Ring-opening Reactions of Cyclopropanated Heterobicyclic Alkenes

293 Pages·2016·7.27 MB·English

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-(XCH )naphthalenes (X=RO, RCO ). The reaction rate
2 2
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.
iv

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.
vi

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
vii

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
viii

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
ix

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
x

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.