EFFORTS TOWARDS THE SYNTHESIS OF SPIROLIGOZYMES AND PHOTOCHEMICAL METHODS FOR ACCESSING CYCLOBUTANOIDS AND CUBANE – LIKE COMPOUNDS
A Dissertation Submitted to the Temple University Graduate Board
In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY
by Steven E. S. Fletcher May 2019
Examining Committee Members:
Scott McN. Sieburth, Advisory Chair, Department of Chemistry Sarah Wengryniuk, Department of Chemistry Steven A. Fleming, Department of Chemistry Dionicio Martinez Solorio, External Member, Drexel University
ii
© Copyright 2019
by
Steven Fletcher All Rights Reserved
iii ABSTRACT
This work describes the culmination of two separate projects. In the first endeavor, efforts to synthesize peptidomimetics are described using trans -hydroxy proline to make a functionalized bis -peptides, or spiroligomers. The bis- peptide was then tested for catalytic activity on esterification reactions. The remainder of this manuscript describes a method to create complex molecular scaffolds using [4 + 4] photocycloaddition of trimethylsilyl substituted benzyl ethers tethered to 2 – pyridones.
Upon irradiation at low concentrations, these structures intramolecularly react to give cyclobutanoid compounds. Initially, it was thought that [4 +4] photoreactions would would yield cyclooctanoid structures. Finally, a meta substituted methyl ester is intramoleculary reacted with a benzyl pyridone and eventually transformed into a dimethyl alcohol, creating a cubane – like structure. This caged structure is then subjected to rearrangement when exposed to strong acid conditions.
iv
I dedicate this dissertation to my great-grandmother, Deolous Crawley, my grandmother,
Erceil Fletcher, my mother, Rhonda Fletcher, family and friends.
v ACKNOWLEDGMENTS
Beginning, enduring and finishing this graduate school journey was one of the most difficult things I have ever done. Let me be frank: Graduate school was hard.
Psychologist Angela Duckworth believes that passion and perservance lead to success and I agree. The past seven years have been challenging and I am grateful for the experience of having returned to school after enjoying a previous career. I am a significantly better chemist and teacher, having acquired a strong foundational understanding of organic chemistry. I would not have made it through graduate school without a few people from Temple University helping me, motivating me along the way, and, in some cases, demanding that I finish.
Professor Scott McNeil Sieburth was one of the first people I met at Temple
University who advised, encouraged, and made me believe earning a Ph.D. is attainable.
Joining his group was one of the best decisions I have made in my graduate school career and I am proud to call him a mentor and friend. Scott, thank you for your open and honest conversations about lab and life. I hope that we will indeed do lunch if we ever end up in San Diego at the same time.
Professor Steven A. Fleming has been an amazing mentor. Being your TA for the
Honors Organic Chemistry courses has been wonderful. Learning from you has made me a more impactful instructor. I am forever grateful for our conversations, also.
I am honored that Professor Sarah Wengryniuk has made me a better chemist by serving on my dissertation committee. Professor Wengryniuk’s willingness to hold me to the highest standards has made me a stronger candidate. I would also like to express my gratitude for Professor Dionicio Martinez Solorio for agreeing to serve as my external
vi committee member. I value his, and all the feedback my committee members have provided.
I would like to thank Dr. Charles DeBrosse for not only keeping the NMR facilities in good working order, but for also being an invaluable resource in NMR interpretation. Dr. Debrosse’s knowledge and wisdom have helped me better understand my research (and my life). Thank you for not retiring until after I graduate!
My knowledge of organic chemistry has been informed by the instruction of
Professor Franklin Davis, Professor Rodrigo Andrade, Professor Steven A. Fleming,
Professor Christian Schafmeister and Dr. Charles Debrosse. I am indebted to these professors for instilling a thrist for knowledge in me.
My time in graduate school has been made more enjoyable through the friendships I have made. Brenden Derstein, Olivia McPherson, Jed Shambeda, Charles
Stockdale, Samer Daher, and Lauren Martin have been great support system and I wish them and all members of the Sieburth group the best of luck. I also would like to thank the members of the Andrade, Dobriener, Schafmeister, Wang, Wengryniuk, and Zdilla labs. I wish you nothing but the best!
I also would like to acknowledge the past and present support staff here in the
Department of Chemistry: Bobbi Johnson, Tanya Santiago, Kafi Chism, Lisa Lomax,
Sharon Kass, Regina Shapiro, Yelena Cerkashina and Patrick Clark. I also would like to thank Professor Serge Jasmin and Professor Alan Thomas for our lively conversations.
I would remiss if I did not take this opportunity to thank my beautiful wife,
Ileabeth Ayala Rodriguez, for supporting me during this arduous journey. If it were not for you helping me through thick and thin, I would not have made it. Thank you for
vii taking care of our son, Esteban, as I pushed through. You are the absolute best and I thank you from the bottom of my heart. Te amo muchisimo!
viii
TABLE OF CONTENTS
Page
ABSTRACT ...... iii
DEDICATION ...... iv
ACKNOWLEDGMENTS ...... v
LIST OF TABLES ...... xi
LIST OF FIGURES ...... xii
LIST OF ILLUSTRATIONS ...... xiii
LIST OF ABBREVIATIONS ...... xv
CHAPTER
1. PEPTIDOMIMETICS...... 20
1.1 Introduction ...... 21
1.1.2 Spiroligomers ...... 21
1.1.3 Applications of the Schafmeister Spiroligomers ...... 24
1.2 Synthesis of Oxime ...... 29
1.2.1 Mechanistic Studies of Oxime 124 ...... 31
1.3 Synthesis of Thiol 125 ...... 31
1.4 Conclusion ...... 35
1.5 Experimental Details ...... 35
1.6 References ...... 50
2. 2-PYRIDONE PHOTOCHEMISTRY...... 54
2.1 Introduction and Motivation ...... 52
ix 2.2 General Principles of Cycloaddition Reactions ...... 53
2.3 Historical Perspective of 2 – Pyridone
Photocycloadditions ...... 54
2.4 [4 + 4] Photocycloadditions: 2-Pyridones and Aromatics ...... 58
2.5 Intermolecular [4 + 4] Photocycloadditions:
2 – Pyridones and 1,3 Dienes ...... 58
2.6 Intramolecular [4 +4] Photocycloadditions:
Silicon Incorporation in 2-Pyridone Photochemistry ...... 62
2.7 Photo [4 + 4]- Cycloaddition of meta –
Substituted Benzene with 2 - Pyridones ...... 62
2.8 Results and Discussion ...... 64
2.8.1 Synthesis of Starting Materials ...... 65
2.8.2 Irradiation of the 2 – Pyridone Trimethyl
Silyl Substituted Benzyl Ethers ...... 67
2.8.3 Concentration Dependence
of the Photoreaction ...... 68
2.8.4 Photochemistry of the
Substrates at Low Concentration ...... 69
2.9 Conclusion ...... 70
2.10 Experimental ...... 73
2.11 References ...... 86
3. CUBANE – LIKE STRUCTURES ...... 90
3.1 Properties of Cubane ...... 90
3.2 Early Synthesis of Cubane ...... 90 x 3.3 Chemical Reactivity of Cubane ...... 92
3.4 Rearrangements...... 93
3.4.1 Cubene ...... 93
3.4.2 Cubylcarbocation ...... 95
3.5 Synthesis of Cubane Type Molecules Using Photochemistry ...... 96
3.6 Results and Discussion ...... 97
3.6.1 Synthesis of Starting Material ...... 98
3.6.2 Initial Test of 2-Pyridone-meta - methylester benzyl ether ...... 99
3.6.3 Sieburth and Khatri [4 +4] metabenzyl – pyridone photocycloaddition ...... 100
3.6.4 Photochemistry of at 25mM using “Flow” Methods ...... 101
3.6.5 Grignard Addition to 349 ...... 101
3.6.6 Rearrangement with Acid ...... 102
3.7 Conclusion ...... 103
3.8 Experimental Details ...... 104
3.9 References ...... 111
APPENDIX A: CHARACTERIZATION OF DATA FOR CHAPTER 1 ...... 115
APPENDIX B: CHARACTERIZATION OF DATA FOR CHAPTER 1 ...... 126
APPENDIX C: CHARACTERIZATION OF DATA FOR CHAPTER 1 ...... 138
xi
LIST OF TABLES
Table Page
1.1 Classification of Peptidomemetics…………………………….……………...... 21
1.2 Effect of Solvent on the Aldol Condensation Reaction………………..…..…... 25
1.3 One Pot Alkylation of Hydantoins……………………………………………... 26
2.1 Substituted Benzene Photocycloadditions ………………………………...... 64
2.2 Photoproducts and Yields of the Trimethylsilane substituted – pyridone ethers……………………………………………………72
xii LIST OF FIGURES
Figure Page
1.1 Examples of Spiroligomers……………………………………….…………..….22
1.2 Bis-peptide Assembly….……………………………………………………..….23
1.3 Time-dependent Catalysis of Methyltrifluoroacetate from Vinyl Trifluoroacetate…………………………...…………………………27
1.4 Alcohol Dimers Used in Catalysis Reaction…………………………………..…28
2.1 Frontier Molecular Orbital Diagram of 1,3-butadiene.…….……………………………………………….....54
2.2 Examples of [4+4] Photocycloaddition Reactions Illustrating (A) Trans and (B) Cis Stereocontrol………………………………. .62
2.3 Three Modes of Benzene Cycloaddition.……………………………..………….62
2.4 TMS Substituted Benzene – 2- Pyridone Ethers…………………………………65
3.1 Cubane……………………………………………………………………………90
3.2 Pyrimidization Angle of Cubene…………………………………………………93
xiii LIST OF SCHEMES
Scheme Page
1.1 Syntheis of Protein Monomer Building Block………………….……………….24
1.2 Synthesis of OAt Ester 119 ………………………..…..…...... 30
1.3 Synthesis of Oxime Spiroligomer 124 …………………………..……..……...... 31
1.4 Retrosynthetic Pathway for the Thiol Catalyst……………………………...... 32
1.5 Retrosynthetic Pathway for the Thiol Catalyst………………………………….33
1.6 Synthesis of Disulfide 125 ………………………………………………………34
2.1 Irradiation of 1-Methyl-2-pyridone and Its Products……………………………52
2.2 [4 +4] Photoproducts of 2-N-Alkylated-2-Pyridone………………………….…56
2.3 Proposed Bimolecular Association of 2-Pyridones……………………………...57
2.4 Evolution of 2-Pyridone Photoreactions………………………………………...60
2.5 Reactions Pathways for Conjugated Enynes with 2-Pyridones………………………………………………………………....61
2.6: Formation of Exocyclic Triene 238 as a Result of Steric Shielding with Silicon…………………....…………….…62
2.7 Photocycloaddition of Anthracene 244 and Naphalene 246 Tethered to Pyridone……………………………….……....63
2.8 Synthesis of Photosubstrate Precursors………………………………………….65
2.9 Synthesis of Photosubstrates 253 – 256 ………………………………………...66
2.10 Initial Test of 2-Pyridone Trimethyl Substituted Benzene Photochemistry……………………………………………...………..67
2.11 Concentration Dependence of 2-Pyridone Photoreaction……………………...68
2.12 Photoproducts of the meta-Benzonitritle – 2-Pyridone Photocycloaddition at 25mM.…………………………………..….69
xiv 2.13 Photoproducts of the para - Trimethyl Substituted Benzene – 2-Pyridone Photocycloaddition…………………………………..70
2.14 Complete Library of Possible [4+4] and Cope Photoproducts…………………………………….………………..71
3.1. Thermal Ring Opening of Cubane…….……….……….……….……….……91
3.2 Eaton and Cole’s Synthesis of the Cubane Ring System…….………………...92
3.3 Reactions of Mono- (314) and 1,2-Diiodocubane (316) ……………………….94
3.4 In Situ Formation of Cubene in a Diels-Alder Reaction……………………… 94
3.5 Rearrangement of Cubylmethyl Alcohol..…….……….……….……….……..95
3.6 Proposed Mechanism for the Conversion of 4-Iodo-1-vinylcubane 328 …………………………………………………...96
3.7 Summary of the Photoproducts of the meta -Benzonitrile – 2-Pyridone Photocycloaddition at 25mM…………………………………………………..97
3.8 Photochemistry of meta-Methylesterbenzene with 2-Pyridones……………….97
3.9 Synthesis of the Photosubstrate Precusors……………………………………..98
3.10 Test Reactions of the Photosubstrate 351 at Various Concentrations…………………………………………………..100
3.11 Buddha Khatri’s Synthesis of Cubane – Like Pyridone Structure…………………………………………………..…101
3.12 Addition of Grignard Reagents………………………………………...……102
3.13 Mechanism for Rearrangement of Cage Structure 350 Upon Exposure to Concentrated Acid………………………………..…..…103
xv
LIST OF ABBREVIATIONS Ac – acetyl
ACN – acetonitrile
Alloc - Allyloxycarbonyl
Bn – benzyl
Boc - tert-Butoxycarbonyl
Boc 2O Di-tert-butyl dicarbonate
Bu – butyl c – cyclo
Cbz Carboxybenzyl
DCM – dichloromethane
DFT – Density functional theory
DIPEA - N,N-Diisoproylethylamine
DIC - N,N′-Diisopropylcarbodiimide
DKP - Diketopiperazine
DMAP 4-Methyldiaminopyridine
DMF – dimethylformamide
DMSO – dimethylsulfoxide
EDT - 1,2-Ethanedithiol
Et – ethyl
EtOAc – ethylacetate
Et 3N- triethylamine
FMO – Frontier Molecular Orbital xvi hr / hrs – hour / hours
HATU O-(7-azabenzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium hexafluorophosphate
HOAt - Hydroxyazabenzotriazole
HOMO – Highest Occupied Molecular Orbital
HBr Hydrobromic acid hv – light i – iso
IR – infrared
LDA – lithium diisopropylamide
LUMO – Lowest Unoccupied Molecular Orbital
M – molar
Me – methyl
MeOH Methanol
μW – microwave
MO – molecular orbital mol – mole mp – melting point n – normal (straight chain)
NMR – nuclear magnetic resonance
NR – no reaction p – para
Ph – phenyl
xvii ppm – parts per million
Pr – propyl pyr. – pyridine
Rf – retention factor rt – room temperature rxn – reaction
SM – starting material
TBS – tert-butyldimethylsilyl
TEA – triethylamine
TFA – trifluoroacetic acid
TFMSA – trifluoromethanesulfonic acid
THF – tetrahydrofuran
TIPS – triisopropylsilyl
TLC – thin layer chromatography
TMEDA – tetramethylethylenediamine
TMS – trimethylsilyl
Ts – tosyl or toluenesulfonic
TsOH p-Toluenesulfonic acid tert – tertiary
UV – ultraviolet
xviii
GENERAL EXPERIMENTAL METHOD
• Anhydrous dichloromethane (DCM), anhydrous N,N -dimethylformamide (DMF),
anhydrous tetrahydrofuran (THF), hydrobromic acid (33 wt% in glacial acetic
acid) (33% HBr/AcOH), and trifluoroacetic acid (TFA) were obtained from Acros
Organics. Ketones, aldehydes, sodium cyanoborohydride (NaBH 3CN), phenyl
isocyanide, N,N’ -diisopropylcarbodiimide (DIC), diisopropylethylamine
(DIPEA), triethylamine (Et 3N) and other anhydrous solvents used in solvent
screening were purchased from Sigma-Aldrich. 1-Hydroxyl-7-azabenzotriazole
(HOAt) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’ -tetramethyluronium
hexafluorophosphate (HATU) was obtained from Genscript. All chemicals were
used directly without further purification.
• HPLC-MS analysis was performed on a Hewlett-Packard Series 1200 with a
Waters Xterra MS C18 column (3.5 mm packing, 4.6 mm x 150 mm) with a
solvent system of H 2O/acetonitrile with 0.1 % formic acid at a flow rate of 0.8
mL/min.
• NMR experiments were performed on a Bruker Avance 500 MHz. Deuterated
solvents were purchased from Sigma-Aldrich. Chemical shifts (#) are reported
relative to CDCl 3, or d6-DMSO, or MeOD.
• Reverse-Phase Purifications were performed on ISCO (Teledyne, Inc.) automated
flash chromatography system with a RediSep Reverse Phase Column using
water/acetonitrile with 0.1% formic acid at a flow rate of 40mL/min.
• Column chromatography was performed either manually using silica gel (Merck
grade 60, 230-400 mesh) or on ISCO (Teledyne, Inc.) automated flash xix chromatography system.
Analytical and preparative thin-layer chromatography (TLC) was performed on pre-coated silica gel plates (250 and 1000 microns) purchased from Analtech Inc.
TLC plates were visualized with UV or in an iodine chamber.
xx
CHAPTER 1
PEPTIDOMIMETICS
1.1 Introduction
A peptidomimetic is a compound that mimics a peptide, or, the binding properties
of natural peptide precursors. 1 Peptidomimetics comprise a broad class of
modulators of protein-protein interactions, or PPIs. PPIs are understood to be
involved in processes at the cellular level and are known to influence biological
functions through proximity induced changes of the characteristics of the protein.
There are four classes of peptidomimetics, Table 1.1, and while compounds in the A
and B classes incorporate peptide-like structures, compounds in the C and D classes
include small molecular scaffolds. 2 More specifically, class A mimetics are peptides
containing mainly the amino acid sequence of the parent peptide. 2 Class B modified
peptides differ from Class A peptides because these compounds contain non-natural
amino acids, major backbone alterations, etc. Foldamers 3 and peptoids 4 are examples
of class B modified peptides. Class C mimetics are highly modified structures with
small molecule character that substitutes the peptide backbone. Finally, Class D
mimetics contain compounds that mimic the bioactive peptide mode of action without
direct linking to its side chain functionalities. 2 Drug development using
peptidomemetics is possible if the biological processes that the peptide affect are
identified (Table 1.1). 2,5
21
1.1.2 Spiroligomers
An example of a class B peptidomimetic is a spiroligomer. Spiroligomer bis- peptides are bicyclic, abiotic building blocks that are synthesized by coupling pairs of amide bonds. 6 This coupling creates ladder-like oligomers with programmable three- dimensional structures, Figure 1.1.6 The development of the spiroligomer takes its inspiration from the syntheses of other unnatural building blocks. Initially, in 1995, the
Iverson group developed synthetic oligomers that employed donor acceptor interactions between aromatic groups, allowing these molecules to adopt a pleated conformation. 7
The same year, the Gellman and Seebach groups developed -peptides that formed helical and sheet-like structures, respectively. 8,9
22 O H HN NH NH H N 2 O N O O N O O N O NH O HN O N N OH O H N N O S O O O N N O O HN H NH 2 N N O H O O
101 102
Figure 1.1: Examples of Spiroligomers.
The synthesis of these spiroligomers commences with large scale preparation of the monomer in stereochemically pure form, Scheme 1.1.6 To prepare the oligomer, amino acids are coupled.6 Subsequent intramolecular aminolysis results in the formation of a diketopiperazine (DKP) ring to afford a spiroligomer with no rotatable bonds in its backbone. 6 Because the synthesis of the oligomer utilizes trans -4- hydroxyproline as its small molecule building block, its classification as a class B peptidometic is appropriate.
Some examples are shown in Figure 1.1.
23 1. Assembly
2. Rigidification
Bis-a mino acids Bis-peptides
Figure 1.2: Bis-peptide Assembly 6.
Historically, as reported by Levins and Schafmeister, spiroligomer synthesis began with the widely available trans -4-hydroxy-L-proline 103 , the nitrogen of which was protected using the carboxybenzyl group, Scheme 1.1 . The Cbz protected prolinol was then oxidized using Jones reagent and upon exposure to isobutylene gave the tert- butyl oxopyrrolidinecarboxylate 104 . The oxopyrrolidine was then exposed to Bucherer-
Bergs 10 conditions, forming two diastereomeric hydantoins 105 and 106 . After purification and separation via chromatography, the diastereomers can be further functionalized. The S,S diastereomer 105 was hydrolyzed to form the amino acid 107 and upon exchange of the Cbz protecting group with a Boc group, the protecting amino acid 108 was produced. To produce building blocks for a range of oligomers the mixture of hydantoins 112 could be derivatized, Table 1.2.
24
Scheme 1.1 Synthesis of Proline Monomer Building Block.
1.1.3 Applications of the Schafmeister Spiroligomers
Spiroligomers have been used in a variety of ways, including charge transfer studies 11,12 , molecular scaffolds,11,13 metal binding studies,14–16 catalysis,17–19 protein binding,20 and molecular rulers.21 Zhao, Schafmeister, and coworkers have extensively tested a series of spiroligomers derived from trans-4-hydroxyproline with appended hydrophobic groups as catalysts for aldol reactions.18 In one such example, a spiroligomer carrying the hydrophobic benzyl and phenyl substituents on either side of the hydantoin was found to catalyzed the aldol reaction to high yield with excellent diastereoseletivity and enantioselectivity, Table 1.3. 18 Notably, the group reports that spiroligomers with an aromatic group syn to the carboxylic acid were better catalysts than those made with small hydrophobic groups.
25
Table 1.2: One Pot Alkylation of Hydantoins. 22
R R H 1 1 O N O N O N O O O HN a N b N * R2 * R2 * N N N Cbz CO 2t-Bu Cbz CO 2t-Bu H CO 2t-Bu
112 113 114
(a) i. DMF, R1-X, K2CO 3 time varies; ii, R2-X, K2CO 3, overnight; (b) 1:1 DCM/ (33% HBr/AcOH) to remove Cbz/t-Bu protecting groups.
26 Table 1.3. Effect of Solvent on the Aldol Condensation Reaction.
O N N O O 10 mol% O O OH O N OH + H H TFA O2N NO 2 Solvent, 25oC, 12 h
109 11 0 111 entry Solvent Product: dr ee SM ratio
1 H2O >98:2 >98:2 >98
2 MeOH 76:24 >98:2 >98
3 IPA >98:2 91:9 94
4 t-BuOH >98:2 90:10 94
5 DMSO 60:40 78:22 89
6 DMF 41:59 79:21 87
7 DCM 97:3 86:14 96
8 MeCN 79:21 88:12 92
9 toluene 98:2 96:4 96
10 Et 2O >98:2 95:5 93
11 EtOAc >98:2 94:6 93
12 Hexane >98:2 95:5 97
13 THF >98:2 94:6 95
14 cyclohexanone >98:2 92:8 93
27 The methods for making these compounds have also evolved. Initially, compounds and substitutions of 114 were made by coupling an aldehyde with the amine through a reductive amination reaction followed by a subsequent isocyanate capping to make the hydantoin. In 2017, a method to increase efficiency of production by utlilizing a one-pot synthesis was investigated. Northrup and Schafmeister reported direct sequential hydantoin alkylation yields at 90% and higher, Table 1.3. 22
Pfieffer and coworkers have optimized yields for spiroligomer synthesis by utilizing the pNZ group as a temporary amine protecting group and the Pfp ester in solid phase synthesis, reporting respectable yields. 23
Kheirabadi and Schafmeister utilized the spiroligomer as an enzyme mimic to catalyze transesterification reactions. Using an ‘inside-out’ strategy, spiroligomers were synthesized to investigate the ideal placement of a pyridine as a general base catalyst with
spiroligomer catalyst O MeOH + O O O CF 3 Me + CDCl 3, rt O CF 3 H CF 3
115 116 117 BnOH
(see Fig. 1.4)
Figure 1.3. Time-Dependent Catalysis of Methyltrifluoroacetate from Vinyl Trifluoroacetate. 19
28 N O
N N
O (S) CF 3 (S) N O OH O N (S) HN CF 3 N O (S) HN O (S) O N O N O O
11 5 N O
N N O (S) (S) N O OH O N (S)
(S) N O H H (S) O N N N CF 3 O N O O O CF 3
11 6
N O
N N (S) O (S) O N OH O N (S) (S) N O N O
11 7 Figure 1.4: Alcohol Dimers Used in Catalysis Reaction. an 29 an alcohol nucleophile to facilitate attack on a vinyl trifluoroacetate electrophile. The transition state for a spiroligomer model was identified computationally and, using those calculations, a spiroligomer mimic of the nucleophilic Ser-His-Glu triad of a typical serine hydrolase was synthesized. This successful strategy lead to the formation of a catalyst that is 2700 times faster than the background reaction with a benzyl alcohol,
Figure 1.3 .19
1.2 Synthesis of Oxime
To investigate ways to improve spiroligomers transesterification catalysts, a way to enhance of the nucleophilicity of the alcohol in Kheirabaldi’s dimer 115 was explored.
During the catalytic cycle, the alcohol is hydrogen bonded to the pyridine in the spiroligomer, allowing the alkoxide to attack the carbonyl carbon on the vinyl trifluoroacetate that is held in place by the urea. If the intermolecular distance of the alcohol oxygen to the ester is shortened, then nucleophilicity of the spiroligomer could be enhanced. It was proposed to shorten this distance by incorporating an oxime into the peptidomimetic.
My work commenced by starting with trans -4-hydroxy-L-proline, the diastereomeric hydantoins were accessed using published conditions 6. The ( S,S ) diastereomer 105 , a Cbz protected proline, was converted to Boc protected hydantoin 107 through the addition of Boc anhydride during hydrogenolysis of the Cbz group. With this compound in hand, 107 was then converted to the free amino acid 108 upon exposure to
Boc anhydride and potassium hydroxide. Amino acid 108 was reductively alkylated with an Alloc protected benzaldehyde, yielding 115. Compound 115 was combined with 3,5- bis(trifluoromethyl)phenyl isocyanate to give the Alloc-protected hydantoin 116.
30 Removal of the t-butyl and Boc protecting groups with trifluoracetic acid revealed the monomer 117 . The free acid salt 117 was N-Alloc protected, yielding protected product
118 . To complete the synthesis of the bis-amino acid, 118 was then transformed into OAt ester upon addition of 1-Hydroxy-7-azabenzotriazole, HOAt, to form 119 , made in situ ,
Scheme 1.2 .
Scheme 1.2: Synthesis of OAt Ester 119.
Diastereomer 105, used previously, was also employed to construct the remaining spiroligomer fragment, Scheme 1.3. Using published conditions,19 protected amino acid
108 was eventually transformed to the free acid 120 . Alloc protected OAt-activated 119 was combined with a solution 120 and diisopropylethylamine (DIPEA) in DMF to give amide product 121 . Removal of the Alloc groups with catalytic tetrakis(triphenylphosphine)-palladium(0) and phenylsilane closed the diketopiperazine ring, yielding product 122. Alcohol 122 was oxidized to aldehyde 123 using 10
31 equivalents of manganese (IV) oxide. Condensing 123 with hydroxylamine hydrochloride gave spiroligomer oxime, 124 (Scheme 1.3) .
Scheme 1.3. Synthesis of Oxime Spiroligomer 124.
1.2.1 Mechanistic Studies of Oxime 124
Unfortunately, transesterification of vinyl trifluoroacetate was not catalyzed by oxime 124 in competition against a background reaction of benzyl alcohol. The oxime’s catalytic activity was not observed.
1.3 Synthesis of Thiol 125
Following the preparation and study of of 124 , efforts were then focused on thiol
125 , substituting the oxygen atom of 122 with a sulfur atom. Studies have corroborated that the more nucleophilic sulfur can make a better catalyst, as a consequence of its in
32 differences in electronegativity and polarizability. 24 Retrosynthetically, the best strategy to access the thiol 125 was to employ 126 and 127 (Scheme 1.4).
Scheme 1.4. Retrosynthetic Pathway for the Thiol Catalyst.
Building catalyst 125 began with S-tert-butyl ortho-thiomethylbenzaldehyde,
Scheme 1.5 .25 Starting with Boc protected amino acid 108 in methanol, Scheme 1. 5, the aldehyde was added and allowed to stir for 30 minutes. Sodium cyanoborohydride was added, yielding carboxylic acid 128 . Coupling of 128 with phenylisocyanate afforded the hydantoin 129 and, upon exposure to trifluoroacetic acid and triisopropylsilane, the free amino acid salt 130 was isolated. Alloc protection of the pyrrolidine nitrogen of 130 gave the protected pyrollidine carboxylic acid 131. Using conditions that were previously described,18,19 131 was transformed to the activated OAt ester 132 . Coupling the phenyl
– pyridine monomer 119, prepared according to the literature 19 , gave N-Alloc protected amino acid 133, Scheme 1.6. Use of catalytic tetrakis(triphenylphosphine)-palladium(0) and phenylsilane and triphenyl phosphine, the diketopiperazine was installed, to give t- butyl protected thiol spiroligomer 134 . Unfortunately, we were unable to access the
33 deprotected thiol 136 after treatment with trifluromethanesulfonic acid. Only the disulfide
135 was formed, preventing us from performing mechanistic studies on the transesterification reactions, Scheme 1.6.
Scheme 1.5. Synthesis of t-Butyl Protected bis-Amino Acid Thiol 132.
34
Scheme 1.6: Synthesis of Disulfide 125.
35 1.4 Conclusion In summary, spiroligomer catalaysts with oxime and thiol nucleophiles were prepared. The oxime failed to show catalytic activity and the thiol was found to be extremely air sensitive. Reductive coupling should be employed to investigate methods to access the thiol dimer. Additionally, if the spiroligomer is accessed, the chemistry should be conducted under oxygen free conditions.
1.5 Experimental Details
The synthesis of the diastereomeric Cbz- protected hydantoins, ( 2S,4S ), (2S,4R ), and their enantiomers (2R,4R ), ( 2R,4S ), 106 from trans -4- hydroxyproline has been published. 6 Additionally, the synthesis of N-Boc protected hydantoins can also be located in the literature. 19
di-tert -Butyl (5 S,8 S)-1-(2-((((Allyloxy)carbonyl)oxy)methyl)benzyl)-3-(3,5- bis(trifluoromethyl)phenyl)-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7,8- dicarboxylate (116): In a 250 mL round bottom flask, reductively alkylated amino acid
115 (2 mmol) and triethylamine (4 mmol) were combined in dry THF (10 mL). The isocyanate (2 mmol) was subsequently added in a single portion and the mixture was stirred at room temperature for 24h. 20 mL saturated NH 4Cl was added and the reaction mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated NaHCO 3 (2 x 50 mL), brine (2 x50 mL), dried over sodium sulfate 36 and concentrated. The crude compound was used for the next step without any purification. 1H NMR (500 MHz, Chloroform-d) δ 8.08 (s, 1H), 7.87 (s, 1H), 7.53 – 7.47
(m, 1H), 7.40 – 7.34 (m, 2H), 7.30 (d, J = 6.8 Hz, 2H), 5.83 (ddt, J = 17.2, 10.4, 5.8 Hz,
1H), 5.30 (s, 2H), 5.26 (dd, J = 17.2, 1.5 Hz, 1H), 5.23 – 5.19 (m, 1H), 5.06 (d, J = 16.2
Hz, 1H), 4.71 (d, J = 16.3 Hz, 1H), 4.60 – 4.50 (m, 2H), 4.39 (t, J = 8.5 Hz, 1H), 3.92 (d,
J = 11.8 Hz, 1H), 3.62 (d, J = 11.8 Hz, 1H), 2.39 (t, J = 11.4 Hz, 1H), 1.97 (t, J = 11.4
Hz, 1H), 1.42 (s, 9H), 1.39 (s, 9H).
(5 S,8 S)-1-(2-((((allyloxy)carbonyl)oxy) methyl)benzyl)-3-(3,5- bis(trifluoromethyl)phenyl)-8-carboxy-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-ium
2,2,2-trifluoroacetate (117): The crude N-Boc protected 116 was dissolved in trifluoroacetic acid (approximately 1 mL/ 50 mg product) and triisopropylsilane (TIS) (53
L/50 mg product) was added as a scavenger. The mixture was allowed to stir for 4h at room temperature. The solvent was removed using vacuum, and the residue was resuspended in DCM (10 mL) an toluene (2 mL). Solvent was removed under reduced pressure to remove excess TFA. The residue was dried under vacuum overnight. The crude compound was used for the next step without any purification.
37
(5 S,8 S)-7-((5 S,8 S)-7-((Allyloxy)carbonyl)-1-(2-
((((allyloxy)carbonyl)oxy)methyl)benzyl)-3-(3,5-bis(trifluoromethyl)phenyl)-2,4- dioxo-1,3,7-triazaspiro[4.4]nonane-8-carbonyl)-2,4-dioxo-3-phenyl-1-(pyridin-4- ylmethyl)-1,3,7-triazaspiro[4.4]nonane-8-carboxylic acid (122):
In a flame-dried vial, the N-Alloc protected bis -amino acid 120 to be activated (0.3 mmol) and HATU (0.29 mmol) were suspended in DMF (final concentration of bis- amino acid is 50 mM) under argon. With stirring, DIPEA (0.6 mmol) was then added in one portion and the mixture was stirred for 1.5 hours at room temperature. The other
Pro4 -amino acid 119 was then suspended in a minimal volume of DMF (~200 L), and
DIPEA (0.6 mmol). Resulting solution was then added to the preactivated amino acid 38 drop wise and allowed to react overnight at room temperature. Once complete, this crude mixture was left in solution. To the crude coupling solution as a result of the reaction that included precursor 121 , phenylsilane (0.9 mmol) was added as a scavenger along with a catalytic amount of tetrakis(triphenylphosphine )-palladium(0) (60 mol). Simultaneous deprotection of the alloc protecting groups and complete diketopiperazine (DKP) closure were observed using C 18 reverse phase HPLC-MS after 24 hour stirring at room temperature. The product was loaded onto celite by adding 5 g celite and removing the solvent in vacuum and purified by silica-gel chromatography with a gradient of 0%
MeOH in DCM to 5% MeOH in DCM. A second purification was then carried out using
C18 reverse phase with a gradient of 0-100% H 2O/ACN with 0.1% formic acid to obtain pure spiroligomer 122. Mass found: 862.1g/mol.
2-(((4 S,5a' S,7' S,10a' S)-1-(3,5-bis(trifluoromethyl)phenyl)-2,2'',5,5',5'',10'-hexaoxo-
1''-phenyl-3''-(pyridin-4-ylmethyl)tetrahydro-1' H,3' H,5' H,8' H- dispiro[imidazolidine-4,2'-dipyrrolo[1,2-a:1',2'-d]pyrazine-7',4''-imidazolidin]-3- yl)methyl)benzaldehyde (123): In a 250 mL roundbottom flask equipped with a magnetic stir bar, spiroligomer 122 and anhydrous THF under Argon. To this, MnO 2 (10 eq) was added and allowed to react overnight. The reaction was then filtered through a
39 bed a celite and then purified using silica chromatography. Mass found: 862.1g/mol.
(E)-2-(((4 S,5a' S,7' S,10a' S)-1-(3,5-bis(Trifluoromethyl)phenyl)-2,2'',5,5',5'',10'- hexaoxo-1''-phenyl-3''-(pyridin-4-ylmethyl)tetrahydro-1' H,3' H,5' H,8' H- dispiro[imidazolidine-4,2'-dipyrrolo[1,2-a:1',2'-d]pyrazine-7',4''-imidazolidin]-3- yl)methyl)benzaldehyde oxime (124): To a 250 mL roundbottom flask equipped with a magnetic stir bar, spiroligomer 123 and THF were added. A solution of hydroxylammonium chloride was added to the mixture dropwise and allowed to react overnight. This mixture was then extracted with EtOAc and then purified with gel silica chromatography to reveal compound 124 . Mass found: 877.1g/mol.
40
(3 S,5 S)-1,5-bis( tert -butoxycarbonyl)-3-((2-(( tert - butylthio)methyl)benzyl)amino)pyrrolidine-3-carboxylic acid (128):
The starting material, pro4 amino acid 108 (3.0 mmol) was dissolved in methanol (20 mL, concentration of 151 mM) and 2-(( tert -Butylthio)methyl)benzaldehyde, prepared from conditions as outlined in the literature 25 (3.0 mmol) was added in a single portion.
The solution was stirred at room temperature for 30 minutes and then NaBH 3CN (188 mg, 3.0 mmol) was added in a single portion as a solid. The homogenous mixture was allowed to stir for 12 hours at room temperature. The progress of the reaction was evaluated at 12 hours by diluting 10 L of the reaction with 500 L acetonitrile and injecting 30 L of this solution into a C 18 reverse phase HPLC- MS. Typically after 12 hours no remaining starting material is seen by LCMS. The reaction mixture was combined with 5-10 g of celite and the solvent was removed using vacuum. The celite bound product was reverse phase purified using a C 18 column with a gradient of 30-100%
H2O/ACN with 0.1% formic acid. The desired fractions were pooled and lyophilized. mp
186-188 oC; IR (neat) 2976, 2864, 1706, 1388, 1159 cm -1; 1H NMR (500 MHz, DMSO- d6, 1% TFA, 350 °C) δ 7.51-7.48 (dd, 1H, J= 8.98, 2.02), 7.44 -7.42 (dd, 1H, J= 9.08,
2.13 Hz), 7.38-7.33 (m, 2H), 4.35-4.25 (m, 3H), 4.15- 4.11, (d, 1H, J= 11.53 Hz), 3.93-
3.89 (s, 2H), 3.69-3.64 (d, 1H, J= 11.53 Hz), 3.01- 2.94 (dd, 1H, J= 21.60, 8.41 Hz),
2.37-2.32 (dd, 1H, J= 13.24, 8.31 Hz), 1.45 (s, 9H), 1.40 (s, 9H), 1.36 (s, 9H); 13 C NMR
41 (125 MHz, DMSO-d6, 350 K) δ 170.3, 158.0, 136.8, 130.24, 130.19, 128.5, 128.9, 126.6,
116.4, 114.3, 80.8, 79.5, 58.4, 52.1, 45. 1, 42.5, 30.2, 30.1, 29.6, 27.6; HPLC analysis
(C 18 reverse phase, 5 min, 5-95% H 2O/ACN containing 0.1% formic acid) tR =2.24 min;
+ HRMS-ESI: m/z calcd for C27 H42 N2O6S (M+H) 523.2844, found 523.2828.
Di-tert -butyl (5 S,8 S)-3-(3,5-bis(trifluoromethyl)phenyl)-1-(2-(( tert - butylthio)methyl)benzyl)-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7,8-dicarboxylate
(129): In a 250 mL round bottom flask, the starting material, reductively alkylated Pro4 amino acid 128 (2 mmol) and triethylamine (4 mmol) were combined in dry THF (5 mL/ mmol of starting material). The isocyanate (2 mmol) was subsequently added in a single portion and the mixture was stirred at room temperature for 24h. 20 mL saturated NH 4Cl was added and the reaction mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated NaHCO 3 (2 x 50 mL), brine (2 x50 mL), dried over sodium sulfate and concentrated. . Flash chromatography (5% MeOH/
DCM) afforded 0.74 mg (46%) of a colorless oil 129 ; IR (neat) 2979, 1725, 1277, 1136
-1 1 cm ; HNMR (CDCl 3) δ 8.09 (s, 2H), 7.83 (s, 1H), 7.31-7.13 (m, 4H), 5.06 (d, J= 16.3
Hz, 1H), 4.68 (d, J= 16.2, 1H), 4.38 (t, J= 8.68, 8.46 Hz, 1H), 3.91 (d, J= 11.6 Hz, 1H),
3.83 (d, J= 12.8 Hz, 1H), 3.73 (d, J=11.6 Hz, 1H), 3.63 (d, J = 11.8 Hz, 1H), 2.39 (dd, J=
42 13. 3, 8.13 Hz, 1H), 1.99 (dd, J= 13.3, 9.41 Hz, 1H), 1.39 (s, 9H), 1.36 (s, 9H) 1.31 (s,
13 9H); CNMR (CDCl 3) δ 172.6, 170.5, 153.6, 153.5, 134.3, 133.2, 132.6, 132.3, 132.1,
131.8, 129.9, 128.8, 128.3, 127.8, 125.6, 123.9, 121.5, 81.1, 77.0, 76.8, 66.0, 58.2, 48.9,
41.1, 34.9, 30.71, 28.2; HPLC analysis (C 18 reverse phase, 5 min, 5-95% H 2O/ACN
+ containing 0.1% formic acid) tR =3.65 min; HRMS calcd for C36 H43 F6N3O6S (M + H)
759.2777, found 760.2841.
(5 S,8 S)-3-(3,5-bis(Trifluoromethyl)phenyl)-1-(2-(( tert -butylthio)methyl)benzyl)-2,4- dioxo-1,3,7-triazaspiro[4.4]nonane-8-carboxylic acid. In a 25-mL, oven-dried, single necked round bottom flask equipped with a magnetic stirring bar (5) (0.0230 g, 30.3
µmol), was combined with TFA (460 µL) and TIS (24.4 µL). The mixture was allowed to stir for 4h at room temperature. The solvent was removed using vacuum, and the residue was resuspended in DCM (10 ml) and toluene (2 ml) and the solvent was removed under reduced pressure to remove excess TFA. Residue was dried under vacuum overnight. The product was reversed phase purified with a gradient of 5-100% H 2O/ACN with 0.1% formic acid. The solution was diluted with EtOAc (14 mL) and washed with NH 4Cl (3 x
5 mL), brine (3 x 5 mL), NaHCO 3 (3 x 5 mL), brine again (2 x 5 mL), dried (Na 2SO 4) and concentrated to yield a colorless oil.
43
(5 S,8 S)-3-(3,5-bis(Trifluoromethyl)phenyl)-1-(2-(( tert -butylthio)methyl)benzyl)-2,4- dioxo-1,3,7-triazaspiro[4.4]nonane-8-carboxylic acid compound with 2,2,2- trifluoroacetate (130): The crude N-Boc protected material 129 was dissolved in trifluoroacetic acid (approximately 1 mL/ 50 mg product) and triisopropylsilane (TIS) (53
L/50 mg product) was added as a scavenger. The mixture was allowed to stir for 4h at room temperature. The solvent was removed using vacuum, and the residue was resuspended in DCM (10 mL) an toluene (2 mL). Solvent was removed under reduced pressure to remove excess TFA. The residue was dried under vacuum overnight. The product was used without any purification.
44
(5 S,8 S)-7-((Allyloxy)carbonyl)-3-(3,5-bis(trifluoromethyl)phenyl)-1-(2-(( tert - butylthio)methyl)benzyl)-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-8-carboxylic acid
(131): Functionalized trifluorocarboxylate 130 (2 mmol) was dissolved in THF (50
0 mM). The solution was cooled to 0 C with an ice bath. Et 3N (20 mmol) was added to the solution followed by drop-wise addition of allyl chloroformate (20 mmol) over 10 minutes. The reaction mixture was stirred at 0 0C for 0.5 h; after which the ice bath was removed and the mixture was allowed to stir overnight at room temperature. Saturated ammonium chloride (20 mL) was then added and the product was extracted with EtOAc
(100 mL). The organic layer was washed with brine and dried over sodium sulfate and loaded onto celite (combined with 5 g celite and the solvent was evaporated). The product was then purified using silica-gel flash chromatography with a gradient of 0%
MeOH in DCM to 5% MeOH in DCM. 1H NMR (500 MHz, Chloroform-d) δ 8.24 – 8.03
(m, 1H), 7.90 (s, 1H), 7.36 (d, J = 7.5 Hz, 0H), 7.30 (d, J = 1.9 Hz, 0H), 7.20 (d, J = 7.5
Hz, 0H), 5.86 (ddt, J = 16.4, 10.9, 5.6 Hz, 0H), 5.25 (t, J = 14.7 Hz, 1H), 5.10 (d, J = 16.0
Hz, 0H), 4.78 (d, J = 16.5 Hz, 0H), 4.62 (s, 1H), 3.93 – 3.83 (m, 1H), 3.77 (d, J = 11.1
Hz, 1H), 3.31 (d, J = 12.0 Hz, 0H), 2.85 (dd, J = 13.4, 9.4 Hz, 0H), 2.49 (dd, J = 13.8, 8.5
Hz, 0H), 1.37 (s, 5H).
45
(4 S,5a' S,7' S,10a' S)-1-(3,5-bis(Trifluoromethyl)phenyl)-3-(2-(( tert - butylthio)methyl)benzyl)-1''-phenyl-3''-(pyridin-4-ylmethyl)tetrahydro-
3' H,5' H,8' H,10' H-dispiro[imidazolidine-4,2'-dipyrrolo[1,2-a:1',2'-d]pyrazine-7',4''- imidazolidine]-2,2'',5,5',5'',10'-hexaone (134): In a flame-dried vial, the N-Alloc protected bis -amino acid 132 to be activated (0.3 mmol) and HATU (0.29 mmol) were suspended in DMF (final concentration of bis-amino acid is 50 mM) under argon. With stirring, DIPEA (0.6 mmol) was then added in one portion and the mixture was stirred for
1.5 hours at room temperature. The other Pro4 -amino acid 108 was then suspended in a minimal volume of DMF (~200 L), and DIPEA (0.6 mmol). Resulting solution was then
46 added to the preactivated amino acid drop wise and allowed to react overnight at room temperature. Once complete, this crude mixture was left in solution.
To the crude coupling product 133 , phenylsilane (0.9 mmol) was added as a scavenger along with a catalytic amount of tetrakis(triphenylphosphine )-palladium(0) (60 mol).
Simultaneous deprotection of the alloc protecting groups and complete diketopiperazine
(DKP) closure were observed using C18 reverse phase HPLC-MS after 24 hour stirring at room temperature. The product was loaded onto celite by adding 5 g celite and removing the solvent in vacuum and purified by silica-gel chromatography with a gradient of 0%
MeOH in DCM to 5% MeOH in DCM. A second purification was then carried out using
C18 reverse phase with a gradient of 0-100% H 2O/ACN with 0.1% formic acid to obtain pure spiroligomer 134.
(4 S,5a' S,7' S,10a' S)-1-(3,5-bis(Trifluoromethyl)phenyl)-3-(2-
(mercaptomethyl)benzyl)-1''-phenyl-3''-(pyridin-4-ylmethyl)tetrahydro-
3' H,5' H,8' H,10' H-dispiro[imidazolidine-4,2'-dipyrrolo[1,2-a:1',2'-d]pyrazine-7',4''- 47 imidazolidine]-2,2'',5,5',5'',10'-hexaone (135): In 25 mL flame dried round bottom flask equipped with a magnetic stir bar under argon, thioanisole (100 ) and EDT (50
L) were added, along with spiroligomer 134 (58 mol) and allowed to cool to 0 oC and allowed to stir for five minutes. TFMSA was added dropwise with the vessel was stirred vigourously to dissipate heat. The acid was evaporated and the mixture was purified by silica-gel chromatography with a gradient of 0% MeOH in DCM to 5% MeOH in DCM.
Molecular weight found 878.2.
48 1.6 References.
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49 Oligomers. Nature 1997 , 387 , 381–384.
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(12) Chakrabarti, S.; Parker, M. F. L.; Schafmeister, C. E.; Waldeck, D. H.
Experimental Evidence for Water Mediated Electron- Transfer Through Bis-
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2044–2045.
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Expansion in a Bis(Peptide)-Based Mechanical Molecular Actuator. Chem. - A
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50 Designed Spiroligozyme Catalyst That Mimics the Ketosteroid Isomerase
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52 CHAPTER 2
2-PYRIDONE PHOTOCHEMISTRY
2.1 Introduction and Motivation
Photochemistry of the pyridone is interesting for a myriad of reasons including knowledge of the products that can be accessed, more specifically, the beta lactam 203 and cyclooctadiene 202 (Scheme 2.1). 1 Additionally, the short-lived excited state, interesting influence of substituents and minimal solvent effects make the study of pyridone photochemistry that much more rewarding. Pyridone photochemistry is primarily an example of cycloaddition, which represents a very broad category of concerted chemical reactions.
Cycloaddition reactions are orbital symmetry-controlled pericyclic reactions. 2
These reactions occur when two unsaturated molecules undergo an addition reaction to yield cyclic products, and are classified according to the number of electrons participating in the reaction, the nature of the orbitals undergoing the change, and the stereochemical mode of cycloaddition. 3 In order for these reactions to occur, there must be bonding overlap between p-orbitals at the terminal carbons of each -electron system.
Fulfilling this requirement allows new sigma bonds to be formed, and this reactivity can be rationalized using Frontier Molecular Orbital Theory (FMO) and the Woodward-
Hoffmann rules. 4,5 O H O N hv N N O N O H 201 202 203 [4+4]-dimer photoisomer
Scheme 2.1: Irradiation of 1-methyl-2-pyridone and its products.
53
2.2 General Principles of Cycloaddition Reactions
The formation of new − bonds from – bonds during a cycloaddition reaction follows either a thermal or photochemical pathway and, depending on the number of electrons involved, an optimum pathway can be determined. Using a [4+4] cycloaddition reaction of two butadiene molecules as an example, the favorable pathway for the pericyclic reaction proceeds through photochemistry (Figure 2.1). In this scenario, two possible interactions are allowed. In the first case, the highest occupied molecular orbital
(HOMO), is assigned to one diene, a 4 component, while the lowest unoccupied molecular orbital (LUMO), is assigned to the excited state diene, another 4 component.
The HOMO of the of the diene has a symmetry operation that is identical to the symmetry operation of the LUMO of the excited state of the diene, favorable to a bonding interaction. If the LUMO were instead assigned to the diene and the HOMO assigned to the excited state of the diene, both the HOMO and LUMO would still possess the same symmetry operations, allowing for bonding p-orbital overlap to be achieved.
There are other types of cycloadditions, such as the [4+2] Diels-Alder reaction, and these are all governed by the Woodward – Hoffman rules. 4
54 Figure 2.1 4: Frontier molecular orbital diagram of 1,3-butadiene. a) photoexcitation of an electron into the excited state. b) HOMO/LUMO interactions of the ground and excited states.
The first photocycloaddition reaction, reported in 1867 by Fritzche, was the [4+4] reaction of anthracene, yielding its dimer.6 Our research involved testing pyridones with other diene-containing molecules for possible [4+4] and [2+2] photocycloaddition reactions. Of the two constitutional isomers of pyridones, 2-pyridone and 4-pyridone, this research focused on the photochemistry and photocycloadditions of the former.
2.3 Historical Perspective of 2-Pyridone Photocycloadditions
In 1960, Taylor and co-workers first described the photoproduct of 1-methyl-2- pyridone as a dimer with a trans head-to-tail structure, among others, Scheme 2.1.7 A short-lived, (0.2 ns) singlet excited state,8 resulting from irradiation at about 300 nm, typically using a Pyrex filter, gave rise to the dimers. 1 The photocycloadditions can be achieved with suitable high-, medium-, and low pressure mercury lamps 9, along with fluorescent light setups such as the Rayonet reactor.
When the reaction commences, there is a competition between the inter- and intramolecular products, which can be controlled by varying the initial pyridone
55 concentration. In 1974, Nakamura and coworkers reported all four possible approach dependent [4+4] adducts and elaborated on the solvent effects, shown in Scheme 2.2.10 A head-to -tail A or head-to -head approach C, where the carbonyls are situated far from each other would yield trans photo-dimers 205 and 207 . A head-to -tail B or head-to - head approach D would give cis photo-dimers 206 and 208 .10 Applying heat to the cis dimers results in a [3,3]- rearrangement of the 1,5-cyclooctadienes to the divinylcyclobutanes 209, 210, and 211 .
At concentrations above 0.1 M, the dimers are the major product whereas isomerization to give 203 dominates at concentrations below 0.01M. 10 It is important to note that the pathways to dimerization and isomerization are not affected by the type of solvent used and similar product ratios are achieved when the photocycloaddition is performed in solvents ranging from water to benzene.10
The lifetime of the 2-pyridone singlet excited state was reported by Sharp and
Hammond, and found to be less less than 0.2 ns. In addition they concluded that unsensitized dimerization of 2-pyridone does not involve a triplet excited state. 11
In 1985, in an attempt to rationalize formation of trans head-to-tail 205 as the major product products, Matsushima and coworkers theorized a bimolecular association of 2-pyridones before photoexcitation (Scheme 2.3). They suggested that this association of the 2-pyridones must occur to yield the observed photodimers. Without this bimolecular pre-association, the short lived excited state would preclude dimerization.12
Formation of the trans dimer may occur through two major pathways, a
56 O O N R R N R R N N
O O A 205
N O trans, head-to-tail trans, head-to-tail R approach
204
O O
N N O R O R N N R R B 207
trans, head-to-head trans, head-to-head approach
O H H O O N 65ºC R N N N ≡ N R R R R N O N N H H R R O O R O O 209 N O C 206 hv R cis, head-to-tail cis, head-to-tail approach 204
O O H H O N N R R N ≡ O N N O O R 65ºC O H H N N R R O R R N R 210 D 208
cis, head-to-head cis, head-to-head + approach O H H N R ≡ N N R R O H H N O O R 21 1
Scheme 2.2: [4+4] Photoproducts of 2-N-alkylated-2-pyridone. hydrogen-bond dimer E or a dipole-dipole influenced association F, depending on the substitution of the nitrogen. Because dimers were formed from both N-substituted and N-
57 H 2-pyridones, the authors were convinced that dipole-dipole interactions are the guiding force explaining why the trans head-to-tail adduct is the major product.
When considering substituent effects, the [4+4] reaction can occur when the pyridone is substituted with a methyl group at any point on the ring.13 However, the 2- pyridone [4+4] photodimerization does not occur when the pyridone carries 4-alkoxy, 5- carboalkoxy or 6-chloro groups, due in part to alternate photo reaction pathways. With alkoxy substitution at C4, photoisomerization and not dimerization occurs. Interestingly, cross- [4+4] - cycloaddition is possible between 4-alkoxy and 4-unsubstituted 2-pyridone mixtures. Finally, the photoreaction tolerates electron withdrawing and electron donating groups on the ring.
O N R R = H R N R = Me 212 O 201 k k’
H O O N N R N N H O O R = H R E N F 213 R = Me R O 205 N O
Scheme 2.3: Proposed bimolecular association of 2-pyridones.
To achieve successful intra molecular [4+4] cycloadditions using 2-pyridones, the tether length and point of attachment must be considered. When a three-atom tether is employed, the cycloaddition yields a 2:1 mixture of cis and trans products. Four carbon tethers yield only the trans isomer. 13
58 2.4 [4+4] Photocycloadditions: 2-Pyridone and Aromatics
Besides dimerization and isomerization, 2-pyridones have the ability to undergo
[4+4] photocycloadditions with other aromatics. For example, triazolopyridine, in the presence of pyridone, will yield a trans cross product. Naphthalene and 2-pyridone will form a cis product upon irradiation. 13
2.5 Intermolecular [4+4] Photocycloadditions: 2-Pyridones and 1,3-Dienes
The ability to control the regio- and stereoselectivity in 2-pyridone
photochemistry is necessary for utility in considering the synthesis of natural products.
Sieburth and coworkers 14 have shown an approach to the synthesis of taxol using
intramolecular photocycloaddition of 2-pyridones in one of their steps, (Figure 2.2A ).
Cycloaddition was successful, producing a photoproduct containing the two quaternary centers needed for the synthesis of taxol. In the synthesis of the ring system of fusicoccin
A, Figure 2.2B,15 irradiating 228 followed by epoxidation using DMDO gave 229 . The
stereo- and regioselectivity of these molecules was controlled by synthesizing tethers attached at head positions of one 2-pyridone (C-3) and to the tail positions of a second 2-
pyridone (C-3) through a three or four atom connection. Olefins, cyclic and acyclic
59 Figure 2.2: Examples of [4+4] Photocycloaddition Reactions Illustrating (A) Trans and (B) Cis Stereocontrol. dienes, and other pi systems can also photochemically react with the 2-pyridone, and intramolecularity can control stereo- and regiochemistry, Figure 2.2.
60 Sato and colleagues observed that when cyclic dienes react with 2-pyridones, the major products are a mixture of cis and trans adducts (Scheme 2.4).16,17 The s-cis configuration of the 1,3-cyclopentadiene and the formation of the product are consistent with a [4+4] pathway as the mechanism for the concerted reaction.16 Acyclic dienes utilize a different pathway and, as the products suggest, a [2+2] reaction pathway would be a reasonable explanation regarding the formation of the cyclobutanoid products. In
1999, Sieburth and co-workers continued the study of conjugated pi systems, however these studies were conducted intramolecularly.18 Irradiating 221 formed cyclobutene
Scheme 2.4: Evolution of 2-Pyridone Photoreactions.
61 223 , (Scheme 2.4B). Formation of 222 was consistent with [4+4] cycloaddition of the s- trans diene, producing a cis/trans cyclooctadiene product that undergoes a spontaneous
[3,3] rearrangement to give the observed 223. Upon heating, the divinylcyclobutane 223 rearranged to cis/cis 1,5-cyclooctadiene through a [3,3] sigmatropic shift 18 .
The investigation of the conjugated pi system was then expanded to enynes, and, depending on how the conjugated system was tethered, via either an -ene or -yne connection, the observed products changed. When the photosubstrate was attached to the ene end of the enyne, the major product was cyclobutane 232 19 . Conversely, when the connection was to the alkyne end (234) , the photocycloaddition proceeded through a
[4+4] pathway, to give a highly strained 1,2,5-cyclooctatriene that underwent subsequent dimerizations and other transformations of the highly strained product 235 , Scheme 2.5.
Scheme 2.5: Reactions Pathways for Conjugated Enynes with 2- Pyridone.
62 2.6 Intramolecular [4+4] photocycloadditions: Silicon incorporation in 2-pyridone photochemistry
Expanding on the knowledge of [4+4] cycloadditions, Sieburth and Kulyk took inspiration from Johnson 20 and others and installed a diisopropylsilyl moiety in the three atom bridge of an enyne to a 2-pyridone. Via [4+4] photocycloaddition a 1,2,5- cyclooctatriene was obtained, which contained the incorporated diisopropyl group in a position to protect the reaction from the cyclic allene. For the case of 236 , the allene underwent a 1,3 – proton shift to quantitatively give triene 238 .
Si hv Si [1,3 H] Si O O O
[4+4] N N O O 236 237 238
Scheme 2.6: Formation of Exocyclic Triene 238 as a Result of Steric Shielding with Silicon.
2.7 Photo-[4+4]-Cycloaddition of meta -Substituted Benzenes with 2-Pyridones
The photochemistry of benzene has been studied for over 50 years.21,22 When alkenes photoreact with benzene, ortho, meta or para cycloadditions can result (Figure
A A A A + B B B B ortho meta para 239 240 [2 +2] [3 +2] [2 +2] 241 242 243
Figure 2.3: Three modes of benzene cycloaddition.
63 2.3). Pyridones are known to react photochemically with many different groups including other pyridones, 1,3 dienes, and other aromatic compounds.1 For example, when anthracene or naphthalene is attached to a 2-pyridone, rapid [4+4] cycloaddition occurs to form products 245, 247 and 248 , respectively, Scheme 2.7.23,24 However, when benzene is similarly tethered to pyridone and irradiated, it is inert. Motivated by the work of
Okumura and Gilbert,25,26 Sieburth and coworkers endeavored to explore meta substituted benzene substrates, Table 2.1. 27
O
O N O
N
244 245
O O O N O N O N
246 247 248
Scheme 2.7: Photocycloaddition of anthracene 244 and naphalene 246 tethered to pyridone
Although benzene is unreactive as a photochemistry partner with 2-pyridone 27 , when substituted benzenes are introduced, an efficient [4+4] photocycloaddition is observed.
Sieburth and Khatri 27 have demonstrated that when electron withdrawing groups such as nitrile are installed on the meta position, a number of products resulting from pyridone cycloaddition with the substituted benzenes were found (Table 2.1). Once the meta substitution was deemed successful, a library of electron withdrawing and electron
64 donating substituents were found to promote this reactivity. Although the role of the substituent facilitating the cycloaddition has not yet been made clear, maximizing and building on the utility of this new chemistry has been the most recent focus of the
Sieburth lab.
Table 2.1: Substituted Benzene Photocycloadditions
2.8 Results and Discussion
Silicon has been found to be a very useful substituent in organic synthesis.
Incorporating a silicon moiety onto a benzene ring to investigate the feasibility of producing a [4+4] photocycloadditions seemed to be a logical next step (Figure 2.4). It was proposed to synthesize cyclooctanoids from a benzene, carrying a trimethylsilyl group affixed to the ortho, meta, para positions, tethered to a 2-pyridone. In addition, a
2-pyridone containing dimethylsilyl moiety as part of the tether to a benzene ring (256) was also considered. The ability to access cyclooctanoids using a trimethylsilyl substituted benzene ring such as 253 or 254 would further elaborate on the 2-pyridone
[4+4] cycloaddition methodology and result in incorporation of silicon in many unique molecular scaffolds (Figure 2.4).
65 2.8.1 Synthesis of Starting Materials
TMS TMS O O N O N O
253 254
Me Me Si O O
N O TMS N O
255 256 Figure 2.4: TMS Substituted Benzene – 2-Pyridone Ethers
Synthesis of photosubstrates 253 – 255 was straightforward as outlined in
Schemes 2.8 and 2.9. Starting with hydroxymethyl pyridone 257 , transformation into the corresponding chloride 258 was successful using thionyl chloride in dichloromethane and
258 was used without purification . The Williamson ether synthesis coupling partners
260-262 were made in one step from commercially available starting material. The appropriate bromobenzyl alcohol was treated with two equivalents of n-butyllithium
a. OH SOCl2 Cl
N O DCM N O
257 258
b. nBuLi, Br TMSCl TMS
Et 2O, 0ºC OH OH
259 260 Scheme 2.8: Synthesis of the Photosubstrate Precursors
66 followed by an excess of trimethylsilyl chloride in a solution of tetrahydrofuran to give the appropriate trimethylsilyl substituted alcohols 260 - 262 .
TMS Cl TMS NaH O N O THF, 0ºC N O OH 80% 258 260 253
TMS Cl NaH TMS O N O THF, 0ºC N O OH 78% 258 261 254
TMS Cl NaH O N O N O TMS OH THF, 0ºC 76% 258 262 255
OH Me Me Et 3N Si Si O N O Cl THF, 0ºC N O 60% 257 263 256
Scheme 2.9: Synthesis of the Photosubstrates 253 – 256.
A Williamson ether synthesis, using sodium hydride in tetrahydrofuran with pyridone chloride 258 and the trimethylsilylbenzyl alcohols 260 - 262 afforded the coupled products 253 - 255 with yields ranging from 78 – 80%. To make the dimethylsilyl ether
256 , dimethylphenylchlorosilane 263 was added to a solution of 3-hydroxymethyl pyridone 257 in tetrahydrofuran and triethylamine, and afforded coupled ether 256 in
60% yield.
67 2.8.2 Irradiation of the 2-pyridone trimethylsilyl substituted benzyl ethers i
With photosubstrate 255 in hand, we can now examine the photochemical pathways of the trimethylbenzyl substituted ethers and ideally obtain [4 + 4]
O O TMS O N O hv N O + Complex N Mixture N O TMS C6D6, 5 ºC O TMS O
255 264 TMS
265 Scheme 2.10: Initial Test of 2-Pyridone Trimethylsilyl Substituted Benzene Photochemistry. photoproducts. A 25 mM solution in anhydrous deuterated benzene was prepared and transferred to a 5 mm NMR spectrometer tube. Irradiation of the aryl tethered pyridone with an ultraviolet light above 290 nm (nominally 300 nm) was achieved with a medium- pressure mercury lamp in a water-cooled jacket with a Pyrex filter. After 3 hours of irradiation (monitoring by NMR), the starting 255 had been consumed. However, a mixture of products was obtained, with dimer 265 as the major component, Scheme 2.10.
i This work would not have been possible without the exploratory chemistry conducted by Darius Vrubliauskas, currently a graduate student in the Vanderwal Group at University of California, Irvine.
68 2.8.3 Concentration Dependence of the Photoreaction
Because the photoproducts in the initial reaction did not allow us to access [4 + 4] photoproducts and a significant amount of dimer compound 265 , this observation lead us to ponder what had happened during the reaction. As noted earlier, Nakamura reported that the dimer is the major product when solutions of 2-pyridones at concentrations greater than 0.1 M are irradiated, while isomerization dominates at concentrations below
0.01M (Scheme 2.11). 10 According to a report by Sieburth and Khartri, at low
Scheme 2.11: Concentration dependence of 2-pyridone photoreaction.
concentrations (0.025 – 0.030 M), they were able to access [4+4] photoisomers 267 and
268 (Scheme 2.14).27 This reaction is complicated by additional reactions. Photoproduct
268 undergoes a thermal [3,3] sigmatrophic shift, producing secondary product 270 . In addition, continued irradiation induces octadiene 268 to undergo a [2+2] cycloaddition, forming the new photoproduct 269 .
Photodimerization of 255 to give 265 is an intermolecular process whereas photoreaction of 255 to give 271 is intramolecular. It is surprising that decreasing the concentration of the tethered pyridone would allow the [4+4] photoproducts to be accessed.
69 O O O
O N O N O hv hv, 4 hrs O + N O CN NC N CN CN 266 267 268 269
[3,3]
O O N
CN 270
Scheme 2.12: Photoproducts of the meta -Benzonitrile – 2-Pyridone Photocycloaddition at 25mM.
2.8.4 Photochemistry of the Substrates at Low Concentration
The para-trimethylsilylbenzyl-2-pyridone ether 255 (see Scheme 2.10) was irradiated for 90 minutes in a 5 mM solution of deuterated benzene, at which point the starting material was consumed as shown in Scheme 2.13. Our results were fascinating.
Although we were expecting [4+4] photoproducts, after irradiation, we were able to recover the isomer as the Cope product 272 , in 10% yield. Additionally, the dimer 265 was isolated in 4% yield. Using this as a test reaction, the silane photosubstrates 253 –
256 were irradiated in toluene using a ‘flow’ reaction setup. Flow chemistry was used because larger quantities of substrates could be processed without disturbing the light source. The photochemistry was performed in toluene from 2 – 8 oC. Interestingly, we were only able to isolate the dimer. The results are shown in Table 2.2.
70
O O O O O O N O N N N O TMS hv, 90 min hv ≡ TMS [3,3] H H TMS TMS
255 271 272 272
+
O O TMS
N
N
O O
TMS
265 Scheme 2.13: Photoproducts of the para -Trimethyl Substituted Benzene – 2-Pyridone Photocycloaddition.
2.9 Conclusion
The ability to make [4+4] photoreactions occur using trimethylsilyl substituted
benzene – pyridone ethers was demonstrated. However, only the Cope rearrangement
were able to be isolated due to a rapid isomerization. These photoproducts can still be
functionalized, and functionalization can include transformations such as halogenation
and ozonolysis.
71 O O O O O N O N N hv, hv 255 ≡ 0ºC, toluene TMS [3,3] H H 90 min TMS TMS
271 272 272
O O O O O N O N N hv TMS TMS ≡ [3,3] H TMS
hv, 253 273 275 275 0ºC, toluene 90 min O O O O TMS O N O N TMS TMS N hv
[3,3] H H
274 276 276
O O O O O N O N N hv ≡ [3,3] TMS H H TMS TMS hv, 254 0ºC, toluene 277 279 279 90 min O O O O O N O N TMS TMS TMS N hv ≡ [3,3] H H
278 280 280
O O O O O Si N O N Si Si N hv, hv 256 0ºC, toluene ≡ 90 min [3,3] H H
281 282 282
Scheme 2.14: Complete Library of Possible [4+4] and Cope Photoproducts.
72
Table 2.2 : Photoproducts and Yields of the Trimethylsilane Substituted – Pyridone ethers.
Although the yields listed are unexpectedly abysmal, the results reported are isolated
yields. If the experiment were to be reproduced, adding an internal standard to the NMR
tubes would help determine the yields of all products as a results of photoirradiation.
73 2.10 Experimental
General Procedure 2.1 – Photochemistry: Batch Reactions: A solution of the substrate to be irradiated was prepared in the indicated solution. These substrates were irradiated for 90 minutes (unless otherwise indicated) using a water-cooled, Pyrex- filtered 450W medium-pressure mercury vapor. The reaction progress was monitored by
1H NMR or TLC. After completion, the reaction mixture was concentrated in vacuo .
Purification by column chromatography gave the title compound as indicated.
Note: Due to heat given off by the light source, the air temperature within the photo reaction container was typically 35 oC (as monitored by a probe inside the container).
The temperature of the reaction could be controlled by placing the entire set-up inside a
Dewar flask with circulating water and ice.
Flow Reaction Setup: Using the light source described above, FEP tubing
(0.187” OD x 0.125” ID) was wrapped once aroud a Pyrex water-cooling jacket with an external diameter of 5 centimeters . The tubing length was such that it had an internal volume (in contact with the light source) of 40 mL. A KD Scientific syringe pump was used to drive the solution and control the flow rate (irradiation time). Reaction progress was monitored by TLC.
74 O LAH CH 3I OH OH OH 0 ºC K CO , MeOH N O N O N O 2 3 H reflux H 283 284 257 3-(Hydroxymethyl)-1-methylpyridin-2(1 H)-one (257): 28,29 To a flame dried round bottom flask was added THF (200 mL) which was cooled to 0 oC. While stirring, lithium aluminum hydride (4.10 g, 107.8 mol) was added in several portions at 0 oC. After 30 minutes, 2-hydroxynicotinic acid (10.1g, 71.9 mmol) was added in several small portions taking care to allow the gas evolution to subside. The mixture was stirred, slowly warmed to rt and then refluxed for 14 hours. The reaction mixture was cooled to rt and then the reaction vessel was immersed in an ice water bath to cool it to 0 oC. To the reaction mixture was added ether. Slow, sequential addition of water (4.09 mL), 15% aqueous sodium hydroxide (4.09 mL) and the addition of water (12.3 mL) produced a white suspension. After magnesium sulfate and Celite ™ were added to this suspension, the solids were filtered and and the solid residue was extracted with methanol in a
Soxhlet extractor for 4 days. The filtrate and extracts were concentrated in vacuo . The crude pyridone alcohol was dissolved in anhydrous methanol (150 mL) and potassium carbonate (24.8 g, 179.7 mmol) was added while the mixture was stirring. To the suspension was added methyl iodide (22.4 g, 359.5 mmol) and the reaction stirred overnight. The solid potassium carbonate was placed into a Soxhlet extractor for 4 days with ethyl acetate, changing the round bottom and adding fresh solvent once per day. The combined organics were concentrated in vacuo and purified by silica-gel chromatography to afford the known compound as a colorless solid (65%). R f = 0.21 (3% MeOH/DCM).
75 1 H NMR (500 MHz, CDCl 3) δ = 7.30 (ddt, J= 6.7, 1.8, 0.8, 1H), 7.26 (dd, J= 6.8, 1.9,
1H), 6.19 (t, J= 6.8, 1H), 4.57 (s, 2H), 3.57 (s, 3H)
nBuLi, Br TMSCl TMS
Et 2O, 0ºC OH OH
259 260
(2-(Trimethylsilyl)phenyl)methanol (260): 30 To a flame dried 250 mL round bottom flask equipped with a stirbar, (2-bromophenyl)methanol (1.00 g, 5.34 mmol) and diethyl ether (10 mL) were added with stirring under argon while stirring and cooled to 0 oC. N-
Butyllithium (4.8 mL, 12 mmol) was added dropwise over a period of 15 minutes and allowed to react for 30 minutes. Freshly distilled trimethylsilyl chloride (3.43 mL, 27 mmol) was added dropwise at 0 oC and the mixture was allowed to react overnight. The reaction mixture was cooled to 0 oC and saturated aqueous ammonium hydroxide was added. The aqueous phase was extracted with ethyl acetate and the combined organics were washed with brine. The combinded organic layers were concentrated in vacuo and purified by silica-gel chromatography to afford the title compound, 260 , as a yellow oil
(50%) 1H NMR (500 MHz, Chloroform-d) δ 7.55 (dd, J = 7.4, 1.4 Hz, 1H), 7.48 (ddd, J =
7.6, 1.4, 0.7 Hz, 1H), 7.41 (td, J = 7.5, 1.5 Hz, 1H), 7.30 (td, J = 7.4, 1.3 Hz, 1H), 4.77 (s,
2H), 0.36 (s, 9H).
76 TMS
OH
261
(3-(Trimethylsilyl)phenyl)methanol (260): 30 To a flame dried 250 mL round-bottom flask equipped with a stirbar, (3-bromophenyl)methanol (1.00 g, 5.34 mmol) and diethyl ether were added under argon while stirring and cooled to 0 oC. N-butyllithium (4.8 mL,
12 mmol) was added dropwise over a period of 15 minutes and allowed to react for 30 minutes. Freshly distilled trimethylsilyl chloride (3.43 mL, 27 mmol) was added dropwise at 0 oC and the mixture was allowed to stir overnight. The reaction mixture was cooled to 0 oC and saturated aqueous ammoniuim hydroxide was added to quench the mixture. The organic layers were extracted with ethyl acetate and subsequently washed with brine. The combined organic layers were concentrated in vacuo and purified by silica-gel chromatography to afford the title compound, 261, as a yellow oil (50%). 1H
NMR (500 MHz, Chloroform-d) δ 7.53 (d, J = 1.6 Hz, 1H), 7.48 (ddd, J = 5.3, 3.4, 1.2
Hz, 1H), 7.43 – 7.34 (m, 2H), 4.70 (s, 2H), 0.29 (s, 9H).
TMS
HO 262
(4-(Trimethylsilyl)phenyl)methanol (262) To a flame dried 250 mL roundbottom flask equipped with a stirbar, (3-bromophenyl)methanol (1.00 g, 5.34 mmol) and diethyl ether were added under argon, the solution was stirring and cooled to 0 oC, then n-butyllithium
(4.8mL, 12 mmol) was added dropwise over a period of 15 minutes and allowed to react
77 for 30 minutes. Freshly distilled trimethylsilyl chloride (3.43 mL, 27 mmol) were added dropwise at 0 oC and the mixture was allowed to react overnight. The reaction mixture was cooled to 0 oC and saturated aqueous ammoniuim hydroxide was added to quench the mixture. The organic layers were extracted with ethyl acetate and subsequently washed with brine. The combinded organic layers were concentrated in vacuo and purified by silica-gel chromatography to afford the title compound, 262, as a yellow oil
(50%). 1H NMR (500 MHz, Chloroform-d) δ 7.54 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 7.5,
0.7 Hz, 2H), 4.69 (s, 2H), 0.28 (s, 9H).
TMS Cl NaH O N O THF, 0ºC OH N O TMS
258 262 255
1-Methyl-3-(((4-(trimethylsilyl)benzyl)oxy)methyl)pyridin-2(1 H)-one (255): To a flame dried 50-mL round bottom flask equipped with a magnetic stirbar was added pyridone alcohol 257 (0.600 g, 4.31 mmol) was added DCM (10 mL). The reaction flask was vented while thionyl chloride (1.06 mL, 4.74 mmol) was added dropwise. After the evolution of gas subsided, the reaction was allowed to proceed for 2 hours. Upon completion of the reaction, as indicated by TLC, the reaction mixture was concentrated in vacuo . To another flame dried flask was added sodium hydride in mineral oil (168 mg,
31.4 mmol) and THF (12 mL) was added and then cooled to 0 oC. A solution of 262
(0.755 g, 4.19 mmol) in THF (13.6 mL) was added dropwise to the mixture containing
258 over 30 minutes. The reaction was allowed to stir overnight. Upon completion, as indicated by TLC, the mixture was diluted with saturated aqueous ammonium chloride
78 and water. The layers were separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with water, brine and then dried over anhydrous sodium sulfate and concentrated in vacuo to give crude chloride 258 .
The crude product was purified via silica gel chromatography to afford the title compound as a colorless oil (80%).
Rf = 0.19 in 40% EtOAc/hexanes IR (neat): 2951, 2871, 2160, 2032, 1648,1584, 1476,
1263, 1215, 833,806 cm -1. 1H NMR (500 MHz, Chloroform-d) δ 7.51 (m, J = 7.9 Hz,
3H), 7.38 (d, J = 7.7 Hz, 2H), 7.22 (dd, J = 6.7, 1.8 Hz, 1H), 6.20 (t, J = 6.8 Hz, 1H),
4.65 (s, 2H), 4.52 (s, 2H), 3.55 (s, 3H), 0.26 (s, 9H). 13 C NMR (126 MHz, Chloroform-d)
δ 161.7, 140.6, 137.3, 136.4, 135.5, 132.6, 129.8, 128.3, 127.8, 105.7, 73.3, 67.4, 37.4, -
1.2.
TMS
O
N O
253
1-Methyl-3-(((2-(trimethylsilyl)benzyl)oxy)methyl)pyridin-2(1 H)-one (253): To a flame dried 50-mL round bottom flask equipped with a magnetic stirbar was added pyridone alcohol 257 (0.600 g, 4.31 mmol) and added DCM (10 mL). The reaction flask was vented while thionyl chloride (1.06 mL, 4.74 mmol) was added dropwise. After the evolution of gas subsided, the reaction was allowed to proceed for 2 hours. Upon completion of the reaction, as indicated by TLC, the reaction mixture was concentrated in vacuo to give crude . To another flame dried flask was added sodium hydride in mineral oil (168 mg, 31.4 mmol) and THF (12 mL) was added and then cooled to 0 oC. A solution
79 of 260 (0.755 g, 4.19 mmol) in THF (13.6 mL) was added dropwise to the mixture containing crude 258 over 30 minutes. The reaction was allowed to stir overnight. Upon completion, as indicated by TLC, the reaction mixture was diluted with saturated aqueous ammonium chloride and water. The layers were separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with water, brine and then dried over anhydrous sodium sulfate and concentrated in vacuo . The crude product was purified via silica gel chromatography to afford the title compound as a colorless oil (75%). Rf = 0.19 in 40% EtOAc/hexanes. IR (neat): 2951, 2873, 2519,
2160, 2031, 1648, 1583, 1458, 1435, 1411, 1373, 1315, 1264, 1247, 1207, 1127, 1099,
980, 955, 937, 834 cm -1. 1H NMR (500 MHz, Chloroform-d) δ 7.70 – 7.43 (m, 2H), 7.37
(td, J = 7.5, 1.5 Hz, 1H), 7.28 (dd, J = 7.4, 1.3 Hz, 1H), 7.28 – 7.18 (m, 1H), 6.19 (t, J =
6.8 Hz, 1H), 4.73 (s, 2H), 4.55 (s, 2H), 3.56 (s, 1H), 0.32 (s, 9H). 13 C NMR (126 MHz,
Chloroform-d) δ 161, 143.5, 138.4, 136.3, 135.3, 134.6, 129.2, 128.4, 127.0, 105.7, 73.3,
67.4, 37.5, 0.3.
TMS O
N O
254 1-Methyl-3-(((3-(trimethylsilyl)benzyl)oxy)methyl)pyridin-2(1 H)-one (254): To a flame dried 50-mL round bottom flask equipped with a magnetic stirbar was added pyridone alcohol 257 (0.600 g, 4.31 mmol) was added DCM (10 mL). The reaction flask was vented while thionyl chloride (1.06 mL, 4.74 mmol) was added dropwise. After the evolution of gas subsided, the reaction was allowed to proceed for 2 hours. Upon completion of the reaction, as indicated by TLC, the reaction mixture was concentrated in vacuo . To another flame dried flask was added sodium hydride (168 mg, 31.4 mmol) and
80 THF (12 mL) was added and then cooled to 0 oC. A solution of 261 (0.755 g, 4.19 mmol) in THF (13.6 mL) was added dropwise to the mixture containing 258 over 30 minutes.
The reaction was allowed to stir overnight. Upon completion, as indicated by TLC, the reaction mixture was diluted with saturated aqueous ammonium chloride and water. The layers were separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with water, brine and then dried over anhydrous sodium sulfate and concentrated in vacuo . The crude product was purified via silica gel chromatography to afford the title compound as an orange oil (80%). Rf = 0.19 in 40%
EtOAc/hexanes. IR (neat): 2952, 2871, 2160, 2932, 1648, 1584, 1564, 1458, 1435, 1412,
1374, 1315, 1264, 1248, 1214, 1098, 1080, 834, 608, 554 cm -1. 1H NMR (500 MHz,
Benzene-d6) δ 7.64 (s, 1H), 7.46 – 7.35 (m, 3H), 7.24 (t, J = 7.5 Hz, 1H), 6.20 – 6.06 (m,
1H), 5.54 (t, J = 6.8 Hz, 1H), 4.75 (s, 2H), 4.49 (s, 2H), 2.85 (s, 3H), 0.22 (s, 9H). 13 C
NMR (126 MHz, CDCl 3) δ 171.9, 142.2, 141.0, 134.0, 134.6, 128.2, 74.5, 71.4, 66.0,
59.1, 31.4, 30.8 , 0.0.
OH Me Me Et 3N Si Si O N O Cl THF, 0ºC N O 60% 257 263 256
3-(((Dimethyl(phenyl)silyl)oxy)methyl)-1-methylpyridin-2(1 H)-one (256): To a flame dried 150-mL round bottom flask equipped with a magnetic stirbar was added pyridone alcohol 257 (0.318 g, 2.34 mmol) and THF (10 mL). After cooling to 0 oC, freshly distilled triethylamine (414 L) was added to the reaction vessel and the mixture stirred for 30 minutes. A solution of phenyldimethylsilylchloride 263 (0.318 g, 2.34mmol) in
THF (8.5 mL) was added dropwise to the mixture over 30 minutes. The reaction was 81 allowed to stir overnight. Upon completion, as indicated by TLC, the reaction mixture was diluted with saturated aqueous ammonium chloride and water after 1 day. The layers were separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with water, brine and then dried over anhydrous sodium sulfate and concentrated in vacuo . The crude product was purified via silica gel chromatography to afford the title compound as a yellow oil (62%). Rf = 0.23 in 40%
EtOAc/hexanes. IR (neat): 3055, 2953, 2873, 2160.17, 2031, 1649, 1584, 1563, 1459,
1427, 1374, 1314, 1248, 1099,979, 954, 934, 830, 769, 644, 555 cm -1. 1H NMR (500
MHz, Chloroform-d) δ 7.60 (dd, J = 7.5, 1.8 Hz, 2H), 7.52 (dd, J = 6.8, 1.8 Hz, 1H), 7.45
– 7.32 (m, 3H), 7.19 (dd, J = 6.7, 2.0, 1.0 Hz, 1H), 6.21 (t, J = 6.8 Hz, 1H), 4.65 (s, 2H),
3.53 (s, 3H), 0.44 (s, 6H). 13 C NMR (126 MHz, Chloroform-d) δ 161.4, 137.4, 137.1,
136.0, 134.0, 133.0, 129.7, 127.9, 105.8, 62.9, 60.5, 37.2, 29.7.
O O TMS
N
N
O O
TMS
265
(1 S,2 R,6 S)-3,7-Dimethyl-1,5-bis(((4-(trimethylsilyl)benzyl)oxy)methyl)-3,7- diazatricyclo[4.2.2.2 2,5 ]dodeca-9,11-diene-4,8-dione (265): A solution of 255 (1.22 mg, 4.5 μmol ) in C 6D6 (1.2 mL) was treated according to general procedure 2.1 in an
NMR tube. The crude material was purified by column chromatography with 0 – 40% 82 EtOAc/ hexanes to afford the title compound as a colorless oil: R f = 0.2 in 40% EtOAc/ hexanes. IR (neat)= 1657, 1607, 1596, 1578, 1512, 1334, 1218, 1289, 1185, 1106, 718,
704, 608 cm -1. 1H NMR (500 MHz, Chloroform-d) δ 7.50 (d, J = 7.8 Hz, 4H), 7.31 (d, J =
7.6 Hz, 4H), 6.64 (d, J = 2.6 Hz, 2H), 6.57 (t, J = 2.7 Hz, 2H), 5.04 – 4.40 (m, 4H), 4.29
(d, J = 2.8 Hz, 2H), 3.92 (d, J = 11.0 Hz, 2H), 3.79 (d, J = 11.0 Hz, 2H), 2.80 (s, 6H),
13 0.26 (s, 18H ). C NMR (126 MHz, CDCl 3) δ 171.9, 142.2, 141.0, 134.0, 134.6, 128.2,
127.0, 74.5, 71.4, 66.0, 59.1, 31.4, 30.8 , 0.00.
O O
N
TMS H H
272
(7a S,7b R)-5-Methyl-9-(trimethylsilyl)-7a,7b-dihydro-1H,3 H- benzo[3,4]furo[3',4':1,4]cyclobuta[1,2-c]pyridin-4(5 H)-one (272): A solution of 255
(75 mg, 249 L) in toluene (100 mL) was treated according to general procedure 2.1 using the Flow Reaction Setup. (4mg, 5% yield).Purified by column chromatography with 0 – 40% EtOAc/ hexanes to afford the title compound as a colorless oil (10% yield):
Rf = 0.83 in 40% EtOAc/ hexanes. IR (neat): 2954, 2160, 2027, 1713, 1651, 1437, 1396,
1290, 1247, 1207, 1103, 1061, 932, 836, 802, 748, 492 cm -1. 1H NMR (500 MHz,
Benzene-d6) δ 5.88 (d, J = 9.7 Hz, 1H), 5.46 – 5.40 (m, 2H), 5.35 (dd, J = 9.7, 1.4 Hz,
1H), 4.57 (d, J = 8.9 Hz, 1H), 4.33 (d, J = 12.6 Hz, 6H), 3.75 (d, J = 9.0 Hz, 1H), 3.73 (d,
J = 9.2 Hz, 1H), 3.35 (d, J = 9.1 Hz, 1H), 3.13 (dd, J = 9.5, 4.8 Hz, 1H), 3.02 (dd, J = 9.5,
13 4.5, 1.1 Hz, 2H), 2.69 (s, 3H), 0.07 (s, 9H). C NMR (126 MHz, CDCl 3) δ 168.0, 136.5,
134.4, 132.0, 127.0 122.9, 105.6, 81.5, 79.9, 65.0, 58.8, 46.5, 44.7, 36.7, 0.00.
83
O O TMS
N
H H
276
(7a S,7b S)-5-methyl-11-(trimethylsilyl)-7a,7b-dihydro-1H,3 H- benzo[3,4]furo[3',4':1,4]cyclobuta[1,2-c]pyridin-4(5 H)-one (276): A solution of 253
(75 mg, 249 L) in C 6D6 (100 mL) was treated according to general procedure 2.1:
Flow conditions . The mixture was purified by column chromatography with 0 – 40%
EtOAc/ hexanes to afford the title compound as a colorless oil (4 mg/ 5% yield ): R f =
0.83 in 40% EtOAc/hexanes. IR=2160, 2032, 1250, 904, 839, 649, 432 cm -1. 1H NMR
(500 MHz, Benzene-d6) δ 6.57 (d, J = 6.7 Hz, 1H), 6.27 (dd, J = 8.0, 1.4 Hz, 1H), 5.92
(ddd, J = 7.7, 6.8, 0.7 Hz, 1H), 5.80 (dd, J = 8.2, 6.8 Hz, 1H), 5.42 (dd, J = 8.2, 1.6 Hz,
1H), 5.16 (d, J = 8.9 Hz, 1H), 4.08 (d, J = 9.4 Hz, 1H), 3.79 (d, J = 9.4 Hz, 1H), 3.43 (d,
J = 8.9 Hz, 1H), 2.92 (ddd, J = 9.6, 6.8, 1.6 Hz, 1H), 2.72 – 2.59 (m, 1H), 2.56 (s, 3H),
13 0.08 (s, 9H). C NMR (126 MHz, C 6D6) δ 174.2, 149.6, 149.4, 143.9, 138.1, 134.6,
132.8, 77.5, 74.9, 68.7, 66.2, 61.3, 45.0, 36.0, 0.2.
84 O O
N
H H TMS
279
(7a S,7b R)-5-methyl-9-(trimethylsilyl)-7a,7b-dihydro-1H,3 H-benzo[3,4]furo
[3',4':1,4]cyclobuta[1,2-c]pyridin-4(5 H)-one (279) : A solution of 252 (75 mg, 249 L) in C 6D6 (100 mL) was treated according to general procedure 2.1 . The crude mixture was purified by column chromatography with 0 – 40% EtOAc/ hexanes to afford the title compound as a colorless oil (4 mg, 5% yield ): R f = 0.53 in 40% EtOAc/hexanes. IR =
2160, 2031, 1653, 1559, 904, 839, 726, 650, 476, 488 cm -1. 1H NMR (500 MHz,
Benzene-d6) δ 6.03 (dt, J = 5.5, 0.8 Hz, 1H), 5.75 (dd, J = 9.8, 5.5 Hz, 1H), 5.46 (dd, J =
8.2, 1.6 Hz, 1H), 5.39 (d, J = 9.8 Hz, 1H), 4.83 (d, J = 9.1 Hz, 1H), 4.52 (dd, J = 8.3, 4.1
Hz, 1H), 3.85 (d, J = 9.0 Hz, 1H), 3.69 (d, J = 9.2 Hz, 1H), 3.59 (d, J = 9.4 Hz, 1H), 3.28
(d, J = 9.2 Hz, 1H), 3.07 (ddd, J = 9.4, 4.2, 1.7 Hz, 1H), 2.71 (s, 3H), -0.01 (s, 9H). 13C
NMR (126 MHz, CDCl 3) δ 150.5, 143.1, 136.9, 134.0, 133.4, 131.6, 128.6, 124.9, 106.6,
80.2, 76.3, 63.8, 60.1, 36.6, 0.00.
Si O O
N
N
O O Si
284 (1 S,2 R,6 S)-1,5-bis(((Dimethyl(phenyl)silyl)oxy)methyl)-3,7-dimethyl-3,7- diazatricyclo[4.2.2.22,5]dodeca-9,11-diene-4,8-dione (284): A solution of 256 (75 mg,
249 L) in C 6D6 (100 mL) was treated according to general procedure 2.1 . Purified by
85 column chromatography with 0 – 40% EtOAc/ hexanes to afford the title compound as a colorlessoil (5% yield ). Rf= 0.6 in 40 EtOAc/hexanes. IR (neat): 3110, 2448, 2160,
2030, 1978, 1658, 1698, 1597, 1514, 1447, 1334, 1220, 1107, 983, 783, 706 cm -1. 1H
NMR (500 MHz, Chloroform-d) δ 7.56 (dd, J = 7.5, 1.9 Hz, 2H), 7.48 – 7.34 (m, 2H),
6.60 (d, J = 2.5 Hz, 2H), 6.49 (t, J = 2.6 Hz, 2H), 4.15 (d, J = 2.8 Hz, 2H), 4.08 (d, J =
11.7 Hz, 2H), 3.91 (d, J = 11.7 Hz, 6H), 2.77 (s, 2H), 0.38 (d, J = 5.3 Hz, 12H).
TMS
O O
N
N
O O TMS
284 (1 S,2 R,6 S)-3,7-Dimethyl-1,5-bis(((3-(trimethylsilyl)benzyl)oxy)methyl)-3,7- diazatricyclo[4.2.2.22,5]dodeca-9,11-diene-4,8-dione (284): A solution of 254 (75 mg,
249 L) in C 6D6 (100 mL) was treated according to general procedure 2.1 . The mixture was purified by column chromatography with 0 – 40% EtOAc/ hexanes to afford the title
1 compound as a colorlessoil (5% yield ): H NMR (500 MHz, Benzene-d6) δ 7.63 (dt, J =
1.2, 0.6 Hz, 2H), 7.39 (dt, J = 7.2, 1.3 Hz, 4H), 7.37 – 7.31 (m, 4H), 7.28 – 7.20 (m, 4H),
6.16 (t, J = 2.7 Hz, 2H), 6.01 (d, J = 2.5 Hz, 4H), 4.41 (d, J = 2.5 Hz, 3H), 3.79 (d, J =
7.6 Hz, 4H), 3.77 (s, 4H), 3.59 (d, J = 11.0 Hz, 2H), 2.31 (s, 6H), 0.25 (s, 18H).
86
2.11 References
(1) Sieburth, S. M. Photochemical Reactivity or Pyridones. CRC Handbook of
Photochemistry and Photobiology ; CRC Press, 2004.
(2) Jones Jr., M.; Fleming, S. Organic Chemistry ; Fahlgren, E., Ed.; W.W. Norton &
Company, Inc., 2010.
(3) Singh, J.; Singh, J. Cycloaddition Reactions. In Photochemistry and Pericyclic
Reactions (3rd Edition) ; New Academic Science, 2012; pp 58–110.
(4) Woodward, R. B.; Hoffmann, R. The Conservation of Orbital Symmetry. Angew.
Chemie - Int. Ed. 1969 , 8 (11), 781–852.
(5) Fukui, K.; Yonezama, T.; Shingu, H. A Molecular Orbital Theory or Reactivity in
Aromatic Hydrocarbons. J. Chem. Phys. 1951 , 20 , 722–725.
(6) Fritzsche. Ueber Die Festen Kohlenwasserstoffe Des Steinkohlentheers. J. fur
Prakt. Chemie 1867 , 101 (1), 333–343.
(7) Taylor, E. C.; Paudler, W. W. Photodimerization of Some Alpha, Beta Unsaturated
Lactams. Tetrahedron Lett. 1960 , 25 , 1–3.
(8) Trecker, D. J. Photodimerizations. Org. Phtochem. 1968 , 2, 63–116.
(9) Selms, R. C. De; Schleigh, W. R. Heterocyclodienone Photochemistry I. Photo-2-
Pyridone. Tetrahedron Lett. 1972 , 34 (3), 68–70.
87 (10) Nakamura, Y.; Kato, T.; Morita, Y. Structures of the Four Possible [4 + 4]
Cycloaddition Products Formed on Photodimerization of N-Alkyl-2-Pyridones. J.
Chem. Soc. Perkins Trans. 1 1982 , 1187.
(11) Sharp, K. J.; Hammond, G. S. Photoreactions of N-Methyl-2-Pyridone. Mol.
Photochem. 1970 , 2, 225–250.
(12) Matsushima, R.; Terada, K. Photoreactions of Alkylated 2-Pyridones. Perkin
Trans. 2 1985 , No. 9, 1445–1448.
(13) Taylor, E. C.; Kan, R. O. Photochemical Dimerization of 2-Aminopyridines and 2-
Pyridones. J. Am. Chem. Soc. 1963 , 85 (6), 776–784.
(14) Sieburth, S. M.; Chen, J.; Ravindran, K.; Chen, J.-L. A 2-Pyridone Photo-[4 + 4]
Approach to the Taxanes. J. Am. Chem. Soc. 1996 , 118 , 10803.
(15) Sieburth, S. M.; McGee K.F., J.; Al-Tel, T. H. Fusicoccin Ring System by [4 + 4]
Cycloaddition. Control of Diastereoselectivity through Hydrogen Bonding. J. Am.
Chem. Soc. 1998 , 120 (3), 587–588.
(16) Kanaoka, Y.; Ikeda, Y.; Sato, E. PHOTOCHEMISTRY OF 2-PYRIDONES.
PHOTOADDITION WITH CONJUGATED DIENES. Heterocycles 1984 , 1 (2),
645.
(17) Sato, E.; Ikeda, Y.; Kanaoka, Y. PHOTOADDITION OF 2-PYRIDONES TO
CONJUGATED DIENES." Heterocycles 1989 , 28 , 117–120.
(18) Sieburth, Scott Mc N.; Zhang, F. INTRAMOLECULAR
88 PHOTOCYCLOADDITION OF 1,3-DIENES WITH 2-PYRIDONES Scott.
Tetrahedron Lett. 1999 , 40 , 3527–3530.
(19) Kulyk, S.; Dougherty Jr, W. G.; Scott Kassel, W.; Zdilla, M. J.; Sieburth, S. N.
Intramolecular Pyridone/Enyne Photocycloaddition: Partitioning of the [4 + 4] and
[2 + 2] Pathways. Org. Lett. 2011 , 13 (9), 2180–2183.
(20) Price, J. D.; Johnson, R. P. Small-Ring Cyclic Cumulenes: Synthesis of a
Kinetically Stable Eight Membered Ring Allene. Tetrahedron Lett. 1986 , 27 (39),
4679–4682.
(21) Bryce-Smith, D. Organometallic Compounds of the Alkali Metals. Part VI.
Evidence for the Formation of Free Alkyl Radicals during Certain Wurtz
Reactions. Homolytic Reactions between Alkyl-Lithium Compounds and Alkyl
Halides. J. Chem. Soc. 1956 , 0, 1603–1610.
(22) Bryce-Smith, D.; Gilbert, A. The Organic Photochemistry of Benzene—I.
Tetrahedron 1976 , 32 , 1309–1326.
(23) Khatri, B. B.; Kulyka, S.; Sieburth, S. M. Enyne [4+4] Photocycloaddition with
Polycyclic Aromatics. Org. Chem. Front. 2014 , 1, 961.
(24) Sieburth, S. M. N.; McGee, K. F.; Zhang, F.; Chen, Y. Photoreactivity of 2-
Pyridones with Furan, Benzene, and Naphthalene. Inter- and Intramolecular
Photocycloadditions. J. Org. Chem. 2000 , 65 (7), 1972–1977.
(25) Okumura, K.; Takamuku, S.; Sakurai, H. Photochemical Reaction of Benzonitrile
89 with 2,3-Dimethylbutadiene. J. Soc. Ind., Jpn. 1969 , 72 (1), 200–203.
(26) Gilbert, A.; Griffiths, O. Substituent-Directed Regioselectivity in the
Photocycloaddition of 2,3-Dimethylbuta-1,3-Diene to the Benzene Ring. J. Chem.
Soc., Perkin Trans. 1 1993 , (13), 1379–1384.
(27) Khatri, B. B.; Vrubliauskas, D.; Sieburth, S. M. N. Photo-[4+4]-Cycloaddition
(Para) of Meta-Substituted Benzenes with 2-Pyridones. Tetrahedron Lett. 2015 , 56
(30), 4520–4522.
(28) Kulyk, S.; Dougherty, W. G.; Kassel, W. S.; Fleming, S. A.; Sieburth, S. M.
Bridged 1 , 2 , 5-Cyclooctatrienes. Org. Lett. 2010 , No. 10, 10–13.
(29) Inouye, M.; Kim, K.; Kitao, T. Selective Coloration of Spiro Pyridopyrans for
Guanosine Derivatives. J. Am. Chem. Soc. 1992 , 114 (2), 778–780.
(30) Clausen, M. H.; Larsen, T. O.; Mier, W.; Pedersen, P. J.; Nissen, F.; Rønnest, M.
H. A Mild Method for Regioselective Labeling of Aromatics with Radioactive
Iodine. Euro. J. Org. Chem. 2013 , 2013 (19), 3970–3973.
90
CHAPTER 3
CUBANE – LIKE STRUCTURES
3.1 Properties of Cubane
Cubane (Figure 3.1) is an interesting molecule because it has a number of physical properties that no other stable hydrocarbon possesses. The structure of the cubane molecule, C 8H8, lends itself to be thermodynamically unstable ∆ =
144 / and highly strained (SE= 161.5 kcal/mol), nevertheless it has a
301 Figure 3.1: Cubane 7 remarkable kinetic stability and is able to withstand temperatures of up to 220 oC. 1–5 At temperatures of 230-260 oC, at constant pressure, the C-C bond can indeed be cleaved,
Scheme 3.1. The activation energy for the pyrolysis of cubane is 43.1 kcal/mol and the origin to the large barrier to ring opening can be explained by the absence of symmetry- allowed pathways for concerted two bond ring opening, and the limited relief in ring strain (72 kcal/ mol) yielded by the conversion of 301 to syn tricyclo[4.2.0.0] octa-3,7- diene due to intermediate 302 en route to 303 , as a result of the homolysis of the carbon- carbon bond. 6
3.2. Early Synthesis of Cubane
Eaton and Cole were the first to report the synthesis of cubane in 1964. The synthesis of the molecular core was the preparation of cubane dimethyl ester 313 and the second was the synthesis of cubane itself, 301 .7,8 Starting with 2-cyclopentenone, 304 ,
91
∆ Hf* = 43 kcal/ mol
∆ (∆H *) = -31 kcal/ mol 301 f 303
302 Scheme 3.1: Thermal Ring Opening of Cubane cubane was accessed in 8 steps with a yield of 12%. Scheme 3.2.7 Eaton was able to achieve this because he employed a highly endo -selective [4 + 2 ] Diels-Alder dimerization of the highly reactive, in situ generated because of the instability of the intermediate, 2-bromocyclopentadienone, which produced the endo-dimer 308A .
Secondly, the [2 + 2 ] ene-enone photocycloaddition of 308A produced 309 . Finally, a double Favorski ring contraction of the cage dione 309 produces the dipotassium dicarboxylate 311 . Esterification of the dicarboxylic acid gave diester 310 . They explain that this sequence demonstrated the intrinsic kinetic stability of the cubane nucleus, as it was not affected during these transformations.
Eaton and Cole also noted that the conversion of diene 307 to its corresponding dimer 308A proceeded with complete stereoselectivity and could be explained using three different rationales (Scheme 3.3). Primarily, the dimerization should occur in accordance with the dimerization of cyclopentadienones and proceed through an endo transition state. Secondly, the authors reasoned that the dienophilic reactivity of 307 would be lowest at the halogen-substituted double bond, stating that one vinyl position should be attached to a bromine, rather than a hydrogen atom. Finally, they postulated that the dipole interactions should be minimized in the transition state geometry for the
Diels-Alder dimerization of 307 , more specifically, the transition state of A should be
92 more favorable than that of B (Figure 2), which explains the formation of 308A as the product.
O O O NBS O Br 2 Et 2NH Br CCl Br 4 pentane/DCM Br ether, -20 ºC Br 0 -10 ºC Br 40%, (3 steps)
304 305 306 307
Br CO 2R 1) 50% aq, KOH, ∆ O O then acidic workup (311) hv (Hg), MeOH, HCl Br
2) MeOH, cat, H2SO 4, ∆ Br RO C 30% (3 steps) (312) then H2O, ∆ 2 O Br O
310 R = Me 309 308A
311 R = K 312 R = H
Scheme 3.2: Eaton and Cole’s Synthesis of the Cubane Ring System
3.3 Chemical Reactivity of Cubane
The chemical activity of the cubane nucleus is interesting and through its extensive study, the cubyl radical 8, which lends itself to hydrogen atom abstraction 9, halogen abstraction 10–12 and decarboxylation 13 , of which some method, based on
Barton 14 , have been dutifully reported. However, in this chapter, further discussion will be devoted to rearrangements involving cubane and its derivatives, including cubene.
93
3.4 Rearrangements
3.4.1 Cubene
The possibility of forming cubene, or 1,2-dehydrocubane, (Figure 3.3) was deemed implausible due to it being one of the most pyrimidalized alkenes. 15–17 Hrovat and Borden calculated the pyridmidization angle to be 84 o (Figure 3.2), and this resulted in a questioning of the probability of the existence of such a molecule. 18 Incredibly, in
1988,
84 o
313
Figure 3.2: Pyrimidization Angle of Cubene
Eaton and coworkers made the discovery when they attempted to synthesize cubane for the first time. When they reacted monoiodocubane in the presence t-butyllithium, only cubyllithium was accessed. When 1,2-diiodocubane was reacted with t-butyllithium they reported that the product mixture contained tert-butyl cubanes and cubylcubanes,
Scheme 3.4.12 The best rationale for this was the presence of a cubene intermediate.
Cubene was also inferred when it reacted with as a Diels-Alder dienophile.
Reaction of 1,2-diiodocubane with tert – butyllithium in the presence of 11,12- dimethylene-9,10-dihydro-9,10-ethanoanthracene, gave the corresponding Diels-Alder adduct 335 formed in 64% yield, Scheme 3.5. The reaction was possible due to the generation of cubene in situ .11
94
(1) I Li
314 315
(2) I I
I Li 316 317
318
319 321
320
Scheme 3.3: Reactions of Mono- (314) and 1,2-Diiodocubane (316)
322 I t-BuLi
I
316 323
Scheme 3.4: In Situ Formation of Cubene in a Diels-Alder Reaction
95
3.4.2 Cubylcarbocation
Eaton, in his studies of cubylmethyl alcohols, proposed the existence of the cubylcarbocation. They reported that these alcohols have a tendency to rearrange if not handled delicately, transforming into homocubyl derivatives via a tight ion pair (Scheme
3.5). 19
Preifer and coworkers postulated the cubylcarbonyl cation while studying the
R
R CR 2OH CHR 2
324 325 326
R
R OH
327 Scheme 3.5: Rearrangement of Cubylmethyl Alcohol (324) polymerization of iodovinylcubane. When the monomer was refluxed in toluene, it unexpectedly rearranged to 4-vinyl-trans- -iodostyrene. The reaction time decreased significantly, from 36 h to 8 h when the Lewis acid BCl 3 was added as a catalyst (Scheme
3.6). 20
96
BCl 3 BCl 3 BCl 3
I I I 328 329 330
BCl 3 BCl 3 ≡
I I I 331 332 332
I I
H 333 334 I
I-
I H
335 336 337
Scheme 3.6: Proposed Mechanism for the Conversion of 4-Iodo-1- Vinylcubanne 328
3.5 Synthesis of Cubane Type Molecules using Photochemistry
In our group, Sieburth and Khatri accessed cubane-type molecules using metasubstituted aryls tethered to pyridones (Chapter 2, Scheme 2.12). 21 The presence of the product 269 motivated and directed our synthetic efforts.
97
O O O
O N O N O hv hv, 4 hrs O + N O CN NC N CN CN 266 267 268 269
[3,3]
O O N
CN 270
Scheme 3.7: Summary of the Photoproducts of the meta -Benzonitrile – 2-Pyridone Photocycloaddition at 25mM.
3.6 Results and Discussion
Exploring the utility of [4+4]-photochemistry to access caged structures and investigating the rearrangement of these cubane-type compounds was carried out using the 3–carbomethoxy benzyl ether of a 2-pyridone, which was prepared using Willamson ether synthesis conditions (Scheme 3.7).
O O O O O [4+4] [2+2] Me N N O O O O N O Me O Me 338 339 340
Scheme 3.8: Photochemistry of meta -Methylesterbenzene with 2-Pyridones
98
3.6.1 Synthesis of Starting Materials
Synthesis of the photosubstrate 338 was straightforward as outlined in Scheme
3.8. Starting from hydroxymethyl pyridone 357, transformation into the corresponding chloride 358 proceeded according to the conditions described in Chapter 2. The
Williamson ether synthesis coupling partner 343 was achieved in two steps from commercially available starting materials. The starting isophthalic acid 341 was esterified with methanol using published conditions22 . The dimethyl isophthalate was then reduced using LiBH 4 in THF to reveal the alcohol coupling partner 343 (Scheme
3.9)22 .
a.
OH SOCl2 Cl
N O DCM N O
257 258
b.
O OH O OMe OH
cat. H2SO 4 LiBH 4 OH MeOH OMe OMe
O O O
341 342 343
OH c. O Cl NaH Me OMe O O N O 0 ºC to RT O N O
258 343 338
Scheme 3.9: Synthesis of the Photosubstrate Precursors.
99
A Williamson ether synthesis, using sodium hydride in tetrahydrofuran with chloromethyl pyridone 257 and alcohol 343 in the afforded the coupled product 338 in a
50% yield.
3.6.2 Initial test of 2-Pyridone-meta -Methylester Benzyl Ether
With photosubstrate 338 available, 5mm NMR tubes containing solutions of photoadduct in benzene at 2.5 and 10 mM concentrations were prepared. Irradiation of these solutions with 290 nm light was performed using a Pyrex filtered 450 W medium- pressure mercury lamp in a water-cooled jacket. After 100 minutes of irradiation
(monitoring by NMR) the starting material in the 2.5 mM sample was consumed and gave the Dewar pyridone 344 exclusively. The 10 mM sample went to completion after
2 hours of reaction time. Once the reaction products were identified, a decision was made to scale up the irradiation at a concentration of 25 mM. Although the NMR vials from the 2.5 mM of photosubstrate reacted faster, the reaction yielded mostly the Cope products 345 and 346 and the Dewar pyridone 344 . The 10mM sample gave us the major product
100
a. 2.5 mM in C6D6 OMe O O O hv O OMe O 4-8 oC, 90 min N O N
338 344
b. 10 mM in C6D6 O O O O O O hv Me O OMe Me N 344 + N OMe + 4-8 oC, 90 min N O O OMe 345 338 346
Scheme 3.10. Test Reactions of the Photosubstrate 351 at Various Concentrations and Expected Products
[4+4] dimerized product and no evidence of the desired caged structure was formed.
3.6.3 Sieburth and Khatri [4+4] metabenzyl – pyridone photocycloadditions
As stated in Chapter 2, Sieburth and Khatri report that meta substituted benzyl – pyridone ethers, upon irradiation, can formed cubane-like cage structures . 21 They discovered that by using a meta substituted ethylester benzyl – pyridone ether, they were able to to isolate the cubane like structure with a yield of 22%. 21 However, long reaction times of up to 15 hours were required for the reaction to go to completion. When
101
O O hv N O O OEt + other products 4-8 oC, 15hrs N O
CO 2Et 22% 347 348
Scheme 3.11: Buddha Khatri’s Synthesis of Cubane – Type Pyridone Structure comparing this to performing the reaction at lower concentrations, this seemed to be the best strategy in order to have enough material to carry through the next steps.
3.6.4 Photochemistry at 25 mM using Flow methods
After establishing that the cubane-like product could be formed from pyridone ether 351 , the photochemistry of the photoadduct was conducted at 25 mM concentration. In order to reduce exposure to carcinogens, we opted to use toluene instead of benzene, and were able to obtain the desired product, 349 , in a 20% yield.
3.6.5 Grignard Addition to 349
After the cage compound 349 was obtained, the cage molecule was subject to addition of methyl and vinyl Grignard reagents, respectively in an attempt to acess products 350 and 351 , Scheme 3.12. Addition of 349 to 10 equivalents of methylmagnesium chloride in THF gave the expected alcohol 361 . However, similarly adding vinylmagnesium chloride, after separation and purification the compound decomposed.
102
a. O O N O 2 eq MeMgCl N O
2.0 M in THF O OH O Me 349 350
2 eq b. O MgCl O N O N O
2.0 M in THF O OH O Me 349 351
Scheme 3.12: Addition of Grignard Reagents
3.6.6 Rearrangement with Acid
After methyl Grignard addition, the next step in the methodology development was to study the carbocation rearrangement. Addition of p-toluenesulfonic acid to a solution of 350 initiated the rearrangement of 350 . We were delighted with the outcome as we were able to access 362 with a 90% yield (Scheme 3.13).
103
O O + N O N O conc. H
H O H OH
350 351
O O N O N O ≡
HO
H2O
352 353
OH
O
354
Scheme 3.13: Mechanism for Rearrangement of Cage Structure 350 upon exposure to concentrated acid.
3.7 Conclusion
We have demonstrated a method to synthesize and rearrange cubane-like molecules using a combination of [4+4] and [2+2] photoreactions of 2-pyridone. These cage-like structures can be synthesized and readily rearranged into more complex structures in the presence of acid. Strained, polycyclic molecules have many different uses and establishing this methodology will help expand the type of chemistry that can be done on cubane-like structures.
104
3.8 Experimental Details
A summary of general experimentation techniques, instrumentation, and purification procedure and reagent handling can be found on page 75 (from Chapter
2.10).
O OH O OMe
cat. H2SO 4 OH MeOH OMe
O O
341 342
Dimethyl isophthalate (342): 22 A solution of isophthalic acid (10.0 g, 60.2 mmol) and 3-
4 drops of conc. H 2SO 4 in dry methanol (100 ml) was heated under reflux overnight. The methanol was evaporated at reduced pressure and the residue was neutralized with saturated NaHCO 3 solution. The resulting solid was filtered off, washed with water and air-dried to get the dimethyl ester of isophthalic acid, 342. Yield (10.0 g, 85 percent), lit.
1 m.p. 64 °C H NMR (300 MHz, CDCl 3): d 8.66 (s, 1H), 8.20 (d, J = 7.4 Hz, 2H), 7.50 (t,
13 J = 7.7 Hz, 1H), 3.92 (s, 6H). C NMR (75 MHz, CDCl 3): d 166.22, 133.8, 130.7, 130.6
128.6, 52.3.
105
O OMe OH
LiBH 4 OMe OMe
O O
342 343
Methyl 3-(hydroxymethyl)benzoate (343): 22 Isophthalic acid dimethyl ester (357) (5.2 g, 26.7mmol) was dissolved in tetrahydrofuran (30 ml). Lithiumborohydride (2M) in tetrahydrofuran (13 mL, 26.7 mmol) was added therein. The reaction mixture was refluxed for 2.5 hours. Purification by column chromatography with 50%
EtOAc/hexanes gave the title compound as a colorless liquid. 1H NMR (500 MHz,
Chloroform-d) δ 8.03 (s, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.43 (t, J
= 7.7 Hz, 1H), 4.75 (s, 2H), 3.91 (s, 3H).
O Cl OH NaH O OMe N O THF, 0ºC N O O OMe 258 343 351
Methyl 3-(((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methoxy)methyl)benzoate
(351): To a flame dried 50-mL round bottom flask equipped with a magnetic stirbar and pyridone alcohol 258 (0.185 g, 1.32 mmol) was added DCM (10 mL). The reaction flask was vented while thionyl chloride (106 L, 1.46 mmol) was added dropwise. After the evolution of gas subsided, the reaction was allowed to proceed for 2 hours. Upon
106 completion of the reaction, as indicated by TLC, the reaction mixture was concentrated in vacuo . To another flame dried flask sodium hydride in oil (168 mg, 31.4 mmol) and THF
(12 mL) was added and then cooled to 0 oC. A solution of 343 (0.208 g, 1.32 mmol) in
THF (5 mL) was added dropwise to the crude 258 over 30 minutes. The reaction was allowed to stir overnight. Upon completion, as indicated by TLC, the reaction mixture was diluted with saturated aqueous ammonium chloride and water. The layers were separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with water, brine and then dried over anhydrous sodium sulfate and concentrated in vacuo . The crude product was purified via silica gel chromatography to afford the title compound (351) as a colorless oil (61%). Rf = 0.17 in
30% EtOAc/hexanes. IR (neat): 3423, 2858, 2160, 2031, 1716, 1648, 1584, 1562, 1424,
1406, 1378, 1285, 1201, 976.22, 870.56, 819, 748, 698, 674, 607 cm -1. 1H NMR (500
MHz, Chloroform-d) δ 7.99 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H),
7.48 – 7.43 (m, 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.19 (dd, J = 6.7, 1.8 Hz, 1H), 6.14 (t, J =
6.8 Hz, 1H), 4.63 (s, 2H), 4.48 (s, 2H), 3.85 (s, 3H), 3.49 (s, 3H). 13 C NMR (126 MHz,
CDCl 3) δ 167.0, 161.7, 138.7, 136.7, 135.9, 132.2, 130.2, 129.4, 105.8, 77.5, 77.2, 77.0,
72.47, 67.6, 52.1, 37.5.
107
O O hv N O O OMe 4-8 oC, 15hrs N O toluene CO 2Me
338 349
Methyl (2a S, 2a1 R, 2a1 S,2b S,4a S,4a1 R,7a S,7a1 R)-2-Methyl-1-oxo-1,2,2a,2b,4a1,7a1- hexahydro-5H,7 H-6-oxa-2-azacyclobuta[ def ]cyclopenta[1,2]-cyclobuta[ jkl ]bi- phenylene-2b1(2a1 H)-carboxylate (349): A solution of 338 (0.630g, 2 mmol) in toluene
(88 mL) was treated according to general procedure 2.1: Flow Chemistry Reaction . Rf
= 0.30 in 30% EtOAc/hexanes . IR (neat); 2921, 2160, 2026, 1711, 1650, 1627, 1437,
1395, 1344, 1270, 1081,932, 802 cm-1. 1H NMR (500 MHz, Chloroform-d) δ 6.24 (dd, J =
9.7, 8.1 Hz, 1H), 6.10 (d, J = 9.7 Hz, 1H), 4.51 (d, J = 9.7 Hz, 1H), 4.41 – 4.29 (m, 1H),
4.06 (d, J = 9.3 Hz, 1H), 3.97 (s, 0H), 3.92 (s, 1H), 3.91 – 3.84 (m, 1H), 3.73 (s, 2H),
3.71 – 3.68 (m, 1H), 3.53 (dddd, J = 8.8, 8.1, 1.6, 0.8 Hz, 1H), 3.01 (dd, J = 6.7, 1.4 Hz,
13 1H), 2.98 (s, 3H), 2.87 (dd, J = 8.1, 6.7 Hz, 1H). C NMR (126 MHz, CDCl 3) δ 173.7,
169.7, 131.7, 128.9, 78.5, 75.1, 68.0, 61.1, 58.0, 55.1, 52.3, 43.4, 42.3, 39.6, 34.6, 25.6.
O O N O MeMgCl N O
2.0 M in THF O OH O Me 349 350
(2a S,2a 1R,2a 1S,2b S,4a S,4a 1R,7a S,7a 1R)-2b 1-(2-Hydroxypropan-2-yl)-2-methyl-
2a,2a 1,2b,2b 1,4a 1,7a 1-hexahydro-5H,7 H-6-oxa-2-
108 azacyclobuta[ def ]cyclopenta[1,2]cyclobuta[ jkl ]biphenylen-1(2 H)-one (361): In a 10- mL vial equipped with a magnetic stirbar under argon, methylmagnesiumchloride
(611 ) and THF (5 mL) was added and cooled to 0 oC. A solution of THF (5 mL) and the starting material, methyl ester 353 (52.7 mg, 183 mol) was added dropwise with stirring over a period of 20 minutes and allowed to react while being monitored by TLC.
The reaction was then quenched with saturated aqueous ammonium chloride and water.
The layers were separated and the aqueous layer was extracted with ethyl acetate (3x).
The combined organic layers were washed with water, brine and then dried over anhydrous sodium sulfate and concentrated in vacuo . The crude product was purified via silica gel chromatography to afford the title compound as a colorless oil (15.4% yield).
-1 1 Rf = 0.2 in 100% hexanes IR (neat): 2962, 2032, 1622, 737 cm . H NMR (500 MHz,
Chloroform-d) δ 6.24 (dd, J = 9.6, 8.3 Hz, 1H), 6.00 (d, J = 9.6 Hz, 1H), 4.51 (d, J = 9.6
Hz, 1H), 4.24 – 4.06 (m, 1H), 3.95 (dd, J = 17.6, 9.4 Hz, 2H), 3.69 (d, J = 9.2 Hz, 1H),
3.65 – 3.56 (m, 1H), 3.21 – 3.12 (m, 2H), 2.96 (s, 3H), 2.77 – 2.69 (m, 1H), 2.52 (d, J =
13 6.8 Hz, 1H), 1.21 (s, 3H), 0.99 (s, 3H). C NMR (126 MHz, CDCl 3) δ 170.1, 131.2,
130.6, 78.8, 77.3, 77.0, 76.8, 75.3, 71.0, 60.7, 57.1, 54.8, 49.7, 40.9, 39.3, 35.8, 33.8,
32.1, 25.5, 23.6.
109
O
N O OH
Tosylic Acid O N OH O 350 354
(5 S,5a S,5b S,11 S)-3a-hydroxy-4,4,10-trimethyl-3,3a,3a1,4,5,5a-hexahydro-6H,8 H-
3,5,5b-(epimethanetriyliminomethano)indeno[1',7':3,4,1]cyclobuta[1,2-c]furan-9- one (354): To a solution of 350 (3mg) in dichlorometheane (1 mL), p-toluenesulfonic acid (3mg) was added in one portion and allow to stir for three days. The crude mixture was washed with sodium bicarbonate twice and then analyzed unpurified. The product was a colorless oil (90% yield). Rf = 0.2 in 100% EtOAc.
IR=
1H NMR (500 MHz, Chloroform-d) δ 6.13 (dd, J = 9.3, 7.9 Hz, 1H), 5.94 (d, J = 9.3 Hz,
1H), 4.34 (d, J = 9.5 Hz, 1H), 4.01 (d, J = 9.2 Hz, 1H), 3.91 (d, J = 9.5 Hz, 1H), 3.86
(ddd, J = 10.5, 4.9, 2.3 Hz, 1H), 3.59 (d, J = 9.2 Hz, 1H), 3.02 (ddd, J = 10.6, 7.8, 3.0 Hz,
1H), 2.99 (s, 3H), 2.64 (ddd, J = 9.7, 5.7, 2.2 Hz, 1H), 2.48 – 2.43 (m, 1H), 1.97 (t, J =
13 5.3 Hz, 1H), 1.10 (s, 3H), 1.04 (s, 3H). C NMR (126 MHz, CDCl 3) δ 129.8, 128.0, 84.1,
81.2, 77.0, 73.5, 64.4, 59.7, 56.5, 51.2, 46.7, 44.7, 43.4, 42.5, 37.5, 35.1, 28.7, 17.7, 17.0,
0.00.
110
O Me O O O
N
359
Methyl 3-(((2-methyl-3-oxo-2-azabicyclo[2.2.0]hex-5-en-4- yl)methoxy)methyl)benzoate (359): A solution of 351 (0.630 g, 2 mmol) in C6D6 (88 mL) was treated according to general procedure 2.1 Flow Chemistry Conditions , to furnish 359 as a colorless oil (6 mg, 10%): Rf = 0.24 in 30% EtOAc/hexanes. IR (neat):
2447, 2160, 2032, 1977, 1725, 1614, 1347, 1259, 1094, 903 cm -1. 1H NMR (500 MHz,
Chloroform-d) δ 7.98 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.43 (t, J
= 7.6 Hz, 1H), 6.65 (d, J = 2.6 Hz, 1H), 6.58 (t, J = 2.7 Hz, 1H), 4.74 – 4.55 (m, 2H),
3.94 (d, J = 11.0 Hz, 1H), 3.92 (s, 3H), 3.81 (d, J = 11.0 Hz, 1H), 2.81 (s, 3H). 13 C NMR
(126 MHz, CDCl 3) δ 139.98, 138.95, 137.33, 131.16, 127.95, 127.61, 71.82, 69.15,
64.12, 56.88, 51.16, 29.27, 28.68, 21.68, 13.11, 0.00.
O O Me N
O OMe 361 Methyl (3a R,11a R)-5-methyl-4-oxo-4,5,7a,7b-tetrahydro-1H,3 H- benzo[3,4]furo[3',4':1,4]cyclobuta[1,2-c]pyridine-8-carboxylate (361):
111
A solution of 338 (0.630g, 2 mmol) in toluene (88 mL) was treated according to general procedure 2.1: Flow Chemistry Reaction . The mixure was purified by column chromatography with 0 – 40% EtOAc/ hexanes to afford the title compound as a colorless oil (4%, 4 mg ): R f = 0.5 in 30% EtOAc/ hexanes. IR (neat): 3120, 2250, 2172, 1710,
1600, 1255, 1113, 909, 834, 729, 618 cm -1. 1H NMR (500 MHz, Chloroform-d) δ 6.95
(dd, J = 6.0, 1.1 Hz, 1H), 6.10 – 5.89 (m, 2H), 5.56 (d, J = 9.7 Hz, 1H), 4.63 (dd, J = 8.0,
4.5 Hz, 1H), 4.32 (d, J = 9.3 Hz, 1H), 4.00 (d, J = 9.1 Hz, 1H), 3.94 (d, J = 17.4 Hz, 1H),
3.72 (s, 3H), 3.68 (dd, J = 9.4, 1.1 Hz, 1H), 3.39 (d, J = 9.3 Hz, 2H), 3.03 (s, 3H). 13 C
NMR (126 MHz, CDCl 3) δ 166.4, 164.3, 131.5, 129.5, 128.0, 124.0, 101.8, 77.9, 76.3,
76.2, 76.0, 62.5, 57.3, 50.8, 44.0, 39.7, 33.7, 0.00.
112
3.9 References
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Effect of Methyl Substitution on Stability and Product Branching. J. Phys. Chem.
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(11) Eaton, P. E.; Maggini, M. Cubene (1, 2-Dehydrocubane). J. Am. Chem. Soc. 1988 ,
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(12) Eaton, P. E.; Tsanaktsidis, J. The Reactions of 1,4-Dihalocubanes with
Organolithiums. The Case for 1,4-Cubadiyl. J. Am. Chem. Soc. 1990 , 112 (2),
876–878.
(13) Della, E. W.; Tsanaktsidis, J. Decarboxylation of Bridgehead Carboxylic Acids by
the Barton Procedure. Aust. J. Chem. 1985 , 39 (12), 2061–2066.
(14) Barton, D. H. R.; Crich, D.; Motherwell, W. B. New and Improved Methods for
the Radical Decarboxylation of Acids. J. Chem. Soc. Commun.. 1983 , No. 18,
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(15) Szeimies, G.; Hamisch, J.; Baumgärtel, O. Organolithium Substitution at a
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(17) Shafer, J.; Szeimies, G. Reaction of 1-Bromo-7-
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(18) Hrovat, D. A.; Borden, W. T. Ab Initio Calculations of the Olefin Strain Energies
of Some Pyramidalized Alkenes. J. Am. Chem. Soc. 1988 , 110 (14), 4710–4718.
(19) Eaton, P. E. Cubanes: Starting Materials for the Chemistry of the 1990s and the
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(20) Carroll, V. M.; Harpp, D. N.; Priefer, R. Thermo-Cage Opening of 4-Iodo-1-
Vinylcubane to a Novel Styrene Derivative. Tetrahedron Lett. 2008 , 49 (17),
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(21) Khatri, B. B.; Vrubliauskas, D.; Sieburth, S. M. N. Photo-[4+4]-Cycloaddition
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Their Preparations and Pharmaceutical Compositions Containing Them, 2004.
115
APPENDIX A: CHARACTERIZATION FOR CHAPTER 1
116
117
118
119
120
121
122
123
124
125
126
APPENDIX B: CHARACTERIZATION FOR CHAPTER 2
TMS
O
N O
253
127
TMS O
N O
254
128
O
N O TMS
255
129
Me Me Si O
N O 256
130
O O TMS
N
H H
276
131
O O TMS
N
H H
276
132
O O
N
H H TMS
279
133
O O
N
TMS H H
272
134
TMS
O O
N
N
O O TMS
284
135
O O TMS
N
N
O O
TMS
265
136
Si O O
N
N
O O Si
284
137
Si O O
N
N
O O Si
284
138
APPENDIX C: CHARACTERIZATION FOR CHAPTER 3 O
O OMe
N O
351
139
O O Me N
O OMe 346
140
O
N O
CO 2Me
349
141
O
N O
OH
350
142
OH
O N
O 354
143
O Me O O O
N
359
144