a 14-Electron Species the Real Catalyst for the General Copper-Mediated Olefin Cyclopropanation? Organometallics 1999, 18 (14), 2601-2609.

44. Salomon, R. G.; Kochi, J. K., Copper(I) Catalysis in Cyclopropanations with Diazo Compounds. Role of Olefin Coordination. J. Am. Chem. Soc. 1973, 95 (10), 3300-3310.

45. Foley, J.; Tyagi, S.; Hathaway, B. J., Crystal Structure of [Cu(bpy)2][PF6]. J. Chem. Soc. Dalton Trans. 1984, 1-5.

46. Skelton, B. W.; Waters, A. F.; White, A. M., Crystal Structure of [Cu(bpy)2][CuCl2]. Aust. J. Chem. 1991, 44, 1207-1215.

47. Sheldrick, G. M., SADABS Version 2.03. University of Gottingen: Germany, 2002.

48. Sheldrick, G. M., SHELXTL 6.1,Crystallographic Computing System. Bruker Analytical X-Ray System: Madison, WI, 2000.

267

Chapter 7

Strong Coordination of Tetraphenylborate Anion to Copper(I) Bipyridine and Phenanthroline Based Complexes and its Effect on Catalytic Activity in Cyclopropanation of Styrene

The synthesis, characterization and cyclopropanation activity of tetrahedral copper(I) complexes with bipyridine and phenanthroline based ligands containing

I strongly coordinated tetraphenylborate anions were reported. Cu (bpy)(BPh4),

I I Cu (phen)(BPh4) and Cu (3,4,7,8-Me4phen)(BPh4) complexes are the first examples in

- 2 which BPh4 counterion chelates a transition metal center in bidentate fashion through 

-interactions with two of its phenyl rings.

7.1 Introduction

The asymmetric transition metal catalyzed transfer of carbene moieties generated from diazo reagents onto the prochiral face of an olefin to form cyclopropane ring is widely used reaction in organic synthesis.1,2 Effective catalytic systems for this reaction require the use of a transition metal complex which facilitates the loss of N2 from the

268

Scheme 7.1. Proposed mechanism for copper(I) catalyzed cyclopropanation of alkenes.

diazo reagent, as well as stabilizes intermediate carbene species against competing carbene dimerization. A variety of transition metal complexes have been found to be active in cyclopropanation reactions and they include the complexes of Fe, Rh, Ru and

Cu. Copper appears to be particularly attractive because of its low cost relative to other transition metal complexes. So far, cationic and neutral copper(I) complexes in conjunction with a C2-symmetric nitrogen based ligands have been successfully used in cyclopropanation reactions. However, despite a tremendous effort directed towards empirical catalyst development, mechanism of this very important synthetic reaction is still not fully understood. It is generally accepted that copper catalyzed cyclopropanation reactions proceed via a copper-carbene complex, as indicated in Scheme 7.1. However,

269

the details of this process are not well-known. Only very recently, copper-carbene complexes have been detected as reaction intermediates in cyclopropanation reactions utilizing low temperature NMR measurements and X-ray diffraction.3-5 Another key mechanistic feature of this reaction includes the role of monomer and counterion, both of which are poorly understood. Mechanistic and computational studies have indicated that copper(I)/olefin complexes in these systems might act as either catalytically active species or resting states.6 Furthermore, the reactivity of cationic copper(I) complexes is strongly influenced by the counterion. Triflates and hexafluorophosphates were found to be highly effective catalysts whereas halides, cyanides, acetates and perchlorate showed little or no catalytic activity.6

7.2 Results and Discussion

In a recent study, our research group reported on the synthesis, characterization and cyclopropanation activity of a series of well-defined [CuI(2,2‘-bpy)(p-M)][A]

- - - 7,8 (M=styrene and methyl acrylate; A=ClO4 , PF6 and CF3SO3 ) complexes (Figure 7.1).

In the solid state, all complexes were distorted trigonal pyramidal in geometry and copper(I) atom was coordinated by two nitrogen atoms of bpy ligand, two oleﬁnic carbon atoms of alkene in the equatorial position, and a weakly coordinated counterion in the axial position. Moreover, in the case of styrene, the axial coordination of counterion observed in the solid state was found to have a small effect on the binding constant of styrene to [CuI(bpy)]+ cations in solution, resulting in similar cyclopropanation activities.

In our effort to isolate and structurally characterize copper(I)/styrene complexes with

- much weaker coordinating anions, we observed a novel mode of coordination of BPh4

270

anions to copper(I) complexes with neutral bidentate nitrogen based ligands. In this article, we report on the synthesis, characterization and cyclopropanation activity of tetrahedral copper(I) complexes with bipyridine and phenanthroline based ligands

- containing strongly coordinated BPh4 anions.

F F F OO F S F P F F O F F 2.388(4) 2.609(2)

N N N N CuI CuI O O O O

O F O F O F F S F Cl F P O F O F O O F 2.591(4) 2.4297(11) 2.9846(12)

N N N N N N CuI CuI CuI

Figure 7.1. Axial coordination of counterion in [CuI(bpy)(π-M)]+ (M = methyl acrylate, styrene) complexes.

I The starting copper(I) complex for the synthesis of Cu (3,4,7,8-Me4phen)(BPh4)

I I (1), Cu (bpy)(BPh4) (2) and Cu (phen)(BPh4) (3) was obtained by methathesis of the

I perchlorate salt [Cu (CH3CN)4][ClO4] with NaBPh4 in CH3CN/H2O, according to modified literature procedure.9 This reaction did not yield the expected

I I [Cu (CH3CN)4][BPh4] complex, but rather [Cu (CH3CN)][BPh4], the composition of

1 which was confirmed by elemental analysis and H NMR. The loss of CH3CN after

I prolonged in vacuo treatment has been observed previously in [Cu (CH3CN)4][BF4] and

271

I 10 [Cu (CH3CN)4][B(C6H5)4] complexes. We were unable to obtain crystals of

I [Cu (CH3CN)][BPh4] suitable for X-ray diffraction studies, however, based on the

I Figure 7.2. Molecular structures of [Cu (3,4,7,8-Me4phen)(BPh4)]*3CH2Cl2 (1), I I Cu (bpy)(BPh4) (2) and Cu (phen)(BPh4) (3) shown with thermal ellipsoids at 50% probability. H atoms and solvent molecules have been omitted for clarity.

molecular structures of 1, 2 and 3 (Figure 7.2), one possibility would include tricoordinated copper(I) complex as indicated in Scheme 7.1. The reaction of

I [Cu (CH3CN)][BPh4] with stoichiometric amount of bipyridine or phenanthroline based ligand in CH2Cl2, followed by slow diffusion of pentane, afforded crystals of 1, 2 and 3 in 92%, 55% and 40% yield, respectively (Scheme 7.2).

Shown in Figure 7.2 are the molecular structures of 1-3. In all three complexes,

I bidentate coordination of the nitrogen ligand was observed (Cu -Nav=2.047(3) Å (1),

272

2.062(3) Å (2) and 2.055(2) Å (3)) and the distorted tetrahedral coordination around CuI atom was completed by two p interactions with C=C double bond of the adjacent phenyl

- I I rings in BPh4 anion (Cu -Cmid,1-2= 2.289(5) Å (1), 2.148(3) Å (2), 2.121(3) Å (3); Cu -

Cmid,3-4=2.073(4) Å (1), 2.236(6) Å (2), 2.203(3) Å (3)). Based on extensive literature

- and CCDB searches, such coordination of BPh4 anion to transition metal complexes has never been observed before. With the exception of one example of 2-coordination

I 2 6 (Cu (NH2CH2CH2NH2)(CO)( -BPh4)), all of the structures reported so far exhibit  -

6 6 11 coordination (e.g. Ru(Cp)( -BPh4) and Rh(P(OMe3)2( -BPh4)).

Scheme 7.2. Synthesis of copper(I) complexes 1-3.

- The coordination of BPh4 to copper(I) center in 1-3 did not result in a significant change in the geometry of the anion. The bent angle between B atom and adjacent C atoms in the coordinated phenyl rings (104.3(2)o (1), 103.1(2)o (2) and 101.92(11)o (3)) was slightly smaller than the corresponding angle for the uncoordinated ones (112.3(2)o

(1), 111.3(2)o (2) and 113.84(11)o (3)). In copper(I) complexes with noncoordinating

- o o 12 BPh4 anions, these two angles are also different (101-105 and 110-114 ).

Furthermore, CuI-C bond distances for -coordinated C=C bonds in phenyl rings

I Figure 7.3. Partial packing diagram of [Cu (2,9-Me2phen)(CH3CN)][BPh4] showing - weak C-HC interactions of coordinated CH3CN (a) and 2,9-Me2phen (b) with BPh4 anion and - stacking interactions between 2,9-Me2phen ligands (c).

(1.412(3) and 1.415(4) Å (1); 1.412(3) and 1.413(4) Å (2); 1.410(2) and 1.4118(18) Å

(3)) did not change significantly upon coordination.

- The coordination of BPh4 anion to copper(I) center can be suppressed using sterically more hindered 2,9-Me2phen. In the case of this ligand, we observed quantitative

I I formation of [Cu (2,9-Me2phen)(CH3CN)][BPh4] complex Figure 7.3) In [Cu (2,9-

Me2phen)(CH3CN)][BPh4], the counterion was found to be non-coordinating.

Additionally, the crystal structure was stabilized by a series of short C-H•••C contacts

- between BPh4 anion and coordinated CH3CN (2.841(2)-2.867(4) Å), as well as 2,9-

Me2phen (2.866-2.894 Å) (Figure 7.3). Short contacts were also observed in structurally

I similar [Cu (2,9-Me2phen)(CH3CN)][PF6] complex (Figure 7.3).

1 o H NMR spectrum of 1 in CD2Cl2 appeared relatively sharp at 22 C and was fully consistent with solid state X-ray structure. The corresponding spectra of 2 and 3 were significantly broadened indicating a fluxional system, which was presumably induced by ligand and/or anion association/dissociation. In all three complexes, the

- proton resonance associated with BPh4 anion were identical to NaBPh4. In the presence of as much as 15 equivalents of alkene (styrene, methyl acrylate and 1-octene), 1H NMR spectra of 1-3 remained unchanged. In other words, no visible shielding of vinyl protons upon coordination was observed, which is typical for copper(I)/alkene complexes.12 This

- results clearly indicate that BPh4 anions strongly coordinate to the copper(I) center.

- I In order to further examine the nature of bonding of BPh4 to Cu in 1-3,

- particularly with respect to s-donation from coordinated C=C bonds in BPh4 and p- backbonding from CuI, we have conducted additional DFT and NBO calculations (see supp. info.). The results obtained for 1 and 2 using three different basis sets (6-31+G(d),

- 6-31G(2d,p) and 6-311++G(2d,p)) indicated that s-donation from BPh4 anion to copper(I) is the dominant interaction (approximately 75%), with the remaining 25% being attributed to classical -backbonding from copper(I). Also, the NBO calculations indicated that B-C n*(Cu) interactions were quite significant, with the charge transfer of the interaction totaling approximately half of the typical C=C -n*(Cu) interaction.

Representative orbital interactions are shown in Figure 7.4.

Table 7.1. Cyclopropanation of styrene in the presence of EDA catalyzed by 1-3.a I b I b I b Catalyst 1 2 3 [Cu ]/[ClO4] [Cu ]/[PF6] [Cu ]/[CF3SO3] Products Ph H 72.4 68.2 73.5 66.9 58.7 58.0 H CO2Et H H 18.1 18.4 18.9 14.7 25.3 27.0 Ph CO2Et EtO2C H 4.5 7.0 5.2 6.7 9.9 8.0

H CO2Et H H 5.0 3.3 2.4 11.7 6.1 7.0

EtO2C CO2Et a I I -3 o [Cu ]0:[EDA]0:[Sty]0=1:50:500, [Cu ]0=1.710 M, (CH2Cl2, 3h, 25 C), % yield is based on 1H NMR (rel. err. are ±10%). bResults from previous study with [CuI(bpy)(π- styrene)][A] complexes, ref. 8.

- In order to further investigate the effect of BPh4 coordination in 1-3 on catalytic activity, cyclopropanation of styrene in the presence of ehtyldiazoacetate (EDA) was conducted. The reactions were performed in CH2Cl2 at room temperature using standard

I reaction conditions [Cu ]0:[Sty]0:[EDA]0=1:500:50. The product distribution was determined by 1H NMR and results are summarized in Table 7.1. For all three complexes, the relative amounts of EDA decomposition products ranged between 2.4 and 7.0%.

Furthermore, the mole percent of trans and cis cyclopropane were very similar. Also, when compared to our previous results using well-defined [CuI(bpy)(p-sty)][A] complexes, 1-3 appear to be more selective towards trans cyclopropane.8

The observed rate constants (kobs) shown in Figure 7.5 for decomposition of EDA

-3 in the presence of externally added styrene were determined to be (kobs=(1.5±0.12)10 min-1 (1), (6.8±0.30)10-3 min-1 (2) and (5.1±0.19)10-3 min-1 (3)). These rates should

depend on the equilibrium constants KO and KL, corresponding to the formation of

I I [Cu (NN)(p-olefin)][A] and [Cu (NN)2][A] complexes, respectively (Scheme 7.2).

I However, our previous results using [Cu (bpy)(p-Sty)][A] complexes indicated that kobs

-2 -1 and KO were relatively independent on the nature of counterion ((1.4±0.041)10 min

3 -1 - -2 -1 3 -1 - and 4.310 M (A=CF3SO3 ) and (1.0±0.025)10 min and 4.410 M (A=PF6 ),

8 respectively). Therefore, assuming constant value for KL, the most reasonable explanation for the decrease in the observed rate constant for decomposition of EDA in

- the case of 1-3 can be attributed to relatively strong coordination of BPh4 anion.

- Furthermore, these data also indicate that the binding constant of BPh4 in 1 is stronger than in 2 or 3, which is presumably induced by the stronger coordination of 3,4,7,8-

Me4phen (pKa=6.58), relative to bpy (pKa=4.60) or phen (pKa=4.80). Detailed kinetic, mechanistic and computational studies of the catalytic activity of copper(I) complexes 1-

3 in cyclopropanation are subject to further investigation in our laboratories.

7.3 Summary and Conclusions

In conclusion, synthesis, characterization and cyclopropanation activity of tetrahedral copper(I) complexes with bipyridine and phenanthroline based ligands

- containing strongly coordinated BPh4 counterions were reported. These complexes are

- the first examples in which BPh4 anion ligates a transition metal center in bidentate fashion through 2  -interactions with two of its phenyl rings.

7.4 Experimental

7.4.1 General Procedures

All materials were obtained commercially and used as received.

I 13 [Cu (CH3CN)4][ClO4] was prepared according to the literature procedure. Solvents

(methylene chloride, pentane, acetonitrile and methanol) were degassed and deoxygenated using Innovative Technology solvent purifier. All manipulations were performed under argon atmosphere in a dry box (<1.0 ppm of O2 and <0.5 ppm of H2O) or using standard Schlenk line techniques. 1H NMR spectra were obtained using Bruker

Avance 400 MHz spectrometer and chemical shifts are given in ppm relative to residual

13 solvent peaks (δ(CD2Cl2) = 5.32 and δ(CDCl3) = 7.26). C NMR spectra were obtained

using Varian Unity Plus 500 MHz FT-NMR spectrometer and chemical shifts are given in ppm relative to residual solvent peaks ((δ(CD2Cl2) = 53.8 and δ(CDCl3) = 77.0). IR spectra were recorded in the solid state or solution using Nicolet Smart Orbit 380 FT-IR spectrometer (Thermo Electron Corporation). UV-Vis spectra were recorded using

Beckman DU530 spectrometer. Elemental analyses for C, H and N were obtained from

Midwest Microlab, LLC. CAUTION: Perchlorate metal salts are potentially explosive and were handled in small quantities and under argon atmosphere.

I 7.4.2 Synthesis of Cu (BPh4)(CH3CN)

I Cu (BPh4)(CH3CN)] was prepared using modified procedure for the synthesis of

I 14 I [Cu (CH3CN)4][B(C6F5)4]. In a typical experiment, [Cu (CH3CN)4][ClO4] (0.500 g, 1.53 mmol) and NaBPh4 (0.523 g, 1.53 mmol) were placed in a Schlenk flask under Ar and 15 mL of CH3CN added. The mixture was stirred at room temperature for 30 minutes and

50 mL of degassed H2O added (via Ar bubbling). The addition of H2O resulted in a formation of a tan precipitate. This tan precipitate was isolated by filtration under Ar

(coarse porosity Schlenk filter frit) and placed under vacuum overnight. Off-white

I Cu (BPh4)(CH3CN) (0.480 g, 74% yield) was transferred into the glove box and stored at

o I -35 C. Cu (BPh4)(CH3CN) can alternatively be synthesized using commercially

I 1 available [Cu (CH3CN)4][PF6] in 65-70% yield. H NMR (300 MHz, CD2Cl2, RT): δ7.1-

- -1 8.1 (m, 20H, BPh4 ), δ1.96 (s, 3H, CH3CN). FT IR (solid): cm , 3051m, 3000w, 2364w

(CH3CN), 2336w (CH3CN), 1592w, 1582w, 1558w, 1478m, 1425m, 1248m, 1177m,

1063m, 1024m, 853m, 733s, 700s, 605s. Anal. Calcd. for C26H23BCuN: C, 73.68; H,

5.47; N, 3.30. Found: C, 73.12; H, 5.40; N, 3.35.

I 7.4.3 Synthesis of Cu (BPh4)(3,4,7,8-Me4phen) (1)

I Cu (BPh4)(CH3CN) (0.100 g, 0.236 mmol) and 3,4,7,8-tetramethyl-1,10- phenanthroline (0.0558 g, 0.236 mmol) were mixed in 2 mL of methylene chloride at room temperature and stirred for 30 minutes. The resulting mixture was layered with 2 mL of pentane and placed in the glove box refrigerator at -35 oC. After 24 hours, yellow needless which were obtained were filtered, washed several times with pentane, and dried

I under vacuum to yield 0.135 g (92% yield) of Cu (BPh4)(3,4,7,8-Me4phen). Crystals suitable for X-ray analysis were obtained by slow diffusion of pentane into a

o 1 dichloromethane solution of the copper complex at -35 C. H NMR (300 MHz, CD2Cl2,

RT): δ8.15 (bs, 2H, -NCHC-, 3,4,7,8-Me4phen), δ8.00 (bs, 2H, -CCHC-, 3,4,7,8-

- - Me4phen), δ7.56 (bs, 8H, o-H, BPh4 ), δ6.97 (t, J=7.4 Hz, 8H, m-H, BPh4 ), δ6.70 (t,

- J=7.0 Hz, 4H, p-H, BPh4 ), δ2.64 (s, 6H, Me, 3,4,7,8-Me4-phen), δ2.47 (s, 6H, Me,

13 - 3,4,7,8-Me4-phen). C NMR (125.78 MHz, CD2Cl2, RT): BPh4 : δ154.5, δ137.4, δ131.1,

δ127.1, 3,4,7,8-Me4phen: δ143.2, δ140.5, δ137.4, δ132.1, δ131.5, δ127.1, δ22.1 (Me),

δ19.3 (Me). FT IR (solid): cm-1, 3036m, 2985m, 1619w, 1593w, 1581w, 1521m, 1479m,

1457m, 1426m, 1388m, 1243m, 1179w, 809m, 732s, 720s, 704s, 605s. Anal. Calcd. for

C40H36BCuN2: C, 77.60; H, 5.86; N, 4.52. Found: C, 77.29; H, 5.89; N, 4.53.

I 7.4.4 Synthesis of Cu (BPh4)(bpy) (2)

I The complex was prepared using the procedure for Cu (BPh4)(3,4,7,8-Me4phen) except that 2,2‘-bipyridine (0.0369 g, 0.236 mmol) was used instead of 3,4,7,8-

1 tetramethyl-1,10-phenanthroline. Yield = 0.0920 g (73 %). H NMR (300 MHz, CD2Cl2,

- RT): δ7.6-8.4 (b, 6H, bpy), δ7.2-7.4 (b, 2H, bpy), δ7.41 (bs, 8H, o-H, BPh4 ), δ6.92 (t,

- - -1 J=7.4 Hz, 8H, m-H, BPh4 ), δ6.70 (t, J=7.4 Hz, 4H, p-H, BPh4 ). FT-IR (solid): cm ,

3052m, 2993m, 1592m, 1677m, 1435m, 1310m, 1146m, 1064w, 1027m, 847w, 745s,

729s, 703s, 606s. Anal. Calcd. for C34H28BCuN2: C, 75.77; H, 5.24; N, 5.20. Found: C,

75.45; H, 5.14; N, 5.23. Crystals suitable for X-ray analysis were obtained by slow diffusion of pentane into a methylene chloride solution of the copper complex at -35 oC.

I 7.4.5 Synthesis of Cu (BPh4)(phen) (3)

I The complex was prepared using the procedure for Cu (BPh4)(3,4,7,8-Me4phen) except that 1,10-phenanthroline (0.0425 g, 0.236 mmol) was used instead of 3,4,7,8-

1 tetramethyl-1,10-phenanthroline. Yield = 0.0860 g (65 %). H NMR (300 MHz, CD2Cl2,

- RT): δ7.6-9.0 (b, 8H, phen), δ7.48 (bs, 8H, o-H, BPh4 ), δ6.92 (t, J=7.3 Hz, 8H, m-H,

- - -1 BPh4 ), δ6.64 (t, J=7.1 Hz, 4H, p-H, BPh4 ). FT IR (solid): cm , 3049m, 3027m, 2993m,

1623w, 1577w, 1509m, 1465m, 1420m, 1140m, 1023m, 837s, 739s, 722s, 702s, 637w,

599s. Anal. Calcd. for C36H28BCuN2: C, 76.80; H, 5.01; N, 4.98. Found: C, 76.69; H,

5.01; N, 5.15. Crystals suitable for X-ray analysis were obtained by slow diffusion of pentane into a methylene chloride solution of the copper complex at -35 oC.

7.4.6 General Procedure for Cyclopropanation of Styrene

In a 20-mL Schlenk flask, copper(I) complex (0.0250 mmol, 1 equiv.) and styrene (1.40 mL, 12.2 mmol, 500 equiv.) were suspended in CH2Cl2 (1.4 mL) and stirred at room temperature for 10 min. To the homogenous solution, EDA (130 L, 1.24 mmol,

50 equiv.) was added in one portion and stirred for 2 hours. Completeness of the reaction was determined by IR spectroscopy, as indicated by the disappearance of the absorption of the diazo group (-N=N-) at 2112 cm-1. The reaction mixture was then exposed to air and the remaining copper(II) complex was removed by passing through a basic alumina

column. The solvent was removed by vacuum evaporation and the product distribution

1 determined by H NMR in CDCl3.

7.4.7 Kinetic Studies.

A solution at time zero was prepared separately by mixing EDA (260 L, 2.47 mmol), styrene (2.8 mL, 24.4 mmol) and CH2Cl2 (2.8 mL) and the IR spectrum was

-1 recorded (νN=N = 2112 cm ). In a 20-mL Schlenk flask, the solution was prepared by dissolving copper(I) complex in styrene (2.80 mL, 24.7 mmol, 2500 equiv.) and CH2Cl2

(2.80 mL). The solution was stirred at room temperature until it became homogeneous

(10 minutes). EDA (260 L, 2.47 mmol, 250 equiv.) was then added in one portion. The consumption of EDA was monitored by collecting 0.2 mL of the reaction solution every

15 minutes and recording the IR spectrum for a period of 3 hours.

7.4.8 X-ray Crystal Structure Determination.

The X-ray intensity data were collected at room temperature or 120 K using graphite-monochromated Mo Kα radiation (λ=0.71073 Å) on a Bruker Smart Apex II

CCD diffractometer. Data reduction included absorption corrections by the multiscan method using SADABS.15 Crystal data and experimental conditions are given in Table

S1. Structures were solved by direct methods and refined by full-matrix least squares using SHELXTL 6.1 bundled software package.16 The H atoms were positioned geometrically (aromatic C-H=0.93 Å, methylene C-H=0.97 Å and methyl C-H=0.96 Å) and treated as riding atoms during subsequent refinement, with Uiso(H)=1.2Ueq(C) or

1.5Ueq(methyl C). The methyl groups were allowed to rotate about their local threefold axes. ORTEP-3 for Windows and Crystal Maker 8.1 were used to generate molecular graphics.17

7.4.9 DFT Calculations

All electronic structure calculations were carrier out using the computational resources at the Center for Computational Sciences at Duquesne University. Two

Cu(L)(BPh4) (L=3,4,7,8-Me4phen (2) and 2,2‘-bipyridine (1)) were geometry optimized using B3LYP/6-31G(d). The results showed excellent agreement with experimentally determined crystal structures. CHARM6 was used to calculate the RMSD between the heavy atoms of the optimized and experimentally determined structures. The RMSD between the X-ray crystal structure and the B3LYP/31-G(d) optimized structure is 0.56 Å and 0.34 Å for 1 and 2 respectively. Geometry optimization was also performed on 1 using MP2/6-31G(d). The RMSD between the X-ray structure and the MP2 optimized structure is 0.85 Å. Several key bond distances were measured and compared to experimentally determined molecular structures (Table S4 and Figures S12-S14). NBO single point calculations were performed only on B3LYP optimized structures and NBO single point were employed with B3LYP in conjunction with 6-31+G(d), 6-311G(2d,p) and 6-311++G(2d,p). Only the comparison between 6-311G(2d,p) and 6-311++G(2d,p) basis sets have been made and both sets yielded the same trend (Table F.6 and Table F.7).

7.5 References

1. Doyle, M. P.; McKervey, M. A.; Ye, T., Modern Catalytic Methods for Organic Synthesis. Wiley: New York, 1998.

2. Pfaltz, A., Comprehensive Asymmetric Catalysis. Springer: Berlin, 1999; Vol. 2.

3. Chelucci, G.; Thummel, R. P., Chiral 2,2'-Bipyridines, 1,10-Phenanthrolines, and 2,2':6',2"-Terpyridines: Syntheses and Applications in Asymmetric Homogeneous Catalysis. Chem. Rev. 2002, 102 (9), 3129-3170.

4. Dai, X.; Warren, T. H., Discrete Bridging and Terminal Copper Carbenes in Copper-Catalyzed Cyclopropanation. J. Am. Chem. Soc. 2004, 126, 10085-10094.

5. Straub, B. F.; Hofmann, P., Copper(I) Carbenes and Intermediates. Angew. Chem. Int. Ed. 2001, 113, 1328-1330.

6. Evans, D. A.; Faul, M. M.; Bilodeau, M. T., Development of the Copper- Catalyzed Olefin Aziridination Reaction. J. Am. Chem. Soc. 1994, 116, 2742- 2753.

7. Pintauer, T., Synthesis, Characterization, and the Role of Counterion in Stabilizing Trigonal Pyramidal Copper(I)/2,2'-Bipyridine Complexes Containing Electron-Poor Methyl Acrylate. J. Organomet. Chem. 2006, 691, 3948-3953.

8. Ricardo, C.; Pintauer, T., Synthesis, Characterization, and the Role of Counterioin I in Cyclopropanation of Styrene Catalyzed by [Cu (2,2'-bpy)(π-CH2=CHC6H5)][A] - - - (A=ClO4 , PF6 and CF3SO3 ) Complexes. J. Organomet. Chem. 2007, 692, 5165- 5172.

9. Liang, H.-C.; Kim, E.; Incarvito, C. D.; Rheingold, A. L.; Karlin, K. D., A Bis- Acetonitrile Two-Coordinate Copper(I) Complexes: Synthesis and Characterization of Highly Soluble B(C6F5)4- Salts of [CuI(MeCN)2]+ and [CuI(MeCN)4]+. Inorg. Chem. 2003, 41, 2209-2212.

10. Ogura, T., Acetonitrile Complexes of Copper(I) Organosulfonates and Tetrafluoroborate. Trans. Met. Chem. 1976, 1 (4), 179-82.

11. Strauss, S. H., The Search for Larger and Mope Weakly Coordinated Anions. Chem. Rev. 1993, 93, 927-942.

12. Braunecker, W. A.; Pintauer, T.; Tsarevsky, N. V.; Kickelbick, G.; Matyjaszewski, K., Crystal Strucutres of [Cu(PMDETA)(p-MA)][BPh4]. J. Organomet. Chem. 2005, 690, 916-924.

13. Munakata, M.; Kitagawa, S.; Asahara, A.; Masuda, H., Synthesis of [Cu(CH3CN)4][ClO4]. Bull. Chem. Soc. Jpn. 1987, 60, 1927-1929.

14. Liang, H.-C.; Kim, E.; Incarvito, C. D.; Rheingold, A.; Karlin, K. D., A Bis acetonitrile two coordinate copper(I) complex: Synthesis and characterization of higly soluble B(C6F5)4- salts of [Cu(MeCN)2]+ and [Cu(MeCN)4]+. Inorg. Chem. 2002, 41, 2209-2212.

15. Sheldrick, G. M., SADABS Version 2.03. University of Gottingen: Germany, 2002.

16. Sheldrick, G. M., SHELXTL 6.1,Crystallographic Computing System. Bruker Analytical X-Ray System: Madison, WI, 2000.

17. Faruggia, L. J., Ortep-3 for Windows- a version of ORTEP-III with a graphical interface (GUI). J. Appl. Cryst. 1997, 30(5, Pt. 1), 565.

AppendixA

Spectroscopic Data for Products Obtained from Copper-Catalyzed Atom Transfer Radical Cascade Reactions in the Presence of Diazo Radical Initiators as Reducing Agents.

287

Figure A.1. 1H NMR of 5,7,7,7-Tetrachloro-1-heptene (A).

288

Figure A.2. 13C NMR of 5,7,7,7-Tetrachloro-1-heptene (A).

289

Figure A.3. 1H NMR of 1,1,5-Trichloro-2-chloromethylcyclohexane (B).

290

Figure A.4. 1H-1H COSY of 1,1,5-Trichloro-2-chloromethylcyclohexane (B).

291

Figure A.5. 1H NMR of 1-Chloro-3-(2,2,2,-trichloroethyl)cyclopentane (C).

292

Figure A.6 13C NMR of 1-Chloro-3-(2,2,2,-trichloroethyl)cyclopentane (C).

293

Figure A.7. 1H NMR of 1,1,1,3,6,8,8,8-Octachlorooctane (D).

294

Figure A.8.1H NMR of 5,7,7,7-Tetrabromo-1-heptene (A2).

295

Figure A.9. 1H NMR of 1,1,5-Tribromo-2-bromomethylcyclohexane (B2).

296

Figure A.10. 13C NMR of 1,1,5-Tribromo-2-bromomethylcyclohexane (B2).

297

Figure A.11. 13C NMR of 1,1,5-Tribromo-2-bromomethylcyclohexane (B2).

298

Figure A.12. DEPT NMR of 1,1,5-Tribromo-2-bromomethylcyclohexane (B2).

299

Figure A.13. 1H NMR of 1-Bromo-3-(2,2,2,-tribromoethyl)cyclopentane (C2).

300

1 Figure A.14. H NMR (CD3Cl, RT, 400 MHz) spectrum of a mixture of cis and trans 1-(3-(Chloromethyl)-4-(2,2,2- trichloroethyl)pyrrolidin-1-yl)-2,2,2-trifluoroethanone.

Appendix B

B.1 Spectroscopic Data

301

302

Figure B.1. 1H NMR of methyl allyl acrylate (3).

303

Figure B.2. 1H NMR of phenylallyl acrylate (4).

304

Figure B.3. 1H NMR of dimethylallyl acrylate (5).

305

Figure B.4. 1H NMR of ethylmethylallyl acrylate (6).

306

Figure B.5. 1H NMR of dimethylallyl methacrylate (7).

307

Figure B.6. 1H NMR of -lactone.

308

Figure B.7. 13C NMR of -lactone.

Appendix C

C.1 Spectroscopic Data of Products Obtained from One-Pot Sequential Azide-Alkyne [3+2] Cycloaddition and Atom Transfer Radical Addition (ATRA)

O 6, 7 4, 5 3 N Cl C O N 3 8 N Cl 9 1 CH2OH 2

Figure C.1.1H-1H COSY spectrum of 3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propyl 2,4,4,4-tetrachloro-2-methylbutanoate (3a).

309

O O 3 6 5 9 6, 7 4, 5 4 7 N N Cl C 1 O N Cl C O N 3 10 N 3 8 N Cl Cl 1 11 3 2 9 CH2OH CH2OH 13 1 C NMR assignments 8 H NMR assignments 2

Figure C.2. 13C-1H HETCOR spectrum of 3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1- yl)propyl 2,4,4,4-tetrachloro-2-methylbutanoate (3a).

310

311

Figure C.3. 13H NMR spectrum of 3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl methacrylate (1).

312

Figure C.4. 13C NMR spectrum of 3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl methacrylate (1).

313

Figure C.5. 1H NMR spectrum of 3-(4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)propyl methacrylate (2).

314

Figure C.6. 1H NMR spectrum of 3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propyl methacrylate (3).

315

Figure C.7. 13C NMR spectrum of 3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propyl methacrylate (3).

316

Figure C.8. 1H NMR spectrum of methyl 1-(3-(methacryloyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (5).

317

Figure C.9. 13C NMR spectrum of methyl 1-(3-(methacryloyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (5).

318

Figure C.10. 1H NMR spectrum of ethyl 1-(3-(methacryloyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (6).

319

Figure C.11. 13C NMR spectrum of ethyl 1-(3-(methacryloyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (6).

320

Figure C.12. 1H NMR spectrum of 3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl 2,4,4,4-tetrachloro-2-methylbutanoate (1a).

321

Figure C.13. 13C NMR spectrum of 3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl 2,4,4,4-tetrachloro-2-methylbutanoate (1a).

322

Figure C.14.1H NMR spectrum of 3-(4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)propyl-2,4,4,4-tetrachloro-2-methylbutanoate (2a).

323

Figure C.15. 13C NMR spectrum of 3-(4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)propyl-2,4,4,4-tetrachloro-2-methylbutanoate (2a).

324

Figure C.16. 1H NMR spectrum of 3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propyl-2,4,4,4-tetrachloro-2-methylbutanoate (3a).

325

Figure C.17. 13C NMR spectrum of 3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)propyl-2,4,4,4-tetrachloro-2-methylbutanoate (3a).

326

Figure C.18. 1H NMR spectrum of methyl-1-(3-(2,4,4,4-tetrachloro-2-methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (5a).

327

Figure C.19. 13C NMR spectrum of methyl-1-(3-(2,4,4,4-tetrachloro-2-methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (5a).

328

Figure C.20. 1H NMR spectrum of of ethyl-1-(3-(2,4,4,4-tetrachloro-2-methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (6a).

329

Figure C.21. 13C NMR spectrum of ethyl-1-(3-(2,4,4,4-tetrachloro-2-methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (6a).

330

Figure C.22. 1H NMR spectrum of methyl-1-(3-(2,4,4,4-tetrabromo-2-methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (12a).

331

Figure C.23. 13C NMR spectrum of methyl-1-(3-(2,4,4,4-tetrachloro-2-methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (12a).

332

Figure C.24. 13C NMR of 1-ethyl 5-(3-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)propyl) 2,2,4-trichloro-4-methylpentanedioate (13a).

333

Figure C.25. 13C NMR of 1-ethyl 5-(3-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)propyl) 2,2,4-trichloro-4-methylpentanedioate (13a).

334

Figure C.26. 1H NMR of 1-ethyl 5-(3-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)propyl) 2,4-dichloro-4-methylpentanedioate (15a).

335

Figure C.27. 13C NMR of 1-ethyl 5-(3-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)propyl) 2,4-dichloro-4-methylpentanedioate (15a).

336

Figure C.28. 1H NMR of 1-(3-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)propyl) 5-methyl 2,4-dichloro-2-methylpentanedioate (16a).

337

Figure C.29. 1H NMR of methyl 1-(3-(2,4-dichloro-4-cyano-2-methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (17a).

338

Figure C.30. 13C NMR of methyl 1-(3-(2,4-dichloro-4-cyano-2-methylbutanoyloxy)propyl)-1H-1,2,3-triazole-4-carboxylate (17a).

339

Figure C.31. 1H NMR spectrum of 4-phenyl-1-(4-(1,3,3,3-tetrachloropropyl)benzyl)-1H-1,2,3-triazole (19a).

340

Figure C.32. 13C NMR spectrum of 4-phenyl-1-(4-(1,3,3,3-tetrachloropropyl)benzyl)-1H-1,2,3-triazole (19a).

341

Figure C.33. 1H NMR spectrum of methyl 1-(4-vinylbe)nzyl)-1H-1,2,3-triazole-4-carboxylate (22).

342

Figure C.34. 13C NMR of spectrum of methyl 1-(4-vinylbenzyl)-1H-1,2,3-triazole-4-carboxylate (22).

343

Figure C.35. 1H NMR spectrum of methyl 1-(4-(1,3,3,3-tetrachloropropyl)benzyl)-1H-1,2,3-triazole-4-carboxylate (22a).

344

Figure C.36. 13C NMR spectrum of methyl 1-(4-(1,3,3,3-tetrachloropropyl)benzyl)-1H-1,2,3-triazole-4-carboxylate (22a).

345

Figure C.37. 13C NMR spectrum of methyl 1-(4-(1,3,3-trichloropropyl)benzyl)-1H-1,2,3-triazole-4-carboxylate (28a).

346

Figure C.38. 1H NMR spectrum of methyl 1-(4-(1,3,3-trichloro-4-ethoxy-4-oxobutyl)benzyl)-1H-1,2,3-triazole-4-carboxylate (23a).

347

Figure C.39. 13C NMR spectrum of methyl 1-(4-(1,3,3-trichloro-4-ethoxy-4-oxobutyl)benzyl)-1H-1,2,3-triazole-4-carboxylate (23a).

348

Figure C.40. 1H NMR spectrum of methyl 1-(4-(1,3,3-trichloro-4-methoxy-4-oxobutyl)benzyl)-1H-1,2,3-triazole-4-carboxylate (24a).

349

Figure C.41. 13C NMR spectrum of methyl 1-(4-(1,3,3-trichloro-4-methoxy-4-oxobutyl)benzyl)-1H-1,2,3-triazole-4-carboxylate (24a).

C.2 Crystallographic Information

Table C.1. Crystal data and structure refinement for 12a.

Identification code 12a

Empirical formula C12 H15 Br4 N3 O4

Formula weight 584.91

Temperature 296(2) K

Wavelength 0.71073 A

Crystal system, space group Monoclinic, P 21/n

Unit cell dimensions a = 11.6637(4) A alpha = 90 deg. b = 6.0493(2) A beta = 98.406(2) deg. c = 26.2815(9) A gamma = 90 deg.

Volume 1834.43(11) A^3

Z, Calculated density 4, 2.118 Mg/m^3

Absorption coefficient 8.795 mm^-1

F(000) 1120

Crystal size 0.32 x 0.09 x 0.05 mm

Theta range for data collection 1.57 to 26.19 deg.

Limiting indices -14<=h<=14, -7<=k<=7, -32<=l<=32

Reflections collected / unique 21440 / 3654 [R(int) = 0.0426]

Completeness to theta = 26.19 99.0 %

Absorption correction Semi-empirical from equivalents

Max. and min. transmission 0.6930 and 0.1676

Refinement method Full-matrix least-squares on F^2

Data / restraints / parameters 3654 / 0 / 210

Goodness-of-fit on F^2 1.363

Final R indices [I>2sigma(I)] R1 = 0.0587, wR2 = 0.1796

R indices (all data) R1 = 0.0785, wR2 = 0.1947

Largest diff. peak and hole 2.685 and -1.162 e.A^-3 Table C.2. Atomic coordinates ( x 10^4) and equivalent isotropic displacement

350

parameters (A^2 x 10^3) for 12a. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______

x y z U(eq) ______

Br(1) 9646(1) 11928(1) 891(1) 49(1) Br(2) 10427(1) 10607(2) 2886(1) 62(1) Br(3) 12352(1) 11645(2) 1241(1) 64(1) Br(4) 10886(1) 7367(2) 989(1) 71(1) C(3) 10447(6) 11869(12) 2191(3) 37(2) C(1) 10866(6) 10281(12) 1303(3) 40(2) C(2) 10637(6) 9918(12) 1848(3) 38(2) C(5) 9245(6) 12978(13) 2076(3) 38(2) C(8) 6605(7) 10001(15) 1140(3) 52(2) C(4) 11404(6) 13698(12) 2277(3) 43(2) C(7) 6400(6) 10615(14) 1669(3) 46(2) C(11) 3244(6) 6013(13) 145(3) 39(2) C(9) 4761(6) 8706(13) 583(3) 42(2) C(10) 4324(6) 6632(12) 483(3) 38(2) O(1) 8386(4) 11480(8) 1981(2) 41(1) O(4) 2637(5) 7381(10) -96(2) 59(2) O(3) 3056(5) 3872(9) 147(2) 51(1) N(2) 5929(5) 6202(12) 988(2) 50(2) N(3) 5075(6) 5141(11) 742(2) 48(2) N(1) 5756(5) 8388(11) 896(2) 41(1) O(2) 9098(5) 14916(8) 2082(2) 56(2) C(12) 2020(8) 3144(16) -164(4) 61(2) C(6) 7213(6) 12401(14) 1896(3) 51(2) ______

351

Table C.3. Bond lengths [A] and angles [deg] for 12a. ______

Br(1)-C(1) 1.934(7) Br(2)-C(3) 1.983(7) Br(3)-C(1) 1.947(7) Br(4)-C(1) 1.948(7) C(3)-C(2) 1.521(10) C(3)-C(5) 1.544(10) C(3)-C(4) 1.565(10) C(1)-C(2) 1.510(10) C(2)-H(2A) 0.9700 C(2)-H(2B) 0.9700 C(5)-O(2) 1.185(9) C(5)-O(1) 1.346(9) C(8)-N(1) 1.469(10) C(8)-C(7) 1.493(11) C(8)-H(8A) 0.9700 C(8)-H(8B) 0.9700 C(4)-H(4A) 0.9600 C(4)-H(4B) 0.9600 C(4)-H(4C) 0.9600 C(7)-C(6) 1.502(10) C(7)-H(7A) 0.9700 C(7)-H(7B) 0.9700 C(11)-O(4) 1.206(9) C(11)-O(3) 1.314(10) C(11)-C(10) 1.479(10) C(9)-N(1) 1.334(9) C(9)-C(10) 1.365(10) C(9)-H(9) 0.9300 C(10)-N(3) 1.367(9) O(1)-C(6) 1.465(9) O(3)-C(12) 1.426(9) N(2)-N(3) 1.278(9) N(2)-N(1) 1.354(10) C(12)-H(12A) 0.9600 C(12)-H(12B) 0.9600 C(12)-H(12C) 0.9600 C(6)-H(6A) 0.9700 C(6)-H(6B) 0.9700

C(2)-C(3)-C(5) 115.4(6) C(2)-C(3)-C(4) 118.2(6) C(5)-C(3)-C(4) 109.2(6) C(2)-C(3)-Br(2) 105.7(5) C(5)-C(3)-Br(2) 102.4(5) C(4)-C(3)-Br(2) 104.0(5) C(2)-C(1)-Br(1) 112.9(5) C(2)-C(1)-Br(3) 115.1(5) Br(1)-C(1)-Br(3) 109.0(3) C(2)-C(1)-Br(4) 106.5(5) Br(1)-C(1)-Br(4) 106.4(3) Br(3)-C(1)-Br(4) 106.4(3)

352

C(1)-C(2)-C(3) 120.7(6) C(1)-C(2)-H(2A) 107.2 C(3)-C(2)-H(2A) 107.2 C(1)-C(2)-H(2B) 107.2 C(3)-C(2)-H(2B) 107.2 H(2A)-C(2)-H(2B) 106.8 O(2)-C(5)-O(1) 124.3(7) O(2)-C(5)-C(3) 123.8(7) O(1)-C(5)-C(3) 111.9(6) N(1)-C(8)-C(7) 112.5(6) N(1)-C(8)-H(8A) 109.1 C(7)-C(8)-H(8A) 109.1 N(1)-C(8)-H(8B) 109.1 C(7)-C(8)-H(8B) 109.1 H(8A)-C(8)-H(8B) 107.8 C(3)-C(4)-H(4A) 109.5 C(3)-C(4)-H(4B) 109.5 H(4A)-C(4)-H(4B) 109.5 C(3)-C(4)-H(4C) 109.5 H(4A)-C(4)-H(4C) 109.5 H(4B)-C(4)-H(4C) 109.5 C(8)-C(7)-C(6) 111.8(7) C(8)-C(7)-H(7A) 109.3 C(6)-C(7)-H(7A) 109.3 C(8)-C(7)-H(7B) 109.3 C(6)-C(7)-H(7B) 109.3 H(7A)-C(7)-H(7B) 107.9 O(4)-C(11)-O(3) 126.3(7) O(4)-C(11)-C(10) 121.6(7) O(3)-C(11)-C(10) 112.1(6) N(1)-C(9)-C(10) 104.7(7) N(1)-C(9)-H(9) 127.7 C(10)-C(9)-H(9) 127.7 C(9)-C(10)-N(3) 108.4(6) C(9)-C(10)-C(11) 127.6(6) N(3)-C(10)-C(11) 124.0(7) C(5)-O(1)-C(6) 115.2(6) C(11)-O(3)-C(12) 115.5(7) N(3)-N(2)-N(1) 108.4(6) N(2)-N(3)-C(10) 108.4(6) C(9)-N(1)-N(2) 110.1(6) C(9)-N(1)-C(8) 130.0(7) N(2)-N(1)-C(8) 119.9(6) O(3)-C(12)-H(12A) 109.5 O(3)-C(12)-H(12B) 109.5 H(12A)-C(12)-H(12B) 109.5 O(3)-C(12)-H(12C) 109.5 H(12A)-C(12)-H(12C) 109.5 H(12B)-C(12)-H(12C) 109.5 O(1)-C(6)-C(7) 108.0(6) O(1)-C(6)-H(6A) 110.1 C(7)-C(6)-H(6A) 110.1 O(1)-C(6)-H(6B) 110.1 C(7)-C(6)-H(6B) 110.1 H(6A)-C(6)-H(6B) 108.4 ______

353

Table C.4. Anisotropic displacement parameters (A^2 x 10^3) for 12a. The anisotropic displacement factor exponent takes the form: -2 pi^2 [ h^2 a*^2 U11 + ... + 2 h k a* b* U12 ] ______

U11 U22 U33 U23 U13 U12 ______

Br(1) 50(1) 47(1) 47(1) 10(1) -2(1) 0(1) Br(2) 64(1) 75(1) 47(1) 11(1) 5(1) 10(1) Br(3) 45(1) 76(1) 72(1) -1(1) 13(1) -6(1) Br(4) 105(1) 42(1) 66(1) -11(1) 13(1) 9(1) C(3) 38(4) 37(4) 34(3) 1(3) -1(3) 5(3) C(1) 46(4) 31(4) 45(4) -3(3) 9(3) 3(3) C(2) 35(4) 34(4) 42(4) 4(3) -3(3) 4(3) C(5) 33(4) 43(4) 36(3) -3(3) -2(3) 4(3) C(8) 51(5) 59(5) 45(4) -4(4) 7(4) -13(4) C(4) 29(4) 31(4) 68(5) -9(3) 5(3) -7(3) C(7) 31(4) 55(5) 50(4) -9(4) 0(3) -9(3) C(11) 39(4) 44(4) 33(3) -4(3) 5(3) 0(3) C(9) 46(4) 44(4) 36(4) 4(3) 4(3) -1(3) C(10) 42(4) 36(4) 33(3) 6(3) 2(3) 5(3) O(1) 30(2) 32(3) 57(3) 0(2) -3(2) -1(2) O(4) 55(4) 52(4) 63(4) 5(3) -11(3) 5(3) O(3) 49(3) 47(3) 52(3) -1(3) -5(2) -11(3) N(2) 46(4) 47(4) 54(4) 7(3) -6(3) 4(3) N(3) 53(4) 41(4) 46(3) 0(3) 0(3) 2(3) N(1) 34(3) 46(4) 42(3) -1(3) 5(2) -3(3) O(2) 56(4) 25(3) 83(4) -8(3) -1(3) -1(2) C(12) 57(5) 63(6) 60(5) -8(4) -4(4) -21(5) C(6) 34(4) 52(5) 62(5) -17(4) -7(3) 10(3) ______

354

Table C.5. Hydrogen coordinates ( x 10^4) and isotropic displacement parameters (A^2 x 10^3) for 12a. ______

x y z U(eq) ______

H(2A) 11285 9077 2024 46 H(2B) 9958 8979 1830 46 H(8A) 6567 11323 929 62 H(8B) 7377 9386 1157 62 H(4A) 12153 13014 2350 64 H(4B) 11277 14614 2562 64 H(4C) 11370 14587 1973 64 H(7A) 6502 9319 1889 55 H(7B) 5607 11119 1658 55 H(9) 4438 10043 461 50 H(12A) 1360 3703 -25 92 H(12B) 1997 1557 -167 92 H(12C) 2004 3681 -509 92 H(6A) 7178 13650 1663 61 H(6B) 6996 12907 2219 61 ______

355

Appendix D

D.1 1H and 13C Spectroscopic Data of Functionalized Polytriazoles.

Figure D.1. 1H NMR of Tris((1-(4-vinylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)amine (TVBTA).

356

Figure D.2. 13C NMR of Tris((1-(4-vinylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)amine (TVBTA).

357

Figure D.3. 1H NMR of Tris((1-(4-(1,3,3,3-tetrachloropropyl)benzyl)-1H-1,2,3-triazol-4- yl)methyl)amine (TBTA(CCl4)3).

358

Figure D.4. 13C NMR of Tris((1-(4-(1,3,3,3-tetrachloropropyl)benzyl)-1H-1,2,3-triazol-4- yl)methyl)amine (TBTA(CCl4)3).

359

Figure D.5. 1H NMR of Tris((1-(4-(1,3,3,3-tetrabromopropyl)benzyl)-1H-1,2,3-triazol-4- yl)methyl)amine (TBTA(CBr4)3).

360

Figure D.6. 13C NMR of Tris((1-(4-(1,3,3,3-tetrabromopropyl)benzyl)-1H-1,2,3-triazol-4- yl)methyl)amine (TBTA(CBr4)3).

361

362

363

Figure D.9. 1H NMR of 4,4',4''-(((4,4',4''-(nitrilotris(methylene))tris(1H-1,2,3-triazole-4,1- diyl))tris(methylene))tris(benzene-4,1-diyl))tris(2,4-dichlorobutanenitrile)) (TBTA(CHCl2CN)3).

364

Figure D.10. 13C NMR of 4,4',4''-(((4,4',4''-(nitrilotris(methylene))tris(1H-1,2,3-triazole-4,1- diyl))tris(methylene))tris(benzene-4,1-diyl))tris(2,4-dichlorobutanenitrile)) (TBTA(CHCl2CN)3).

365

Figure D.11. 1H NMR of trimethyl 4,4',4''-(((4,4',4''-(nitrilotris(methylene))tris(1H-1,2,3- triazole-4,1-diyl))tris(methylene))tris(benzene-4,1-diyl))tris(2,4-dichlorobutanoate) (TBTA(Cl2HCCO2Me)3).

366

Figure D.12. 13C NMR of trimethyl 4,4',4''-(((4,4',4''-(nitrilotris(methylene))tris(1H- 1,2,3-triazole-4,1-diyl))tris(methylene))tris(benzene-4,1-diyl))tris(2,4-dichlorobutanoate) (TBTA(Cl2HCCO2Me)3).

367

D.2 High Resolution Mass Spectroscopic Data of Functionalized Polytriazoles

631.3791 100 [M+Na+]

609.3592 60 [M+H+]

40 % Abundance%

0 600 610 620 630 640 650 m/z Figure D.13. HRMS of Tris((1-(4-vinylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)amine (TVBTA).

368

1093.0548 100 [M+Na+]

+ 40 [M+H ]

% Abundance% 1071.0706

0 1060 1065 1070 1075 1080 1085 1090 1095 1100 m/z Figure D.14. HRMS of Tris((1-(4-(1,3,3,3-tetrachloropropyl)benzyl)-1H-1,2,3-triazol-4- yl)methyl)amine (TBTA(CCl4)3).

369

[M+Na+] 1626.5709 100

80 [M+H+] 60 1604.5386

40 % Abundance %

0 1600 1605 1610 1615 1620 1625 1630 1635 1640

m/z Figure D.15. HRMS of Tris((1-(4-(1,3,3,3-tetrabromopropyl)benzyl)-1H-1,2,3-triazol-4- yl)methyl)amine (TBTA(CBr4)3).

370

[M+H+] 1160.9780 100

40 % Abundance %

0 1150 1155 1160 1165 1170 1175

m/z Figure D.16. HRMS of Dimethyl 4,4'-(((4,4'-((((3-(4-(1,3,3-trichloro-4-methoxy-4- oxobutyl)benzyl)-3H-pyrazol-5-yl)methyl)azanediyl)bis(methylene))bis(1H-1,2,3- triazole-4,1-diyl))bis(methylene))bis(4,1-phenylene))bis(2,2,4-trichlorobutanoate) (TBTA(Cl3CCO2Me)3).

371

[M+Na+] 960.2722 100

60 [M+H+] 938.2882

40 % Abundance %

0 930 935 940 945 950 955 960 965 970

m/z Figure D.17. HRMS of 4,4',4''-(((4,4',4''-(nitrilotris(methylene))tris(1H-1,2,3-triazole- 4,1-diyl))tris(methylene))tris(benzene-4,1-diyl))tris(2,4-dichlorobutanenitrile)) (TBTA(CHCl2CN)3).

372

[M+H+] 100 1053.2524

40 % Abundance %

0 1050 1052 1054 1056 1058 1060

m/z Figure D.18. HRMS of Dimethyl 4,4'-(((4,4'-((((3-(4-(1,3-dihloro-4-methoxy-4- oxobutyl)benzyl)-3H-pyrazol-5-yl)methyl)azanediyl)bis(methylene))bis(1H-1,2,3- triazole-4,1-diyl))bis(methylene))bis(4,1-phenylene))bis(2,2,4-trichlorobutanoate (TBTA(Cl2HCCO2Me)3).

373

Appendix E

Crystallographic Information

I Figure E.1. Crystal packing diagram of [Cu (bpy)(-CH2=CHC6H5)][PF6]*1/2Sty (2).

374

Appendix F

Data for Copper(I) Bipyridine and Phenanthroline Based Complexes and their Effect on Catalytic Activity in Cyclopropanation of Styrene

Table F.1. Crystallographic data and experimental details for [CuI(3,4,7,8- I I I Me4phen)(BPh4)]*3CH2Cl2 (1), Cu (bpy)(BPh4) (2), Cu (phen)(BPh4) (3) and [Cu (2,9- Me2phen)(CH3CN)][BPh4] (4). Compound 1 2 3 4 formula C43H42BCl6CuN2 C34H28BCuN2 C36H28BCuN2 C40H35BCuN3 color/shape yellow/needles orange/prisms orange/prisms yellow/prisms formula weight 873.84 538.93 562.95 632.06 crystal system monoclinic monoclinic monoclinic Monoclinic space group P2(1)/n P2(1)/c P2(1)/c P2(1)/n temp, K 120 150 150 298 cell constants a, Å 11.3092(9) 9.2143(11) 9.7342(7) 11.770(4) b, Å 22.4717(18) 33.258(4) 32.7707(18) 19.641(7) c, Å 16.2473(13) 9.2161(11) 9.4081(5) 14.404(5) , deg 90. 90. 90. 90.12 , deg 95.5850(10) 114.185(2) 117.0020(10) 90.00(4) , deg 90. 90. 90. 90. V, Å3 4109.4(6) 2576.3(5) 2674.0(3) 3330.0(19) Formula units/unit cell 4 4 4 4 -3 Dcalcd, gcm 1.412 1.389 1.398 1.261 , mm-1 0.955 0.875 0.846 0.688 F(000) 1800 1120 1168 1320 diffractometer Bruker Smart Bruker Smart Bruker Smart Bruker Smart radiation, graphite Apext II Apex II Apex II Apex II monochr. Mo K Mo K Mo K Mo K crystal size, mm (=0.71073 Å) (=0.71073 Å) (=0.71073 Å) (=0.71073 Å)  range, deg 0.45 x 0.08 x 0.05 0.38 x 0.20 x 0.40 x 0.30 x 0.35 x 0.25 x range of h,k,l 1.55<  < 27.08 0.09 0.16 0.21 reflections ±14, ±28, ±20 1.22<  < 28.77 1.24<  < 32.97 1.75<  < 26.39 collected/unique 38649/9028 ±12, ±44, ±12 ±14, ±50, - ±14, ±24, ±17 Rint 0.0723 27712/6651 14≤l≤13 28017/6744 refinement method full-matrix 0.1323 35474/9501 0.1740 2 least-squares on F full-matrix 0.0573 full-matrix data/restraints/parameters 9028/0/482 least-squares on full-matrix least-squares on GOF on F2 0.900 F2 least-squares on F2 2 final R indices [I>2(I)] R1=0.0436, 6651/0/344 F 6744/0/409 R indices (all data) wR2=0.0941 0.938 9501/0/361 0.893 -3 max. resid. peaks (e•Å ) R1=0.0750, R1=0.0474, 1.017 R1=0.0456, wR2=0.1038 wR2=0.1033 R1=0.0362, wR2=0.0950 1.351 and -1.285 R1=0.0875, wR2=0.0947 R1=0.1232, wR2=0.1201 R1=0.0544, wR2=0.1221 0.771 and - wR2=0.1044 0.195 and - 0.710 0.490 and - 0.457

375

0.533

Table F.2. Selected bond distances (Å) and angles (o) for 1-3. I I I Cu (3,4,7,8-Me4phen)(BPh4) (1) Cu (bpy)(BPh4) (2) Cu (phen)(BPh4) (3) Distances Cu(1)-N(1) 2.061(2) 2.051(2) 2.0668(12) Cu(1)-N(2) 2.033(2) 2.072(2) 2.0423(12) Cu(1)-C(1) 2.369(3) 2.201(3) 2.2640(13) Cu(1)-C(2) 2.306(2) 2.319(3) 2.2065(14) Cu(1)-C(3) 2.220(3) 2.311(2) 2.3575(13) Cu(1)-C(4) 2.161(2) 2.379(3) 2.2497(15) Cu(1)-B(1) 2.823(3) 2.869(3) 2.9007(16) C(1)-C(2) 1.412(3) 1.412(3) 1.410(2) C(3)-C(4) 1.415(4) 1.413(4) 1.4118(18) B(1)-C(1) 1.655(4) 1.656(4) 1.655(2) B(1)-C(3) 1.658(4) 1.644(4) 1.652(2) B(1)-C(13) 1.634(4) 1.640(4) 1.636(2) B(1)-C(19) 1.642(4) 1.635(4) 1.641(2) Angles N(1)-Cu(1)-N(2) 81.71(8) 80.18(9) 81.91(5) N(2)-Cu(1)-C(2) 109.35(9) 133.98(9) 129.74(5) N(2)-Cu(1)-C(1) 113.71(9) 122.42(9) 122.22(5) N(2)-Cu(1)-C(4) 108.10(9) 92.77(9) 118.84(5) N(2)-Cu(1)-C(3) 145.40(9) 127.21(9) 116.03(5) N(1)-Cu(1)-C(1) 131.65(9) 141.71(9) 138.80(5) N(1)-Cu(1)-C(2) 96.92(9) 105.45(9) 102.08(5) N(1)-Cu(1)-C(3) 121.61(9) 123.79(9) 135.79(5) N(1)-Cu(1)-C(4) 130.09(9) 118.33(9) 100.12(5) C(1)-B(1)-C(3) 104.3(2) 103.1(2) 101.92(11) C(1)-B(1)-C(13) 112.3(2) 111.3(2) 113.84(11)

376

I Figure F.1. Packing diagram of [Cu (BPh4)(3,4,7,8-Me4phen)]*3CH2Cl2 (1), shown with 50% probability displacement ellipsoids.

377

I Figure F.2. Packing diagram of Cu (BPh4)(bpy) (2), shown with 50% probability displacement ellipsoids.

378

I Figure F.3. Packing diagram of Cu (BPh4)(phen) (3), shown with 50% probability displacement ellipsoids.

379

I Figure F.4. Partial packing diagram of [Cu (BPh4)(3,4,7,8-Me4phen)]*3CH2Cl2 showing weak C-HF interactions (dashed lines).

Figure F.5. Typical 6- and 2-coordination modes of tetraphenylborate anion to transition metal complexes, (a) Rh(BPh4)(diphos) and (b) Cu(BPh4)(CO)(en).

380

Table F.3. Selected bond distances (Å) and angles (o) for [CuI(2,9- I Me2phen)(CH3CN)][BPh4] (4) and [Cu (2,9-Me2phen)(CH3CN)][PF6] (5). Distances Angles I [Cu (2,9-Me2phen)(CH3CN)][BPh4] (4) Cu1-N1 1.850(3) N2-Cu1-N3 83.13(11) Cu1-N2 2.041(3) N1-Cu1-N3 139.36(11) Cu1-N3 2.033(2) N1-Cu1-N2 137.49(11) N1-C1 1.138(3) Cu1-N1-C1 178.0(3) B1-C29 1.646(4) C2-C1-N1 178.4(3) B1-C35 1.656(4) B1-C23 1.653(4) B1-C17 1.653(4) I [Cu (2,9-Me2phen)(CH3CN)][PF6] (5) Cu1-N1 2.037(6) N1-Cu1-N2 83.3(2) Cu1-N2 2.011(6) N3-Cu1-N1 136.3(3) Cu1-N3 1.854(6) N3-Cu1-N2 139.9(3) N3-C15 1.117(8) Cu1-N3-C15 172.7(7) N3-C15-C16 179.3(9)

I Figure F.6. Molecular structure of [Cu (2,9-Me2phen)(CH3CN)][BPh4] (4), shown with 30% probability displacement ellipsoids. H atoms have been omitted for clarity.

381

382

I Figure F.8. Molecular structure of [Cu (2,9-Me2phen)(CH3CN)][PF6] (5), shown with 30% probability displacement ellipsoids. H atoms have been omitted for clarity.

383

6H 6H

Me Me 8H

o-H(BPh -) 4 8H

- m-H(BPh4 )

384 2H

-CCH- 4H 2H p-H(BPh -) -NCH- 4

1 I Figure F.9. H HMR spectrum (300 MHz, CD2Cl2, RT) of [Cu (3,4,7,8-Me4phen)][BPh4].

100

80 (C=C,BPh -) 4

385

70 % Reflectance %

1700 1650 1600 1550 1500 Wavelength / nm 60

50 3500 3000 2500 2000 1500 1000 500

Wavelength / cm-1

I Figure F.10. Solid state FT-IR Spectrum of [Cu (3,4,7,8-Me4phen)][BPh4].

100

(CN)=2336 cm-1

386 (C=C,BPh -)

70 4 % Reflectance %

260025002400230022002100 1700 1650 1600 1550 1500 -1 Wavelength / cm -1 Wavelength / cm 60

B Cu NCCH3

50 3500 3000 2500 2000 1500 1000 500

Wavelength / cm-1

I Figure F.11. Solid State FT-IR Spectrum of [Cu (CH3CN)][BPh4].

Table F.4. Comparison of key distances from crystal structure and B3LYP/6-31G(d) and MP2/6-31G(d) optimized structures of 2. On average the key bond distances of the B3LYP/6-31G(d) optimized structure differed from those of the crystal structure by 0.038 Å, while the bond distances of the MP2/6-31G(d) optimized structure differed from the crystal structure by an average of 0.087 Å. Atoms Distance (Å) Crystal B3LYP/ MP2/ Structure 6-31G(d) 6-31G(d) C3-B2 1.656 1.673 1.651 C4-B2 1.644 1.673 1.651 C3-Cu1 2.201 2.169 2.039 C4-Cu1 2.309 2.161 2.034 C3-C7 1.412 1.426 1.436 C3-C8 1.414 1.422 1.424 C4-C9 1.413 1.427 1.436 C4-C10 1.414 1.422 1.424 Cu1-N5 2.073 2.059 1.987 Cu1-N6 2.051 2.054 1.985 B2-Cu1 2.870 2.741 2.582

Table F.5. Comparison of key distances from crystal structure and B3LYP/6-31G(d) optimized structure of 1. On average the key bond distances of the B3LYP/6-31G(d) optimized structure differed from those of the crystal structure by 0.030 Å. Atoms Distance (Å) Crystal Structure B3LYP/6-31G(d) C3-B2 1.655 1.672 C4-B2 1.657 1.672 C3-Cu1 2.306 2.167 C4-Cu1 2.162 2.167 C3-C8 1.412 1.426 C3-C7 1.412 1.422 C4-C10 1.415 1.426 C4-C9 1.421 1.422 Cu1-N5 2.032 2.064 Cu1-N6 2.061 2.064 B2-Cu1 2.823 2.745

387

Figure F.12. Overlay of crystal structure (shown in orange) and B3LYP/6-31G(d) optimized structure (shown in blue) of 2.

388

Figure F.13. Overlay of crystal structure (shown in orange) and MP2/6-31G(d) optimized structure (shown in blue) of 2.

389

Figure F.14. Overlay of crystal structure (shown in orange) and B3LYP/6-31G(d) optimized structure (shown in blue) of 2.

- a Table F.6. Significant  donation from BPh4 anion to copper(I) complexes 1 and 2.

390

Donor Orbital Acceptor Orbital Charge Transfer (kcal/mol) I Cu (3,4,7,8-Me4phen)(BPh4) (1) 6-31+G(d) 6-311G(2d,p) 6-311++G(2d,p) C4-C3  bond Cu n* 20.7 12.4 11.9 C1-C2  bond Cu n* 20.7 12.4 11.9 B1-C4  bond Cu n* 7.5 6.1 8.3 B1-C2  bond Cu n* 7.5 6.1 8.3 Cu n* 7.7 3.0 5.4 C4-C3  bond Cu n* 7.7 3.0 5.4 C1-C2  bond 71.7 43.2 51.1 SUM I Cu (bpy)(BPh4) (2) C1-C2  bond Cu n* 20.6 12.6 14.3 C3-C4  bond Cu n* 20.9 12.7 14.2 B1-C3  bond Cu n* 7.8 6.3 8.6 B1-C1  bond Cu n* 7.7 6.2 8.5 Cu n* 7.8 3.1 5.2 C3-C4  bond Cu n* 7.6 3.0 5.0 C1-C2  bond 72.5 44.0 55.7 SUM aAtom numbering is identical to Figure 1 in the main manuscript. All calculations are NBO single points done with B3LYP and performed on B3LYP/6-31G(d) optimized structures.

391

- Table F.7. -Backbonding interactions between copper(I) complexes 1 and 2 and BPh4 anion.a Donor Orbital Acceptor Orbital Charge Transfer (kcal/mol) I Cu (3,4,7,8-Me4phen)(BPh4) (1) 6-31+G(d) 6-311G(2d,p) 6-311++G(2d,p) LP(4) Cu C1-C2 * 6.9 3.1 6.7 LP(4) Cu C4-C3 * 6.8 3.1 6.7 LP(5) Cu C4-C3 * 2.7 8.4 2.5 LP(5) Cu C1-C2 * 2.6 8.4 2.4 SUM 18.9 22.9 18.3 I Cu (bpy)(BPh4) (2) LP(4) Cu C3-C4 * 6.5 8.0 6.3 LP(4) Cu C1-C2 * 6.8 8.3 6.4 LP(5) Cu C3-C4 * 2.9 3.4 2.5 LP(5) Cu C1-C2 * 2.2 2.6 2.0 SUM 18.3 22.3 17.2 aAtom numbering is identical to Figure 1 in the main manuscript. All calculations are NBO single points done with B3LYP and performed on B3LYP/6-31G(d) optimized structures.

392