Synthesis of 2-Boron Substituted-1,3-Dienes and Their Diels-Alder/Suzuki Cross Coupling Reactions

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SYNTHESIS OF 2-BORON SUBSTITUTED-1,3-DIENES AND THEIR DIELS-ALDER/SUZUKI CROSS COUPLING REACTIONS

LIQIONG WANG

A Dissertation Submitted to the Graduate Faculty of

WAKE FOREST UNIVERSITY GRADUATE SCHOOL OF ARTS AND SCIENCES

in Partial Fulfillment of the Requirements

for the Degree of

DOCTOR OF PHILOSOPHY

Chemistry

August 2012

Winston Salem, North Carolina

Approved By:

Mark E. Welker, Ph.D., Advisor

Anne Glenn, Ph.D., Chair

Uli Bierbach, Ph.D.

Christa L. Colyer. Ph.D.

Paul B. Jones, Ph.D.

ACKNOWLEDGEMENTS

Firstly, I would like to thank the almighty God for all the love and guidance in the process of pursuing my Ph.D. degree. All the love that HE has given is through these generous people whom I will respect and love for the rest of my life.

I would like to extend my deepest and warmest appreciation to my advisor, Dr. Mark E.

Welker, who has instructed and led me in the research and study with great patience and support. Dr. Welker always encouraged me to try new ideas and think about science in a precise and concrete way. The encouragement has led me to break through the messy results and make progress in the project. The benefit from your professional training and personal fascination will eventually have great influence on my career and life.

Also, Dr. Marcus Wright has offered me much help in NMR, chromatography and mass spectrometry. No matter what time and situation you were facing, you were always trying your best to help me to resolve the problems. I would like to thank you for your great patience and generosity.

The crystal analysis in my dissertation was from Dr. Cynthia Day. You also tried to help me to get a good crystal when I could not figure out if it is a crystal. I would like to thank you for all the help.

For the molecular modeling of the compound in the dissertation, I would like to thank

Dr. Fred Salsbury from the Physics Department. His work was a great help in the progress of my research.

Thank you to my committee members, Dr.Ulrich Bierbach, Dr. Paul B. Jones, Dr. Anne

Glenn and Dr. Rebecca Alexander, for taking time out of your busy schedule to read and

correct my dissertation and give me professional instructions to finish my proposals. Also,

I thank Dr. Bierbach for the kind help and suggestions when I looked for a job.

Also, I would like to thank Dr. Christa L. Colyer for your great support in the development of my professional career. You have given me a lot of wise opinions on the job and career. Thank you for always being nice and patient.

To Dr. Al Rives, Dr. S. Bruce King, Dr. Lindsay R. Comstock, Dr. Amanda Jones, Dr.

Susan Tobey and Dr. Akbar Salam, I would like to thank you for the kind help in my study and research.

Many thanks to Mike Thompson, Tommy Murphy, Linda Tuttle, Melissa Doub and

Nancy for your generous help in the past few years.

Also thank you, my former and current lab mates, Dr. Subhasis De, Dr. Ramakrishna R.

Pidaparthi, Maben Ying, Dr. Tanya Pinder, Dr. Sarmad Hindo, Dr. Christopher S. Junker,

Partha Choudhury, Kimberly M. Tillman, Dr. Ken Crook and undergraduates. Each of you has been a source of advice and/or friendship and I have enjoyed working with you all.

I would like to thank all the past and current Chinese students and postdocs in the department: Xiuli, Weibin, Zhaoli, Zhidong, Huajun, Yue, Jiyan, Changkun, Yuhao, Lu,

Lei, Ye, Zhengrui, Zhong, Song, Yuyang, Xin, Lin and Mu, for the friendship and help in these years.

Also, I could not have reached this point without the instruction and encouragement from Dr. Jin Nie, my former advisor from Huazhong University of Science and

Technology. Thank you for helping me overcome all the frustrations and become strong.

Lastly, thank you to my big family: my great father and mother, brothers, sisters, nieces, nephew and my lovely son. Thank you for the amazing love, support and sacrifice for me.

Without you, I could not go through all of this. The last kiss is to my son, Weiwei; my sweetheart, you are always the power source for your mom. You never know how much you mean to mom.

III

TABLE OF CONTENTS

ACKNOWLEDGEMENTS ...... I

TABLE OF CONTENTS ...... IV

LIST OF FIGURES ...... VII

LIST OF TABLES ...... VIII

LIST OF ABBREVIATIONS ...... IX

ABSTRACT ...... XIII

CHAPTER 1 Introduction ...... 1

1.1 Diels-Alder Reactions ...... 1

1.1.1 Mechanism of Diels-Alder Reactions ...... 1

1.1.2 Regioselectivity of Diels-Alder Reactions...... 4

1.1.3 Stereoselectivity of Diels-Alder Reactions ...... 5

1.2 Brief Review of Recent Boronate Substituted Dienes ...... 13

1.2.1 Preparation and Reactions of 1-Boron Substituted-1,3-Dienes ...... 17

1.2.2 Preparation and Reactions of 2-Boron Substituted-1,3-Dienes ...... 22

1.3 Suzuki-Miyaura Cross Coupling Reactions ...... 26

1.4 Rhodium Reaction ...... 30

1.4.1 Advantages of rhodium catalyzed 1,4-addition of enones ...... 30

1.4.2 Catalytic Cycle and Mechanism ...... 32

1.4.3 Reaction Properties ...... 33

1.5 Aims of Current Project ...... 43

CHAPTER 2 Preparation of Boron Substituted Dienes ...... 45

2.1 Results and Discussion ...... 45

2.1.1 Preparation of 2- Diethanolamine Borate Diene 2.4 And 2.6 ...... 45

2.1.2 Resolution of Dimerization Problems and Preparation of Tri-Coordinated

and Tetra-Coordinated Boron-1,3-Dienes ...... 47

2.1.3 Conformation Analysis of 2-Boron Substituted-1,3-Dienes ...... 51

2.2 Attempts to Synthesize Other Boron Substituted Dienes ...... 52

2.2.1 Attempts to Synthesize Sodium 1-(but-1,3-dien-2yl)-5-methyl-2,8,9-trioxa-

1-borabicyclo[3,3,1]nonan-1-uide) ...... 53

2.2.2 Attempts to Synthesize 2-(Buta-1,3-Dien-2-yl)-6-Methyl-1,3,6,2 -

Dioxazaborocane-4.8-Dione ...... 53

2.2.3 Attempts To Synthesize 1-Phenyl-2-Pinacol Boronate-1, 3-Diene ...... 54

2.2.4 Attempts To Synthesize 1-Substituted-2-Boron-1,3-Dienes By Cross-

Metathesis ...... 57

2.3 Conclusion ...... 60

2.4 Experimental Procedures and Characterization Data ...... 61

CHAPTER 3 Diels-Alder Reactions of 2-Boron Substituted-1,3-Dienes ...... 70

3.1 Results and Discussion ...... 70

3.1.1 Diels-Alder Reactions ...... 70

3.1.2 Dimerization of Boron Substituted Dienes ...... 77

3.2 Conclusion ...... 79

3.3 Experimental Procedures and Characterization Data ...... 79

CHAPTER 4 Suzuki Cross Coupling Reactions ...... 87

4.1 Results and Discussion ...... 87

4.1.1 Suzuki Cross Coupling Reactions ...... 87

4.1.2 Tandem Diels-Alder/Suzuki Cross Coupling Reactions...... 90

4.2 Conclusions ...... 99

4.3 Experimental and Characterization Data ...... 99

CHAPTER 5 Unexpected Proton Deboronation Reactions ...... 116

5.1 Rhodium Catalyzed Chemistry With 1-Alkyl-3-Boronate-1,3-Dienes ...... 116

5.2 Conclusion ...... 123

5.3 Experimental and Characterization Data ...... 124

CHAPTER 6 CONCLUSIONS ...... 128

APPENDIX A Crystal Structure Data of Diene 2.4 ...... 147

APPENDIX B NOESY and COSY of Boron Substituted Dienes ...... 169

CURRICULUM VITAE ...... 179

LIST OF FIGURES

Figure 1.1 Diels-Alder Reactions ...... 1

Figure 1.2 Diels-Alder Molecular Orbital Diagram ...... 2

Figure 1.3 Normal, Neutral and Inverse Electron Demand Diels-Alder Reactions ...... 3

Figure 1.4 “Zwitterionic” Model ...... 5

Figure 1.5 General Catalytic Cycle for Suzuki-Miyaura, Heck And Stille Cross-Coupling

Reactions ...... 27

Figure 1.6 General Catalytic Cycle for Suzuki-Miyaura Couplings...... 29

Figure 1.7 Reductive Elimination of Suzuki-Miyaura Couplings ...... 29

Figure 1.8 Applications of New BINAP Ligands ...... 34

Figure 2.1 Mechanism of Ruthenium Catalyzed Cross Metathesis Reactions ...... 58

Figure 3.1 Crystal Structures of BF3 Substituted Diene and Diethanolamineborate-1,3-

Butadiene 2.4 ...... 74

Figure 3.2 NOESY of Diethanolaminoborate-1,3-Butadiene 2.4 ...... 75

Figure 3.3 Thermodynamic Diagram of Dimerization of 2-Boron Substituted Dienes ... 79

Figure 4.1 Comparison of NMR Chemical Shifts of Boron Substituted Diene and

Palladium Substituted Diene in CD3CN ...... 96

Figure 5.1 Catalytic Cycle of Rhodium Catalysis ...... 116

Figure 5.2 Catalytic Cycle of Palladium Catalysis ...... 124

VII

LIST OF TABLES

Table I Attempts for Olefin Cross Metathesis Reactions ...... 59

Table II Attempts for Enyne Cross Metathesis ...... 60

Table III Diels-Alder Reactions of 2-Boron Substituted-1,3-Dienes ...... 71

Table IV Dimerization Experiments of 2-Boron Substituted-1,3-Dienes ...... 78

Table V Optimization of Suzuki Cross Coupling Reaction ...... 88

Table VI Suzuki Cross Coupling Reactions of 2-Boron Substituted-1,3-Dienes ...... 88

Table VII Tandem Diels-Alder/Suzuki cross coupling reactions ...... 91

Table VIII Palladium Catalysts and 2-Palladium Substituted 1,3-Diene ...... 97

Table IX Rhodium Catalyzed Reactions ...... 117

VIII

LIST OF ABBREVIATIONS

Å Angstrom(s)

°C Degree(s) Celsius

Ac Acetyl allyl 2-Propenyl

Ar Aryl atm Atmosphere(s)

BINAP 2,2'-bis(diphenylphosphino)-1,1'-

binaphthalene

Bn Benzyl bs Broad Singlet

Bz Benzoyl

C=O Carbonyl

Calcd Calculated

CD3CN Deuterated Acetonitrile

CDCl3 Deuterated Chloroform cm-1 Wave Numbers

COSY Correlation Spectroscopy

Cp Cyclopentadienyl

Cy Cyclohexane d Doublets dba Dibenzyldeneacetone

D-A Diels-Alder

DCE 1,2-dichloroethane

DCM Dichloromethane dd Double Doublets ddd Double Double Doublets ddt Double Double Triplet

DFT Density Functional Theory

DIPHOS 1,2-bis(diphenylphosphino)ethane

DME Dimethoxyethane

DMF N,N-Dimethylformamide

DMSO Dimethylsulfoxide

EDG Electron Donating Group

EWG Electron Withdrawing Group

Equiv Equivalents

Et Ethyl

Et2O Diethyl Ether

g Grams h Hours

HMBC Heteronuclear Multiple Bond

Coherence

HOMO Highest Occupied Molecular Orbital

HRMS High Resolution Mass Spectrometry

Hz Hertz(s) iPr Isopropyl

J Coupling Constant kcal Kilocalorie

LUMO Lowest Unoccupied Molecular Orbital m Multiplet m Meta m.p. Melting Point m/z Mass to Charge Ratio

Me Methyl

MHz Megahertz(s) min Minutes mol Moles

N/A Not Available nBu Normal Butyl

NMR Nuclear Magnetic Resonance

NOE Nuclear Overhauser Effect

NOESY Nuclear Overhauser Effect

Spectroscopy o Ortho

OTf Trifluoromethanesulfonate p Para

Ph Phenyl

Q Quartet

Rf Retention Factor

S Singlet t Triplet t1/2 Half Life

TLC Thin Layer Chromatography

TMS Trimethylsilyl

X Halide

δ Chemical Shift

XII

ABSTRACT

Dissertation under the direction of Mark E. Welker, Ph.D., Professor of Department of

Chemistry, Wake Forest University

Clerodane diterpenoids represent a large group of secondary metabolites which are distributed widely in nature. Over a thousand members have been isolated to date, many of which possess interesting biological activities: antifeedant, antitumor, antifungal, antibiotic, anti-peptic ulcer and so on. Although synthetic approaches to the trans- clerodanes abound, cis-clerodane syntheses are rare. The long term objective of this research is to make highly reactive dienes which would undergo Diels-Alder (D-A) reactions with sterically crowded dienophiles to construct cis-clerodane compounds.

In previous work, 2-boron-1,3-dienes had shown a high propensity toward self D-A dimerization. Different strategies were tried to prepare dienes without dimerization and seven boron substituted dienes were prepared in good yields. The tri-coordinated boron dienes are less stable than the tetra-coordinated dienes because the boron atom is stabilized by donating electron pairs or groups in the latter type. The reactivity of these boron substituted dienes (2-diethanolaminoborate-1,3-butadiene) in D-A and Suzuki cross coupling reactions were tested and evaluated.

Testing concluded that in D-A reactions high yields (> 90%) were found in the reactions of boron substituted 1,3-dienes and N-phenyl maleimide at room temperature or lower. The fastest diene (2-diethanolaminoborate-1,3-butadiene) reacted with a t1/2 less than 4 minutes at -10 °C. The 2-diethanolaminoborate-1,3-butadiene has a high HOMO energy compared to its BF3 diene counterpart which accelerates its D-A reactions. High

XIII

regioselectivities (16:1) were found in the D-A reactions of unsymmetrical dienophiles and 2-diethanolaminoborate-1,3-butadiene. Both high yields and regioselectivities were achieved in Suzuki cross coupling reactions of the resulting boron substituted D-A cycloadducts. Using this methodology, 2-diethanolaminoborate-1,3-butadiene is a promising precursor in providing a potential tool to asymmetric synthesis.

Three boron substituted dienes reacted with n-phenylmaleimide very quickly, from seconds to 2 hours. All three dienes are stable at 0℃ for more than 2 years. The research also revealed that 4 dienes can be used in tandem D-A/Suzuki cross coupling reactions.

High yields and good selectivities were obtained. The possible mechanism of tandem reactions showed that Pd(II) acts as a Lewis acid catalyst to catalyze the D-A reaction between boron substituted dienes and dienophiles followed by Suzuki cross coupling reactions. A possible unstable novel intermediate, a palladium substituted diene, was observed in the reaction by NMR.

XIV

CHAPTER 1 Introduction

1.1 Diels-Alder Reactions

As the most thoroughly explored cycloaddition reactions since 1928, Diels-Alder reactions have been essential methods to realize the simultaneous construction of substituted cyclohexenes with a high degree of regioselectivity, diastereoselectivity and enantioselectivity. Various ramifications of Diels-Alder reactions have been developed with thousands of papers being published every year.1-3 Obviously, this concerted

(4+2) pericyclic reaction is already an indispensable way to form a carbon-carbon bond in modern organic synthetic chemistry.

Although several reports on asymmetric Diels-Alder reactions have been published,4-6 they are still in the minority compared with many asymmetric oxidative and reductive reactions. We are dedicated to improve the enantioselectivity and diastereoselectivity by employing the main group metal substituted dienes in Diels-Alder reactions.

1.1.1 Mechanism of Diels-Alder Reactions

Diels-Alder reactions have been reported to have two mechanisms: concerted and two step mechanisms. Although some cases occur by a two step mechanism that involve a biradical intermediate, most thermal cycloadditions can be described by a symmetry- allowed one step mechanism (Figure 1.1).7, 8

Figure 1.1 Diels-Alder Reactions

FMO ( Frontier Molecular Orbital ) theory, a powerful practical model, was developed by Kenichi Fukui in the1950's and has been used successfully to explain reactivity and selectivity phenomena in cycloaddition reactions.9, 10 The fundmental principle of FMO is the focus on the highest occupied and lowest unoccupied molecular orbitals (HOMO and

LUMO). The smaller the HOMO-LUMO energy gap, the easier the Diels-Alder reactions are because the lower HOMO-LUMO energy makes a greater contribution to the transition state. For acrolein with an electron withdrawing carbonyl group, which efficiently lowers the LUMO energy of the dienophile, the energy difference between acrylaldehyde and diene are greatly reduced compared with ethylene. So, acrylaldehyde is a better dienophile than ethylene in this case.

Figure 1.2 Diels-Alder Molecular Orbital Diagram

Three types of Diels-Alder reactions are introduced in Figure1.3: normal, neutral and inverse electron demand Diels-Alder reactions.8

In the normal situation, the dominating orbital interaction is HOMO diene – LUMO dienophile, but in the inverse situation, the interaction is LUMO diene-HOMO dienophile.

No matter what type the reaction is, the reaction with the smallest HOMO-LUMO gap is always the fastest one.11

Figure 1.3 Normal, Neutral and Inverse Electron Demand Diels-Alder Reactions An inverse electron demand Diels-Alder reaction was discovered by Yamamoto’s group in 2009. Tropone acts as an electron deficient diene 1.1 reacting with and electron

rich dienophile 1.2 to get a cycloproduct 1.3 with a high yield and high enantioselectivity.12 (Scheme 1.1)

Scheme 1.1

1.1.2 Regioselectivity of Diels-Alder Reactions

In principle, the cycloaddition of substituted dienes and dienophiles gives two regioisomer adducts. Pseudo ortho and para orientations in products are usually favored over the meta orientation. 1- and 2-substituted dienes usually give ortho and para products, respectively (Scheme 1.2). This preference is increased in catalyzed reactions.13

Scheme 1.2 We can use a simple “zwitterionic” device to predict the regioselectivity (Figure 1.5).

Figure 1.4 “Zwitterionic” Model For disubstituted dienes, relative amounts of each depend on electron donating strength of substituents.

1.1.3 Stereoselectivity of Diels-Alder Reactions

The cis principle was found by Alder and Stein in 1937, after the observation that the relative configuration of reactants was preserved in the final products.14

Cis principle: The stereochemistry of substituents in the starting material is retained in the product.15 Since a trans double bond in a six-memebered ring is geometrically impossible, the Diels-Alder cycloaddition can occur only when the diene possesses a cisoid conformation. So, a number of cyclic transoid cyclic dienes have been shown to be unavailable to dienophiles.

Endo principle: The two reactants approach each other in parallel planes which may interact in two different orientations affording endo- and exo- adducts (Scheme 1.3 ).

The most stable transition state is the one with maximum orbital overlap.16 Endo is the

kinetically favored product and usually the major product in Diels Alder reactions.

Several factors, such as steric effects, nature of solvent, dienophile interactions and presence of Lewis acids control the endo to exo ratio in different cases.

Scheme 1.3

Lewis acid catalysis can also change regioselectivity. For example, the BF3 and SnCl4 catalyzed cycloaddition of 2-methoxy-5-methyl-1,4-benzoquinone(1.4) to 1-methyl-1,3- butadiene (1.5) yielding a different regioselectivity: 4:1(1.6, ortho) versus 1:20(1.7 para).13 The monodentate (1.8) and bidentate coordination (1.9) shown below explained the different results (Scheme 1.4).

Scheme 1.4 An example of different endo-exo diastereoselectivity is observed in Scheme 1.5.17

With the catalysis of AlCl3 in room temperature or heating to refluxing, the enantioselectivity of endo to exo is 70%:30% versus 100%:0 for the reaction of dienes penta-1.3-diene and 1-methoxyl-1,3-butadiene with dienophile 1.10.

With high enantioselectivity and diastereoselectivity in the reaction, Diels-Alder reactions provide a powerful tool for the synthesis of enantiomers and diastereoisomers.

Scheme 1.5

1.1.4 Asymmetric Diels-Alder Reactions

Quaternary stereocenters are known to be particular challenges for synthesis because the creation of such centers is complicated by steric repulsion between the carbon substituents.4 Only a few catalytic asymmetric C-C bond forming reactions have been shown to be useful for constructing quaternary carbons. So the construction of asymmetric molecules with quaternary carbon stereocenters represents a very challenging task. The initiation of enantiomers can be started from an enantiotopic face, which produces an pair of enantiomers 1.14 and 1.15 in Scheme 1.6.

Scheme 1.6

Asymmetric induction of D-A reactions may be achieved by using chiral dienophiles, chiral dienes or chiral catalysts. The use of a diene and/or a dienophile with a chiral auxiliary is a common technique to make chiral dienes and dienophiles. In the reaction of cis-2-neopentyloxyisobornyl acrylate 1.17 with cyclopentadiene 1.16,18 virtually quantitative asymmetric induction can be explained by the staggered conformation of the neopentyloxy chain, in which the re-face is shielded by the t-butyl group (Scheme 1.7).

Scheme 1.7 The chiral dienes have been investigated less extensively because of the difficulty of connecting a chiral group to the diene. A useful example has been developed by Trost et al. by using an (s)-O-methylmandeloxy group as a chiral inducing agent to get a chiral diene (Trost diene) 1.19,19, 20 which was described to be the first synthetically useful chiral diene (Scheme 1.8).

An interesting result was reported by Danishefsky’s group about asymmetric Diels-

Alder reactions. They observed the dramatic increase of de value from 50% to 95%

21 (1.20), which was obtained by the combination of chiral diene and catalyst (+)-Eu(hfc)3.

(Scheme 1.8)

Scheme 1.8

A series of levoglucosenone-derived chiral dienophile auxiliaries (1.21) were prepared by the Alejandra G. Suliez group.22 They showed efficient regio- and diastereoselectivities in Diels-Alder reactions (Scheme 1.9).

Scheme 1.9 The use of a chiral catalyst to control the absolute configuration of the product is the most efficient and economical way to introduce enantioselectivity in a reaction. This approach allows the direct formation of chiral compounds from achiral substrates under mild conditions and requires relatively small amounts of enantiopure material, without the removal and recovery of a chiral auxiliary.23, 24 Many chiral Lewis acid catalysts were reported such as B, chiral acyloxy borane catalyst,25-27Al, Cu, Fe, Yb28-31 and Ti32

Lewis acid catalysts.

Scheme 1.10 11

Various chiral Lewis acids have been tested to catalyze D-A reactions.33 However, many reactions of this type employ cyclopentadiene 1.16 as the diene and 2-alkyl acrolein derivatives as the dienophile (Scheme 1.10). There are many examples, that involve more intricate dienes or dienophiles.

Other chiral organic catalysts have been reported recently. Li Deng reported a cinchona alkaloid-derived bifunctional organic catalyst (OD), which showed high enantioselectivity and diastereoselectivity in D-A reactions with pyrones 1.29 (Scheme

1.11). The highest ee value is 94% and exo to endo is 93:7.34

Scheme 1.11

Wanbin Zhang reported a series of catalysts containing C2-symmetric bipyrrolidines which were efficient in asymmetric Diels-Alder reactions ( Scheme 1.12).35

Scheme 1.12

Kikuchi synthesized (R,R) ferrocenyl pinacol via Sm(OTf)3 which showed good potential in asymmetric Diels-Alder reactions (Scheme 1.13).36

Scheme 1.13

1.2 Brief Review of Recent Boronate Substituted Dienes

Organoboron compounds were not attractive until the extraordinary works of two

Nobel Prize winners: H. C. Brown and W. N. Lipscomb. They started the promising work of the organoboron area by the discovery of hydroboration of alkenes and alkynes, which leads to terminal boronate compounds.37, 38

Organoboron compounds are excellent precursors in organic synthesis. As the bridge to construct different organic compounds by Suzuki coupling, rhodium catalysis and various reactions, boron compounds have lots of advantages: readily available, easily handled, some are stable in air and at room temperature, and the apparatus for handling these compounds is simple. Also, boron compounds usually have no extreme toxicity hazards although we need to treat them with care and avoid ingestion or contact.39

The traditional synthesis of aryl- and alkenylborates are from Grignard reagents or lithium reagents and trialkyl borates.40 The general synthetic methods for preparing boron compounds are transmetallation, hydroboration and haloboration.40-42 They are still the basic methods for preparations of organoboron compounds nowadays(Scheme 1.14).

Scheme 1.14 The common boron substrates are chosen from a wide range of compounds such as

BCl3, B(OR)3 and BF3·O(CH2CH3)2 . Due to the problem of formation of trialkylboranes in the procedure of Grignard or organolithium reagents boronation, H. C. Brown proved that triisopropyl borate is the best available alkyl borate to avoid the multiple alkylation of the borates (Scheme 1.15).37, 43

Scheme 1.15

Hydroboration can be conducted in very mild conditions via a cis anti-Markovnikov manner (Scheme 1.16).38

Scheme 1.16 Haloboration (Scheme 1.17) of terminal alkynes is an effective way to synthesize 1- alkenyl borates followed by the displacement of the β-bromine with organozinc reagents, which proceeds strictly with retention of configuration.

Scheme 1.17

Some other methods also were reported (Scheme 1.18).42

Scheme 1.18 Methods for preparation of organoboron dienes have been explored for a long time.

This dissertation briefly introduces some of the recent developments in this area.

High regioselectivity and stereoselectivity are always the goal scientists want to achieve in D-A reactions. Heteroatom substituents can be placed on either the dienophile or diene partner to get higher regioselectivity and stereoselectivity compared with unsubstituted or alkyl substituted ones. That is also the goal of many substituted dienes such as cobaloxime dienyl complexes,44-46 molybdenum and tungsten substituted dienes47, 48 and silane and boron substituted dienes.49-52

1.2.1 Preparation and Reactions of 1-Boron Substituted-1,3-Dienes

Most reported boron substituted dienes are 1-boron substituted-1,3-dienes, especially many 1-(dialkoxyboryl)-1,3-butadienes, sometimes termed 1,3-dienyl-1-boronates, which can be easily prepared by hydroboration of enynes.53-56 Numerous reports of their Diels-

Alder/allylation reactions have been published and this sequence is usually called the

Vaultier tandem sequence. (Scheme 1.19)

Scheme 1.19 The sequence is very useful in the synthesis of clerodanes (Scheme 1.20).57 However, this 1,3-dienylboronate has to react with activated dienophiles, which limits the wide

application of this sequence. Various strategic approaches were performed to overcome this problem. A stoichiometric amount of CsF was used to generate electron rich complexes which were more reactive in cycloaddition (Scheme 1.21).54

Esterification of boronic acids with simple alcohols (primary and secondary) is also a widely used method to get 1-boron substituted 1,3-dienes.43 Organoboronic acids and their esters have attracted much attention due to their practical usefulness for synthetic organic reactions, molecular recognition such as host-guest compounds, and tumor treatment.58 However, there have been very few new developments in the methodology for their preparation.

Scheme 1.20

Scheme 1.21 Ishiyama’s group used palladium and platinum catalyzed borylation of alkenes, alkynes and organic electrophiles with B-B compounds to synthesize organoboronic esters from simple organic substrates (Scheme 1.22).58 But there is only one example to form a 1- pinacol boron substituted-1,3-conjugated diene 1.50.

Scheme 1.22 Some dimetal substituted dienes can be transformed into several new compounds via cross coupling reactions at both metal sites, which demonstrate a potentially wide use in organic synthesis. 1-boryl-4-silyl(stannyl) substituted-1,3-dienes (1.52, 1.56) were synthesized by Naso’s59 and Coleman’s groups (Scheme 1.23).56

Scheme 1.23 1-Boron-substituted-1,3-dienes are usually easily prepared by the hydroboration of an enyne.60 In 1999, Barrett and co-workers used this method to get a 1,3-dienylboronate, which was hydrolyzed to dienyl boronic acid 1.58 and used in a cross coupling reaction

(Scheme 1.24).61 In 2002, Prandi and Venturello reported another way to prepare the dienyl boronic ester1.60 from ,-unsaturated acetals 1.59 (Scheme 1.25).62 These derivatives can be readily reacted with aryl substrates in very mild conditions to get aromatic ketones.

Scheme 1.24

Scheme 1.25

Vaultier and Mortier reported a palladium catalyzed cross coupling of alkenyl zincs and bromo boronate alkenes 1.61 to produce boronate substituted dienes 1.62. These dienes can be used in both intra and intermolecular D-A reactions (Scheme 1.26 ).14

Scheme 1.26

Scheme 1.27 RajanBabu found an efficient way to synthesize 1,4-disubstituted borylstannyl dienes

1.66 by borostannylation of an alkyne (Scheme 1.27).63 These bimetalated alkenes and dienes were used in the Suzuki-Miyaura cross coupling reactions to prepare the polyene side chains of some natural products.

1.2.2 Preparation and Reactions of 2-Boron Substituted-1,3-Dienes

Few reports were found on the preparation of 2-boron substituted-1,3-dienes in contrast to the 1-boron substituted-1,3-dienes prior to 1998. Limited use of early members of this class of compounds is presumably due to their high affinity towards dimerization even at room temperature (Scheme 1.28).14,64

Scheme 1.28 Wrackmeyer and Vollrath reported 2-boron substituted 1,3-dienyl systems in 1998 by the reaction of 1-propyl-1-boroindane 1.69 and dimethyl-di(1-propynyl)silane

generating a 1:0.8:0.6 mixture of siloles (1.70-1.71) (Scheme 1.29).65Also, they obtained diallylborane substituted alkenes through the reactions of triallylborane 1.73 and trialkyl

(1-alkynyl) tin compounds (Scheme 1.30). They found triallylborane proved to be much

65 more reactive than triethylborane (Et3B).

Scheme 1.29

Scheme 1.30 The Welker group got an unusual hydrolysis/oligimerization reaction of a boron substituted-1,3-diene to produce a product named 6,9,16,19-tetraphenyl-5,15-distyryl-

3,13,25,26-tetraoxa-2,12 diborapentacyclo[16.2.2.28,11.12,5.112,15]hexacosa-1(20),7,10,17- tetraene 1.80 ( Scheme 1.31). 53

Scheme 1.31 The formation of the macrocycle was rationalized by a protonolysis of some of the boron carbon bonds in 1-phenyl-1,3-dienyl-3-potassium trifluoroborate 1.77 to generate some 1-phenyl-1,3-butadiene 1.79.66 The terminal double bond of one 1-phenyl-1,3- butadiene molecule obviously participated in an electrophilic addition reaction with the internal alkenes of a second molecule of 1-phenyl-1,3-butadiene after the oxidative reactions . Then the terminal double bond of this second molecule of 1-phenyl-1,3- butadiene participated in a Diels-Alder reaction with a boron substituted diene to get final product 1.78 (Scheme 1.31).

In 2007, Aubert, Vollhardt and coworkers 67 reported a cobalt(I)-mediated preparation of polyborylated cyclohexadienes 1.83 by intermolecular CpCo mediated [2+2+2] cocyclizations of alkynylboronic pinacolate esters 1.81 with alkenes, followed by oxidative demetallation with iron (Ш) chloride (Scheme 1.32).

Scheme 1.32 Trimetal substituted dienes also were synthesized in 2005 by Yusuke’s group (Scheme

1.33).68 The tetrasubstituted dienes 1.86 are prepared by the ruthenium-catalyzed double addition of trimethylsilyldiazomethane 1.84 to alkynes developed by Dixneuf and coworkers by use of alkynylboronates 1.85 instead of alkynes. The tetrasubstituted dienes can be converted into multisubstituted 1,3-butadienes including those having four different organic groups at the 1-, 2-, 3- and 4-positions which have good potential in organic synthesis.

Scheme 1.33 In 2005, Kim and Lee realized the functionalization a variety of vinyl boronate 1.88 containing 1,3-dienes through boron-directed regio- and stereoselective enyne cross

metathesis.69 In the reaction, high chemical yield and regioselectivity were achieved irrespective of substituents on the alkyne and alkene counterparts, whereas Z/E- selectivity was found to be dependent upon the substituents both on the alkyne and alkene.

(Scheme 1.34)

Scheme 1.34 John Soderquist’s group has prepared chiral trans-2-boroyl-1,3-dienes 1.88, which can be used in asymmetric allyborations to provide β-substituted nonracemic chiral homoallenic carbinols 1.90 (Scheme 1.35).70

Scheme 1.35

1.3 Suzuki-Miyaura Cross Coupling Reactions

The most utilized C-C bond forming cross coupling reactions are probably the Heck,

Stille and Suzuki-Miyaura reactions.71 In these reactions, palladium is a tremendously effective catalyst which also plays an important role in a general catalytic cycle (Figure

1.5 ).71 This mechanism explains most cross coupling reactions including oxidative addition of halide, transmetallation and reductive elimination. The Suzuki-Miyaura reaction is preeminent due to its compatibility with a diverse range of functional groups.

It also has good tolerance to the presence of water and proceeds generally with good regio- and stereoselectively with a non-toxic inorganic by-product which can be easily removed from the reaction mixture. Therefore, the Suzuki coupling has been used not only in the lab but also in industrial processes.72, 73

Figure 1.5 General Catalytic Cycle for Suzuki-Miyaura, Heck And Stille Cross-Coupling Reactions

In Suzuki-Miyaura reactions, oxidative addition is usually the rate determining step in a catalytic cycle that affords a stable trans-σ-palladium (B) complex. However, Gebbink reported recently that transmetalation is the rate determining step when they used

Dendriphos ligands in Suzuki cross-coupling reactions.74 The relative reactivity of oxidative addition decreases in the sequence of I > OTf > Br >> Cl for the halide compounds. The structure of alkenyl halides can be preserved in the final products but the inversion effects for allylic and benzylic halides were observed.42 Bulky and electron donating ligands, which generate an electron-rich metal complex, were found to make palladium complexes more reactive in oxidative addition reactions.75

Transmetallation is the hardest step to control in practical experiments since its mechanism still remains obscure and highly dependent on organometallics or reaction conditions used for the couplings.72 In the presence of a negatively charged base, the transmetallation between organopalladium halides and organoboron compounds apparently is accelerated. The reason is that the quaternization of boron with a negatively charged base enhances the nucleophilicity of other organic groups on boron. Thus, the role of the base is to facilitate the slow transmetalation of the boron compounds by forming a more reactive boronate species that can interact with the Pd center and finish transmetalation.76, 77 There is another explanation for the effects of base that the base replaces the halide in the coordination sphere of the palladium complex and facilitates an

78 intramolecular transmetalation (path B). The bases often used are K3PO4, K2CO3, KOH and KF. There is no general rule for the selection of bases except experience.

Figure 1.6 General Catalytic Cycle for Suzuki-Miyaura Couplings Reductive elimination regenerates the palladium (0) complex after the isomeration of the trans form of palladium complex (C) to the corresponding cis-complex (Figure 1.5).79

Figure 1.7 Reductive Elimination of Suzuki-Miyaura Couplings

It is generally accepted that this step is faster when palladium is coordinated to electron-withdrawing and sterically bulky ligands. It has also been shown that for very bulky ligands, the steric properties dominate over the electronic properties.78

1.4 Rhodium Reaction

The newly developed reaction of rhodium catalyzed 1,4-addition of substituted boronic acids to enones has progressed rapidly in the last 10 years. The reaction was discovered in 1997 by Miyaura and other chemists.80, 81 After that, many subsequent reports have appeared.82 Asymmetric carbon-carbon bond forming is very important in asymmetric synthesis but in most cases it is difficult to achieve high yields and excellent enantioselectivities. However, the 1,4-addition of enones by boronic acids provides a good way to this goal. It is already a powerful method to achieve stereoselective C-C bonds and quaternary stereocenters.

1.4.1 Advantages of rhodium catalyzed 1,4-addition of enones

The reaction (Scheme 1.36) has several advantages over other 1,4-additions.83

In this reaction, the organoboronic acids are not so sensitive to oxygen and moisture compared with some other organometallic reagents, such as substituted boron esters.

Therefore, one can conduct reactions in protic media or aqueous solution, which is a good choice for the requirements of green chemistry. The organoboronic acids are much less reactive toward enones without a rhodium catalyst. Thus, we prevent the 1,2-addition to enones by adding the rhodium catalyst.

Groups connecting to boron are generally added to the  position with high enantioselectivity. Both chiral ligands and chiral substituted boronic acids can be used as a chiral resource to generate a new chiral center with high stereoselectivity. The reaction has a large scope for substrates not only for ,-unsaturated ketones, but also for ,- unsaturated aldehydes, esters, amides, imides, 84 and even some metal connecting unsaturated ketones.

Scheme 1.36 Different rhodium catalysts, various ligands and the bases are used in this reaction.

Most rhodium catalysts contain BINAP groups83, 85or BINAP derivatives, which are

83 essential for the generation of chiral centers e.g. [Rh(OH)(S)-binap]2. Because the temperature influences the hydrolysis of boronic acids, usually excess boronic acids are used. A detailed process of the reaction is also shown in Scheme 1.37.86

1.4.2 Catalytic Cycle and Mechanism

The catalytic cycle of phenylboronic acid addition to 2-cyclohexenone was reported in experiments by Hayashi in 2002. (Scheme 1.37) 86 In this cycle, the phenyl rhodium is generated by transmetallation between phenylboronic acid and rhodium complex. Then insertion of the C=C bond of the enone into the phenyl-rhodium bond followed by the isomerization generated a stable oxa--allylrhodium complex. Hydrolysis converted the oxa--allylrhodium into the final product.

Scheme 1.37

1.4.3 Reaction Properties

Ligand Effects

In the first stage, Miyaura’s work was focused on the non-asymmetric 1,4-addition of aryl- and alkenyl-boronic acids to ,-unsaturated ketones.81 Research followed by other chemists which was rapidly transfered to asymmetric synthesis. Among several factors that can influence the stereoselectivities, the chiral ligand has crucial effects on the enantiomeric excess (ee) value and yields. This dissertation only discusses the two most used ligand groups : BINAP and [2.2.2] bicyclooctadiene and their derivatives.

(a) 1,1’-Binaphtyl ligands and its derivatives : (R)or (S)-BINAP(2,2'-bis

(diphenylphosphino) -1,1'-binaphthyl) and some phosphorus ligands.

BINAP is a chiral bisphosphine ligand, which consists of two naphthyl groups linked by a single bond with diphenylphosphino groups at the end of each naphthyl group

(Figure 1.9). Although BINAP has no stereogenic center, it is a chiral molecule. Rotation about the single bond binding the two naphthyl groups is restricted because of the rigidity of their π systems. Almost all 1,4-addition reactions using the BINAP groups produced good yields and over 90% enantioselectivity.87, 88

Some new applications of BINAP ligands employed since 2003 are also demonstrated in Figure 1.8.

Figure 1.8 Applications of New BINAP Ligands (b) Phosphine-olefin are novel types of chiral ligands with potential in asymmetric synthesis. Kasak et al.89 reported their application in conjugate addition of boronic acids to unsaturated esters (Scheme 1.38). They got reasonable yields (up to 88%) and 98% ee.

The mechanism is the same as shown in Scheme 1.37 and an intermediate structure was suggested in Scheme 1.38. The bulky ligand completely prevented the Ar- attacking from the back so as to attain 98% pure (S) product .

Scheme 1.38 Hayashi and coworkers used (R)-Segphos and (R)-P-Phos in the reaction of 1,4-

90 addition of unsaturated esters (Scheme 1.39). Ligand (R)-Segphos and Rh(acac)(C2H4) produced the chiral rhodium catalytic system, which gave the (R)-4-arylchroman-2-ones in over 99% ee. Compared with (R)-Segphos, (R)-BINAP and (R)-P-Phos showed lower reactivity in this reaction. Furthermore, this reaction also showed the temperature influence. 60C was the proper temperature since excess boronic acids were used. At higher temperature (100C), phenylboronic acids were prone to hydrolyze faster leading to the lower yields (70-82%) but same ee value (99%). Lower temperatures (50C) can activate catalysts and substrates efficiently (86% yield and 99%ee).

Other ligands like monodentate phosphoramidites were a good choice for rhodium catalyzed conjugate addition of aryl- and vinyltrifluoroborates.91, 92 High diastereoselectivities were achieved in the reaction. (up to 84% yield of diastereoisomers separated).

Scheme 1.39

Defieber and Norihito proved the [2.2.2] bicyclooctadiene93, 94 is an excellent ligand

(Scheme 1.40) and it can achieve 90% yield and 58% ee at room temperature. At higher temperature (50C), it produced 83-96% yield and 94-97% ee. Conjugate addition to cyclopentenone is difficult to effect with high selectivity but they succeeded using [2.2.2] bicyclooctadiene as a ligand.

Scheme 1.40

Scheme 1.41 (R,R)-Ph-bod* used in the reaction of Scheme 1.41 demonstrated excellent potential to be a chiral ligand in this kind of reaction. Similarly, steric repulsions again cause the generation of (R) product. 94

Different ,-unsaturated Ketones

Rhodium catalyzed 1,4-addition of boronic acids to enones can be applied in large scale for different substrates and some of them are shown below.95, 96 Ryo et al. synthesized chiral organosilicon compounds through this reaction using (R,R)-Bn-bod*as a ligand. Yields and ee values are both satisfying (80-94% yield, >93% ee) (Scheme

1.42).97 In this reaction, ligands (R)-BINAP, (S)-phosphoramidite are inferior compared with (R,R)-Bn-bod. *. Paquin and coworkers used ,-unsaturated Weinreb amides

(Scheme 1.43) as substrates and got high enantioselectivity.98 Substituted pyridines used in this reaction produced a satisfactory yield of 98% (Scheme 1.44).99

Scheme 1.42

Scheme 1.43

Scheme 1.44

Water and Base Effects

In the rhodium-catalyzed 1,4-addition of organoboron reagents to unsaturated ketones , protic solvents have a strong effect on the hydrolysis of oxa--allylrhodium which gives the final product.83 Water is the typical protic solvent in this reaction and accelerates the reaction. Generally, solvents used in this reaction are mixtures of water and dioxane.

Yasuhiro et al used heterogeneous catalysts ( rhodium complexes immobilized on the

100 polymer) in water catalyzing 1,4-addition of ArB(OH)2. Up to 93% yield was attained and the catalysts can be recovered and reused for 3 times.

The reaction is strongly inhibited by acid.101 Both protic acids and Lewis acids act as strong inhibitors. Introduction of base can remarkably enhance the reaction speed. A proposed active intermediate is L2RhOH generated in-situ and accelerates transmetallation (Scheme 1.45).

Scheme 1.45 The Rh(I) catalyzed conjugate addition of substituted boronic acids offers a general solution for the synthesis of chiral compounds as mentioned before. However, in certain conditions, 1,2-addition occurs competing with 1,4-addition in unsaturated aldehydes

(Scheme 1.45).102

Different ligands lead to different reaction directions. Generally speaking, the polarization of the C-Rh bond plays a key role in the competition. Donating ligands increase the nucleophilicity of the organic group on the rhodium metal. t-Bu3P does not catalyze the conjugate 1,4-addition seletively but produces 1,2-addition product. A reasonable catalytic cycle is shown in Scheme 1.46.102 Transmetallation is the key step in the cycle. Because the dppf complex is more Lewis acidic than the tert-butylphosphine complex then coordination of dppf complex and the nitro group retards the addition to nitrobenzaldehydes.

A fine-tuning for the enantioselectivity by changing various ligands’ R groups is shown in Scheme 1.47.98 It is a potential way to control the 1,2- and 1,4-addition by changing the ligands too.

Scheme 1.46

Scheme 1.47 A chemoselective reaction of 1,6-addition to 2,4-dienoate esters was reported by Csaky et al.95 Changes of starting dienoate materials and organoboronic acids resulted in different reaction paths (Scheme 1.48).

Scheme 1.48 The rhodium catalyzed asymmetric 1,4-addition of organoboron reagents provides a perfect method for enantioselective introduction of aryl and alkenyl groups to the  position of electron deficient olefins. Since it holds many advantages in asymmetric synthesis, a promising future for its further application in various fields such as total synthesis, pharmaceutical areas and environmental chemistry is possible. More research of this reaction can be focused on the following:

1. Although protic solvents can promote environmentally friendly chemistry development, we have to consider that the 1,4-addition products are hydrolyzed compounds. If we can get boron enolates as the product, the application scope will be enlarged.83 Therefore, aprotic polar solvents may be a good choice.

2. Different ligands have different enantioselectivities in various reactions. The research in this area is still a hotspot.

3. Water as solvent and heterogeneous catalysis in water are also attractions for green chemistry workers. Especially asymmetric synthesis of heterogeneous catalysts in water is a challenge. There are few reports about organometallic substrates in this reaction.

Research in this area is also promising. 1,2-and 1,4- addition competition is a good method for chemists to design and control reaction products by tuning the ligands, solvents and other factors.103

1.5 Aims of Current Project

Previous research by our group showed the superiority of 2-metal substituted 1,3-dienes to 1-metal substituted 1,3-dienes104 both in terms of rate enhancement and stereoselectivity in D-A reactions. As 2-boron-substituted dienes have wide applications in D-A and cross coupling reactions, which will lead to decalin core structures synthesis, our project will focus on their synthesis and cross coupling reactions. The other reasons that we selected boron substituted dienes are the wide varieties of protocols in their preparations, air and moisture stability, and easy handling and storage relative to other main group metal substituted dienes.

However, the synthesis of 2-boron substituted dienes had proved difficult according to the research of other groups since they all obtained a dimerization product of diene by self D-A reactions.105,64 The current project begins with the synthesis and purification of

2-boron-substituted dienes. Although many different types of organoboron species are known in the literature, dienyl borates are rarely reported because they are easily

polymerized in the preparation process and difficult to separate by the usual silica gel column chromatography.

The long term goal of this project is to apply the methodology to access substituted cis- fused decalin core structures that are otherwise difficult to make. Many natural products have the decalin core, such as clerodane diterpenoids.106 Although reports in the trans- clerodanes are abundant, cis-clerodanes syntheses are rare. Since we have already shown the exo selective cobalt mediated D-A reactions could be used to synthesize cis-fused bicyclic compounds related to known diterpenes, the same trends are expected to be applicable to our main group substituted dienes.

CHAPTER 2 Preparation of Boron Substituted Dienes

2.1 Results and Discussion

2.1.1 Preparation of 2- Diethanolamine Borate Diene 2.4 And 2.6

Previous Welker group member Subhasis De prepared a monomeric 2-BF3-1,3-butyl diene in high yield and studied its D-A/cross coupling reactions under mild conditions.49

This dienyltrifluoroborate also showed a high activity in rhodium catalysis. Therefore, dienyltrifluoroborate can serve as a potential building block for the construction of other complex molecules.

However, the purification of boron compounds is still a most difficult task. The dienyltrifluoroborate is anionic with low organic solvent solubility. We began to search for other neutral boron compounds. Diethanolamine dienylboronates (2.4) seemed reasonable because they have a nitrogen lone electron pair donating to the boron atom generating an electron rich diene.

In the first attempt at the preparation of diethanolamine dienylboronates we used the dienyl trimethoxy boronate to react with diethanolamine in THF. We did get the product

(2.4) (NMR) but we could not separate it from the hard solid reaction mixture (Scheme

2.1). After that, efforts were made to prepare 2.4 via a direct esterification route from dienyl boronic acid (2.5) and diethanolamine.

Scheme 2.1 In the preparation of the series of diethanolamine boronate-1,3-butadienes, we found that when N-phenyl diethanolamine reacts with boronic acid, there is no desired product observed by NMR. The benzene ring may conjugate with the lone pair electrons of nitrogen resulting in the failure of formation of the N-B bond. A series of 11BNMR were performed on BF3 substituted diene and diethanolamineborate-1,3-butadienes under different temperatures. Diethanolamine boronate-1,3-butadiene (2.4) was found to have a stronger N-B bond than N-methyl diethanolamine boronate-1,3-butadiene(2.6). When the temperature was raised gradually to 60oC, there is only one boron peak in diethanolamine boronate-1,3-butadiene but an extra small peak appears in N-methyl diethanolamine boronate-1,3-butadiene, which is consistent with some N-B bond equilibration at higher temperature.107-109 Also, when the similar N-donating group 2.41 (3,3’-

(methylazanediyl)dipropanoic acid)) was tried in a similar way, no product was detected by NMR and GC-MS.

Scheme 2.2

2.1.2 Resolution of Dimerization Problems and Preparation of Tri- Coordinated and Tetra-Coordinated Boron-1,3-Dienes

After the successful preparation of non-ionic 2-boron substituted-1,4-dienes, the same methods have been tried to synthesize other non-ionic 2-boron substituted-1,4-dienes. But

Diels-Alder dimerization was reported by Carreaux in 2002, which indicated that 2- pinacol borate-1,3-diene has a high propensity of dimerization.64 Also, several groups have reported that for 2-substituted-1,3-dienes, they have a high propensity for dimerization through self Diels-Alder reactions (Scheme 2.3).110, 111 Diene 2.38 and 2.40 all dimerized to yield dimers 2.39 and 2.41.

Scheme 2.3 From the calculation of Carreaux,64 2-boryl-1,3-butadienes are more active dienophiles than 1,3-butadienes and the double bond closer to the boron atom is more reactive in a thermal cycloaddition. Para-selectivity predominates in the final product, which is the same result of dimerization of 2-carboxymethoxybutadiene.111(Scheme 2.4)

The reductive dechlorination of the pinacol ester of the (1,4-dichloro-2-buten-2- yl)boronic acid in dry DMF was used to obtain the monomer of 1,3-butadien-2-yl) boronate in the presence of CrCl2. Even though it was performed at room temperature, the dimerization occurred and the final product turned out to be dimer in 75% yield.

When we tried to use the same procedure used to prepare 2.4 to obtain pinacol ester of 2-

boryl-1,3-butadiene 2.37 in CHCl3, which is a good solvent for the synthesis of diene 2.4 and 2.6, we obtained the same product as Carreaux’s group (Scheme 2.5).

Scheme 2.4

Scheme 2.5

This result led us to suspect the high temperature (62oC) to be the main cause of the dimerization in this procedure, so the milder conditions were explored by employing sodium sulfate, molecular sievse and resin as dehydration reagents at room temperature or higher (Scheme 2.6).

Scheme 2.6 Kabalka’s group used a Dean-Stark apparatus to remove water from the refluxing system and then KOH was added to form the cyclic triolboronate 2.20 (Scheme 2.7).112

Scheme 2.7 However, when the same method was attempted to get tetra-coordinated boron substituted dienes, the high temperature proved to be a problem. We could not get the

desired product 2.40; only decomposed compounds were obtained at 50 oC and no monomer of 2-boron substituted dienes was found at low temperatures (Scheme 2.7).

Before sodium hydride was tried in this procedure, it was suspected that a very strong base, which would enhance the dimerization of monomeric dienes. But the final results surprisingly showed NaH is the perfect reagent to synthesize the monomeric dienes 2.36-

2.39 (Scheme 2.8). Also, the preparation of an ionic 2-boron substituted diene 2.40 was also achieved with a good yield.

Scheme 2.8

2.1.3 Conformation Analysis of 2-Boron Substituted-1,3-Dienes

Further investigation of the conformation of the five dienes in Scheme 2.8 reveals an interesting result. From NOESYspectra in Appendix B, the σ bond between C2 and C3 in dienes 2.36, 2.38, 2.39 is rotating in deuterated DMSO, but for dienes 2.37 and 2.40, s- trans predominates over s-cis in solution (Scheme 2.9). The rotation around the σ bond between C2 and C3 in diene 2.37 may be sterically hindered by the four methyl groups close to boron. The bulky triol group in diene 2.40 maybe behave similarly.

Scheme 2.9

2.2 Attempts to Synthesize Other Boron Substituted Dienes

2.2.1 Attempts to Synthesize Sodium 1-(but-1,3-dien-2yl)-5-methyl-2,8,9- trioxa-1-borabicyclo[3,3,1]nonan-1-uide) The nucleophilicity of a boron atom is enhanced significantly by quaternization with an anionic ligand.113 The cyclic triolborates are exceptionally stable in air and water.

Moreover, they are more soluble in organic solvents than potassium trifluoroborates. So, we attempted to prepare tetracoordinated organoboron complexe 2.26 expecting the tetra-coordinated boron atom to increase the electron density of diene by the following sequence:

Scheme 2.10 However, we only obtained an intermediate product 2-(buta-1,3-dien-2-yl)-1,3,6,2- dioxazaborocane (2.25) and failed in the last step in which we suspect the high steric strain of the ring destabilizes the whole structure.

2.2.2 Attempts to Synthesize 2-(Buta-1,3-Dien-2-yl)-6-Methyl-1,3,6,2 - Dioxazaborocane-4.8-Dione

Scheme 2.11

In this reaction, esterification of the boronic acid failed at low temperature (rt) and high temperature (refluxing ) caused the decomposition of diene. The reason is the same as discussed above: the N-electron withdrawing group destabilized the structure. We also tried the di-sodium salt of N-methyliminodiaacetic acid 2.43 to react with boronic acid in refluxing CHCl3 (Scheme 2.12). However, we did not get 2.27 but rather decomposed diene.

Scheme 2.12

2.2.3 Attempts To Synthesize 1-Phenyl-2-Pinacol Boronate-1, 3-Diene

Billingsley et al. used iodobenzene via Suzuki coupling to prepare a boronate substituted benzene.114 They used high temperature (refluxing) and stable iodo compounds to get product 2.28. We attempted to prepare a similar product, diene 2.29, employing the same procedure but failed (Scheme 2.13). The reason might be the decomposition of unstable iodo diene 2.42 at high temperature. We tried refluxing and appeared to get polymerization. Finally, chloro diene was also tried but no positive results were obtained.

Scheme 2.13

A borylation procedure similar to Scheme 2.1 was tried. We did not get 2.45, 2.44 failed to transmetallate to Grignard reagent. Probably, the reason is the thermodynamic instability of 2.44 and decomposition occurred when the temperature was above 55˚C。

Scheme 2.14 In 2004, Grubbs reported the synthesis of a vinyl borate 2.31via n-butyllithium reacting with vinyl iodide and pinacol borate.115

Scheme 2.15 The same procedure was performed in the following reaction and iodo diene was found to be very reactive in the exchange of lithium and iodine, which led to a dimer of diene

2.33 by GC (Scheme 2.16).

Scheme 2.16 Cross coupling was also tried with this isopropoxy pinacol borate reagent but instead we isolated an isopropoxy substituted diene 2.35 (Scheme 2.17).

Scheme 2.17

2.2.4 Attempts To Synthesize 1-Substituted-2-Boron-1,3-Dienes By Cross- Metathesis

Olefin cross-metathesis is a powerful synthesis tool for the preparation of functionalized alkenes due in large part to the N-heterocyclic carbene groups in Grubbs catalysts.116 Grubbs catalysts have been extensively investigated in olefin cross metathesis and enyne cross metathesis.117-119 Because a multitude of factors influence olefin reactivity in cross metathesis, we investigated the different Grubbs catalysts and olefins in different conditions to carry out vinyl boronate metathesis. According to the research of Chatterjee and Grubbs, vinyl boronates usually react with any terminal olefins very quickly.116, 120 In the research of Crowe and Goldberg, styrenes are electron deficient partners in CM reactions matching with some electron rich olefins. Since

conjugated vinyl boronates are electron rich, we tried the route as a simple reaction to hopefully produce boron dienes (Figure 2.1).116

Figure 2.1 Mechanism of Ruthenium Catalyzed Cross Metathesis Reactions

Table I Attempts for Olefin Cross Metathesis Reactions

Entry Catalyst R1 R2 T Time

(h)

1 Grubbs 2nd Ph rt 20

nd 2 Grubbs 2 rt 20

3 Grubbs 2nd Ph rt 20

nd 4 Grubbs 2 rt 20

5 Grubbs 2nd Ph rt 12

6 [1,3-Bis(2-methylphenyl)-2- Ph rt 20 imidazolidinylidene]dichloro(benzylidene) (tricyclohexylphosphine)ruthenium(II)

7 [1,3-Bis(2-methylphenyl)-2- Ph rt 20 imidazolidinylidene]dichloro(2- isopropoxyphenylmethylene)ruthenium(II)

Grubbs 2nd : [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene] dichloro(phenylmethylene) (tricyclohexylphosphine)ruthenium

Table II Attempts for Enyne Cross Metathesis

Entry R1 R2 T Time(h)

1 BF3K Ph rt 19

2 BF3K rt 19

3 BF3K Ph rt 19

4 BF3K Ph reflux 19

5 BF3K reflux 19

6 Ph rt

7 rt 22

8 Ph rt 22

In Table I and Table II, we just recovered starting materials and no products were found. In this type of reaction, development of novel catalysts of ruthenium may be helpful in the future.

2.3 Conclusion

New methodology has been developed to synthesize 2-boron substituted-1,3-dienes. A series of dienes were synthesized with high yields and stability at -10 ˚C. This method overcomes the difficulties of dimerization through self Diels-Alder reactions of dienes in

previous methods. Synthesis of 1-substituted-3-boron-1,3-dienes through cross metathesis requires new catalysts and methodology to realize the goal.

2.4 Experimental Procedures and Characterization Data

General: The 1H NMR were recorded on a Brucker Avance 500MHz spectrometer and

Brucker Avance 300MHz spectrometer operating at 500.13MHz and 300.13MHz respectively. 13C NMR were recorded on a Bruker Avance 300MHz spectrometer and

Bruker Avance 500MHz spectrometer operating at 75.48MHz and 125.77MHz respectively. Chemical shifts were reported in parts per million () relative to tetramethylsilane (TMS), or the residual proton resonances in the deuterated solvents: chloroform (CDCl3) and dimethyl sulfoxide (DMSO). Coupling constants (J values) were reported in hertz (Hz).

All elemental analyses were performed by Atlantic Microlabs Inc., GA. High resolution mass spectrometric (HRMS) analyses were performed at Caudill Laboratories of University of North Carolina at Chapel Hill and Mass Spectrometry Lab, School of

Chemical Sciences, University of Illinois at Urbana-Champaign.

All reactions were carried out under an inert atmosphere unless otherwise noted. Flash chromatography was performed using thick walled glass chromatography columns and ultrapure silica gel. Ether and pentane were distilled over Na. Absolute ethanol and methanol were used without further purification. THF was purchased from Fischer

Scientific in the form of solvent kegs and purified using the centrally located solvent dispensing system developed by J.C. Meyer. Deuterated solvents were purchased from

Cambridge Isotope Laboratories and dried over molecular sieves. Magnesium sulfate, magnesium small turnings, iodobenzene, 4-iodobenzotrifluoride, 2-iodoanisole, 4-

iodoanisole, ethyl acrylate, N-phenylmaleimide and N-phenyl methyl maleimide were purchased from Aldrich Chemical Company and used as received. 2-Chloro-1,3-diene, 50% in xylene (Chloroprene) was purchased from Pfaltz & Bauer, INC and used as received.

General procedure 1 for preparing 2.4 and 2.6

A mixture of magnesium (1.0 g, 41.1 mmol), 1, 2-dibromoethane (0.5 mL,5.3 mmol), and

THF (10 mL) was refluxed under nitrogen for 15 min to activate the magnesium. To the mixture anhydrous zinc chloride (0.6g, 4.1mmol) in THF (60 mL) was added and reflux was continued for another 15 min. 2-Chloro-1,3-butadiene (4.9 mL, 25 mmol) (density

0.915 g/mL, 50 % in xylene) and 1,2-dibromoethane (0.95 g, 5 mmol) in THF (30 mL) were added dropwise over a period of 30 min. This addition was controlled so as to bring the mixture into a gentle reflux. The color of the contents changed gradually from grayish white to greenish black. The mixture was heated to reflux for an additional 30 min after completion of the addition. The Grignard reagent thus obtained was immediately added dropwise to a solution of trimethoxyborane (4.25 mL, 38.5 mmol) in THF (25 mL) using a double-ended needle. The addition was controlled in such a way that the internal temperature of the mixture was maintained below –60 °C all the time. After completion of the addition, the solution was allowed to warm to room temperature quickly. The cloudy grey colored reaction mixture was stirred for 1 h . To the resulting mixture at room temperature, 0.5 M HCl solution (100 mL) was added. The reaction mixture was extracted with Et2O (2 × 75 mL). The combined colorless clear organic layers were dried over MgSO4, and the volatiles were removed by rotovap (30 °C , 20 Torr) to yield diene boronic acid.

Preparation of 2.4

General procedure 1 was followed to get a diene boronic acid, then the boronic acid was added at once to a solution of diethanolamine (0.8 equiv, 22.5 mmol, 8.411g) dissolved in

THF (100 mL). Sodium sulfate (8 g) was added and refluxed for 6 hours. At the end of the reaction, the flask was cooled to room temperature. Solid Na2SO4 was separated from the solution by filtration. The solution 250 mL was reduced by 200 mL using a rotary evaporator.

A cold bath was used to induce crystallization. After 4 h, the solid was filtered and washed with cold chloroform. The product 2 was obtained as white needles following drying under vacuum (2.40 g, 14.4 mmol, 62.4%).

1 H NMR (300 MHz, CDCl3)  6.51 (dd, J =17.9, 10.9 Hz, 1H-H3), 5.46–5.40 (m, 3H),

4.98 (dd, J=17.9, 1.9 Hz, 1H-H4), 5.18 (s, 1H-H7), 4.05 (m, 2H-H5,9), 3.89 (m, 2H-

13 H5,9), 3.31 (m, 2H-H6,8), 2.76 (m, 2H- H6,8). C NMR (300, MHz, CDCl3)  143.6-C3,

124.3-C4, 114.6- C1, 63.4-C5,9, 52.1-C6,8, the signal of carbon (C2) next to a tetravalent boron is generally not observed due to quadrupolar broadening. 121 Elemental anal. calcd for C8H14BNO2: C, 57.53; H, 8.45. Found: 57.06, 8.44.

Preparation of 1,3-Butadiene-2-diethanolamine borate 2.6

General procedure 1 was followed to get the boronic acid, then the boronic acid was added at once to a solution of N-methyl diethanolamine (0.8 equiv, 22.5mmol, 4.545g) dissolved in THF (100 mL). Sodium sulfate (8 g) was added and refluxed for 6 hours. At the end of the reaction, the flask was cooled to room temperature. Solid Na2SO4 was separated from the solution by filtration. The solution 200 mL was reduced by 150 mL using a rotary evaporator. Pentane (10 mL) was added to precipitate the product and product 2.6 was obtained as a white solid following filtration and washing with cold pentane under vacuum. (2.7 g, 15 mmol, 60%).

1 H NMR (300 MHz, CDCl3)  6.58 (dd, J =17.6, 10.7Hz, 1H), 5.58 (m, 1H), 5.52-5.55

(m, 2H), 4.95 (dd, J=10.9, 2.6 Hz, 1H), 4.09 (m, 2H), 3.99 (m, 2H), 3.09 (m, 2H), 2.96

13 (m, 2H), 2.62 (s, 3H) C NMR (300, MHz, CDCl3)  143.6, 124.3, 114.6, 63.4, 52.1

13C NMR (300, MHz, DMSO)  143.5, 124.0, 113.6, 61.5, 59.8, 45.7

HRMS calcd for C9H16BNO2: 181.1274+Na=204.1172, found M+Na=204.1172

General procedure 2 for preparing 2.36-2.40

A mixture of mixture of magnesium (1.0 g, 41.1 mmol), 1, 2-dibromoethane (0.5 mL,

5.3 mmol), and THF (10 mL) was refluxed under nitrogen for 15 min to activate the magnesium. To the mixture, anhydrous zinc chloride (0.6 g, 4.1mmol) in THF (60 mL) was added and reflux was continued for another 15 min. 2-chloro-1,3-butadiene (4.9 mL,

25 mmol) (density 0.915 g/mL, 50 % in xylene) and 1,2-dibromoethane (0.95 g, 5 mmol) in THF (30 mL) were added dropwise over a period of 30 min. This addition was

controlled so as to bring the mixture into a gentle reflux. The color of the contents changed gradually from grayish white to greenish black. The mixture was heated to reflux for an additional 30 min after completion of the addition. The Grignard reagent thus obtained was immediately added dropwise to a solution of trimethoxyborane (4.25 mL, 38.5 mmol) in THF (25 mL) using a double-ended needle. The addition was controlled in such a way that the internal temperature of the mixture was maintained below –60 °C all the time. After completion of the addition, the solution was allowed to warm to room temperature quickly. The cloudy grey colored reaction mixture was stirred for 1 h . To the resulting mixture at room temperature, 0.5 M HCl solution (100 mL) was added slowly. The reaction mixture was extracted with Et2O (2×75 mL). The combined colorless clear organic layers were dried over MgSO4, and the volatiles were removed by rotovap (30 °C, 20 mm) to yield diene boronic acid.

Preparation of 1,3-Butadiene-(2-propane-1,3-diol)- borate 2.36

General procedure 2 was followed to get diene boronic acid. The dried diene boronic acid was added at once to a solution of propane-1,3-diol (0.7eq, 17.5 mmol, 1.33g) dissolved in THF (100 mL). Sodium hydride (1.5 eq, 37.5 mmol, 0.86g) was added slowly to the mixture at room temperature. The solvent was removed by rotovap after 2 hours. Then dry THF (3×100 mL) was added to dissolve and wash the solid. The solid was removed by filtration and all the solution was removed by rotovap to get the white solid product 2.36 (1.62g, 11.73mmol, 67%).

1H NMR (300 MHz, DMSO)  6.32 (dd, J =17.3, 10.5 Hz, 1H), 5.50 (dd, J=17.3,3.8 Hz,

1H), 5.06 (dd, J=17.3, 5.8Hz, 2H), 4.70 (dd, J=10.5, 3.8Hz, 1H), 3.62 (ddd, J=11.1, 4.3,

2.2Hz, 2H), 3.50 (td, J= 2.6, 11.0, 11.0Hz, 2H), 1.61 (m, 1H), 1.04 (dt, J=2.6, 2.6, 12.2Hz,

1H) 13C NMR (300, MHz, DMSO)  145.5, 113.1, 112.4, 60.4, 30. HRMS: calcd for

C7H11BO2: 138.0852, found 138.08522.

Preparation of 1,3-Butadiene-(2-pinacol)- borate 2.37

General procedure 2 was followed to get diene boronic acid. The dried diene boronic acid was added at once to a solution of pinacol (0.7eq, 17.5 mmol, 2.07g) dissolved in THF

(100 mL). Sodium hydride (1.5 eq, 37.5 mmol, 0.86 g) was added slowly to the mixture at room temperature. The solvent was removed by rotovap after 2 hours. Then dry THF

(2×100 mL) followed by dry diethyl ether (2×100 mL) was added to dissolve and wash the solid. The solid was removed by filtration and all the solution was removed by rotovap to get the white solid product 2.37(1.83g, 10.15mmol, 58%).

1H NMR (300 MHz, DMSO)  6.28 (dd, J =17.5, 10.6 Hz, 1H), 5.40 (dd, J=17.5,

3.4Hz,1H), 5.08(d,J= 6.3Hz, 1H), 4.81 (d, J= 6.3, Hz, 1H), 4.71 (dd, J=10.6, 3.4Hz, 1H),

1.00 (s, 6H), 0.86 (s, 6H) 13C NMR (300, MHz, DMSO)  145.7, 116.5, 112.9, 76.5, 26.7,

25.3 HRMS: calcd for C10H17BO2: 180.1322, found: 180.13217

Preparation of 1,3-Butadiene-(2-(2’,2’-dimethyl-propane-1,3-diol))- borate 2.38

General procedure 2 was followed to get diene boronic acid. The dried diene boronic acid was added at once to a solution of 2,2-dimethylpropane-1,3-diol (0.7eq, 17.5 mmol,

1.82g) dissolved in THF (100 mL). Sodium hydride (1.5 eq, 37.5 mmol, 0.86 g) was added slowly to the mixture at room temperature. The solvent was removed by rotovap after 2 hours. Then dry THF (2×100 mL) followed by dry diethyl ether (2×100 mL) was added to dissolve and wash the solid. The solid was removed by filtration and all the solution was removed by rotovap to get the white solid product 2.38 (1.92 g, 11.55 mmol,

66%).

1H NMR (300 MHz, DMSO)  6.30 (dd, J =17.5, 10.6 Hz, 1H), 5.40 (dd, J=17.5,

3.7Hz,1H), 5.02(m,2H), 4.66 (dd, 10.6, 3.8Hz, 1H), 3.13(s, 4H), 0.91 (s, 3H), 0.54(s, 3H)

13C NMR (300, MHz, DMSO)  145.6, 119.0, 112.3, 32.1, 24.0, 22.7 HRMS: calcd for

C9H15BO2 : 166.1165, found: 166.11652

Preparation of sodium 2-(buta-1,3-dien-2-yl)-6-methyl-1,3,2-dioxaborocan-6-olate 2.39

General procedure 2 was followed to get diene boronic acid. The dried diene boronic acid was added at once to a solution of 3-methylpentane-1,3,5-triol (0.7 eq, 2.34 g,17.5 mmol,) dissolved in THF (100 mL). Sodium hydride (1.5 eq, 37.5 mmol, 0.86 g) was

added slowly to the mixture at room temperature. The solvent was removed by rotovap after 2 hours. Then dry acetone (2×100 mL) was added to dissolve and wash the solid.

The solid was removed by filtration and all the solution was removed by rotovap to get the white solid product 2.39 (2.15 g, 11.03 mmol, 63%).

1H NMR (300 MHz, DMSO)  6.21 (dd, J =17.6, 10.7 Hz, 1H), 5.45 (dd, J=17.6,

3.9Hz,1H), 4.97(d,J= 6.4Hz, 1H), 4.82 (d, J= 6.4, Hz, 1H), 4.64 (dd, 10.7, 3.9Hz, 1H),

3.70 (m, 2H), 3.39 (m, 2H), 1.38(t, J=5.7, 4H), 0.97 (s, 3H) 13C NMR (300, MHz, DMSO)

 145.2, 116.5, 112.3, 64.3, 56.3, 41.4, 34.2 HRMS: calcd for C10H16BNaO3: 218.1090-

Na=195.1192, found: 195.1192

Preparation of sodium 1-(buta-1,3-dien-2-yl)-4-methyl-2,6,7-trioxa-1-borabicyclo(2,2,2) octan-1-uide 2.40

General procedure 2 was followed to get diene boronic acid. The dried diene boronic acid was added at once to a solution of 2-(hydroxymethyl)-2-methylpropane-1,3diol (0.7 eq, 2.10 g,17.5 mmol,) dissolved in THF (100 mL). Sodium hydride (1.5 eq, 37.5 mmol,

0.86 g) was added slowly to the mixture at room temperature. The solvent was removed by rotovap after 2 hours. Dry acetone (3×100 mL) was added to dissolve and wash the solid. The solid was removed by filtration and all the solution was removed by rotovap to get the white solid product 2.40 (2.68 g, 13.13 mmol, 75%).

1H NMR (300 MHz, DMSO)  6.18 (dd, J =17.1, 10.5 Hz, 1H), 5.40 (dd, J=17.1,

3.8Hz,1H), 4.90(dd,J=15.2, 6.0Hz, 1H), 4.65 (dd, J= 10.5, 3.8Hz, 1H), 3.49 (s, 6H), 0.43

(s, 3H) 13C NMR (300, MHz, DMSO)  144.5, 118.0, 113.0, 73.1, 34.4, 16.3 HRMS: calcd for C9H14BNaO3: 204.0934+H=205.1012, found: M+H=205.1012

CHAPTER 3 Diels-Alder Reactions of 2-Boron Substituted- 1,3-Dienes 3.1 Results and Discussion

3.1.1 Diels-Alder Reactions

All the 2-boron substituted dienes were tried in Diels-Alder reactions to test their reactivity with dienophiles. (Table III) Among these dienes, the diethanolamine borate diene (2.4, entry 1) has proven to be significantly more reactive and more regioselective

122, 123 in Diels-Alder reactions compared to its BF3 diene counterpart (Scheme 3.1).

Qualitatively, we initially noticed that whereas the BF3 diene required 16 h of heating at

95-100oC in a sealed tube in toluene with N-phenylmaleimide to obtain >90% yield of cycloadduct, the diethanolamine borate diene (2.4) reacted with this same dienophile to afford a 98% isolated yield of cyclaoadduct 3.1 in Table III after only 15 minutes at

25oC!

Table III Diels-Alder Reactions of 2-Boron Substituted-1,3-Dienes

Tem Tim Yield(%)/ Entr Dien Solven Dienophile p e Product Regioselectivit y e t (oC) (h) y

1 2.4 CHCl 20 0.25 3 98 /NA 3.1

CHCl 20 2 2 2.6 3 90/NA 3.2

toluen 20 3 3 2.40 e 92/NA 3.3

CHCl3 4 2.4 61 6 84/16.4:1 3.4

THF 5 2.4 61 8 95/4:1 3.5

toluen 6 2.6 e 110 20 90/3:1

3.6

toluen 110 20 7 2.6 e 75/3:1 3.7

THF No product NA 8 2.36 20 20

toluen No product NA 9 2.36 e 110 20

toluen 10 2.40 e 100 12 40/2:1(NMR) 3.8

2.40 THF 11 20 12 40/NA(NMR) 3.9

toluen 2.40 12 e 100 12 80/2:1(NMR) 3.13 toluen 2.40 No product 13 e 100 12 NA

toluen No product NA 14 2.37 e 100 12

2.37 THF No product NA 15 20 20

16 THF No product NA 2.38 20 20

THF 40/NA(NMR) 17 2.39 20 20 3.12

toluen 53/NA 18 2.36 e 66 10 (From GC) 3.10

toluen No product (Get NA e diene back) 19 2.37 66 10

toluen 10/ 20 2.38 e 66 10 NA(From GC) 3.11

Scheme 3.1

We tried to get more quantitative rate constant data about this Diels-Alder reaction via

NMR spectroscopy but when we tried to perform this reaction under pseudo first order

o conditions at -10 C, we could only confirm that t1/2 is less than 4 minutes. Attempts to get more accurate kinetic data using NMR at -40oC resulted instead in diene precipitation.

So, the diene (2.4) is by far the most reactive main group element substituted diene we have made in the boron or silicon substituted series to date. What is perhaps even more surprising to us is that in our group, Marcus Wright prepared a cobaloxime substituted diene with a very short half life (t1/2=9.2 min) in Diels-Alder reactions at room temperature. This diethanolamineborate diene is even more reactive than it124 and those cobaloxime dienes consistently favored the s-cis conformation in the solid state (Scheme

3.2).

Scheme 3.2 Diene (2.4) is in the s-trans conformation in the solid state (Figure 3.1) but in this case we suspect that the preference for the s-trans conformer is due to intermolecular hydrogen bonding between the N-H and one of the adjacent molecule’s borate oxygens.

This hydrogen bonding would make a C(2)-C(3) dihedral angle of 50-60o on the order of those we observed in cobaloxime diene solid state structures unfavorable. At 25oC in

CDCl3, we saw no evidence for the s-cis conformer by NOESY (Figure 3.2).

The boron substituted diene 2.4 thus obtained has C1 (5.23 vs 5.04, 4.96 (d6-DMSO) and C3 (6.31 vs. 6.19) H’s which are significantly more deshielded than the BF3 substituted diene. In the solid state (Figure 3.1), C(1)-C(2) and C(2)-C(3) bond lengths 73

were virtually identical in both dienes whereas B-C(2) (1.609(5)Å vs 1.576(13)Å) and

C(3)-C(4) (1.308(6)Å vs 1.279(13)Å) were significantly longer in the diethanolamine borate diene 2.4.

In an effort to further understand this reactivity difference, geometry-optimization with

DFT using the B3LYP functional and a 6-31G(d) basis set followed by population analysis was performed using Gaussian 03 on 2-diethanolaminoborate-1,3-butadiene (2.4) and its BF3 diene counterpart.

Figure 3.1 Crystal Structures of BF3 Substituted Diene and Diethanolamineborate-1,3-Butadiene 2.4 2-Diethanolaminoborate-1,3-butadiene (2.4) has a HOMO energy of -6.00 eV, whereas its BF3 diene counterpart has a HOMO energy of -12.58 eV. These energies are consistent with our observations that 2-diethanolaminoborate-1,3-butadiene (2.4) is more reactive than its BF3 diene counterpart. Furthermore, a Mulliken population analysis indicates a build-up of electron density on carbons C1 and C4 of 0.15e and 0.14e, respectively, in 2-diethanolaminoborate-1,3-butadiene compared to its BF3 diene counterpart, which is also consistent with our observations.

Figure 3.2 NOESY of Diethanolaminoborate-1,3-Butadiene 2.4 In addition to enhanced Diels-Alder reaction rates, we also noted greatly improved regioselectivities (Table III). Whereas the BF3 diene required 36 h of heating to 95-

100oC in a sealed tube in ethanol to provide a 3.3:1 mixture of regioisomers from reaction with ethyl acrylate, the diethanolamine borate diene reacted with this same dienophile at reflux for 6 h to provide a 16.4:1 mixture of para (1,4) to meta (1,3) isomers in identical isolated yield. Similarly, when we used a citraconimide derivative, we isolated cycloadduct (3.5) in high yield although with reduced regioselectivity (4:1). However, the BF3 diene proved unreactive with citraconic acid derived dienophiles. This diethanolamine borate diene (2.4) once again reacted under much milder conditions and with better regioselectivity than highly reactive silicon substituted dienes we have also reported previously.125

Other D-A reactions was tried with dienes 2.6-2.40. Diene 2.6 has a similar structure to

2.4 and it was found to be a reactive diene in D-A reactions with N-phenylmaleimide too

(Table III, Entry 2). After 2 hours, D-A product was formed with a high yield of 90% in

CHCl3. For diene 2.6, CH2Cl2 was not a good solvent since it has a low boiling point in the D-A reactions with di- and trisubstituted dienophiles, ethyl acrylate and 2-methyl N- phenylmaleimide (Entry 6, 7). Diene 2.6 was not reactive in CH2Cl2 after refluxing for

16 hours but was reactive in CHCl3 after 20 hours with a yield of 80%. Toluene is the best solvent in the reaction (90%) compared with CHCl3 because it has a high boiling point and a good solubility for all dienes. In this reaction, regioselectivity (3:1) was found to be lower than diene 2.4.

Diene 2.40 is also a reactive diene in a D-A reaction with N-phenylmaleimide. We can get a complete cycloadduct with a yield of 92% after 3 hours (entry 3) at room temperature. When diene 2.40 reacted with ethyl acrylate and diethyl fumarate, only a 40% yield of product was found from NMR and GC without separation. Cycloproduct was found with 80% yield when it reacted with sterically hindered dienophiles 2-methyl-N- phenylmaleimide and ethyl methacrylate.

Diene 2.36 (entry 8, 18) can react with N-phenylmaleimide to give a 53% yield at high temperature (66oC) and diene 2.38 gives a yield of 10% under the same conditions (entry

20). But for less reactive dienophiles, no D-A products were found (entry 9,14). Dienes

2.37 and 2.39 were found to have no reactivity in D-A reactions (entry 14, 15, 17, 19 ).

According to the results above we can conclude that tetra-coordinate boron substituted dienes are more reactive than tri-coordinate boron substituted dienes in D-A reactions.

When tetra-coordinate boron substituted dienes react with N-phenylmaleimide, fast

reaction rates and high yields were observed. Tri-coordinate boron substituted dienes are less reactive mainly because tetra-coordinate dienes all have an electron donating group or atom enriching the electron density of boron. It eventually enriches the electron density of the whole diene system to promote the HOMO energy and accelerates the reaction rate of D-A reactions.

3.1.2 Dimerization of Boron Substituted Dienes

When D-A reactions were conducted at high temperatures, we noticed that no dimers of boron substituted dienes were observed in NMR. This interesting result is different from previously reported work as discussed in the Introduction.64, 95,103 From Table IV, only a trace of dimers were observed from GC. The results showed that after the formation of monomer of dienes, they are very stable at high temperature. Compared with the formation of dimers, tri-coordinated boron substituted dienes can be formed at low temperature. The first postulation of dimerization is that monomers may be kinetic products and dimers may be thermodynamic products. For diene 2.39 and 2.38, higher temperatures were required to get TS2 than 2.36 and 2.37 from the experiments (Figure

3.3).

However, some monomers showed no dimerization at high temperature (Table 2.2).

Temperature is not the only factor in this reaction. Further research showed that Lewis acid could also be responsible for the self D-A reaction (Scheme 2.3, 2.4, 2.5). All

2+ + dimerizations occur in the presence of CrCl2 , Mg or H that could act as catalysts for self D-A reactions. When these 2 factors exist in the reaction system, the monomer will have a high propensity to become a dimer.

Table IV Dimerization Experiments of 2-Boron Substituted-1,3-Dienes

D-A dimer

Diene Solvent T(oC) t(h) Final product (NMR and

GC)

2.36 Toluene 60 6 2.36 No

2.37 Toluene 60 6 2.37 No

2.36 THF 66 24 2.36 Trace

2.37 66 24 2.37 Trace THF 2.38 24 2.38 Trace THF 66 2.39 24 2.39 No THF 66 2.36 12 2.36 No CH3CN 82 2.37 12 2.37 No CH3CN 82 2.38 12 2.38 No CH3CN 82 2.39 12 2.39 No CH3CN 82

Figure 3.3 Thermodynamic Diagram of Dimerization of 2-Boron Substituted Dienes

3.2 Conclusion

2-Boron substituted-1,3-dienes have proven to be very reactive dienes compared to other 2-main group element or 2-transition metal element substituted dienes for Diels-

Alder reactions that we have prepared to date. Diethanolamine borate diene has the fastest rate in uncatalyzed Diels-Alder reactions studied so far. Tri-coordinated boron substituted dienes are less reactive than tetra-coordianted dienes presumably because of their lower electron density.

3.3 Experimental Procedures and Characterization Data

General: The 1H NMR were reported on a Brucker Avance 500 MHz spectrometer and

Brucker Avance 300 MHz spectrometer operating at 500.13 MHz and 300.13 MHz

respectively. 13C NMR were recorded on a Bruker Avance 300 MHz spectrometer and

Bruker Avance 500 MHz spectrometer operating at 75.48 MHz and 125.77 MHz respectively. Chemical shifts were reported in parts per million () relative to tetramethylsilane (TMS), or the residual proton resonances in the deuterated solvents: chloroform (CDCl3). Coupling constants (J values) were reported in hertz (Hz).

Chemical Sciences, University of Illinois at Urbana-Champaign.

Scientific in the form of solvent kegs and purified using a solvent dispensing system developed by J.C. Meyer. Deuterated solvents were purchased from Cambridge Isotope

Laboratories and dried over molecular sieves. Magnesium sulfate, magnesium small turnings, iodobenzene, 4-iodobenzotrifluoride, 2-iodoanisole, 4-iodoanisole, ethyl acrylate, N-phenylmaleimide and N-phenyl methyl maleimide were purchased from

Aldrich Chemical Company and used as-received. 2-Chloro-1,3-diene, 50% in xylene

(Chloroprene) was purchased from Pfaltz & Bauer, Inc. and used as-received.

Isomer ratios were calculated by NMR (13C NMR experiment with inverse gated 1H- decoupling)126, 127

General Procedure for Diels-Alder Reactions:126

For dienes 2.4, 2.6 and 2.40

Diene and dienophile (1: 5) were dissolved in chloroform (2.4 and 2.6) or toluene (2.40) in a round bottom flask at room temperature. The white product was precipitated with pentane and obtained by vacuum filtration.

For dienes 2.36, 2.37, 2.38 and 2.39

Diene and dienophile (1: 5) were dissolved in THF (or toluene) in a round bottom flask at room temperature. In refluxing reactions, toluene was used as a solvent. The white product was precipitated with pentane and obtained by vacuum filtration.

Preparation of 3.1

Diene 2.4 (0.167 g, 1 mmol) and dienophile N-phenylmaleimide (0.865 g, 5 mmol) were dissolved in chloroform (15 mL) in a round bottom flask at room temperature. After stirring for 15 min., the product 3.1 was obtained by precipitation as a white powder

(0.330g, 0.97mmol, 98%) following addition of pentane (50 mL), vacuum filtration, and drying under vacuum.

1 H NMR (300 MHz, CDCl3)  7.49 -7.40 (m, 3H), 7.15-7.11(m, 2H), 6.26 (m, 1H), 4.78

(s, 1H), 4.03-3.94 (m, 3H), 3.61(dt, J =9.70, 3.20, 1H), 3.37-3.27 (m, 2H), 3.20 (m, 1H),

2.95 (ddd, J =12.3, 12.1, 6.2 Hz, 1H), 2.82-2.54 (m, 4H), 2.31(m, 1H), 2.17 (m, 1H).

13 C NMR (300 MHz, CDCl3)  183.7, 180.0, 132.0, 129.8, 129.4, 128.9, 126.3, 63.6, 63.0,

52.4, 51.0, 41.4, 40.3, 26.0, 25.8. The signal of the vinyl carbon next to tetravalent boron was not observed due to quadrupolar broadening.128

+ + HRMS calcd for C18H21BN2O4 [M+H] = 341.1672, found [M+H] = 341.1673

Preparation of 3.2

Diene 2.6 (0.181 g, 1 mmol) and dienophile N-phenylmaleimide (0.865 g, 5 mmol) were dissolved in chloroform (15 mL) in a round bottom flask at room temperature. After stirring for 2 hours, the product 3.2 was obtained by precipitation as a white powder

(0.318 g, 0.90 mmol, 90%) following addition of pentane (50 mL), vacuum filtration, and drying under vacuum.

1 H NMR (300 MHz, CDCl3)  7.43(t, J =7.6Hz, 2H), 7.35 (t, J=7.4Hz,1H), 7.23 (d,J=

7.6Hz, 2H), 6.35 (m, 1H), 3.98 (m, 4H), 3.21 (m, 2H), 3.05 (m, 2H), 2.81 (m, 2H), 2.69

13 (m, 2H), 2.44(s, 3H), 2.38 (m, 2H). C NMR (300, MHz, CDCl3)  180.4, 179.8, 132.5,

132.2, 129.0, 128.8, 126.2, 62.0, 61.7, 60.9, 60.4, 46.4, 39.7,39.5, 26.5, 24.8.

EA: calcd: C 64.43; H 6.54; Found : C 63.73, H 6.43

Preparation of 3.3

Diene 2.40 (0.204 g, 1 mmol) and dienophile N-phenylmaleimide (0.865 g, 5 mmol) were dissolved in toluene (15 mL) in a round bottom flask at room temperature. After stirring for 2 hours, the product 3.3 was obtained by precipitation as a white powder (0.347 g,

0.92 mmol, 92%) by addition of pentane (50 mL), vacuum filtration, and drying under high vacuum.

1H NMR (300 MHz, DMSO)  7.43 (m, 2H), 7.37 (m, 1H), 7.26 (m, 2H), 5.64(m, J=1H),

3.49 (s, 6H), 3.03 (m, 1H), 2.92 (m, 1H), 2.19(m, 4H), 0.44(s, 3H). 13C NMR (300, MHz,

DMSO)  179.8, 179.7, 132.8, 128.6, 128.8, 127.9, 127.2, 73.3, 72.6, 34.5, 26.4, 23.6,

16.3 HRMS: calcd: 377.1410-Na+H=355.1597 found 355.1591

Preparation of 3.4

Diene 2.4 (0.167 g, 1 mmol) and dienophile ethyl acrylate (0.700g, 7 mmol) were dissolved in chloroform (15 mL) in a round bottom flask and refluxed for 6 h. The white product was precipitated with pentane (150 mL) and obtained by vacuum filtration followed by drying under high vacuum, (0.224 g, 0.84 mmol, 84%).

1 H NMR (300 MHz, CDCl3)  5.91 (m, 1H), 4.86 (s, 1H), 4.12 (q, J = 7.25, 2H), 3.97 (m,

2H), 2.89 (m, 2H), 3.224 (m, 2H), 2.79 (m, 2H), 2.48 (m, 1H), 2.23 (m, 2H), 2.11(m, 2H),

13 1.99 (m, 1H), 1.76 (s, 1H), 1.25 (t, J = 7.25, 3H). C NMR (300 MHz, CDCl3)  Major isomer: 176.7, 139.9 (vinyl carbon next to the boron), 126.9, 62.85, 62.81, 60.0, 51.2,

40.1, 39.8, 28.6, 26.4, 25.9, 14.0. Minor isomer selected resonances: 176.2, 127.6, 24.7,

24.6 Major isomer : minor isomer = 16.4 : 1

Elemental anal. calcd. for C13H22BNO4: C, 58.45; H, 8.30. Found: 58.17, 8.32.

Preparation of 3.5

Diene 2.4 (0.167 g, 1 mmol) and dienophile 2-methyl-N-phenylmaleimide (0.16 g, 1.6 mmol) were dissolved in chloroform (10 mL) in a round bottom flask and refluxed for 6 h.

The white product was precipitated with pentane (150 mL) and obtained by vacuum filtration followed by drying under high vacuum (0.336 g, 0.95 mmol, 95%).

1 H NMR (300 MHz, CDCl3)  7.48-7.37 (m, 3H), 7.14 (s, 1H), 7.12 (s, 1H), 6.26 (m, 1H),

4.88 (s, 1H), 3.99 (m, 3H), 3.61 (m, 1H), 3.21(m, 1H), 2.92 (m, 2H), 2.79 (m, 1H), 2.68

(m, 2H), 2.57 (m, 1H), 2.17 (d, J = 15.0 Hz, 1H), 1.97 (d, J = 15.0 Hz, 1H), 1.47 (s, 3H).

13 C NMR (300 MHz, CDCl3)  Major isomer : 183.0, 182.9, 132.3, 131.0, 129.6, 129.2,

126.6, 63.9, 63.3, 52.6, 51.8, 49.4, 45.4, 35.7, 26.0, 23.4.

The signal of the vinyl carbon next to tetravalent boron was not observed due to quadrupolar broadening. 128

Minor isomer found: 179.8, 130.1, 63.3, 53.0, 48.4, 46.9, 34.7, 27.2, 24.7 Major isomer : minor isomer = 4:1 + + HRMS calcd for C19H23BN2O4 [M+H] =355.1830, found [M+H] = 355.1825

Preparation of 3.6

Diene 2.6 (0.181 g, 1 mmol) and dienophile ethyl acrylate (0.500g, 5 mmol) were dissolved in chloroform (10 mL) in a round bottom flask and refluxed for 6 h. The white product was precipitated with pentane (150 mL) and obtained by vacuum filtration followed by drying under high vacuum (0.252 g, 0.90 mmol, 90%).

1 H NMR (300 MHz, CDCl3)  6.05 (m, 1H), 4.07 (q, J=7.2 Hz, 2H), 3.97 (m, 2H), 3.90

(m, 2H), 3.01(m, 3H), 2.67 (m, 2H), 2,55 (s, 3H), 2.44 (m, 1H), 2.24 (m, 1H), 2.09 (m,

2H), 1.93 (m, 1H), 1.57 (m, 1H), 1.25 (t, 7.2 Hz, 3H)

13 C NMR (300, MHz, CDCl3) Major isomer:  176.6, 130.2, 62.0, 60.3, 59.8, 46.3, 39.7,

28.7, 27.0, 25.9, and 14.1

Minor isomer’s peaks found:  177.0, 131.4, 59.9, 59.1, 59.0, 46.4, 40.1, 30.2, 29.1, 25.6, and 25.2

HRMS calcd for C14H24BNO4: 281.1798 +Na=304.1696, found: M+Na=304.1696

Preparation of 3.7

Diene 2.6 (0.181 g, 1 mmol) and dienophile 2-methyl-N-phenylmaleimide (0.500 g, 5 mmol) were dissolved in chloroform (10 mL) in a round bottom flask and refluxed for 6h.

The white product was precipitated with pentane (150 mL) and obtained by vacuum filtration followed by drying under high vacuum (0.276 g, 0.75 mmol, 75%).

1 H NMR (300 MHz, CDCl3)  Major isomer: 7.42 (t, J =7.8 Hz, 2H), 7.36 (t, J=7.2

Hz,1H), 7.22 (d,J= 7.8 Hz, 2H), 6.33 (m, 1H), 3.97 (m, 4H), 3.04 (m, 2H), 2.87 (m, 2H),

2.78 (m, 3H), 2.40 (s, 3H), 2.39 (m, 1H), 2.05 (dt, J=15, 7 Hz, 1H), 1.46 (s, 3H)

Minor isomer found: 2.41(s), 1.43 (s)

13 C NMR (300, MHz, CDCl3)  Major isomer: 182.6, 179.0, 132.6, 132.3, 129.0, 128.2,

126.1, 61.8, 60.9, 60.4, 47.3, 46.6, 44.2, 35.5, 26.3, 25.3, 25.2

Minor isomer found: 182.5, 179.6, 125.9, 61.8, 47.6, 44.3, 33.7, 26.9, and 25.0

HRMS calcd for C20H25BN2O4: calcd: 368.1907, found: 368.19075

Preparation of 3.13

Diene 2.40 (0.102 g, 0.5 mmol) and dienophile 2-methyl-N-phenylmaleimide (0.935 g,

5 mmol) were dissolved in toluene (10 mL) in a sealed tube. After refluxing for 18 hours, the product 3.13 was observed from NMR and MS. No further separation was conducted.

The crude product was used in Suzuki cross coupling reactions which will be described in the next chapter.

CHAPTER 4 Suzuki Cross Coupling Reactions

4.1 Results and Discussion

4.1.1 Suzuki Cross Coupling Reactions

In order to prove that 2-boron substituted dienes (2.4) can serve as a synthon for a host of other organic dienes, we took cycloadducts (3.1-3.7) and proved that they could be cross coupled efficiently to iodobenzene, 4-trifluoromethyl-1-iodobenzene, and 4- iodoanisole.

Based on the initial D-A reactions, a series of Suzuki cross coupling reactions were performed and conditions were optimized (Table V). The optimization conditions were achieved by the Suzuki coupling reactions of boron cycloadduct (3.1) and iodobenzene compounds shown in Table V.

We found in the solvent CH3CN, Pd2(dba)3 proved optimal in cross coupling reactions

(Table V, entry 3) with a high yield of 75%. Later we determined the best solvent for this reaction is a mixture of CH3CN and C2H5OH (5:1).

Table V Optimization of Suzuki Cross Coupling Reaction

Entry R [Pd](0.5%) Solvent Base Ligand Time Yielda Isomer

(10%) (h) (%) ratio

(major:

minor)b

1 H Pd(OAc)2 C2H5OH K2CO3 _ 6 35 16.6:1

2 H PdCl2(dppf) CH3CN K2CO3 _ 10 59 16.5:1

3 H O CH3CN K2CO3 _ 10 75 17.1:1 Pd2 3

4 H PdCl2(PPh3)2 DMF CsF CuI 5 33 18.0:1

5 CF3 PdCl2(dppf) CH3CN K2CO3 PPh3 10 63 18.2:1

6 CF3 Pd(OAc)2 C2H5OH K2CO3 PPh3 6 33 18.1:1

7 CF3 Pd(OAc)2 CH3CN K2CO3 _ 10 54 16.9:1 a Isolated yields b Identified by GC

Table VI Suzuki Cross Coupling Reactions of 2-Boron Substituted-1,3- Dienes

Entry D-A Product (#) R % yield Isomer ratio Product

1 H 85 17:1 3.4

4.1

2 CF3 97 18:1 3.4 4.2

3 OMe 80 18:1 3.4 4.3

4 H 64 NA 3.1 4.4

5 CF3 70 NA 3.1 4.5

6 OMe 60 NA 3.1 4.6

7 H 58 3:1 3.5 4.7

8 CF3 70 3:1 3.5

4.8

9 OMe 75 3:1

3.5 4.9

10 3.2 H 92 NA 4.4

11 H 68* 3:1 3.6 4.1

12 H 60* 1:0.8 3.7 4.7

2 % Pd2(dba)3[Tris(dibenzylideneacetone)dipalladium (0) ], acetonitrile : ethanol = 5ml:1ml, boron compounds (0.1 g) : iodobenzene compounds = 1: 2 , K2CO3 (3 eq). reaction time: 36h. Isomer ratio: 4.1-4.3 were identified by GC, 4.7-4.9 were identified by NMR. *Entry 11 and entry 12: D-A product were not separated before Suzuki cross coupling reactions.

Cross coupled cycloadducts 4.1-4.9 were all isolated in good to excellent yield and regioselectivities observed in the original Diels-Alder reactions persisted after cross coupling.

4.1.2 Tandem Diels-Alder/Suzuki Cross Coupling Reactions

Tandem reactions are well known as efficient processes in organic synthesis.129 They have a number of significant advantages to organic chemists: efficiently reduced

operation steps, no isolation and handling problems of intermediates especially for some harsh and toxic intermediates, economic use of chemicals, etc.130 We have achieved a promising approach in tandem D-A/Suzuki cross coupling reactions by using 2-boron-1,

3-dienes, iodobenzene and dienophiles to obtain some multi-substituted cyclohexenes.

Table VII Tandem Diels-Alder/Suzuki cross coupling reactions

%Yield /Isomer Entry Diene Dienophile Product Ratio

1 2.36 4.4 73/NA

2 2.36 4.7 71/2:1

3 2.40 4.7 79/2:1

4 2.40 4.1 63/3:1

Diene 5 2.37 No product decomposed

Diene 6 2.37 No product decomposed

7 2.38 4.7 65/2:1

8 2.39 4.7 72/2:1

Diene 9 2.4 No product decomposed

Diene 10 2.6 No product decomposed

According to Table VII, dienes 2.36, 2.38, 2.40 and 2.39 can react in tandem D-A/

Suzuki cross coupling reactions with good yields. For the most reactive dienes 2.4 and

2.6 in Diels-Alder reactions, no positive results were observed. We observed diene decomposition, perhaps because the amine groups in 2-boron-1,3-butadienes are reactive in tandem conditions eventually causing the decomposition of dienes. Diene 2.37 is the most unreactive diene in this group since it has a room temperature solution phase s-trans structure (Appendix B), which also explains the reactivity in tandem D-A/Suzuki cross coupling reactions. We have extensively investigated the mechanisms of tandem D-

A/Suzuki cross coupling reactions as shown in Scheme 4.1.

Scheme 4.1 Control reactions were conducted in different conditions and we found Path1 unlikely in the reaction (Scheme 4.2). If Path 1 were occurring, we would expect to isolate diene

4.10, but we found decomposed dienes by GC/MS and NMR. The Path 2 was proven to be possible for diene 2.40 in entry 3 and 4 since we observed the D-A products 4.11 from boron substituted dienes and 2-methyl-N-phenyl maleimide (Scheme 4.3). From the previous results in Chapter 3, 2.40 is a tetra-coordinated boron substituted diene which is more reactive in D-A reactions than tri-coordinated boron substituted dienes 2.36, 2.38,

2.39. Further experiments were conducted to test if dienes 2.36, 2.38, 2.39 also follow

Path 2 in this reaction but we did not see boron cycloadducts like 4.11 (Scheme 4.4).

Scheme 4.2

Scheme 4.3

Scheme 4.4

Scheme 4.5

More control reactions were conducted in the presence of Pd(CH3CN)2Cl2 (Scheme

4.5) because Pd(0) usually changes to Pd(II) via oxidative addition when iodobenzene is

added to the system (Figure 1.6). We found Pd (II) plays an important role in the reaction to catalyze D-A reactions between boron substituted dienes and dienophiles. So the Path

2 is the plausible mechanism for tandem D-A/Suzuki cross coupling reactions.

Also, we investigated Path 3 via a palladium substituted diene as an intermediate.

From the NMR data, when palladium was added to diene 2.36, some changes were found after 30 minutes at room temperature. When we heated the solution to 50 ˚C for 3 h, the transmetallation happened very fast and what we postulate as a palladium substituted diene 4.8 was observed (Scheme 4.6) and (Figure 4.1). Isolation and separation of this diene was tried by filtration but this failed. This diene 4.8 was only stable in acetonitrile solution.

Scheme 4.6

Figure 4.1 Comparison of NMR Chemical Shifts of Boron Substituted Diene and Palladium Substituted Diene in CD3CN

Palladium catalysts with different oxidation states and ligand sets were tried in order to evaluate the transmetallation with diene 2.36 (Table VIII). Before Pd(dba)3 was added to diene 2.36 in deuterated acetonitrile, it has to be oxidized by air to change to Pd(II).

When N2 was used to degas the solvent, only a small amount of 4.8 was observed. Pd(II) was proven to be more active than Pd (0) in this transmetallation reaction (Table VIII, entry 2 and 3). It only takes a few seconds to 1 minute for Pd(II) to transmetallate to boron substituted diene to give 4.8 (entry 2 and 3) at room temperature but 3 hours at

50˚C or 60˚C for Pd (0) (entry 1 and 4).

The palladium substituted diene possibly has a ligand of CH3CN which coordinates with Pd to stabilize the whole structure. From Table VIII, the ligands also are important.

DBA and pincer are better ligands (entry1 and 4) than PPh3 and CH3CN (entry 2 and 3).

The palladium substituted diene with DBA and pincer can be stable for 3 days (entry1 and 4) in a sealed tube but only 3 hours with PPh3 and CH3CN.

Table VIII Palladium Catalysts and 2-Palladium Substituted 1,3-Diene

Entry Time Stability of

[Pd] Solvent T(˚C) Palladium

Diene

1 Pd2(dba)3 CD3CN 50 3 h 3d

2 Pd(CH3CN)2Cl2 25 1 min 3h CD3CN

3 Pd(PPh3)2Cl2 25 1 min 12h CD3CN 4 Pd(Pincer) 60 12 h 2d CD3CN

Further reactions were tried to prove path 3 by adding 2-methyl-N-phenylmaleimide to

4.8 (Scheme 4.7). No 4.9 was observed from NMR. Then the same conditions in D-

A/Suzuki cross couplings were tried in this reaction. But no 2.17 except decomposed palladium catalyst was observed from NMR and GC-MS. So, path 3 is unlikely the mechanism for this reaction.

Scheme 4.7

4.2 Conclusions

2-boron substituted dienes have demonstrated good reactivities and high regioslectivities in stepwise and tandem D-A/Suzuki cross coupling reactions, which can serve as excellent synthons for a host of organic dienes via cross coupling. The mechanism research disclosed that Pd(II) could act as a Lewis acid catalyst to catalyze D-

A reaction of boron substituted dienes. Also, a possible palladium substituted-1,3-diene as a new intermediate was observed in the reactions. Reactions showed that Pd(0) has to be oxidized to Pd(II) to realize transmetallation to the boron substituted diene. The reactivity of the possible palladium substituted diene is awaiting further investigation.

4.3 Experimental and Characterization Data

General procedure for stepwise Suzuki cross coupling reactions:

Boron compounds and iodoaromatic compounds were added to a N2 flushed flask with

Pd2(dba)3 and K2CO3 in acetonitrile and ethanol (30 mL). The mixture was refluxed for

36 h and cooled to room temperature. The solution was filtered through silica gel to remove catalysts. The filtrate was quenched with water (50 mL) and extracted with Et2O

(4×50 mL). The combined organic layers were dried over MgSO4 and volatiles were removed by rotary evaporation. The resulting cross-coupled cycloadduct residue was purified by flash chromatography (ethyl ether: hexane=1:1).

Optimization of conditions: 2% Pd2(dba)3 [Tris(dibenzylideneacetone)dipalladium (0) ], acetonitrile : ethanol = 5:1, boron cycloadduct : iodoaromatic compounds = 1: 2 , K2CO3

(3 equiv). reaction time: 36 h.

General procedures for Tandem Diels-Alder/ Suzuki cross coupling reactions

Diene and dienophile (1:4) were added to a N2 flushed high pressure resistance thick wall tube with Pd2(dba)3 and K2CO3 in acetonitrile and ethanol (5 mL). Iodobenzene was added. The mixture was sealed and refluxed for 24 h and cooled to room temperature.

The solution was filtered through silica gel to remove catalysts. The filtrate was quenched with water (50 mL) and extracted with Et2O (4×50 mL). The combined organic layers were dried over MgSO4 and volatiles were removed by rotary evaporation. The final product was purified by flash chromatography (ethyl acetate: hexane=6:1).

Preparation of ethyl-4-phenyl cyclohex-3-enecarboxylate 4.1

Following the general procedure, iodobenzene (0.204 g, 1 mmol) and 3.4 (0.133 g, 0.5 mmol ) were added along with Pd2(dba)3 (10 mg, 0.01mmol ) and K2CO3 (0.207 g, 1.5 mmol) to a flask under N2 (30 mL acetonitrile and ethanol). The flask was heated and refluxed for 36 h and worked up as described in the general procedure. The resulting brown oily crude product mixture was subjected to flash chromatography to yield the cross-coupled product 4.1 as a light yellow oil (0.098 g, 0.43 mmol, 85%). 1H NMR data was identical to that previously reported.131

1 H NMR (300 Hz, CDCl3)  7.39–7.28 (m, 4H), 7.22 (m, 1H), 6.11–6.08 (m, 1H), 4.169

(q, J = 7.3 Hz, 2H), 2.60 (m, 1H), 2.54–2.42 (m, 4H), 2.25–2.14 (m, 1H), 1.84 (m, 1H),

1.27 (t, J = 7.3 Hz, 3H).

100

Major isomer: minor isomer = 17.5:1

Preparation of ethyl 4-[4-(trifluoromethyl)-phenyl]cyclohex-3-enecarboxylate 4.2

Following the general procedure, 4-iodobenzotrifluoride (0.272 g, 1 mmol) and 3.4

(0.133 g, 0.5mmol ) were added along with Pd2(dba)3 (10 mg, 0.01mmol) and

K2CO3(0.207 g, 1.5 mmol) to a flask under N2 (30 mL acetonitrile and ethanol). The flask was heated and refluxed for 36 h and worked up as described in the general procedure.

The resulting brown oily crude product mixture was subjected to flash chromatography to yield the cross-coupled product 4.2 as a light yellow oil (0.144 g, 0.484 mmol, 97%). 1H

NMR data was identical to that previously reported.131

1 H NMR (300 MHz, CDCl3)  7.48 (d, J =8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.11 (m,

1H), 4.10 (q, J = 7.3 Hz, 2H), 2.55 (m, 1H), 2.47–2.39 (m, 4H), 2.13 (m, 1H), 1.79 (m,

1H), 1.209 (t, J = 7.3 Hz, 3H).

Major isomer: minor isomer = 18:1

Preparation of ethyl-4-(2-methoxyphenyl)-cyclohex-3-enecarboxylate 4.3

101

Following the general procedure, 2-iodoanisole (0.234 g, 1 mmol) and 3.4 (0.133 g, 0.5 mmol ) were added along with Pd2(dba)3 (10 mg, 0.01mmol) and K2CO3 (0.207 g, 1.5 mmol) to a flask under N2 (30 mL acetonitrile and ethanol). The flask was heated and refluxed for 36 h and worked up as described in the general procedure. The resulting brown oily crude product mixture was subjected to flash chromatography to yield the cross-coupled product 4.3 as a light yellow oil (0.104 g, 0.40 mmol, 80%). 1H NMR data was identical to that previously reported. 131

1 H NMR (300 Hz, CDCl3)  7.21 (ddd, J = 8.6, 7.4, 1.8 Hz, 1H), 7.103 (dd, J = 7.4, 1.8

Hz, 1H), 6.90 (ddd, J = 8.6, 7.4, 1.0 Hz, 1H), 6.85 (d, J = 8.6 Hz, 1H), 5.75 (m, 1H),

4.166 (q, J = 7.3 Hz, 2H), 3.80 (s, 1H), 2.64 (m, 1H), 2.55–2.37 (m, 4H), 2.10 (m, 1H),

1.82 (m, 1H), 1.28 (t, J = 7.3 Hz, 3H)

Major isomer: minor isomer = 21.3:1

Preparation of 2,5-diphenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione 4.4

Following the general procedure, iodobenzene (0.204 g, 1 mmol) and 3.1 (0.170 g,

0.5 mmol) were added along with Pd2(dba)3 (10 mg, 0.01 mmol) and K2CO3 (0.207 g, 1.5 mmol) to a flask under N2 (30 mL acetonitrile and ethanol). The flask was heated and refluxed for 36 h and worked up as described in the general procedure. The resulting brown oily crude product mixture was subjected to flash chromatography to yield the

102

cross-coupled product 4.4 as a white solid (0.097 g, 0.32 mmol, 64%). 1H NMR data was identical to that previously reported. 50

1 H NMR (300 Hz, CDCl3)  7.28–7.45 (m, 8H), 7.10–7.20 (m, 2H), 6.15–6.27 (m, 1H),

3.44 (ddd, J = 9.5, 6.9, 2.5 Hz, 1H), 3.35 (ddd, J = 9.5, 6.9 2.5 Hz, 1H), 3.26 (dd, J = 15.5,

2.5 Hz, 1H), 2.95 (ddd, J = 15.5, 6.9, 2.5Hz, 1H), 2.64 (ddt, J = 15.5, 6.9, 2.5 Hz, 1H),

2.40–2.50 (m, 1H).

Preparation of 2-phenyl-5-[4-(trifluoromethyl)phenyl]-3a,4,7,7a-tetrahydo-1H-isoindole-

1,3(2H)-dione 4.5

Following the general procedure, 4-iodobenzotrifluoride (0.272 g, 1 mmol) and 3.1

(0.170 g, 0.5 mmol ) were added along with Pd2(dba)3 (10 mg, 0.01 mmol) and K2CO3

(0.207 g, 1.5 mmol) to a flask under N2 (30 mL acetonitrile and ethanol). The flask was heated and refluxed for 36 h and worked up as described in the general procedure. The resulting brown oily crude product mixture was subjected to flash chromatography to yield the cross-coupled product 4.5 as a white solid (0.112 g, 0.3 mmol, 60%).

1 H NMR (300 MHz, CDCl3)  7.58 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.42 (t,

J =8.0 Hz, 2H), 7.3 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 6.31 (m, 1H), 3.48 (ddd,

J = 9.1, 7.4, 2.5 Hz, 1H), 3.38 (ddd, J = 9.1, 7.4, 2.5 Hz, 1H), 3.26 (dd, J = 15.5, 2.7 Hz,

1H), 2.98 (ddd, J = 15.5, 7.1, 2.7 Hz, 1H), 2.65 (ddt, J = 15.5, 7.1, 2.7 Hz, 1H), 2.43–2.50

13 2 (m, 1H). C NMR (300 MHz, CDCl3)  179.2, 179.0, 144.0, 139.5, 132.1, 129.9 ( JC–F =

103

1 3 32.6 Hz), 129.5, 129.1, 126.7,126.3 ( JC–F = 273.1 Hz), 126.2, 125.9( JC–F = 3.8 Hz),

125.8, 40.4, 39.7, 27.8, 25.7.

+ + HRMS calcd for C21H16F3NO2 [M+H] = 372.1211, found [M+H] = 372.1211.

Preparation of 5-(4-methoxyphenyl)-2-phenyl-3a,4,7,7a-tetrahydro-1H-isoindole-

1,3(2H)-dione 4.6

Following the general procedure, 4-iodoanisole (0.234 g, 1 mmol) and 3.1(0.170 g, 0.5 mmol ) were added along with Pd2(dba)3 (10 mg, 0.01mmol) and K2CO3 (0.207 g, 1.5 mmol) to a flask under N2 (30 mL acetonitrile and ethanol). The flask was heated and refluxed for 36 h. The resulting brown oily crude product mixture was subjected to flash chromatography to yield the cross-coupled product 4.6 as a white solid (0.099 g,

0.3 mmol, 60%). 1H NMR data was identical to that previously reported. 50

1H NMR (300 Hz, CDCl3)  7.43–7.28 (m, 5H), 7.15 (d, J = 7.6 Hz, 2H), 6.86 (d, J = 8.7

Hz, 2H), 6.12 (m, 1H), 3.80 (s, 3H), 3.42 (ddd, J = 9.3, 7.0, 2.6 Hz, 1H), 3.33 (ddd, J =

9.3, 7.0, 2.5 Hz,1H), 3.26 (dd, J = 15.5, 2.5 Hz, 1H), 2.95 (ddd, J = 15.5, 6.9, 2.5 Hz, 1H),

2.64 (ddt, J = 15.5, 6.9, 2.5 Hz, 1H), 2.40−2.50 (m, 1H).

Preparation of 3a-methyl-2,6-diphenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione

4.7

104

Followed the general procedure, 4-iodobenzene (0.204 g, 1 mmol) and 3.5 (0.178 g,

0.5 mmol ) were added along with Pd2(dba)3 (10 mg, 0.1mmol) and K2CO3 (0.207 g, 1.5 mmol) to a flask under N2 (30 mL acetonitrile and ethanol). The flask was heated and refluxed for 36 h and worked up as described in the general procedure. The resulting brown oily crude product mixture was subjected to flash chromatography to yield the cross-coupled product 4.7 as a white solid (0.0887 g, 0.28 mmol, 58%).

1 H NMR (300 MHz, CDCl3)  Major isomer: 7.42–7.23 (m, 8H), 7.16 (m, 1H), 7.13 (m,

1H), 6.19 (m, 1H), 3.28 (ddd, J = 15.3, 2.4 Hz, 1H), 3.01 (dd, J = 6.6, 2.4 Hz, 1H), 2.89

(dd, J = 6.6 Hz, 1H), 2.65 (ddt, J = 15.3, 6.6, 2.4 Hz, 1H), 2.12 (ddd, J = 15.3, 3.7, 2.4 Hz,

1H), 1.53 (s, 3H).

Minor isomer found: 3.18 (d, J = 15.3), 2.46 (d, J = 15.3), 2.34 (d, J = 15.3)

13 C NMR (300 MHz, CDCl3) Major isomer:  182.2, 178.4, 140.2, 140.0, 132.3, 129.4,

128.9, 128.6, 127.5, 126.4, 125.6, 123.5, 48.3, 45.5, 34.4, 28.3, 25.9.

Minor isomer found: 181.6, 178.3, 140.6, 140.3, 128.5, 125.5, 47.5, 45.1, 36.3, 25.4

+ + HRMS calcd for C21H19NO2 [M+H] = 318.1494, found [M+H] = 318.1494.

Major isomer: minor isomer = 3:1

Preparation of 3a-methyl-2-phenyl-6-[4-(trifluoromethyl)phenyl]-3a,4,7,7a-tetrahydro-

1H-isoindole-1,3(2H)-dione 4.8

105

Following the general procedure, 4-iodobenzotrifluoride (0.272 g, 1 mmol) and 3.5

(0.177 g, 0.5 mmol ) were added along with Pd2(dba)3 (10 mg, 0.01 mmol) and K2CO3

(0.207 g, 1.5 mmol) to a flask under N2 (30 mL acetonitrile and ethanol). The flask was heated and refluxed for 36 h and worked up as described in the general procedure . The resulting brown oily crude product mixture was subjected to flash chromatography to yield the cross-coupled product 4.8 as a white solid (0.135 g, 0.35 mmol, 70%).

1 H NMR (300 MHz, CDCl3)  Major isomer: 7.58 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0

Hz, 2H), 7.44–7.32 (m, 3H), 7.14–7.11 (m, 2H), 6.29 (m, 1H), 3.29 (dd, J = 15.2, 2.5 Hz,

1H), 3.05 (dd, J = 6.50, 2.5 Hz, 1H), 2.93 (m, 1H), 2.68 (ddt, J = 15.2, 6.5, 2.5 Hz, 1H),

2.15 (m, 1H), 1.56 (s, 3H); Minor isomer found: 3.188 (d, J = 15.2), 2.35 (dt, J = 15.2,

2.5 Hz)

13 C NMR APT (300 MHz, CDCl3)  Major isomer: 181.9, 178.4, 143.9, 139.5, 132.2,

2 1 129.8, 129.6, 129.4 ( JC–F = 33.3 Hz) , 126.7, 126.3, 126.1, 125.9( JC–F = 273.3 Hz),

3 125.5 ( JC–F =4Hz), 48.2, 44.9, 34.5, 28.1, 24.7 Minor isomer found: 180.0, 176.5,

140.0, 47.5, 45.6, 36.5, 30.6, 26.1.

+ + HRMS calcd for C22H18F3NO2 [M+H] = 386.1368, found [M+H] = 386.1368.

Major isomer: minor isomer = 3:1

Preparation of 6-(4-methoxyphenyl)-3a-methyl-2-phenyl-3a,4,7,7a-tetrahydro-1H- isoindole-1,3(2H)-dione 4.9

106

Following the general procedure, 4-iodoanisole (0.234 g, 1 mmol) and 3.5 (0.178 g,

0.5 mmol) were added along with Pd2(dba)3 (10 mg, 0.01mmol) and K2CO3 (0.207 g, 1.5 mmol) to a flask under N2 (30 mL acetonitrile and ethanol). The flask was heated and refluxed for 36 h and worked up as described in the general procedure. The resulting brown oily crude product mixture was subjected to flash chromatography to yield the cross-coupled product 4.9 as a white solid (0.134 g, 0.39 mmol, 78%).

1 H NMR (300 MHz, CDCl3)  Major isomer: 7.38 (d, J = 7.5 Hz, 2H), 7.31 (d, J = 8.7

Hz, 2H), 7.26 (m, 1H), 7.13 (d, J = 7.5 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 6.1 (m, 1H),

3.80 (s, 3H), 3.25 (dd, J = 15.4, 2.4 Hz, 1H), 2.99 (dd, J = 6.5, 2.4 Hz, 1H), 2.86 (dd, J =

15.4, 6.5 Hz, 1H), 2.61 (ddt, J = 15.4, 6.5, 2.4 Hz, 1H), 2.16 (dd, J = 15.4, 2.4 Hz, 1H),

1.50 (s, 3H); Minor isomer selected resonances: 3.15 (d, J = 15.4), 2.44 (m), 2.30 (m).

13 C NMR (300 MHz, CDCl3)  182.3, 178.5, 159.5, 139.8, 133.1, 132.4, 129.4, 128.8,

127.0, 126.8, 122.0, 114.3, 55.6, 48.4, 45.1, 36.7, 30.6, 25.9.

Elemental anal. calcd for C22H21NO3: C, 76.06; H, 6.09. Found: 76.34, 6.31.

Major isomer: minor isomer = 3:1

Preparation of 2,5-diphenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione 4.4 from

3.2 (Table VI, entry 10)

107

Following the general procedure, iodobenzene (0.204 g, 1 mmol) and 3.2 (0.177 g,

1 H NMR (300 Hz, CDCl3)  7.28–7.45 (m, 8H), 7.10–7.20 (m, 2H), 6.15–6.27 (m, 1H),

3.44 (ddd, J = 9.5, 6.9, 2.5 Hz, 1H), 3.35 (ddd, J = 9.5, 6.9 2.5 Hz, 1H), 3.26 (dd, J = 15.5,

2.5 Hz, 1H), 2.95 (ddd, J = 15.5, 6.9, 2.5Hz, 1H), 2.64 (ddt, J = 15.5, 6.9, 2.5 Hz, 1H),

2.40–2.50 (m, 1H).

Preparation of ethyl-4-phenyl cyclohex-3-enecarboxylate 4.1from 3.6 (Table VI, entry

11)

Diene 2.6 (0.090 g, 0.5 mmol) and dienophile ethyl acrylate (0.250g, 2.5 mmol) were dissolved in chloroform (5 mL) in a round bottom flask and refluxed for 6 h. The flask was cooled down to room temperature. Iodobenzene (0.204 g, 1mmol) was added along with Pd2(dba)3 (10 mg, 0.01mmol ) and K2CO3 (0.207 g, 1.5 mmol) to the crude product in the flask under N2 (30 mL acetonitrile and ethanol). The flask was heated and refluxed for 36 h and worked up as described in the general procedure. The resulting brown oily

108

crude product mixture was subjected to flash chromatography to yield the cross-coupled product 4.1 as a light yellow oil (0.082 g, 0.34 mmol, 68%). 1H NMR data was identical to that previously reported.131

1 H NMR (300 Hz, CDCl3)  7.39–7.28 (m, 4H), 7.22 (m, 1H), 6.11–6.08 (m, 1H), 4.169

(q, J = 7.3 Hz, 2H), 2.60 (m, 1H), 2.54–2.42 (m, 4H), 2.25–2.14 (m, 1H), 1.84 (m, 1H),

1.27 (t, J = 7.3 Hz, 3H).

Major isomer: minor isomer = 3:1

Preparation of 3a-methyl-2,6-diphenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione

4.7 from 3.7 (Table VI, entry 12)

Diene 2.6 (0.090 g, 0.5 mmol) and dienophile 2-methyl-N-phenylmaleimide (0.250g, 2.5 mmol) were dissolved in chloroform (5 mL) in a round bottom flask and refluxed for 6h.

The flask was cooled down to room temperature. 4-Iodobenzene (0.204 g, 1 mmol) was added along with Pd2(dba)3 (10 mg, 0.1mmol) and K2CO3 (0.207 g, 1.5 mmol) to a flask under N2 (30 mL acetonitrile and ethanol). The flask was heated and refluxed for 36 h and worked up as described in the general procedure. The resulting brown oily crude product mixture was subjected to flash chromatography to yield the cross-coupled product 4.7 as a white solid (0.095 g, 0.3 mmol, 60%). 1H NMR data was identical to that previously reported.123

109

1 H NMR (300 MHz, CDCl3)  7.42–7.23 (m, 8H), 7.16 (m, 1H), 7.13 (m, 1H), 6.19 (m,

1H), 3.28 (ddd, J = 15.3, 2.4 Hz, 1H), 3.01 (dd, J = 6.6, 2.4 Hz, 1H), 2.89 (dd, J = 6.6 Hz,

1H), 2.65 (ddt, J = 15.3, 6.6, 2.4 Hz, 1H), 2.12 (ddd, J = 15.3, 3.7, 2.4 Hz, 1H), 1.53 (s,

3H).

Major isomer: minor isomer =1:0.8

Tandem Diels-Alder/Suzuki cross coupling reactions:

Entry 1 of Table VII: preparation of 4.4

Diene 2.36 (0.10g, 0.72mmol) and N-phenylmaleimide (0.50g, 2.88mmol) (1:4) were added to a N2 flushed high pressure resistance thick wall tube with Pd2(dba)3 and K2CO3 in acetonitrile (10 mL). Iodobenzene (0.59 g, 2.88 mmol) (diene:iodobenzene=1:4) was added to the mixture. The tube was sealed and refluxed for 24 h and cooled to room temperature. The solution was filtered through silica gel to remove catalysts. The filtrate was quenched with water (50 mL) and extracted with Et2O (4×50 mL). The combined organic layers were dried over MgSO4 and volatiles were removed by rotary evaporation.

The final product was purified by flash chromatography (ethyl acetate: hexane=4:1). 4.4 was obtained as a white powder (0.16 g, 0.52 mmol, 73%) 1H NMR data was identical to that previously reported.50

1 H NMR (300 Hz, CDCl3)  7.28–7.45 (m, 8H), 7.10–7.20 (m, 2H), 6.15–6.27 (m, 1H),

3.44 (ddd, J = 9.5, 6.9, 2.5 Hz, 1H), 3.35 (ddd, J = 9.5, 6.9 2.5 Hz, 1H), 3.26 (dd, J = 15.5,

110

2.5 Hz, 1H), 2.95 (ddd, J = 15.5, 6.9, 2.5Hz, 1H), 2.64 (ddt, J = 15.5, 6.9, 2.5 Hz, 1H),

2.40–2.50 (m, 1H).

Entry 2 of Table VII: preparation of 4.7

Diene 2.36 (0.10 g, 0.72 mmol) and 2-methyl-N-phenylmaleimide (0.54 g , 2.88 mmol)

(1:4) were added to a N2 flushed high pressure resistance thick wall tube with Pd2(dba)3 and K2CO3 in acetonitrile and ethanol (10 mL). Iodobenzene (0.29 g, 1.44 mmol)

(diene:iodobenzene=1:2) was added to the mixture. The tube was sealed and refluxed for

24h and cooled to room temperature. The solution was filtered through silica gel to remove catalysts. The filtrate was quenched with water (50 mL) and extracted with Et2O

(4×50 mL). The combined organic layers were dried over MgSO4 and volatiles were removed by rotary evaporation. The final product was purified by flash chromatography

(ethyl acetate: hexane=6:1). 4.7 was obtained as a white powder (0.19 g, 0.52 mmol,

71%)

1 H NMR (300 MHz, CDCl3)  Major isomer: 7.42–7.23 (m, 8H), 7.16 (m, 1H), 7.13 (m,

1H), 6.19 (m, 1H), 3.28 (ddd, J = 15.3, 2.4 Hz, 1H), 3.01 (dd, J = 6.6, 2.4 Hz, 1H), 2.89

(dd, J = 6.6 Hz, 1H), 2.65 (ddt, J = 15.3, 6.6, 2.4 Hz, 1H), 2.12 (ddd, J = 15.3, 3.7, 2.4 Hz,

1H), 1.53 (s, 3H).Minor isomer found: 3.18 (d, J = 15.3), 2.46 (d, J = 15.3), 2.34 (d, J =

15.3)

111

13 C NMR (300 MHz, CDCl3) Major isomer:  182.2, 178.4, 140.2, 140.0, 132.3, 129.4,

128.9, 128.6, 127.5, 126.4, 125.6, 123.5, 48.3, 45.5, 34.4, 28.3, 25.9.

Minor isomer found: 181.6, 178.3, 140.6, 140.3, 128.5, 125.5, 47.5, 45.1, 36.3, 25.4

+ + HRMS calcd for C21H19NO2 [M+H] = 318.1494, found [M+H] = 318.1494.

Major isomer: minor isomer = 2:1

Entry3 of Table VII: preparation of 4.7

Diene 2.40 (0.10 g, 0.49 mmol) and 2-methyl-N-phenylmaleimide (0.37 g , 1.96 mmol)

(1:4) were added to a N2 flushed high pressure resistance thick wall tube with Pd2(dba)3 and K2CO3 in acetonitrile and ethanol (10 mL). Iodobenzene (0.20 g, 0.98 mmol)

(diene:iodobenzene=1:2) was added to the mixture. The tube was sealed and refluxed for 24h and cooled to room temperature. The solution was filtered through silica gel to remove catalysts. The filtrate was quenched with water (50 mL) and extracted with Et2O

(4×50 mL). The combined organic layers were dried over MgSO4 and volatiles were removed by rotary evaporation. The final product was purified by flash chromatography

(ethyl acetate: hexane=6:1). 4.7 was obtained as a white powder (0.12 g, 0.39 mmol,

79%). 1H NMR was identical to that previously reported. 123

1 H NMR (300 MHz, CDCl3)  7.42–7.23 (m, 8H), 7.16 (m, 1H), 7.13 (m, 1H), 6.19 (m,

1H), 3.28 (ddd, J = 15.3, 2.4 Hz, 1H), 3.01 (dd, J = 6.6, 2.4 Hz, 1H), 2.89 (dd, J = 6.6 Hz,

112

1H), 2.65 (ddt, J = 15.3, 6.6, 2.4 Hz, 1H), 2.12 (ddd, J = 15.3, 3.7, 2.4 Hz, 1H), 1.53 (s,

3H).

Entry 4 of Table VII: preparation of 4.1

Diene 2.40 (0.10 g, 0.49 mmol) and ethyl acrylate (0.098 g , 0.98 mmol) (1:2) were added to a N2 flushed high pressure resistance thick wall tube with Pd2(dba)3 and K2CO3 in acetonitrile and ethanol (10 mL). Iodobenzene (0.20 g, 0.98 mmol)

(4×50 mL). The combined organic layers were dried over MgSO4 and volatiles were removed by rotary evaporation. The final product was purified by flash chromatography

(ethyl ether: hexane=1:1). 4.1 was obtained as a light yellow liquid. (0.071 g, 0.31 mmol,

63%).

1H NMR data was identical to that previously reported.131

1 H NMR (300 Hz, CDCl3)  7.39–7.28 (m, 4H), 7.22 (m, 1H), 6.11–6.08 (m, 1H), 4.169

(q, J = 7.3 Hz, 2H), 2.60 (m, 1H), 2.54–2.42 (m, 4H), 2.25–2.14 (m, 1H), 1.84 (m, 1H),

1.27 (t, J = 7.3 Hz, 3H).

Major isomer: minor isomer = 3:1

113

Entry 7 of Table VII: preparation of 4.7

Diene 2.38 (0.10g, 0.60mmol) and 2-methyl-N-phenylmaleimide (0.45 g , 2.40 mmol)

(1:4) were added to a N2 flushed high pressure resistance thick wall tube with Pd2(dba)3 and K2CO3 in acetonitrile and ethanol (10 mL). Iodobenzene (0.50 g, 2.4 mmol)

(diene:iodobenzene=1:4) was added to the mixture. The tube was sealed and refluxed for 24h and cooled to room temperature. The solution was filtered through silica gel to remove catalysts. The filtrate was quenched with water (50 mL) and extracted with Et2O

(4×50 mL). The combined organic layers were dried over MgSO4 and volatiles were removed by rotary evaporation. The final product was purified by flash chromatography

(ethyl acetate: hexane=6:1). 4.7 was obtained as a white powder (0.12 g, 0.39 mmol,

65%). 1H NMR was identical to that previously reported. 123

1 H NMR (300 MHz, CDCl3)  7.42–7.23 (m, 8H), 7.16 (m, 1H), 7.13 (m, 1H), 6.19 (m,

1H), 3.28 (ddd, J = 15.3, 2.4 Hz, 1H), 3.01 (dd, J = 6.6, 2.4 Hz, 1H), 2.89 (dd, J = 6.6 Hz,

1H), 2.65 (ddt, J = 15.3, 6.6, 2.4 Hz, 1H), 2.12 (ddd, J = 15.3, 3.7, 2.4 Hz, 1H), 1.53 (s,

3H).

Entry 8 of Table VII preparation of 4.7

Diene 2.39 (0.10g, 0.46mmol) and 2-methyl-N-phenylmaleimide (0.34 g, 1.83 mmol)

(1:4) were added to a N2 flushed high pressure resistance thick wall tube with Pd2(dba)3 and K2CO3 in acetonitrile and ethanol (10mL). Iodobenzene (0.37g, 1.83mmol)

114

(4×50 mL). The combined organic layers were dried over MgSO4 and volatiles were removed by rotary evaporation. The final product was purified by flash chromatography

(ethyl acetate: hexane=6:1). 4.7 was obtained as a white powder (0.10g, 0.33 mmol, 72%).

1H NMR was identical to that previously reported. 123

1 H NMR (300 MHz, CDCl3)  7.42–7.23 (m, 8H), 7.16 (m, 1H), 7.13 (m, 1H), 6.19 (m,

1H), 3.28 (ddd, J = 15.3, 2.4 Hz, 1H), 3.01 (dd, J = 6.6, 2.4 Hz, 1H), 2.89 (dd, J = 6.6 Hz,

1H), 2.65 (ddt, J = 15.3, 6.6, 2.4 Hz, 1H), 2.12 (ddd, J = 15.3, 3.7, 2.4 Hz, 1H), 1.53 (s,

3H).

115

CHAPTER 5 Unexpected Proton Deboronation Reactions

5.1 Rhodium Catalyzed Chemistry With 1-Alkyl-3-Boronate-1,3- Dienes

High diastereoselectivities and enantioselectivities in reactions have become primary tasks for organic chemists. Our project may also someday lead to the improvement of diastereoselectivities and enantioselectivities such as the construction of cis-decalin ring junctures and other natural products.132-134 The proposed catalytic cycle outlined below is an analog to Hayashi’s rhodium catalyzed 1,4 addition of organoboron reagents to enones.

Figure 5.1 Catalytic Cycle of Rhodium Catalysis

116

In the first step, the catalytic cycle starts with 1-alkyl-2-boronate-1,3-diene where the transmetallation occurs with rhodium catalysts.106 There would be an option to attach optically active ligands such as (R) or (S)- BINAP to induce controlled chirality into the product as demonstrated in various examples of rhodium catalyzed asymmetric 1,4 addition reactions.135-137 The next step of the cycle is the Diels–Alder reaction between a rhodium dienyl complex with a dienophile. It is also anticipated that the rhodium dienyl complex would be in a conformation close to s-cis and would react rapidly with a variety of dienophiles through exo transition states similar to the reported cobalt dienes.106, 138

The success of the overall scheme depends upon two factors106 (i) faster reactivity of the rhodium dienyl complex in [4 + 2] cycloadditions than the corresponding boron dienyl and (ii) its preferential reactivity towards [4 + 2] cycloaddition rather than 1,4-addition with dienophiles. The final step in the Hayashi reaction is demetallation where the rhodium carbon bond is cleaved via hydrolysis and regeneration of the catalyst occurs.

We have tried some rhodium catalysis of diethanolamine borate diene 2.4. Because this diene is very reactive in Diels-Alder reaction with N-phenyl maleimide, we chose the ethyl acrylate and 2-methyl –N-phenyl maleimide to do rhodium catalysis after the control experiments showed negative results. Other boronate dienes and dienophiles also have been tested in this reaction, with the results summarized in Table IX.

Table IX Rhodium Catalyzed Reactions

0 Entry Diene Dienophile Solvent/H2O Catalyst T( C) Ligand Base T(h) Product

1 Toluene/ rt 19 no 2.4 Rh(COD)2OTf

117

H2O (5:1)

Toluene/ 2 40 20 no 2.4 Rh(COD) OTf H O (5:1) 2 2

3 Toluene 50 20 D-A 2.4 Rh(COD)2OTf

4 Toluene 50 20 trace 2.4 Rh(COD)2OTf

Toluene/ 5 50 20 no 2.4 Rh(COD)2OTf H2O (5:1)

Toluene/ 6 rt 20 no 2.4 Rh(COD)2OTf H2O (5:1)

Toluene/ 7 50 20 no 2.4 Rh(COD)2OTf H2O (5:1)

Toluene/ 8 rt BINAP 20 no 2 Rh(COD)2OTf H2O (5:1)

Toluene/ 9 50 BINAP 20 no 2 Rh(COD)2OTf H2O (5:1)

Toluene/ 10 100 BINAP 20 no 2 Rh(COD)2OTf H2O (5:1)

11 Toluene/ rt KOH 17 no 2 Rh(COD)2OTf BINAP H2O (5:1)

12 Toluene/ 50 KOH 17 no 2 Rh(COD)2OTf BINAP H2O (5:1)

Dioxane/ 13 50 KOH 17 no 2 CH3OH Rh(COD)2OTf BINAP (5:1)

14 1 THF/ 55 Et N 36 trace Rh(COD) OTf 3 2 H2O(10:1)

118

THF/ 15 2 no Rh(COD)2OTf 55 Et3N 36 H2O(10:1)

THF/ 16 3 no Rh(COD) OTf 55 Et N 36 H O(10:1) 2 3 2

Toluene/ 2.40 BINAP no Rh(COD)2OTf 55 12 H2O (5:1)

Toluene/ 18 2.40 BINAP no Rh(COD)2OTf 55 12 H2O (5:1)

Toluene/

C2H5OH 19 2.40 BINAP no Rh(COD)2OTf 55 12 (5:1)

Toluene/

C2H5OH 20 2.40 BINAP D-A Rh(COD) OTf 55 14 (5:1) 2

Toluene/

C2H5OH 21 2.40 BINAP D-A Rh(COD) OTf 55 14 (5:1) 2

Toluene/

(CH3)3COH 22 2.40 BINAP trace Rh(COD)2OTf 55 18 (20:1)

Toluene/

(CH3)3COH 23 2.40 BINAP 70 Cu(OTf)2 90 24 (20:1)

119

Toluene/

(CH3)3COH 24 2.40 BINAP D-A Cu(OTf) 90 24 (20:1) 2

Toluene/

(CH3)3COH 25 2.4 BINAP D-A Cu(OTf) 90 24 (20:1) 2

Toluene/

(CH3)3COH 26 2.4 s-BINAP D-A Cu(OTf) 90 24 (20:1) 2

Toluene/

(CH3)3COH 27 2.4 Cu(OTf) / BINAP 82 2 90 36 (20:1) Rh(COD) OTf 2

Toluene/

(CH3)3COH 28 2.40 Cu(OTf) / BINAP 80 2 90 36 (20:1) Rh(COD)2OTf

Diene 2.4: , diene 2: diene 3:

The rhodium dienyl complex must be more reactive than the boron dienyl starting materials in the subsequent Diels-Alder reactions if enantioselective catalysis is ever to be successful one day. So, the boron substituted diene has to be slow in Diels-Alder reactions and fast in transmetallation. In Table IX, entry 27, the first reaction is a better choice for us to try rhodium catalysis. In the transmetallation step, it has be to faster than

120

hydrolysis of the carbon-rhodium bond to finish the cycle. Different catalysts and different solvents have been tried. We started with the solvents that have been used by

139 other chemists and former students: toluene/H2O, dioxane, toluene /t-butanol. Also, different temperatures: room temperature, 50ºC and refluxing. Toluene/H2O and dioxane have been tried and we found water decomposed the dienes. Toluene /t-butanol showed good stability and reactivity in the reaction.

In Table IX, entries 1,2,5-7, diene 2.4 decomposed in the reaction , and we only got dienophile back. The reason might be that water is not a good proton provider for dienes or, nitrogen in diene 2.4 coordinated with rhodium catalyst and deactivated diene 2.4. In entry 4, after we used water to separate the product, trace product was seen by GC-MS.

When the water was used again in entry 5, no product was found. Two silane substituted dienes were also tried in this reaction, but no product was found (entries 8-16). In entry

14 we also saw trace product by GC but we could not improve the yield with this diene.

So, we suspect that dienes 2.4 and 2.6 are not good diene partners in rhodium catalysis, or else the dienophile (2-methyl-N-phenylmalemide) is not a good choice. Then other possible boronate dienes and dienophiles were also tested in this reaction. In entries 17-

19, diene 2.40 was used but no products were found. In entries 17-19, we found ethanol can decompose N-phenyl maleimide as shown in Scheme 5.1. From COSY, HMBC and

HMQC, these two structures, 5.1 and 5.2 have similar signals and no further attempts were made to assign a product structure.

121

Scheme 5.1 Then another proton source, t-butanol was used to replace ethanol and a positive result was obtained in entry 23 when copper triflate acted as the catalyst. Finally we found the best conditions (entries 27 & 28) to get the desired products. Rhodium and copper catalysis is the best catalysis system and the optimized solvent is toluene/t-butyl methanol in 900C for 36 hours. (Scheme 5.2)

Scheme 5.2

122

Scheme 5.3 Some boron substituted Diels-Alder cycloadduct was found in the final product (5%,

NMR). This result implies that the mechanism of this reaction might not follow the mechanism we proposed in Figure 5.1. Chiral HPLC was used to separate the enantiomers 5.3 of the product and we found the chiral BINAP ligand did not influence the reaction. The two enantiomers of product 5.3 were obtained as a 1:1 mixture. The mechanism follows the path in Scheme 5.3. There might be two reasons in this reaction:

1) Boron substituted dienes do not transmetallate well to rhodium or copper. 2) The rate of boron substituted dienes reacting with dienophiles is faster than transmetallation.

5.2 Conclusion

The rhodium catalytic cycle has been tried with various boron substituted dienes and dienophiles. Although the final product was achieved in good yield, the mechanism was 123

ddifferent from the original proposal. This catalytic system is not a good choice for rhodium catalysis through transmetallation. However, from the result of the tandem D-

A/Suzuki cross coupling reactions, an intermediate palladium substituted diene was observed in NMR tube (Scheme 4.5). We can expect the replacement of palladium for rhodium may be a good future choice in this catalytic cycle (Figure 5.2).

Figure 5.2 Catalytic Cycle of Palladium Catalysis

5.3 Experimental and Characterization Data

Preparation of 3a-methyl-2-phenyl-3a, 4, 7, 7a-tetrahydro-1H-isoindole-1,3(2H)-dione

5.3 (Table IX, Entry 27)

124

Diene 2.4 (83.5 mg, 0.5 mmol) was added to a N2 flushed thick wall tube with

Rh(COD)2OTf (18.7 mg, 0.04 mmol, 8%) , Cu(OTf)2 (19.91 mg,0.055 mmol, 11%) and

(S)-BINAP (20 mg, 0.03 mmol, 6%) in toluene (10 mL) at rt for 30 mins. 2-Methyl-N- phenyl-maleimide (93.5 mg, 0.5 mmol) was added to the mixture followed by t-butanol

(0.5 mL). The tube was sealed and heated up to reflux for 36 h then cooled to room temperature. The solution was filtered through a silica gel pad to remove catalysts. The filtrate was quenched with water (30 ml) and extracted with Et2O (3×50 mL). The combined organic layers were dried over MgSO4 and volatiles were removed by rotary evaporation. The resulting residue was purified by chromatography (ethyl ether: hexane =

1:4). The final product was obtained as a white powder (0.099 g, 0.41mmol, 82%).

1H NMR (300 MHz, CDCl3)  7.45(m, 3H), 7.24(m, 2H), 5.98(m, 2H), 2.84(m, 1H),

2.72(m, 1H), 2.66 (m, 1H), 2.33(m, 1H), 2.00(m, 1H), 1.46 (s, 3H).

13C NMR (300 MHz, CDCl3)  161.9, 176.3, 132.1, 129.0, 126.5, 126.1, 127.7, 127.5,

126.7, 47.4, 44.3, 32.7, 24.5, 23.9. HRMS calcd for C15H15NO2 =241.1103, found

241.1103.

Preparation of 2-phenyl-3a, 4, 7, 7a-tetrahydro-1H-isoindole-1,3(2H)-dione 5.4 (Table

IX, Entry 28)

125

Diene 2.40 (102 mg, 0.5 mmol) was added to a N2 flushed thick wall tube with

Rh(COD)2OTf (18.7 mg, 0.04 mmol, 8%) , Cu(OTf)2 (19.91 mg,0.055 mmol, 11%) and

(S)-BINAP (20 mg, 0.03 mmol, 6%) in toluene (10 mL) in rt for 30 mins. N-phenylmaleimide (87 mg, 0.5 mmol) was added to the mixture followed by t-butanol (0.5 mL).

The tube was sealed and heated up to reflux for 36 h then cooled to room temperature.

The solution was filtered through a silica gel pad to remove catalysts. The filtrate was quenched with water (30ml) and extracted with Et2O (3×50 mL). The combined organic layers were dried over MgSO4 and volatiles were removed by rotary evaporation. The resulting residue was purified by chromatography (ethyl ether: hexane = 1:4). The final product was obtained as a white powder (0.090 g, 0.40 mmol, 80%).1H NMR data was identical to that previously reported.50

1 H NMR (300 MHz, CDCl3)  7.32–7.47 (m, 3H), 7.22 (m, 2H), 5.98 (m, 2H), 3.25 (m,

2H), 2.74 (dq, J = 2.2, 2.2, 2.0, 4.0 Hz, 1H), 2.69 (dq, J = 2.2, 2.2, 2.0, 4.0 Hz, 1H), 2.34

13 (m, 1H), 2.28 (m, 1H). C NMR (300 MHz, CDCl3)  179.1, 132.0, 129. 1, 128.5, 127. 3,

126.4, 39.2, 23.7

Preparation of 2-phenyl-3a, 4, 7, 7a-tetrahydro-1H-isoindole-1,3(2H)-dione 5.4 (Table

IX, Entry 23)

Diene 2.40 (102 mg, 0.5 mmol) was added to a N2 flushed thick wall tube with

Cu(OTf)2 (19.91 mg,0.055 mmol, 11%) and (S)-BINAP (20 mg, 0.03 mmol, 6%) in toluene (10 mL) at rt for 30 mins. Then N-phenyl-maleimide (87 mg, 0.5 mmol) was

126

added to the mixture followed by t-butanol (0.5 mL). The tube was sealed and heated up to 55˚C for 24 h then cooled to room temperature. The solution was filtered through a silica gel pad to remove catalysts. The filtrate was quenched with water (30 mL) and extracted with Et2O (3×50 mL). The combined organic layers were dried over MgSO4 and volatiles were removed by rotary evaporation. The resulting residue was purified by chromatography (etheyl ether: hexane = 1:4). The final product was obtained as a white powder (0.079 g, 0.35 mmol, 70%). 1H NMR data was identical to that previously reported.

1 H NMR (300 MHz, CDCl3)  7.32–7.47 (m, 3H), 7.22 (m, 2H), 5.98 (m, 2H), 3.25 (m,

2H), 2.74 (dq, J = 2.2, 2.2, 2.0, 4.0 Hz, 1H), 2.69 (dq, J = 2.2, 2.2, 2.0, 4.0 Hz, 1H), 2.34

13 (m, 1H), 2.28 (m, 1H). C NMR (300 MHz, CDCl3)  179.1, 132.0, 129. 1, 128.5, 127. 3,

126.4, 39.2, 23.7

127

CHAPTER 6 CONCLUSIONS

The dimerization of boron substituted dienes were resolved. A series of monomers of tri- and tetra coordinated boron substituted dienes were prepared at low temperature.

Tetra- coordinated boron substituted dienes were proven to be more active than tri- coordinated complexes. High yields and regioselectivities were found in the D-A reactions and maintained in Suzuki Miyaura cross coupling reactions. Boron substituted dienes are good synthons for a host of organic dienes via D-A/cross coupling reactions. A possible new intermediate palladium substituted diene was observed in mechanism research. The stability varies with the different ligands coordinated with Pd.

128

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146

APPENDIX A Crystal Structure Data of Diene 2.4

Structure a22n / C8H14NO2B – CHCl3

X-Ray Crystallographic Comments

X-ray crystallographic data has been deposited with the CCDC and allocated dposition number CCDC 736603. The asymmetric unit in crystalline C8H14NO2B – CHCl3 contains one C8H14NO2B molecule and one chloroform molecule of crystallization. All displacement ellipsoids are drawn at the 50% probability level.

Brief Experimental Description to be Included as Text or as a Footnote at Time of

Publication

Colorless plate-shaped crystals of C8H14NO2B – CHCl3 are, at 203(2) K,

9 orthorhombic, space group Pna21 – C 2v (No. 33) (1) with a = 19.587(3) Å, b = 7.742(1)

3 3 Å, c = 9.104(1) Å, V = 1380.6(3) Å and Z = 4 formula units {dcalcd = 1.378 g/cm ;

-1 a(MoK ) = 0.648 mm }. A full hemisphere of diffracted intensities (1968 30-second frames with a  scan width of 0.30) was measured for a single domain specimen using graphite-monochromated MoK radiation (= 0.71073 Å) on a Bruker SMART APEX

CCD Single Crystal Diffraction System (2). X-rays were provided by a fine-focus sealed x-ray tube operated at 50kV and 30mA.

Lattice constants were determined with the Bruker SAINT software package using peak centers for 1895 reflections having 8.07°≤ 2 ≤ 40.42°. A total of 10091

147

integrated absorption-corrected reflection intensities having 2((MoK )< 49.98 were produced using the Bruker program SAINT(3); 2411 of these were unique and gave Rint =

0.040 with a coverage which was 99.5% complete. The Bruker software package

SHELXTL was used to solve the structure using “direct methods” techniques. All stages

2 of weighted full-matrix least-squares refinement were conducted using Fo data with the

SHELXTL Version 6.12 software package(4).

The final structural model incorporated anisotropic thermal parameters for all nonhydrogen atoms and isotropic thermal parameters for all hydrogen atoms.

All hydrogen atoms on the diene (H1A, H1B, H3, H4A and H4B) as well as the amine hydrogen atom (H1N) were located in a difference Fourier and included in the structural model as independent isotropic atoms whose parameters were allowed to vary in least-squares refinement cycles. The remaining hydrogen atoms were included in the structural model as fixed atoms (using idealized sp3-hybridized geometry and C-H bond lengths of 0.98 – 0.99 Å) "riding" on their respective carbon atoms. The isotropic thermal parameters for these hydrogen atoms were fixed at a value 1.2 times the equivalent isotropic thermal parameter of the carbon atom to which they are covalently bonded. A total of 169 parameters were refined using one restraint and 2411 data. Final agreement factors at convergence are:

R1(unweighted, based on F) = 0.045 for 2083 independent “observed” reflections having 2(MoK )< 49.98 and I>2(I); R1(unweighted, based on F) = 0.053

2 and wR2(weighted, based on F ) = 0.096 for all 2411 independent reflections having 2(MoK )< 49.98. The largest shift/s.u. was 0.000 in the final refinement cycle. The final difference map had maxima and minima of 0.258 and

148

3 -0.167 e-/Å , respectively. The absolute structure was determined by refinement of the Flack parameter x (5) ; x refined to a final value of 0.03(8) .

Acknowledgment

The authors thank the National Science Foundation (grant CHE-0234489) for funds to purchase the x-ray instrument and computers.

References

(1) International Tables for Crystallography, Vol A, 4th ed., Kluwer Academic

Publishers: Boston (1996).

(2) Data Collection: SMART (Version 5.628) (2002). Bruker-AXS, 5465 E. Cheryl

Parkway, Madison, WI 53711-5373 USA.

(3) Data Reduction: SAINT (Version 6.45) (2003). Bruker-AXS, 5465 E. Cheryl

Parkway, Madison, WI 53711-5373, USA and Sheldrick, G. M. (2006). SADABS

(Version 2006/3). University of G öttingen, Germany..

(4) G. M. Sheldrick (2001). SHELXTL (Version 6.12). Bruker-AXS, 5465 E. Cheryl

Parkway, Madison, WI 53711-5373 USA.

(5) Flack, H. D. (1983). Acta Cryst. A39, 876-881.

Table 1. Crystal data and structure refinement for C8H14NO2B – CHCl3

Identification code a22nfinal

Empirical formula C9 H15 B Cl3 N O2

149

Formula weight 286.38

Temperature 203(2) K

Wavelength 0.71073 Å

Crystal system Orthorhombic

9 Space group Pna21 - C 2v (No. 33)

Unit cell dimensions a = 19.587(3) Å

b = 7.742(1) Å

c = 9.104(1) Å

Volume 1380.6(3) Å3

Z 4

Density (calculated) 1.378 g/cm3

Absorption coefficient 0.648 mm-1

F(000) 592

Crystal size 0.30 x 0.09 x 0.04 mm3

Theta range for data collection 4.03 to 24.99°

Index ranges -23≤h≤23, -9≤k≤9, -10≤l≤10

Reflections collected 10091

Independent reflections 2411 [R(int) = 0.0396]

Completeness to theta = 24.99° 99.5 %

Absorption correction Multi-scan (SADABS)

Max. and min. transmission 0.8383 and 0.6862

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 2411 / 1 / 169

150

Goodness-of-fit on F2 1.105

Final R indices [I>2σ(I)] R1 = 0.0446, wR2 = 0.0924

R indices (all data) R1 = 0.0534, wR2 = 0.0961

Absolute structure parameter 0.03(8)

Largest diff. peak and hole 0.258 and -0.167 e-/Å3

------

R1 =  ||Fo| - |Fc|| /  |Fo|

Replace

Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters

(Å2x 103) for C8H14NO2B – CHCl3. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

______

x y z U(eq)

______

Cl(1) 2882(1) 2158(2) 2449(1) 83(1)

Cl(2) 2277(1) 2273(2) 5318(2) 88(1)

Cl(3) 2845(1) -875(1) 4234(1) 79(1)

C(9) 2923(2) 1369(4) 4236(4) 46(1)

151

B(1) 4744(2) 3757(5) 6048(4) 33(1)

N(1) 4623(1) 5484(3) 7112(3) 33(1)

O(1) 5329(1) 4375(3) 5169(2) 39(1)

O(2) 4119(1) 3711(3) 5208(2) 38(1)

C(1) 5536(2) 1348(5) 6878(6) 64(1)

C(2) 4910(2) 2020(4) 6950(3) 38(1)

C(3) 4414(2) 1167(4) 7904(4) 50(1)

C(4) 3760(2) 1477(6) 8032(5) 60(1)

C(5) 5713(2) 5560(4) 6025(4) 40(1)

C(6) 5189(2) 6688(4) 6739(4) 41(1)

C(7) 3834(2) 5403(4) 5161(4) 44(1)

C(8) 3932(2) 6101(4) 6696(4) 44(1)

______

152

Table 3. Bond lengths [Å] and angles [°] for C8H14NO2B – CHCl3

______

Cl(1)-C(9) 1.739(4) Cl(3)-C(9) 1.744(4)

Cl(2)-C(9) 1.749(3)

B(1)-O(2) 1.445(4) B(1)-C(2) 1.609(5)

B(1)-O(1) 1.477(4) B(1)-N(1) 1.668(4)

N(1)-C(8) 1.483(4) N(1)-C(6) 1.488(4)

N(1)-H(1N) 0.84(3)

O(1)-C(5) 1.419(4) O(2)-C(7) 1.424(4)

C(1)-C(2) 1.334(5) C(1)-H(1A) 0.89(4)

C(2)-C(3) 1.461(5) C(1)-H(1B) 0.99(5)

C(3)-C(4) 1.308(6) C(3)-H(3) 0.90(4)

C(5)-C(6) 1.496(4) C(4)-H(4A) 0.99(4)

C(7)-C(8) 1.511(5) C(4)-H(4B) 0.98(3)

Cl(1)-C(9)-Cl(3) 110.2(2) Cl(3)-C(9)-Cl(2) 109.6(2)

Cl(1)-C(9)-Cl(2) 110.7(2)

153

O(2)-B(1)-O(1) 112.3(3) C(8)-N(1)-C(6) 114.8(2)

O(2)-B(1)-C(2) 114.9(3) C(8)-N(1)-B(1) 103.9(2)

O(1)-B(1)-C(2) 113.0(2) C(6)-N(1)-B(1) 105.3(2)

O(2)-B(1)-N(1) 101.9(2) C(8)-N(1)-H(1N) 109.4(19)

O(1)-B(1)-N(1) 99.5(2) C(6)-N(1)-H(1N) 109.2(19)

C(2)-B(1)-N(1) 113.7(2) B(1)-N(1)-H(1N) 114(2)

C(5)-O(1)-B(1) 108.8(2) C(7)-O(2)-B(1) 109.0(2)

C(2)-C(1)-H(1A) 118(3) C(4)-C(3)-C(2) 128.4(4)

C(2)-C(1)-H(1B) 115(2) C(4)-C(3)-H(3) 111(2)

H(1A)-C(1)-H(1B) 125(4) C(2)-C(3)-H(3) 120(3)

C(1)-C(2)-C(3) 117.7(4) C(3)-C(4)-H(4A) 119(2)

C(1)-C(2)-B(1) 119.1(3) C(3)-C(4)-H(4B) 124(2)

C(3)-C(2)-B(1) 123.2(3) H(4A)-C(4)-H(4B) 117(3)

O(1)-C(5)-C(6) 104.7(2)

N(1)-C(6)-C(5) 104.1(2)

O(2)-C(7)-C(8) 104.6(3)

N(1)-C(8)-C(7) 103.7(2)

154

______

____

Table 4. Anisotropic displacement parameters (Å2x 103) for C8H14NO2B – CHCl3.

The anisotropic displacement factor exponent takes the form: -2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ]

______

U11 U22 U33 U23 U13 U12

______

Cl(1) 68(1) 116(1) 65(1) 39(1) -13(1) -34(1)

Cl(2) 55(1) 103(1) 105(1) -23(1) 21(1) 8(1)

Cl(3) 96(1) 56(1) 83(1) 7(1) 3(1) -4(1)

C(9) 32(2) 60(2) 45(2) 1(2) -1(2) -6(2)

B(1) 34(2) 40(2) 24(2) -4(2) 1(1) -3(2)

N(1) 44(2) 33(1) 22(1) 1(1) 0(1) -3(1)

O(1) 38(1) 52(1) 27(1) -6(1) 3(1) -11(1)

O(2) 37(1) 42(1) 35(1) -7(1) -5(1) -5(1)

C(1) 56(2) 36(2) 99(4) -3(2) -18(3) 3(2)

C(2) 44(2) 31(2) 40(2) -9(1) -7(2) -5(1)

C(3) 78(3) 28(2) 43(2) 2(2) 1(2) -4(2)

C(4) 75(3) 50(2) 55(2) 0(2) 18(2) -16(2)

155

C(5) 45(2) 45(2) 31(2) 6(2) -2(1) -17(2)

C(6) 58(2) 34(2) 29(2) 5(1) -3(2) -13(2)

C(7) 38(2) 49(2) 45(2) 2(2) -10(2) 0(1)

C(8) 49(2) 39(2) 43(2) -1(2) 3(2) 9(2)

______

156

Table 5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10

3) for C8H14NO2B – CHCl3

______

x y z U(eq)

______

H(9) 3371 1682 4663 55

H(1N) 4632(13) 5280(40) 8010(40) 26(8)

H(1A) 5620(20) 360(60) 7360(50) 67(13)

H(1B) 5830(20) 1820(60) 6080(50) 84(15)

H(3) 4543(19) 280(50) 8480(50) 63(12)

H(4A) 3490(20) 800(50) 8730(50) 76(13)

H(4B) 3523(16) 2410(40) 7500(40) 49(10)

H(5A) 6019 6244 5402 48

H(5B) 5986 4952 6764 48

H(6A) 5373 7234 7626 49

H(6B) 5033 7591 6063 49

H(7A) 3348 5360 4905 53

H(7B) 4073 6123 4440 53

H(8A) 3911 7366 6704 52

157

H(8B) 3585 5645 7367 52

______

158

Table 6. Torsion angles [°] for C8H14NO2B – CHCl3

______

O(2)-B(1)-N(1)-C(8) 1.0(3)

O(1)-B(1)-N(1)-C(8) 116.4(2)

C(2)-B(1)-N(1)-C(8) -123.2(3)

O(2)-B(1)-N(1)-C(6) -120.0(2)

O(1)-B(1)-N(1)-C(6) -4.7(3)

C(2)-B(1)-N(1)-C(6) 115.7(3)

O(2)-B(1)-O(1)-C(5) 136.3(3)

C(2)-B(1)-O(1)-C(5) -91.8(3)

N(1)-B(1)-O(1)-C(5) 29.2(3)

O(1)-B(1)-O(2)-C(7) -81.2(3)

C(2)-B(1)-O(2)-C(7) 147.8(3)

N(1)-B(1)-O(2)-C(7) 24.4(3)

O(2)-B(1)-C(2)-C(1) 132.9(3)

O(1)-B(1)-C(2)-C(1) 2.3(4)

N(1)-B(1)-C(2)-C(1) -110.2(3)

O(2)-B(1)-C(2)-C(3) -49.7(4)

O(1)-B(1)-C(2)-C(3) 179.7(3)

N(1)-B(1)-C(2)-C(3) 67.2(4)

C(1)-C(2)-C(3)-C(4) -172.2(4)

B(1)-C(2)-C(3)-C(4) 10.4(5)

B(1)-O(1)-C(5)-C(6) -43.9(3)

159

C(8)-N(1)-C(6)-C(5) -133.0(3)

B(1)-N(1)-C(6)-C(5) -19.3(3)

O(1)-C(5)-C(6)-N(1) 38.3(3)

B(1)-O(2)-C(7)-C(8) -41.2(3)

C(6)-N(1)-C(8)-C(7) 90.6(3)

B(1)-N(1)-C(8)-C(7) -23.9(3)

O(2)-C(7)-C(8)-N(1) 40.0(3)

______

160

Table 7. Hydrogen bonds for C8H14NO2B – CHCl3 [Å and °].

______

____

D-H...A d(D-H) d(H...A) d(D...A) <(DHA)

______

____

N(1)-H(1N)...O(1)#A 0.84(3) 1.98(3) 2.787(3) 161(3)

______

____

Symmetry transformations used to generate equivalent atoms:

#A -x+1,-y+1,z+1/2

161

Least-squares planes (x,y,z in crystal coordinates) and deviations from them

(* indicates atom used to define plane)

Plane 1

5.0842 (0.0326) x + 4.2998 (0.0122) y + 7.1928 (0.0087) z = 8.3678 (0.0147)

* -0.0260 (0.0017) C1

* -0.0035 (0.0027) C2

* 0.0632 (0.0029) C3

* -0.0437 (0.0020) C4

* 0.0101 (0.0009) B1

-0.0590 (0.0048) O1

-0.9320 (0.0049) O2

1.4560 (0.0051) N1

Rms deviation of fitted atoms = 0.0366

Plane 2

5.7480 (0.0488) x + 4.3356 (0.0097) y + 7.0537 (0.0071) z = 8.6119 (0.0210)

Angle to previous plane (with approximate esd) = 2.15 ( 0.24 )

162

* -0.0056 (0.0010) O1

* 0.0102 (0.0019) B1

* -0.0112 (0.0021) C2

* 0.0065 (0.0012) C1

0.0063 (0.0055) C3

-0.1446 (0.0079) C4

Rms deviation of fitted atoms = 0.0087

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Selected plots

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Projection down b axis of unit cell

Dashed lines represent hydrogen-bonding interactions

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Intermolecular Hydrogen-bonding Interaction

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Projection down c axis of unit cell

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APPENDIX B NOESY and COSY of Boron Substituted Dienes

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CURRICULUM VITAE

LIQIONG WANG

Born April 12th, 1975, Yunnan, China

UNDERGRADUATE Yunnan Normal University, Kunming, STUDY(B.S.) Yunnan, China, 1996

GRADUATE STUDY: (M.S.) Huazhong University of Science and Technology, Wuhan, Hubei, China, 2003

GRADUATE STUDY: (Ph.D.) Wake Forest University Winston Salem, North Carolina, USA 2006-present

SCHOLASTIC AND PROFESSIONAL EXPERIENCE:

Qujing Normal University – Teacher 2003-2006

Wake Forest University – Teaching Assistant 2006 – 2007

Wake Forest University – Research Assistant 2007-2012

HONORS AND AWARDS

Alumni Travel Award, Wake Forest University, 2009

Alumni Travel Award, Wake Forest University, 2010

Alumni Travel Award, Wake Forest University, 2011

PROFESSIONAL SOCIETIES

American Chemical Society, August 2007 to present, Organic Chemistry Division

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PUBLICATIONS

Liqiong Wang, Mark E. Welker. Tandem Diels-Alder/Suzuki reactions of 2-boron substituted 1,3-dienes. Manuscript under preparation.

Liqiong Wang, Cynthia S. Day, Marcus W. Wright, Mark E. Welker. Preparation and Diels-Alder/cross coupling reactions of a 2-diethanolaminoboron-substituted 1,3-diene. Beilstein Journal of Organic Chemistry, 2009, 5, No. 45.

Subhasis De; John M. Solano, Liqiong Wang, Mark E. Welker. Rhodium catalyzed tandem Diels-Alder/hydrolysis reactions of 2-boron-substituted 1,3-dienes. Journal of Organometallic Chemistry 2009, 694(15), 2295-2298.

PRESENTATIONS

Liqiong Wang; Mark E. Welker. Palladium Catalyzed Boron Substituted Dienes. (Oral) Abstracts of papers, 63rd Southeast Regional Meeting of the American Chemical Society, Richmond, VA, United States, October 26-29, 2011

Liqiong Wang; Mark E. Welker; Marcus W. Wright, Cynthia Day. Synthesis and fast Diels-Alder/cross coupling reactions of boron substituted 1,3-dienes. (Oral) Abstracts of papers, 240th ACS National Meeting, Boston, MA, United States, August 22-26, 2010

Liqiong Wang; Mark E. Welker; Marcus W. Wright, Cynthia Day. Preparation and Diels-Alder/Cross Coupling Reactions of Boron Substituted 1,3-Dienes. (Oral) Abstracts of papers, 61st Southeast Regional Meeting of the American Chemical Society, San Juan, Puerto Rico, October 21-24 ,2009

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