Ring-Opening Reactions of Cyclopropanated Heterobicyclic Alkenes

Ring-opening Reactions of Cyclopropanated Heterobicyclic Alkenes

by Emily Terada Carlson

A Thesis presented to The University of Guelph

In partial fulfilment of requirements for the degree of Doctor of Philosophy in Chemistry

Guelph, Ontario, Canada

 Emily Terada Carlson, August, 2016

ABSTRACT

RING-OPENING REACTIONS OF CYCLOPROPANATED HETEROBICYCLIC ALKENES

Emily Terada Carlson Advisor: University of Guelph, 2016 Prof. William Tam

Synthetic organic chemistry centers around the development of useful reaction sequences.

The primary objectives are to improve chemical transformations by making them more efficient and economical, to derive novel compounds and make them widely accessible, and to provide the scientific community with a better understanding of chemical behaviour so that new processes can be applied in the manufacture of similar structures, often with medicinal value. This thesis describes the construction of various novel heterotricyclo[3.2.1.02,4]octanes, and their subsequent ring-opening reactions to afford uniquely functionalized and structurally appealing organic frameworks.

The first part of this work concerns the preparation of some common heterobicyclic alkenes and their derivatization by palladium-catalyzed diazocyclopropanation. This produced over 40 novel cyclopropanes with satisfactory yields (64-98%) and complete exo stereoselectivity. A higher equivalency of diazomethane was required to drive the reaction to completion for substrates bearing bulky substituents near the cyclopropanation site.

Later portions of this work address transition metal or acid-catalyzed ring-opening reactions of the cyclopropanated heterobicycloalkenes, focusing on 7-oxa and 7- azabenzonorbornadienes. These studies have been subdivided into three types, each providing a unique class of product(s).

Type 1 ring-openings led to the formation of cis-1,2-dihydro-2-methylnaphthalenols or polycyclic γ-lactams with facile incorporation of alkyl or aryl nucleophiles from organocuprates.

Aromatization could be utilized to convert the dihydronaphthalenols to 2-methylnaphthalenes.

Type 2 ring-openings proceeded with thermal acid-catalyzed conditions using alcohol or carboxylic acid nucleophiles, producing 2-(XCH2)naphthalenes (X=RO, RCO2). The reaction rate was found to increase with the acidity of the reaction medium.

Type 3 ring-openings were discovered in conjunction with type 2-ring opening studies when bridgehead-substituted cyclopropanated oxabenzonorbornadienes underwent expansion to benzo-fused seven-membered rings. A greater proportion of type 3 product relative to type 2 product was obtained at lower reaction temperatures.

Mechanisms for each transformation were supported by intramolecular reactions of cyclopropanated azabenzonorbornadienes under type 1 ring-opening conditions, or by tethered nucleophile-bearing substrates under type 2 and type 3 ring-opening conditions. Thus, several more novel polycyclic lactams, lactones and cyclic ethers were born. As the substrates of this investigation are still largely unexplored, future work in this area is promising.

Acknowledgments

Thank you, William, for your constant support and for making this thesis work possible.

Your guidance over the years has given me confidence in my work and helped me ask more critical questions. Thank you Professors Schwan, Manderville and Dmitrienko for being on my Advisory

Committee and for encouraging me to think outside the box. To my Examination Committee members whom I am grateful to have the opportunity to meet - Professor Christine Gottardo and

Professor Michael Denk - your critique is very much appreciated. Also, thank you William, Adrian,

Selim, and Mike for showing me in my undergraduate years that I could pursue my passion in a field that I was a total novice to.

To the Tam Group members and friends I’ve had the opportunity to work with - thank you for your patience and willingness to share your knowledge with me. Especially Katrina and Beka:

I really couldn’t ask for better lab mates. Thanks for inspiring me with your team efforts, and for organizing events for the group like the escape room or trivia nights, as well as cooking and dinner parties at your place. It’s been really fun.

I’d like to thank friends and faculty of the department including Professors Lori Jones,

Glenn Penner, Aziz Houmam, and Kate Stuttaford, who have had a strong impact on my early years of chemical education, not to mention former students Mike Sproviero, Chad, Jordan, Stefan,

Renee and Neil for being great role models. A special thank you to Linda Allen for shaping my path - I miss you very much. Thanks Rob for all your help in safety and lab techniques and to

Wojciech for providing office space to our group in difficult times. Thanks to NMR Centre members Peter, Valerie, Andy and Sameer for sharing your knowledge, to Dr. Wang and Dr.

Lough for MS and XRD analysis, and to Dr. Blanchard’s group for providing us with N-O or N-

N bicyclic alkenes. Thanks also to the Machine Shop, Electronics Shop, and everyone else who

v has helped me along the way, including Aaron, Adam, Erwin and Matt. I am grateful to our department, the University of Guelph and (GWC)2 for providing me with several graduate scholarships, and a wonderful learning environment.

Finally, a note to my family and friends: I’d like to thank my parents and Obachama in

Japan and my grandparents in Michigan for all their love, and for supporting my choice to study in Canada. Papa, thanks for homeschooling me and fostering my interest in science. 日本を離れ

て 8 年間、遠くからえみちゃんの事を見守ってくれて、ありがとう。Grandma and

Grandpa, thanks for keeping me company via Skype each weekend, and for letting me visit Vista on the longer breaks. To the Moores and Robertsons, thank you for warmly embracing me, and for introducing me to your fun family traditions. The use of Grumps’ car has also been a big help in the last couple years. Mike, I really can’t thank you enough for being such a loving and understanding Fiancé. We’ve been through a lot together, but your optimism has always kept me going strong. Thanks for listening to me talk about organic chemistry. Also, thanks to the Jugglers of the University of Guelph. Our gatherings and road trips helped punctuate my work so I could return to the lab with even more ambition.

A quote from a disputable source says “It is good to have an end to journey toward; but it is the journey that matters, in the end.” My time at the University of Guelph has been a truly rewarding experience, and it will always be a memory that I prize.

A sincere thank you to all.

Table of Contents

Table of Contents vi List of Supporting Data and Appendices ix List of Tables x List of Figures xi List of Schemes xii List of Abbreviations and Symbols xviii

Chapter 1: Introduction

1.1 - Heterobicycloalkenes 2

1.2 - Ring-Opening Reactions of Oxa- and Azabenzonorbornadienes 4

1.3 - Synthesis of Oxa- and Azabenzonorbornadienes 10

1.3.1 - General Overview 10 1.3.2 - Preparation of Arynes 11 1.3.3 - Preparation of Substituted Furans and Pyrroles 15 1.3.4 - Preparation of Heterobicyclic Alkenes 17

1.4 - Cyclopropanated Heterobicycloalkenes 24

1.4.1 - Research Premise and Hypothesis 24 1.4.2 - Ring Strain and Reactivity of Cyclopropanes 25

1.5 - Summary and Overview 29

1.6 - References 30

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Chapter 2: Cyclopropanation of Heterobicycloalkenes

2.1 - Introduction 39 2.2 - Palladium-catalyzed Cyclopropanation with Diazomethane 44 2.3 - Results and Discussion 47 2.3.1 - Cyclopropanation of 7-Oxabicycloalkenes 47 2.3.2 - Cyclopropanation of 2-Oxa-3-Azabicyclic and 2,3-Diazabicyclic Alkenes 54 2.3.3 - Cyclopropanation of 7-Azabenzonorbornadienes 56

2.4 - Conclusion 59 2.5 - Experimental 60 2.6 - References 75

Chapter 3: Type 1 Ring-Opening Reactions of Cyclopropanated Oxabenzonorbornadienes with Organocuprates: Synthesis of Dihydronaphthols

3.1 - Introduction 80 3.1.1 - Organocopper Reagents 81 3.2 - Results and Discussion 83 3.3 - Conclusion 98 3.4 - Experimental 98 3.5 - References 112

Chapter 4: Type 2 Ring-Opening Reactions of Cyclopropanated Oxabenzonorbornadienes under Acid Catalysis: Synthesis of Naphthalenes

4.1 - Introduction 116 4.2 - Results and Discussion 118 4.2.1 - Alcohol Nucleophiles 118 4.2.2 - Carboxylic Acid Nucleophiles 123 4.3 - Conclusion 134 4.4 - Experimental 135 4.5 - References 146

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Chapter 5: Type 3 Ring-Opening Reactions of Cyclopropanated Oxabenzonorbornadienes: Synthesis of 7-Membered Rings

5.1 - Introduction 150 5.1.1 - Cycloadditions 151 5.1.2 - Ring-closing Metathesis 153 5.1.3 - Ring-expansions and Rearrangements 154 5.1.4 - Type 3 Ring-opening Reactions of Cyclopropanated Oxabenzonorbornadienes 157 5.2 - Results and Discussion 158 5.3 - Conclusion 169 5.4 - Experimental 170 5.5 - References 179

Chapter 6: Tandem Ring-Opening and Intramolecular Ring-Closure Reactions of Cyclopropanated Azabenzonorbornadienes

6.1 - Introduction 184 6.2 - Results and Discussion 184 6.2.1 - Reactions using Organocuprates 184 6.2.2 - Reactions using Acid Catalysts 194 6.3 - Conclusion 195 6.4 - Experimental 196 6.5 - References 203

Chapter 7: Intramolecular Reactions of Cyclopropanated Oxabenzonorbornadienes

7.1 - Introduction 206 7.2 - Results and Discussion 207 7.3 - Conclusion 212 7.4 - Experimental 212 7.5 - References 216

Chapter 8: Prospective

8.1 - Introduction 218 8.2 - Future Work 219 8.3 - Conclusion 224 8.4 - Experimental 224 8.5 - References 226

List of Supporting Data and Appendices

Appendix A: Representative NMR Spectra

Chapter 2: compounds 2.10w, 2.24, 2.26l 229

Chapter 3: compounds 3.2a, 3.3a, 3.5, 3.25a and 3.25b 234

Chapter 4: compounds 4.2k, 4.11, 4.3i, 4.3p 241

Chapter 5: compounds 5.22a, 5.23a, and 5.28 246

Chapter 6: compound 6.3a 249

Chapter 7: compounds 7.9 and 7.10 250

Chapter 8: compound 8.2 252

Appendix B: X-ray Data

Chapter 2: compound 2.10t 253

Chapter 5: compound 5.23a 263

List of Tables

Table 2.1 Former cyclopropanation attempts of 7-oxabenzonorbornadiene 2.9a. 43

Table 2.2 First cyclopropanations of 7-oxabenzonorbornadienes. 49

Table 2.3 Cyclopropanation of C1-, C2-, and arene-substituted 7- 52 oxabicycloalkenes. Table 2.4 Cyclopropanation of N-substituted bicyclic [2.2.1] hydrazines 2.23a- 55 c.

Table 2.5 Cyclopropanation of 7-azabenzonorbornadienes. 58

Table 3.1 Common types of organocopper reagents. 82

Table 3.2 Nucleophile and solvent effects on type 1 ring-opening reactions of 85 3.1a. Table 3.3 Effects of organocuprate nucleophiles on type 1 ring-opening 87 reactions of 3.1a. Table 3.4 Effects of substitution pattern of the substrate toward type 1 ring- 89 opening reactions of 3.1. Table 3.5 Acid-catalyzed dehydration of dihydronaphthalenols 3.2 to 90 naphthalenes 3.3. Table 4.1 Effect of substitution pattern of cyclopropanated 119 oxabenzonorbornadiene in type 2 ring-opening reactions with alcohol nucleophiles. Table 4.2 Effect of acid catalyst and reaction temperature on type 2 ring- 125 opening reactions of cyclopropanated oxabenzonorbornadiene. Table 4.3 Effect of solvent and nucleophile equivalency on type 2 ring-opening 126 reactions of cyclopropanated 7-oxabenzonorbornadiene. Table 4.4 Effect of nucleophile on type 2 ring-opening reactions of 128 cyclopropanated 7-oxabenzonorbornadiene. Table 4.5 Effect of substrate functionalization on type 2 ring-opening reactions 129 of cyclopropanated oxabenzonorbornadiene with carboxylic acid nucleophiles. Table 5.1 Optimizations of acid catalyst for type 3 ring-opening of 5.21. 160

Table 5.2 Effect of alcohol nucleophile on p-TsOH-catalyzed type 3 ring- 160 opening of 5.21.

Table 5.3 Effect of substrate on p-TsOH-catalyzed type 3 ring-opening of 5.21. 163

Table 6.1 Effects of organocuprate nucleophiles on type 1 ring-opening 186 reactions of 6.1a. Table 6.2 Effect of substrate functionality on type 1 ring-opening reactions of 187 cyclopropanated azabenzonorbornadiene.

List of Figures

Figure 1.1 Representative examples of [2.2.1] bicycloalkenes. 2 Figure 1.2 Two distinct faces of [2.2.1] bicyclic compounds. 4 Figure 1.3 Strain energies in cycloalkanes. 27 Figure 2.1 Common diazo precursors for cyclopropanation reactions (R,R’=H, 41 alkyl). Figure 2.2 1H NMR coupling analysis used to deduce the stereochemistry of 50 2.10a-r. Figure 2.3 Two molecules of cyclopropane 2.10t interacting via weak H-bonds 57 (dashed lines). Figure 2.4 Observed NOE correlation for cyclopropane 2.24a. 56 Figure 2.5 Equilibrium between N-X invertomers and between C-N rotational 59 isomers of some cyclopropanated azabenzonorbornadienes. Figure 2.6 Experimental apparatus for diazo cyclopropanations of 62 heterobicycloalkenes. Figure 3.1 1H NMR spectral expansion of δ 8.8-2.8 ppm region showing the 87 conversion of 3.2a to 3.3a. Figure 3.2 Extent of conversion of 3.2a to 3.3a over time as determined by 1H 88 NMR integrations. Figure 5.1 Structures of some seven-membered ring-containing bioactive 150 compounds. Figure 5.2 Steric argument of bulky bridgehead substituent with arene hydrogen. 164 Figure 5.3 Observed NOE signals in support of the structure 5.44. 168 Figure 6.1 Core framework 6.10a used as a carboxylic acid receptor. 193 Figure 7.1 Fused polycyclic systems arising from intramolecular ring-openings 211 of this work.

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List of Schemes

Scheme 1.1 Two possible types of ring-opening of a heterobenzonorbornadiene. 5 Scheme 1.2 Transition metal catalyzed nucleophilic ring-opening of 6 oxabenzonorbornadienes and their applications. Scheme 1.3 Transition metal catalyzed nuclophilic ring-openings of 7 azabenzonorbornadienes. Scheme 1.4 Comparison of β-elimination between acylic and constrained 8 heterobicyclic systems. Scheme 1.5 Mechanism to explain trans-selective opening with organocuprates. 9 Scheme 1.6 Comparison of ring-openings by internal or external nucleophile 10 delivery. Scheme 1.7 General synthesis of heterobenzonorbornadienes. 11 Scheme 1.8 Common approaches to aryne formation. 12 Scheme 1.9 Mechanism of benzyne formation by ortho-deprotonation and halide 12 elimination. Scheme 1.10 Synthesis of ortho-disubstituted arenes used in the present study. 13 Scheme 1.11 Mechanism of benzyne generation by diazotization and 14 decomposition. Scheme 1.12 Generation of benzyne by fluoride-induced desilylation. 15 Scheme 1.13 Methods for the preparation of 2-alkyl and 2-arylfurans. 15 Scheme 1.14 Preliminary attempts to convert 2-substituted furans to 2-substituted 16 pyrroles. Scheme 1.15 Proposed synthesis of C2-alkyl and aryl-substituted pyrroles from 2- 17 bromopyrrole. Scheme 1.16 Observed reluctance to cycloaddition between N-methyl pyrrole and 18 intended dienophile. Scheme 1.17 Evidence for retro-Deils-Alder reaction between pyrrole 1.21 and 18 alkyne 1.22. Scheme 1.18 Rearrangement and aromatization of cycloadduct 1.25 1.26. 19 Scheme 1.19 Synthesis of N-protected azabenzonorbornadienes 1.1a-e for the 20 present work.

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Scheme 1.20 Preparations of 7-azabenzonorbornadienes 1.1f-h for the present 20 work. Scheme 1.21 Synthesis of arene-substituted azabenzonorbornadienes 1.1i-k. 21 Scheme 1.22 Preparation of bridgehead substituted azabenzonorbornadienes 1.1l-n. 21 Scheme 1.23 Futile attempts to generate N-methyl azabenzonorbornadiene 1.1o. 22 Scheme 1.24 Explanation for low yield of adduct 1.1o and the formation of 1.27. 23 Scheme 1.25 Preparation of 2-pyridyl-fused oxabicycloalkene 1.30. 23 Scheme 1.26 Proposed types of ring-opening of cyclopropanated 25 oxabenzonorbornadiene. Scheme 1.27 First syntheses of 4-membered and 3-membered cyclic alkanes by 26 Perkin Jr. Scheme 1.28 Transition metal-catalyzed cyclopropanes openings resulting in 1,3- 28 or 1,2-addition. Scheme 1.29 Regioselective cyclopropane cleavage driven by radical stability. 28 Scheme 2.1 Formation of zinc carbenoid and stereospecific Simmons-Smith 40 cyclopropanation. Scheme 2.2 Stereocontrolled cyclopropanation between two competitive directing 40 groups, demonstrated by Johnson. Scheme 2.3 1,3-Dipolar cycloaddition of diazoalkane with alkene to produce 1- 42 pyrazoline 2.7, and subsequent loss of dinitrogen to yield cyclopropane 2.8. Scheme 2.4 Evidence for participation of a palladacyclobutane in a carbenoid- 45 mediated reaction. Scheme 2.5 Generally accepted mechanism of palladium-catalyzed 46 cyclopropanation of alkenes. Scheme 2.6 Sander’s cyclopropanation of C2-substituted 7-oxa[2.2.1]bicyclic 54 alkene. Scheme 2.7 Cyclopropanation of 2-oxa-3-azabicycloalkene 2.21. 55 Scheme 2.8 Uncatalyzed cyclopropanation of azabenzonorbornadiene with 57 diazomethane. Scheme 2.9 Unsuccessful attempts to cyclopropanate azabenzonorbornadiene 57 2.25a.

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Scheme 3.1 First examples of type 1 ring-opening reactions of 3.1a. 80 Scheme 3.2 Former trials of type 1 opening using Grignard and organolithium 81 reagents. Scheme 3.3 Disproportionation reactions of orgaocuprates. 83 Scheme 3.4 Unsuccessful attempts to promote type 1 ring-opening using in situ 85 generated organolithium reagents as precursors to organocuprates. Scheme 3.5 Unsuccessful attempt to promote type 1 ring-opening using Stryker’s 86 reagent. Scheme 3.6 Unsuccessful attempt to promote type 1 ring-opening using 2-thienyl 86 nucleophile. Scheme 3.7 Type 1 ring-opening reaction of 3.4 with no apparent aromatization. 90 Scheme 3.8 Proposed mechanism for type 1 ring-opening reactions. 91 Scheme 3.9 Labelling experiment showing that bridgehead deprotonation in type 91 1 ring-opening with organocuprates happens by an external base. Scheme 3.10 Type 1 ring-opening reaction of bridgehead halogenated substrate 92 3.10 with displacement of bromine by hydrogen. Scheme 3.11 Possible mechanism for the formation of debrominated product 3.11. 92 Scheme 3.12 Sterically-controlled reduction of carbonyl group by hydride delivery 93 from an n-butyl group of a Gilman cuprate. Scheme 3.13 Attempt to determine the source of transferable hydrogen. 93 Scheme 3.14 An unexplained hydride transfer observed by Posner and Babiak. 94 Scheme 3.15 Unsuccessful results observed with the use of arene-halogenated 94 substrates. Scheme 3.16 Isomers arising from C1-carbonyl substituted starting materials 3.23 95 or 3.24. Scheme 3.17 Proposed mechanism for formation of diastereomers 3.25a and 3.25b. 96 Scheme 3.18 Lipshutz’s ester to ketone conversion observed during conjugate 97 addition. Scheme 4.1 First examples of type 2 ring-opening reactions reported by Haner. 116 Scheme 4.2 Type 2 ring-opening of 4.1a with various acid catalysts and alcohol 117 nucleophiles.

Scheme 4.3 Type 2 ring-opening with carboxylic acid or bromide nucleophiles. 117 Scheme 4.4 Proposed mechanism for type 2 ring-opening of 4.1a 117 Scheme 4.5 Type 2 ring-openings of C1-substituted compounds with alcohol 120 nucleophiles which resulted in complicated mixtures of products. Scheme 4.6 Reaction of 4.1k resulting in two products, 4.2k and 4.11, assigned 121 by NOESY. Scheme 4.7 Possible lithium-halide exchange to ascertain relative halide 121 positioning. Scheme 4.8 Mechanism accounting for formation of by-product 4.11 containing 122 two equivalents of nucleophile. Scheme 4.9 Formation and assignment of 1,3-substituted product 4.3p. 130 Scheme 4.10 Formation of 4.3g in the absence of an external acid catalyst. 130 Scheme 4.11 Unsuccessful reactions toward type 2 ring-opening under basic 131 conditions. Scheme 4.12 Use of pyridinium tribromide as bromide source in type 2 ring- 132 openings. Scheme 4.13 Literature ring-opening of cyclopropane with the use of boronic acid. 132 Scheme 4.14 Attempted ring-opening of 4.1a using phenylboronic acid. 133 Scheme 4.15 Possible test to determine the transferable proton source in type 2 133 openings Scheme 4.16 Attempted acid-catalyzed ring-opening of cyclopropanated N-O 134 bicycloalkene. Scheme 5.1 Example of [4+3] cycloadditions to afford 7-membered rings. 151 Scheme 5.2 Example of a [5+2] cycloaddition to afford 7-membered rings. 152 Scheme 5.3 Formation of a 7-membered ring using a tether in [4+2] 152 cycloaddition. Scheme 5.4 Preparation of the eastern fragment 5.5 of (-)-balanol. 153 Scheme 5.5 Ring-closing metathesis in the total synthesis of (+)-chinensiolide B. 153 Scheme 5.6 General methods of ring-expansion to seven-membered rings. 154 Scheme 5.7 Homolysis of [4.1.0] system 5.7, showing expansion to a 155 chlorocycloheptene.

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Scheme 5.8 Heterolysis of [4.1.0] system, showing expansion to a seven- 155 membered product 5.13. Scheme 5.9 Expansion of [3.2.0] system to a seven-membered ring 5.15. 156 Scheme 5.10 Electrocyclic rearrangement with cyclopropane scission to afford a 156 seven-membered ring 5.16 in the synthesis of confertin 5.17 and damsinic acid 5.18. Scheme 5.11 Expansion of six- to seven-membered system 5.19 by migratory shift 157 involving a pendant group. Scheme 5.12 First observation of type 3 ring-opening of cyclopropanated 158 oxabenzonorbornadienes. Scheme 5.13 Formation of tert-butyl ether 5.22e and its deprotection to alcohol 162 5.22e’. Scheme 5.14 Experiment to investigate relative stereochemistry of the two alkoxy 162 groups in type 3 ring-opened products by use of benzyl alcohol as the nucleophile. Scheme 5.15 Experiment to investigate relative stereochemistry of the two alkoxy 162 groups in type 3 ring-opened products by use of a short chain tethered diol. Scheme 5.16 Seven-membered ring formation in the presence and absence of 165 nucleophilic attack. Scheme 5.17 Proposed mechanism for the formation of compound 5.28 in the 165 absence of an external nucleophile. Scheme 5.18 Proposed mechanism for the concurrent formation of type 2 and type 166 3 products. Scheme 5.19 Reaction of 5.21 with carboxylic acid nucleophile forming mostly 167 type 2 product. Scheme 5.20 Complications arising from acid-catalyzed reactions of some C1- 168 primary alkyl substituted cyclopropanated oxabenzonorbornadienes. Scheme 5.21 Proposed mechanism for the formation of 5.44. 169 Scheme 6.1 First ring-opening example of azabenzonorbornadiene with 185 organocuprate. Scheme 6.2 Unsuccessful attempt to ring-open a dibrominated substrate with 188 organocuprates. Scheme 6.3 Proposed mechanism for γ-lactam formation by type 1 ring-opening 189 of cyclopropanated 7-azabenzonorbornadiene.

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Scheme 6.4 Lactam formation by carbanion attack on carbamate by Gopalan et al. 190 Scheme 6.5 Possible transformations of cyclopropanated N- 190 acylazabenzonorbornadienes. Scheme 6.6 Nucleophilic ring-closure of N-acylated aminosulfone derivatives and 191 subsequent dehydration reported by Gopalan et al. Scheme 6.7 Electrocyclic ring-opening and ring-closures to afford framework 192 6.10. Scheme 6.8 Synthesis of γ-lactam framework 6.10 by cuprate conjugate addition- 192 cyclization. Scheme 6.9 Preparation of triazolium salt with incorporation of lactam framework 193 6.10a. Scheme 6.10 Deprotection of N-Boc substituent by attempted acid-mediated ring- 194 opening. Scheme 6.11 Inert behaviour of N-phenylated azabenzonorbornadiene 6.1k under 194 acidic ring-opening conditions. Scheme 6.12 Intramolecular lactonization observed with uncyclopropanated 195 azabenzonorbornadiene 6.13. Scheme 7.1 Intramolecular ring-opening reactions of tethered oxabicycloalkenes. 206 Scheme 7.2 Envisioned transformation of 7.4 to derivatives bearing tethered 207 nucleophiles. Scheme 7.3 Functional group interconversions of ethyl ester-tethered substrate 208 7.4. Scheme 7.4 Predicted reactivity preference for type 3 over type 2 ring-opening. 208 Scheme 7.5 First observation of intramolecular type 3 and type 2 ring-openings 209 by tethered carboxylic acid nucleophile. Scheme 7.6 Intramolecular type 2 and type 3 ring-openings by tethered alcohol- 210 containing substrate. Scheme 7.7 Preparation of 2-atom tethered substrate for intramolecular ring- 210 opening consideration. Scheme 7.8 Proposed mechanism of intramolecular type 3 ring-openings. 211 Scheme 8.1 Summary of general conversions observed in this work. 218 Scheme 8.2 Possible influences of substituted cyclopropanes on intramolecular 220 cyclizations.

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Scheme 8.3 Experimental [3+2] approach to construct a trisubstituted furan which 221 was successfully transformed into a novel oxabenzonorbornadiene in this research. Scheme 8.4 Thiiranation of oxabenzonorbornadiene by Arisawa and coworkers. 221 Scheme 8.5 Examples of known heter [2+1] cycloadditions on bicyclic alkenes. 222 Scheme 8.6 Current (top) and possible novel (bottom) route to prepare Rotigotine. 222 Scheme 8.7 Possible cyclopropanation of known chiral oxabenzonorbornadiene. 223

List of Abbreviations and Symbols

Ac acetyl AcOH acetic acid Ar aryl acac acetylacetonato AIBN azobisisobutyronitrile d6 hexadeuterated (NMR solvent) Boc butoxycarbonyl Bn benzyl br s broad singlet (1H NMR) n-Bu n-butyl t-Bu tert-butyl Bs para-bromobenzenesulfonyl C1-/ C2-/ C3- carbon 1 / carbon 2 / carbon 3 Cbz carboxybenzyl CSA camphorsulfonic acid Cy cyclohexyl d doublet (1H NMR) or day(s) δ chemical shift 2D two-dimentional DABCO 1,4-diazabicyclo[2.2.2]octane DCE 1,2-dichloroethane DCM dichloromethane DEAD diethyl azodicarboxylate DFT density functional theory DMAD dimethyl acetylenedicarboxylate DMAP 4-dimethylaminopyridine DMF dimethylformamide DMSO dimethylsulfoxide DMSO-d6 dimethylsulfoxide, deuterated (6 deuteria) DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone Et ethyl EtOH ethanol

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Et3N triethylamine EI electron impact ionization (mass spectrometry) ESI electrospray ionization (mass spectrometry) equiv. equivalent(s) EWG electron withdrawing group GOESY gradient nuclear Overhauser effect spectroscopy gem geminal h hour(s) Hex hexyl HMBC heteronuclear multiple bond coherence spectroscopy HPLC high performance liquid chromatography HRMS high-resolution mass spectroscopy HSQC heteronuclear single quantum coherence spectroscopy hν light (irradiation) ID inner diameter IR infrared spectroscopy iPr iso-propyl iPrOH iso-propanol J coupling constant (NMR) JMOD J-modulated spin-echo LDA lithium diisopropylamide m multiplet (1H NMR) Me methyl MeCN acetonitrile MeOH methanol MO molecular orbital mol mole Ms methanesulfonyl MW microwave NBS N-bromosuccinimide NMU N-nitroso-N-methylurea NMR nuclear magnetic resonance NOE nuclear Overhauser effect NOESY nuclear Overhauser effect spectroscopy Ns para-nitrobenzenesulfonyl ν frequency (IR) OD outer diameter Ph phenyl PhMe toluene pKa logarithm (base 10) of acid dissociation constant pTsOH para-toluenesulfonic acid (used interchangeably with pTsOH∙H2O) pTsOH∙H2O para-toluenesulfonic acid monohydrate Piv pivaloyl PPTS pyridinium para-toluenesulfonate py pyridine q quartet

RCM ring-closing metathesis rt room temperature RM alkyl (or aryl) metal complex 1 s singlet ( H NMR) sept septet (1H NMR) SN1 unimolecular nucleophilic substitution SN2 bimolecular nucleophilic substitution SN2’ bimolecular nucleophilic substitution with (allylic) rearrangment t triplet (1H NMR) t-Bu tert-butyl TFAA trifluoroacetic anhydride TFA trifluoroacetic acid Tf triflyl, trifluoromethanesulfonyl, trifluoromethylsulfonyl THF tetrahydrofuran TLC thin-layer chromatography TMS trimethylsilyl TMSI trimethylsilyl iodide TOF time of flight (mass spectrometry) Ts para-toluenesulfonyl

Chapter 1: Introduction

1.1 Heterobicycloalkenes

Bicylic alkenes constitute a diverse class of chemical compounds, and are valuable tools in many synthetic organic transformations. Among these, the particular heterobicycloalkenes 1.1 and 1.2 - colloquially known as azabenzonorbornadiene and oxabenzonorbornadiene - have been of interest to our group in recent years, and will be key players of this thesis project (Figure 1.1).

The chemistry of [2.2.1] heterobicycloalkenes largely differs from that of its carbobicyclic analogues (1.3 or 1.4). The presence of an N or O atom in the annular scaffold causes appreciable changes in physical and chemical properties of the molecule, which are reflected in its reactivity.

In particular, the curvature of the framework can be modified by the number and type of atoms that comprise the system, which defines the overall shape, electronic nature and orbital overlap, and steric accessibility of the molecule to its chemical environment, as well as other physical properties, including ring strain.

Figure 1.1. Representative examples of [2.2.1] bicycloalkenes.

Due to their unideal geometries, bridged bicycloalkenes often prefer to relieve innate strain by severing one or more of their bonds, which can be accomplished via ring-opening reactions

(Section 1.2). Relative to strictly carbon-based bicycloalkenes, heterobicycloalkenes more rapidly undergo ring-opening reactions for two reasons: first, the heteroatom behaves as a good leaving group, improving the ability of the bicycloalkene to undergo substitution-like ring scissions involving the bridging carbon-heteroatom bond;1 and second, the higher electronegativity of the bridging atom (carbon < nitrogen < oxygen) results in an overall increased ring-strain energy, making oxabicycloalkenes especially reactive.2, 3 Indeed, relative strain energy calculations show that benzonorbornadiene is less reactive toward ring-opening than azabenzonorbornadiene, which is less reactive than oxabenzonorbornadiene, and absolute ring strain energy values available for norbornadiene 1.3 (27.6 kcal), azanorbornadiene (33.0 kcal/mol), and oxanorbornadiene (35.8 kcal/mol) also reflect this.4

One other distinct feature of [2.2.1] bicyclic systems is their dual-faced nature. The exo face overlooks the upper portion of the tent-like structure (Figure 1.2) and is comprised of 5 atoms

ABCDE (shaded), or ABC’D’E on each side of the bridge, while the endo face is sheltered on the bottom, consisting of 6 atoms BCDED’C’ (bolded), excluding the bridge atom A (or X). The majority of reactions occur on the exo face due to steric and electronic accessibility which is especially pronounced with heterobicycloalkenes, whose heteroatoms permit coordination and increase electron density on the exo face to favour face-selective reactions.5

In the next section, conventional ring-opening reactions of heterobicycloalkenes will be discussed. For the remainder of this chapter, the focus will shift toward recent contributions from the Tam group which have largely spawned the current thesis research.

Figure 1.2. Two distinct faces of [2.2.1] bicyclic compounds.

1.2 Ring-Opening Reactions of Oxa- and Azabenzonorbornadienes

Of the many types of reactions which heterobicycloalkenes can undergo, ring-opening reactions are particularly powerful reactions, as they can produce a wide variety of cyclic or acyclic products with defined stereochemistry in a single step.6-10 The reactions are often transition metal or acid-catalyzed, and allow for the expansion of organic frameworks through the creation of new bonds. Although both electrophilic and nucleophilic ring-opening reactions are known, this work will focus nearly exclusively on nucleophilic ring-openings mediated by transition metal and acid catalysts.

In general, nucleophilic ring-opening reactions of oxa- and azabicyclic alkenes proceed by nucleophilic attack on the substrate and cleavage of the bicycloalkene’s carbon-heteroatom bond, with the heteroatom serving as a leaving group. If the leaving group is in an allylic position, two types of bimolecular nucleophilic substitution could occur. One possibility is that the nucleophile may attack directly at the bridgehead atom (a), displacing the carbon-heteroatom bond without altering the position of the double bond (Scheme 1.1). This type of direct displacement, or SN2 reaction, affords dihydronaphthalene derivatives with 1,4-substitution. The second possibility arises if nucleophilic attack occurs at an alkene carbon (b). This causes a repositioning of the

double bond which forces open the carbon-heteroatom bridge in an SN2’ fashion. The products arising from this second mode of substitution with allylic rearrangement are 1,2-substituted. The majority of heterobicycloalkenes are reported to undergo the latter SN2’ type ring-openings, although both types of ring-opening have been documented.11

Scheme 1.1. Two possible types of ring-opening of a heterobenzonorbornadiene.

Another important aspect of a ring-opening reaction is the stereochemistry which arises upon nuclophilic attack. If the nuclophile approaches from the endo face, then the resulting ring- opened product would have a 1,2-trans disubstitution pattern. On the other hand, if the nucleophile were to attack from the exo face, then the product would result in 1,2-cis stereochemistry. The endo or exo preference is in large determined by the nature of the catalyst and the nucleophile which participate in the reaction.

To illustrate, ring-opening reactions of oxabenzonorbornadiene 1.2 typically generate 1,2- dihydronaphthalen-1-ols (Scheme 1.2). The cis-compounds 1.5 can be prepared via rhodium-,12 palladium-,13 or nickel-catalyzed14 addition of an arene nucleophile, or palladium-15 or nickel-

mediated16 addition of an alkyl nucleophile. The trans-isomers 1.6 are formed through rhodium- mediated addition of a heteroatomic nucleophile, 17 or copper-catalyzed addition of an alkyl nuclceophile. 18 Reductive openings of 1.2 with hydride nucleophiles can also produce the unsubstituted product, 1.7.19 Further transformations of these ring-opened products can lead to the synthesis of biologically active compounds such as arnottin I (an antibiotic, 1.8)20 or sertraline (an antidepressant, 1.9).21

Scheme 1.2. Transition metal catalyzed nucleophilic ring-opening reactions of oxabenzonorbornadiene and their applications.

Similarly, ring-opening reactions of N-protected azabenzonorbornadienes 1.1 (Scheme

1.3) include rhodium-mediated attack of alkynyl nucleophiles,22 palladium-catalyzed openings with alkynyl, 23 , 24 alkyl, 25 or aryl nucleophiles, 26 and nickel-catalyzed opening with aryl nucleophiles,14 all which produce cis-products 1.10; iridium-catalyzed opening with carboxylic acid,2 alcohol, 27 or amine nucleophiles, 28 copper-catalyzed opening with alkyl and aryl nucleophiles,29, 30 and rhodium-catalyzed opening with amine nucleophiles,31-34 which produce trans-products 1.11.

Scheme 1.3 Transition metal catalyzed nuclophilic ring-opening reactions of azabenzonorbornadienes.

An explanation as to why palladium catalysts produce cis stereochemical products has been given in analogy to Heck coupling. For acyclic alkenes, syn addition of Ar-Pd-X to the olefin is followed by bond rotation to allow for syn β-hydride elimination which yields trans alkenes.35

With cyclic compounds such as heteronorbornene derivatives, this bond rotation is not possible, and thus elimination of the adjacent β-hydrogen Ha cannot take place (Scheme 1.4). Furthermore, elimination of bridgehead hydrogen Hb is also not possible, as this would lead to the formation of an extremely strained double bond which is not feasible according to Bredt’s rule: a double bond cannot exist at the bridgehead position of a bridged bicyclic system unless the rings are sufficiently large to accommodate the planarity of sp2 hybridization.36, 37 In this special case, a β-heteroatom elimination ensues to cleave the carbon-heteroatom bond, giving cis-1,2-substitution.38 In fact, β- elimination of oxygen is highly favourable, and the process is thermodynamically driven by the

formation of strong metal-oxygen bonds. Other literature reports for β-oxygen elimination include chromium,39 cobalt,40 and rhodium intermediates.41, 42 It is known that the metal (M) must have an unoccupied coordination site and that the M-C-C-H dihedral angle must be very small in order for

β-elimination to proceed.43,44 β-Elimination of nitrogen proceeds by an analogous process.45

Scheme 1.4. Comparison of β-elimination between acylic and constrained heterobicyclic systems.

In contrast, an explanation as to why copper catalysts yield trans-1,2-substituted products has been suggested by Carretero and Arrayas in their work of copper-catalyzed ring-openings of heterobicyclic alkenes using Grignard reagents.29, 46 Although it is possible that a (π- allyl)copper(III) species 1.12 is involved (Scheme 1.5), the regioselectivity is more consistent with an SN2’ reaction (Scheme 1.1) in which the organocuprate attacks the olefin from the endo face, anti with respect to the leaving group (whose leaving ability is enhanced by coordination to magnesium). The resulting allyl-copper complex 1.13 could then undergo reductive elimination

faster than equilibration to allyl complex 1.14, providing the observed ring-opened product, 1.15, upon quenching.

Scheme 1.5. Mechanism to explain trans-selective opening with organocuprates.

The origin of the trans stereochemistry with heteroatom nucleophiles can be understood in a similar manner. It is believed that the nucleophile does not complex with the catalyst, but remains free to attack as an independent, external nucleophile. Once the metal catalyst has coordinated with the heterobicycloalkene, the exo face is sterically less accessible due to shielding by the metal complex. The free nucleophile thus prefers to approach from the endo face (Scheme 1.6).

Our group has recently investigated nucleophilic ring-opening reactions on unsymmetrical bridgehead (C1)-substituted oxabicycloalkenes.47,48 Such studies have been particularly insightful as they provide information on regiochemical preference of nucleophilic attack, which helps assess electronic and steric effects of substituents toward reaction. Considering this, it was exciting to note that although many ring-opening studies have been addressed using substituted azabenzonorbornadienes (Scheme 1.3, above), none of the investigated azabicycloalkenes bore

C1-substituents. This is due to the fact that it is challenging to prepare C2-substituted pyrroles,

which are precursors to the substituted azabenzonorbornadienes. In fact, very few pyrroles with simple mono/di-substitution are commercially available. Therefore, in one portion of this work an attempt was made to produce C1-substituted azabicycloalkenes (Sections 1.3.3 and 1.3.4). The present work also sought to investigate the regiochemical outcome of heterobicycloalkene C2- substitutions, as well as more remote arene substitution on ring-opening reactions.

Scheme 1.6. Comparison of ring-openings by internal or external nucleophile delivery.

1.3 Synthesis of Oxa- and Azabenzonorbornadienes

1.3.1 – General Overview

Heterobenzonorbornadienes are prepared via the Diels-Alder [4+2] cycloaddition reaction between benzyne (1.16) and a suitable diene (1.17) - either furan (for oxabicyclics) or pyrrole (for azabicyclic compounds; Scheme 1.7). Benzyne is a particularly reactive and unstable species; as such, it must be generated in situ following one of various methods (section 1.3.2). Furans and pyrroles are commercially available, although certain substitution modes are uncommon and require preparation in the laboratory (section 1.3.3). In this section, various methods to arrive at heterobenzonorbornadienes will be introduced, with emphasis on the methodologies which were used to generate the compounds used in studies of later chapters.

Scheme 1.7. General synthesis of heterobenzonorbornadienes.

1.3.2 – Preparation of arynes

Arynes can be generated through various routes including the use of aryl cations, anions, radicals, and neutral or zwitterionic species (Scheme 1.8).49 Traditionally, generation of benzyne has required harsh conditions such as treatment with strong base or high temperatures. The methods used in this work draw upon several common strategies, such as deprotonation, metal- halogen exchange, diazotization and desilylation, which will each be introduced below.

Deprotonation of aryl halides with ortho elimination can be easily carried out from common commercial reagents lacking functionalities ortho to the leaving group (Scheme 1.9). The mechanism of this transformation has been investigated by Huisgen, Roberts, Bunnett, and

Dunn,50-55 giving rise to the popular kinetic profile of two counteracting effects where the more electronegative halogens (X = F > Cl > Br > I) increase the acidity of the ortho protons to accelerate the deprotonation step, whereas the more nucleofugal halogens (X = I > Br > Cl > F) accelerate the elimination step. These two factors combined result in an overall rate of reaction (from 1.18 to

1.16) where X = Br > I > Cl >> F (Scheme 1.9). One problem with ortho deprotonation is that arenes bearing multiple chemically non-equivalent ortho protons could produce regiochemical mixtures of products. This issue has been addressed by Bunnett and coworkers,56 and will not be

discussed here, as the ortho deprotonation approach was used for only few preparations in the present work which proceeded without any regioichemical complications.

Scheme 1.8. Common approaches to aryne formation.

Scheme 1.9. Mechanism of benzyne formation by ortho-deprotonation and halide elimination.

A second route to benzyne is through metal-halogen exchange. 57 Treatment of ortho- dihalides with alkali metals or alkaline earth metals leads to either Grignard-type exchange with magnesium which typically requires high temperatures, or exchange with lithium which proceeds at low temperatures. 58 Ortho-disubstituted halides provide more reliable regiocontrol during elimination, unlike what is observed when metalating monohalogenated arenes (as discussed in

the previous section). When two different halogens exist on the ring, two outcomes are possible for metal-halogen exchange and, generally, the less electronegative halogen exchanges first. Most ortho-dihalides in the present work only contained two of the same type of halogen, which simplified the situation. A disadvantage of this method is that it requires the presence of a specific ortho-difunctionalized aromatic precursor. In the present work, these were prepared either by

59 stirring the arene overnight with Br2 and I2 (Scheme 1.10a), or by ortho bromination and tosylation of substituted hydroxyarenes, which is a modification of a transformation described by

Stretton and coworkers (Scheme 1.10b).60

Scheme 1.10. Synthesis of ortho-disubstituted arenes used in the present study.

A third approach, which was widely utilized in the current work, is through diazotization of ortho-aminobenzoic acid (anthranilic acid) derivatives. 61 Treatment of ortho-aminobenzoic acids with isoamyl nitrite leads to the production of the diazonium salt (benzene diazonium carboxylate), which is explosive when isolated dry,62 though careful heating leads to extrusion of carbon dioxide and dinitrogen gas, producing benzyne. In contrast to the former two approaches, the diazotization method (Scheme 1.11) proceeds under neutral conditions, and under proper precautionary measures is a readily scalable (>50g) and inexpensive method. Trapping benzyne

produced in this way, over 30 different oxa- and azabicyclic compounds were prepared for the present investigation.

The last method pertinent to this work is fluoride-induced desilylation, which has become a popular method of aryne generation in recent years. Many precursors to this approach are now commercially available. 63 The most common example includes 2-(trimethylsilyl)phenyl trifluoromethanesulfonate 1.19 (Scheme 1.12), which upon treatment with caesium fluoride gives benzyne through attack of fluoride on silicon, generating an anion ortho to the triflate leaving group (1.20), which readily eliminates to give benzyne, 1.16.64 This milder method avoids strongly basic and nucleophilic reaction conditions where functional group compatibility poses a concern, and is thus more tolerant to various functionalities on the aryne.65-67

Scheme 1.11. Mechanism of benzyne generation by diazotization and decomposition.

Scheme 1.12. Generation of benzyne by fluoride-induced desilylation.

1.3.3 – Preparation of substituted furans and pyrroles

Furans and pyrroles are at the heart of heterocyclic organic chemistry. Although these aromatic heterocycles have been popular synthons for decades, the commercial availabilities of 2- substituted furans and pyrroles have remained rather limited. In recent years our group has recognized the importance of 2-bromofuran (1.17a) as a key intermediate for the preparation of various C2-alkyl and aryl substituted furans, and has devised an efficient sequence to generate

1.17a,68 followed by either iron-catalyzed coupling to incorporate an alkyl group, or palladium- catalyzed coupling to introduce an aryl group (Scheme 1.13).69

Scheme 1.13. Methods for the preparation of 2-alkyl and 2-arylfurans.

Probing the literature, it was evident that no such reliable method had yet been reported for the preparation of 2-substituted pyrroles. This was an obvious impediment to azabicycloalkene research (to date, 2-methyl pyrrole has been the only 2-alkylpyrrole prepared 70 , 71 since its

introduction in 1979).72 To arrive at various C1-substituted azabenzonorbornadienes, two different strategies were proposed.

The first strategy involved the conversion of furans to pyrroles (Scheme 1.14). This approach seemed viable since the process is already being utilized industrially. 73 However, attempts to convert C2-substituted furans to C2-substituted pyrroles using similar literature conditions74 at best only led to trace quantities of products,75 and it appeared that much higher temperatures and pressures may be required. Further attempts involving catalysts such as zeolite and neutral or basic alumina 76 still resulted in negligible or seemingly undesirable product formation. As such, this first method was set aside.

Scheme 1.14. Preliminary attempts to convert 2-substituted furans to 2-substituted pyrroles.

The second strategy more closely resembled the method with 2-bromofuran. Although a known synthesis of 2-bromo-N-Bocpyrrole (1.17b, Scheme 1.15) has been in existence for some time, 77 no research was found to convert the 2-bromo functionality to an alkyl or aryl substituent.

Taking the N-protected pyrrole, it was envisioned that one could a) conduct lithium-halide exchange and trap with a suitable organohalide, b) conduct iron-catalyzed coupling with a

Grignard reagent, much like those reported for our furan chemistry, or c) carry forth a palladium- catalyzed Suzuki-type aryl coupling reaction, which was also successful for our furan studies

(Scheme 1.15). Through these means, 2-methyl pyrrole, 2-trimethylsilyl pyrrole, and 2-tert-

butyldimethylsilyl pyrrole were prepared, as were 2-cyclohexyl, and 2-isopropyl pyrrole, but in low yields.75 Although this second approach did provide the desired 2-substituted pyrroles, the yields were generally unimpressive and isolations were nontrivial. This work was also therefore set aside for future consideration, perhaps following optimization studies.

Scheme 1.15. Proposed synthesis of C2-alkyl and aryl-substituted pyrroles from 2- bromopyrrole.

1.3.4 – Preparation of Heterobicyclic Alkenes

The last step in preparation of [2.2.1] heterobicyclic precursors for this work involves the

Diels-Alder [4+2] cycloaddition reaction. Although many oxabicycloalkenes were prepared in this work, the following discussion will focus primarily on the preparation of azabicycloalkenes since the synthesis of aza compounds is a newer research subject for our group, and the preparations of oxa compounds are readily accessible through our former publications.78

Pyrroles are typically more reluctant to participate in Diels-Alder cycloadditions than furans, due to their increased aromaticity.79 In fact, for a while it was believed that pyrroles did not undergo Diels-Alder reactions but proceeded by α-substitution instead. This notion stemmed from the observation that N-methyl pyrrole reacted with 3,6-pyridazinedione to afford a 2,5- disubstituted pyrrole in good yield (Scheme 1.16).80

Scheme 1.16. Observed reluctance to cycloaddition between N-methyl pyrrole and intended dienophile.

As such, early attempts to synthesize 7-azanorbornadiene utilized pyrroles bearing substituents at the 2- and 5-positions to minimize potential substitution reactions, and N-carbonyl substituents were exploited to diminish the pyrrole’s aromatic character. Reactions of such pyrroles (1.21) with dienophiles (1.22), however, resulted in retro-Diels-Alder reactions (producing 1.23), suggesting the instability of the cycloadduct (1.24) under the tested reaction conditions (Scheme 1.17).81

Scheme 1.17. Evidence for retro-Deils-Alder reaction between pyrrole 1.21 and alkyne 1.22.

For the synthesis of benzo adducts 1.25, challenges included the rearrangement of the cycloadducts 1.25 to 2-naphthylamines 1.26 when bridgehead substituents were present (Scheme

1.18).82 The authors of this work noted that azabicyclic compounds were far less stable than their oxabicyclic analogues. If the bridgehead positions were not occupied, 1-naphthylamines resulted in place of 2-naphthylamines. Despite such impediments, the fortunate persistence of many chemists has led to a gradual accumulation of azabenzonorbornadienes over the years.83, 84

Scheme 1.18. Rearrangement and aromatization of cycloadduct 1.25 to 1.26.

Today, the most commonly employed N-protected azabenzonorbornadiene is probably N- butoxycarbonyl (N-Boc) azabenzonorbornadiene 1.1a, which is readily prepared by Diels-Alder reaction between commercial N-Boc pyrrole and benzyne (Scheme 1.19).32, 85 Once prepared, the carbamate 1.1a can be converted to other useful N-substituted derivatives such as 1.1b-d through removal of the Boc group86-88 and trapping with an appropriate electrophile.89 In the present work, use of acetyl chloride as the electrophile allowed for a novel preparation of alkene 1.1e.90,75 Other

N-substituted azabicyclics 1.1f,91 1.1g,92 and 1.1h91 were obtained by Diels-Alder cycloaddition between the appropriate N-functionalized pyrrole and an aryne generated between ortho- aminobenzoic (or naphthoic) acid and isopentyl nitrite.

Scheme 1.19. Synthesis of N-protected azabenzonorbornadienes 1.1a-e for the present work.

Scheme 1.20. Preparations of 7-azabenzonorbornadienes 1.1f-h for the present work.

Arene-substituted azabenzonorbornadienes 1.1i-k were made by derivatization25 and lithium-halide exchange on the arene (Scheme 1.21).26 Although 1.1k could be prepared from a commercial ortho-aminobenzoic acid,90 based off another literature report,93 a modified approach was devised which applied the same lithium halide exchange strategy as 1.1i and 1.1j.

Scheme 1.21. Synthesis of arene-substituted azabenzonorbornadienes 1.1i-k.

Preparation of bridgehead substituted azabenzonorbornadienes was also accomplished in several different ways. Compound 1.1l was prepared by Boc-protection of the commercially available methyl-2-pyrrole carboxylate followed by cycloaddition, 94 1.1m was prepared directly from 2-bromo-N-Bocpyrrole, while lithium-halide exchange and trapping with methyl iodide at the 2-position allowed for the preparation of 1.1n (Scheme 1.22). It is interesting to note that although a few similar bridgehead substituted azabenzonorbornadienes were recently prepared, many bear more complex substituents and none are intended for general use.95, 96

Scheme 1.22. Preparation of bridgehead substituted azabenzonorbornadienes 1.1l-n.

In addition, the anticipated synthesis of N-methyl azabenzonorbornadiene 1.1o was attempted in several different ways in this work (Scheme 1.23), although none resulted in the desired adduct. Of the several references which were followed,97-104 specific challenges arose with a recent procedure in which benzyne generation was not clearly described (a),103 and a hydride reduction methodology (b) which is notorious for resulting in a mixture of compounds which are difficult to separate.104 Lastly, use of the diazotization method (c) resulted in isolation of what appeared to be compound 1.27. Formation of 1.27 can be explained using Bryce and Vernon’s argument that pyrroles bearing N-electron-withdrawing substituents (COOR, SO2Ar) react smoothly to the desired adduct since the N-substituent suppresses attack of benzyne at nitrogen, while N-methyl adduct is isolable at best in low yield, as it can rearrange to 1-naphthylamine 1.28 or further react with benzyne to afford adducts 1.29 or the observed compound 1.27 (Scheme

1.24).105

Scheme 1.23. Futile attempts to generate N-methyl azabenzonorbornadiene 1.1o.

Scheme 1.24. Explanation for low yield of adduct 1.1o and the formation of 1.27.

Unlike many of the other heterobicyclic alkenes, the preparation of a 2-pyridyl-fused oxabicycloalkene 1.30 was carried out through fluoride-induced desilylation (Scheme 1.25).106

The oxa- and azabenzonorbornadienes obtained though these methods were then converted to cyclopropanes for the present research, which will be described next.

Scheme 1.25. Preparation of 2-pyridyl-fused oxabicycloalkene 1.30.

1.4 Cyclopropanated Heterobicycloalkenes

1.4.1 – Research Premise and Hypothesis

It is often stated that olefins and cyclopropanes possess similar chemical features. 107

Despite this, studies which compare analogous reactivity between the two structures are sparse.

One biological example shows that haloperoxidates (chloro from Cadariomyces fumago, bromo from Penicillus capitalus) add to cyclopropanes in a manner similar to addition across C=C bonds.108 Driven by the versatile ring-opening reactions of heterobenzonorbornadienes, our group saw value in the preparation of cyclopropanated heterobenzonorbornadiene, which would presumably allow for exploration of novel ring-opening reactions on an even more strained structure. Through this research, our group has been the first to synthesize cyclopropanated oxa- and azabenzonorbornadienes, and investigate the scope of their ring-opening chemistry.

Taking cyclopropanated oxabenzonorbornadiene 1.31, three distinct ring-opening types were predicted, based on the position (a-c) of nucleophilic attack (Scheme 1.26).109 It is worth commenting that the designations initially given to each mode of ring-opening (“types 1-3”)108 have been modified slightly over the years and have been renamed to fit our chronological order of discovery of each type. If the nucleophile were to attack at the bridgehead position (a), then direct displacement of the C-O bond should give rise to what will be referred to as a “type 1” ring- opening, to afford compound 1.32. If, instead, the nucleophile were to attack at the external cyclopropane position (b), then a distinct “type 2” ring-opening route would furnish a different framework 1.33. Alternatively, if the nucleophile were to attack at the internal cyclopropane position (c), then a “type 3” ring-opening is anticipated, to afford a seven-membered annular structure 1.34. While each of these transformations was met with an unexpected surprise, the

present work successfully demonstrated that each of the three types of ring-openings is indeed possible, under specific reaction conditions. These results will be presented in Chapters 3-5.

Although azabenzonorbornadienes are less reactive than oxabenzonorbornadienes, it seemed reasonable to speculate that similar chemistry would be possible for cyclopropanated azabenzonorbornadienes, as well. Once again, the successful ring-opening chemistry for cyclopropanated azabenzonorbornadienes revealed a surprising transformation (Chapter 6).

Scheme 1.26. Proposed types of ring-opening of cyclopropanated oxabenzonorbornadiene.

1.4.2 – Ring Strain and Reactivity of Cyclopropanes

Before concluding this chapter, a section devoted to the discovery and reactivity of cyclopropanes should provide a more complete background to the cyclopropanated substrates of this research. A more comprehensive discussion on the preparation of cyclopropanes will follow in Chapter 2.

Until the late 1800s it was generally believed that 3 or 4-membered cycloalkanes did not exist. In 1876, Meyer reported a reaction which should hypothetically give rise to a 3-carbon ring, but instead formed unsaturated open-chain compounds, and concluded that cyclopropanes could not be made.110 Although Fisher did not dismiss the idea of small rings, he also thought that they would be too unstable to impart any significance to the chemical community.111 A select few chemists, however, were not convinced of these views. Freund is usually cited as the first to discover cyclopropanes in 1882,112 although Perkin Jr., who was working under Baeyer, was also one who devoted much of his time in this area111 until he finally succeeded in the construction of the first four-membered carboxylic acid in 1883 (Scheme 1.27a) 113, 114 and shortly after, the analogous three-membered cyclic malonic ester (Scheme 1.27b).115 It was these latter two works which led to the Baeyer strain theory (1885),116 which states that deviations from ideal tetrahedral angles of 109˚ cause cycloalkanes other than cyclopentane to be strained.117 Despite the initial oversight by Baeyer that cycloalkanes are all planar species, today a more accurate understanding of bonding geometries reveals that while larger rings can adopt flexible conformations that relieve strain, smaller rings are limited by planarity, orbital overlap, and repulsive interactions. The resulting relative strain energies in cycloalkanes generate a picture which shows especially high strain in cyclopropanes (Figure 1.3).118-120

Scheme 1.27. First syntheses of 4-membered and 3-membered cyclic alkanes by Perkin Jr.

30 25 20 15 Khoury et al. 10 Wiberg

5 Strain Energy (kcal/mol) 0 2 4 6 8 Ring Size

Figure 1.3. Strain energies in cycloalkanes.

Today, we know that cyclopropanes can be prepared in a variety of ways (Chapter 2) and that they can be ring-opened using many different catalysts. These include transition metal catalysts such as gold,121 silver, 122 palladium,123or nickel,124 and can involve anions, cations, or radicals. For example, the cleavage of phenylcyclopropane with lead, thallium or mercury produces regioselective 1,3-organometallic adducts whose carbon-metal bonds can be further cleaved and transformed (Scheme 1.28),125 while treatment of the same cyclopropane with gold

(Au3+) causes isomerization to an alkene, affording 1,2-adducts.126 Another example illustrating regioselectivity is the dissolving-metal reduction of cyclopropane 1.35, where the relative stability of radicals (secondary in 1.36 over primary in 1.37) determines the direction of preferential cyclopropane cleavage to provide the major product 1.38 (Scheme 1.29).127

Cyclopropanes play important roles in biologically active natural products and pharmaceutical substances.107, 128-132 Cyclopropane-opening chemistry is utilized in the syntheses of compounds such as (+)-crotogoudin133 and isoquinoline derivatives.134 Often the cyclopropane bears characteristic substituents such as electron-withdrawing carbonyl, sulfonyl or cyano groups, or alkylidene moieties,135 where electronic activation or coordination to the double bond allows

for controlled openings to proceed, and in recent years, ring-opening of donor-acceptor cyclopropanes have become exceedingly popular. 136 - 138 Our current focus is on opening of cyclopropanes which bear no meaningful substituents, and for such plain cyclopropanes, PtCl2 is one of the few catalysts known to promote its ring-opening.139, 140

Scheme 1.28. Transition metal catalyzed cyclopropane-openings resulting in 1,3- or 1,2- addition.

Scheme 1.29. Regioselective cyclopropane cleavage driven by radical stability.

For the present thesis work, organocopper-catalyzed ring-openings have been highly successful in promoting type 1 ring-opening reactions (Chapters 3 and 6). A few other metal catalysts including lithium, cerium, zinc, and zirconium have also resulted in successful ring- openings with cleavage of the cyclopropane. Since copper, cerium or zirconium are not generally known to promote the opening of cyclopropanes, the results from this work suggest new reaction conditions which may be used in a broader context of cyclopropane-opening reactions.

Palladium and platinum have also been investigated in our laboratories to catalyze ring- opening reactions of cyclopropanated heterobicycloalkenes. Both of these metals have caused the cyclopropanated 7-oxabenzonorbornadiene system to undergo type 2 ring-opening reactions.

Acid-catalyzed ring-openings with alcohol nucleophiles, much like those of former reports on cyclopropane opening with p-toluenesulfonic acid and alcohol,141 also resulted in type 2 and type

3 ring-opening reactions, which will be described in Chapters 4 and 5.

1.5 – Summary and Overview

Transition metal catalyzed nucleophilic ring-opening reactions of heterobicycloalkenes abound in the literature. However, there has been no precedent for studies examining the ring-opening (or any other) reactivity of cyclopropanated oxa- or azabenzonorbornadienes. With a large collection of heterobenzonorbornadienes in hand, cyclopropanation and subsequent ring-opening chemistry could be explored on this novel family of compounds. In the next chapter, palladium-catlayzed cyclopropanation will be presented, while later chapters will then discuss findings of organocuprate-mediated and acid-catalyzed ring-openings of cyclopropanated oxa- and azabicycloalkenes.

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Chapter 2: Cyclopropanation of Heterobicycloalkenes

Selected content of this chapter can also be found in the following papers:

McKee, M.; Haner, J.; Carlson, E.; Tam, W. Synthesis 2014, 46, 1518.

Carlson, E.; Duret, G.; Blanchard, N.; Tam, W. Synth. Commun. 2016, 46, 55.

Lough, A. J.; Carlson, E.; Tam, W. IUCrData, 2016, 1, x160341.

Carlson, E.; Tam, W. Synthesis 2016, 48, 2449.

Chapter 2: Cyclopropanation of Heterobicycloalkenes

2.1 - Introduction

Cyclopropanes are versatile structural units in synthetic chemistry. Due to their prevalence in natural products of plant, fungal, and microbial-origin, 1 stereoselective cyclopropanation reactions have received much attention in recent years.2,3 As was addressed in Chapter 1, the high ring-strain of cyclopropanes makes them synthetically appealing tools to produce more complex structures.4,5

Cyclopropanation reactions typically involve carbene-derived (carbenoid) intermediates, although ylides or carbanions may also be used.6-8 Probably the most well-known carbenoid cyclopropanation is the Simmons-Smith cyclopropanation of alkenes (Scheme 2.1),9 where zinc carbenoid 2.1 has been deemed responsible for the delivery of a methylene unit across the alkene’s

C=C bond.10 This reaction is stereospecific and highly chemoselective, tolerating a wide variety of olefins, and compatible with a broad class of functionalities including ketones, esters, enamines and enol ethers, to name a few. 11 Shortly after the Simmons-Smith cyclopropanation was publicized, Wittig showed that treating zinc iodide with 1-2 equivalents of diazomethane also promoted formation of carbenoid 2.1 or the related bis(iodomethyl)zinc reagent 2.2 (Scheme

2.1).12

Furukawa and co-workers further noted that by using Et2Zn in place of a Zn/Cu couple, an

13,14 analogous reactive species, presumably EtZnCH2I, could be prepared. Today, the use of other metals such as samarium and mercury is commonplace,15 and certain functional groups such as

hydroxyl groups are used as synthetic tools to direct the stereochemistry of cyclopropanation: for instance, Johnson was one of the first to report stereocontrolled cyclopropanation using hydroxysulfoximine 2.3 possessing two competitive directing groups, which resulted in product

2.4 with cyclopropanation having occurred syn to the hydroxyl group.16

Scheme 2.1. Formation of zinc carbenoid and stereospecific Simmons-Smith cyclopropanation.

Scheme 2.2. Stereocontrolled cyclopropanation between two competitive directing groups, demonstrated by Johnson.

Charette has also been a major contributor to asymmetric variants of the Simmons-Smith approach,17 introducing more robust and long-lived carbenoids which effectively cyclopropanate a broader class of alkenes.18,19 These newer methods have been used to construct nucleosides20,21 and other natural metabolites,22-24 and the mechanism of cyclopropanation is well understood based on directing effects seen with Lewis basic allylic functionalities, and computational predictions.25, 26

Another common approach to cyclopropanation involves transition metal-catalyzed decomposition of diazo compounds. By reacting diazo reagents, namely diazoalkanes (Figure 2.1), with transition metals such as copper, nickel, cobalt, rhodium, or palladium, metal carbenoid complexes (RR’C=MLn; where M=metal, Ln=ligand(s)) are generated. Overall, the reaction of a diazoalkane with an alkene is an irreversible process, forming cyclopropane and dinitrogen gas.

Figure 2.1. Common diazo precursors for cyclopropanation reactions (R,R’=H, alkyl).

In some instances, diazocyclopropanation may also occur in the absence of a transition metal catalyst. This is often depicted as a two-step conversion, with 1,3-dipolar cycloaddition between the diazoalkane 2.5 and alkene 2.6 furnishing a pyrazoline intermediate 2.7, followed by either thermal or photochemical loss of dinitrogen to produce the cyclopropane 2.8 (Scheme 2.3).27

The thermal approach is sometimes referred to as the Kishner cyclopropane synthesis28 after the

Russian chemist Nikolai Kishner who observed that pyrazolines, made from reacting hydrazine and α,β-unsaturataed carbonyl compounds, underwent thermal extrusion of N2 resulting in

cyclopropanes.29 Although the mechanism of the Kishner cyclopropanation is not fully understood, it has been a topic of extensive research.30-32 Similarly, the photochemical mechanism has also been well investigated. 33 While the intermediates are highly reactive and most diazo cyclopropanations are complete in ~10 minutes, 34 reactions are often left longer to permit concentrations of the diazo species to reach threshold dilution levels which are deemed to be safe.

Scheme 2.3. 1,3-Dipolar cycloaddition of diazoalkane with alkene to produce 1-pyrazoline

2.7, and subsequent loss of dinitrogen to yield cyclopropane 2.8.

Despite the numerous methodologies (including those addressed above) which have proven successful for the cyclopropanation of [2.2.1] carbobicyclic alkenes,14 very few cyclopropanations of [2.2.1] heterobicycloalkenes have been published,35-37 and most of these result in substituted cyclopropanes38-41 which complicate comparison of the reactivity of a simple cyclopropane moiety to an alkene. A former member of our group, Haner, was the first to seek a reliable method of unsubstituted cyclopropanation of 7-oxabenzonorbornadiene, 2.9a (Table 2.1).42 Although many of these early attempts were futile, their exploration eventually led to promising conditions.

Table 2.1. Former cyclopropanation attempts of 7-Oxabenzonorbornadiene 2.9a.

Entry Cyclopropanating Conditions X Yield (%) agent 1 IZnCH2I Zn(s), CH2I2, glyme, 90 ˚C H 0

2 IZnCH2I Zn(s), CH2I2, CH2Cl2, reflux H 0

3 EtZnCH2I Et2Zn, CH2I2, -20 ˚C H 0

4 CF3C(O)ZnCH2I Et2Zn, CH2I2, CF3COOH, H 0

CH2Cl2, 0 ˚C to rt / -15 ˚C

5 (acac)2Ni=CH2 tBuSO2CH3, MeLi, cat. Ni(acac)2, H/Me 0

THF, reflux

6 CHBr3, NaOH(aq), 2mol% Et3NBnCl, Br trace

rt/40 ˚C

7 CHCl3 (4 equiv.), NaOH(aq), Cl 60

2mol% Et3NBnCl, 40 ˚C

b 8 N2CHCOOEt, Cu(acac)2, PhH, reflux H/COOEt 61

9 CH2N2 NMU (10 equiv.), KOH(aq), H 90

5 mol% Pd(OAc)2, Et2O, 0 ˚C to rt

® 10 CH2N2 Diazald (1.5-3 equiv.), KOH(aq), H 89-96

5 mol% Pd(OAc)2, Et2O, 0 ˚C to rt aIsolated yields after column chromatography. b 2:1 dr of endo:exo COOEt products (both exo cyclopropanated) by 1H NMR analysis. All results obtained by former Tam group members Haner or Uhlig.

Among the methods that were screened were the use of a Simmons-Smith zinc carbenoid

9 14 variant (entries 1-2), Et2Zn with CH2I2 (entry 3), introduction of an external Y group in

43 YZnCH2I (entry 4), and methylene transfer from α-carbanionic lithium tert-butyl methyl sulfone under nickel-catalysis (entry 5),44 yet none of these methods afforded the desired product 2.10a.

In addition, dihalocarbenes were used to prepare geminal dihalocyclopropanes 2.10b or 2.10c in hopes of reductive removal of the halogen atoms (entries 6-7). While the dibromocyclopropane

2.10b was observed in only trace quantities, the dichlorocyclopropane 2.10c could be obtained at low yields (16-20%). Still, reduction of the chlorine atoms led to only trace amounts of product which were not easily isolable.42 Finally, when probing transition-metal catalyzed decomposition of diazo compounds, promising results were observed. Using copper-catalyzed cyclopropanation with ethyl diazoester (entry 8), an appreciable 61% yield of cyclopropanated product 2.10a was obtained, although both diastereomers (COOEt oriented exo or endo) were present and were not readily separable. Finally, when diazomethane was used under palladium-catalysis, the desired cyclopropane 2.10a was produced in excellent yields as the single exo stereoisomer (entries 9-10).

Both commercial diazomethane precursors N-nitroso-N-methylurea (NMU) and Diazald® were tested, showing the best results with <3 equivalents of Diazald® (89-96%, entry 10). These last

36 conditions using Pd(OAc)2 closely follow methods reported by Miller and Ji, and were the first successful and high-yielding cyclopropanations of 7-oxabenzonorbornadienes.42,45

2.2 - Palladium-catalyzed cyclopropanation with diazomethane

Although many metal salts including Ni, Pd, Cu, Fe, Ru, Co, Zn, U, and Os react with diazomethane,46,47 palladium salts have been shown to be especially effective at decomposing

diazomethane, allowing for facile cyclopropanation in the presence of an alkene. 48 Unlike rhodium(II) or copper(I)-catalyzed cyclopropanations which most likely occur in a concerted fashion involving metal carbenes, palladium-catalyzed cyclopropanation is believed to take place through a stepwise mechanism.49 Based on an observation made by Taber and coworkers (Scheme

2.4), 50 after conversion of diazo precursor 2.11 to palladium carbenoid 2.12 it appears that participation of a palladacyclobutane 2.13 is key in accounting for the formation of cyclopentenone

2.14, along with minor intramolecular cyclopropanation side-products.

Scheme 2.4. Evidence for participation of a palladacyclobutane in a carbenoid-mediated reaction.

The currently accepted general mechanism of palladium-catalyzed cyclopropanation is supported by computational work using the DFT method with the B3LYP functional.51 It is believed that the Pd(II) precatalyst is reduced to its active Pd(0) state by diazomethane (A, Scheme

2.5), since other Pd(0) systems have also been shown to promote cyclopropanation.52 The active

Pd(0) species then coordinates to the reactant alkene in a bridged η2-fashion (2.15), which is in equilibrium with a κC-diazomethane-bound intermediate 2.16 which releases dinitrogen in a rate

limiting step (B). Although diazomethane can coordinate to palladium through either the terminal nitrogen (κN) or by the carbon (κC), computations show that κN complextes are unlikely to participate in the catalytic cycle as not only are their Gibbs free energy values relatively high, but coordination through carbon would be necessary for facile loss of dinitrogen. The resulting (η2- alkene)Pd=CH2 carbene complex 2.17 rearranges to palladacyclobutane 2.18 which undergoes reductive elimination (C) yielding the cyclopropane product.

Scheme 2.5. Generally accepted mechanism of palladium-catalyzed cyclopropanation of alkenes.

This mechanism, however, still poses some uncertainties. DFT calculations using the BP86

2 functional predict the participation of a tri-coordinated Pd(η -alkene)3 complex, whereas those

2 using the B3LYP functional predict a di-coordinated Pd((η -alkene)2 (both of which are simplified

as 2.15 in Scheme 2.5). The relative stability of the species involved largely depends on reaction temperature and alkene structure. Thus, the exact coordination mode during the cyclopropanation of heterobicycloalkenes is likely a more dynamic and complicated picture, involving coordination to multiple equivalents of alkene (η2-alkene or heteroatom) which later rearranges intramolecularly to palladacyclobutane 2.18.

2.3 - Results and Discussion

At the outset of this work, several procedural assessments were conducted to allow for the routine use of a toxic and potentially explosive diazoalkane. It was decided that the reaction apparatus should only be tampered with when the solvent level had dropped significantly (when more Et2O must be added by syringe), and that the reaction should be left 12-24h to allow for any

45 trace amounts of CH2N2 to vent off prior to work-up. Other important changes were also made to the apparatus which improved unidirectional gas flow, and the catalyst loading was reduced from 5 mol% to 1 mol%. Once these modifications were in place, the current project began with the cyclopropanation of various substituted 7-oxabenzonorbornadienes.

2.3.1 – Cyclopropanation of 7-Oxabicycloalkenes

The first series of reactions with 7-oxabenzonorbornadienes successfully provided a large collection of cyclopropanes with various aromatic or bridgehead (C1) substituents (Table 2.2).53

Although a minor side product was sometimes noted by TLC, this was only obtained in trace (<5%) quantities and its isolation was nontrivial. While this was suggested to be a 1-pyrazoline, attempts

to intercept this intermediate (section 2.3.3) were not successful. As the purpose of the present work was to prepare cyclopropanes to be used in subsequent studies, no further effort was made in characterizing these minor species. In general, all conversions were high-yielding with complete stereoselectivity for the exo isomer. Cyclopropanation of parent compound 2.9a resulted in 90% isolated yield, and other arene substituted bicyclics 2.9b-g (entries 2-7) showed similarly appreciable results with the exception of the phenanthrene derivative (entry 2) whose starting material 2.9b and product 2.10b both exhibited difficulty entering solution.

As the focus was shifted to bridgehead substitution, the variability in yields was more pronounced, and appeared to correlate with bulkiness of the bridgehead substituent. This was not surprising, as the substitution was now closer to the reaction site of diazomethane addition. For instance, comparing C1, C4-dimethylated compound 2.10h to that of C1-monomethylated compound 2.10i, a nearly 20% difference in yield was noted, with starting material recovered from trial 2.10h (entries 8 and 9). Although no trend was evident for alkyl chain length with primary

C1-substituted compounds 2.10i-k, comparison of primary (2.10i) to secondary (2.10l) to tertiary

(2.10m) C1-substituents revealed that as the substituent size increased, the product yield decreased

(the reaction was incomplete, entries 9-13), suggesting interference between the substituent and the cyclopropanation process. This was also seen with cyclopropanes 2.10n and 2.10o, bearing moderately bulky bromo and hydroxymethyl substituents (entries 14 and 15), while an unexpectedly high yield was observed when bridgehead carbonyl groups were present (entries 16 and 17). Although reaction of ortho-dimethylated substrate 2.9r was also attempted, unfortunately the mixture of products 2.10r and 2.10r’ could not be separated (entry 18).

Table 2.2. First cyclopropanations of 7-oxabenzonorbornadienes.

Entry Product Yield (%)a Entry Product Yield (%)a

1 2.10a 90 10 2.10j 96

2 2.10b 64 11c 2.10k 85

3 2.10c 76 12 2.10l 85b

4 2.10d 85 13d 2.10m 68b

5 2.10e 95 14 2.10n 87

6 2.10f 90 15 2.10o 77b

7 2.10g 94 16e 2.10p 96

8 2.10h 71b 17 2.10q 96

2.10r 9d 2.10i 93 18c 62 2.10r’

a Isolated yields after column chromatography.b Isolated yields based on reacted starting material. c Mixture of regiosisomers in 1.4:1 ratio (r:r’) determined by 1H NMR. All results obtained by McKee accompanied by Carlson,d or Sproule.e

For each of the above cyclopropanes, analysing J coupling constants in the 1H NMR spectrum for bridgehead protons Ha to cyclopropyl protons Hb (Figure 2.2) made it clear that only the exo isomer was formed in all cases. All bridgehead protons were observed as singlets, indicating a near 90° Ha-C-C-Hb dihedral angle, which was consistent with the J=0-2 Hz expected for the exo isomer. The endo isomer instead should have a dihedral angle of approximately 42°, giving rise to a coupling constant of ~5 Hz, which was not observed in any of the acquired 1H

NMR spectra.

Figure 2.2. 1H NMR coupling analysis used to deduce the stereochemistry of 2.10a-r.

Before proceeding to investigate the cyclopropanation of other heterobicycloalkenes, several more procedural modifications were made, which improved both safety aspects and chemistry. In all previous optimizations, changing the reaction solvent had not been a factor of consideration. However, as noted above, the difficulty of certain substrates to enter Et2O led to incomplete reaction or low yields. Cyclopropanation of substrate 2.9aa (Table 2.3, entry 1; Z=n- pentyl) resulted in 11% recovery of 2.99aa with only 51% of 2.10aa isolated, and compound 2.9s

(Table 2.3, entry 5; Z=TMS) also exhibited a difficulty entering solution. Probing the literature, it was noted that solvents such as toluene, dichloromethane, dioxane, chloroform, or tetrahydrofuran

(THF) could be used in reactions employing diazomethane.54-56 Screening the solubilities of

substrates in some of these solvents, it was found that THF in fact did a better job of dissolving several of the alkenes. Use of THF suggested another potential benefit: since evaporation was less of a concern due to the higher boiling point, frequent monitoring and periodic addition of solvent to the reaction vessel could be avoided. In practice, no appreciable solvent loss could be noted even after 24 hours and comparable or improved results were seen for all reactions. It was also found that by using a more dilute 25% w/v solution and increasing the addition rate, the generation of CH2N2 gas was steadier (and there was reduced risk of solid deposition which could impede gas flow, which occurred with a more viscous 50% w/v NaOH solution). Accordingly, the glassware dimensions were modified to accommodate larger volumes. Additionally, reactions were monitored by TLC after subjection to the usual amount (2.6 equiv) of diazomethane, and if incomplete conversion were noted the substrates were further resubjected to cyclopropanation with an additional quantity of diazomethane until full conversion was observed. As such, for all subsequent cyclopropanations three principle modifications have been made: 1) a change in reaction solvent, 2) a dilution of the aqueous NaOH solution used, and 3) a procedural change which allowed for complete consumption of the heterobicycloalkene.

Applying these changes, several more related substrates were cyclopropanated (Table 2.3).

As stated, equal or improved yields were observed for compounds 2.10a, 2.10h, and 2.10m (entries

2-4), and 8 new cyclopropanes were successfully prepared, each in good to excellent yields.

Table 2.3. Cyclopropanation of C1-, C2-, and arene-substituted 7-oxabicycloalkenes.

Entry Product Yield (%)a Entry Product Yield (%)a

1 2.10aa 7 2.10u 89 51b

2 2.10a 90 8 2.10v 81 b [90]

3 2.10h 89 9 2.10w 85 [71]b

85 4 2.10m 10 2.10x 94 [68]b

5 2.10s 75 11 2.10y 72

6 2.10t 82 12 2.10z 65

a b Isolated yields after column chromatography. Isolated yields using Et2O as solvent.

Alkenes 2.9m and 2.9s bearing bulky bridgehead substituents (tert-butyl and trimethylsilyl) underwent the desired cyclopropanation affording 85% and 75% of cyclopropane 2.10m and 2.10s, respectively (entries 4 and 5). Cyclopropanes 2.10t and 2.10u substituted at both bridgehead and

arene positions were obtained in good yields (entries 6 and 7), although the synthesis of 2.10u was carried out with 5 equivalents of CH2N2. Cyclopropane 2.10v bearing a bridgehead ethyl propanoate group was obtained in a comparable 81% yield (entry 8). Unlike all other cyclopropanes in this work whose bridgehead proton Ha produced a singlet, cyclopropane 2.10v showed a doublet for Ha at 5.04 ppm, with J=2.3 Hz. As this J value was sufficiently close to 2

Hz, the cyclopropane of 2.10v was also concluded to be exo with respect to the [2.2.1] bicyclic framework (vide supra; Figure 2.2). Additionally, tetradeuterated cyclopropane 2.10w was obtained in 85% yield (entry 9), which was comparable to its undeuterated parent version 2.10a.

Although most cyclopropanes derived from oxabenzonorbornadiene were isolated as oils, compound 2.10t was obtained as a white solid, and therefore could be recrystallized for X-ray diffraction analysis. As such, the molecular structure of 2.10t made available the first accurate picture of cyclopropanated heterobicycloalkenes, clearly showing exo stereochemistry of the cyclopropane on the bicyclic framework (Appendix B). The crystal structure revealed a weak H- bonding interaction between bridgehead hydrogens and methoxy oxygens of neighboring molecules, forming a dimer with a C2-rotational axis of symmetry (Figure 2.3).57 The observed geometry was in good agreement with early arguments made through analysis of J coupling constants.

Figure 2.3. Two molecules of cyclopropane 2.10t interacting via weak H-bonds (dashed lines).

Next, cyclopropanation of substrates bearing C2-functionalities was attempted, to further examine the effect of substituent proximity with respect to the cyclopropanation site. Although a larger amount of diazomethane was required for both C2-electron-donating and electron- withdrawing substrates (6 equivalents for 2.9x and 8 equivalents for 2.9y), each alkene underwent cyclopropanation smoothly, furnishing the desired exo cyclopropanated products in good yields

(94% for 2.10x and 72% for 2.10y; entries 10 and 11). The yield obtained for product 2.10y was comparable to that of a literature cyclopropanation of a similar C2-substituted 7-oxanorbornene

2.19 to 2.20 (70% over 2 steps; Scheme 2.6).37 Furthermore, alkene 2.9z containing a pyridyl ring was successfully derivatized to 2.10z (entry 12), showing that the present transformation could be applied to hetarene-containing bicyclic substrates, as well.

Scheme 2.6 Sander’s cyclopropanation of C2-substituted 7-oxa[2.2.1]bicyclic alkene.

2.3.2 – Cyclopropanation of 2-oxa-3-azabicyclic and 2,3-diazabicyclic alkenes

Applying the above modified conditions on 2-oxa-3-azabicyclic alkene 2.21, it was found that the quantity of diazomethane could be reduced (from 8 equivalents as in Miller and Ji’s work, to 2.6 equivalents), as well as the catalyst loading (from 5 mol% to 1 mol%). The reaction proceeded well in THF, giving an isolated yield of 97% for 2.22 (Scheme 2.7), relative to the previously reported 96% when conducted in Et2O. These results were encouraging, and since there

was no precedent of structurally similar 2,3-diazabicyclic alkenes (2.23) partaking in cyclopropanation reactions, these compounds were investigated next.

Scheme 2.7. Cyclopropanation of 2-oxa-3-azabicycloalkene 2.21.

Not surprisingly, bicyclic hydrazines 2.23a-c with various N-substituents all resulted in excellent yields (≥94%) of cyclopropanes 2.24a-c (Table 2.4). Due to the fluxional nitrogen- containing framework of 2.24a-c, product peaks were severely broadened with lower intensity in the 1H and 13C NMR spectra. Thus, although 4J-coupling (W-coupling) could not be verified between Ha and Hb, irradiation of Hc in a NOESY experiment on compound 2.24a displayed positive enhancement for the peak of Ha’ (as well as for the peak of Hc’), proving an exo positioning of cyclopropane ring (Figure 2.4). As with cyclopropane 2.22, ring-openings of products 2.24a-c may potentially be useful in building nucleoside derivatives, which serve as key intermediates for the preparation of antitumor and antiviral agents.36

Table 2.4. Cyclopropanation of N-substituted bicyclic [2.2.1] hydrazenes 2.23a-c.

Entry Alkene R Product Yield (%)a 1 2.23a COOtBu 2.24a 95 2 2.23b COOiPr 2.24b 94 3 2.23c COOCH2Ph 2.24c 98 aIsolated yield after column chromatography.

Figure 2.4. Observed NOE correlation for cyclopropane 2.24a.

2.3.3 – Cyclopropanation of 7-azabenzonorbornadienes

Finally, a selection of N-substituted, arene-substituted, and C1-substituted 7- azabenzonorbornadienes 2.25a-n were prepared (Chapter 1, section 1.3.4) for cyclopropanation.

As there was literature precedent of 7-azabenzonorbornadiene 2.25o undergoing cyclopropanation by 1,3-dipolar cycloaddition in the absence of palladium (Scheme 2.8),58 it was essential to test whether substrates lacking the C2 electron-withdrawing functionalities could also undergo the uncatalyzed route of cyclopropanation. Although Tigchelaar commented that 1% of dipolar cycloadduct could be isolated from his large (~5g) scale cyclopropanation of oxabenzonorbornadiene, a similar side product could not be observed in the present work, even with reactions at relatively large (~ 3g) scales. Pohmer and Wittig observe a near-quantitative yield of dipolar cycloadduct in their reaction, although they do not mention its conversion to a cyclopropane.59 Since it could not be simply assumed that the reaction conditions optimized for cyclopropanation of oxabenzonorbornadienes were also optimal for cyclopropanating azabenzonorbornadienes, a reassessment of traditional cyclopropanation methods was conducted for this study (Scheme 2.9).

Scheme 2.8. Uncatalyzed cyclopropanation of azabenzonorbornadiene with diazomethane.

When tert-butoxycarbonyl (Boc) protected azabenzonorbornadiene 2.25a was reacted with diazomethane in the absence of transition metal catalyst, as described by Prinzbach and coworkers, no reaction was observed. As suggested by Schemes 2.6 and 2.8, it is possible that the uncatalyzed conditions only proceed with highly electron-deficient alkenes (i.e. those bearing COOR groups at the C2-position). Efforts were also made to intercept any potential pyrazoline intermediate by minimizing exposure of the reaction mixture to heat or light (by wrapping the reaction vessel in aluminum foil), although no intermediate could be detected. Attempts to cyclopropanate 2.25a by methods of Simmons and Smith,9, 60 or a modification thereof,61 Furukawa,13,14 and Wittig,12 were all unsuccessful, producing complicated mixtures of compounds or minimal reaction after several days.

Scheme 2.9. Unsuccessful attempts to cyclopropanate azabenzonorbornadiene 2.25a.

When the diazocyclopropanation was revisited in the presence of catalytic palladium acetate, 2.25a reacted smoothly, producing compound 2.26a in nearly quantitative yield. Applying these conditions to the variously substituted azabenzonorbornadienes led to moderate to excellent yields of the corresponding cyclopropanes 2.26a-l (Table 2.5). The highest yields were observed for compounds bearing N-alkoxycarbonyl groups (95-98%, entries 1-3), and other N-substituted substrates also underwent efficient conversion (≥86%, entries 4-7). Arene-subtituted compounds produced comparable but slightly lower yields in general (75-87%, entries 8-11), and when bridgehead substituted compound 2.25l was reacted, the yield was reduced even more (entry 12).

Table 2.5. Cyclopropanation of 7-Azabenzonorbornadienes

Entry Product Yield (%)a Entry Product Yield (%)a

1 2.26a 98 7 2.26g 92

2 2.26b 95 8 2.26h 80

3 2.26c 98 9 2.26i 87

4 2.26d 86 10 2.26j 86

5 2.26e 91 11 2.26k 75

6 2.26f 90 12 2.26l 68

aIsolated yields after column chromatography.

It was thought that the approach of diazomethane to the reaction site could also be influenced by the position and bulk of the N-substituent. At room temperature, 1H and 13C NMR spectra of cyclopropanated 7-azabenzonorbornadienes (2.26) in CDCl3 display broadened or duplicate peaks from distinct states due to inversion about nitrogen 62,63 or from rotation along the

64 C-N bond (Figure 2.5). At high temperature or in DMSO-d6 these peaks were seen to coalesce.

It is known that some invertomers exist as separate species long enough for different outcomes to be obtained from reaction of each unique isomer.65 An improved understanding of the interaction of the N-substituents with neighboring species in the palladium-catalyzed mechanism may explain why higher yields are observed with N-carboxyalkyl substituents.

Figure 2.5. Equilibrium between N-X invertomers and between C-N rotational isomers of some cyclopropanated azabenzonorbornadienes.

2.4 - Conclusion

In conclusion, the present work reports the development of a viable and improved method for the palladium-catalyzed diazo cyclopropanation of a variety of [2.2.1] heterobicycloalkenes, including 2-oxa-3-azabicyclic and 2,3-diazabicyclic alkenes, as well as 7-oxabenzonorbornadienes and 7-azabenzonorbornadienes. Complete exo stereoselectivity was observed for cyclopropanation

of all heterobicycloalkenes tested, which was supported by J-coupling constants and X-ray diffraction analysis. Using this safer modified approach, over 30 novel cyclopropanes have been prepared, with especially high yields obtained for 2-oxa-3-azabicyclic and 2,3-diazabicyclic alkenes (94-98%). Overall, cyclopropanes of 7-oxa and azabenzonorbornadienes were efficiently prepared for use in further transformations, which will be described in Chapters 3-6.

2.5 - Experimental

General Information: All reactions were carried out using a continuous flow apparatus under inert atmosphere. Commercial reagents and catalysts were used without further purification, and were racemates of both enantiomers. Column chromatography was performed on 230-400 mesh silica gel following standard techniques,66 and analytical thin-layer chromatography (TLC) was performed on pre-coated silica gel 250 μm 60 F254 aluminum plates, visualized by UV light

(λ=254 nm) and p-anisaldehyde stain. IR spectra were obtained as NaCl or KBr discs on a Nicolet

380-FTIR spectrometer, or as solids on an ALPHA platinum single reflection diamond ATR spectrophotometer. 1H, 2H, and 13C NMR spectra were recorded on Avance 400 MHz or 600 MHz spectrometers equipped with cryoprobes and are reported in parts per million (ppm) from the

1 13 solvent as internal standard (residual CHCl3: δ 7.24 ppm ( H at 400/600 MHz) or δ 77.0 ppm ( C at 100/125 MHz)). The 19F NMR spectrum for 2.10c was recorded on a Bruker Avance 600 MHz spectrometer in CDCl3 and is reported in parts per million (ppm) from CFCl3 as the external standard. HRMS samples were ionized by electron impact (EI) or electrospray ionization (ESI) and detection of the ions was performed by time of flight (TOF). Melting points were measured using open capillary tubes in an Electrothermal MEL-TEMP® model 1001D instrument.

General Procedure: HAZARD ALERT! Diazomethane can be fatal if inhaled and capable of detonation if appreciably concentrated. All glassware and joints must consist of smooth, polished glass. Refer to Figure 2.6: Reactor [C], equipped with a small stir bar, was charged with alkene

(1.2 – 17.7 mmol), Pd(OAc)2 (1 mol% of alkene) and tetrahydrofuran (40 mL) and was capped with septum [E]. To the outlet of reactor [C] was connected in series with Tygon tubing [I] an empty bubbler [J] to serve as a suck-back trap and a glass inlet tube [K] inserted into filter flask

[L]. Bubbler [L] was filled in advance with an acetic acid-water mixture (1:1). The outlet of bubbler [L] was connected to a piece of Tygon tubing [Ic] directed to the back of the fumehood.

Reactor [C] was then securely fitted to the end of tube [Hb] while cooling its contents in an ice bath. Funnel [A] was filled with 25% (12.5 M) aqueous sodium hydroxide (100-150 equivalents to alkene) ensuring that stopper [D] was tightly shut, and the funnel was capped with septum [E].

Flask [B], equipped with a large stir bar, was charged with Diazald® (2.6-8 equivalents to alkene) and 95% EtOH (50-100 mL), and the solution was stirred. Flask [B] was then fitted with a stopper

[G] containing the inert gas inlet [F], tubing [Ha], and funnel [A]. The apparatus was clamped at both funnel [A] and flask [B] and a slow stream of argon was passed through the system such that

~3 bubbles per second (bps) were observed from tube [Ha]. Once a constant flow rate of 3-5 bps was established, 25% sodium hydroxide solution was added from funnel [A] into flask [B] at a rate of 1-2 mL/min, maintaining efficient stirring and bubbling. Formation of the light yellow

® CH2N2 gas was observed with the dissolution of Diazald . Once the reaction was complete (based on TLC), both septa [E] were removed and the apparatus was left to vent any trace CH2N2 (8-16 hours). Reactor [C] was removed and its contents were suction filtered through Celite®. The filter cake was washed with several portions (4 × 10-20 mL) of Et2O which was then concentrated and purified by column chromatography (hexanes/ethyl acetate mixture).

Figure 2.6. Experimental apparatus for diazo cyclopropanations of heterobicycloalkenes. A:

Custom-made dropping funnel. B: 500 mL round bottom flask with side arm and wide neck equipped with extra-large stir bar. C: Reactor vessel (50 mL) with small hole at end of inlet tube.

D: Stopcock. E: Tightly fitted 24/40 rubber septum. F: Glass nitrogen/argon inlet (9 mm OD). G:

#12 Rubber stopper with two 9 mm bored holes. H: High density polyethylene tubing (7 mm ID) with sharp edges smoothed with a heat gun. I: Tygon® tubing. J: Empty bubbler as suck-back trap for AcOH bubbler. K: Glass inlet tube. L: Filter flask with AcOH:H2O (1:1). M: Room temperature water bath. N: 0 °C ice-water bath. Note: OD = outer diameter; ID = inner diameter.

exo-Cyclopropanated oxabenzonorbornadiene 2.10aa (Table 2.3, entry 1): Yield = 1.08 g

-1 (51 %); yellow oil; Rf = 0.30 (EtOAc: Hexanes = 1:19); IR (NaCl, ν, cm ) 3073, 3047, 3001, 2955,

1 2934, 2870, 1456, 1240, 1052, 920; H NMR (400 MHz, CDCl3): δ 7.35-7.33 (m, 1H), 7.30-7.28

(m, 1H), 7.17-7.14 (m, 2H), 5.16 (s, 1H), 2.23 (m, 2H), 1.80-1.69 (m, 3H), 1.65-1.60 (m, 4H),

1.45-1.42 (m, 1H), 1.28-1.19 (m, 1H), 1.10-1.02 (m, 3H), 1.02-0.98 (m, 1H); 13C NMR (100 MHz, 62

CDCl3):  149.8, 148.9, 125.9, 125.8, 119.3, 118.5, 87.5, 77.5, 32.7, 30.3, 24.4, 22.8, 22.7, 22.5,

+ 14.6, 14.3. [M ] calcd. For C16H20O: 228.1514. Found: 228.1510.

exo-Cyclopropanated oxabenzonorbornadiene (2.10a; Table 2.3, entry 2): Yield = 2.45 g

-1 (90 %); clear oil; Rf = 0.52 (EtOAc: hexanes = 1:4). IR (NaCl, ν, cm ): 3049, 2999, 1457, 1054,

1 955, 834, 755, 644. H NMR (400 MHz, CDCl3):  7.24 (m, 2H), 7.09 (m, 2H), 5.05 (s, 2H), 1.50

(td, J = 5.2, 3.6 Hz, 1H), 1.20 (dd, J = 6.7, 3.6 Hz, 2H), 0.86 (td, J = 6.7, 5.2, 1H); 13C NMR (100

MHz, CDCl3):  147.8, 125.8, 119.1, 77.8, 19.9, 14.1.

exo-Cyclopropanated oxabenzonorbornadiene 2.10h (Table 2.3, entry 3): Yield = 2.88 g

-1 (89 %); white solid; Rf = 0.65 (EtOAc: hexanes = 1:4); m.p. = 38-40°C. IR (NaCl, ν, cm ): 3047,

1 1450, 1381, 1280, 1146, 862, 753. H NMR (400 MHz, CDCl3): 7.18 (m, 2H), 7.14 (m, 2H), 1.73

(s, 6H), 1.58 (dt, J = 5.0, 3.4 Hz, 1H), 1.22 (dd, J = 6.6, 3.4 Hz, 2H), 0.81 (td, J = 6.6, 5.0, 1H);

13 C NMR (100 MHz, CDCl3):  151.0, 125.7, 117.7, 83.5, 26.6, 15.5, 13.8.

exo-Cyclopropanated oxabenzonorbornadiene 2.10m (Table 2.3, entry 4): Yield = 1.37 g

-1 (85 %); white solid; Rf = 0.59 (EtOAc: hexanes = 1:4); m.p. = 44-46°C. IR (NaCl, ν, cm ): 3047,

1 2976, 1459, 1364, 1067, 923, 752. H NMR (400 MHz, CDCl3):  7.43 (m, 1H), 7.26 (m, 1H),

7.10 (m, 2H), 5.01 (s, 1H), 1.56 (dt, J = 5.2, 3.6, Hz, 1H), 1.26 (s, 9H), 1.24 (td, J = 6.8, 3.6 Hz,

13 1H), 1.16 (td, J = 6.8, 3.6 Hz, 1H), 0.96 (td, J = 6.8, 5.2 Hz, 1H); C NMR (100 MHz, CDCl3): 

149.7, 148.4, 125.4, 125.3, 120.8, 119.1, 93.4, 77.3, 34.0, 26.7, 22.9, 20.0, 16.5.

exo-Cyclopropanated oxabenzonorbornadiene 2.10s (Table 2.3, entry 5): Yield = 799 mg

-1 (75 %); yellow solid; Rf = 0.33 (EtOAc: hexanes = 1:19); m.p. = 35-36 ˚C. IR (KBr, ν, cm ): 3046,

1 3001, 2959, 2900, 1454, 1249, 1051, 840, 751; H NMR (400 MHz, CDCl3): δ 7.35-7.34 (m, 1H),

7.30-7.28 (m, 1H), 7.17-7.14 (m, 2H), 5.16 (s, 1H), 1.50-1.47 (m, 1H), 1.26-1.24 (m, 2H), 0.99-

13 0.94 (m, 1H), 0.36 (s, 9H); C NMR (100 MHz, CDCl3): δ 150.9, 148.8, 125.5, 125.2, 119.2,

+ 119.1, 79.7, 79.1, 22.8, 20.2, 15.0, -2.9; HRMS: Calculated for C14H18SiO [M] : 230.1127. Found:

230.1122.

exo-Cyclopropanated oxabenzonorbornadiene 2.10t (Table 2.3, entry 6): Yield = 1.74 g

-1 (82 %); beige solid; Rf = 0.25 (EtOAc: hexanes = 1:9); m.p. = 132-134 ˚C. IR (KBr, ν, cm ): 3005,

1 2983, 2937, 2834, 1495, 1436, 1259, 1043, 809; H NMR (400 MHz, CDCl3): δ 6.68 (ABq, JAB=

8.8 Hz, ΔδAB = 9.8 Hz, 2H), 5.19 (s, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 1.86 (s, 3H), 1.52-1.49 (m,

13 1H), 1.38-1.33 (m, 1H), 1.28-1.24 (m, 1H), 0.86-0.82 (m, 1H); C NMR (100 MHz, CDCl3): δ

147.8, 146.9, 138.2, 137.9, 111.2, 111.0, 85.4, 75.1, 56.1, 56.0, 23.9, 22.6, 16.8, 14.0; HRMS:

+ Calculated for C14H16O3 [M] : 232.1099. Found: 232.1092.

exo-Cyclopropanated oxabenzonorbornadiene 2.10u (Table 2.3, entry 7): Yield = 90.8 mg

-1 (89 %); white solid; Rf = 0.55 (EtOAc: hexanes = 1:9); m.p. = 149-150 ˚C. IR (neat, ν, cm ): 3009,

1 2953, 2904, 2833, 1493, 1256, 1242, 1044, 828; H NMR (600 MHz, CDCl3): δ 6.66 (s, 2H), 5.33

(s, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 1.41-1.40 (m, 1H), 1.24-1.22 (m, 2H), 0.92-0.89 (m, 1H), 0.26

13 (s, 9H); C NMR (125 MHz, CDCl3): δ 147.13, 147.09, 140.2, 138.1, 111.0, 110.2, 80.5, 78.0,

77.4, 56.3, 55.2, 22.7, 19.8, 15.1, -2.8.

exo-Cyclopropanated oxabenzonorbornadiene 2.10v (Table 2.3, entry 8): Yield = 1.28 g

-1 (81 %); yellow oil; Rf = 0.23 (EtOAc: hexanes = 1:9); IR (KBr, ν, cm ): 3048, 2984, 2932, 1732,

1 1314, 1053, 1034; H NMR (400 MHz, CDCl3): δ 7.28-7.27 (m, 1H), 7.23-7.22 (m, 1H), 7.16-7.14

(m, 2H), 5.04 (d, J=2.3 Hz, 1H), 4.21-4.15 (m, 2H), 2.67-2.51 (m, 4H), 1.58-1.55 (m, 1H), 1.31-

13 1.27 (m, 4H), 1.12-1.09 (m, 1H), 0.94-0.90 (m, 1H); C NMR (100 MHz, CDCl3): δ 173.63, 148.9,

148.6, 125.9, 119.3, 118.2, 86.3, 77.5, 60.4, 29.5, 25.2, 22.5, 22.3, 14.7, 14.3; HRMS: Calculated

+ for C16H18O3 [M] : 258.1256. Found: 258.1251.

exo-Cyclopropanated oxabenzonorbornadiene 2.10w (Table 2.3, entry 9): Yield = 930 mg

-1 (85 %); colorless oil; Rf = 0.24 (EtOAc: hexanes = 1:19); IR (KBr, ν, cm ): 3075, 3053, 3003,

1 2246, 1457, 1448, 1193, 1161, 1044, 952, 735; H NMR (400 MHz, CDCl3): δ 7.38-7.36 (m, 2H),

13 7.23-7.21 (m, 2H), 1.61 (m, 1H), 0.98 (m, 1H); C NMR (100 MHz, CDCl3): δ 148.0, 126.0, 119.3,

2 77.3 (t, J=32 Hz), 19.6 (t, J=26 Hz), 14.1; H NMR (61.4 MHz, CDCl3): 5.15 (br s, 2H), 1.29 (br

+ s, 2H); HRMS: Calculated for C11H6D4O [M] : 162.0983. Found: 162.0986.

exo-Cyclopropanated oxabenzonorbornadiene 2.10x (Table 2.3, entry 10): Yield = 510 mg

-1 (94%); clear oil; Rf = 0.23 (EtOAc: hexanes = 1:19). IR (NaCl, ν, cm ): 3069, 2973, 2932, 1453,

1 1435, 1385, 1169, 1132, 1006. H NMR (400 MHz, CDCl3):  7.38-7.35 (m, 1H), 7.32-7.30 (m,

1H), 7.27-7.21 (m, 2H), 5.05 (s, 1H), 1.79-1.77 (m, 1H), 1.78 (s, 3H), 1.11-1.08 (m, 1H), 1.05 (s,

13 3H), 0.83-0.80 (m, 1H); C NMR (100 MHz, CDCl3):  149.2, 148.4, 125.7, 125.4, 119.4, 119.0,

+ 86.6, 77.1, 28.9, 28.4, 18.7, 14.6, 13.0. HRMS: Found: Calculated for C13H15O [M+H] : 187.1117.

Found: 187.1112.

exo-Cyclopropanated oxabenzonorbornadiene 2.10y (Table 2.3, entry 11): Yield = 380 mg

-1 (72%); yellow solid; Rf = 0.49 (EtOAc: hexanes = 1:1); m.p. = 60-62 °C. IR (NaCl, ν, cm ): 3052,

1 2983, 2934, 1721, 1374, 1279, 1241, 1140, 759; H NMR (400 MHz, CDCl3):  7.45-7.44 (m, 1H),

7.32-7.31 (m, 1H), 7.19-7.12 (m, 2H), 5.29 (s, 1H), 5.11 (s, 1H), 4.10-3.99 (m, 2H), 2.14 (t, J=4.7

Hz, 1H), 1.96-1.93 (m, 1H), 1.80-1.77 (m, 1H), 1.23 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz,

CDCl3):  172.0, 147.0, 146.9, 126.2, 126.1, 122.0, 119.4, 78.4, 77.6, 60.6, 34.4, 33.1, 22.7, 14.2;

+ HRMS: Calculated for C14H14O3 [M] : 230.0943. Found: 230.0940.

exo-Cyclopropanated oxabenzonorbornadiene 2.10z (Table 2.3, entry 12): Yield = 140 mg

-1 (65%); beige solid; Rf = 0.28 (EtOAc: hexanes = 1:1); m.p. = 45-47 °C. IR (NaCl, ν, cm ): 3054,

1 3043, 3002, 2927, 1578, 1400, 1258, 952, 830, 642; H NMR (400 MHz, CDCl3):  8.20 (dd,

J=5.3 Hz, 1.1 Hz, 1H), 7.52 (dd, J=7.3 Hz, 1.1 Hz, 1H), 7.01 (dd, J=7.3 Hz, 5.3 Hz, 1H), 5.11 (s,

1H), 5.06 (s, 1H), 1.61-1.59 (m, 1H), 1.41-1.7 (m, 1H), 1.32-1.28 (m, 1H), 1.01-0.97 (m, 1H); 13C

NMR (100 MHz, CDCl3):  169.3, 145.4, 141.0, 126.5, 120.5, 77.8, 77.1, 20.4, 18.4, 14.3; HRMS:

+ Calculated for C10H9NO [M] : 159.0684. Found: 159.0689.

exo-6-oxa-7-N-butoxycarbonyltricyclo[3.2.1.02,4]oxazine, 2.22 (Scheme 2.7): Yield = 907 mg

(97%); white solid; Rf = 0.25 (EtOAc: hexanes = 1:4); m.p. = 72-74 ˚C (lit. 83-85 ˚C); IR (KBr,

-1 1 ν, cm ): 2982, 1722, 1478, 1393, 1163, 909, 734; H NMR (400 MHz, CDCl3): δ 4.78 (m, 1H),

4.56 (m, 1H), 1.53 (d, J = 11.5 Hz, 1H), 1.50 (s, 9H), 1.45-1.38 (m, 3H), 0.39-0.33 (m, 2H); 13C

NMR (100 MHz, CDCl3): δ 157.8, 81.9, 80.7, 60.8, 28.3, 27.7, 13.9, 12.9, 4.1; Spectral data are consistent with those previously reported.36

exo-6-oxa-7-N-butoxycarbonyltricyclo[3.2.1.02,4]hydrazine, 2.24a (Table 2.4, entry 1): Yield

= 516 mg (95 %); white solid; Rf = 0.08 (EtOAc: hexanes = 1:9); m.p. = 117-119 ˚C. IR (KBr, ν,

-1 1 cm ): 2977, 2932, 1737, 1694, 1367, 1339, 1164, 1111; H NMR (400 MHz, CDCl3): 4.68 (br s,

1H), 4.42 (br s, 1H), 1.59 (m, 1H), 1.43 (s, 18H), 1.31 (d, J=11.3 Hz, 1H), 1.20-1.06 (m, 2H),

13 0.42-0.39 (m, 1H), 0.33-0.28 (m, 1H); C NMR (125 MHz, CDCl3): δ [156.9, 156.3, 155.3] (C=O; peaks appear broadened due to relative orientation about nitrogen in different isomers),[31] [80.2,

80.0], [61.3, 60.4, 59.6], 27.1, 25.8, [13.4, 13.0, 11.6, 11.1], 3.6; HRMS: Calculated for

+ C16H26N2O4 [M] : 310.1893. Found: 310.1890.

exo-6-oxa-7-N-isopropoxycarbonyltricyclo[3.2.1.02,4]hydrazine, 2.24b (Table 2.4, entry 2):

Yield = 803 mg (94 %); white solid; Rf = 0.27 (EtOAc: hexanes = 1:4); m.p. = 55-57 ˚C; IR (KBr,

-1 1 ν, cm ): 2980, 2938, 1739, 1694, 1468, 1373, 1339, 1104; H NMR (400 MHz, CDCl3): δ 4.88

(br s, 2H), 4.66 (br s, 1H), 4.41 (br s, 1H), 1.28 (d, J=11.4 Hz, 1H), 1.17 (s, 14H), 1.03 (br d, J=8.6

13 Hz, 1H), 0.38-0.35 (m, 1H), 0.29-0.23 (m, 1H); C NMR (125 MHz, CDCl3): δ [157.9, 157.5,

157.2] (C=O; peaks appear broadened due to relative orientation about nitrogen in different isomers), [69.7, 69.5], [62.0, 61.1], 26.5, 21.7, [13.9, 12.2], 4.3; HRMS: Calculated for

+ C14H22N2O4 [M] : 282.1580. Found: 282.1585.

exo-6-oxa-7-N-carboxybenzyltricyclo[3.2.1.02,4]hydrazine, 2.24c (Table 2.4, entry 3): Yield =

-1 629 mg (98%); colourless oil; Rf = 0.15 (EtOAc: hexanes = 3:17). IR (KBr, ν, cm ): 3032, 1739,

1 1703, 1455, 1388, 1321, 1267, 1191, 1111; H NMR (400 MHz, CDCl3): δ 7.34 (br s, 10H), 5.23

(m, 4H), 4.84 (s, 1H), 4.60 (s, 1H), 1.72-1.18 (m, 4H), 0.47 (br s, 1H), 0.38 (m, 1H); 13C NMR

(125 MHz, CDCl3): δ [158.3, 157.8] (C=O; peaks appear broadened due to relative orientation about nitrogen in different isomers), 135.8, 128.3, 127.9, 127.7, 67.7, [62.6, 61.6], 26.8, [14.1,

+ 12.0], 4.5; HRMS: Calculated for C22H22N2O4 [M] : 378.1580. Found: 378.1583.

exo-Cyclopropanated azabenzonorbornadiene 2.26a (Table 2.5, entry 1): Yield = 1.61 g

-1 (98%); white solid; Rf = 0.30 (EtOAc: hexanes = 1:9); m.p. = 48-50 °C. IR (NaCl, ν, cm ): 3053,

1 3011, 2978, 2931, 1698, 1367, 1172, 1093, 1050, 739; H NMR (400 MHz, CDCl3): δ 7.28-7.26

(br s, 2H), 7.11-7.07 (m, 2H), 5.05 (br s, 1H), 4.94 (br s, 1H), 1.37 (s, 9H), 1.34-1.31 (m, 1H),

13 1.21-1.19 (m, 2H), 1.01-0.96 (m, 1H); C NMR (100 MHz, CDCl3): δ 154.9, [148.0, 147.6], 125.7,

+ [120.1, 119.6], 79.9, [61.0, 60.2], 28.3, [21.5, 20.8], 15.9; HRMS: Calculated for C16H19NO2 [M] :

257.1416; found: 257.1412.

exo-Cyclopropanated azabenzonorbornadiene 2.26b (Table 2.5, entry 2): Yield = 511 mg

-1 (95%); white solid; Rf = 0.28 (EtOAc: hexanes = 1:4); m.p. = 162-163 °C. IR (NaCl, ν, cm ): 3077,

1 3028, 2957, 1697, 1450, 1368, 1257, 1106. H NMR (400 MHz, CDCl3):  7.31 (br s, 2H), 7.12

(m, 2H), 5.14 (br s, 1H), 5.03 (br s, 1H), 3.61 (s, 3H), 1.43 (m, 1H), 1.25 (m, 2H), 1.01 (m, 1H);

13 C NMR (100 MHz, CDCl3):  156.0, [147.9, 147.4], 125.9, [120.2, 119.7], [60.7, 60.5], 52.5,

[21.3, 20.7], 16.0. HRMS: Calculated for C13H13NO2: 215.0946; found: 215.0941.

exo-Cyclopropanated azabenzonorbornadiene 2.26c (Table 2.5, entry 3): Yield = 178 mg

-1 (98%); white solid; Rf = 0.20 (EtOAc: hexanes = 1:9); m.p. = 79-82 °C. IR (NaCl, ν, cm ): 3031,

1 3012, 2944, 1702, 1453, 1392, 1338, 1246, 1080, 819. H NMR (400 MHz, CDCl3): δ 7.39-7.24

(m, 7H), 7.18-7.11 (m, 2H), 5.20 (s, 1H), 5.11 (s, 1H), 5.09 (s, 1H), 5.03 (s, 1H), 1.41-1.39 (m,

13 1H), 1.27-1.24 (m, 2H), 1.08-1.03 (m, 1H); C NMR (100 MHz, CDCl3): δ 155.3, [147.8, 147.4],

136.5, 128.5, 127.9, 127.7, 125.9, 120.2, 119.7, 66.8, [60.8, 60.7], [21.3, 20.7], 16.0; HRMS:

Calculated for C19H17NO2: 291.1259; found: 291.1260.

exo-Cyclopropanated azabenzonorbornadiene 2.26d (Table 2.5, entry 4): Yield = 348 mg

-1 (86%); white solid; Rf = 0.38 (EtOAc: hexanes = 3:7); m.p. = 160-162 ˚C. IR (NaCl, ν, cm ): 3046,

1 3030, 2978, 2965, 1613, 1454, 1199, 1044, 746; H NMR (400 MHz, CDCl3): δ 7.28-7.26 (m, 2H),

7.11-7.08 (m, 2H), 5.44 (br s, 1H), 5.40 (br s, 1H), 1.25-1.20 (m, 3H), 1.17 (s, 9H), 1.01-0.96 (m,

13 1H); C NMR (100 MHz, CDCl3): δ 174.3, [147.7, 147.0], 125.9, [120.2, 119.1], [61.6, 59.1],

+ 38.7, 27.7, [21.3, 19.5], 15.7; HRMS: Calculated for C16H19NO [M] : 241.1467; found: 241.1471.

exo-Cyclopropanated azabenzonorbornadiene 2.26e (Table 2.5, entry 5): Yield = 517 mg

-1 (91%); beige solid; Rf = 0.08 (EtOAc: hexanes = 1:1); m.p. = 103-105 ˚C. IR (neat, ν, cm ): 3027,

1 3004, 1625, 1446, 1230, 1204, 1082, 1033, 811; H C NMR (400 MHz, CDCl3): δ 7.34-7.29 (m,

2H), 7.15-7.13 (m, 2H), 5.47 (s, 1H), 4.94 (s, 1H), 1.98 (s, 3H), 1.30-1.28 (m, 2H), 1.17-1.14 (m,

13 1H), 1.08-1.04 (m, 1H); C NMR (100 MHz, CDCl3): δ 166.8, 147.4, 146.8, 126.1, 125.8, 120.2,

119.4, 61.6, 58.2, 21.5, 21.1, 20.0, 15.9. HRMS: Calculated for C13H13NO: 199.0997; found:

199.0999.

exo-Cyclopropanated azabenzonorbornadiene 2.26f (Table 2.5, entry 6): Yield = 660 mg

-1 (90%); beige solid; Rf = 0.62 (EtOAc: hexanes = 1:1); m.p. = 193-195 °C. IR (NaCl, ν, cm ): 3066,

1 2994, 1337, 1161, 1093, 1042, 1024, 908, 776, 732, 693; H NMR (400 MHz, CDCl3): δ 7.27-7.25

(m, 2H), 6.91-6.89 (m, 4H), 6.81-6.79 (m, 2H), 4.89 (s, 2H), 2.25 (s, 3H), 2.03-2.02 (m, 1H), 1.27-

13 1.24 (m, 2H), 1.06 (app q, J= 6.4 Hz, 1H); C NMR (100 MHz, CDCl3): δ 145.7, 142.7, 135.3,

128.9, 127.7, 125.7, 120.3, 63.2, 21.7, 21.4, 16.5. HRMS: Calculated for C18H17NSO2: 311.0980; found: 311.0985.

exo-Cyclopropanated azabenzonorbornadiene 2.26g (Table 2.5, entry 7): Yield = 968 mg

-1 (92%); white solid; Rf = 0.47 (EtOAc: hexanes = 1:9); m.p. = 116-118 °C. IR (neat, ν, cm ): 3056,

1 2998, 1595, 1497, 1451, 1317, 1247, 1077, 945,822. H NMR (400 MHz, CDCl3): δ 7.39-7.37 (m,

2H), 7.22-7.14 (m, 4H), 6.85-6.81 (m, 3H), 4.99 (s, 2H), 2.15-2.12 (m, 1H), 1.44-1.41 (m, 2H),

13 1.11-1.06 (m, 1H); C NMR (100 MHz, CDCl3): δ 147.9, 147.4, 128.9, 125.8, 121.2, 119.8, 117.2,

+ 63.5, 21.7, 16.0; HRMS: Calculated for C17H15N [M] : 233.1204; found: 233.1201.

exo-Cyclopropanated azabenzonorbornadiene 2.26h (Table 2.5, entry 8): Yield = 243 mg

-1 (80%); white solid; Rf = 0.35 (EtOAc: hexanes = 1:9); m.p. = 168-169 °C. IR (neat, ν, cm ): 3005,

1 2970, 2932, 1682, 1423, 1365, 1253, 1161, 1092, 872; H NMR (400 MHz, CDCl3): δ 7.82-7.80

(m, 2H), 7.68 (br s, 1H), 7.65 (br s, 1H), 7.48-7.46 (m, 2H), 5.19 (br s, 1H), 5.08 (br s, 1H), 1.38

13 (s, 9H), 1.33-1.30 (m, 1H), 1.27-1.25 (m, 2H), 0.97-0.93 (m, 1H); C NMR (100 MHz, CDCl3):

δ 155.2, 145.1, 132.3, [128.2, 128.0], 125.7, [118..4, 117.8], 80.1, [60.8, 60.0], 28.3, [20.6, 20.0],

13.4; HRMS: Calculated for C20H21NO2: 307.1572; found: 307.1569.

exo-Cyclopropanated azabenzonorbornadiene 2.26i (Table 2.5, entry 9): Yield = 560 mg

-1 (87%); white solid; Rf = 0.50 (EtOAc: hexanes = 1:4); m.p. = 121-122°C. IR (NaCl, ν, cm ): 3007,

1 2975, 2929, 1701, 1392, 1366, 1253, 1173, 1092; H NMR (400 MHz, CDCl3): δ 7.09 (br d, J=3.4

Hz, 2H), 5.01 (br s, 1H), 4.91 (br s, 1H), 2.25 (s, 6H), 1.39 (s, 9H), 1.31-1.27 (m, 1H), 1.21-1.19

13 (m, 2H), 0.97 (app q, J=6.4 Hz, 1H); C NMR (100 MHz, CDCl3): δ 154.7, [145.7, 145.4], 133.4,

[121.7, 121.1], 79.8, [60.8, 59.9], 28.3, [21.6, 21.0], 19.9, 15.7; HRMS: Calculated for C18H23NO2:

285.1729; found: 285.1722.

exo-Cyclopropanated azabenzonorbornadiene 2.26j (Table 2.5, entry 10): Yield = 1.33 g

-1 (86%); white solid; Rf = 0.50 (EtOAc: hexanes = 1:4); m.p. = 131-133°C. IR (NaCl, ν, cm ): 3013,

2977, 2935, 1699, 1477, 1392, 1367, 1253, 1169, 1095, 1050, 872, 825. 1H NMR (400 MHz,

CDCl3): δ 7.52 (br s, 2H), 5.00 (br s, 1H), 4.91 (br s, 1H), 1.41-1.38 (m, 1H), 1.37 (s, 9H), 1.21-

13 1.19 (m, 2H), 1.01 (app q, J=6.5 Hz, 1H); C NMR (100 MHz, CDCl3):  154.7, [149.0, 148.6],

[125.6, 125.0], 121.4, 80.6, [60.6, 59.8], 28.2, [21.1, 20.4], 15.7; HRMS: Calculated for

C16H17NO2Br2: 412.9626; found: 412.9620.

exo-Cyclopropanated azabenzonorbornadiene 2.26k (Table 2.5, entry 11): Yield = 227 mg

-1 (75%); beige solid; Rf = 0.16 (EtOAc: hexanes = 1:4); m.p. = 120-122 °C. IR (neat, ν, cm ): 3004,

1 1692, 1484, 1352, 1288, 1166, 1074, 1067, 858. H NMR (400 MHz, CDCl3): δ 6.93 (s, 1H), 6.89

(s, 1H), 4.96 (s, 1H), 4.86 (s, 1H), 3.82 (s, 6H), 1.33 (s, 9H), 1.31-1.28 (m, 1H), 1.15-1.12 (m, 2H),

13 0.96-0.91 (m, 1H); C NMR (100 MHz, CDCl3): δ 154.9, 146.5, [140.6, 140.1], [105.6, 105.2],

79.9, [61.3, 60.4], [56.3, 56.2], 28.3, [21.9, 21.2], 16.2; HRMS: Calculated for C18H23NO4:

317.1627; found: 317.1622.

exo-Cyclopropanated azabenzonorbornadiene 2.26l (Table 2.5, entry 12): Yield = 358 mg

-1 (68%); yellow solid; Rf = 0.28 (EtOAc: hexanes = 1:3); m.p. = 76-77 °C. ATR (neat, ν, cm ):

1 3047, 3009, 2971, 1743, 1706, 1308, 1245, 1154, 864; H NMR (400 MHz, CDCl3): δ 7.78 (br d,

J = 6.9 Hz, 1H), 7.26 (m, 1H), 7.16-7.08 (m, 2H), 5.02 (br s, 1H), 3.89 (s, 3H), 1.94-1.91 (m, 1H),

1.51-1.47 (m, 1H), 1.31-1.27 (m, 1H), 1.22 (s, 9H), 1.09-1.04 (m, 1H); 13C NMR (100 MHz,

CDCl3): δ 169.6, 156.7, 147.6, 145.8, 126.0, 121.5, 120.0, 81.2, 71.4, 62.9, 52.1, 27.9, 26.6, 21.9,

16.4; HRMS Calculated for C18H21NO4: 315.1471; found: 315.1468.

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58 Kaupp, G.; Perreten, J.; Leute, R.; Prinzbach, H. Chem. Ber. 1970, 103, 2288.

59 Pohmer, L.; Wittig, G. Chem. Ber. 1956, 89, 1334.

60 Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1959, 81, 4256.

61 Stenstrøm, Y. Synth. Commun. 1992, 22, 2801.

62 Yoshikawa, K.; Bekki, K.; Karatsu, M.; Toyoda, K.; Kamio, T.; Morishima, I. J. Am. Chem.

Soc. 1976, 98, 3272.

63 (a) Malpass, J.R.; Walker, M.P. J. Chem. Soc. Chem. Commun. 1979, 13, 585. (b) Rautenstrauch,

V. J. Chem. Soc. D. Chem. Commun. 1969, 1122. (c) Durrant, M.L.; Malpass, J.R. Tetrahedron

1995, 51, 7063. (d) Davies, J.W.; Durrant, M.L.; Naylor, A. ; Malpass, J.R. Tetrahedron 1995, 51,

8655.

64 Warrener, R.N. Progress in Heterocyclic Chemistry, Volume 13, Gribble, G.W.; Gilchrist, T.L.

Ed. Elsevier Science, Ltd., Oxford, 2001, Chapter 2.

65 Weibel, J.-M.; Blanc, A.; Pale, P. Silver in Organic Chemistry, Harmata, M. Ed. John Wiley &

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Chapter 3: Type 1 Ring-Opening Reactions of Cyclopropanated

Oxabenzonorbornadiene with Organocuprates:

Synthesis of Dihydronaphthalenols

Selected content of this chapter can also be found in the following paper:

Carlson, E.; Haner, J.; McKee, M.; Tam, W. Org. Lett., 2014, 16, 1776.

Chapter 3: Type 1 Ring-Opening Reactions of Cyclopropanated

Oxabenzonorbornadiene with Organocuprates: Synthesis of Dihydronaphthalenols

3.1 - Introduction

The first type of ring-opening reaction of cyclopropanated oxabenzonorbornadiene 3.1a was discovered upon treatment with various organometallic reagents in THF (Scheme 3.1).1 The product was found to be a 4-substituted cis-1,2-dihydro-2-methylnaphthalenol (3.2), with evident cleavage of the cyclopropane ring. The reaction was found to work especially well for higher-order cyanocuprates including phenyl, methyl, and n-butyl nucleophiles.

Scheme 3.1. First examples of type 1 ring-opening reactions of 3.1a.

Following the above work which was initiated by Haner, and which suggested promise with other organometallic species, McKee further probed the behaviour of 3.1a using Grignard and organolithium reagents, which consistently resulted in negligible to low yields of 3.2 (Scheme

3.2).2 While no product was observed using Grignard reagent, the use of organolithium reagent resulted in 3.2 as the sole product in ~20% yield. No appreciable difference was seen with increased temperature for either reagent.

Scheme 3.2. Former trials of type 1 opening using Grignard and organolithium reagents.

From these early results, it was evident that organocopper reagents had a strong potential for type 1 ring-opening, and that other unexplored organometallic nucleophiles may offer desirable outcomes. As such, the present work on ring-opening of 3.1a commenced with the screening of such reagents.

3.1.1 – Organocopper reagents

Copper is one of the oldest transition metals to appear in organic synthesis. 3 Many organocopper reagents have made their way into ring-opening transformations of oxabicyclic systems,4 including those of oxabenzonorbornadiene.5-7 Some properties which make copper- based reagents synthetically appealing include their ease of handling, mildness, accessibility, and the high chemo-, regio-, and stereoselectivities they impart in the construction of carbon-carbon bonds.8,9 Despite the highly variable chemical formulae of organocopper compounds,10,11 those central to organocuprate chemistry are commonly found in the +1 oxidation state of copper, with coordination to one or more transferable nucleophilic R groups. A common classification system of organocopper compounds is shown in Table 3.1.

Table 3.1 Common types of organocopper reagents

Type Preparation (Example) Formulae Mono-organocopper reagent RM + CuX RCu Lower-order homocuprate 2RM + CuX R2CuM Lower-order heterocuprate RM + CuZ RCu(Z)M Higher-order homocuprate 3RM + CuX R3CuM2 Higher-order heterocuprate 2RM + CuZ R2Cu(Z)M2

Similar to organolithium compounds, organocopper compounds exist as aggregates, often involving a complex equilibrium. Characterization of such species has been challenging, leading to disputes regarding their accurate structures.12,13 Thus, although broad classifications such as those of Table 1 help distinguish the unique reactivities of cuprates - homoleptic versus heteroleptic, or lower order (having two ion pairs) versus higher order (having more than two ion pairs) - the structural understanding of the distinct species partaking in specific reactions is still quite rudimentary in most cases. Knowledge of the relative ligand transferability has also led to the development of heterocuprates with “dummy ligands” or non-transferable groups, allowing for conservation of valuable ligands.9 Many cuprates are thermally unstable and so are generated in situ at low temperatures by addition of organolithium or organomagnesium to a Cu(I) species under inert conditions.12 In general, thermal stability of the organocuprate increases in the order

RCu < RCuL < MCuR2 such that higher order cuprates are more stable than lower order cuprates.4,14 The R group on the cuprate contributes to its overall stability, and cuprates bearing alkyl groups containing a β-hydrogen can be less stable, as disproportionation may proceed to alter the transferable R group’s structure (Scheme 3.3).15 Typically an organocuprate’s stability based on R group increases in the order alkyl < aryl ≈ alkenyl < alkynyl. As disproportionation cannot take place in the absence of a β-hydrogen, reactions of cuprates at higher temperatures tend to focus on methyl, aryl, and other R groups without β-hydrogens.

CH3CH2Cu → CH2=CH2 + Cu-H

CH3CH2Cu + Cu-H → CH3CH3 + 2 Cu

Scheme 3.3. Disproportionation reactions of organocuprates.

In terms of reactivity, the relatively high electronegativity of copper (χp = 1.9) distinguishes copper-based compounds from other common organometallic reagents. In comparison with organolithium or Grignard reagents, the carbon-metal bond of an organocopper compound is less polarized. Often this is illustrated by the conjugate addition of organometallic reagents to α,β- unsaturated carbonyl compounds: while a Grignard reagent’s carbon-magnesium bond is highly polar, making the hard nucleophile prefer to attack the hard carbonyl carbon, in the presence of copper the transferable organic group behaves as a soft nucleophile and preferentially attacks the

β-position with improved MO overlap.16-18 Such differences in the hardness of a nucleophile may have been the cause of differences observed between Haner and McKee’s results.

3.2 - Results and Discussion

At first, several different organomegallic reagents and solvents were screened to optimize the conditions for type 1 ring-openings of the parent cyclopropane 3.1a (Table 3.2). The stereochemistry of product 3.2a was determined by comparison of its NMR data (1H, 13C, HSQC, and GOESY) with that of a structurally similar cis-2-methyl-1,2-dihydronaphthalen-1-ol (R=H).19

Treatment with organocerium reagent (entry 1) showed minimal reaction. Since organocerium compounds are relatively hard nucelophiles (as evidenced by the popular Luche reduction), the

low reactivity as seen with Grignard and organolithium reagents (Scheme 3.2) was not surprising.

The use of organozirconium reagent nBu4Zr resulted in a modest yield of 3.2a (entry 2), while

Yamamoto’s reagent (entry 3) gave no reaction. In contrast, the use of Gilman cuprates prepared from copper(I) halide salts resulted in improved yields of dihydronaphthalenol 3.2a. Within this series, it was observed that chloride and bromide derivatives were more effective than the iodide, providing 3.2a in a moderate yield of > 55% after 8 hours (entries 4-6). During these trials, an aromatic side product 3.3a was noted for the first time. With higher-order cuprates, encouraging yields of 3.2a were found with small proportions of 3.3a (entries 7, 8). Finally, various solvents were screened. The choice of diethyl ether dramatically improved the yield to a near-quantitative conversion, possibly by changing the cuprate structure (entry 9),3 while reactions in toluene, hexanes, or dichloromethane proved unsuccessful (entries 10-12), and use of 1,4-dioxane as co- solvent proved challenging due to its high melting point (entry 13). As such, the combination of higher-order cyanocuprate in diethyl ether was deemed to be optimal for use in further studies.

Some less accessible organolithium reagents were also prepared, although their use in further transformations were unsuccessful. Following Knochel’s preparation of cyclohexyllithium

(Scheme 3.4a),20 reaction with 3.1a resulted in negligible transfer of a cyclohexyl nucleophile, but direct attack of the tert-butyl nucleophile was noted by 1H NMR, suggesting that lithium-halide exchange was incomplete. Also attempted was deprotonation of a terminal alkyne to afford an alkynyl nucleophile (Scheme 3.4b), although this reaction also proved futile. The use of Stryker’s reagent as a hydride source was attempted, although no reaction was observed for this either

(Scheme 3.5). Not surprisingly, the use of 2-thienyl nucleophile from its higher-order cuprate resulted in an unconventional array of products, likely as a result of the reluctance of these dummy- type ligands to transfer (Scheme 3.6; vide supra).

Table 3.2. Nucleophile and Solvent Effects on Type 1 Ring-Opening Reactions of 3.1a.

entry Organometallic solvent Time (h) Recovered Yield Yield reagent 3.1a (%)a 3.2a (%)a 3.3a (%)a 1 nBuCeCl2 THF 24 91 4 0 2 nBu4Zr THF 24 0 30 0 3 nBuCu.BF3 THF 72 92 0 0 4 nBu2CuLi.LiI THF 8 65 30 2 5 nBu2CuLi.LiBr THF 8 22 67 2 6 nBu2CuLi.LiCl THF 8 35 58 2 7 nBu3CuLi2.LiCl THF 8 20 71 3 8 nBu2CuCNLi2 THF 8 29 69 2 9 nBu2CuCNLi2 Et2O 8 2 95 2 10 nBu2CuCNLi2 Toluene 8 91 0 0 11 nBu2CuCNLi2 Hexanes 8 96 0 0 12 nBu2CuCNLi2 DCM 8 95 0 0 b 13 nBu2CuCNLi2 Dioxane 8 65 10 0 a Isolated yield after column chromatography. b1:4 dioxane:THF mixture (THF was added to inhibit freezing of solvent at -78 ˚C); yield was determined by 1H NMR.

Scheme 3.4. Unsuccessful attempts to promote type 1 ring-opening using in situ generated organolithium reagents as precursors to organocuprates.

Scheme 3.5. Unsuccessful attempt of type 1 ring-opening using Stryker’s reagent.

Scheme 3.6. Unsuccessful attempt of type 1 ring-opening using 2-thienyl nucleophile.

The results of ring-opening of 3.1a using different higher-order cyanocuprate nucleophiles are presented in Table 3.3. Relative to n-butyl (entry 1), the methyl nucleophile (entry 2) was especially unreactive, resulting in 40% recovery of 3.1a after a full week. This likely resulted from the low transferability of methyl relative to n-butyl ligand from the cuprate. Using an excess of cuprate at higher temperature, the reaction was driven further towards completion (entry 3), with moderate yield of 3.2 and formation of 3.3. Reactions with the ethyl nucleophile also showed that the longer the reaction was left, the greater the consumption of starting material and formation of side product 3.3 (entries 4-6). A similar observation was made for the hexyl nucleophile (entries

7-8). From this it became clear that aromatization proceeded readily in the sealed reaction vessel under reaction conditions. iPr and tBu nucleophiles showed relatively fast conversion albeit similar proportions of 3.2 and 3.3 were recovered (entries 9, 10), while surprisingly the phenyl nucleophile appeared to produce 3.2 without any isolable 3.3 (entry 11). Upon closer examination, it also became clear that 3.2 converts to 3.3 on standing at room temperature. This conversion could be readily monitored by 1H NMR, and was traced over a period of 2 months (Figures 3.1 and 3.2).

Table 3.3. Effects of organocuprate nucleophiles on type 1 ring-opening reactions of 3.1a.

Entry Nucleophile Time Recovered Product Yield 3.2 Yield 3.3 (R) (h) 3.1a (%)a Identifier (%)a (%)a 1 nBu 8 2 a 95 2 2 Me 160 40 b 59 0 3b Me 48 16 b 64 19 4 Et 16 48 c 50 2 5 Et 120 49 c 10 28 6 Et 160 15 c 10 64 7 Hex 30 35 d 40 1 8 Hex 140 0 d 18 77 9 iPr 40 3 e 45 47 10 tBu 30 37 f 12 20 11 Ph 48 60 g 23 0 a Isolated yield after column chromatography. b 10 equiv. of organocuprate, heated to 65-75 ˚C.

Figure 3.1. 1H NMR spectral expansion of δ 8.8-2.8 ppm region showing the conversion of

3.2a to 3.3a.

30 25 20 15 10 5 0

Extent Extent dehydrationof (%) 0 0.5 1 1.5 2 Time elapsed (months)

Figure 3.2. Extent of conversion of 3.2a to 3.3a over time as determined by 1H integrations.

The results from ring-opening reactions of derivatized cyclopropanes 3.1, bearing various substituents on the arene as well as at the bridgehead position, are presented in Table 3.4. Relative to the unsubstituted reaction of 3.1a (entry 1), substrates bearing para-disubstituted arenes appeared to show moderate reactivity towards ring-opening with surprisingly short duration

(entries 2-3). Once again, it was observed that reactions left for longer periods experienced extensive aromatization (entries 3-5). In contrast, the ortho-dimethoxy derivative showed no signs of reacting (entry 6), which was not surprising as similar differences in reactivity between similar ortho- and para- compounds have been noted previously.21 C1-alkyl substituted substrates all showed good reactivity and complete regioselectivity for nucleophilic attack at the unsubstituted bridgehead carbon, but required longer reaction times overall (entries 7-11). C1-methyl substituted

3.1 showed moderate conversion after 48 hours, although it was not until the reaction was left for nearly a week that the consumption of 3.1 was near complete (entries 7-8). Ethyl and n-butyl substituents produced >75% yields of 3.2 with minimal or undetectable 3.3 after 140-160 h (entries

9-10). The ring-opening also worked for the bulky C1-tert-butyl substituent, showing no production of 3.3 (entry 11).

Table 3.4. Effects of substitution pattern of the substrate toward type 1 ring-opening reactions of 3.1.

Entry X Y Z Time (h) Identifier Recovered Yield 3.2 Yield 3.3 3.1 (%)a (%)a (%)a 1 H H H 8 a 2 95 2 2 Me H H 4 h 9 64 0 3 OMe H H 1 i 78 15 7 4 OMe H H 20 i 55 24 14 5 OMe H H 48 i 51 12 51 6 H OMe H 160 j 96 0 0 7 H H Me 48 k 35 59 4 8 H H Me 120 k 9 48 21 9b H H Et 140 l 7 81 12 10 H H nBu 160 m 20 76 0 11 H H tBu 160 n 22 61 0 a Isolated yield after column chromatography. b 5 equivalents of organocuprate.

Conversion of dihydronaphthalenols 3.2 to 3.3 could also be induced by acid-catalyzed elimination: when p-TsOH (10 mol %) was added to a solution of 3.2 dissolved in Et2O and heated to 100 ˚C, rapid production of 3.3 was observed after only 1-2 hours (Table 3.5), even for dihydronaphthalenols 3.2b, 3.2c and 3.2l which generally had a lower tendency to aromatize under ring-opening conditions (Tables 3.3, 3.4).

Table 3.5. Acid-catalyzed dehydration of dihydronaphthalenols 3.2 to naphthalenes 3.3.

Entry R R’ Time (h) Product Yield (%)a 1 Me H 1 3.3b 50 2 Et H 1 3.3c 74 3 nBu Et 2 3.3l 80 a Isolated yield after column chromatography.

To test whether aromatization could be suppressed, a reaction with substrate 3.4 lacking a removable proton at its C2-position was performed (Scheme 3.7). This reaction was left for an entire week with no apparent aromatization – the sole product observed was 3.5 after several attempts. However, the reaction was slower to proceed overall and was still found to be incomplete at this time. It appears that aromatization can be blocked through use of C2-substituted substrates which do not allow for dehydration with the imminent hydroxyl group.

Scheme 3.7. Type 1 ring-opening reaction of 3.4 with no apparent aromatization.

To account for the formation of 3.2 in type 1 ring-opening reactions, the following general mechanism seemed plausible (Scheme 3.8). Following attack of an organometallic nucleophile at the bridgehead position of 3.1a and cleavage of its C-O bond to give 3.6, a basic species present in the reaction medium removes a bridgehead proton. An internal rearrangement of electrons ensues to force open the cyclopropane, generating 3.7. Upon quenching, both anionic C and O atoms of 3.7 become protonated, giving rise to the observed product, 3.2.

Scheme 3.8. Proposed mechanism for type 1 ring-opening reactions.

In Haner’s first version of the proposed mechanism, two routes were suggested: either the bridgehead proton is removed intermolecularly, or intramolecularly (by the alkoxy anion). In hopes to determine the identity of the base involved in proton removal, some labelling experiments and attempts to trap reaction intermediates were carried out, both in Haner’s work, and in the present study. The first mechanistic study undertaken invoked the use of tetradeuterated substrate

3.8 under normal reaction conditions. The obtained product showed three peaks in its 2H NMR

(which had not been acquired previously), and was supported by 1H and 13C NMR spectra to be that of the structure 3.9 (Scheme 3.9). An alcohol OH proton was clearly visible in 1H NMR spectra of compound 3.9. In addition, some very informative mechanistic insight has been obtained by studies with cyclopropanated azabenzonorbornadienes (Chapter 6).

Scheme 3.9. Labelling experiment showing that bridgehead deprotonation in type 1 ring- opening with organocuprates happens by an external base.

Unexpectedly, reaction of C1-bromo substituted substrate 3.10 gave rise to a product which did not contain the halogen, but instead had a hydrogen in its place, at 93% yield (Scheme 3.10).

This was confirmed by the fact that the 1H and 13C NMR data of 3.11 were identical to that of 3.2a obtained by ring-opening the parent 3.1a.

Scheme 3.10. Type 1 ring-opening reaction of bridgehead halogenated substrate 3.10 with displacement of bromine by hydrogen.

The displacement of bromine by hydrogen was not surprising considering that the presumed intermediate 3.12 is likely unstable due to the geminal placement of bulky bromine and oxygen atoms (Scheme 3.11). Although the carbonyl species 3.13 was not isolable, if this intermediate were indeed formed, then this scenario is thought to be similar to that reported by

Posner and Babiak,9 or Scott and Cotton,22 where hydride transfer from the organocuprate species has occurred. In Scott and Cotton’s work, a 1,2-reduction of saturated ketone 3.14 takes place with a hydride from the Cu-H species delivered to the less hindered endo face of the framework, due to the bulky gem-dimethyl groups at the C-7 position, to produce 3.15 (Scheme 3.12).

Scheme 3.11. Possible mechanism for the formation of debrominated product 3.11.

Scheme 3.12. Sterically-controlled reduction of carbonyl group by hydride delivery from an n-butyl group of a Gilman cuprate.

This is in accordance with the present observation where reduction of carbonyl 3.13 by hydride delivery from the less hindered face (as described in section 3.1.1), results in the observed product, 3.2. It was thought that by reacting each of the two classes of organocuprates – those that bear β-hydrogens, and those that do not – with 3.10, the hydride transfer process may become clear.

When the reaction was repeated with Ph2Cu(CN)Li2, hydride delivery surprisingly still took place to form 3.2g in 27% yield (Scheme 3.13). A similar phenomenon was noted by Posner and Babiak,9 comparing the reactivities of diphenylcopperlithium and dimethylcopperlithium with 3.16

(Scheme 3.14). Although treatment with phenylcuprate effected the expected transformation to

3.17, treatment with methylcuprate resulted in unexpected hydride transfer (3.18), which could not have occurred from a β-hydrogen on the cuprate, as the methyl group does not have any β- hydrogens. This suggests that the hydride must originate from another source such as the ethereal solvent, or the transfer may involve a radical mechanism. Radical species are known to cause decomposition even for compounds having no C-H bonds at a position β- to the C-Cu bond.23

Scheme 3.13. Attempt to determine the source of transferable hydrogen.

Scheme 3.14. An unexplained hydride transfer observed by Posner and Babiak.

Other noteworthy observations made during the course of substrate studies include the reaction of substrates bearing 1) aromatic halide substituents and 2) C1-carbonyl substituents.

When substrates 3.21 and 3.22 bearing aromatic halide substituents were subjected to the copper- catalyzed reaction conditions, a complicated mixture of 5 or more inseparable products resulted in under 1 hour for both starting materials (Scheme 3.15).

Scheme 3.15. Unsuccessful results observed with the use of arene-halogenated substrates.

This could be explained by the basis that organocopper reagents react with aryl and alkyl halides via substitution reactions. The classical Ullmann reaction (copper-catalyzed coupling of two organohalides) is similar in concept.24,25 The halogen in aryl halides is activated by metal

26 complexes, such as organocuprates, in various ways. Since R2Cu(CN)Li2 is similar in

27 composition to R3CuLi2, which is known to undergo halide substitution readily in Et2O, it is

likely that under the present reaction conditions any halide substituent on the aromatic ring is readily coupled to the organic group of the cuprate. This substitution could occur at multiple halides, or at only some of the halides, and if ring-opening occurs on these C-C coupled species, then this could explain the mixture of products observed.

When substrates bearing C1-carbonyl substituents 3.23 and 3.24 were subjected to ring- opening, a set of diastereomers resulted (Scheme 3.16). In the case of 3.23 (C1-Ac), the diastereomeric ratio was consistently 2:1 whereas with 3.24 (C1-COOMe), the diasteromeric ratio was always 1:1, as determined by 1H NMR peak integrations.

Scheme 3.16. Isomers arising from C1-carbonyl substituted starting materials 3.23 or 3.24.

The structures of these products were assigned based on evidence by 1H, JMOD, HSQC,

HMBC, difference NOE, high-temperature 1H and 13C NMR experiments, as well as J coupling constants, and was supported by simulated NMR spectra, IR, HPLC and HRMS results. In the 1H

NMR, as well as JMOD spectra, it was apparent that each set of peaks appeared as duplicate pairs.

This was particularly obvious for the case of 3.25, as the peak integrations or intensities of one

isomer’s set was readily distinguishable from the other’s. The 2D NMR spectra also confirmed this, as none of the carbon peaks from one set were attached to any of the protons from the second set. To further ascertain that the duplicate peaks arose from a set of stereoisomers and not due to two equilibrium species separated by a high energy barrier, spectra were acquired at temperatures of 297 K, 328 K and 348 K, which showed no appreciable peak coalescence. In addition, a difference NOE method introduced by Ley and coworkers to distinguish diasteromers from an interconverting equilibrium was applied.28 The results of this method (NOE seen for only a unique peak set) suggested that the two species were diastereomers, and not the same compound. Most conclusive was the fact that analytical HPLC showed two distinct peaks. From these results, a detailed assignment could be made for the proposed structure 3.25, and a similar yet less rigorous analysis (1H, JMOD, HSQC, spectral simulation match, HRMS) supported the structure of 3.26. It was obvious that the organocuprate was not participating in the typical type 1 ring-opening manner, as there was no incorporation of nucleophile (n-butyl) at the bridgehead position, and the cyclopropane was intact. Furthermore, the fact that the site of carbonyl attachment showed two chiral outcomes implied the presence of a planar intermediate to which hydride delivery could occur from one of two faces. From this, two mechanisms could be proposed (Scheme 3.17).

Scheme 3.17. Proposed mechanism for formation of diastereomers 3.25a and 3.25b.

In one scenario (path A), coordination of a metallic species (presumably the cuprate) to the substrate 3.23 (as in 3.27 or coordinating with the cyclopropane) promotes electrophilic ring- opening of the oxabicyclic framework, leading to the formation of a tertiary carbocationic intermediate 3.28. This intermediate is likely short-lived and readily quenched by a hydride from the reaction medium, similar to the case with 3.10, above (Scheme 3.11). Although one might question the likelihood of an α-keto cation’s existence, such species are known and have been a topic of investigation by Creary.29,30 This simple mechanism, however, does not account for the

2:1 ratios for the two diastereomers, and may benefit from CD3Li.LiI labelling experiments to determine the source of the delivered hydride. Alternatively, it is possible that a radical mechanism is involved (path B), with keto-enol tautomerization to reform the carbonyl moiety. Attempts were made to separate 3.25a and 3.25b by functionalizing the hydroxyl group, although such treatment still resulted in a 2:1 mixture of different products which could not be separated.

As for the COOMe version 3.24, nucleophilic attack has occurred at the carbonyl of the ester. Similar conversions of esters to ketones (effectively the same transformation as using

Weinreb amides) with organocuprates is indeed a known process.31 Lipshutz reports near-identical conditions to the present work which results in ketone formation (Scheme 3.18), which reinforces the present rationale.32 With the ester to ketone conversion explained, the rest of the mechanism is probably analogous to that of the acetyl example, 3.23, with the only uncertainty being the sequence of steps.

Scheme 3.18. Lipshutz’s ester to ketone conversion observed during conjugate addition.

It is worth noting that all C1-substituted substrates which underwent the expected type 1 ring-opening reactions possessed electron-donating (alkyl) substituents. There may be a yet unrevealed explanation as to why C1-electron-withdrawing groups modify the reactivity of cyclopropanated oxabenzonorbornadienes toward ring-openings.

3.3 - Conclusion

The first type of ring-opening reactions of cyclopropanated 7-oxabenzonorbornadienes was explored to create a new and reliable route to a large number of novel cis-2-methyl-1,2- dihydronaphthalen-1-ols. Nucleophile studies showed that primary, secondary, tertiary and aromatic organic nucleophiles can be used, and that the reaction is compatible with substrates bearing aromatic, C1, or C2-substituents. Complete regioselectivity of nucleophilic attack was observed for reactions involving unsymmetrical C1- or C2-substituted substrates. Other organometallic nucleophiles were also seen to induce this transformation, albeit at lower yields.

Further investigations into the scope of type 1 ring-opening reactions may unveil new and more direct routes for total syntheses of bioactive compounds, or may provide valuable insight for the reactivity of similarly strained systems.

3.4 - Experimental

General Information: All experiments were conducted under an inert atmosphere of dry nitrogen or argon. Glassware was oven-dried overnight. Column chromatography, TLC, melting point determination, IR, NMR, and HRMS analyses were performed as described in Chapter 2.

Reagents: Commercial reagents were used without further purification. Grignard and organolithium reagents were titrated against a dry solution of LiCl with iodine as an indicator,2a,b or against (±)-menthol using 9H-fluorene as an indicator, respectively.33-35 Dried and degassed solvents were obtained from an LC-SPS solvent purification system supplied with dry packed columns containing 3 Å molecular sieves. Cyclopropanated 7-oxabenzonorbornadienes 36 and organometallic reagents37-42 were prepared according to literature procedures.

General procedure for Cu-catalyzed ring-opening reactions with higher order cyanocuprates: CuCN (0.56 mmol, 3 equiv.) was weighed into an oven-dried Schlenk flask with stir bar, which was evacuated and refilled with nitrogen or argon three times. Et2O (4 mL) was added, and the suspension was cooled to -78 ˚C. To this, an organolithium reagent (1.14 mmol, 6 equiv.) was added dropwise with constant stirring to prepare the corresponding cyanocuprate.

Cyclopropanated 7-oxabenzonorbornadiene 3.1 (0.19 mmol, 1 equiv.), weighed in an oven-dried vial purged with inert gas, was transferred to the organocuprate solution by cannula with Et2O rinses (3 × 0.5 mL). The cooling bath was removed and the flask was sealed. Upon completion of the reaction, the mixture was cooled to 0-5 ˚C and quenched by dropwise addition of 9:1 saturated aqueous NH4Cl: conc.NH4OH (pH 9-10). The mixture was extracted with CH2Cl2 (3 × 20 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified by column chromatography (hexanes/ethyl acetate mixture).

Acid-catalyzed conversion of dihydronaphthalenols 3.2 to 3.3: p-TsOH (10 mol %) was added to a solution of 3.2 dissolved in Et2O in a tightly-sealed screw-cap vial with polytetrafluoroethylene (PTFE) thread-seal tape and was heated to 100 ˚C for 1-2 h. The reaction mixture was cooled to room temperature and set aside overnight. The crude product was purified by column chromatography (hexanes/ethyl acetate mixture).

(1S*,2S*)-4-Butyl-2-methyl-1,2-dihydronaphthalen-1-ol (3.2a; Table 3.3, entry 1): (38.1 mg,

-1 95 % yield). Yellow oil; Rf (1:4 EtOAc: Hexanes): 0.37; FTIR (KBr, ν, cm ): 3449, 2961, 2932,

1 2253, 908, 734, 651; H NMR (400 MHz, CDCl3): δ 7.39-7.27 (m, 4H), 5.56 (m, 1H), 4.50 (m,

1H), 2.60 (m, 1H), 2.46 (m, 2H), 1.61 (br s, 1H), 1.54 (m, 2H), 1.42 (m, 2H), 1.20 (d, J= 7.4 Hz,

13 3H), 0.96 (t, J= 7.3 Hz, 3H); C NMR (100 MHz, CDCl3): δ 137.8, 135.8, 133.3, 128.4, 128.1,

+ 127.5, 127.4, 123.4, 72.2, 35.1, 32.2, 30.8, 22.9, 14.6, 14.2; HRMS: Calculated for C15H20O [M] :

216.1514. Found: 216.1506.

1-Butyl-3-methylnaphthalene (3.3a; Table 3.3, entry 1): (0.6 mg, 2 % yield). Yellow oil; Rf

(1:4 EtOAc: Hexanes): 0.67; FTIR (KBr, ν, cm-1): 3051, 2955, 2930, 2860, 1627, 1602, 1509,

1 1465, 1419, 1396, 1376, 1028, 863, 844, 780, 745; H NMR (400 MHz, CDCl3): δ 7.98 (m, 1H),

7.75 (m, 1H), 7.46 (s, 1H), 7.42 (m, 2H), 7.16 (s, 1H), 3.02 (t, J=7.7 Hz, 2H), 2.47 (s, 3H), 1.71

13 (m, 2H), 1.46 (m, 2H), 0.96 (t, J=7.4 Hz, 3H); C NMR (100 MHz, CDCl3): δ 138.7, 134.9, 134.1,

130.1, 128.1, 128.0, 125.3, 125.2, 124.7, 123.7, 33.0, 32.7, 22.9, 21.6, 14.0; HRMS: Calculated

+ for C15H18 [M] : 198.1409. Found: 198.1403.

100

(1S*,2S*)-2,4-Dimethyl-1,2-dihydronaphthalen-1-ol (3.2b; Table 3.3, entry 3): (21.8 mg, 64%

-1 yield). Yellow oil; Rf (1:4 EtOAc: Hexanes): 0.35; FTIR (KBr, ν, cm ): 3388, 2976, 2896, 1088,

1 1048, 911, 880, 735, 649; H NMR (400 MHz, CDCl3): δ 7.38-7.25 (m, 4H), 5.58 (m, 1H), 4.51

(br d, J = 4.6 Hz, 1H), 2.60 (m, 1H), 2.09 (s, 3H), 1.60 (br s, 1H), 1.20 (d, J= 7.4 Hz, 3H); 13C

NMR (100 MHz, CDCl3): δ 137.5, 134.2, 131.6, 129.3, 128.7, 127.8, 127.5, 123.7, 72.3, 35.4,

+ 19.3, 14.7; HRMS: Calculated for C12H14O [M] : 174.1045. Found: 174.1039.

1,3-Dimethylnaphthalene (3.3b; Table 3.3, entry 3): (5.8 mg, 19 % yield). Yellow oil; Rf (1:4

EtOAc: Hexanes): 0.65; FTIR (KBr, ν, cm-1): 3067, 3050, 3016, 2920, 2856, 1630, 1602, 1509,

1 1466, 1441, 1411, 1376, 1027, 859, 844, 772, 745; H NMR (400 MHz, CDCl3): δ 7.92 (m, 1H),

7.73 (m, 1H), 7.43 (m, 3H), 7.15 (br s, 1H), 2.64 (br s, 3H), 2.45 (br s, 3H); 13C NMR (100 MHz,

CDCl3): 135.0, 134.0, 133.8, 130.8, 128.9, 127.8, 125.6, 125.2, 124.8, 123.9, 21.6, 19.2; HRMS

+ (ESI): Calculated for C12H13 [M+H] : 157.1017. Found: 157.1009.

(1S*,2S*)-4-Ethyl-2-methyl-1,2-dihydronaphthalen-1-ol (3.2c; Table 3.3, entry 4): (16.3 mg,

-1 50 % yield). Yellow oil; Rf (1:4 EtOAc: Hexanes): 0.36; FTIR (KBr, ν, cm ): 3439, 2970, 2933,

1 2252, 1638, 1453, 1377, 907, 731, 650; H NMR (400 MHz, CDCl3): δ 7.37-7.22 (m, 4H), 5.55

(m, 1H), 4.48 (dd, J = 7.3, 4.8 Hz, 1H), 2.59 (m, 1H), 2.47 (m, 2H), 1.58 (d, J= 2.6 Hz, 1H), 1.20

13 (d, J= 7.4 Hz, 3H), 1.16 (t, J= 7.4 Hz, 3H); C NMR (100 MHz, CDCl3): δ 137.5, 136.9, 133.2,

128.3, 127.4, 127.3, 126.8, 123.1, 72.0, 34.9, 24.9, 14.4, 12.9; HRMS: Calculated for C13H16O

[M]+: 188.1201. Found: 188.1206.

101

1-Ethyl-3-methylnaphthalene (3.3c; Table 3.3, entry 4): (0.6 mg, 2 % yield). Yellow oil; Rf (1:4

EtOAc: Hexanes): 0.67; FTIR (KBr, ν, cm-1): 3049, 2965, 2932, 2873, 1602, 1508, 1466, 867, 781,

1 744; H NMR (400 MHz, CDCl3): δ 7.98 (m, 1H), 7.74 (m, 1H), 7.46 (s, 1H), 7.40 (m, 2H), 7.16

13 (s, 1H), 3.07 (q, J= 7.5 Hz, 2H), 2.47 (s, 3H), 1.36 (t, J=7.5 Hz, 3H); C NMR (100 MHz, CDCl3):

δ 139.9, 135.0, 134.0. 129.9, 127.9, 127.1, 125.3, 125.2, 124.7, 123.4, 25.7, 21.6, 15.0; HRMS:

+ Calculated for C13H14 [M] : 170.1096. Found: 170.1102.

(1S*,2S*)-4-Hexyl-2-methyl-1,2-dihydronaphthalen-1-ol (3.2d; Table 3.3, entry 7): (28.4 mg,

-1 40 % yield). Yellow oil; Rf (1:4 EtOAc: Hexanes): 0.38; FTIR (KBr, ν, cm ): 3425, 2957, 2928,

1 2857, 1638, 1485, 1453, 1377, 1042, 937, 829, 759, 653; H NMR (400 MHz, CDCl3): δ 7.39-7.23

(m, 4H), 5.56 (m, 1H), 4.50 (dd, J= 7.6, 4.8 Hz, 1H), 2.60 (m, 1H), 2.44 (m, 2H), 1.86 (d, J= 4.0

Hz, 1H), 1.73 (m, 2H), 1.27 (m, 6H), 0.91 (d, J= 7.3 Hz, 3H), 0.90 (t, J= 6.9 Hz, 3H); 13C NMR

(100 MHz, CDCl3): δ 137.6, 135.6, 133.0, 128.2, 127.8, 127.3, 127.2, 123.2, 71.9, 34.9, 32.3, 31.6,

+ 29.3, 28.4, 22.6, 14.3, 14.0.; HRMS: Calculated for C17H24O [M] : 244.1827. Found: 244.1819.

1-Hexyl-3-methylnaphthalene (3.3d; Table 3.3, entry 7): (0.7 mg, 1 % yield). Yellow oil; Rf

(1:4 EtOAc: Hexanes): 0.73; FTIR (KBr, ν, cm-1): 3051, 2955, 2928, 2857, 1603, 1509, 1466,

1 1396, 1376, 1029, 862, 844, 781, 745; H NMR (400 MHz, CDCl3): δ 7.98 (m, 1H), 7.75 (m, 1H),

7.46 (s, 1H), 7.42 (m, 2H), 7.16 (s, 1H), 3.01 (t, J=8.2 Hz, 2H), 2.47 (s, 3H), 1.72 (m. 2H), 1.45

13 (m, 2H), 1.33 (m, 4H), 0.89 (t, J= 7.0 Hz, 3H); C NMR (100 MHz, CDCl3): δ 138.8, 135.0,

102

134.1, 130.1, 128.1, 128.0, 125.4, 125.2, 124.7, 123.7, 33.1, 31.8, 30.9, 29.6, 22.7, 21.7, 14.1;

+ HRMS: Calculated for C17H22 [M] : 226.1722. Found: 226.1729.

(1S*,2S*)-2-Methyl-4-isopropyl-1,2-dihydronaphthalen-1-ol (3.2e; Table 3.3, entry 9): (10.0

-1 mg, 45 % yield). Yellow oil; Rf (1:4 EtOAc: Hexanes): 0.37; FTIR (KBr, ν, cm ): 3434, 2967,

1 2253, 1638, 1466, 1383, 908, 733, 651; H NMR (400 MHz, CDCl3): δ 7.37-7.20 (m, 4H), 5.54

(m, 1H), 4.44 (dd, J= 7.7, 4.6 Hz, 1H), 2.98 (m, 1H), 2.58 (m, 1H), 1.60 (d, J= 8.4 Hz, 1H), 1.19

13 (d, J= 7.0 Hz, 3H), 1.17 (d, J= 7.0 Hz, 3H), 1.13 (d, J= 6.8 Hz, 3H); C NMR (100 MHz, CDCl3):

δ 141.7, 137.9, 132.9, 128.2, 127.4, 127.2, 124.6, 123.1, 72.0, 34.8, 28.0, 22.5, 21.9, 14.5; HRMS:

+ Calculated for C14H18O [M] : 202.1358. Found: 202.1350.

3-Methyl-1-isopropylnaphthalene (3.3e; Table 3.3, entry 9): (9.5 mg, 47 % yield). Yellow oil;

-1 Rf (1:4 EtOAc: Hexanes): 0.72; FTIR (KBr, ν, cm ): 3047, 2961, 2869, 1625, 1602, 1509, 1463,

1 1399, 1383, 1364, 866, 844, 782, 745; H NMR (600 MHz, CDCl3): δ 7.84 (m, 1H), 7.53 (m, 1H),

7.19 (m, 3H), 7.01 (m, 1H), 3.50 (m, 1H), 2.53 (s, 3H), 1.43 (d, J= 6.8 Hz, 6H); 13C NMR (125

MHz, CDCl3): δ 144.4, 135.0, 134.2, 129.5, 128.2, 125.3, 125.2, 124.7, 124.0, 123.1, 28.4, 23.5,

+ 21.8; HRMS: Calculated for C14H16 [M] : 184.1252. Found: 184.1246.

103

(1S*,2S*)-4-tert-Butyl-2-methyl-1,2-dihydronaphthalen-1-ol (3.2f; Table 3.3, entry 10): (5.9

-1 mg, 12 % yield). White solid; mp: 62-67 ˚C; Rf (1:4 EtOAc: Hexanes): 0.37; FTIR (KBr, ν, cm ):

1 3389, 2960, 2929, 2872, 1481, 1453, 1394, 1366, 1504, 1040, 757; H NMR (400 MHz, CDCl3):

δ 7.68 (d, J= 7.6 Hz, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 7.20 (m, 1H), 5.67 (dd, J = 3.2, 0.8 Hz, 1H),

4.36 (dd, J= 8.2, 4.3 Hz, 1H), 2.52 (m, 1H), 1.59 (d, J= 8.5 Hz, 1H), 1.34 (s, 9H), 1.19 (d, J= 7.3

13 Hz, 3H); C NMR (100 MHz, CDCl3): δ 144.0, 139.1, 132.6, 127.7, 127.5, 126.9, 126.7, 126.5,

+ 72.2, 35.0, 34.9, 31.0, 14.7; HRMS: Calculated for C15H20O [M] : 216.1514. Found: 216.1506.

1-tert-Butyl-3-methylnaphthalene (3.3f; Table 3.3, entry 10): (9.5 mg, 20 % yield). Off-white

-1 semi-solid; Rf (1:4 EtOAc: Hexanes): 0.66; FTIR (KBr, ν, cm ): 3051, 2992, 2956, 2872, 1625,

1 1605, 1509, 1480, 1462, 1396, 1365, 1250, 1193, 868, 846, 786, 749; H NMR (400 MHz, CDCl3):

δ 8.39 (m, 1H), 7.76 (m, 1H), 7.47 (s, 1H), 7.39 (m, 2H), 7.30 (s, 1H), 2.47 (s, 3H), 1.54 (s, 9H);

13 C NMR (100 MHz, CDCl3): δ 145.8, 135.4, 134.4, 129.6, 128.9, 126.7, 126.2, 125.7, 124.6,

+ 123.7, 35.9, 31.8, 21.9; HRMS: Calculated for C15H18 [M] : 198.1409. Found: 198.1416.

104

(1S*,2S*)-2-Methyl-4-phenyl-1,2-dihydronaphthalen-1-ol (3.2g; Table 3.3, entry 11): (21.3

-1 mg, 23 % yield). White solid; mp: 88-91 ˚C; Rf (1:4 EtOAc: Hexanes): 0.34; FTIR (KBr, ν, cm ):

3394, 2976, 2898, 2250, 1640, 1453, 1383, 1087, 1047, 910, 880, 733, 648; 1H NMR (400 MHz,

CDCl3): δ 7.40 (m, 1H), 7.34 (m, 5H), 7.23 (m, 3H), 7.06 (m, 1H), 5.78 (m, 1H), 4.58 (dd, J= 7.0,

4.8 Hz, 1H), 2.73 (m, 1H), 1.61 (d, J= 7.9 Hz, 1H), 1.27 (d, J= 7.4 Hz, 3H); 13C NMR (100 MHz,

CDCl3): δ 139.7, 138.7, 137.7, 132.9, 130.9, 128.7, 128.2, 128.1, 127.7, 127.4, 127.2, 126.0, 71.8,

+ 35.5, 14.2; HRMS: Calculated for C17H16O [M] : 236.1201. Found: 236.1193.

(1S*,2S*)-4-Butyl-2,5,8-trimethyl-1,2-dihydronaphthalen-1-ol (3.2h; Table 3.4, entry 2):

-1 (45.3 mg, 64 % yield). Yellow oil; Rf (1:4 EtOAc: Hexanes): 0.33 FTIR (KBr, ν, cm ): 3403, 2976,

1 2929, 1640, 1453, 1383, 1087, 1047, 909, 879, 733; H NMR (600 MHz, CDCl3): δ 6.96 (ABq,

JAB= 7.8 Hz, ΔδAB = 12.7 Hz, 2H), 5.50 (br s, 1H), 4.45 (m, 1H), 2.82 (m, 1H), 2.39 (s, 6H), 2.38

(m, 2H), 1.50 (d, J= 9.6 Hz, 1H), 1.39 (m, 1H), 1.32 (J= 7.5 Hz, 6H), 0.86 (t, J= 7.1 Hz, 3H); 13C

NMR (125 MHz, CDCl3): δ 139.0, 137.7, 133.0, 132.8, 131.7, 131.6, 129.9, 129.3, 68.4, 35.7,

+ 34.4, 31.8, 23.0, 22.7, 19.0, 15.8, 13.9; HRMS: Calculated for C17H24O [M] : 244.1827. Found:

244.1822.

105

(1S*,2S*)-4-Butyl-5,8-dimethoxy-2-methyl-1,2-dihydronaphthalen-1-ol (3.2i; Table 3.4,

-1 entry 4): (6.7 mg, 24 % yield). Yellow oil; Rf (1:4 EtOAc: Hexanes): 0.26; FTIR (KBr, ν, cm ):

1 3444, 1632, 1480, 1257, 906, 731, 650; H NMR (600 MHz, CDCl3): δ 6.79 (ABq, JAB= 9.0 Hz,

ΔδAB = 16.5 Hz, 2H), 5.42 (br s, 1H), 4.78 (m, 1H), 3.81 (s, 3H), 3.75 (s, 3H), 3.00 (m, 1H), 2.40

(m, 1H), 2.29 (m, 1H), 1.62 (d, J=8.7 Hz, 1H), 1.40 (m, 1H), 1.30 (m, 3H), 1.28 (d, J=7.5 Hz, 3H),

13 0.86 (t, J= 7.2 Hz, 3H); C NMR (125 MHz, CDCl3): δ 150.9, 150.4, 136.9, 129.5, 128.4, 123.2,

112.3, 110.8, 64.6, 56.1, 56.0, 35.8, 34.2, 31.8, 22.7, 15.6, 14.0; HRMS: Calculated for C17H24O3

[M]+: 276.1725. Found: 276.1718.

5-Butyl-1,4-dimethoxy-7-methylnaphthalene (3.3i; Table 3.4, entry 4): (3.2 mg, 14 % yield).

-1 Yellow-green oil; Rf (1:4 EtOAc: Hexanes): 0.55; FTIR (KBr, ν, cm ): 2953, 2858, 2834, 1623,

1608, 1460, 1433, 1408, 1372, 1268, 1252, 1240, 1200, 1136, 1097, 1047, 976, 861, 791, 731; 1H

NMR (600 MHz, CDCl3): δ 7.92 (s, 1H), 7.10 (s, 1H), 6.66 (ABq, JAB= 8.4 Hz, ΔδAB = 16.9 Hz,

2H), 3.94 (s, 3H), 3.88 (s, 3H), 3.21 (t, J=7.9 Hz, 2H), 2.47 (s, 3H), 1.62 (m, 2H), 1.44 (m, 2H),

13 0.96 (t, J=7.4 Hz, 3H); C NMR (125 MHz, CDCl3): δ 151.7, 149.4, 139.8, 134.9, 131.1, 128.2,

123.2, 119.1, 103.6, 103.3, 55.8, 55.4, 37.6, 35.2, 23.1, 21.5, 14.1; HRMS: Calculated for C17H22O2

[M]+: 258.1620. Found: 276.1630.

106

(1S*,2S*)-4-Butyl-1,2-dimethyl-1,2-dihydronaphthalen-1-ol (3.2k; Table 3.4, entry 7): (22.0

-1 mg, 59 % yield). Yellow oil; Rf (1:4 EtOAc: Hexanes): 0.38; FTIR (KBr, ν, cm ): 3047, 2974,

1 2931, 2252, 1383, 1047, 908, 732, 650; H NMR (600 MHz, CDCl3): δ 7.58 (m, 1H), 7.25 (m,

3H), 5.76 (d, J= 5.6 Hz, 1H), 2.47 (m, 1H), 2.35 (m, 2H), 1.78 (s, 1H), 1.49 (m, 5H), 1.36 (m, 2H),

13 0.96 (d, J= 7.0 Hz, 3H), 0.91 (t, J= 7.3 Hz, 3H); C NMR (125 MHz, CDCl3): δ 141.8, 134.2,

132.7, 129.6, 127.5, 127.1, 123.8, 123.1, 73.9, 40.7, 32.1, 30.5, 28.0, 22.6, 13.9, 13.3; HRMS:

+ Calculated for C16H22O [M] : 230.1671. Found: 230.1665.

1-Butyl-3,4-dimethylnaphthalene (3.3k; Table 3.4, entry 7): (1.4 mg, 4 % yield). Yellow oil; Rf

(1:4 EtOAc: Hexanes): 0.70; FTIR (KBr, ν, cm-1): 2957, 2931, 2862, 2250, 1601, 1513, 1466,

1 1383, 908, 733, 650; H NMR (600 MHz, CDCl3): δ 8.05 (d, J=8.6Hz, 1H), 8.02 (d, J=8.1 Hz,

1H), 7.47 (m, 2H), 7.16 (s, 1H), 3.01 (t, J= 7.9 Hz, 2H), 2.58 (s, 3H), 2.47 (s, 3H), 1.72 (m, 2H),

13 1.46 (m, 2H), 0.98 (t, J= 7.4 Hz, 3H); C NMR (125 MHz, CDCl3): δ 136.3, 133.2, 132.6, 130.5,

129.2, 129.1, 125.2, 124.3, 124.2, 124.1, 33.2, 32.7, 22.9, 20.7, 14.4, 14.0; HRMS: Calculated for

+ C16H20 [M] : 212.1565. Found: 212.1560.

107

(1S*,2S*)-4-Butyl-1-ethyl-2-methyl-1,2-dihydronaphthalen-1-ol (3.2l; Table 3.4, entry 9):

-1 (55.4 mg, 81 % yield). Yellow oil; Rf (1:4 EtOAc: Hexanes): 0.46; FTIR (KBr, ν, cm ): 3425,

1 1638, 1045; H NMR (400 MHz, CDCl3): δ 7.59 (m, 1H), 7.24 (m, 3H), 5.78 (d, J= 6.1 Hz, 1H),

2.46 (m, 2H), 2.30 (m, 1H), 1.89 (m, 1H), 1.75 (m, 1H), 1.69 (s, 1H), 1.49 (m, 2H), 1.37 (m, 2H),

13 0.92 (m, 6H), 0.79 (t, J= 7.5 Hz, 3H); C NMR (100 MHz, CDCl3): δ 140.4, 134.2, 133.1, 129.4,

127.1, 127.0, 125.1, 123.0, 76.5, 38.6, 32.2, 30.5, 22.7, 14.1, 13.1, 8.4; HRMS: Calculated for

+ C17H24O [M] : 244.1827. Found: 244.1833.

4-Butyl-1-ethyl-2-methylnaphthalene (3.3l; Table 3.4, entry 9): (7.8 mg, 12 % yield). Yellow

-1 oil; Rf (1:4 EtOAc: Hexanes): 0.70; FTIR (KBr, ν, cm ): 3071, 2959, 2870, 1601, 1514, 1456,

1 1377, 1055, 1036, 874, 757; H NMR (400 MHz, CDCl3): δ 8.00 (m, 2H), 7.43 (m, 2H), 7.12 (s,

1H), 3.07-2.95 (m, 4H), 2.43 (s, 3H), 1.68 (m, 2H), 1.44 (m, 2H), 1.22 (t, J= 7.6 Hz, 3H), 0.94 (t,

13 J= 7.3 Hz, 3H); C NMR (100 MHz, CDCl3): δ 136.3, 135.2, 132.1, 131.8, 130.8, 129.3, 125.2,

+ 124.3, 124.1, 124.0, 33.0, 32.7, 22.9, 21.5, 19.8, 14.3, 13.9; HRMS: Calculated for C17H22 [M] :

226.1722. Found: 226.1731.

(1S*,2S*)-1,4-Dibutyl-2-methyl-1,2-dihydronaphthalen-1-ol (3.2m; Table 3.4, entry 10):

-1 (21.9 mg, 76 % yield). Yellow oil; Rf (1:4 EtOAc: Hexanes): 0.50; FTIR (KBr, ν, cm ): 3390,

1 2976, 2930, 2898, 1643, 1453, 1382, 1088, 1047, 880; H NMR (400 MHz, CDCl3): δ 7.51 (m,

1H), 7.23 (m, 3H), 5.76 (d, J= 6.2 Hz, 1H), 2.49 (m, 2H), 2.43 (m, 1H), 1.84 (m, 1H), 1.70 (m,

108

2H), 1.46 (m, 2H), 1.36 (m, 3H), 1.20 (m, 2H), 1.07 (m, 1H), 0.91 (m, 6H), 0.79 (t, J= 7.3 Hz,

13 3H); C NMR (100 MHz, CDCl3): δ 140.7, 134.2, 133.0, 129.5, 127.1, 126.9, 124.9, 123.0, 76.4,

+ 39.3, 38.8, 32.1, 30.4, 26.2, 23.1, 22.6, 14.04, 14.00, 12.9; HRMS: Calculated for C19H28O [M] :

272.2140. Found: 272.2149.

(1R*,2S*)-4-Butyl-1-tert-butyl-2-methyl-1,2-dihydronaphthalen-1-ol (3.2n; Table 3.4, entry

-1 11): (23.3 mg, 61 % yield). Yellow oil; Rf (1:4 EtOAc: Hexanes): 0.58; FTIR (KBr, ν, cm ): 3418,

1 2980, 1643, 1454, 1045, 740; H NMR (400 MHz, CDCl3): δ 7.61 (m, 1H), 7.28 (m, 2H), 7.23 (m,

1H), 5.77 (d, J= 6.5 Hz, 1H), 2.83 (m, 1H), 2.46 (m, 1H), 2.31 (m, 1H), 1.62 (s, 1H), 1.53-1.40

13 (m, 4H), 0.93-0.90 (m, 6H), 0.90 (s, 9H); C NMR (100 MHz, CDCl3): δ 137.4, 134.8, 133.2,

130.5, 128.1, 127.0, 126.2, 122.1, 79.2, 40.0, 34.4, 32.2, 30.1, 26.3, 23.0, 15.0, 14.0; HRMS:

+ Calculated for C19H28O [M] : 272.2140. Found: 272.2149.

(1S*,2S*)-4-Butyl-2-methyl-1,2-dihydronaphthalen-1-ol (3.11; Scheme 3.10): (19.5 mg, 93 % yield). The characterization data for this compound was identical to that of compound 3.2a.

109

(1S*,2S*)-4-Phenyl-2-methyl-1,2-dihydronaphthalen-1-ol (3.2g; Scheme 3.13): (9.4 mg, 27 % yield). The characterization data for this compound was identical to that previously observed

(Table 3.3, entry 11).

(1S*)-4-Butyl-1,2,2-trimethyl-1,2-dihydronaphthalen-1-ol (3.5; Scheme 3.7): (38.3 mg, 75%

-1 yield); clear oil; Rf (1:19 EtOAc: Hexanes): 0.17; FTIR (KBr, ν, cm ): 3485, 2960, 2930, 2871,

1 1483, 1467, 1365, 1144, 1080, 1038; H NMR (400 MHz, CDCl3): δ 7.64-7.62 (m, 1H), 7.30-7.25

(m, 3H), 5.55 (t, J= 1.2 Hz, 1H), 2.55-2.47 (m, 1H), 2.38-2.31 (m, 1H), 1.81 (s, 1H), 1.53-1.51 (m,

2H), 1.50-1.41 (m, 2H), 1.41 (s, 3H), 1.14 (s, 3H), 0.99 (s, 3H), 0.95 (t, J=7.3 Hz, 3H); 13C NMR

(100 MHz, CDCl3): δ 143.6, 135.3, 133.5, 132.6, 127.6, 126.9, 123.6, 122.9, 76.9, 39.3, 32.1, 30.6,

+ 23.6, 22.7, 22.3, 21.7, 14.0; HRMS: Calculated for C17H24O [M] : 244.1827. Found: 244.1822.

(1S*,2S*)-4-Butyl-1,2,3-trideutero-2-methyl-1,2-dihydronaphthalen-1-ol (3.9; Scheme 3.9):

1 (38.6 mg, 74% yield); clear oil; Rf (1:9 EtOAc: Hexanes): 0.32; H NMR (400 MHz, CDCl3): δ

110

7.35 (d, J= 8.3 Hz, 1H), 7.31 (m, 2H), 7.24 (m, 1H), 2.49-2.39 (m, 2H), 1.70 (br s, 1H), 1.52 (m,

13 2H), 1.38 (m, 2H), 1.17 (s, 3H), 0.92 (t, J = 7.3 Hz, 3H); C NMR (100 MHz, CDCl3): δ 137.6,

135.6, 133.1, 128.3, 127.3, 123.3, 41.6, 32.0, 30.6, 26.1, 23.3, 22.7, 14.2, 14.0; 2H NMR (61 MHz,

+ CDCl3): 5.60 (br s, 1H), 4.48 (br s, 1H), 2.58 (br s, 1H); HRMS: Calculated for C15H17D3O [M] :

219.1702. Found: 219.1705. Spectra agree with previous data.1

Diastereomers 3.25a/b (Scheme 3.17): 63% (32.8 mg) combined yield with 2:1 ratio for 3.25a:

1 3.25b; yellow oil; Rf (1:9 EtOAc: Hexanes): 0.07; H NMR (600 MHz, CDCl3): 7.69 (br d, J=7.8

Hz, 0.5H), 7.66 (br d, J=7.8 Hz, 1H), 7.31-7.28 (m, 1.5H), 7.22-7.20 (m, 1.5H), 7.12 (br d, J=7.5

Hz, 1H), 6.80 (br d, J=7.7 Hz, 0.5H), 5.11 (br s, 1H), 5.03 (br s, 0.5H), 4.05 (br s, 1H), 3.96 (br d,

J=4.0 Hz, 0.5H), 2.23 (s, 1.5H), 2.10 (s, 3H), 2.05 (br s, 0.5H), 1.97 (br s, 1H), 1.82-1.77 (m,

1.5H), 1.54-1.50 (m, 1.5H), 0.65-0.61 (m, 0.5H), 0.57-0.54 (m, 0.5H), 0.53-0.50 (m, 1H), 0.17 (m,

1 1H); H NMR (600 MHz, Benzene-d6): δ 7.79 (d, J=7.8 Hz, 1.5H), 7.14-7.12 (m, 1.5H), 7.00-6.95

(m, 1.5H), 6.83 (d, J=4.8 Hz, 1H), 6.78 (d, J=5.2 Hz, 0.5H), 5.09 (d, J=2.4 Hz, 1H), 4.70 (d, J=2.0

Hz, 0.5H), 3.73 (d, J=2.8 Hz, 0.5H), 3.67 (br s, 1H), 1.90 (s, 1.5H), 1.89 (br s, 1H), 1.64 (s, 3H),

1.51 (m, 1H), 1.27 (m, 0.5H), 1.17 (m, 1H), 1.01 (br s, 0.5H), 0.86 (m, 0.5H), 0.25 (m, 0.5H), 0.16

13 (m, 1H), 0.05 (m, 0.5H), 0.01 (m, 1H); C NMR (100 MHz, CDCl3; minor product in brackets):

δ (208.2), 206.2, 135.5, (134.6), 127.6, (127.6), 127.0, (126.0), 125.5, (125.5), 125.44, (124.6),

(124.3), 124.1, 65.1, (65.0), 52.9, (49.6), 25.8, (25.3), 15.6, (15.6), (10.6), 9.6, (0.07), -0.00;

+ HRMS: Calculated for C13H14O2 [M] : 202.0994. Found: 202.0987.

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Diastereomers 3.26a/b (Scheme 3.17): 63% (35.1 mg) combined yield in 2:1 ratio for 3.26a:

1 3.26b; yellow oil; Rf (1:4 EtOAc: Hexanes): 0.20; H NMR (400 MHz, CDCl3): δ 7.50 (m, 2H),

7.12 (m, 2H), 7.03 (m, 2H), 6.94 (m, 1H), 6.58 (d, J=7.6 Hz, 1H), 4.98 (d, J=4.0 Hz, 1H), 4.85 (d,

J=4.4 Hz, 1H), 3.91 (d, J=0.8 Hz, 1H), 3.84 (d, J=4.0 Hz, 1H), 2.43-2.30 (m, 2H), 2.30-2.23 (m,

2H), 2.05 (br s, 2H), 1.85 (m, 2H), 1.61 (m, 2H), 1.45 (m, 4H), 1.27 (m, 2H), 1.16 (m, 2H), 0.73

(t, J=7.3 Hz, 3H), 0.64 (t, J=7.3 Hz, 3H), 0.40 (m, 1H), 0.00 (m, 1H); 13C NMR (100 MHz,

CDCl3): δ 210.3, 208.3, 137.8, 136.8, 130.0, 130.0, 128.9, 128.0, 127.5, 127.44, 127.41, 126.8,

126.3, 126.2, 67.4, 67.1, 54.4, 51.1, 40.1, 39.9, 25.8, 25.5, 22.3, 22.1, 17.8, 17.7, 13.9, 13.8, 12.9,

+ 11.9, 2.3, 2.1; HRMS: Calculated for C16H20O2 [M] : 244.1463. Found: 244.1471.

3.5 - References

1 Haner, J. M.Sc. Thesis, University of Guelph, 2011.

2 McKee, M. M.Sc, Thesis, University of Guelph, 2013.

3 Krause, N. Modern Organocopper Chemistry, Wiley-VHC, 2002, Weinheim, Chapter 1.

4 Lautens, M.; Felice, C.D.; Huboux, A. Tetrahedron Lett. 1989, 30, 6817.

5 Millet, R.; Gremand, L.; Bemardez, T.; Palais, L. ; Alexakis, A, Synthesis, 2009, 12, 2101.

112

6 Arrayás, R.G.; Cabrera, S.; Carretero, J.C. Org. Lett. 2003, 5, 1333.

7 Arrayás, R.G.; Cabrera, S.; Carretero, J.C. Org. Lett. 2005, 7, 219.

8 Lipshutz, B.H.; Wilhelm, R.S.; Kozlowski, J.A.; Parker, D. J. Org. Chem. 1984, 49, 3928.

9 Posner, G.H.; Babiak, K.A. J. Organomet. Chem. 1979, 177, 299.

10 Jukes, A.E. Adv. Organomet. Chem. 1974, 12, 215.

11 Taylor, R.J.K. Organocopper Reagents. A Practical Approach. Harwood, L.M., Moody, C.J.

Ed. Oxford University Press, New York, 1994, Chapter 1.

12 Lipshutz, B.H.; James, B. J. Org. Chem. 1994, 59, 7585.

13 Bertz, S.H.; Miao, G.; Eriksson, M. Chem. Commun. 1996, 815.

14 Lindley, J. Tetrahedron 1984, 40, 1433.

15 Whitesides, G.H.; Stedronsky, E.R.; Casey, C.P.; San Fillippo, J. J. Am. Chem. Soc. 1970, 92,

1426.

16 Kharasch, M.S.; Tawney, P.O. J. Am. Chem. Soc. 1941, 63, 2308.

17 Cunha, S.; Rodovalho, W.; Azevedo, N.R.; Mendonҫa, M.O.; Lariucci, C.; Vencato, I. J. Braz.

Chem. Soc. 2002, 13, 629.

18 Fukui, K. Acc. Chem. Res. 1971, 4, 57.

19 Zhang, T.-K.; Yuan, K.; Hou, X.-L. J. Organomet. Chem. 2007, 692, 1912.

20 Seel, S.; Dagousset, G.; Thaler, T.; Frischmuth, A.; Karaghiosoff, K.; Zipse, H.; Knochel, P.

Chem. Eur. J. 2013, 19, 4614.

21 Ballantine, M.; Menard, M.L.; Tam, W. J. Org. Chem. 2009, 74, 7570.

22 Scott, L.T.; Cotton, W.D. Chem. Commun. 1973, 9, 320.

23 Whitesides, G.M.; Panek, E.J.; Stedronsky Jr., E.R. J. Am. Chem. Soc. 1972, 94, 232.

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24 Ullmann, F.; Bielecki, J. Ber. Dtsch. Chem. Ges. 1901, 34, 2174.

25 Fanta, P.E. Synthesis 1974, 9.

26 Lindley, J. Tetrahedron 1984, 40, 1433.

27 Ashby, E.; Lin, J.J. J. Org. Chem. 1977, 42, 2805.

28 Ley, S.V., Hu, D.X., and Grice, P. J. Org. Chem. 2012, 77, 5198.

29 Creary, X. J. Am. Chem. Soc. 1981, 103, 2463.

30 Creary, X.; Geiger, C.C. J. Am. Chem. Soc. 1982, 104, 4151.

31 Kim, S.; Lee, J.I. J. Org. Chem. 1983, 48, 2608.

32 Lipshutz, B.H. Tetrahedron Lett. 1983, 24, 127.

33 Krasovskiy, A.; Knochel, P. Synthesis. 2006, 5, 890.

34 Love, B.E.; Jones, E.G. J. Org. Chem. 1999, 64, 3755.

35 Li, J.J.; Limberakis, C.; Pflum, D.A. Modern Organic Synthesis in the Laboratory; Oxford

University Press, Inc.: New York, 2007; Chapter 1.

36 McKee, M.; Haner, J.; Carlson, E.; Tam, W. Synthesis 2014, 46, 1518.

37 Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett. 1984, 25, 4233.

38 Yamamoto, Y.; Maruyama, K; J. Am. Chem. Soc. 1978, 100, 3240.

39 Lipshutz, B.H.; Ellsworth, E.L.; Siahaan, T.J. J. Am. Chem. Soc. 1989, 111, 1351.

40 Kronenburg, C.M.P.; Amijs, C.H.M.; Jastrezebski, J.T.B.H.; Lutz, M.; Spek, A.L.; van Koten,

G. Organometallics 2002, 21, 4662.

41 Lipshutz, B.H.; Wilhelm, R.S.; Kozlowski, J.A. J. Org. Chem. 1984, 49, 3938.

42 Uehata, K.; Nishida, M.; Nishida, A. Chem Lett. 2012, 41, 73.

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Chapter 4: Type 2 Ring-Opening Reactions of Cyclopropanated

Oxabenzonorbornadienes under Acid Catalysis:

Formation of 2-Substituted Naphthalenes

Selected content of this chapter can also be found in the following papers:

Tigchelaar, A.; Haner, J.; Carlson, E.; Tam, W. Synlett. 2014, 25, 2355.

Carlson, E.; Hong, D.; Tam, W. Synthesis, 2016, in press.

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Chapter 4: Type 2 Ring-Opening Reactions of Cyclopropanated Oxabenzonorbornadienes

under Acid Catalysis: Formation of 2-Substituted Naphthalenes

4.1 - Introduction

Type 2 ring-opening reactions of cyclopropanated 7-oxabenzonorbornadiene were first discovered under palladium or platinum-catalyzed conditions, in Haner’s thesis work (Scheme 4.1, first two entries).1,2 The isolated reaction product upon use of methanol as the nucleophile was found to be 2-(methoxymethyl)naphthalene, with spontaneous dehydration in the reaction medium.

Scheme 4.1 First examples of type 2 ring-opening reactions reported by Haner.

Haner noted that the same conversion could be effected under protic conditions, providing a near- quantitative yield (Scheme 4.1, lowermost entry), and this was further probed by Tigchelaar in his

M.Sc. thesis work (Scheme 4.2) where the acid-catalyst, nucleophile, and reaction temperatures were optimized.3 Tigchelaar found that the reaction did not proceed without an acid catalyst, and use of para-toluenesulfonic acid at 90 ˚C was the most successful of the reaction conditions screened. Several different alcohol nucleophiles were reacted with 4.1a, showing that type 2 ring- opening proceeds with primary, secondary and tertiary alcohols, but not with phenol.

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Scheme 4.2 Type 2 ring-opening of 4.1a with various acid catalysts and alcohol nucleophiles.

In these initial works, it was shown that carboxylic acids or halides could serve as effective nucleophiles, as well (Scheme 4.3). Comparisons of the observed reactivity of 4.1a with carbocyclic analogues were also drawn, addressing the unexpected mode of type 2 ring-opening which had occurred. Based on this data, a general mechanism was proposed (Scheme 4.4):

Scheme 4.3 Type 2 ring-opening with carboxylic acid or bromide nucleophiles.

Scheme 4.4 Proposed mechanism for type 2 ring-opening of 4.1a.

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Initial protonation of the oxygen of 4.1a allows for scission of a C-O bridge bond (4.6) to form cationic intermediate 4.7. Subsequent attack of the nucleophile at the external cyclopropane position produces compound 4.8 which is evidently unstable and dehydrates (4.9) under acidification and heating to form 4.10. It is, however, possible that nucleophilic attack and ring- opening may occur as one concerted step (4.6’). Although one unsymmetrical example of a bridgehead-substituted variant of 4.1a in Tigchelaar’s work confirmed formation of one regioisomer alone, no other cyclopropanated oxabenzonorbornadienes were available at this time to conduct further substrate studies. Thus, the present work began by testing the applicability and scope of type 2 ring-openings using methanol as the nucleophile with a broader set of functionalized substrates (section 4.2.1), and later, other nucleophiles including carboxylic acids and bromide were also investigated (section 4.2.2).

4.2 - Results and Discussion

4.2.1 – Alcohol Nucleophiles

When symmetrically functionalized substrates 4.1a-f were subjected to acid-catalyzed type

2 ring-opening conditions with methanol as the nucleophile, the expected 2-methoxymethyl naphthalenes were obtained (Table 4.1). Relative to the parent compound (entry 1), substrate 4.1b bearing para-dimethoxy groups reacted rapidly, with decent conversion (entry 2). Ortho- dimethoxy-substituted substrate 4.1c reacted surprisingly quickly, and due to product decomposition (observed by 1H NMR at 120 h), the desired alkoxynaphthalene could not be isolated (entry 3). Ortho-dibrominated compound 4.1d was extremely slow to react and low- yielding (entry 4), and the tetrafluorinated compound 4.1e also showed no signs of reaction after

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half a week (entry 5). In contrast, bridgehead dimethyl-substituted substrate 4.1f reacted smoothly to give the desired product in 79% yield (entry 6). When unsymmetrical substrates bearing C1- substituents were subjected to reaction, by-products were observed. The quantity of by-product obtained from the C1-methyl substituted substrate 4.1g was minimal (~5%), with the expected product 4.2g obtained in 91% (entry 7). Thus, it was no surprise that this by-product went unnoticed in Tigchelaar’s experiments. This side reaction was much more pronounced with C1- tert-butyl substituted substrate 4.1h, diminishing the yield of the expected product (4.2h) to only

49% (entry 8). As the structure of the by-products became clear, their importance in the current research was soon realized; these will be a topic of discussion of the next chapter.

Table 4.1. Effect of substitution pattern of cyclopropanated oxabenzonorbornadiene in type

2 ring-opening reactions with alcohol nucleophiles.

Entry X Y Z Z’ Time (h) Recovered Product Yield 4.1 (%)a (%)a 1 H H H H 90 0 4.2a 82 2 OMe H H H 8 3 4.2b 56 3 H OMe H H 120 0 4.2c 0 4 H Br H H 240 32 4.2d 20 5b F F H H 120 0 4.2e 0 6 H H Me Me 22 0 4.2f 79 7 H H Me H 15 0 4.2g 91 8 H H tBu H 20 0 4.2h 49 aIsolated yields after column chromatography. bReaction was heated at 110 ˚C.

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In addition, a distinct product arising from the reaction of C1-ethyl substituted substrate

4.1i (Scheme 4.5) was isolated, and will also be addressed in the next chapter. Reaction with C1- acetyl substituted substrate 4.1j (Scheme 4.5) produced a mixture of two nearly identical and inseparable compounds.

Scheme 4.5. Type 2 ring-openings of C1-substituted compounds with alcohol nucleophiles which resulted in complicated mixtures of products.

C1-Brominated compound 4.1k resulted in a mixture of two distinct products, 4.2k and

4.11 whose regiochemical substitution pattern was determined by the multiplicity and coupling constants of aromatic protons in their 1H NMR spectra (where Ha and Hb were apparent singlets), as well as by NOESY experiments (Scheme 4.6). Incorporation of a second methoxy group in 4.11 was evidenced by the chemical shifts of two methoxy 13C NMR peaks, and was supported by

HRMS data. Although it was deemed unnecessary, an alternative mode of assignment would have been to conduct lithium halide exchange on 4.2k and trap with methyl iodide (Scheme 4.7), to confirm that its product 4.12 is identical to the product obtained from the ring-opening of C1- methyl substituted compound 4.1g.

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Scheme 4.6. Reaction of 4.1k resulting in two products, 4.2k and 4.11, assigned by NOESY.

Scheme 4.7. Possible lithium-halide exchange to ascertain relative halide positioning.

The formation of products 4.2k and 4.11 could be accounted for by the following mechanism (Scheme 4.8). Protonation and ring-opening of 4.1 progresses through carbocation

4.13. It appears that formation of the tertiary carbocation (on the carbon closest the bromide) is still preferred in this case over the secondary carbocation. Formation of 4.2k proceeds in the usual fashion (middle row) while formation of 4.11 must take place with further displacement of the bromide. This is possible if methanol adds to the intermediate cation 4.14, creating an unstable geminal haloalkoxy group which drives expulsion of the bromide (4.15). The second equivalent of nucleophile may then attack to form the first C=C bond (4.16), and dehydration could proceed as usual to give 4.11. Further studies should consider the use of other bridgehead electron- withdrawing groups. One such example is seen in the next section (section 4.2.2).

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Scheme 4.8. Mechanism accounting for formation of by-product 4.11 containing two equivalents of nucleophile.

In summary, acid-mediated type 2 ring-openings of cyclopropanated oxabenzonorbornadienes with alcohol nucleophiles were observed with various substrates. By- products were observed in most cases when the substrates bore bridgehead substituents. NOESY was used in the determination of regiochemistry of some unsymmetrical products, and the discussion of some other unexpected results from this study will be continued in this chapter.

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4.2.2 – Carboxylic Acid Nucleophiles

Following the study with alcohols, carboxylic acids were next investigated as nucleophiles.

To begin, acetic acid was selected as both nucleophile and solvent, and a variety of reaction conditions were screened (Table 4.2). With acetic acid as the sole acid source (no added catalyst), no reaction was observed (entry 1), which was consistent with Haner’s observation. The same result was seen at elevated temperatures over 10 days (entry 2). Since carboxylic acids are strongly associated by dimeric hydrogen-bonding (H-bonding), it could be that carboxylic acids by themselves are too involved in this pairing to protonate the bicycloalkene’s oxygen atom. It was thought that when external acids are introduced, either interruption of the H-bonding clusters may allow for more facile protonation of the substrate, or that the concentration of protons in solution in general is much higher when a lower pKa acid catalyst is added, which is able to expedite the slow step of the reaction. When sulfuric acid was introduced, the reaction took place almost instantaneously at room temperature (entries 3-5), although the product yield was consistently

~60% and a very small amount of a side-product (~10%) was also observed. Nitric acid was noticeably slower to catalyze the reaction, which was still incomplete at 120 hours (entry 6). Nitric acid, which was purchased as an aqueous solution (68-70% assay) suggested a product with water as the nucleophile (~40%), alongside near equal amounts (~35%) of the expected product. This is in accord with Tigchelaar’s observation of a complicated mixture arising upon use of nitric acid as the catalyst for type 2 opening with methanol nucleophile. Tetrafluoroboric acid required a full week to reach a similar level of conversion (entry 7), and although heating the reaction increased the reaction rate appreciably, no significant improvement in yield was seen (entry 8). Camphor sulfonic acid showed slow conversion when the reaction was heated to 40 ˚C (entry 9), while pyridinium para-toluenesulfonate required heating to 90 ˚C to obtain similar results (entry 10).

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When methanol was supplied to the reaction mixture, no reaction was observed (entry 11), suggesting that simple disruption of the H-bonding is not the driving force, but that a relatively low pKa of the acid is also needed. Finally, use of para-toluenesulfonic acid monohydrate showed decent conversion at room temperature (entry 12), which was enhanced at higher temperatures

(entries 13-15), and the highest yield of 70% was obtained when the reaction was run at 90 ˚C for

20 hours (entry 15). Overall, the reaction was cleanest when using HBF4 or p-TsOH. The rates of reaction suggested some correlation with the pKa of each acid introduced: the lower the pKa of the acid used (H2SO4 ~ p-TsOH < HNO3 < HBF4 < CSA < PPTS < MeOH), the faster the ring- opening reaction tended to be, which was more noticeable with the weaker acids.

The effect of solvent and nucleophile equivalency were then screened (Table 4.3). Relative to when acetic acid was the sole reaction medium (entry 1), addition of acetonitrile led to a reduction in yield, which was also noted with the use of toluene (entries 2 and 3). This reduction in yield was even more pronounced with the use of dimethyl sulfoxide (entry 4), which only gave

44% yield after one week. Although reaction in 1,4-dioxane afforded reasonably good yields, the transformation took nearly two days to complete (entry 5), whereas similar results were seen with the use of 1,2-dichloroethane (entry 6), which gave 74% of product after only 28 hours. When the amount of acetic acid was reduced to 8 equivalents (entry 7), the reaction was found to produce similar results as when it was used as the solvent (entry 6). At smaller equivalents of acetic acid, the yield was seen to suffer noticeably (entries 8 and 9).

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Table 4.2. Effect of acid catalyst and reaction temperature on type 2 ring-opening reactions of cyclopropanated oxabenzonorbornadiene.

Entry Acid Temp. (˚C)a Time (h) Recovered Yield 4.3a catalyst 4.1a (%)b (%)b 1 None rt 48 88 0 2 None 90 240 64 0

3 H2SO4 rt 20 0 50

4 H2SO4 rt 3 0 54

5 H2SO4 rt 1 0 59

6 HNO3 rt 120 12 48

7 HBF4 rt 168 0 65

8 HBF4 90 20 0 69 9c CSA 40 168 44 36 10c PPTS 90 168 27 33 11c MeOH 90 168 61 0 12 pTsOH rt 168 36 41 13 pTsOH 40 30 5 55 14 pTsOH 60 24 0 66 15 pTsOH 90 20 0 70 art = room temperature, 19-23 ˚C. bIsolated yield by column chromatography. cNo reaction observed by TLC at room temperature for 22 hours; thus, reactions were heated.

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Table 4.3. Effect of solvent and nucleophile equivalency on type 2 ring-opening reactions of cyclopropanated oxabenzonorbornadiene.

Entry Solvent x Time Recovered Yield 4.3a (h) 4.1a (%)a (%)a 1 None >50 20 0 70 2 MeCN >50 20 0 54 3 PhMe >50 28 0 67 4 DMSO >50 168 11 44 5 Dioxane >50 48 7 68 6 DCE >50 28 0 74 7 DCE 8 18 0 73 8 DCE 4 24 0 63 9 DCE 2 24 0 48 aIsolated yield by column chromatography.

Using the above optimized conditions, several different carboxylic acid nucleophiles were then tested for type 2 ring-opening (Table 4.4). This resulted in a collection of diverse products with moderate to good yields. Relative to acetic acid (entry 1), the primary n-butyric acid nucleophile produced comparable yield of corresponding ring-opened product 4.3b after 22 hours

(entry 2). Use of cyclopentane carboxylic acid resulted in similar yield of 4.3c after an additional day (entry 3), and pivalic acid gave comparable yield of 4.3d after a further day of reaction (entry

4). It thus appears that the rate of nucleophilic attack decreases in the order of primary > secondary

> tertiary, although the product yields do not differ appreciably within this series. When acrylic acid or benzoic acid was used as the nucleophile, once again a very similar yield of product was 126

isolated, although the reaction duration was much shorter for these sp2-hybridized nucleophiles

(entries 5-6). When sp-hybridized propiolic acid was used, the reaction was complete after only 1 hour, with no starting material observed by NMR, although product 4.3g could only be isolated in

29% yield (entry 7). These faster reaction times for these nucleophiles may in fact be a result of the higher acidity of these acids. When methoxyacetic acid and 2-naphthoxyacetic acid were subjected to reaction, both transformations were complete after 6 hours (entries 8 and 9). The fact that 2-naphthoxyacetic acid resulted in a much lower yield had to do largely with the reduced solubility of the solid nucleophile and product, both in the reaction medium, as well as during extraction steps. It is likely that improved yields could be observed by better choice of solvent for this particular reaction. Finally, haloacetic acids were tested. Reactions using either chloro- or bromoacetic acids were complete at roughly two hours, and moderate yields were observed for each. The chlorinated product 4.3j could only be isolated in ~40% yield, while the brominated product 4.3k was isolable in ~50% yield (entries 10 and 11). All reactions were left until complete consumption of starting material was confirmed by 1H NMR. As such, in these latter trials where lower yields were obtained, it appeared that decomposition had occurred in the heated reaction medium.

Lastly, type 2 ring-opening reactions of cyclopropanated oxabenzonorbornadiene were carried out on variously functionalized substrates (Table 4.5). Overall, transformations were lower yielding than the parent compound (entry 1), but moderate (21-60%). Substrate 4.1 bearing bridgehead methyl groups underwent ring-opening smoothly, furnishing expected product 4.3l in

60% yield after 20 hours (entry 2). Placement of para-dimethyl groups did not affect the reaction rate, but isolation was cumbersome and yields suffered noticeably (entry 3). Presence of methoxy

127

groups in these positions allowed a slight improvement in yield with a more rapid reaction rate

(entry 4), while the orientation of methoxy groups ortho to each other showed a drastic increase in rate (entry 5), with all starting material fully consumed in one hour. Finally, reaction of unsymmetrically acetylated substrate 4.1p was reacted, which resulted in a slow conversion but with one regioisomeric product alone (entry 6).

Table 4.4. Effect of nucleophile on type 2 ring-opening reactions of cyclopropanated oxabenzonorbornadiene.

Entry R pKa of RCOOHa Time (h) Product Yield (%)b 1 Me 4.764 18 4.3a 73 2c nPr 4.815 22 4.3b 72 3c Cyclopentyl 4.986 48 4.3c 76 4c tBu 5.054 68 4.3d 70 4 5 H2C=CH 4.25 32 4.3e 63 6c Ph 4.174 24 4.3f 70 7c HC≡C 1.847 1 4.3g 29 c 4 8 MeOCH2 3.53 6 4.3h 75 8 9 NpOCH2 3.2 6 4.3i 16 4 10 ClCH2 2.86 2 4.3j 37 4 11 BrCH2 2.86 2 4.3k 51 aValues according to literature references. bIsolated yields by column chromatography. cTrial conducted by/with Daniel Hong.

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Table 4.5. Effect of substrate functionalization on type 2 ring-opening reactions of cyclopropanated oxabenzonorbornadiene.

Entry X Y Z Z’ Time (h) Product Yield (%)a 1 H H H H 18 4.3a 73 2 H H Me Me 20 4.3l 60 3 Me H H H 14 4.3m 33 4 OMe H H H 7 4.3n 45 5 H OMe H H 1 4.3o 40 6 H H Ac H 96 4.3p 21 aIsolated yield by column chromatography.

The structure of this product 4.3p was determined to be that of the 1,3-substitution product

(as opposed to the 1,2-substitution product). Assignment of the structure of 4.3p was made by the absence of ortho coupling (expected J~6-9 Hz) for aromatic protons Hb and Hc (Scheme 4.9), and supported by selective gradient NOE experiments, where irradiation of protons Hg resulted in clear enhancement of both Hb and Hc, and irradiation of Hb resulted in signal enhancement for the protons

Hg, Hc and Hd which is within an expected NOE radius. This once again raises the point that the regioselectivity of ring-opening for C1-electron-withdrawing group also proceeds via a non- conventionally stabilized carbocationic intermediate.9 Thus, all regioisomers in the present work were found to produce 1,3-substituted naphthalene derivatives, regardless of the nature of the bridgehead substituent.

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Scheme 4.9. Formation and assignment of 1,3-substituted product 4.3p.

Further investigations on the significance of the acidity of the reaction medium was also carried out. Taking the carboxylic acid with the lowest pKa used in the present work (Table 4.4), it was found that type 2 ring-opening could occur even in the absence of an added acid (Scheme

4.10). While the corresponding reaction supplied with para-toluenesulfonic acid was complete in

1 hour, however, the same reaction without this acid source took 3 days to go to completion. This shows that type 2 ring-openings can take place as long as the reaction conditions meet a sufficiently acidic threshold, and the rate of ring-opening is dependent on the overall acidity (either by contribution of the nucleophilic carboxylic acid, or a supplied acidic reagent).

Scheme 4.10. Formation of 4.3g in the absence of an external acid catalyst.

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Next, the opposite extreme was considered. Since epoxides, aziridines, and other strained systems are known to undergo base-induced ring-openings, 10 , 11 anionic methoxide was also considered as a potential nucleophile. However, the combination of NaOMe, MeOH did not prove successful after heating the reaction at 90 ˚C for 5 days (Scheme 4.11). Similarly, acetate anion did not react but instead resulted in full recovery of unreacted starting material after 3 days. These two results complement Haner’s observation that the type 2 reaction did not work using Na2CO3.

As such, thus far it appears that type 2 ring-openings of 4.1a only proceed under acidic conditions, but not under basic ones.

Scheme 4.11. Unsuccessful reactions toward type 2 ring-opening under basic conditions.

Lewis acids were tested next. As there was precedent in our group of using boron tribromide to obtain 2-bromomethylnaphthalene 4.5 (Scheme 4.3), these conditions were applied.

Reaction with AlCl3 and with BBr3 both resulted in immediate colour change of the reaction mixture from clear to black, and the disappearance of starting material by TLC was evident within

30 minutes. However, upon 1H NMR analysis the expected product peaks could not be seen, and the crude product mixture was extremely complex. As a different bromide source, pyridinium tribromide was supplied instead, which resulted in a smooth conversion to the 2- bromomethylnaphthalene (Scheme 4.12).

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Scheme 4.12. Use of pyridinium tribromide as bromide source in type 2 ring-opening.

Boronic acids in general have pKa~9. The organic moiety of boronic acids can serve as nucleophiles in conjugate addition reactions, in the presence or absence of a metal catalyst.12

Oxabicycloalkenes have been successfully ring-opened using boronic acids,13 and a recent study

(2015)14 has shown that boronic acids catalyzed by palladium in aqueous solution are capable of inducing cyclopropane ring-openings (Scheme 4.13). Although the literature substrate 4.17 was activated by the presence of two strongly electron-withdrawing groups (COOEt, CN), its opening by boronic acids prompted a quick investigation with boronic acids in the current study, as well.

Disappointingly, 4.1a showed no sign of reacting in the presence of phenylboronic acid in toluene at 90 ˚C after 3 days (Scheme 4.14). The same reaction with added triphenylphosphine and palladium (II) acetate also showed no sign of reacting after 2 days either.

Scheme 4.13. Literature ring-opening of cyclopropane with the use of boronic acid.

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Scheme 4.14. Attempted ring-opening of 4.1a using phenylboronic acid.

From the above results, acid-catalyzed type 2 ring-openings were found to proceed best with low pKa acids as well as strongly acidic nucleophiles. As the catalyst appears to influence the rate-determining step, the epoxide opening of the oxabicyclic framework is likely the slow step in the reaction, and not the nucleophilic attack. Future work should consider kinetic correlations of this reaction to better understand the contributions of the acid catalysts. Ultimately, it would be desirable if the unaromatized intermediate 4.18 could be trapped, perhaps at lower temperatures and under non-acidic conditions. If 4.18 could be isolated, reaction using deuterated acetic acid may confirm the source of the transferable proton (Scheme 4.15).

Scheme 4.15. Possible test to determine the transferable proton source in type 2 openings.

Lastly, it is noteworthy that cyclopropanated N-O bicycle 4.19 was also subjected to the optimized type 2 ring-opening conditions (Scheme 4.16). This reaction resulted in a clean conversion within an hour to a product with most probable structure 4.20, which was reproducible over several attempts. The stereochemistry of 4.20 was not determined. Although at first it was

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thought that N-O bond cleavage took place on substrate 4.19 (to produce 4.21), comparison of the

1H and 13C NMR spectra of product 4.20 to that of 4.21 from the literature showed that the two compounds were clearly not the same structures.15 Moreover, it was evident that one equivalent of methanol had reacted with 4.19, since a sharp 3H singlet at ~3.5 ppm was visible. Our group has observed similar openings with the uncyclopropanated N-O bicyclic compound,16 which also suggested that an N-OH moiety is present in 4.20. Type 2 reactions of cyclopropanated N-O or N-

N bicyclic compounds were set aside for future work.

Scheme 4.16. Attempted acid-catalyzed ring-opening of cyclopropanated N-O bicycloalkene.

4.3 – Conclusion

In summary, the present work has shown that certain nucleophiles - namely alcohols and carboxylic acids - are capable of promoting type 2 ring-opening reactions of cyclopropanated 7- oxabenzonorbornadienes under acid-catalyzed conditions. The isolated products from each of these reactions were 2-(alkoxymethyl)naphthalenes and 2-(acylmethyl)naphthalenes, respectively, as a likely result of dehydroaromatization. For both classes of oxygen nucleophile, use of para- toluenesulfonic acid catalyst at 90 ˚C showed the greatest success. Synthesis of 2-

(alkoxymethyl)naphthalenes in this manner offers a new and economical alternative to

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cycloaromatization or cycloisomerization which requires silver or gold-catalysts and temperatures

≥ 450 ˚C.11,17,18 For type 2 ring-openings using carboxylic acids, it was found that the amount of nucleophile could be reduced to 8 equivalents without noticeably diminishing yields. Various nucleophiles and substrates were compatible with the reaction, and the acidity of carboxylic acids was found to affect the rate of reaction. The benzylic ethers and esters thus obtained may be useful in preparing biologically active compounds such as the antitumor drug neocarzinostatin, and derivatives of quinine or estradiol. 19 - 21 Furthermore, knowledge of type 2 ring-opening of cyclopropanated 7-oxabenzonorbornadiene may help in predicting the reactivities of similarly strained fused-ring compounds.

4.4 - Experimental

General Information: Commercial reagents were used without further purification.

Cyclopropanated oxabenzonorbornadiene was prepared as previously reported. 22 , 23 Solvent

(dichloroethane) was obtained from an LC-SPS solvent purification system supplied with dry packed columns containing 3 Å molecular sieves. Column chromatography, TLC, melting point determination, IR, NMR, and HRMS analyses were performed as described in Chapter 2. Selective

1D gradient NOE experiments were conducted with a mixing time value (D8) of 0.7-0.8.

General Procedure: Acid-catalyzed ring-opening of cyclopropanated oxabenzonorbornadiene with alcohol nucleophiles: In a small screw-cap vial containing a stir- bar, cyclopropanated oxabenzonorbornadiene 4.1 (30.0 mg, 1.0 equiv.) was dissolved in alcohol

(0.5 mL). The reaction was cooled to 0 ˚C, and p-toluenesulfonic acid monohydrate (0.1 equiv.) was added as a solid. The reaction was stirred at 0 ˚C briefly and gradually brought to room

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temperature. The vial was sealed and secured tightly with polytetrafluoroethylene (PTFE) thread- seal tape and paraffin film, and heated to 90 or 110 ˚C with continuous stirring for 15–330 h. The crude product was directly loaded onto a chromatography column and purified (EtOAc–hexanes mixture).

General Procedure: Acid-catalyzed ring-opening of cyclopropanated oxabenzonorbornadiene with carboxylic acid nucleophiles: In a small screw-cap vial containing a stir-bar, cyclopropanated oxabenzonorbornadiene 4.1 (30.0 mg, 1.0 equiv.) was dissolved in dichloroethane (0.25 mL), and the solution was stirred briefly. Carboxylic acid (8 equiv.) was introduced and para-toluenesulfonic acid monohydrate (0.1 equiv.) was added as a solid, and rinsed with dichloroethane (0.25 mL). The vial was sealed and gradually brought to 90

˚C with continuous stirring until the solution darked to a translucent brown colour and no starting material was observed (by TLC or 1H NMR). The reaction mixture was cooled to room temperature and quenched by dropwise addition of saturated aqueous sodium bicarbonate and transferred to a separatory funnel with water and dichloromethane rinses. The aqueous layer was extracted with dichloromethane (3×10 mL), and the combined organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The organic concentrate was purified by column chromatography (2:98-5:95 EtOAc–hexanes mixture) to give the corresponding ring-opened product.

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1,4-Dimethoxy-6-(methoxymethyl)naphthalene (4.2b; Table 4.1, entry 2): Yield: 18.9 mg

-1 (56%); clear oil; Rf = 0.29 (EtOAc–hexanes, 1:9). IR (ν, cm ): 3076, 2996, 2934, 2833, 1604,

1 1463, 1271, 1246, 1095, 804. H NMR (600 MHz, CDCl3): δ 8.18 (d, J=8.6 Hz, 1H), 8.13 (s, 1H),

7.49 (dd, J=8.6, 1.4 Hz, 1H), 6.68 (ABq, JAB=8.4 Hz, ΔδAB = 8.8 Hz, 2H), 4.62 (s, 2H), 3.941 (s,

13 3H), 3.937 (s, 3H), 3.39 (s, 3H). C NMR (125 MHz, CDCl3): δ 149.5, 135.7, 126.1, 125.8, 125.6,

+ 122.2, 120.6, 103.4, 103.2, 74.9, 58.0, 55.7. HRMS: [M] calcd. for C14H16O3: 232.1099; found:

232.1106. Spectral data are consistent with those previously reported.9

2,3-Dibromo-6-(methoxymethyl)naphthalene (4.2d; Table 4.1, entry 4): 20% (12.8 mg); red

-1 solid; mp 40–42 ˚C; Rf = 0.38 (EtOAc–hexanes, 1:9). IR (ν, cm ): 3058, 2989, 2926, 2884, 2851,

1 1582, 1453, 1102, 903, 888, 821. H NMR (600 MHz, CDCl3): δ 8.11 (s, 1H), 8.10 (s, 1H), 7.69

13 (m, 1H), 7.65 (s, 1H), 7.46 (m, 1H), 4.58 (s, 2H), 3.42 (s, 3H). C NMR (100 MHz, CDCl3): δ

137.4, 133.0, 132.6, 132.2, 132.0, 127.1, 127.0, 125.0, 122.3, 121.9, 74.4, 58.4. HRMS: [M]+ calcd. for C12H10OBr2: 327.9098; found: 327.9108.

2-(Methoxymethyl)-1,4-dimethylnaphthalene (4.2f; Table 4.1, entry 6): 79% (41.7 mg); beige

-1 solid; mp 39–42 ˚C; Rf = 0.54 (EtOAc–hexanes, 1:9). IR (ν, cm ): 3070, 2974, 2923, 2815, 1716,

1 1447, 1389, 1192, 1104, 1077, 754. H NMR (600 MHz, CDCl3): δ 8.11 (m, 1H), 8.00 (m, 1H),

7.52 (m, 2H), 7.32 (s, 1H), 4.64 (s, 2H), 3.44 (s, 3H), 2.67 (s, 3H), 2.65 (s, 3H). 13C NMR (125

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MHz, CDCl3): δ 133.0, 132.4, 132.3, 131.9, 130.6, 127.9, 125.4, 125.2, 124.6, 124.5, 73.3, 58.1,

+ 19.3, 13.9. HRMS: [M] calcd. for C14H16O: 200.1201; found: 200.1207.

3-(Methoxymethyl)-1-bromonaphthalene (4.2k; Scheme 4.6): 11% (4.1 mg); clear semi-solid;

-1 Rf = 0.39 (1:9 EtOAc: Hexanes); FTIR (ν, cm ): 3053, 2924, 2821, 1601, 1380, 1258, 1102, 768;

1 H NMR (400 MHz, CDCl3): δ 8.19 (d, J=8.4 Hz, 1H), 7.78 (d, J=7.3 Hz, 1H), 7.77 (s, 1H), 7.73

13 (s, 1H), 7.56 (m, 1H), 7.52 (m, 1H), 4.57 (s, 2H), 3.42 (s, 3H); C NMR (100 MHz, CDCl3): δ

136.4, 134.3, 131.4, 129.5, 128.2, 127.2, 126.93, 126.92, 126.2, 123.0, 73.9, 58.3; HRMS: [M]+ calcd. for C12H11OBr: 249.9993; found 250.0002.

1,3-Dimethoxymethylnaphthalene (4.11; Scheme 4.6): 52% (16.1 mg); yellow oil; Rf = 0.22

(1:9 EtOAc: Hexanes); FTIR (ν, cm-1): 3054, 2926, 2819, 1581, 1403, 1283, 1110, 840; 1H NMR

(400 MHz, CDCl3): δ 8.21 (br d, J=6.4 Hz, 1H), 7.75 (br d, J=7.4 Hz, 1H), 7.47-7.44 (m, 2H),

13 7.34 (s, 1H), 6.81 (s, 1H), 4.58 (s, 2H), 4.00 (s, 3H), 3.41 (s, 3H); C NMR (100 MHz, CDCl3): δ

155.7, 135.9, 134.1, 127.4, 126.6, 125.2, 125.1, 121.9, 118.8, 103.3, 75.1, 58.0, 55.5; HRMS: [M]+ calcd. for C13H14O2: 202.0994; found 202.0988.

2-bromomethylnaphthalene (4.5; Scheme 4.12): 57% (25.9 mg); white solid, mp = 50-52 ˚C; Rf

1 = 0.26 (Hexanes); 3051, 2967, 2920, 1597, 1360, 767; H NMR (400 MHz, CDCl3):  7.83-7.79

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13 (m, 4H), 7.50-7.46 (m, 3H), 4.66 (s, 2H); C NMR (100 MHz, CDCl3):  135.1, 133.2, 133.1,

128.8, 128.0, 127.9, 127.7, 126.8, 126.6, 126.5, 34.1; Spectral data are consistent with those previously reported.24

Acetic acid, 2-naphthalenylmethyl ester (4.3a; Table 4.4, entry 1): 73% (23.8 mg); white solid;

-1 mp: 50-53 ˚C (lit. 53-55 ˚C); Rf = 0.22 (EtOAc-hexanes, 2:98); IR (ν, cm ): 3056, 2952, 1732,

1 1223, 1022, 821, 743, 479; H NMR (400 MHz, CDCl3):  7.90-7.86 (m, 4H), 7.55-7.48 (m, 3H),

13 5.30 (s, 2H), 2.16 (s, 3H); C NMR (100 MHz, CDCl3):  170.8, 133.2, 133.1, 133.0, 128.3, 128.0,

127.6, 127.3, 126.2, 1261, 125.8, 66.3, 21.0; Spectral data are consistent with those previously reported.25,26

Butanoic acid, 2-naphthalenylmethyl ester (4.3b; Table 4.4, entry 2): 72% (39.0 mg); yellow

-1 1 oil; Rf = 0.32 (EtOAc-hexanes, 5:95); IR (ν, cm ): 3056, 2964, 2875, 1731, 1169, 814, 473; H

NMR (600 MHz, CDCl3):  7.83-7.80 (m, 4H), 7.48-7.43 (m, 3H), 5.26 (s, 2H), 2.35 (t, J = 7.5

13 Hz, 2H), 1.70-1.66 (m, 2H), 0.94 (t, J= 7.3 Hz, 3H); C NMR (125 MHz, CDCl3):  173.6, 133.6,

133.2, 133.1, 128.4, 128.0, 127.7, 127.3, 126.3, 126.2, 125.9, 66.2, 36.3, 18.5, 13.7. HRMS [M]+ calcd. for C15H16O2: 228.1150; found: 228.1155.

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Cyclopentane carboxylic acid, 2-naphthalenylmethyl ester (4.3c; Table 4.4, entry 3): 76%

-1 (38.0 mg); clear oil; Rf = 0.27 (EtOAc-hexanes, 5:95); IR (ν, cm ): 3055, 2955, 2870, 1726, 1601,

1 1508, 1451, 1173, 1145, 815, 472; H NMR (400 MHz, CDCl3):  7.88-7.84 (m, 4H), 7.53-7.49

(m, 3H), 5.30 (s, 2H), 2.84 (p, J= 8.0 Hz, 1H), 1.96-1.85 (m, 4H), 1.78-1.72 (m, 2H), 1.63-1.60

13 (m, 2H); C NMR (100 MHz, CDCl3):  176.7, 133.7, 133.2, 133.1, 128.4, 128.0, 127.7, 127.2,

+ 126.3, 126.2, 125.8, 66.2, 43.9, 30.1, 25.8. HRMS [M] calcd. for C17H18O2: 254.1307; found:

254.1301.

Propanoic acid, 2,2-dimethyl-, 2-naphthalenylmethyl ester (4.3d; Table 4.4, entry 4): 70%

-1 (30.3 mg); clear oil; Rf = 0.23 (EtOAc-hexanes, 5:95); IR (ν, cm ):3056, 2971, 2872, 1725, 1478,

1 1279, 1141, 814, 733, 472; H NMR (400 MHz, CDCl3):  7.83-7.78 (m, 4H), 7.48-7.41 (m, 3H),

13 5.24 (s, 2H), 1.22 (s, 9H); C NMR (100 MHz, CDCl3):  178.4, 133.9, 133.2, 133.0, 128.3, 128.0,

127.7, 126.9, 126.3, 126.2, 125.6, 66.2, 38.9, 27.2 (3C); Spectral data are consistent with those previously reported.27

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2-Propenoic acid, 2-naphthalenylmethyl ester (4.3e; Table 4.4, entry 5): 63% (28.8 mg); clear

-1 oil; Rf = 0.30 (EtOAc-hexanes, 1:9); IR (ν, cm ): 3055, 2954, 2108, 1719, 1405, 1176, 967, 809;

1 H NMR (400 MHz, CDCl3):  7.86-7.83 (m, 4H), 7.51-7.47 (m, 3H), 6.47 (dd, J= 17.3 Hz, 1.4

Hz, 1H), 6.19 (dd, J= 17.3 Hz, 10.4 Hz, 1H), 5.87 (dd, J= 10.4 Hz, 1.4 Hz, 1H), 5.36 (s, 2H); 13C

NMR (100 MHz, CDCl3):  166.1, 133.3, 133.2, 133.1, 131.3, 128.4, 128.3, 128.0, 127.7, 127.4,

+ 126.4, 126.3, 125.9, 66.5; HRMS [M] calcd. for C14H12O2: 212.0837; found: 212.0842.

Benzoic acid, 2-naphthalenylmethyl ester (4.3f; Table 4.4, entry 6): 70% (41.5 mg); white

-1 solid; mp: 45-47 ˚C; Rf = 0.21 (EtOAc-hexanes, 5:95); IR (ν, cm ): 3058, 2975, 1706, 1599, 1506,

1 1450, 1311, 1274, 1261, 819, 699, 679; H NMR (400 MHz, CDCl3):  8.12 (m, 2H), 7.94 (s, 1H),

13 7.89 (m, 3H), 7.60-7.47 (m, 6H), 5.56 (s, 2H); C NMR (100 MHz, CDCl3):  166.5, 133.4, 133.2,

133.14, 133.10, 130.1, 129.8, 128.5, 128.4, 128.0, 127.8, 127.4, 126.4, 126.3, 125.9, 66.9. HRMS

+ [M] calcd. for C18H14O2: 262.0994; found: 262.0999.

2-Propynoic acid, 2-naphthalenylmethyl ester (4.3g; Table 4.4, entry 7): 29% (17.9 mg); white

-1 solid; mp: 89-92 ˚C; Rf = 0.18 (EtOAc-hexanes, 5:95); IR (ν, cm ): 3061, 2940, 2112, 1703, 1227,

1 822, 749, 716; H NMR (400 MHz, CDCl3):  7.90-7.87 (m, 4H), 7.54-7.49 (m, 3H), 5.41 (s, 2H),

141

13 2.93 (s, 1H); C NMR (100 MHz, CDCl3):  152.6, 133.3, 133.1, 131.9, 128.6, 128.1, 128.0, 127.8,

+ 126.6, 126.5, 125.9, 75.2, 74.5, 68.1. HRMS [M] calcd. for C14H10O2: 210.0681; found: 210.0688.

Methoxyacetic acid, 2-naphthalenylmethyl ester (4.3h; Table 4.4, entry 8): 75% (32.4 mg);

-1 white solid; mp: 30-32 ˚C; Rf = 0.14 (EtOAc-hexanes, 5:95); IR (ν, cm ): 3053, 2994, 2927, 2889,

1 2869, 2827, 1737, 1449, 1212, 1192, 1124, 829, 740; H NMR (400 MHz, CDCl3):  7.87 (m, 4H),

13 7.54 (m, 3H), 5.40 (s, 2H), 4.13 (s, 2H), 3.49 (s, 3H); C NMR (100 MHz, CDCl3):  170.2,

133.19, 133.15, 132.8, 128.5, 128.0, 127.8, 127.7, 126.5, 126.4, 126.0, 69.9, 66.8, 59.5. HRMS

+ [M] calcd. for C14H14O3: 230.0943; found: 230.0949.

Naphthoxyacetic acid, 2-naphthalenylmethyl ester (4.3i; Table 4.4, entry 9): 16% (13.2 mg);

-1 white solid; mp: 98-100 ˚C; Rf = 0.10 (EtOAc-hexanes, 5:95); IR (ν, cm ): 3054, 2971, 1738, 1597,

1 1272, 1215, 1190, 1170, 1061, 841; H NMR (400 MHz, CDCl3):  7.84-7.79 (m, 6H), 7.64 (d,

J=8.1 Hz, 1H), 7.52 (m, 2H), 7.44 (m, 3H), 7.28 (m, 1H), 7.07 (d, J=2.5 Hz, 1H), 5.46 (s, 2H),

13 4.85 (s, 2H); C NMR (100 MHz, CDCl3):  168.8, 155.7, 134.2, 133.2, 133.1, 132.5, 129.8, 129.4,

128.5, 129.1, 127.8, 127.73, 127.68, 126.9, 126.54, 126.47, 126.4, 125.9, 124.2, 118.6, 107.1, 67.2,

+ 65.4; HRMS [M] calcd. for C23H18O3: 342.1256; found: 342.1263.

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Chloroacetic acid, 2-naphthalenylmethyl ester (4.3j; Table 4.4, entry 10): 37% (16.2 mg);

-1 white solid; mp: 50-51 ˚C; Rf = 0.44 (EtOAc-hexanes, 25:75); IR (ν, cm ): 3059, 3026, 2955, 1747,

1 1310, 1185, 962, 828; H NMR (600 MHz, CDCl3):  7.84 (m, 4H), 7.51-7.49 (m, 2H), 7.46-7.45

13 (m, 1H), 5.37 (s, 2H), 4.11 (s, 2H); C NMR (125 MHz, CDCl3):  167.3, 133.3, 133.2, 132.3,

+ 128.6, 128.1, 127.9, 127.8, 126.6, 126.5, 125.9, 68.1, 41.0; HRMS [M] calcd. for C13H11O2Cl:

234.0448; found: 234.0441.

Bromoacetic acid, 2-naphthalenylmethyl ester (4.3k; Table 4.4, entry 11): 51% (22.6 mg);

-1 white solid; mp: 48-49 ˚C; Rf = 0.48 (EtOAc-hexanes, 25:75); IR (ν, cm ): 3024, 2964, 1718, 1270,

1 1230, 966, 816; H NMR (600 MHz, CDCl3):  7.87-7.84 (m, 4H), 7.51-7.50 (m, 2H), 7.47-7.46

13 (m, 1H), 5.37 (s, 2H), 3.90 (s, 2H); C NMR (125 MHz, CDCl3):  167.1, 133.3, 133.2, 132.4,

+ 128.6, 128.1, 127.8 (2C), 126.52, 126.46, 125.9, 68.1, 25.9; HRMS [M] calcd. for C13H11O2Br:

277.9942; found: 277.9948.

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Acetic acid, 1,4-dimethyl-2-naphthalenylmethyl ester (4.3l; Table 4.5, entry 2): 60% (24.1

-1 mg); Yellow oil; Rf = 0.19 (EtOAc-hexanes, 5:95); IR (ν, cm ): 3072, 2942, 1732, 1224, 1021,

1 729; H NMR (400 MHz, CDCl3):  8.15-8.12 (m, 1H), 8.04-8.01 (m, 1H), 7.59-7.56 (m, 2H),

13 7.33 (s, 1H), 5.33 (s, 2H), 2.71 (s, 3H), 2.70 (s, 3H), 2.14 (s, 3H); C NMR (100 MHz, CDCl3): 

171.1, 132.9, 132.7, 132.4, 131.6, 130.2, 128.3, 125.81, 125.78, 124.8, 124.6, 65.3, 21.1, 19.4,

+ 14.2; HRMS [M] calcd. for C15H16O2: 228.1150; found: 228.1156.

Acetic acid, 5.8-dimethyl-2-naphthalenylmethyl ester (4.3m; Table 4.5, entry 3): 33% (8.8

-1 mg); yellow oil; Rf = 0.58 (EtOAc-hexanes, 1:1); IR (ν, cm ): 3067, 3010, 2963, 2924, 2862, 1737,

1 1061, 1512, 1442, 1367, 1226, 1025, 826; H NMR (400 MHz, CDCl3):  7.99 (d, J=8.6 Hz, 1H),

7.95 (br s, 1H), 7.51 (d, J=1.6 Hz, 1H), 7.19 (s, 2H), 5.27 (s, 2H), 2.64 (s, 3H), 2.63 (s, 3H), 2.11

13 (s, 3H); C NMR (100 MHz, CDCl3):  171.0, 132.7, 132.5, 132.4 (2C), 132.3, 126.8, 126.7,

125.5, 125.3, 124.5, 66.8, 21.1, 19.4 (2C).

Acetic acid, 5,8-dimethoxy-2-naphthalenylmethyl ester (4.3n; Table 4.5, entry 4): 45% (13.5

-1 mg); yellow oil; Rf = 0.38 (EtOAc-hexanes, 1:4); IR (ν, cm ): 3000, 2938, 2835, 1733, 1603, 1462,

1 1365, 1270, 1214, 1086, 801; H NMR (400 MHz, CDCl3):  8.20 (d, J= 8.8 Hz, 1H), 8.19 (s, 1H),

7.48 (dd, J= 8.6 Hz, 1.8 Hz, 1H), 6.71 (s, 2H), 5.27 (s, 2H), 3.96 (s, 3H), 3.95 (s, 3H), 2.13 (s,

144

13 3H); C NMR (100 MHz, CDCl3):  171.0, 149.42, 149.40, 133.3, 126.1, 126.0, 125.9, 122.4,

+ 121.5, 103.62, 103.60, 66.7, 55.8, 55.7, 21.1; HRMS [M] calcd. for C15H16O4: 260.1049; found:

260.1055.

Acetic acid, 6,7-dimethoxy-2-naphthalenylmethyl ester (4.3o; Table 4.5, entry 5): 40% (8.6

-1 mg); white solid; mp: 66-68 ˚C Rf = 0.24 (EtOAc-hexanes, 1:9); IR (ν, cm ): 3004, 2955, 2831,

1 1736, 1492, 1254, 1227, 1163; H NMR (400 MHz, CDCl3):  7.69 (d, J= 7.9 Hz, 1H), 7.68 (s,

1H), 7.32 (dd, J= 8.4 Hz, 1.6 Hz, 1H), 7.12 (s, 2H), 5.23 (s, 2H), 4.006 (s, 3H), 4.003 (s, 3H), 2.12

13 (s, 3H); C NMR (100 MHz, CDCl3):  171.1, 149.8, 131.6 (2C), 128.9 (2C), 126.8, 126.2, 124.5,

+ 106.3, 106.1, 66.7, 55.9 (2C), 21.2; HRMS [M] calcd. for C15H16O4: 260.1049; found: 260.1053.

Acetic acid, 3-(1-acetyl)naphthalenylmethyl ester (4.3p; Table 4.5, entry 6): 21% (11.5 mg);

-1 brown solid; mp: 66-68 ˚C Rf = 0.44 (EtOAc-hexanes, 1:1); IR (ν, cm ): 3001, 2931, 1727, 1662,

1 1506, 1439, 1367, 1240, 1032; H NMR (400 MHz, CDCl3):  8.68 (d, J= 8.5 Hz, 1H), 7.98 (br, s, 1H), 7.90 (d, J= 1.7 Hz, 1H), 7.87 (d, J= 8.1 Hz, 1H), 7.62-7.61 (m, 1H), 7.60-7.54 (m, 1H),

13 5.29 (s, 2H), 2.76 (s, 3H), 2.15 (s, 3H); C NMR (100 MHz, CDCl3):  201.7, 170.9, 136.1, 133.9,

132.4, 132.0, 129.8, 128.6, 128.5, 128.4, 126.9, 125.9, 65.9, 30.1, 21.1; HRMS [M]+ calcd. for

C15H14O3: 242.0943; found: 242.0950.

145

cis-1-(N-tert-Butoxycarbonyl-N-hydroxyamino)-3-methoxy bicyclo [3.1.0] hexane (4.20;

-1 Scheme 4.16): 52% (23.8 mg); yellow oil; Rf (1:1 EtOAc: Hexanes): 0.55; FTIR (ν, cm ): 3280,

1 2977, 2931, 1693, 1392, 1367, 1334, 1309, 1170, 1107; H NMR (400 MHz, CDCl3): δ 6.77 (br s,

1H), 4.47 (d, J= 7.5 Hz, 1H), 4.42 (dt, J= 8.1 Hz, 4.6 Hz, 1H), 3.33 (s, 3H), 2.02-1.96 (m, 1H),

1.77-1.73 (m, 1H), 1.44 (s, 9H), 1.42 (m, 1H), 1.34 (m, 1H), 0.52 (m, 1H), 0.40 (m, 1H); 13C NMR

+ (100 MHz, CDCl3): δ 156.8, 82.12, 82.11, 60.3, 57.0, 33.0, 28.3, 20.6, 20.5, 4.2; HRMS [M] calcd. for C12H21NO4: 243.1471; found 243.1465.

4.5 – References

1 Haner, J. M.Sc. Thesis, University of Guelph, 2011.

2 Bäckwall, J.-E.; Björkman, E.E.; Pettersson, L.; Siegbahn, P.; Strich, A. J. Am. Chem. Soc.

1985, 107, 7408.

3 Tigchelaar, A. M.Sc. Thesis, University of Guelph, 2013.

4 Jencks, W.P.; Regenstein, J. In Ionization Constants of Acids and Bases, Handbook of

Biochemistry; Sober, M.A. Ed. Chemical Rubber Company: Cleaveland, 1968, 305.

5 Harris, D.C. In Quantitative Chemical Analysis 8th ed., W.H. Freeman and Company: New

York, 2010, AP11.

146

6 Armarego, W.L.F; Chai, C.L.L. In Purification of Laboratory Chemicals, 6th ed. Elsevier Inc.:

Oxford, 2009, 194.

7 Carey, F.A.; Sundberg, R.A In Advanced Organic Chemistry Part A: Structure and Mechanisms,

5th ed. Springer: New York, 2007, 1.

8 Velkov, T.; Horne, J.; Laguerre, A.; Jones, E.; Scanlon, M.J.; Porter, C.J.H. Chem. Biol. 2007, 14,

452.

9 (a) Creary, X. J. Am. Chem. Soc. 1981, 103, 2463. (b) Creary, X.; Geiger, C.C. J. Am. Chem.

Soc. 1982, 104, 4151.

10 Mao, H.; Joly, G.J.; Peeters, K.; Hoornaert, G.J.; Compernolle, F. Tetrahedron 2001, 57, 6955.

11 Halton, B.; Kay, A.J.; Zhi-mei, Z.; Boese, R.; Haumann, T. J. Chem. Soc,. Perkin Trans. 1

1996, 1445.

12 Sieber, J.D.; Liu, S.; Morken, J.P. J. Am. Chem. Soc. 2007, 129, 2214.

13 Zhang, T.K.; Mo, D.L.; Dai, L.X.; Hou, X.L. Org. Lett. 2008, 10, 3689.

14 Yin, J.; Hyland, C.J.T. J. Org. Chem. 2015, 80, 6529.

15 The spectra of compound 4.21 were provided by Cheng Ji via Miller lab: [email protected]: 1H

NMR (600 MHz, CDCl3) δ 5.24 (br s, 1H), 4.28-4.29 (m, 1H), 4.06 (m, 1H), 2.09 (m, 1H), 1.66-

1.70 (m, 1H), 1.52-1.57 (m, 3H), 1.45 (s, 9H), 0.49-0.53 (m, 1H), -0.06--0.04 (m, 1H); 13C NMR

(150 MHz, CDCl3) 155.5, 79.3, 74.0, 52.2, 38.4, 28.7, 24.5, 22.8, 6.9; HRMS (FAB) calcd. For

+ C11H20NO3 [M+H] : 214.1438, found 214.1451.

16 Machin, B.P.; Howell, J.; Mandel, J.; Blanchard, N.; Tam, W. Org. Lett. 2009, 11, 2077.

17 Shibata, T.; Ueno, Y.; Kanda, K. Synlett 2006, 411.

18 Engler, T.A.; Shechter, H. J. Org. Chem. 1999, 64, 4247.

147

19 Hughes, T.S.; Carpenter, B.K. J. Chem. Soc., Perkin Trans. 2 1999, 2291.

20 Myers, A.G. Tetrahedron Lett. 1987, 28, 4493.

21 Álvarez-Bercedo, P.; Martin, R. J. Am. Chem. Soc. 2010, 132, 17352.

22 McKee, M.; Haner, J.; Carlson, E.; Tam, W. Synthesis 2014, 46, 1518.

23 Carlson, E.; Duret, G.; Blanchard, N.; Tam, W. Synth. Commun. 2016, 46, 55.

24 Kim, T.-S.; J. Org. Chem. 2006, 71, 8276.

25 Ly, T.; Krout, M.; Pham, D.K.; Tani, K.; Stoltz, B.M.; Julian, R.R. J. Am. Chem. Soc. 2007,

129, 1864.

26 Guan, B.-T.; Xiang, S.-K.; Wiang, B.; Sun, Z.; Wang, Y.; Zhao, K.; Zhang, J. J. Am. Chem.

Soc. 2008, 130, 3268.

27 Rao, C.B.; Chinnababu, B.; Venkateswarlu, Y. J. Org. Chem. 2009, 74, 8856.

148

Chapter 5: Type 3 Ring-Opening Reactions of Cyclopropanated

Oxabenzonorbornadienes: Synthesis of Seven-Membered Rings

149

Chapter 5: Type 3 Ring-Opening Reactions of Cyclopropanated

Oxabenzonorbornadienes: Synthesis of Seven-Membered Rings

5.1 - Introduction

The pursuit for new methods to construct seven-membered rings stems from the common occurrence of these systems in bioactive natural products. From simple terpenoids to complex structures such as prostratin,1 lyconadin A,2 guanacastepene A,3 or colchicine (Figure 5.1),4 seven- membered rings abound in nature. Often, the preparation of these organic frameworks is achieved through cycloaddition, ring-closing metathesis, or ring-expansion reactions. The current work introduces a novel ring-expansion method to prepare seven-membered carbocyclic frameworks, which can be compared to some of these common methodologies.

Figure 5.1. Structures of some seven-membered ring-containing bioactive compounds.

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5.1.1 – Cycloaddition

A quick literature search proves that the preparation of seven-membered heterocycles by cycloadditions has been quite extensively studied,5,6 and unique methods to construct carbocyclic versions have been emerging.7 While recent works have been broadening the scope of three- component cycloadditions to five-,8 six-,9 and eight-membered ring synthesis,10 three-component cycloadditions that lead to seven-membered rings are sparse.11 In theory, these include [3+3+1],

[4+2+1], [3+2+2], or [5+1+1] cycloadditions, which may become more accessible over the next few decades. Two-component cycloadditions are more conventional for the construction of seven- membered rings, and include [4+3], [5+2], and [6+1] cycloadditions.

Generally, [4+3] cycloadditions take place between 1,3-dienes and allyl cations to give cycloheptenes (Scheme 5.1).12 Allyl cations often contain a group Y which has the potential to stabilize the imminent cation. Karahanaenone (5.1) and its isomer (5.2) were produced by [4+3] cycloaddition between isoprene 5.3 and allyl cation of 5.4 formed by zinc insertion.13 The yields were unimpressive since the diene 5.3 could easily adopt the unreactive s-trans conformation.14

Similar [4+3] chemistry utilizing iron carbonyls was also popularized by Noyori’s works.15

Scheme 5.1. Example of [4+3] Cycloadditions to afford 7-membered rings.

151

As for [5+2] cycloadditions, Wender has promoted rhodium-catalyzed cycloadditions of vinylcyclopropanes and alkynes to yield cycloheptadienes in good yields (Scheme 5.2).16 These reactions have made their way into many syntheses of natural products17 such as (+)-dictamnol,18

19 20 (+)-aphanamol I, and (+)-allocyathin B2.

Scheme 5.2. Example of a [5+2] cycloaddition to afford 7-membered rings.

[6+1] cycloadditions are rare, and the closest example is probably cyclopropanation of a

6-membered ring which is then cleaved, effectively generating a 7-membered ring. 21 This transformation will be considered under the topic of ring-expansions, to be addressed shortly.

Finally, it is worth noting intramolecular cycloadditions which indirectly produce seven- membered rings. For instance, in Ragan’s work, the focal reaction is an intramolecular [4+2] cycloaddition. However, the adjoining tether creates a fused 7-membered ring (Scheme 5.3).22

Intramolecular reactions to create 7-membered rings will be the topic of Chapter 7.

Scheme 5.3. Formation of a 7-membered ring using a tether in [4+2] cycloaddition.

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5.1.2 – Ring-closing Metathesis

Ring-closing metathesis (RCM) is an effective strategy for medium-sized ring construction.23 The eastern fragment 5.5 of the natural metabolite (-)-balanol was prepared in two different ways through RCM reactions (Scheme 5.4).24 The total synthesis of the bioactive lactone

(+)-chinensiolide B, 5.6 (Scheme 5.5),25 was also achieved through selective alkene RCM which helped develop the analogous synthesis of psilostachyin C.26 These latter works show advances in

RCM chemistry which were initially cumbersome for the preparation of tri- or tetra-substituted cyclic alkenes.27

Scheme 5.4. Preparation of the eastern fragment 5.5 of (-)-balanol.

Scheme 5.5. Ring-closing metathesis in the total synthesis of (+)-chinensiolide B.

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5.1.3 – Ring-expansions and Rearrangements

A common alternative to the cyclization of straight-chain compounds is the expansion of smaller cyclic compounds of ring size 3-6 or fused bicyclic systems into seven-membered rings.

Many of these reactions are introduced at the undergraduate level, in the form of pinacol, Schmidt or Beckmann rearrangements, or the de Mayo reaction and retro-aldol sequence.28

Several of the most common approaches of ring-expansion are shown in Scheme 5.6. Some methods make use of strain associated with small rings, such as 3- or 4-membered rings, which may be transient or intermediate species generated in a reaction. Hetero- or homolysis of the bridge in [4.1.0] or [3.2.0] systems allows for formation of seven-membered rings in the first two approaches illustrated. A third possibility invokes an electrocyclic reaction such as the Cope rearrangement which promotes lysis of the bridge bond.29,30 A fourth possibility involves rings with an attached Z group. The Z moiety usually imparts carbene-like character, or a charge, making it available to be incorporated into the ring by a migratory shift or insertion reaction. Z could also be a constituent of a bicyclic system, where ring-expansion occurs at the expense of the adjacent ring which undergoes ring contraction.31

Scheme 5.6. General methods of ring-expansion to seven-membered rings.

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For instance, in a radical chlorination study of norcarane 5.7, creation of a radical adjacent to the cyclopropane caused rearrangement to homoallyl radicals 5.8 or 5.9 (Scheme 5.7). 32

Stereoelectronic effects controlled the direction of preferential lysis of bonds a or b, and subsequent chlorination led to 5.10 as the major and 5.11 as the minor product.

Scheme 5.7. Homolysis of [4.1.0] system 5.7, showing expansion to a chlorocycloheptene.

In a stereoselective preparation of the pseudoguaianolide confertin, 33 generation of a tertiary carbocation next to a strained cyclopropane (Scheme 5.8) led to rearrangement and ring- expansion forming a homoallyl cation 5.12 which is trapped by the tethered carboxylic acid. The lactone 5.13 was obtained in >80% yield.

Scheme 5.8. Heterolysis of [4.1.0] system, showing expansion to seven-membered product

5.13. 155

An example of the expansion of [3.2.0] bicyclic systems is the thermal [2+2] cycloaddition of 1-methoxyindene with dimethyl acetylenedicarboxylate (DMAD; Scheme 5.9). According to the Woodward-Hoffman rules, ring-opening of cyclobutene 5.14 to 5.15 is predicted to be photochemically allowed but thermally forbidden. As predicted, it was found that irradiation of

5.14 at room temperature led to quantitative production of 5.15, while thermal conversion of 5.14 to 5.15 was difficult and required high temperatures of >200 ˚C.34 As an illustration of the third class of expansion, Cope rearrangement gave ring-expanded structure 5.16, which could be used in the synthesis of confertin 5.17 and damsinic acid 5.18 (Scheme 5.10).35

Scheme 5.9. Expansion of a [3.2.0] system to a seven-membered ring 5.15.

Scheme 5.10. Electrocyclic rearrangement with cyclopropane scission to afford a seven- membered ring 5.16 in the synthesis of confertin 5.17 and damsinic acid 5.18.

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The last example can be seen in the work of Proctor’s group36 where treatment of various

α-tetralone derivatives under Prévost reaction conditions (Scheme 5.11) led to the seven- membered acetal 5.19 and eventual hydrolysis to the corresponding product 5.20 (obtained as a ketone which tautomerizes to its enol form as shown when Y=CN).

Scheme 5.11. Expansion of six- to seven-membered system 5.19 by migratory shift involving a pendant group.

5.1.4 – Type 3 Ring-Opening Reactions of Cyclopropanated Oxabenzonorbornadiene

Type 3 ring-opening reactions of this work fall under the category of ring-expansion reactions, closely resembling the lysis of [4.1.0] systems described above. The overall transformation occurs with scission of the internal cyclopropane bond and incorporation of a nucleophile in the process. The reactions in this project utilize inexpensive reagents and an economical one-pot acid-catalyzed set-up, suggesting a practical new synthesis of seven- membered rings.

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5.2 - Results and Discussion

While conducting acid-catalyzed ring-opening studies on C1-tert-butyl substituted compound 5.21, two prominent spots were detected by TLC. Isolation of each of these two spots resulted in a ~1:1 distribution of type 2 to type 3 ring-opened products, 5.22a and 5.23a, respectively (Scheme 5.12). NMR and HRMS experiments confirmed that two equivalents of the alcohol nucleophile were incorporated into the type 3 product, and that only one diastereomer of

5.23a was obtained. The flexibility of the seven-membered ring made it difficult to discern whether the methoxy groups were cis or trans with respect to each other, although NOESY and J-coupling analysis of the protons on the ring were seen as distinguishing features between the two outcomes.37 The following experimental data and mechanistic considerations suggested that the methoxy groups were trans relative to each other, and later, X-ray diffraction analysis of 5.23a confirmed this (Appendix B).

Scheme 5.12. First observation of type 3 ring-opening of cyclopropanated oxabenzonorbornadienes.

To better understand the above transformation and to optimize the reaction, 5.21 was subjected to various conditions (Table 5.1). It was found that with no external acid source, no reaction took place, which was consistent with our former experiments (Chapter 4). Introduction

158

of sulfuric acid resulted in nearly equal proportion of type 2 and type 3 products in moderate yields

(entry 2), and these similar proportions were seen with a slightly increased yield when using fluoroboric acid (entry 3). Use of pyridinium para-toluenesulfonate resulted in very slow reaction

(entry 4). With camphorsulfonic acid and para-toluenesulfonic acid (p-TsOH), excellent conversion was observed at 90 ˚C, and lowering the reaction temperature showed that at 60 ˚C the reaction could still proceed rapidly with increased formation of the type 3 product (entries 5-8).

Between these two acids, p-TsOH suggested a more pronounced increase in the proportion of type

3 product and, as such, p-TsOH was used to investigate the reaction at even lower temperatures.

At 40 ˚C, the reaction took two days to complete, and suggested an even slighter increase in type

3 product, 5.23a (entry 9). At 30 ˚C, no apparent increase in the proportion of 5.23a was seen and the reaction took considerably longer to proceed (entry 10). This reaction was also tested at room temperature (~20 ˚C), but the starting material 5.21 was not fully reacted even after an entire week

(entry 11). Thus, the best conditions were selected as p-TsOH catalyst at 40 ˚C. Though subtle, this temperature-dependent product distribution also suggests that type 2 products, which are aromatic, are thermodynamic products of the reaction, while type 3 products are kinetic products.

To probe the scope of different steric and electronic properties of the nucleophile on this ring-expansion reaction, several primary, secondary, and tertiary alcohol nucleophiles were selected and reacted with substrate 5.21. These reactions, however, were performed prior to completion of the optimizations of Table 5.1, and thus were performed at 90 ˚C. As such, future work should consider repeating these trials at 40 ˚C. The following results are still expected to provide the reader with a good first approximation (Table 5.2).

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Table 5.1. Optimizations of acid catalyst for type 3 ring-opening of 5.21.

Entry Acid catalyst Temperature Time (h) Recovered Yield 5.22a Yield 5.23a (˚C) 5.21 (%)a (%)a (%)a 1 None 90 72 97 0 0 2 H2SO4 90 24 0 34 36 3 HBF4 90 24 0 43 50 4 PPTS 90 144 0 38 48 5 CSA 90 24 0 42 56 6 CSA 60 24 0 40 54 7 pTsOH 90 20 0 49 51 8 pTsOH 60 20 0 31 57 9 pTsOH 40 48 0 26 67 10 pTsOH 30 192 0 33 58 11b pTsOH rt 168 ~10 ~30 ~55 aIsolated yield by column chromatography. bYields estimated by 1H NMR.

Table 5.2. Effect of alcohol nucleophile on p-TsOH-catalyzed type 3 ring-opening of 5.21.

Entry R Time Product Yield 5.22 Yield 5.23 (h) Identifier (%)a (%)a 1b Me 20 a 49 51 2 Et 20 b 45 55 3 iPr 20 c 75 20 4 Cy 20 d 74 20 5 tBu 168 e 25 Trace 6c Bn 96 f 42 58 aYield based on 1H NMR unless otherwise indicated. bIsolated yield by column chromatography. cPerformed at 40 ˚C.

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Each reaction took place with concurrent formation of both type 2 and type 3 ring-opened products, though the relative product distribution was found to differ with properties of the nucleophile. Primary alcohol nucleophiles reacted efficiently, giving nearly equal proportions of type 2 and type 3 product. Although column chromatographic isolation was nontrivial for many of these cases, 1H NMR integrations and successful isolations all supported a ~1:1 ratio of product mixtures of 5.22 and 5.23 for primary alcohols (entries 1 and 2). When secondary alcohol nucleophiles were used, the relative distribution was closer to 4:1 in favour of the type 2 product

(entries 3 and 4). Using a tertiary alcohol, the reaction took a week to reach completion (entry 5), and the NMR spectrum of the crude reaction mixture showed convoluted peaks from the formation of side product 5.22e’ (Scheme 5.13), as well as possible decomposition products. Only minor peaks suggesting type 3 products could be seen. In another experiment using benzyl alcohol, significant proportions of both 5.22 and 5.23 were visible by 1H NMR spectroscopy (entry 6), such that anti installation of the second equivalent of nucleophile (Scheme 5.14) was still a valid consideration (for a full proposed mechanism, see Scheme 5.18).

It was then considered that if syn addition were instead taking place, use of a short chain diol may permit intramolecular nucleophilic attack. Intramolecular anti addition should not occur due to the unfavourable geometric constraint by the tether. As such, 5.21 was reacted with ethylene glycol (Scheme 5.15, n=1). It was found that in the presence of excess diol, two equivalents of ethylene glycol were incorporated in the type 3 product (via route “a”) instead of one equivalent

(via route “b”), which was in support of the trans stereochemistry of the two nucleophilic groups.

This reaction was repeated with butanediol (n=3), showing the same result. Since the products were very polar and difficult to separate from the high-boiling diol, Kugelrohr distillation was carried out to remove any diol in excess, and the resulting mixture of type 2 and type 3 products

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were separated by column chromatography. When the amount of ethylene glycol used in the reaction was limited to 1 equivalent, the product was almost exclusively type 2 product (with only suggested trace amounts of type 3 product).

Scheme 5.13. Formation of tert-butyl ether 5.22e and its deprotection to alcohol 5.22e’.

Scheme 5.14. Experiment to investigate relative stereochemistry of the two alkoxy groups in type 3 ring-opened products by use of benzyl alcohol as the nucleophile.

Scheme 5.15. Experiment to investigate relative stereochemistry of the two alkoxy groups in type 3 ring-opened products by use of a short chain tethered diol.

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Some other bridgehead substituted variants of cyclopropanated oxabenzonorbornadiene were also examined. As was alluded to in Chapter 4, bridgehead methyl-substituted compound

5.24 was one such substrate which afforded a type 3 product (Table 5.3). When the size of the bridgehead substituent was decreased from a tert-butyl to a methyl group, the relative proportions of type 2 to type 3 compounds were markedly reduced (entries 1 and 2). Reaction with C1,C2- dimethyl substituted substrate 5.25 also gave only trace yields of the type 3 ring-opened product

(entries 3 and 4). It is possible that as the size of the bridgehead substituent increases, the cation at the benzylic position of 5.26 becomes less planar with the benzene ring due to steric crowding of the bridgehead substituent and the nearest aromatic proton (Figure 5.2). Since type 2 products are planar structures (which are not favourable in this instance), this restriction to meet planarity may instead lead to a relative increase in the formation of a more geometrically flexible type 3 framework, containing a seven-membered ring which could adopt a staggered-type conformation.

Table 5.3. Effect of substrate on p-TsOH-catalyzed type 3 ring-opening of 5.21.

Entry W Z Time Product Yield 5.22 Yield 5.23 (h) Identifier (%)a (%)a 1 H tBu 20 a 49 51 2 H Me 15 i 91 5 3 Me Me 15 j 86 Trace 4b Me Me 48 j 88 Trace aIsolated yield by column chromatography. bReaction performed at 40 ˚C.

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Figure 5.2. Steric argument of bulky bridgehead substituent with arene hydrogen.

When C1-hydroxymethylated substrate 5.27 was reacted with methanol, the type 2 product

5.22k was observed along with a nearly equal proportion of ring-expanded product 5.28 (Scheme

5.16). Product 5.28 suggested the lack of incorporation of methanol. When the same reaction was conducted in the absence of an alcohol, some valuable information was gained: ring-expansion to

5.28 still occurred in 64% yield without nucleophilic attack (Scheme 5.16). A possible mechanism for the formation of 5.28 is described as follows (Scheme 5.17): treatment of 5.27 with acid catalyst drives electrophilic ring-opening of the oxabicyclic framework in favour of the secondary carbocationic intermediate 5.29 due to the electron-withdrawing (-I) contribution of the hydroxymethyl group. Although the cation of 5.29 should be relatively stable, the relief of ring- strain in the adjacent cyclopropane presumably drives ring-expansion to 5.30. A similar rearrangement was described by Crombie,38 as well as by Hart.39 In this light, the cyclopropane cleavage is more so an electrophilic ring-opening, rather than a nucleophile-driven one.

Neighboring group participation of the tertiary hydroxyl group in 5.30 may help stabilize this cation, and deprotonation (as shown in 5.31) produces enol 5.32, which rearranges with dehydration (5.33) to aldehyde 5.28. Structural assignment of 5.28 was aided by a 1H NMR resonance diagnostic of an aldehyde proton (~10 ppm), and the presence of a sharp, intense IR band at 1683 cm-1, consistent with the aldehyde being conjugated (expected ~1680 cm-1).40

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Scheme 5.16. Seven-membered ring formation in the presence and absence of nucleophilic attack.

Scheme 5.17. Proposed mechanism for the formation of compound 5.28 in the absence of an external nucleophile.

With the above in mind, the mechanism for the formation of compound 5.23 was rationalized (Scheme 5.18): Protonation and opening of the ether bridge (5.34) forms cation 5.26, which can either undergo the typical type 2 ring-opening by cleavage of bond “a” (which is still thought to be driven by nucleophilic attack, since rearrangement to a primary carbocation is not likely favourable on its own), and cleavage of bond “b” (as discussed above) to afford a seven- membered ring system.41 Since the products 5.23 are obtained as single pairs of enantiomers and not as mixtures of diastereomers, the carbocations involved in intermediate steps are probably not free cations.42 Thus, neighboring group participation of the hydroxyl group (5.35) likely directs

165

the approach of a nucleophile to the opposite face (5.36). From this intermediate (5.37), a similar bridging process with the alkoxy group could be responsible for the departure of the hydroxyl moiety (5.38) and installation of a second equivalent of nucleophile (5.39). Such occurrences of weak neighboring group participation with alkoxy groups are known.43

Scheme 5.18. Proposed mechanism for the concurrent formation of type 2 and type 3 products.

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The reaction was also extended to acetic acid as the nucleophile, although in this case only the type 2 product 5.40 could be obtained in meaningful quantities. The presence of the type 3 product was only suggested in trace amounts (<5%) in the NMR spectrum of the crude reaction mixture (Scheme 5.19).

Scheme 5.19. Reaction of 5.21 with carboxylic acid nucleophile forming mostly type 2 product.

Reaction of C1-primary alkyl substituted substrates 5.41-5.43 resulted in messy side product formation (Scheme 5.20). TLC suggested that the reactions were complete at 1 hour, and an unexpected compound was isolated cleanly from the reaction of C1-ethyl-bearing substrate 5.43, which when characterized by 1H, JMOD, HSQC, HMBC, NOE, IR and HRMS, and compared to a simulated spectrum, suggested the structure 5.44. Irradiation of HK in 5.44 showed NOE in protons A, F, H, and I (Figure 5.3), and irradiation of HH similarly showed enhancement of protons

A, F, I, and K. One way that such a structure could arise may be through the following mechanism

(Scheme 5.21): After formation of carbocation 5.45, deprotonation of a methylene proton gives alkene 5.46, which undergoes acidic dehydration and ring-expansion to 5.47. Cation 5.47 is in allylic resonance with cation 5.48, to which methanol could have added. By repeating the reaction with a substrate bearing a secondary bridgehead substituent (e.g. C1-isopropyl), the difference in

167

relative stability could be insightful, especially if the analogous product is observed in higher yield.

Reactions using substrate 5.43 with a different nucleophile may also provide useful information.

Scheme 5.20. Complications arising from acid-catalyzed reactions of some C1-primary alkyl substituted cyclopropanated oxabenzonorbornadienes.

Figure 5.3. Observed NOE signals in support of the structure 5.44.

168

Scheme 5.21. Proposed mechanism for the formation of 5.44.

5.3 - Conclusion

The present work has led to the discovery of type 3 ring-opening reactions with a new route to seven-membered rings which contain trans-1,2-dialkoxy groups. This novel and stereoselective construction of medium-ring structures may prove superior to currently accessible preparations, which are limited by cumbersome reaction sequences.44 Although the transformation is currently only seen with C1-substituted substrates, especially with bulky substituents, the one-pot procedure is simple, economical, and a seemingly practical addition to current syntheses of seven-membered rings.

In the future, other type 3 ring-opening products will most certainly be observed through continued studies of cyclopropanated oxabenzonorbornadiene’s series of reactions. These should be tested for various other nucleophiles to make the products more separable from each other, and

169

consider reducing the nucleophile to one equivalent to investigate the mechanism of type 3 ring- opening. Repeating the reaction with C1-phenyl, iso-propyl or cyclohexyl groups at the bridgehead position would be interesting to note the change in product distribution, as well.

5.4 - Experimental

General Information: Commercial reagents were used without further purification.

Cyclopropanated oxabenzonorbornadiene was prepared as previously reported. 45,46 A Büchi®

GKR-51 350 W Kugelrohr oven was used to remove high-boiling solvent from product mixtures.

Static sublimation was performed in a vacuum-sealed glass tube over an increasing temperature gradient of 40-70 ˚C over two weeks. Column chromatography, TLC, melting point determination,

IR, NMR, and HRMS analyses were performed as described in Chapter 2.

General Procedure: Acid-catalyzed ring-opening of cyclopropanated oxabenzonorbornadiene with alcohol nucleophiles: Using 5.21 and heating to 40 ˚C, procedures closely follow that of Chapter 4 using alcohol nucleophiles.

1-tert-Butyl-3-(Methoxymethyl)naphthalene (5.22a; Table 5.2, entry1): Yield: 13.2 mg (49%);

-1 yellow oil; Rf = 0.44 (EtOAc–hexanes, 1:4). IR (ν, cm ): 3053, 2957, 1461, 1396, 1366, 1100,

1 876, 751. H NMR (600 MHz, CDCl3): δ 8.42 (d, J =8.4 Hz, 1H), 7.84 (m, 1H), 7.64 (s, 1H), 7.46–

13 7.42 (m, 3H), 4.59 (s, 2H), 3.43 (s, 3H), 1.62 (s, 9H). C NMR (100 MHz, CDCl3): δ 146.5, 135.0,

170

134.6, 131.1, 129.6, 126.9, 126.0, 124.9, 124.6, 123.2, 75.1, 58.2, 36.1, 31.8. HRMS: [M]+ calcd for C16H20O: 228.1514; found 228.1519.

9-tert-butyl-trans-5,6-dimethoxy-6,7-dihydro-5H-benzocycloheptene (5.23a; Table 5.2, entry

- 1): Yield: 15.6 mg (51%); white solid; mp = 35-36 ˚C; Rf = 0.25 (EtOAc–hexanes, 1:4). IR (ν, cm

1 1 ): 3057, 2952, 2824, 1477, 1462, 1095, 755. H NMR (400 MHz, CDCl3): δ 7.55-7.52 (m, 1H),

7.42-7.40 (m, 1H), 7.30-7.28 (m, 2H), 6.13 (t, J=7.3 Hz, 1H), 4.12 (d, J=7.9 Hz, 1H), 3.52 (m,

1H), 3.49 (s, 3H), 3.41 (s, 3H), 2.26-2.20 (m, 1H), 1.55-1.49 (m, 1H), 1.25 (s, 9H). 1H NMR (400

MHz, (CD3)2CO): δ 7.53-7.50 (m, 1H), 7.49-7.41 (m, 1H), 7.32-7.29 (m, 2H), 6.13 (t, J=7.4 Hz,

1H), 4.06 (d, J=7.6 Hz, 1H), 3.44 (m, 1H), 3.40 (s, 3H), 3.33 (s, 3H), 2.22-2.17 (m, 1H), 1.46-1.41

13 (m, 1H), 1.23 (s, 9H). C NMR (100 MHz, CDCl3): δ 149.2, 138.4, 138.1, 127.6, 126.4, 126.3,

+ 123.6, 122.1, 91.4, 85.1, 58.3, 57.7, 36.4, 30.9, 28.2. HRMS: [M] calcd for C17H24O2: 260.1776; found 260.1771.

1-tert-Butyl-3-(ethoxymethyl)naphthalene (5.22b) and 9-tert-butyl-trans-5,6-diethoxy-6,7- dihydro-5H-benzocycloheptene (5.23b; Table 5.2, entry 2): Yield: 54.0 mg (5.22b:5.23b =

1 -1 45:55 measured by H NMR); yellow oil. 5.22b: Rf = 0.67 (EtOAc–hexanes, 1:19); IR (ν, cm ):

1 3052, 2968, 2929, 2870, 1366, 1133, 1099, 871; H NMR (400 MHz, CDCl3): δ 8.44 (m, 1H), 7.86

(m, 1H), 7.66 (br s, 1H), 7.47-7.42 (m, 3H), 4.65 (s, 2H), 3.59 (q, J=7.2 Hz, 2H), 1.63 (s, 9H),

13 1.28 (t, J=7.0 Hz, 3H); C NMR (100 MHz, CDCl3): δ 146.4, 135.1, 135.0, 131.0, 129.6, 126.8,

+ 125.9, 124.8, 124.5, 123.3, 73.1, 65.8, 36.1, 31.8, 15.3. HRMS: [M] calcd for C17H22O: 242.1671;

171

-1 found 242.1666. 5.23b: Rf = 0.68 (EtOAc–hexanes, 1:19).; IR (ν, cm ): 3056, 2970, 2928, 2868,

1 1476, 1368, 1345, 1118, 1087, 754; H NMR (400 MHz, CDCl3): δ 7.57-7.55 (m, 1H), 7.38-7.26

(m, 1H), 7.27-7.24 (m, 2H), 6.14 (t, J=7.4 Hz, 1H), 4.18 (d, J=8.0 Hz, 1H), 3.65 (m, 2H), 3.57 (m,

2H), 3.47 (m, 1H), 2.11 (m, 1H), 1.58 (m, 1H), 1.53 (m, 6H), 1.21 (s, 9H). 13C NMR (100 MHz,

CDCl3): δ 148.9, 139.2, 138.1, 127.5, 126.3, 126.1, 123.8, 122.4, 89.8, 83.4, 66.0, 65.7, 36.4, 30.9,

+ 29.9, 15.8, 15.5. HRMS: [M] calcd for C19H28O2: 288.2089; found 288.2096.

1-tert-Butyl-3-(isopropoxymethyl)naphthalene (5.22c) and 9-tert-butyl-trans-5,6- diisopropoxy-6,7-dihydro-5H-benzocycloheptene (5.23c; Table 5.2, entry 3): Yield: 38.1 mg

(5.22c:5.23c = 75:20 measured by 1H NMR); yellow oil. IR (ν, cm-1): 3054, 2967, 2931, 2871,

1 1464, 1395, 1174, 1123, 1065, 876; 5.22c: Rf = 0.56 (EtOAc–hexanes, 1:19); H NMR (400 MHz,

CDCl3): δ 8.45 (m, 1H), 7.87 (m, 1H), 7.67 (br s, 1H), 7.50 (d, J=1.4 Hz, 1H), 7.49-7.42 (m, 2H),

4.67 (s, 2H), 3.77 (sept, J=6.1 Hz, 1H), 1.65 (s, 9H), 1.28 (s, 3H), 1.27 (s, 3H); 13C NMR (100

MHz, CDCl3): δ 146.3, 135.5, 135.1, 131.0, 129.6, 126.8, 125.7, 124.8, 124.4, 123.3, 71.0, 70.4,

+ 36.1, 31.8, 22.2. HRMS: [M] calcd for C18H24O: 256.1827; found 256.1824. 5.23c: Rf = 0.56

1 (EtOAc–hexanes, 1:19); H NMR (400 MHz, CDCl3): δ 7.66 (m, 1H), 7.37 (m, 1H), 7.26 (m, 2H),

6.18 (t, J=7.4 Hz, 1H), 4.24 (d, J=8.0 Hz, 1H), 3.84 (sept, J=6.1 Hz, 1H), 3.65 (sept, J=6.1 Hz,

1H), 3.57 (m, 1H), 2.05 (m, 1H), 1.64 (m, 1H), 1.24 (s, 9H), 1.23 (d, J=6.1 Hz, 3H), 1.21 (d, J=6.1

13 Hz, 3H), 1.16 (d, J=6.1 Hz, 3H), 1.12 (d, J=6.1 Hz, 3H). C NMR (100 MHz, CDCl3): δ 148.8,

172

140.5, 137.7, 127.3, 126.1, 125.9, 124.4, 122.6, 88.3, 81.3, 72.0, 71.7, 36.4, 31.3, 31.0, 23.1, 22.94,

+ 22.87 22.2. HRMS: [M] calcd for C21H32O2: 316.2402; found 316.2400.

1-tert-Butyl-3-(cyclohexoxymethyl)naphthalene (5.22d) and 9-tert-butyl-trans-5,6- dicyclohexoxy-6,7-dihydro-5H-benzocycloheptene (5.23d; Table 5.2, entry 4): Yield: 44.6 mg

1 (5.22d:5.23d = 74:20 measured by H NMR); yellow oil. 5.22d: Rf = 0.67 (EtOAc–hexanes, 1:19);

-1 1 IR (ν, cm ): 3053, 2928, 2854, 1449, 1363, 1088; H NMR (400 MHz, CDCl3): δ 8.44 (dd, J=7.8

Hz, 1.7 Hz, 1H), 7.76 dd, J= 7.6 Hz, 1.3 Hz, 1H), 7.67 (br s, 1H), 7.50 (br s, 1H), 7.50-7.42 (m,

2H), 4.70 (s, 2H), 3.41 (m, 1H), 2.00 (m, 2H), 1.80 (m, 2H), 1.63 (s, 9H), 1.59 (m, 1H), 1.42-1.23

13 (m, 5H); C NMR (100 MHz, CDCl3): δ 146.2, 135.7, 135.1, 131.0, 129.6, 126.8, 125.6, 124.7,

+ 124.4, 123.3, 77.0, 70.1, 36.1, 32.4, 31.8, 25.9, 24.2. HRMS: [M] calcd for C21H28O: 296.2140; calcd for C21H28O: 296.2140; found 296.2130. 5.23d: Rf = 0.68 (EtOAc–hexanes, 1:19); IR (ν,

-1 1 cm ): 3054, 2855, 1730, 1449, 1363, 1084; H NMR (400 MHz, CDCl3): δ 8.45 (d, J=8.5 Hz, 1H),

7.35 (m, 1H), 7.23 (m, 2H), 6.08 (t, J=7.4 Hz, 1H), 4.26 (d, J=8.0 Hz, 1H), 3.61 (m, 1H), 3.29 (m,

13 1H), 2.29 (m, 1H), 1.97-1.18 (m, 22H), 1.21 (s, 9H); C NMR (100 MHz, CDCl3): δ 148.8, 140.7,

137.6, 127.3, 126.9, 126.1, 125.9, 122.6. 88.2, 80.8, 78.1, 77.8, 36.4, 33.5, 33.4, 33.1, 32.5, 31.3,

+ 31.0, 24.6, 24.3. HRMS: [M] calcd for C27H40O2: 396.3028; found 396.3024.

173

1-tert-Butyl-3-(tert-butoxymethyl)naphthalene (5.22e; Table 5.2, entry 5): Yield: 8.2 mg (25%

1 -1 measured by H NMR); brown oil; Rf = 0.80 (EtOAc–hexanes, 1:1). IR (ν, cm ): 3055, 2952, 2869,

1 1364, 1049, 752; H NMR (400 MHz, CDCl3): δ 8.41 (br d, J= 7.8 Hz, 1H), 7.83 (m, 1H), 7.67

13 (br s, 1H), 7.47-7.42 (m, 3H), 4.82 (s, 2H), 1.61 (s, 9H), 1.19 (s, 9H); C NMR (100 MHz, CDCl3):

δ 146.7, 139.4, 137.3, 135.1, 129.6, 126.9, 125.0 (2C), 124.7, 122.7, 62.8, 36.1, 31.8, 31.6, 31.2.

+ HRMS: [M] calcd for C19H26O: 270.1984; found 270.1976.

1-tert-Butyl-3-(hydroxymethyl)naphthalene (5.22e’; Table 5.2, entry 5): Yield: 10.6 mg

-1 (36%); brown oil; Rf = 0.57 (EtOAc–hexanes, 1:1). IR (ν, cm ): 3343, 3053, 2956, 2872, 1365,

1 1023, 752; H NMR (400 MHz, CDCl3): δ 8.43 (m, 1H), 7.84 (m, 1H), 7.67 (br s, 1H), 7.47 (br s,

1H), 7.47-7.42 (m, 2H), 4.82 (d, J=6.0 Hz, 1H), 1.69 (t, J= 6.0 Hz, 1H), 1.61 (s, 9H); 13C NMR

(100 MHz, CDCl3): δ 146.7, 137.2, 135.1, 131.1, 129.6, 126.9, 125.0 (2C), 124.7, 122.7, 65.9,

+ 36.1, 31.8; HRMS: [M] calcd for C15H18O: 214.1358; found 214.1356.

1-tert-Butyl-3-(benzyloxymethyl)naphthalene (5.22f) and 9-tert-butyl-trans-5,6-dibenzyloxy-

6,7-dihydro-5H-benzocycloheptene (5.23f; Table 5.2, entry 6): Yield: 44.1 mg (5.22f:5.23f

1 -1 =42:58 measured by H NMR); yellow oil; Rf = 0.26:0.31 (EtOAc–hexanes, 1:19). IR (ν, cm ):

13 3063, 3031, 2954, 2867, 1573, 1362, 1175, 1027; C NMR (100 MHz, CDCl3): δ 149.1, 146.5,

139.2, 138.6, 138.43, 138.36, 138.2, 136.1, 135.0, 134.7, 133.1, 129.7, 129.6, 128.6, 128.5, 128.4,

128.32, 128.28, 128.2, 127.9, 127.8, 127.7, 127.6, 127.5, 126.9, 126.4, 126.1, 124.9, 123.9, 123.3,

1 89.7, 83.4, 72.5, 72.4, 72.2, 66.7, 36.4, 36.1, 31.8, 31.0, 29.7; 5.22f: H NMR (400 MHz, CDCl3):

δ 8.43 (m, 1H), 7.84 (br s, 1H), 7.50 (br s, 1H), 7.50-7.42 (m, 2H), 7.41-6.30 (m, 6H), 5.41 (s, 2H),

174

+ 1 5.30 (s, 2H), 1.68 (s, 9H); HRMS: [M] calcd for C22H24O: 304.1827; found 304.1822. 5.23f: H

NMR (400 MHz, CDCl3): δ 8.08 (m, 1H), 7.53 (m, 1H), 7.44-7.23 (m, 12H), 6.13 (t, J= 7.2 Hz,

1H), 5.35 (s, 2H), 4.71 (s, 2H), 4.46 (m, 1H), 3.80 (m, 1H), 2.18 (m, 1H), 1.63 (m, 1H), 1.20 (s,

+ 9H); HRMS: [M] calcd for C29H32O2: 412.2402; found 412.2398.

1-tert-Butyl-3-(hydroxyethoxymethyl)naphthalene (5.22g; Scheme 5.14): Yield: 9.1 mg

-1 (47%); yellow oil; Rf = 0.50 (EtOAc–hexanes, 1:1). IR (ν, cm ): 3404, 2955, 2926, 2871, 1461,

1 1395, 1365, 1192, 1133, 1108, 1062, 907; H NMR (400 MHz, CDCl3): 8.43 (br d, J=8.4 Hz, 1H),

7.84 (m, 1H), 7.66 (br s, 1H), 7.50-7.43 (m, 3H), 4.71 (s, 2H), 3.80 (m, 2H), 3.66 (m, 2H), 2.06

13 (br s, 1H), 1.63 (s, 9H); C NMR (100 MHz, CDCl3): δ 146.7, 135.0, 134.3, 131.1, 129.6, 126.9,

+ 126.1, 125.0, 124.7, 123.2, 73.7, 71.4, 62.0, 36.1, 31.8; HRMS: [M] calcd for C17H22O2:

258.1620; found 258.1628.

9-tert-Butyl-trans-5,6-hydroxyethoxy-6,7-dihydro-5H-benzocycloheptene (5.23g; Scheme

-1 5.14): Yield: 12.3 mg (51%); white semi-solid; Rf = 0.08 (EtOAc–hexanes, 1:1). IR (ν, cm ): 3354,

1 3060, 2951, 2867, 1476, 1359, 1095, 1069, 1051, 755; H NMR (400 MHz, CDCl3): 7.54-7.52 (m,

1H), 7.37-7.35 (m, 1H), 7.27-7.23 (m, 2H), 6.11 (t, J=7.6 Hz, 1H), 4.31 (d, J=8.4 Hz, 1H), 3.84-

3.78 (m, 6H), 3.77-3.74 (m, 1H), 3.71-3.68 (m, 1H), 3.57-3.41 (m, 1H), 3.40 (br s, 1H), 3.39 (br s,

13 1H), 2.18-2.12 (m, 1H), 1.58-1.54 (m, 1H), 1.20 (s, 9H); C NMR (100 MHz, CDCl3): δ 149.5,

137.8, 137.5, 127.66, 126.62, 126.60, 123.7, 121.8, 90.6, 83.5, 72.0, 71.1, 62.0, 61.9, 36.5, 30.9,

+ 29.0; HRMS: [M] calcd for C19H28O4: 320.1988; found 320.1981.

175

1-tert-Butyl-3-(hydroxybutoxymethyl)naphthalene (5.22h; Scheme 5.14): Yield: 9.2 mg

-1 (25%); yellow oil; Rf = 0.63 (EtOAc). IR (ν, cm ): 3374, 2952, 2870, 2110, 1365, 1086, 1046,

1 750; H NMR (400 MHz, CDCl3): 8.41 (m, 1H), 7.83 (m, 1H), 7.62 (s, 1H), 7.47-7.39 (m, 3H),

4.64 (s. 2H), 3.64 (br t, J=5.6 Hz, 2H), 3.55 (t, J=5.6 Hz, 2H), 2.11 (br s, 1H), 1.73-1.67 (m, 4H),

13 1.61 (s, 9H); C NMR (100 MHz, CDCl3): δ 146.5, 135.0, 134.6, 131.1, 129.6, 126.8, 126.0, 124.9,

+ 124.6, 123.2, 73.4, 70.3, 62.8, 36.1, 31.8, 30.2, 26.7; HRMS: [M] calcd for C19H26O2: 286.1933; found 286.1928.

9-tert-Butyl-trans-5,6-hydroxybutoxy-6,7-dihydro-5H-benzocycloheptene (5.23h; Scheme

-1 5.14): Yield: 23.0 mg (69%); white semi-solid; Rf = 0.31 (EtOAc). IR (ν, cm ): 3354, 2947, 2867,

1 1360, 1260, 1120, 1088, 1050, 754; H NMR (400 MHz, CDCl3): 7.49-7.47 (m, 1H), 7.36-7.34

(m, 1H), 7.25-7.23 (m, 2H), 6.07 (t, J=7.3 Hz, 1H), 4.17 (d, J=8.1 Hz, 1H), 3.67-3.54 (m, 7H)

3.52-3.47 (m, 1H), 3.39-3.35 (m, 1H), 3.30-2.95 (br s, 2H), 2.20-2.14 (m, 1H), 1.74-1.64 (m, 8H),

13 1.51-1.44 (m, 1H), 1.19 (s, 9H); C NMR (100 MHz, CDCl3): δ 149.4, 138.2, 138.1, 127.6, 126.4

(2C), 123.7, 122.0, 89.8, 83.1, 70.3, 69.6, 62.64, 62.58, 36.4, 30.9, 30.4, 30.1, 28.3, 27.0, 26.8;

+ HRMS: [M] calcd for C23H36O4: 376.2614; found 376.2608.

176

3-(Methoxymethyl)-1-methylnaphthalene (5.22i; Table 5.3, entry 2): Yield: 30.7 mg (91%);

-1 yellow oil; Rf = 0.32 (EtOAc–hexanes, 1:9). IR (ν, cm ): 3052, 2924, 1193, 1132, 1100, 910, 868,

1 734. H NMR (400 MHz, CDCl3): δ 7.98 (d, J =7.8 Hz, 1H), 7.83 (d, J =7.2 Hz, 1H), 7.64 (s, 1H),

7.53–7.46 (m, 2H), 7.31 (s, 1H), 4.58 (s, 2H), 3.42 (s, 3H), 2.69 (s, 3H). 13C NMR (100 MHz,

CDCl3): δ 135.3, 134.7, 133.5, 132.2, 128.5, 126.4, 125.8, 125.7, 125.0, 124.0, 74.9, 58.2, 19.4.

+ HRMS: m/z [M] calcd for C13H14O: 186.1045; found 186.1041.

9-Methyl-trans-5,6-methoxy-6,7-dihydro-5H-benzocycloheptene (5.23i; Table 5.3, entry 2):

-1 Yield: 3.5 mg (5%); yellow oil; Rf = 0.32 (EtOAc–hexanes, 1:9). IR (ν, cm ): 3070, 3026, 2928,

1 2824, 1727, 1446, 1101, 768, 752. H NMR (400 MHz, CDCl3): δ 7.52-7.50 (m, 1H), 7.29-7.26

(m, 3H), 5.96 (m, 1H), 4.09 (d, J=7.6 Hz, 1H), 3.67 (m, 1H), 3.47 (s, 3H), 3.35 (s, 3H), 2.22 (m,

13 1H), 2.10 (s, 3H), 1.69-1.63 (m, 1H). C NMR (100 MHz, CDCl3): δ 139.5, 137.4, 137.2, 126.9,

+ 126.7, 125.9, 124.6, 124.3, 93.2, 85.5, 58.6, 57.6, 28.5, 21.9. HRMS: m/z [M] calcd for C14H18O2:

218.1307; found 218.1299.

3-(Methoxymethyl)-1,2-dimethylnaphthalene (5.22j; Table 5.3, entry 3): Yield: 20.3 mg

-1 (87 %); yellow oil; Rf = 0.35 (EtOAc–hexanes, 1:9). IR (ν, cm ): 3068, 3052, 2979, 2870, 2815,

1 1725, 1375, 1192, 1103, 1084, 880. H NMR (400 MHz, CDCl3): δ 8.02 (d, J=8.4 Hz, 1H), 7.79

(d, J=8.0 Hz, 1H), 7.67 (s, 1H), 7.50-7.46 (m, 1H), 7.44-7.40 (m, 1H), 4.62 (s, 2H), 3.45 (s, 3H),

13 2.62 (s, 3H), 2.45 (s, 3H). C NMR (100 MHz, CDCl3): δ 134.5, 132.6, 132.4, 132.0, 131.7, 128.5,

+ 126.1, 125.8, 124.8, 123.8, 74.4, 58.1, 15.6, 14.8. HRMS: m/z [M] calcd for C14H16O: 200.1201; found 200.1211.

177

3-(Methoxymethyl)-1-hydroxymethylnaphthalene (5.22k; Scheme 5.16): Yield: 4.7 mg

-1 (23 %); yellow oil; Rf = 0.08 (EtOAc–hexanes, 1:4). IR (ν, cm ): 3421, 3058, 2923, 1453, 1085,

1 874; H NMR (400 MHz, CDCl3): δ 8.11 (d, J=8.0 Hz, 1H), 7.87 (m, 1H), 7.76 (s, 1H), 7.57-7.50

13 (m, 3H), 5.17 (s, 2H), 4.62 (s, 2H), 3.45 (s, 3H), 1.26 (br s, 1H); C NMR (100 MHz, CDCl3): δ

136.7, 135.2, 133.8, 130.8, 128.7, 127.0, 126.4, 126.2, 125.1, 123.6, 74.7, 63.7, 58.3.

7H-Benzocycloheptene-5-carboxaldehyde (5.28; Scheme 5.16): Yield: 16.6 mg (64%); yellow

-1 oil; Rf = 0.51 (EtOAc–hexanes, 1:9). IR (ν, cm ): 3027, 2973, 2838, 2720, 1683, 1618, 1596, 1485,

1 1438, 1218, 1077, 867; H NMR (400 MHz, CDCl3): 9.68 (s, 1H), 7.84-7.82 (m, 1H), 7.40-7.36

(m, 3H), 6.87 (t, J=7.4 Hz, 1H), 6.70 (d, J=9.9 Hz, 1H), 6.00 (dt, J=8.2 Hz, 6.5 Hz, 1H), 2.62 (dd,

13 J=7.1 Hz, 6.8 Hz, 2H); C NMR (100 MHz, CDCl3): δ 192.3, 151.1, 140.0, 137.2, 131.7, 131.0,

+ 130.0, 129.3, 128.3, 127.5, 126.0, 26.7; HRMS: [M] calcd for C12H10O: 170.0732; found

170.0727.

Acetic acid, 3-(1-tert-butyl)naphthalenylmethyl ester, (5.40; Scheme 5.19): Yield: 31.0 mg

-1 (88%); yellow oil; Rf = 0.46 (EtOAc–hexanes, 1:19). IR (ν, cm ): 3054, 2991, 2957, 2874, 1737,

1 1607, 1365, 1221, 1024, 972; H NMR (400 MHz, CDCl3): 8.43 (d, J=8.4 Hz, 1H), 7.86-7.84 (m,

1H), 7.69 (s, 1H), 7.48-7.45 (m, 3H), 5.23 (s, 2H), 2.13 (s, 3H), 1.62 (s, 9H); 13C NMR (100 MHz,

178

CDCl3): δ 146.8, 134.9, 132.3, 131.3, 129.7, 126.86, 126.85, 125.1, 125.0, 123.4, 66.8, 36.1, 31.8,

+ 21.1; HRMS: [M] calcd for C17H20O2: 256.1463; found 256.1471.

5-(2-Methoxyethyl)-7H-benzocycloheptene (5.44; Scheme 5.21): Yield: 3.6 mg, (12 %); yellow

-1 oil; Rf (EtOAc: Hexanes 1:9): 0.46; FTIR (ν, cm ): 3053, 2975, 2930, 2887, 2817, 1481, 1372,

1 1100, 764; H NMR (400 MHz, CDCl3): δ 7.77-7.76 (m, 1H), 7.32-7.31 (m, 1H), 7.26-7.24 (m,

2H), 6.59 (d, J=9.6 Hz, 1H), 6.05 (m, 1H), 5.97 (t, J=7.8 Hz, 1H), 4.16 (q, J=6.6 Hz, 1H), 3.34

(s, 3H), 2.34-2.31 (m, 1H), 2.25-2.21 (m, 1H), 1.12 (d, J=6.4 Hz, 3H); 13C NMR (100 MHz,

CDCl3): δ 138.5, 137.6, 137.2, 131.2, 130.2, 129.5, 127.9, 127.5, 126.0, 125.6, 81.0, 55.9, 25.4,

+ 21.5; HRMS: Calculated for C14H16O [M] : 200.1201; found 200.1209.

5.5 – References

1 Gustafson, K.R.; Cardellina II, J.H.; McMahon, J.B.; Gulakowski, R.J.; Ishitoya, J.; Szallasi,

Z.; Lewin, N.E.; Blumberg, P.M.; Weislow, O.S. J. Med. Chem. 1992, 35, 1978.

2 Nishimura, T.; Unni, A.K.; Yokoshima, S.; Fukuyama, T. J. Am. Chem. Soc. 2011, 133, 418.

3 Brady, S.F.; Singh, M.P.; Janso, J.E.; Clardy, J. J. Am. Chem. Soc. 2000, 122, 2116.

4 Hart, D.J.; Tanis, S.P.; Evans, D.A. J. Am. Chem. Soc. 1981, 103, 5813.

5 Hassenrück, K.; Martin, H.D. Synthesis 1988, 569.

179

6 Mock, W.L. Pericyclic Reactions Volume 2. Marchand, A.P.; Lehr, R.E. Ed. Academic Press,

Inc. New York, 1977, Chapter 3.

7 Alcázar, P.; Cruz, I.; González-Romero, C.; Cuevas-Yañez, E.; Díaz, E.; Tamariz, J.; Jiménenz-

Vázquez, H.A.; Corona-Becerril, E.; Toscano, R.A.; Fuentes-Benítes, A. Tetrahedron 2015, 71,

1604.

8 Kamal, A.; Sastry, K.N.V.; Chandrasekhar, D.; Mani, G.S.; Adiyala, P.R.; Nanubolu, J.B.;

Singarapu, K.K.; Maurya, R.A. J. Org. Chem. 2015, 80, 4325.

9 Kröger, D.; Brockmeyer, F.; Kahrs, C. Org. Biomol. Chem. 2015, 13, 7223.

10 Wender, P.A.; Gamber, G.G.; Hubbard, R.D.; Zhang, L. J. Am. Chem. Soc. 2002, 124, 2876.

11 Han, X.; Li, H.; Hughes, R.P.; Wu, J. Angew. Chem. Int. Ed. 2012, 51, 10390.

12 Hoffmann, H.M.R. Angew. Chem. Int. Ed. Engl. 1984, 23, 1.

13 Sakurai, H.; Shirahata, A.; Hosomi, A. Angew. Chem. Int. Ed. Engl. 1979, 18, 163.

14 Hoffmann, H.M.R. Angew. Chem. Int. Ed. Engl. 1973, 12, 819.

15 Noyori, R. Acc. Chem. Res. 1979, 12, 61.

16 Wender, P.A. Takahashi, H.; Witulski, B. J. Am. Chem. Soc. 1995, 117, 4720.

17 Ylijoki, K.E.O.; Stryker, J.M. Chem. Rev. 2013, 113, 2244.

18 Wender, P.A.; Fuji, M.; Husfeld, C.O.; Love, J.A. Org. Lett. 1999, 1, 137.

19 Wender, P.A.; Zhang, L. Org. Lett. 2000, 2, 2323.

20 Wender, P.A.; Bi, F.C.; Brodney, M.A.; Gosselin, F. Org. Lett. 2001, 3, 2105.

21 Ye, T.; McKervey, M.A. Chem. Rev. 1994, 94, 1091.

22 Ragan, J.A.; Murry, J.A.; Castaldi, M.J.; Conrad, A.K.; Jones, B.P.; Li, B.; Makowski, T.W.;

McDermott, R.; Sitter, B.J.; White, T.D.; Young, G.R. Org. Process Res. Dev. 2001, 5, 498.

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23 Maier, M.E. Angew. Chem. Int. Ed. 2000, 39, 2073.

24 Fürstner, A. Thiel, O.R. J. Org. Chem. 2000, 65, 1738.

25 Elford, T.G.; Hall, D.G. J. Am. Chem. Soc. 2010, 132, 1488.

26 Li, C.; Tu, S.; Wen, S.; Li, S. ; Chang, J. ; Shao, F. ; Lei, X. J. Org. Chem. 2011, 76, 3566.

27 Lei, X.; Li, H. Top. Curr. Chem. 2012, 327, 163.

28 Challand, B.D.; Hikino, H.; Kornis, G.; Lange, G.; de Mayo, P. J. Org. Chem. 1969, 34, 794.

29 Vogel, E. Angew. Chem. Int. Ed. Engl. 1963, 2, 1.

30 Vogel, E.; Ott, K.-H.; Gajek, K. Justus Liebigs Ann. Chem. 1961, 644, 172.

31 Kantorowski, E.J.; Kurth, M.J. Tetrahedron 2000, 56, 4317.

32 Boikess, R.S.; MacKay, M.; Blithe, D. Tetrahedron Lett. 1971, 401.

33 Marshall, J.A.; Ellison, R.H. J. Am. Chem. Soc. 1976, 98, 4312.

34 Doyle, T.W. Can. J. Chem. 1970, 48, 1629.

35 Wender, P.A.; Eissenstat, M.A.; Filosa, M.P. J. Am. Chem. Soc. 1979, 101, 2196.

36 El-Hossini, M.S.; McMullough, K.J.; McKay, R.; Proctor, G.R. Tetrahedron Lett. 1986, 27,

3783.

37 Personal communication: Professor Michael Denk, Dr. Sameer Al-Abdul-Wahid, June 2016.

38 Crombie, L.; Firth, P.A.; Houghton, R.P.; Whiting, D.A.; Woods, D.K. J. Chem. Soc., Perkin

Trans 1. 1972, 642.

39 Hart, H.; Huang, I. J. Org. Chem. 1974, 39, 1005.

40 Pavia, D.L.; Lampman, G.M.; Kriz, G.S.; Vyvyan, J.R. Introduction to Spectroscopy, 4th ed.

International Student Edition, Brooks/Cole Cengage Learning, Belmont, 2009, Chapter 2.

41 Julia, M.; Julia, S. Bull. Soc. Chim. Fr. 1960, 1072.

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42 Wharton, P.S.; Kretchmer, R.A.; Kilian, R.J.; Oda, T. J. Org. Chem. 1974, 39, 3755.

43 Ahluwalia, V.K.; Parashar, R.K. Organic Reaction Mechanisms, 2nd ed. Alpha Science

International Ltd. Harrow, 2005, Chapter 1. (b) Bodalski, R.; Jankowski, S.; Glowka, M.L.;

Filipiak, T.; Quin, L.D. J. Org. Chem. 1994, 59, 5173.

44 Nicolaou, K.C.; Guy, R.K. Angew. Chem. Int. Ed. 1995, 34, 2090.

45 McKee, M.; Haner, J.; Carlson, E.; Tam, W. Synthesis 2014, 46, 1518.

46 Carlson, E.; Duret, G.; Blanchard, N.; Tam, W. Synth. Commun. 2016, 46, 55.

182

Chapter 6: Tandem Ring-opening and Intramolecular Ring-closure Reactions

of Cyclopropanated Azabenzonorbornadienes

Content of this chapter has been published in the following paper:

Carlson, E.; Tam, W. Org. Lett., 2016, 18, 2134.

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Chapter 6: Ring-Opening Reactions of Cyclopropanated Azabenzonorbornadiene:

Synthesis of Polycyclic γ-Lactams

6.1 - Introduction

To obtain a more complete picture of the studies conducted with cyclopropanated 7- oxabenzonorbornadienes, experiments involving ring-opening reactions of cyclopropanated 7- azabenzonorbornadienes were desired. Azabenzonorbornadienes allow for tuning of chemical and physical properties of the heterocyclic bridge via N-substitution. This could aid in the analysis of ring-opening mechanisms of similar cyclopropanated heterobicycloalkenes.

6.2 - Results and Discussion

6.2.1 - Reactions using Organocuprates

When substrate 6.1a was subjected to the previously successful conditions using higher- order cyanocuprate in ether, the expected carbamic acid tert-butyl ester 6.2a did not arise, but γ- lactam 6.3a was observed instead (Scheme 6.1). The structure of 6.3a was deduced by the disappearance of the tBu peak in NMR spectra, along with 2D NMR data (HSQC, HMBC), and was consistent with a strong IR band present at 1683 cm-1 diagnostic of a C=O stretching frequency in 5-membered lactams.1

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Scheme 6.1. First ring-opening example of azabenzonorbornadiene with organocuprate.

Although the reaction was incomplete at 7 hours, which was roughly the duration at which cyclopropanated oxabenzonorbornadienes were fully consumed (Chapter 3), it was found to go to completion after a day (Table 6.1, entries 1 and 2). The longer reaction time observed for cyclopropanated azabenzonorbornadiene 6.1a is consistent with the general tendency of azabicyclic systems having a lower reactivity toward ring-opening reactions than their oxabicyclic counterparts.2 Various other alkyl and aryl nucleophiles also produced the corresponding lactams,

6.3b-g (entries 3-12). While ethyl (entry 3) and n-hexyl (entry 4) demonstrated similar reactivity as n-butyl (entries 1-2), the methyl nucleophile was particularly unreactive, with 89% recovery of

6.1a after almost 6 days at room temperature (entry 5), as was seen previously (Chapter 3). Use of excess cuprate with heating prompted full consumption of starting material at 64 hours, although the product had decomposed (entry 6). Reacting with excess methyl nucleophile at room temperature resulted in 75% of the desired product after one day (entry 7). iso-Propyl nucleophile reacted smoothly furnishing 73% product in this time (entry 8), whereas tert-butyl nucleophile was less reactive and required 96 hours to reach completion (entries 9-11). Once again, the lower

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reactivity of tert-butyl nucleophile may arise as a consequence of its lower selectivity in ligand transfer from the organocuprate,3 as the bulky phenyl nucleophile was seen to react efficiently in

24 hours (entry 12).

Table 6.1. Effects of Organocuprate Nucleophiles on Type 1 Ring-Opening Reactions of 6.1a.

Entry Nucleophile Time (h) Recovered 6.1a (%)a Product Yield (%)a 1 nBu 7 39 6.3a 58 2 nBu 24 0 6.3a 92 3 Et 24 0 6.3b 90 4 Hex 24 0 6.3c 87 5 Me 140 89 6.3d 0 6b Me 64 0 6.3d 0 7c Me 24 0 6.3d 75 8 iPr 24 0 6.3e 73 9 tBu 24 73 6.3f 12 10 tBu 72 31 6.3f 50 11 tBu 96 0 6.3f 69 12 Ph 24 0 6.3g 62 a Isolated yield after column chromatography. b 10 equivalents of organocuprate, heated to 75 ˚C. c 10 equivalents of organocuprate, rt.

Next, the ring-opening reaction was tested on substituted variants of 6.1a (Table 6.2). With respect to the reaction of 6.1a (entry 1), substrates with ortho-disubstitution (6.1h-j) gave no clear distinction of substituent effects, resulting in a wide range of product yields (entries 2-4). When

N-phenyl substituted substrate 6.1k was subjected to the reaction conditions, no reaction was observed, even after a full week (entry 5). Although ring-opening may proceed when other N-aryl compounds bearing strong electron-withdrawing groups are used, further work is required to verify

186

this. The current results, however, show that an N-alkoxycarbonyl group is key in affecting the transformation at hand. Based on a possible mechanism that could explain the formation of 6.3

(scheme 6.4, vide infra), it seemed that any N-alkoxycarbonyl substituted substrate should produce an identical structure 6.3a, since the -OR moiety of the carbamate is lost during reaction. To test this, compounds 6.1l and 6.1m, bearing N-COOMe and N-Cbz groups respectively, were allowed to undergo ring-opening using the same n-butyl nucleophile (entries 6 and 7). As predicted, the products arising from 6.1l and 6.1m were identical to that prepared from 6.1a, as confirmed by their 1H and 13C NMR spectra. Unlike the ring-opening reactions of cyclopropanated oxabenzonorbornadienes (Chapter 3) which underwent aromatization, the aza compounds did not aromatize, resulting in good overall yields of the stereochemically preserved product (56-98%).

The inertness of product 6.3 may be due to stabilizing effects of the tether, as well as the poorer nucleofugacity of nitrogen-based functional groups relative to oxygen-based ones.4

Table 6.2. Effect of substrate functionality on type 1 ring-opening reactions of cyclopropanated azabenzonorbornadiene.

Entry X Y, Y Time (h) Recovered 6.1 (%)a Product Yield (%)a 1 COOtBu H, H 24 0 6.3a 92 2 COOtBu Me, Me 24 0 6.3h 87 3 COOtBu OMe, OMe 24 0 6.3i 56 4 COOtBu -(CH=CH)2- 24 0 6.3j 98 5 Ph H, H 168 88 6.3k 0 6 COOMe H, H 24 0 6.3a 87 7 COOBn H, H 24 0 6.3a 86 a Isolated yield after column chromatography.

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When ortho-dibrominated substrate 6.1n was subjected to the above ring-opening conditions, the reaction produced a mixture of compounds, much like that observed for the dibrominated oxabicylic version (Chapter 3). This is compelling evidence that the organocuprates are not compatible with substrates bearing halogens on the aromatic ring, under the present ring- opening conditions. The complex mixture suggests that the reaction undergoes coupling and other side-reactions between the organometallic reagent and the aryl halide moiety (Scheme 6.2).

Scheme 6.2. Unsuccessful attempt to open a dibrominated substrate with organocuprates.

Formation of γ-lactams 6.3 likely proceeds through a mechanism akin to type 1 ring- opening of cyclopropanated oxabenzonorbornadienes (Chapter 3), with the main difference arising when the azabicyclic N-substituent is electrophilic (i.e. X=COOR), allowing for nucleophilic acyl substitution to ensue (Scheme 6.3). Initial attack of a nucleophile at the bridgehead of 6.1 causes

C-N bond cleavage and generation of intermediate 6.4, from which a bridgehead proton is removed. This leads to scission of the cyclopropane, producing carbanion 6.5. Protonation of nitrogen allows for subsequent attack of carbanion on the carbamate moiety of 6.6, with displacement of the alkoxy group (6.7) and formation of lactam, 6.3.

188

Scheme 6.3. Proposed mechanism for γ-lactam formation by type 1 ring-opening of cyclopropanated 7-azabenzonorbornadiene.

If substrates bearing electron-withdrawing groups on the cyclopropane (in place of CH2) were reacted as above, it is possible that a different mode of ring-opening may be observed. To verify this, future studies should involve cyclopropanated 7-azabenzonorbornadienes with substitution on the cyclopropane. In addition, the entity of the base participating in type 1 mechanisms is currently unknown. Deuterium labelling experiments at the bridgehead position may help in elucidating the source of this basic species.

The last few steps in the above mechanism (6.6 to 6.3) are almost identical to a cyclization documented by Gopalan and coworkers, where intramolecular attack of a carbanion on a carbamate was used to prepare hydroxamic acid derivatives (Scheme 6.4). 5,6 In their work, the carbanion stabilized by an electron-withdrawing group (EWG) was generated upon treatment by base. The conditions used for this conversion (basic solution at −78 °C in THF) mirrors those which were used in the current work. Therefore, it is not surprising that such ring-closure could follow ring-opening of both azabicycle and cyclopropane. Gopalan’s group writes that removal of the N-H proton of the carbamate destroys the electrophilicity of the carbonyl group, making it so

189

that the carbanion nuclophile cannot attack.7 Thus, once intermediate 6.4 is generated (Scheme

6.3), immediate protonation of the nitrogen must follow, which allows for attack of the methylene carbanion. This intramolecular attack should be fast and favourable according to Baldwin’s rules of 5-exo-trig approach from the corresponding Bürgi-Dunitz angle with respect to the carbonyl.

Scheme 6.4. Lactam formation by carbanion attack on carbamate by Gopalan et al.

When the reaction was repeated with N-Piv and N-Ac azabenzonorbornadienes, a mixture of products arose. It is thought that a similar nucleophilic attack of the carbanion on the carbonyl group may result in the formation of a hydroxylated intermediate, which could further undergo elimination reactions (Scheme 6.5). This is in accordance to reports from another study conducted by Gopalan’s group using N-acylated compounds (Scheme 6.6).7 Preliminary analysis of NMR spectra are inconclusive whether a similar transformation is taking place, yielding both the alcohol

6.8 and the dehydrated product 6.9.

Scheme 6.5. Possible transformations of cyclopropanated N-acyl azabenzonorbornadienes.

190

Scheme 6.6. Nucleophilic ring-closure of N-acylated aminosulfone derivatives and subsequent dehydration reported by Gopalan et al.

Alternatively, it is possible that cyclization to a lactam is not taking place with these carbonyl species, although the complexity of these reaction product mixtures did not lend itself to a facile determination of these products. In fact, in the present work, upon using nBu2CuCNLi2, the product mixture of at least two compounds was not readily separable. The close polarity between the unknown entities suggests that the compounds may possess relatively similar functional groups.

In this work the mode of formation of 6.3 contrasts previous syntheses of structurally similar γ-lactams 6.10. In 1971, Oppolzer reported a thermal rearrangement of an N-(1- benzocyclobutenyl)vinylacetamide via a proposed ring-opening of the cyclobutene ring which gives an ortho-quinodimethane intermediate 6.11 which was subsequently trapped by the irreversibility of the intramolecular cycloaddition (Scheme 6.7).8

191

Scheme 6.7. Electrocyclic ring-opening and ring-closures to afford framework 6.10.

Another method described by Koot and coworkers9 involves a conjugate addition reaction with an organocuprate reagent to furnish intermediate 6.12 at 92% yield. Deacylation of 6.12 and cationic cyclization by TiCl4 afforded the cis-tricyclic lactam 6.10a (J=6.4 Hz) in 95% yield

(Scheme 6.8).

Scheme 6.8. Synthesis of γ-lactam framework 6.10 by cuprate conjugate addition-cyclization.

Recently, several more publications have arrived at this same core framework 6.10a, possessing one more saturation in ring B (J=6.5 Hz for cis protons of tetrahydro-core)10 than in the present investigation (J=7.2 Hz and 7.3 Hz for the cis protons (4.80 and 3.35 ppm). These works have stressed the importance of organic framework 6.10a (Figure 6.1). Moore and coworkers discuss the design of a heterocyclic receptor primed for carboxylic acids, which has ideal binding geometry when a γ or δ-lactam with cis-fusion is present between rings B and C, and ring B is saturated.11 Based on our current strategy, it should be possible to prepare such ortho- arene substituted frameworks with carboxylic acid-binding capabilities.

192

Figure 6.1. Core framework lactam 6.10a used as a carboxylic acid receptor.

This cis-fused system of 6.10a is also a precursor to triazolium salts which are chiral carbene catalysts for highly efficient conjugate nucleophilic acylation, transesterification, polymerization, and benzoin condensation reactions (Scheme 6.9). 12 Ennis’ synthesis of the framework 6.10a has been a long-time chemists’ favourite starting from an α-tetralone.11, 13

However, selective reduction of the alkene in ring B of the lactams obtained in the present work could offer an improved stereoselective syntheses of 6.10a which to date only provides up to 22% of 6.10a over 6 steps. Furthermore, reduction of the carbonyl in 6.10a would produce carbocyclic versions of martinelline receptor agonists, whose total synthesis has been attracted much interest over the years.14-16

Scheme 6.9. Preparation of triazolium salt with incorporation of lactam framework 6.10a.

193

6.2.2 - Reactions using Acid Catalysts

Halogenated substrate 6.1n which produced complicated mixtures of species under cuprate-mediated reaction conditions was also briefly investigated under acid-catalysis. However, it was clear that deprotection of the N-substituent was simply occurring, as seen by the disappearance of the tBu peak, and no sign of cyclopropane opening was apparent by characteristic cyclopropane peaks visible in the corresponding 1H NMR spectra (Scheme 6.10).

Scheme 6.10. Deprotection of N-Boc substituent by attempted acid-mediated ring-opening.

A similar reaction was then repeated with the N-phenyl substrate 6.1k, as this functionality was thought to better tolerate acidic conditions, although this compound unfortunately showed no signs of reacting after an entire week (Scheme 6.11). Thus, future type 2 ring-openings of cyclopropanated azabicyclic compounds should likely consider non-acidic catalysts, such as various transition metal catalysts (e.g. palladium, platinum, etc).

Scheme 6.11. Inert behaviour of N-phenylated azabenzonorbornadiene 6.1k under acidic ring-opening conditions.

194

On closing, it is worth noting that uncyclopropanated azabenzonorbornadienes bearing N- carbamate moieties 6.13 have been shown to undergo palladium-catalyzed ring-opening with methyl-2-iodobenzoate and tandem intramolecular ring-cyclization and amidation to afford the cis-fused δ-lactam 6.14 (Scheme 6.12).17 Thus, similar palladium-catalyzed conditions should be explored with the cyclopropanated azabenzonorbornadienes in the future, as well.

Scheme 6.12. Intramolecular lactonization observed with uncyclopropanated azabenzonorbornadiene 6.13.

6.3 - Conclusion

To conclude, the present work on ring-opening reactions of cyclopropanated azabenzonorbornadienes has led to the discovery of an efficient one-pot synthesis of tri- and tetracyclic γ-lactams possessing 1,2-cis stereochemistry. The overall process allows for the formation of two new carbon-carbon bonds, and no aromatization was observed, resulting in excellent yields of lactams in up to 98% using higher-order cyanocuprates in ether. The reaction scope was sufficiently broad to tolerate primary, secondary and tertiary alkyl, as well as aromatic carbon nucleophiles, as well as various ortho-arene substituents on the azabicyclic substrates. The transformation is thought to involve an intramolecular attack of an intermediate carbanion nucleophile on the carbamate’s carbonyl moiety. Formation of γ-lactams lends indirect evidence

195

and support to the formerly proposed mechanism of type 1 ring-openings of cyclopropanated oxabenzonorbornadienes (Chapter 3), and the present transformation may provide a more direct access to polycyclic γ-lactams which could serve as heterocyclic receptors, receptor agonists, or chiral catalysts. Although type 2 and type 3 ring-openings were not yet observed, future studies involving other transition metal-catalyzed processes may effect these ring-opening modes.

6.4 - Experimental

General Information: All experiments were conducted under inert atmosphere of dry argon.

Glassware was oven-dried overnight. Column chromatography, TLC, melting point determination,

IR, NMR, and HRMS analyses were performed as described in Chapter 2.

18 Reagents: Commercial reagents, Et2O, and higher order cyanocuprate reagents were used as described in Chapter 3. Cyclopropanated 7-azabenzonorbornadienes were prepared as described in Chapter 2.

General procedure for Cu-catalyzed ring-opening reactions with higher order cyanocuprates: Using CuCN (0.41 mmol, 3 equiv.), Et2O (4-6 mL including rinses), organolithium reagent (0.83 mmol, 6 equiv.), and cyclopropanated 7-azabenzonorbornadiene 6.1

(0.14 mmol, 1 equiv.), procedures closely follow those described in Chapter 3.

196

(3aR*,9bS*)-5-Butyl-1,3,3a,9b-tetrahydro-2H-benzo[g]indol-2one, 6.3a (Table 6.1, entry 1):

-1 (30.8 mg, 92% yield). White solid; mp: 141-143 ˚C; Rf (EtOAc): 0.14; IR (ν, cm ): 3194, 2943,

1 2923, 1683, 1425, 1373; H NMR (400 MHz, CDCl3): δ 7.35-7.28 (m, 2H), 7.24-7.18 (m, 2H),

6.37 (br s 1H), 5.43 (d, J=2.8 Hz, 1H), 4.77 (d, J=7.2 Hz, 1H), 3.31 (br dd J=8.2 Hz, 7.3 Hz, 1H),

2.75 (m, 1H), 2.47-2.35 (m, 2H), 2.30 (dd, J=16.5 Hz, 3.0 Hz, 1H), 1.50 (m, 2H), 1.36 (m, 2H),

13 0.91 (t, J=7.2 Hz, 3H); C NMR (100 MHz, CDCl3): δ 176.9, 135.0, 132.7, 131.4, 128.94, 128.87,

127.7, 125.4, 123.8, 55.2, 37.9, 34.9, 32.3, 30.5, 22.6, 14.0; HRMS: Calculated for C16H19NO

[M]+: 241.1467. Found: 241.1471.

(3aR*,9bS*)-5-Ethyl-1,3,3a,9b-tetrahydro-2H-benzo[g]indol-2one, 6.3b (Table 6.1, entry 3):

-1 (20.5 mg, 90% yield). White solid; mp: 163-164 ˚C; Rf (EtOAc): 0.14; IR (ν, cm ): 3182, 3077,

1 2996, 2905, 1686, 1455, 1371; H NMR (400 MHz, CDCl3): δ 7.35-7.29 (m, 2H), 7.24-7.17 (m,

2H), 6.11 (br s 1H), 5.43 (d, J=1.2 Hz, 1H), 4.77 (d, J=7.3 Hz, 1H), 3.31 (dd J=7.9 Hz, 7.7 Hz,

1H), 2.75 (m, 1H), 2.47-2.41 (m, 2H), 2.31 (dd, J=16.5 Hz, 2.9 Hz, 1H), 1.14 (t, J=7.4 Hz, 3H);

13 C NMR (100 MHz, CDCl3): δ 176.9, 136.3, 132.7, 131.3, 129.0, 128.8, 127.7, 124.4, 123.6, 55.2,

+ 37.9, 34.9, 25.2, 12.8; HRMS: Calculated for C14H15NO [M] : 213.1154. Found: 213.1151.

197

(3aR*,9bS*)-5-Hexyl-1,3,3a,9b-tetrahydro-2H-benzo[g]indol-2one, 6.3c (Table 6.1, entry 4):

-1 (34.8 mg, 87% yield). Beige solid; mp: 147-149 ˚C; Rf (EtOAc): 0.15; IR (ν, cm ): 3433, 3201,

1 2928, 2859, 1690, 1454, 1377; H NMR (400 MHz, CDCl3): δ 7.37-7.32 (m, 2H), 7.26-7.22 (m,

2H), 6.46 (br s 1H), 5.47 (d, J=2.8 Hz, 1H), 4.80 (d, J=7.3 Hz, 1H), 3.34 (br dd J=7.7 Hz, 7.7 Hz,

1H), 2.78 (m, 1H), 2.51-2.38 (m, 2H), 2.34 (dd, J=16.4 Hz, 3.1 Hz, 1H), 1.58-1.51 (m, 2H), 1.42-

13 1.30 (m, 6H), 0.90 (t, J=6.8 Hz, 3H); C NMR (100 MHz, CDCl3): δ 176.9, 135.1, 132.7, 131.5,

128.89, 128.86, 127.7, 125.4, 123.8, 55.2, 37.9, 34.9, 32.6, 31.7, 29.3, 28.3, 22.7, 14.1; HRMS:

+ Calculated for C18H23NO [M] : 269.1780. Found: 269.1785.

(3aR*,9bS*)-5-Methyl-1,3,3a,9b-tetrahydro-2H-benzo[g]indol-2one, 6.3d (Table 6.1, entry

-1 7): (17.0 mg, 75% yield). White solid; dec 152 ˚C; Rf (EtOAc): 0.13; IR (ν, cm ): 3161, 3065,

1 1695, 1493, 1440, 1373; H NMR (300 MHz, CDCl3): δ 7.30-7.06 (m, 4H), 6.12 (br s 1H), 5.40

(d, J=1.2 Hz, 1H), 4.74 (d, J=7.3 Hz, 1H), 3.27 (dd J=7.9 Hz, 7.7 Hz, 1H), 2.71 (m, 1H), 2.29 (dd,

13 J=16.5 Hz, 2.9 Hz, 1H), 2.00 (s, 3H); C NMR (75 MHz, CDCl3): δ 176.8, 133.3, 130.9, 130.8,

+ 129.0, 128.5, 127.8, 126.3, 123.9, 55.2, 37.7, 34.9, 19.3; HRMS: Calculated for C13H13NO [M] :

199.0997. Found: 199.0995.

198

(3aR*,9bS*)-5-isoPropyl-1,3,3a,9b-tetrahydro-2H-benzo[g]indol-2one, 6.3e (Table 6.1, entry

-1 8): (19.8 mg, 73% yield). White solid; mp: 146-148 ˚C; Rf (EtOAc): 0.17; IR (ν, cm ): 3173, 3070,

1 2958, 1689, 1493, 1452, 1369; H NMR (400 MHz, CDCl3): δ 7.39 (d, J=7.7 Hz, 1H), 7.35-7.31

(m, 1H), 7.22-7.16 (m, 2H), 5.70 (br s 1H), 5.43 (d, J=2.9 Hz, 1H), 4.77 (d, J=7.2 Hz, 1H), 3.31

(dd J=8.2 Hz, 7.3 Hz, 1H), 2.95-2.89 (m, 1H), 2.79-2.73 (m, 1H), 2.30 (dd, J=16.5 Hz, 3.0 Hz,

13 1H), 1.16 (d, J=6.7 Hz, 3H), 1.11 (d, J=6.7 Hz, 3H); C NMR (100 MHz, CDCl3): δ 176.8, 140.9,

132.5, 131.5, 129.1, 129.0, 127.5, 123.6, 122.3, 55.1, 38.0, 34.9, 28.0, 22.4, 22.0; HRMS:

+ Calculated for C15H17NO [M] : 227.1310. Found: 227.1315.

(3aR*,9bS*)-5-tert-Butyl-1,3,3a,9b-tetrahydro-2H-benzo[g]indol-2one, 6.3f (Table 6.1, entry

-1 11): (20.6 mg, 69% yield). White solid; mp: 156-158 ˚C; Rf (EtOAc): 0.15; IR (ν, cm ): 3214,

1 3073, 2958, 2905, 1691, 1488, 1367; H NMR (400 MHz, CDCl3): δ 7.72 (d, J= 8.0 Hz, 1H), 7.32-

7.27 (m, 1H), 7.18 (d, J= 4.2 Hz, 2H), 5.92 (br s 1H), 5.55 (d, J=2.8 Hz, 1H), 4.68 (d, J=7.0 Hz,

1H), 3.25 (dd J=7.6 Hz, 7.6 Hz, 1H), 2.76 (m, 1H), 2.31 (dd, J=16.4 Hz, 2.4 Hz, 1H), 1.32 (s, 9H);

199

13 C NMR (100 MHz, CDCl3): δ 176.8, 143.0, 132.4, 132.3, 129.7, 128.2, 127.2, 127.0, 124.8, 55.5,

+ 38.3, 35.1, 35.0, 30.9; HRMS: Calculated for C16H19NO [M] : 241.1467. Found: 241.1461.

(3aR*,9bS*)-5-Phenyl-1,3,3a,9b-tetrahydro-2H-benzo[g]indol-2one, 6.3g (Table 6.1, entry

-1 12): (19.2 mg, 62% yield). Beige solid; mp: dec 175 ˚C; Rf (EtOAc): 0.14; IR (ν, cm ) 3289, 2915,

1 1683, 1670, 1292, 1262; H NMR (300 MHz, CDCl3): δ 7.38-7.19 (m, 8H), 7.03 (d, J=1.4 Hz,

1H), 6.39 (br s 1H), 5.60 (d, J=3.0 Hz, 1H), 4.87 (d, J=7.3 Hz, 1H), 3.50-3.43 (m, 1H), 2.87-2.78

13 (m, 1H), 2.39 (dd, J=16.5 Hz, 3.2 Hz, 1H); C NMR (75 MHz, CDCl3): δ 176.7, 139.6, 138.6,

132.7, 131.3, 128.9, 128.4, 128.2, 127.5, 126.5, 55.2, 37.6, 35.3; HRMS: Calculated for C18H15NO

[M]+: 261.1154. Found: 261.1161.

(3aR*,9bS*)-5-Butyl-7,8-dimethyl-1,3,3a,9b-tetrahydro-2H-benzo[g]indol-2one, 6.3h (Table

-1 6.2, entry 2): (18.1 mg, 87% yield); beige solid; mp: 164-165 ˚C; Rf (EtOAc): 0.24; IR (ν, cm ):

1 3165, 3078, 2963, 2923, 2860, 1693, 1505, 1470, 1372, 790; H NMR (400 MHz, CDCl3): δ 7.11

(s, 1H), 6.94 (s, 1H), 5.56 (br s, 1H), 5.36 (d, J=2.4 Hz, 1H), 4.70 (d, J=7.1 Hz, 1H), 3.29 (br dd

J=7.6 Hz, 7.5 Hz, 1H), 2.76 (m, 1H), 2.45-2.39 (m, 2H), 2.38 (dd, J=16.4 Hz, 2.6 Hz, 1H), 2.27

200

(s, 3H), 2.25 (s, 3H), 1.53 (m, 2H), 1.49 (m, 2H), 0.94 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz,

CDCl3): δ 176.6, 137.1, 136.0, 135.0, 130.4, 130.3, 128.7, 125.2, 124.6, 55.0, 38.0, 35.1, 32.2,

+ 30.5, 22.6, 19.9, 19.4, 14.0; HRMS: Calculated for C18H23NO [M] : 269.1780. Found: 269.1785.

(3aR*,9bS*)-5-Butyl-7,8-dimethoxy-1,3,3a,9b-tetrahydro-2H-benzo[g]indol-2one, 6.3i

- (Table 6.2, entry 3): (13.3 mg, 68% yield); white solid; dec 188 ˚C; Rf (EtOAc): 0.09; IR (ν, cm

1 1 ): 3174, 3075, 2950, 2927, 2865, 2834, 1678, 1518, 1231, 1181, 879; H NMR (400 MHz, CDCl3):

δ 6.87 (s, 1H), 6.72 (s, 1H), 5.88 (br s, 1H), 5.34 (d, J=3.8 Hz, 1H), 4.71 (d, J=7.3 Hz, 1H), 3.90

(s, 3H), 3.89 (s, 3H), 3.32 (br dd J=7.6 Hz, 7.5 Hz, 1H), 2.76 (m, 1H), 2.44-2.36 (m, 2H), 2.31

(dd, J=12.6 Hz, 3.0 Hz, 1H), 1.55-1.50 (m, 2H), 1.48-1.37 (m, 2H), 0.93 (t, J=7.2 Hz, 3H); 13C

NMR (100 MHz, CDCl3): δ 176.7, 148.9, 148.1, 134.6, 126.0, 124.0, 123.7, 112.1, 107.7, 56.1,

+ 55.2, 37.9, 35.2, 32.4, 30.5, 22.6, 14.0; HRMS: Calculated for C18H23NO3 [M] : 301.1678. Found:

301.1671.

(3aR*,11bS*)-5-Butyl-1,3,3a,11b-tetrahydro-2H-naphtho[2,3-g]indol-2-one, 6.3j (Table 6.2,

-1 entry 4): (20.1 mg, 98% yield); white solid; dec 167 ˚C; Rf (EtOAc): 0.19; IR (ν, cm ): 3200,

201

2956, 2922, 1674, 1501, 1426, 1365, 1303, 1254, 1207, 1125, 965, 758, 735; 1H NMR (400 MHz,

CDCl3): δ 7.83-7.78 (m, 1H), 7.76 (s, 2H), 7.63 (s, 1H), 7.49-7.43 (m, 2H), 6.00 (br s, 1H), 5.52

(d, J=1.8 Hz, 1H), 4.90 (d, J=6.6 Hz, 1H), 3.35 (br dd, J=7.6 Hz, 7.6 Hz, 1H), 2.80 (m, 1H), 2.64-

2.47 (m, 2H), 2.33 (dd, J=16.4 Hz, 2.5 Hz, 1H), 1.64-1.56 (m, 2H), 1.47-1.41 (m, 2H), 0.96 (t,

13 J=7.3 Hz, 3H); C NMR (100 MHz, CDCl3): δ 176.6, 135.4, 133.8, 132.5, 130.3, 130.1, 128.2,

127.4, 126.6, 126.3, 126.2, 122.7, 55.6, 38.2, 35.2, 32.4, 30.5, 22.7, 14.1; HRMS: Calculated for

+ C20H21NO [M] : 291.1623. Found: 291.1620.

(3aR*,9bS*)-5-Butyl-1,3,3a,9b-tetrahydro-2H-benzo[g]indol-2one, 6.3a (Table 6.2, entry 6):

(26.3 mg, 87 % yield). The characterization data for this compound was identical to that of compound 6.3a.

(3aR*,9bS*)-5-Butyl-1,3,3a,9b-tetrahydro-2H-benzo[g]indol-2one, 6.3a (Table 6.2, entry 7):

(27.2 mg, 86 % yield). The characterization data for this compound was identical to that of compound 6.3a.

202

6.5 References

1 Michigan State University; The Nature of Vibrational Spectroscopy; https://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/Spectrpy/InfraRed/irspec1.htm; accessed December 23, 2015.

2 (a) Long, Y.; Wang, W.; Yang, D.; Jiang, H.; Chen, K.; Fang, Y. Mol. Divers. 2014, 18, 101. (b)

Yang, D.; Long, Y.; Wu, Y.; Zuo, X.; Tu, Q.; Fang, S.; Jiang, L.; Wang, S.; Li, C. Organometallics

2010, 29, 5936.

3 Manderville, W.H.; Whitesides, G.M. J. Org. Chem. 1974, 39, 400.

4 Jiang, Z.-Y.; Zhang, C.-H.; Gu, F.-L.; Yang, K.-F.; Lai, G.-Q.; Xu. L.-W.; Xia, C.-G. Synlett

2010, 8, 1251.

5 Liu, Y.; Jacobs, H.K.; Gopalan, A.S. J. Org. Chem. 2009, 74, 782.

6 Liu, Y.; Jacobs, H.K.; Gopalan, A.S. Tetrahedron 2011, 67, 2206.

7 Hernandez, N.M.; Sedano, M.J.; Jacobs, H.K.; Gopalan, A.S. Tetrahedron Lett. 2003, 44, 4035.

8 Oppolzer, W. J. Am. Chem. Soc. 1971, 93, 3834.

9 Koot, W.-J.; Hiemstra, H.; Speckamp, W.N. Tetrahedron Lett. 1992, 33, 7969.

10 Nieman, J.A.; Ennis, M.D. Org. Lett. 2000, 2, 1395.

11 Moore, G.; Papamicaël, C.; Levacher, V.; Bourguignon, J.; Dupas, G. Tetrahedron 2004, 60,

4197.

12 Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem. Int. Ed. 2006, 45, 1463.

13 Ennis, M.D.; Hoffman, R.L.; Ghazal, N.B.; Old, D.W.; Mooney, P.A. J. Org. Chem. 1996, 61,

5813.

203

14 Powell, D.A.; Batey, R.A. Org. Lett. 2002, 4, 2913.

15 Xia, C.; Heng, L.; Ma, D. Tetrahedron Lett. 2002, 43, 9405.

16 Ikeda, S.; Shibuya, M.; Iwabuchi, Y. Chem. Commun. 2007, 5, 504.

17 Huang, K.-L.; Guo, C.; Cheng, L.-J.; Xie, L.-G.; Zhou, Q.-L.; Xu, X.-H.; Zhu, S.-F. Adv.

Synth. Catal. 2013, 355, 2833.

18 (a) Lipshutz, B.H.; Wilhelm, R.S.; Kozlowski, J.A.; Parker, D. J. Org. Chem. 1984, 49, 3922.

(b) Lipshutz, B.H.; Wilhelm, R.S.; Kozlowski, J.A. J. Org. Chem. 1984, 49, 3938.

204

Chapter 7: Intramolecular Ring-opening Reactions of Cyclopropanated

Oxabenzonorbornadienes

205

Chapter 7: Intramolecular Ring-Opening Reactions of Cyclopropanated

Oxabenzonorbornadienes

7.1 - Introduction

One final and integral piece of work for the series of ring-opening studies invokes intramolecular ring-opening reactions. In the past, our group has examined intramolecular reactions of norbornadiene-tethered nitrones and nitrile oxides,1-4 although intramolecular ring- opening reactions of heterobicycloalkenes had not been pursued. Probably the closest literature occurrences to these are Lautens’ intramolecular ring-opening reactions by organometallic nucleophiles on [3.2.1] oxabicyclic systems (Scheme 7.1, a, b)5 and that of an alcohol nucleophile on a [2.2.1] oxabenzonorbornadiene under rhodium-catalyzed conditions (Scheme 7.1, c).6

Scheme 7.1. Intramolecular ring-opening reactions of tethered oxabicycloalkenes.

206

In the third example (c), if a chiral phosphine is present only one enantiomer of racemic

7.1 is capable of undergoing cyclization to 7.2 since the complementary enantiomer cannot cyclize.

If an external nucleophile (i.e. a secondary amine) is added, then intermolecular ring-opening was found to proceed, forming 7.3.

In the present work, the realization that the ester moiety of 7.4 could be readily converted to oxygen-based nucleophiles successful in acid-mediated type 2 and type 3 ring-openings (7.5 and 7.6; Chapters 4 and 5) opened the door to intramolecular investigations. It was also conceived that conversion to a halide (e.g. X=Br) could lead to carbon-based intramolecular nucleophiles, similar to those of type 1 ring-openings (Scheme 7.2).

Scheme 7.2. Envisioned transformation of 7.4 to derivatives bearing tethered nucleophiles.

7.2 - Results and Discussion

To begin, functional group interconversions of cyclopropane 7.4 were carried out to obtain carboxylic acid 7.5 (by saponification) and primary alcohol 7.6 (by reduction; Scheme 7.3).

Formation of an intramolecular type 3 product seemed especially favourable, as attack of the tethered oxygen nucleophile would lead to cyclization of a 6-membered ring (Scheme 7.4, path a), as opposed to cyclization of a 7-membered ring (path b) expected from type 2 opening.

207

Scheme 7.3. Functional group interconversions of ethyl ester-tethered substrate 7.4.

Scheme 7.4. Predicted reactivity preference for type 3 over type 2 ring-opening.

As expected, the reaction of 7.5 afforded δ-lactone 7.7 as the major product in 78% yield, with evident dehydration as determined by 1H NMR, JMOD, HSQC, and HMBC, as well as IR data.

The intense band at 1733 cm-1 for a C=O group in a 6-membered lactone and the absence of a broad O-H stretching band were particularly good indicators of this. A second minor product (7.8) was found in ~15% yield which, by TLC, showed similar features as previously observed type 2 ring-opening products (i.e. type 2 products generally stain white under para-anisaldehyde, while

3 products stain dark blue). Thus, it appeared that the tether was sufficiently flexible and capable of attacking at either the internal or external cyclopropane carbon (labelled “6” or “7” in Scheme

208

7.4), with preferential attack at the “7” position both at 90 ˚C or 40 ˚C. Dehydration appears to have occurred with anti removal of hydrogen from carbon “6” (rather than from carbon “4”) in the case of type 2 product 7.8, as it produces the more stable naphthalene core, whereas in type 3 product 7.7 it was not possible to remove a proton from carbon “6” since this proton is positioned cis with respect to the departing hydroxyl group, forcing deprotonation at carbon “4”.

Scheme 7.5. First observation of intramolecular type 3 and type 2 ring-openings by tethered carboxylic acid nucleophile.

For alcohol 7.6, the reaction temperature was reduced to 40 ˚C to mimic the optimized conditions for type 3 ring-opening with alcohol nucleophiles. Once again, two products were observed (one staining white by para-anisaldehyde, the other staining blue), and these were determined to be compounds 7.9 and 7.10 (Scheme 7.6). The structural assignments were again supported by 1H, JMOD, HSQC and HMBC, data, while dehydration was evident by the absence of a prominent O-H stretch in their IR spectra, and supported by HRMS. The ratios of type 2 to type 3 product this time were, however, approximately 1:1. The reason for this difference in product distribution is yet unclear.

209

Scheme 7.6. Intramolecular type 2 and type 3 ring-openings by tethered alcohol-containing substrate.

Reduction of the readily available 7.11 afforded alcohol 7.12 with a two atom tether

(Scheme 7.7) which, as expected, was too short to attack intramolecularly (refer to Chapter 5,

Scheme 5.15 for results of this attempt). Synthesis of substrates with longer hetero-tethers (e.g. by reacting 7.12 with silyl-protected haloalcohols which could be removed by non-acidic conditions) should be further considered in future work.

Scheme 7.7. Preparation of 2-atom tethered substrate for intramolecular ring-opening consideration.

Thus far, the successful intramolecular ring-openings demonstrate a method to generate seven-membered rings fused into polycyclic systems in two different ways: the type 3 reaction generates an alicyclic seven-membered ring B via ring-expansion of substrate, whereas the type 2

210

reaction generates a seven-membered ring C’ utilizing the tether as a major portion of the imminent seven-membered ring (Figure 7.1). These examples serve as a proof-of-concept, and it would be of interest in future works to utilize other X nucleophiles (such as nitrogen or carbon nucleophiles) to arrive at similar polycyclic fused systems.

Figure 7.1. Fused polycyclic systems arising from intramolecular ring-openings of this work.

The mechanism of these conversions closely parallels those described in Chapter 5.

Drawing from evidence of spontaneous ring-expansion (Scheme 5.16), it is likely that the seven- membered cyclic framework of products 7.7 and 7.9 is formed by C-C bond cleavage (7.14;

Scheme 7.8) prior to nucleophilic attack (7.15). As noted, anti dehydration limits removal of a proton to occur from the exocyclic position with respect to the seven-membered ring.

Scheme 7.8. Proposed mechanism of intramolecular type 3 ring-openings.

211

7.3 - Conclusion

In conclusion, the first intramolecular reactions of C1-tethered cyclopropanated oxabenzonorbornadienes were discovered. Tethers of chain length 2-4 bearing oxygen nucleophiles in the form of alcohols or carboxylic acids were tested, resulting in successful conversion of the four-atom tethered substrates to benzene-fused tricyclic frameworks containing six- and seven-membered rings. Further investigations of intramolecular ring-openings with different tether lengths or nucleophilic atoms should be considered in future works, with potential application toward efficient syntheses of biologically active polycyclic frameworks.

7.4 – Experimental

General Information: Commercial reagents were used without further purification.

Cyclopropanated oxabenzonorbornadiene was prepared as previously reported.7 Solvent (THF,

DCE, DMF) was obtained from an LC-SPS solvent purification system supplied with dry packed columns containing 3 Å molecular sieves. Column chromatography, TLC, melting point determination, IR, NMR, and HRMS analyses were performed as described in Chapter 2.

Procedure for Saponification: Substrate 7.4 (50.1 mg, 0.194 mmol) was added to a vial with stir bar. 25% Aqueous NaOH solution was supplied, the vial was capped, and the reaction was stirred at 90 ˚C overnight. Upon completion of the reaction, the NaOH was quenched with an acid (dil.

HCl or AcOH with cooling) and the aqueous layer was extracted with EtOAc (3 × 10 mL), dried over MgSO4, filtered, and concentrated in vacuo.

Procedure for Hydride Reduction: Substrate 7.4 (237.7 mg, 0.9207 mmol) or 7.12 (204.1 mg,

1.01 mmol) was dissolved in THF under argon and was transferred by cannula into a dry vial

212

containing a stir bar, lithium aluminum hydride, and THF at 0 ˚C with stirring. The reaction was warmed to 90 ˚C with continued stirring and left overnight to react. Upon consumption of 7.4, the reaction was quenched with saturated NaHCO3, extracted with CH2Cl2 (3 × 10 mL), dried over

MgSO4, filtered, and concentrated in vacuo.

Acid-catalyzed ring-opening of cyclopropanated oxabenzonorbornadiene with alcohol nucleophiles: Procedures closely follow those described in Chapters 4 and 5.

exo-Cyclopropanated oxabenzonorbornadiene 7.5 (Scheme 7.3) Yield = 164.2 g (66 %); white

-1 solid; Rf = 0.31 (1:1 EtOAc: hexanes); m.p.= 124-125 ˚C. FTIR (ν, cm ): 3047-2630, 3001, 1702,

1 1441, 1345, 1320, 1060, 908; H NMR (400 MHz, CDCl3): δ 11.79 (br s, 1H) 7.32-7.17 (m, 4H),

5.09 (s, 1H), 2.77-2.56 (m, 4H), 1.61-1.58 (m, 1H), 1.37-1.32 (m, 1H), 1.17-1.13 (m, 1H), 0.98-

13 0.94 (m, 1H); C NMR (100 MHz, CDCl3): δ 180.0, 148.7, 148.5, 126.1, 126.0, 119.3, 118.2, 86.4,

+ 77.6, 29.4, 24.9, 22.6, 22.3, 14.8; HRMS: Calculated for C14H15O3 [M+H] : 231.1021. Found:

+ 231.1025; Calculated for C14H14O3Na [M+Na] : 253.0841; found: 253.0846.

213

exo-cyclopropanated oxabenzonorbornadiene 7.6 (Scheme 7.3) Yield = 147.8 mg (74 %);

-1 yellow oil; Rf = 0.47 (EtOAc); FTIR (ν, cm ): 3386, 3046, 3000, 2947, 2873, 1456, 1052, 921,

1 906; H NMR (400 MHz, CDCl3): δ 7.30-7.28 (m, 1H), 7.24-7.22 (m, 1H), 7.16-7.14 (m, 2H),

5.07 (s, 1H), 3.70 (t, J= 6.2 Hz, 2H), 2.59 (m=br s, 1H), 2.30 (t, J=7.76 Hz, 1H), 1.88 (m, 2H),

13 1.58 (m, 1H), 1.32 (m, 1H), 1.13 (m, 1H), 0.93 (m, 1H); C NMR (100 MHz, CDCl3): δ 149.2,

148.5, 125.9, 125.8, 119.3, 118.4, 87.3, 77.6, 63.0, 27.8, 26.8, 22.7, 22.4, 14.7; HRMS: Calculated

+ for C14H16O2 [M] : 216.1150; found: 216.1155.

Tricyclic δ-lactone 7.7 (Scheme 7.5): 32.1 mg (78%). clear oil; Rf (1:1 EtOAc: Hexanes): 0.59;

FTIR (ν, cm-1): 3056, 3021, 1733, 1670, 1484, 1428, 1390, 1338, 1212, 1061, 1018; 1H NMR (400

MHz, CDCl3): δ 7.32-7.28 (m, 2H), 7.26-7.24 (m, 1H), 7.18-7.15 (m, 1H), 6.47 (br d, J=10.5 Hz,

1H), 5.97 (t, J = 4.1 Hz, 1H), 5.87-5.82 (m, 1H), 5.29-5.26 (m, 1H), 3.24-3.22 (m, 2H), 2.89-2.86

13 (m, 1H), 2.73-2.65 (m, 1H); C NMR (100 MHz, CDCl3): δ 169.7, 140.8, 135.1, 133.9, 131.3,

+ 131.1, 128.4, 128.1, 127.9, 125.4, 119.8, 81.0, 35.7, 30.7; HRMS: Calculated for C14H12O2 [M] :

212.0837; found 212.0831.

Tricyclic ε-lactone 7.8 (Scheme 7.5): 8.7 mg (21%); white solid; Rf (1:1 EtOAc: Hexanes): 0.44; mp = 256-258 ˚C; FTIR (ν, cm-1): 3064, 3045, 2972, 2900, 1730, 1353, 1303, 1223, 1159, 798; 1H

NMR (400 MHz, CDCl3): δ 8.09 (d, J=8.0 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.0 Hz,

1H), 7.57-7.54 (m, 1H), 7.51-7.47 (m, 1H), 7.38 (d, J=8.0 Hz, 1H), 5.37 (br s, 2H), 3.45 (m, 2H),

13 2.74 (m, 2H); C NMR (100 MHz, CDCl3): δ 173.1, 137.7, 134.0, 131.9, 130.4, 128.9, 128.5,

214

+ 127.2, 126.8, 126.2, 123.6, 67.2, 35.9, 25.7. HRMS: Calculated for C14H12O2 [M] : 212.0837; found: 212.0831.

Tricyclic ether 7.9 (Scheme 7.6): (7.6 mg, 34% yield); clear oil; Rf (1:9 EtOAc: Hexanes): 0.49;

FTIR (ν, cm-1): 3057, 3020, 2957, 2903, 2832, 1649, 1485, 1445, 1428, 1274, 1208, 1091, 1046;

1 H NMR (400 MHz, CDCl3): δ 7.31-7.21 (m, 3H), 7.13-7.11 (m, 1H), 6.46 (d, J=11.6 Hz, 1H),

5.96 (m, 1H), 5.89 (m, 1H), 4.72 (m, 1H), 4.07 (m, 1H), 3.81 (m, 1H), 2.79-2.72 (m, 1H), 2.62-

13 2.56 (m, 1H), 2.42-2.29 (m, 2H); C NMR (100 MHz, CDCl3): δ 142.0, 138.6, 135.1, 131.0, 130.1,

+ 128.6, 127.8, 127.4, 127.3, 123.1, 77.7, 61.1, 34.5, 25.9; HRMS: Calculated for C14H14O [M] :

198.1045; found: 198.1041.

Tricyclic ether 7.10 (Scheme 7.6): (7.1 mg, 32% yield); white solid; Rf (1:9 EtOAc: Hexanes):

0.37; m.p.= 107-108 ˚C. FTIR (ν, cm-1) 3051, 2941, 2843, 1512, 1462, 1390, 1263, 1104, 1038,

1 815; H NMR (400 MHz, CDCl3): δ 8.16 (br d, J=8.4 Hz, 1H), 7.85 (m, 1H), 7.68 (br d, J=8.4 Hz,

1H), 7.54-7.50 (m, 1H), 7.48-7.44 (m, 1H), 7.32 (d, J=8.4 Hz, 1H), 4.88 (s, 2H), 4.14 (m, 2H),

13 3.50 (m, 2H), 1.95 (m, 2H); C NMR (100 MHz, CDCl3): δ 138.5, 137.4, 133.4, 131.7, 128.8,

+ 127.1, 126.3, 126.0, 125.3, 123.6, 74.9, 74.6, 29.2, 27.4; HRMS: Calculated for C14H14O [M] :

198.1045; found: 198.1049.

215

exo-cyclopropanated oxabenzonorbornadiene 7.12 (Scheme 7.7): 155.7 mg (84%) White solid;

1 H NMR (400 MHz, CDCl3): δ 7.28 (m, 2H), 7.15 (m, 2H), 5.10 (s, 1H), 4.35 (br d, J= 12.6 Hz,

1H), 4.26 (br d, J=12.6 Hz), 1.90 (br s, 1H), 1.61 (m, 1H), 1.34 (m, 1H), 1.15 (m, 1H), 0.93 (m,

13 1H); C NMR (100 MHz, CDCl3): δ 148.6, 146.9, 126.2, 126.1, 119.4, 118.8, 88.1, 77.8, 61.4,

22.1, 20.8, 14.4; Spectral data were consistent with that previously reported.8

7.5 - References

1 Tranmer, G.K.; Tam, W. J. Org. Chem. 2001, 66, 5113.

2 Yip, C.; Handerson, S.; Tranmer, G.; Tam, W. J. Org. Chem. 2001, 66, 276.

3 Tranmer, G.K.; Keech, P.; Tam, W. Chem. Commun. 2000, 863.

4 Yip, C.; Handerson, S.; Jordan, R.; Tam, W. Org. Lett. 1999, 1, 791.

5 Lautens, M.; Kumanovic, S. J. Am. Chem. Soc. 1995, 117, 1954.

6 Webster, R.; Bӧing, C.; Lautens, M. J. Am. Chem. Soc. 2009, 131, 444.

7 Carlson, E.; Duret, G.; Blanchard, N.; Tam, W. Synth. Commun. 2016, 46, 55.

8 McKee, M.; Haner, J.; Carlson, E.; Tam, W. Synthesis 2014, 46, 1518.

216

Chapter 8: Prospective

217

8.1 - Introduction

The present work has demonstrated several versatile approaches to the making and breaking of strained polycyclic systems, with the synthesis of more than 40 novel cyclopropanes and well over 50 different ring-opened products obtained through unprecedented routes. Scheme

8.1 summarizes the general scope of reactions investigated in this research:

Scheme 8.1. Summary of general conversions observed in this work.

218

In Chapter 1, heterobicylic alkenes were prepared while new 2-substituted heterocycles and their [4+2] cycloadducts were explored. Chapter 2 described cyclopropanations of these alkenes by palladium-catalyzed decomposition of diazomethane. In Chapters 3-5, three types of ring-opening of cyclopropanated oxabenzonorbornadiene were presented, as observed experimentally. With type 1 ring-opening reactions (Chapter 3), the 2-methylnaphthalen-1-ol products could be lost to aromatization, although the use of C2-substituted substrates permitted stereochemical preservation by inhibiting dehydration. Both type 2 and type 3 ring-opening reactions (Chapters 4 and 5) were observed under acid-catalyzed thermal conditions, where type 2 ring-openings proceeded well in the presence of alcohol and carboxylic acid nucleophiles, as well as halide nucleophiles. Type 3 ring-openings afforded ring-expanded products with incorporation of two equivalents of external nucleophile. Research in this area is still in its infancy, and mechanistic work should be continued. Intramolecular reactions (Chapter 7) could more easily permit a wide variety of tethered nucleophilic atoms to attack in a controlled type 3 fashion.

Chapter 6 summarized the findings made with ring-opening reactions of cyclopropanated azabenzonorbornadienes. Discovery of intramolecular cyclizations to afford lactams shed light on the mechanism of type 1 ring-opening reactions, formerly proposed with oxa-compounds. In addition to some suggestions that were already put forth in earlier chapters and in this introduction, some long-term research ideas will be given below.

8.2 – Future Work

The effect of substitution on the cyclopropane ring should be further investigated. This thesis has considered two examples of C2-substituted oxabenzonorbornadienes (one electron-

219

donating, and one electron-withdrawing group). Peterson has looked at studies involving various

3-substituted furans which may have utility in the creation of other C2-substituted oxabicyclic alkenes to be cyclopropanated. Alternatively, having substituents on the external carbon of the cyclopropane may steer the direction of ring-opening to favour one product over another. For instance, the geminal dimethyl effect or other effects could influence the efficiency of intramolecular ring-closures (Scheme 8.2). Thus far, only dihalogenated cyclopropanes1,2 and carbonylated cyclopropanes1,3 have been considered by our group. Although preparation may be non-trivial, other carbene cyclopropanations could allow for the synthesis of substituted cylcopropanes which should lead to interesting research projects.4

Scheme 8.2. Possible influences of substituted cyclopropanes on intramolecular cyclizations.

On this topic, it is worth noting that heterocyclic building blocks may be arrived at through other methods not described in Chapter 1 of this thesis. For instance, during the course of the present study, a novel C1, C2, and C3- trisubstituted oxabenzonorbornadiene was prepared by exploring a furan synthesis described by Liang’s group (Scheme 8.3).5

220

Scheme 8.3. Experimental [3+2] approach to construct a trisubstituted furan which was successfully transformed into a novel oxabenzonorbornadiene in this research.

Diverging slightly, thiiranation6 of oxabenzonorbornadiene was reported in the literature just last year (Scheme 8.4). If aziridination7 or epoxidation8-10 which are known for bicyclic alkenes

(Scheme 8.5) could be similarly performed on heterobenzonorbornadienes in place of cyclopropanation, it would be interesting to observe whether or not similar frameworks differing only in heteroatomic functionalities should arise,11 to provide new syntheses of structures such as

Rotigotine, an antiparkinsonian treatment (Scheme 8.6). 12 Kristensen’s group reports copper- catalyzed ring-openings of aziridines,13 which may show similarities to the copper-catalyzed ring- opening in this work. It is likely that the reactivity towards ring-opening is altered in the presence of a thiirane, epoxide, or aziridine, which may be interesting to pursue.

Scheme 8.4. Thiiranation of oxabenzonorbornadiene by Arisawa and coworkers.

221

Scheme 8.5. Examples of known hetero [2+1] cycloadditions on bicyclic alkenes.

Scheme 8.6. Current (top) and possible novel (bottom) route to prepare Rotigotine.

Chapter 3 suggests that other transition metal-based reagents such as organozirconium and organocerium compounds could offer viable options as nucleophiles in ring-opening. Screening of various other transition metal-based reagents such as palladium or platinum, and possibly cerium, zirconium, or even iridium, molybdenum, or rhodium may allow for the use of amine-based nucleophiles, as well as other heteroatom nucleophiles, in future ring-opening studies.14

222

It would also be desirable if the ring-openings could be made asymmetric. This would enhance the practical appeal of such reactions toward pharmaceutical applications. Use of chiral catalysts is one such approach, and use of chiral substrates is another possibility (Scheme 8.7).15

Scheme 8.7. Possible cyclopropanation of known chiral oxabenzonorbornadiene.

Another direction of this work is to expand the reaction scope to include hetarene-fused heterobicycloalkenes.16,17 Hetarenes were only briefly touched on in this thesis (Chapter 2), in the form of 2-pyridine-fused oxanorbornadiene. 3-pyridine-fused oxanorbornadiene is also a common substrate, as are many others.18 Although some of these are unstable compounds depending on the positioning of the heteroatom,19 many more interesting studies could stem from new sites of heteroatom incorporation into the substrate, which may affect binding properties to catalysts, as well as electronic properties such as overall electrophilicity of the substrate.

Finally, expansion to include other [2.2.1] bicyclic frameworks would be of value.

Although ring-openings of the cyclopropanated 2,3-diazabicycloalkenes were not pursued in this work due to their synthetically nonsuggestive mode of opening, this path of research should not be ignored. Comparison to known ring-opening modes of the uncyclopropanated parent compound could help promote this work in future studies.20

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8.3 – Conclusion

It is clear that much is yet to be discovered through the research of cyclopropanated heterobicycloalkenes. Future work on C2-substituted pyrroles could further broaden the scope of chemistry in this area, allowing for regiochemical information to be gained with azabicyclic compounds. More examples of substituted cyclopropanes should be considered, as well as methods to allow for the use of amine or phosphine-based nucleophiles, as well as asymmetric ring-opening reactions. A broader class of substrates could also be investigated, including those containing a larger number of heteroatoms in the framework to increase ring strain or introduce new binding properties of the molecule.

8.4 – Experimental

General Information: Commercial reagents were used without further purification. Solvent

(DCM and THF) was obtained from an LC-SPS solvent purification system supplied with dry packed columns containing 3 Å molecular sieves. Column chromatography, TLC, melting point determination, IR, NMR, and HRMS analyses were performed as described in Chapter 2.

Procedure for the preparation of 8.1: To a stirred solution of 2-bromoacetophenone (5 mmol) in 30 mL of dichloromethane (DCM), 1,4-diazabicyclo[2.2.2]octane (DABCO; 0.4 mmol) was added, and this was stirred at room temperature for 30 minutes. Anhydrous potassium carbonate

(5 mmol) was then added, followed by dimethylacetylenedicarboxylate (DMAD; 2 mmol) with continuous stirring for 16 hours. Water (50 mL) was added to quench and the crude reaction mixture was extracted with DCM (3× 50 mL). The combined organic layer was washed with brine

224

and dried over MgSO4, concentrated in vacuo and purified by chromatography (1:4 ethyl acetate:hexanes mixture).

Procedure for the preparation of 8.2: To a stirred solution of 8.1 (1.2 mmol) and anthranilic acid

(0.77 mmol) in THF (5 mL) brought to reflux, isopentyl nitrite (0.77 mmol) was added dropwise by syringe over 5-10 minutes. The solution was allowed to stir for another 4 hours at reflux while it darkened to an orange brown colour. The reaction was quenched with water (10 mL), extracted with ether (3×10 mL), and the combined organic layer was dried over MgSO4, concentrated in vacuo and purified by chromatography (ethyl acetate/hexanes mixture).

3,4-Di(methoxycarbonyl)-2-phenylfuran, 8.1 (Scheme 8.3): (302 mg, 58 % yield). Yellow solid; mp: 35-

-1 36 ˚C; Rf (1:4 EtOAc: Hexanes): 0.26; FTIR (NaCl, ν, cm ): 3151, 2954=2, 1721, 1548, 1437, 1272, 1162,

1 1056; H NMR (400 MHz, CDCl3): δ 8.00 (d, J=3.0 Hz, 1H), 7.74-7.72 (m, 2H), 7.46-7.40 (m, 3H), 3.92

13 (d, J=3.6 Hz, 3H), 3.88 (d, J=3.6 Hz, 3H); C NMR (100 MHz, CDCl3): δ 52.1, 52.8, (113.8, 120.0), 126.4,

128.7, 129.5, (146.5, 154.3, 162.5, 165.1); Spectral data are consistent with those previously reported.5

2,3-Di(methoxycarbonyl)-1-phenyl-7-oxabenzonorbornadiene, 8.2 (Scheme 8.3): 75 mg, 30 % yield).

-1 Yellow oil; Rf (1:4 EtOAc: Hexanes): 0.25; FTIR (NaCl, ν, cm ): 3080, 2953, 1720, 1638, 1435, 1272,

1 750; H NMR (400 MHz, CDCl3): δ 7.58-7.55 (m, 2H), 7.42-7.35 (m, 5H), 7.04-7.01 (m, 2H), 6.03 (d,

13 J=0.3 Hz, 1H), 3.70 (s, 3H), 3.63 (s, 3H); C NMR (100 MHz, CDCl3): δ 165.2, 162.1, 156.6, 148.2, 147.8,

147.5, 133.1, 129.0, 128.8, 126.8, 126.1, 122.0, 121.2, 82.2, 52.42, 52.39; HRMS: Calculated for C20H16O5

[M]+: 336.0998. Found: 336.1001.

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8.5 - References

1 Haner, J. M.Sc. Thesis, University of Guelph, 2011.

2 Tigchelaar, A. M.Sc. Thesis, University of Guelph, 2013.

3 Villeneuve, K.; Tam, W. Organometallics 2006, 25, 843.

4 Horino, Y.; Takahashi, Y.; Kobayashi, R.; Abe, H. Eur. J. Org. Chem. 2014, 35, 7818.

5 Fan, M.; Yan, Z.; Liu, W.; Liang, Y. J. Org. Chem. 2005, 70, 8204.

6 Arisawa, M.; Ichikawa, T.; Yamaguchi, M. Chem. Commun. 2015, 51, 8821.

7 Dauban, P.; Dodd, R.H. J. Org. Chem. 1999, 64, 5304.

8 Although the chemical synthesis of epoxidized oxabenzonorbornadiene has not been reported, its biological synthesis in rats has been described: Sims, P. Biochem. J. 1965, 95, 608.

9 Photochemical conversion of 7-oxanorbornadiene to its epoxide derivative has been reported back in 1986: Prinzbach, H.; Bingmann, H.; Markert, J.; Fischer, G.; Knothe, L.; Eberbach, W.;

Brokatzky-Geiger, J. Chem. Ber. 1986, 119, 589.

10 (a) Nocquet, P.-A.; Opatz, T. Eur. J. Org. Chem. 2016, 2016, 1156. (b) Chang, J.; Xie, W.;

Wang, L.; Ma, N.; Cheng, S.; Xie, J. Eur. J. Med. Chem. 2006, 41, 397.

11 Refer to p.77 of Haner’s M.Sc. thesis (see above reference 1) where intramolecular cyclization by oxygen nucleophile was not successful.

12 Webster, R.; Boyer, A.; Fleming, M.J.; Lautens, M. Org. Lett. 2010, 12, 5418.

13 Bornholdt, J.: Felding, J.; Clausen, R.P.; Kristensen, J.L. Chem. Eur. J. 2010, 16, 12474.

14 Pearson, R.G.; Figdore, P.E. J. Am. Chem. Soc. 1980, 102, 1541.

15 Webster, R.; Lautens, M. Org. Lett. 2009, 11, 4688.

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16 (a) Kaufmann, T.; Boettcher, F. Angew. Chem. 1961, 73, 65. (b) Martens, R.; den Hertog, H.

Tetrahedron Lett. 1962, 643. (c) Nam, H.; Leroi, G. J. Am. Chem. Soc. 1988, 110, 4096. (d)

Mariet, N.; Ibrahim-Ouali, M.; Parrain, J.; Santelli, M. J. Mol. Struct. 2004, 679, 53. (e) Connon,

S.; Hegarty, A. Eur. J. Org. Chem. 2004, 16, 3477. (f) Connon, S.; Hegarty, A. J. Chem. Soc.,

Perkin Trans. 1. 2000, 1245.

17 (a) Sapountzis, I.; Lin, W.; Fischer, M.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 4364. (b)

Lin, W.; Chen, L.; Knochel, P. Tetrahedron 2007, 63, 2787.

18 Carroll, F.; Robinson, T.; Brieaddy, L.; Atkinson, R.; Mascarella, W.; Damaj. M.; Martin, B.;

Navarro, H. J. Med. Chem. 2007, 50, 6383.

19 (a) Reddy, G.; Bhatt, M. Tetrahedron Lett. 1980, 3627. (b) Whitney, S.; Winters, M.;

Rickborn, B. J. Org. Chem. 1990, 55, 929. (c) Xie, C.; Zhang, Y. Org. Lett. 2007, 9, 781.

20 Jijy, E.; Prakash, P.; Baiju, T.V.; Shimi, M.; Yamamoto, Y.; Suresh, E.; Radhakrishnan, K.V.

Synthesis 2014, 46, 2643.

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Appendix: Representative Spectra and Supporting Data

For other experimental NMR spectra, see the Supporting Information sections of the following:

Chapter 2: McKee, M.; Haner, J.; Carlson, E.; Tam, W. Synthesis 2014, 46, 1518.

Carlson, E.; Duret, G.; Blanchard, N.; Tam, W. Synth. Commun. 2016, 46, 55.

Carlson, E.; Tam, W. Synthesis 2016, in press.

Chapter 3: Carlson, E.; Haner, J.; McKee, M.; Tam, W. Org. Lett. 2014, 16, 1776.

Chapter 4: Tigchelaar, A.; Haner, J.; Carlson, E.; Tam, W. Synlett. 2014, 25, 2355.

Carlson, E.; Hong, D.; Tam, W. Synthesis. 2016, in press.

Chapter 6: Carlson, E.; Tam, W. Org. Lett. 2016, 18, 2134.

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Appendix A: Representative NMR data

Chapter 2

1 400 MHz H NMR spectrum of cyclopropane 2.10w in CDCl3

2 61.4 MHz H NMR spectrum of cyclopropane 2.10w in CDCl3

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13 100 MHz C NMR (JMOD) spectrum of cyclopropane 2.10w in CDCl3

230

600 MHz selective gradient NOE spectrum of 2.24a in CDCl3

1 400 MHz H NMR spectrum of cyclopropane 2.24a in CDCl3

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13 125 MHz C NMR (JMOD) spectrum of cyclopropane 2.24a in CDCl3

13 125 MHz C NMR spectrum of cyclopropane 2.24a in CDCl3

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1 400 MHz H NMR spectrum of 2.26l in CDCl3

13 100 MHz C NMR (JMOD) spectrum of 2.26l in CDCl3

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Chapter 3

1 400 MHz H NMR spectrum of 3.2a in CDCl3

13 100 MHz C NMR (JMOD) spectrum of 3.2a in CDCl3

234

1 400 MHz H NMR spectrum of 3.3a in CDCl3

13 100 MHz C NMR (JMOD) spectrum of 3.3a in CDCl3

235

1 400 MHz H NMR spectrum of 3.5 in CDCl3

13 100 MHz C NMR (JMOD) spectrum of 3.5 in CDCl3

236

1 600 MHz H NMR spectrum of 3.25a and 3.25b in CDCl3

1 600 MHz H NMR spectrum of 3.25a and 3.25b in benzene-d6

237

13 100 MHz C NMR (JMOD) spectrum of 3.25a and 3.25b in CDCl3

238

400/100 MHz 2D HSQC spectrum of 3.25a and 3.25b in CDCl3

239

400/100 MHz 2D HMBC spectrum of 3.25a and 3.25b in CDCl3

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Chapter 4

1 600 MHz H NMR spectrum of 4.2k in CDCl3

1D gradient NOE spectrum of 4.2k in CDCl3

13 100 MHz C NMR (JMOD) spectrum of 4.2k in CDCl3

241

1 600 MHz H NMR spectrum of 4.11 in CDCl3

1D gradient NOE spectrum of 4.11 in CDCl3

13 125 MHz C NMR (JMOD) spectrum of 4.11 in CDCl3

242

1 400 MHz H NMR spectrum of 4.3i in CDCl3

13 100 MHz C NMR (JMOD) spectrum of 4.3i in CDCl3

243

13 135-125 ppm Expansion of 100 MHz C NMR (JMOD) spectrum of 4.3i in CDCl3

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1 600 MHz H NMR spectrum of 4.3p in CDCl3

13 125 MHz C NMR (JMOD) spectrum of 4.3p in CDCl3

245

Chapter 5

1 600 MHz H NMR spectrum of 5.22a in CDCl3

13 125 MHz C NMR (JMOD) spectrum of 5.22a in CDCl3

246

1 400 MHz H NMR spectrum of 5.23a in CDCl3

13 100 MHz C NMR (JMOD) spectrum of 5.23a in CDCl3

247

1 400 MHz H NMR spectrum of 5.28 in CDCl3

13 100 MHz C NMR (JMOD) spectrum of 5.28 in CDCl3

248

Chapter 6

1 400 MHz H NMR spectrum of 6.3a in CDCl3

13 100 MHz C NMR (JMOD) spectrum of 6.3a in CDCl3

249

Chapter 7

1 400 MHz H NMR spectrum of 7.9 in CDCl3

13 100 MHz C NMR (JMOD) spectrum of 7.9 in CDCl3

250

1 400 MHz H NMR spectrum of 7.10 in CDCl3

13 100 MHz C NMR (JMOD) spectrum of 7.10 in CDCl3

251

Chapter 8

1 300 MHz H NMR spectrum of 8.2 in CDCl3

13 75 MHz C NMR (JMOD) spectrum of 8.2 in CDCl3

252

Appendix B: X-ray data

Chapter 2

ORTEP structure of 2.10t from X-Ray Diffraction analysis (d15156).

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Table 1. Crystal data and structure refinement for d15156 (2.10t). Identification code d15156 (2.10t) Empirical formula C14 H16 O3 Formula weight 232.27 Temperature 147(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group C2/c Unit cell dimensions a = 16.401(2) Å α = 90°. b = 6.9386(9) Å β = 97.089(3)°. c = 20.666(2) Å γ = 90°. Volume 2333.8(5) Å3 Z 8 Density (calculated) 1.322 Mg/m3 Absorption coefficient 0.092 mm-1 F(000) 992 Crystal size 0.330 x 0.230 x 0.060 mm3 Theta range for data collection 1.986 to 27.530°. Index ranges -21<=h<=21, -8<=k<=9, -17<=l<=26 Reflections collected 17093 Independent reflections 2681 [R(int) = 0.0369] Completeness to theta = 25.242° 100.0 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7456 and 0.7027 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2681 / 0 / 157 Goodness-of-fit on F2 1.017 Final R indices [I>2sigma(I)] R1 = 0.0409, wR2 = 0.0909 R indices (all data) R1 = 0.0672, wR2 = 0.1038 Extinction coefficient n/a Largest diff. peak and hole 0.270 and -0.203 e.Å-3

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Table 2. Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x103) for d15156 (2.10t). U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______x y z U(eq) ______O(1) 299(1) 8242(2) 928(1) 19(1) O(2) 994(1) 10383(2) 2840(1) 25(1) O(3) 2671(1) 10494(2) 655(1) 25(1) C(1) 1174(1) 9435(2) 1773(1) 17(1) C(2) 498(1) 7949(2) 1623(1) 19(1) C(3) 926(1) 5976(2) 1652(1) 21(1) C(4) 677(1) 4617(2) 1092(1) 25(1) C(5) 1367(1) 6032(2) 1051(1) 19(1) C(6) 1129(1) 8013(2) 754(1) 18(1) C(7) 1586(1) 9463(2) 1222(1) 17(1) C(8) 2278(1) 10607(2) 1204(1) 18(1) C(9) 2524(1) 11778(2) 1740(1) 19(1) C(10) 2099(1) 11766(2) 2288(1) 19(1) C(11) 1425(1) 10565(2) 2312(1) 17(1) C(12) 1118(1) 8263(2) 30(1) 26(1) C(13) 1035(1) 11913(3) 3290(1) 38(1) C(14) 3354(1) 11738(3) 625(1) 32(1) ______

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Table 3. Bond lengths [Å] and angles [°] for d15156 (2.10t). ______O(1)-C(2) 1.4474(17) O(1)-C(6) 1.4598(16) O(2)-C(11) 1.3776(16) O(2)-C(13) 1.4074(19) O(3)-C(8) 1.3755(16) O(3)-C(14) 1.4218(18) C(1)-C(11) 1.382(2) C(1)-C(7) 1.3951(19) C(1)-C(2) 1.5177(19) C(2)-C(3) 1.536(2) C(2)-H(2A) 1.0000 C(3)-C(4) 1.510(2) C(3)-C(5) 1.5137(19) C(3)-H(3A) 1.0000 C(4)-C(5) 1.509(2) C(4)-H(4A) 0.9900 C(4)-H(4B) 0.9900 C(5)-C(6) 1.536(2) C(5)-H(5A) 1.0000 C(6)-C(12) 1.503(2) C(6)-C(7) 1.527(2) C(7)-C(8) 1.3886(19) C(8)-C(9) 1.393(2) C(9)-C(10) 1.4006(19) C(9)-H(9A) 0.9500 C(10)-C(11) 1.391(2) C(10)-H(10A) 0.9500 C(12)-H(12A) 0.9800 C(12)-H(12B) 0.9800 C(12)-H(12C) 0.9800 C(13)-H(13A) 0.9800 C(13)-H(13B) 0.9800 C(13)-H(13C) 0.9800 C(14)-H(14A) 0.9800 256

C(14)-H(14B) 0.9800 C(14)-H(14C) 0.9800 C(2)-O(1)-C(6) 97.26(10) C(11)-O(2)-C(13) 117.86(12) C(8)-O(3)-C(14) 116.97(12) C(11)-C(1)-C(7) 121.62(13) C(11)-C(1)-C(2) 133.42(12) C(7)-C(1)-C(2) 104.93(12) O(1)-C(2)-C(1) 100.24(10) O(1)-C(2)-C(3) 102.13(11) C(1)-C(2)-C(3) 106.21(11) O(1)-C(2)-H(2A) 115.4 C(1)-C(2)-H(2A) 115.4 C(3)-C(2)-H(2A) 115.4 C(4)-C(3)-C(5) 59.87(9) C(4)-C(3)-C(2) 116.57(13) C(5)-C(3)-C(2) 101.93(12) C(4)-C(3)-H(3A) 120.4 C(5)-C(3)-H(3A) 120.4 C(2)-C(3)-H(3A) 120.4 C(5)-C(4)-C(3) 60.20(9) C(5)-C(4)-H(4A) 117.8 C(3)-C(4)-H(4A) 117.8 C(5)-C(4)-H(4B) 117.8 C(3)-C(4)-H(4B) 117.8 H(4A)-C(4)-H(4B) 114.9 C(4)-C(5)-C(3) 59.93(10) C(4)-C(5)-C(6) 116.73(12) C(3)-C(5)-C(6) 103.18(11) C(4)-C(5)-H(5A) 120.1 C(3)-C(5)-H(5A) 120.1 C(6)-C(5)-H(5A) 120.1 O(1)-C(6)-C(12) 109.65(12) O(1)-C(6)-C(7) 99.92(10) C(12)-C(6)-C(7) 119.96(12) O(1)-C(6)-C(5) 101.35(11) 257

C(12)-C(6)-C(5) 118.17(12) C(7)-C(6)-C(5) 104.78(11) C(8)-C(7)-C(1) 120.60(13) C(8)-C(7)-C(6) 134.34(12) C(1)-C(7)-C(6) 105.01(12) O(3)-C(8)-C(7) 117.17(12) O(3)-C(8)-C(9) 124.78(13) C(7)-C(8)-C(9) 118.05(12) C(8)-C(9)-C(10) 120.98(13) C(8)-C(9)-H(9A) 119.5 C(10)-C(9)-H(9A) 119.5 C(11)-C(10)-C(9) 120.64(13) C(11)-C(10)-H(10A) 119.7 C(9)-C(10)-H(10A) 119.7 O(2)-C(11)-C(1) 117.11(12) O(2)-C(11)-C(10) 124.83(13) C(1)-C(11)-C(10) 118.04(12) C(6)-C(12)-H(12A) 109.5 C(6)-C(12)-H(12B) 109.5 H(12A)-C(12)-H(12B) 109.5 C(6)-C(12)-H(12C) 109.5 H(12A)-C(12)-H(12C) 109.5 H(12B)-C(12)-H(12C) 109.5 O(2)-C(13)-H(13A) 109.5 O(2)-C(13)-H(13B) 109.5 H(13A)-C(13)-H(13B) 109.5 O(2)-C(13)-H(13C) 109.5 H(13A)-C(13)-H(13C) 109.5 H(13B)-C(13)-H(13C) 109.5 O(3)-C(14)-H(14A) 109.5 O(3)-C(14)-H(14B) 109.5 H(14A)-C(14)-H(14B) 109.5 O(3)-C(14)-H(14C) 109.5 H(14A)-C(14)-H(14C) 109.5 H(14B)-C(14)-H(14C) 109.5 ______258

Table 4. Anisotropic displacement parameters (Å2x 103) for d15156 (2.10t). The anisotropic displacement factor exponent takes the form: -2U2[ h2 a*2U11 + ...+ 2 h k a* b* U12 ] ______U11 U22 U33 U23 U13 U12 ______O(1) 15(1) 21(1) 22(1) 0(1) 0(1) 0(1) O(2) 30(1) 25(1) 23(1) -5(1) 11(1) -5(1) O(3) 25(1) 28(1) 23(1) -3(1) 10(1) -7(1) C(1) 16(1) 14(1) 20(1) 2(1) 1(1) 0(1) C(2) 18(1) 20(1) 19(1) 0(1) 3(1) -2(1) C(3) 22(1) 17(1) 23(1) 1(1) 3(1) -1(1) C(4) 27(1) 16(1) 31(1) -2(1) 2(1) -3(1) C(5) 18(1) 16(1) 24(1) -3(1) 3(1) 0(1) C(6) 18(1) 17(1) 21(1) -1(1) 3(1) -1(1) C(7) 18(1) 13(1) 18(1) 0(1) 0(1) 2(1) C(8) 18(1) 16(1) 19(1) 2(1) 3(1) 1(1) C(9) 16(1) 16(1) 24(1) 1(1) 1(1) -3(1) C(10) 20(1) 16(1) 19(1) -2(1) 0(1) 0(1) C(11) 19(1) 16(1) 18(1) 1(1) 3(1) 2(1) C(12) 31(1) 26(1) 20(1) -1(1) 2(1) -6(1) C(13) 53(1) 36(1) 30(1) -13(1) 20(1) -7(1) C(14) 30(1) 34(1) 35(1) -3(1) 15(1) -12(1) ______

259

Table 5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for d15156 (2.10t). ______x y z U(eq) ______H(2A) 27 8064 1885 23 H(3A) 1212 5476 2074 25 H(4A) 822 3239 1154 30 H(4B) 148 4864 818 30 H(5A) 1946 5565 1073 23 H(9A) 2988 12596 1735 23 H(10A) 2273 12587 2646 22 H(12A) 1676 8113 -85 39 H(12B) 911 9551 -97 39 H(12C) 758 7287 -198 39 H(13A) 652 11671 3609 57 H(13B) 886 13120 3059 57 H(13C) 1595 12013 3516 57 H(14A) 3577 11538 211 48 H(14B) 3779 11452 988 48 H(14C) 3177 13081 654 48 ______

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Table 6. Torsion angles [°] for d15156 (2.10t). ______C(6)-O(1)-C(2)-C(1) 53.68(11) C(6)-O(1)-C(2)-C(3) -55.53(11) C(11)-C(1)-C(2)-O(1) 147.94(15) C(7)-C(1)-C(2)-O(1) -34.35(13) C(11)-C(1)-C(2)-C(3) -106.10(17) C(7)-C(1)-C(2)-C(3) 71.61(14) O(1)-C(2)-C(3)-C(4) -27.71(15) C(1)-C(2)-C(3)-C(4) -132.31(13) O(1)-C(2)-C(3)-C(5) 34.38(13) C(1)-C(2)-C(3)-C(5) -70.21(13) C(2)-C(3)-C(4)-C(5) 88.68(14) C(3)-C(4)-C(5)-C(6) -90.21(14) C(2)-C(3)-C(5)-C(4) -113.95(13) C(4)-C(3)-C(5)-C(6) 113.46(13) C(2)-C(3)-C(5)-C(6) -0.49(14) C(2)-O(1)-C(6)-C(12) -179.66(12) C(2)-O(1)-C(6)-C(7) -52.73(11) C(2)-O(1)-C(6)-C(5) 54.68(12) C(4)-C(5)-C(6)-O(1) 29.64(15) C(3)-C(5)-C(6)-O(1) -33.09(13) C(4)-C(5)-C(6)-C(12) -90.13(16) C(3)-C(5)-C(6)-C(12) -152.87(13) C(4)-C(5)-C(6)-C(7) 133.21(13) C(3)-C(5)-C(6)-C(7) 70.48(13) C(11)-C(1)-C(7)-C(8) 1.4(2) C(2)-C(1)-C(7)-C(8) -176.63(12) C(11)-C(1)-C(7)-C(6) 179.16(13) C(2)-C(1)-C(7)-C(6) 1.12(14) O(1)-C(6)-C(7)-C(8) -150.61(15) C(12)-C(6)-C(7)-C(8) -30.9(2) C(5)-C(6)-C(7)-C(8) 104.75(17) O(1)-C(6)-C(7)-C(1) 32.10(13) C(12)-C(6)-C(7)-C(1) 151.76(13) C(5)-C(6)-C(7)-C(1) -72.55(13) 261

C(14)-O(3)-C(8)-C(7) 176.96(13) C(14)-O(3)-C(8)-C(9) -3.2(2) C(1)-C(7)-C(8)-O(3) 177.28(13) C(6)-C(7)-C(8)-O(3) 0.3(2) C(1)-C(7)-C(8)-C(9) -2.6(2) C(6)-C(7)-C(8)-C(9) -179.56(14) O(3)-C(8)-C(9)-C(10) -178.34(13) C(7)-C(8)-C(9)-C(10) 1.5(2) C(8)-C(9)-C(10)-C(11) 0.8(2) C(13)-O(2)-C(11)-C(1) -158.53(14) C(13)-O(2)-C(11)-C(10) 22.9(2) C(7)-C(1)-C(11)-O(2) -177.80(13) C(2)-C(1)-C(11)-O(2) -0.4(2) C(7)-C(1)-C(11)-C(10) 0.9(2) C(2)-C(1)-C(11)-C(10) 178.31(14) C(9)-C(10)-C(11)-O(2) 176.62(13) C(9)-C(10)-C(11)-C(1) -2.0(2) ______

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Chapter 5

ORTEP structure of 5.23a from X-Ray Diffraction analysis (d1683).

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Table 7. Crystal data and structure refinement for d1683 (5.23a). Identification code d1683 (5.23a) Empirical formula C17 H24 O2 Formula weight 260.36 Temperature 147(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 8.9716(10) Å = 80.493(3)°. b = 9.5283(10) Å = 73.205(4)°. c = 9.8080(12) Å  = 69.547(3)°. Volume 750.14(15) Å3 Z 2 Density (calculated) 1.153 Mg/m3 Absorption coefficient 0.073 mm-1 F(000) 284 Crystal size 0.330 x 0.290 x 0.200 mm3 Theta range for data collection 2.175 to 27.707°. Index ranges -11<=h<=11, -12<=k<=12, -12<=l<=12 Reflections collected 24158 Independent reflections 3493 [R(int) = 0.0291] Completeness to theta = 25.242° 100.0 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7456 and 0.7234 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 3493 / 0 / 176 Goodness-of-fit on F2 1.025 Final R indices [I>2sigma(I)] R1 = 0.0402, wR2 = 0.0948 R indices (all data) R1 = 0.0542, wR2 = 0.1041 Extinction coefficient n/a Largest diff. peak and hole 0.289 and -0.235 e.Å-3

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Table 8. Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x103) for d1683 (5.23a). U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______x y z U(eq) ______O(1) 2511(1) 10665(1) 8472(1) 24(1) O(2) 230(1) 10537(1) 6879(1) 26(1) C(1) 2669(1) 9390(1) 7794(1) 18(1) C(2) 1988(1) 9985(1) 6467(1) 20(1) C(3) 2484(2) 8751(1) 5444(1) 22(1) C(4) 2311(1) 7292(1) 6229(1) 21(1) C(5) 3352(1) 6402(1) 6992(1) 18(1) C(6) 4761(1) 6898(1) 7009(1) 18(1) C(7) 6401(2) 6010(1) 6537(1) 23(1) C(8) 7683(2) 6519(2) 6518(1) 26(1) C(9) 7354(2) 7929(2) 6953(1) 26(1) C(10) 5733(2) 8846(1) 7383(1) 22(1) C(11) 4435(1) 8351(1) 7407(1) 18(1) C(12) 2426(2) 10359(2) 9957(1) 35(1) C(13) -458(2) 12081(2) 7135(2) 34(1) C(14) 3061(2) 5039(1) 7973(1) 22(1) C(15) 1567(2) 4716(2) 7825(2) 38(1) C(16) 2732(2) 5403(2) 9522(2) 41(1) C(17) 4541(2) 3610(2) 7681(2) 49(1) ______

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Table 9. Bond lengths [Å] and angles [°] for d1683 (5.23a). ______O(1)-C(12) 1.4218(16) O(1)-C(1) 1.4248(13) O(2)-C(13) 1.4160(15) O(2)-C(2) 1.4316(14) C(1)-C(11) 1.5218(16) C(1)-C(2) 1.5376(16) C(1)-H(1A) 1.0000 C(2)-C(3) 1.5334(16) C(2)-H(2A) 1.0000 C(3)-C(4) 1.5095(17) C(3)-H(3A) 0.9900 C(3)-H(3B) 0.9900 C(4)-C(5) 1.3388(16) C(4)-H(4A) 0.9500 C(5)-C(6) 1.5014(16) C(5)-C(14) 1.5365(17) C(6)-C(7) 1.3997(16) C(6)-C(11) 1.4090(16) C(7)-C(8) 1.3907(18) C(7)-H(7A) 0.9500 C(8)-C(9) 1.3830(19) C(8)-H(8A) 0.9500 C(9)-C(10) 1.3908(18) C(9)-H(9A) 0.9500 C(10)-C(11) 1.3939(16) C(10)-H(10A) 0.9500 C(12)-H(12A) 0.9800 C(12)-H(12B) 0.9800 C(12)-H(12C) 0.9800 C(13)-H(13A) 0.9800 C(13)-H(13B) 0.9800 C(13)-H(13C) 0.9800 C(14)-C(15) 1.5252(18) C(14)-C(17) 1.5313(18) 266

C(14)-C(16) 1.5361(19) C(15)-H(15A) 0.9800 C(15)-H(15B) 0.9800 C(15)-H(15C) 0.9800 C(16)-H(16A) 0.9800 C(16)-H(16B) 0.9800 C(16)-H(16C) 0.9800 C(17)-H(17A) 0.9800 C(17)-H(17B) 0.9800 C(17)-H(17C) 0.9800 C(12)-O(1)-C(1) 113.00(9) C(13)-O(2)-C(2) 115.05(10) O(1)-C(1)-C(11) 112.30(9) O(1)-C(1)-C(2) 107.02(9) C(11)-C(1)-C(2) 111.61(9) O(1)-C(1)-H(1A) 108.6 C(11)-C(1)-H(1A) 108.6 C(2)-C(1)-H(1A) 108.6 O(2)-C(2)-C(3) 107.31(9) O(2)-C(2)-C(1) 110.13(10) C(3)-C(2)-C(1) 111.78(9) O(2)-C(2)-H(2A) 109.2 C(3)-C(2)-H(2A) 109.2 C(1)-C(2)-H(2A) 109.2 C(4)-C(3)-C(2) 112.00(10) C(4)-C(3)-H(3A) 109.2 C(2)-C(3)-H(3A) 109.2 C(4)-C(3)-H(3B) 109.2 C(2)-C(3)-H(3B) 109.2 H(3A)-C(3)-H(3B) 107.9 C(5)-C(4)-C(3) 122.84(11) C(5)-C(4)-H(4A) 118.6 C(3)-C(4)-H(4A) 118.6 C(4)-C(5)-C(6) 116.82(10) C(4)-C(5)-C(14) 123.59(11) C(6)-C(5)-C(14) 119.15(10) 267

C(7)-C(6)-C(11) 118.47(11) C(7)-C(6)-C(5) 122.24(10) C(11)-C(6)-C(5) 119.11(10) C(8)-C(7)-C(6) 121.03(11) C(8)-C(7)-H(7A) 119.5 C(6)-C(7)-H(7A) 119.5 C(9)-C(8)-C(7) 120.18(11) C(9)-C(8)-H(8A) 119.9 C(7)-C(8)-H(8A) 119.9 C(8)-C(9)-C(10) 119.61(11) C(8)-C(9)-H(9A) 120.2 C(10)-C(9)-H(9A) 120.2 C(9)-C(10)-C(11) 120.85(11) C(9)-C(10)-H(10A) 119.6 C(11)-C(10)-H(10A) 119.6 C(10)-C(11)-C(6) 119.80(11) C(10)-C(11)-C(1) 120.67(10) C(6)-C(11)-C(1) 119.47(10) O(1)-C(12)-H(12A) 109.5 O(1)-C(12)-H(12B) 109.5 H(12A)-C(12)-H(12B) 109.5 O(1)-C(12)-H(12C) 109.5 H(12A)-C(12)-H(12C) 109.5 H(12B)-C(12)-H(12C) 109.5 O(2)-C(13)-H(13A) 109.5 O(2)-C(13)-H(13B) 109.5 H(13A)-C(13)-H(13B) 109.5 O(2)-C(13)-H(13C) 109.5 H(13A)-C(13)-H(13C) 109.5 H(13B)-C(13)-H(13C) 109.5 C(15)-C(14)-C(17) 107.98(12) C(15)-C(14)-C(16) 108.03(12) C(17)-C(14)-C(16) 108.57(13) C(15)-C(14)-C(5) 111.73(10) C(17)-C(14)-C(5) 112.59(11) C(16)-C(14)-C(5) 107.80(10) 268

C(14)-C(15)-H(15A) 109.5 C(14)-C(15)-H(15B) 109.5 H(15A)-C(15)-H(15B) 109.5 C(14)-C(15)-H(15C) 109.5 H(15A)-C(15)-H(15C) 109.5 H(15B)-C(15)-H(15C) 109.5 C(14)-C(16)-H(16A) 109.5 C(14)-C(16)-H(16B) 109.5 H(16A)-C(16)-H(16B) 109.5 C(14)-C(16)-H(16C) 109.5 H(16A)-C(16)-H(16C) 109.5 H(16B)-C(16)-H(16C) 109.5 C(14)-C(17)-H(17A) 109.5 C(14)-C(17)-H(17B) 109.5 H(17A)-C(17)-H(17B) 109.5 C(14)-C(17)-H(17C) 109.5 H(17A)-C(17)-H(17C) 109.5 H(17B)-C(17)-H(17C) 109.5 ______

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Table 10. Anisotropic displacement parameters (Å2x 103) for d1683 (5.23a). The anisotropic displacement factor exponent takes the form: -22[ h2 a*2U11 + ...+ 2 h k a* b* U12 ] ______U11 U22 U33 U23 U13 U12 ______O(1) 32(1) 20(1) 22(1) -6(1) -9(1) -6(1) O(2) 19(1) 21(1) 38(1) -7(1) -11(1) 0(1) C(1) 19(1) 17(1) 19(1) -4(1) -6(1) -5(1) C(2) 19(1) 18(1) 21(1) -2(1) -7(1) -3(1) C(3) 25(1) 21(1) 21(1) -4(1) -10(1) -3(1) C(4) 19(1) 21(1) 24(1) -7(1) -7(1) -4(1) C(5) 17(1) 17(1) 20(1) -6(1) -2(1) -3(1) C(6) 17(1) 19(1) 17(1) 0(1) -6(1) -5(1) C(7) 20(1) 22(1) 24(1) -1(1) -5(1) -3(1) C(8) 16(1) 32(1) 25(1) 1(1) -5(1) -4(1) C(9) 21(1) 36(1) 23(1) 3(1) -8(1) -14(1) C(10) 24(1) 25(1) 20(1) 0(1) -7(1) -10(1) C(11) 18(1) 20(1) 15(1) 1(1) -6(1) -6(1) C(12) 47(1) 37(1) 22(1) -9(1) -9(1) -12(1) C(13) 28(1) 24(1) 44(1) -12(1) -9(1) 2(1) C(14) 19(1) 19(1) 27(1) -2(1) -5(1) -6(1) C(15) 38(1) 36(1) 50(1) 7(1) -17(1) -23(1) C(16) 57(1) 45(1) 28(1) 5(1) -10(1) -30(1) C(17) 34(1) 19(1) 73(1) 5(1) 6(1) -2(1) ______

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Table 11. Hydrogen coordinates (x 104) and isotropic displacement parameters (Å2x 10 3) for d1683 (5.23a). ______x y z U(eq) ______H(1A) 1975 8816 8461 22 H(2A) 2412 10820 5954 23 H(3A) 1786 9087 4758 27 H(3B) 3639 8585 4895 27 H(4A) 1425 6991 6178 25 H(7A) 6641 5045 6225 28 H(8A) 8789 5897 6205 31 H(9A) 8229 8269 6959 31 H(10A) 5508 9822 7663 26 H(12A) 2318 11271 10366 52 H(12B) 1471 10027 10433 52 H(12C) 3429 9566 10094 52 H(13A) -1653 12393 7278 51 H(13B) 6 12672 6313 51 H(13C) -205 12246 7991 51 H(15A) 587 5590 8079 57 H(15B) 1419 3842 8464 57 H(15C) 1737 4507 6836 57 H(16A) 3647 5677 9628 61 H(16B) 2628 4521 10166 61 H(16C) 1712 6245 9760 61 H(17A) 5472 3735 7920 73 H(17B) 4838 3423 6669 73 H(17C) 4259 2757 8267 73 ______

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Table 12. Torsion angles [°] for d1683 (5.23a). ______C(12)-O(1)-C(1)-C(11) -82.00(13) C(12)-O(1)-C(1)-C(2) 155.18(10) C(13)-O(2)-C(2)-C(3) -147.34(11) C(13)-O(2)-C(2)-C(1) 90.77(12) O(1)-C(1)-C(2)-O(2) -75.43(11) C(11)-C(1)-C(2)-O(2) 161.33(9) O(1)-C(1)-C(2)-C(3) 165.38(9) C(11)-C(1)-C(2)-C(3) 42.13(13) O(2)-C(2)-C(3)-C(4) -77.69(12) C(1)-C(2)-C(3)-C(4) 43.16(13) C(2)-C(3)-C(4)-C(5) -73.62(14) C(3)-C(4)-C(5)-C(6) -1.72(17) C(3)-C(4)-C(5)-C(14) 170.68(11) C(4)-C(5)-C(6)-C(7) -121.27(13) C(14)-C(5)-C(6)-C(7) 65.98(15) C(4)-C(5)-C(6)-C(11) 53.70(15) C(14)-C(5)-C(6)-C(11) -119.05(12) C(11)-C(6)-C(7)-C(8) 2.76(18) C(5)-C(6)-C(7)-C(8) 177.75(11) C(6)-C(7)-C(8)-C(9) -0.77(19) C(7)-C(8)-C(9)-C(10) -1.28(19) C(8)-C(9)-C(10)-C(11) 1.29(18) C(9)-C(10)-C(11)-C(6) 0.74(17) C(9)-C(10)-C(11)-C(1) -176.41(11) C(7)-C(6)-C(11)-C(10) -2.72(17) C(5)-C(6)-C(11)-C(10) -177.88(10) C(7)-C(6)-C(11)-C(1) 174.46(10) C(5)-C(6)-C(11)-C(1) -0.69(16) O(1)-C(1)-C(11)-C(10) -16.07(15) C(2)-C(1)-C(11)-C(10) 104.12(12) O(1)-C(1)-C(11)-C(6) 166.77(10) C(2)-C(1)-C(11)-C(6) -73.04(13) C(4)-C(5)-C(14)-C(15) 7.05(17) C(6)-C(5)-C(14)-C(15) 179.28(11) 272

C(4)-C(5)-C(14)-C(17) 128.78(14) C(6)-C(5)-C(14)-C(17) -59.00(16) C(4)-C(5)-C(14)-C(16) -111.50(13) C(6)-C(5)-C(14)-C(16) 60.73(14) ______

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