synthesis of cyclobutenes and bicyclo[2.1.0]

175 Pages·2014·7.52 MB·English

ECOLE CENTRALE MARSEILLE
Institut des Sciences Moléculaires de Marseille (UMR 7313)

THESE DE DOCTORAT
Pour obtenir le garde de:
DOCTEUR DE L’ECOLE CENTRALE MARSEILLE
Discipline: Sciences Chimiques
Ecole Doctotale des Sciences Chimiques ED 250

SYNTHESIS OF CYCLOBUTENES AND
BICYCLO[2.1.0]PENTANES THROUGH PLATINUM
AND RUTHENIUM-CATALYZED REACTIONS

Présentée par
Zhenjie NI

Directeurs de thèse: Dr. Alphonse TENAGLIA et Dr. Laurent GIORDANO

JURY

Dr. Elisabet Duñach Université de Nice-Sophia Antipolis Rapporteur
Pr. Jean-Marc Campagne Institut Charles Gerhardt, Montpellier Rapporteur
Dr. Yves Gimbert Université Joseph Fourier, Grenoble Examinateur
Dr. Alphonse Tenaglia Aix-Marseille Université Directeur de thèse
Dr. Laurent Giordano Ecole Centrale Marseille Directeur de thèse
Acknowledgements

First and foremost I would like to extend my deepest gratitude to my thesis
advisors, Dr. Alphonse TENAGLIA and Dr. Laurent GIORDANO for the opportunity
to work and learn in their laboratories. They devoted a considerable portion of their
time for my experiments and my manuscripts. With their assistance and
encouragement, I could successfully complete this thesis. From them, I learned much.
I would like to thank the members of the committee: Dr. Elisabet Duñach, Pr.
Jean-Marc Campagne and Dr. Yves Gimbert for the examination of the contents of the
manuscript.
I gratefully acknowledges: Dr. Innocenzo DE RIGGI for help with the NMR, Dr.
Sabine CHEVALLIER-MICHAUD for help with LC-MS, Dr. Hervé CLAVIER for
his helpful suggestions and Dr. David GATINEAU for his kindness. My gratitude also
goes to the people in our laboratory: Dr. Damien HERAULT, Pr. Gérard BUONO, Pr.
Frédéric FOTIADU, Dr. Julien LECLAIRE, Dr. Didier NUEL, Dr. Delphine
MORALEDA, Dr. Guillaume POISSON, Dr. Duc Hanh NGUYEN, Dr. Karel
LE-JEUNE, Mr. Pierre-Thomas SKOWRON, Mr. Lionel GRAUX and Mr. Sébastien
LEMOUZY. It has been a pleasure to have you as my teachers or friends.
I am grateful for the support of my parents, Guihua ZHUANG and Gongquan NI,
whom allowed me to pursue my dreams. I would like to thank my girl friend Ran
ZHAO, who always supported and encouraged me in the past three years.
At last, I gratefully acknowledge the China Scholarship Council (CSC) for the
doctoral scholarship.
I
List of Abbreviations

AcOH acetic acid
acac acetylacetonate
Anal. elemental analysis
aq. aqueous
BHT Butylated hydroxytoluene
BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
Boc N-tert-butoxycarbonyI
Bn benzyl
Bz benzoyl
br broad (spectroscopy)
cat. catalytic
calcd calculated
cod cyclooctadiene
COSY COrrelation spectroScopY
Cp cyclopentadienyl
Cp* pentamethylcyclopentadienye
δ NMR scale
d doublet
DCE 1,2-dichloroethane
DCM dichloromethane
DEPT Distortionless Enhancement by Polarization Transfer
DIAD diisopropylazodicarboxylate
DMA dimethylacetamide
DMAD dimethyl acetylenedicarboxylate
DMAP 4-dimethylamino pyridine
DMF dimethylformamide
DMP Dess-Martin periodinane
DMPU N,N'-dimethyl-N,N'-propylene urea
DMSO dimethylsulfoxide
dppe 1,2-diphenylphosphinoethane
II
EDC·HCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride
ee enantiomeric excess
equiv equivalent
h hour
HMBC Heteronuclear Multiple Bond Correlation
HMQC Heteronuclear Multiple-Quantum Correlation
HOBt 1-hydroxybenzotriazole hydrate
HPLC High Performance Liquid Chromatography
HRMS High Resolution Mass Spectroscopy
Hz hertz
IR infrared spectroscopy
λ wavelength
M molarity
m multiplet
MCPs methylenecyclopropanes
MeCN acetonitrile
m.p. melting point
Ms methanesulfonyl
NBS N-bromosuccinimide
NMP N-methylpyrrolidone
NOESY Nuclear Overhauser Enhancement SpectroscopY
PE petroleum ether
Rf retention factor value
rt room temperature
s singlet
t triplet
TBAF tetra-butylammonium fluoride
TBAI tetra-butylammonium iodide
TBS tert-butyldimethylsilyl
TC thiophene-2-carboxylate
TCPC tetracarbomethoxypalladacyclopentadiene
Tf trifluoromethanesulfonyl
III
TFA trifluoroacetic acid
THF tetrahydrofuran
TIPS triisopropylsilyl
TMS trimethylsilyl
Ts para-toluenesulfonyl

IV
Table of Contents

General Introduction ················································································································ 1
Chapter I Bibliographic Overview of Transition-Metal Catalyzed Synthesis of
Cyclobutenes ····························································································································· 3
Introduction ····························································································································· 4
1.1 Transition-metal Catalyzed Intermolecular [2+2] Cycloadditions of Alkenes and
Alknynes ································································································································· 5
1.1.1 Nickel ························································································································· 5
1.1.2 Palladium ···················································································································· 7
1.1.3 Ruthenium ·················································································································· 8
1.1.4 Cobalt ······················································································································· 11
1.1.5 Rhodium ··················································································································· 14
1.1.6 Gold ·························································································································· 15
1.1.7 Silver ························································································································· 16
1.1.8 Rhenium ··················································································································· 17
1.1.9 Iridium ······················································································································ 17
1.1.10 Iron ························································································································· 17
1.1.11 Copper····················································································································· 18
1.2 Transition-metal Catalyzed Intramolecular [2+2] Cycloadditions of Enynes ················ 20
1.2.1 Palladium ·················································································································· 20
1.2.2 Platinum ···················································································································· 21
1.2.3 Gold ·························································································································· 25
1.2.4 Ruthenium ················································································································ 29
1.2.5 Nickel ······················································································································· 32
1.2.6 Gallium ····················································································································· 33
1.2.7 Cobalt ······················································································································· 33
1.3 Transition-metal Catalyzed Intramolecular [2+2] Cycloadditions of Allenynes ············ 34
1.3.1 Platinum ···················································································································· 34
1.3.2 Rhodium ··················································································································· 35
1.3.3 Molybdenum ············································································································· 36
1.4 Cyclobutenes Formation Through Metal-Catalyzed Ring Expansion Reactions ··········· 37
1.4.1 Platinum ···················································································································· 37
1.4.2 Palladium ·················································································································· 38
1.4.3 Silver ························································································································· 39
1.4.4 Rhodium ··················································································································· 40
1.4.5 Gold ·························································································································· 41
1.4.6 Copper ······················································································································ 42
Conclusion ···························································································································· 44
V
Chapter II Cyclobutene Formation in PtCl -Catalyzed Cycloisomerizations of
2
Heteroatom-Tethered 1,6-Enynes ·························································································· 45
Introduction ··························································································································· 46
2.1 Purpose of the initial project ··························································································· 50
2.2 Preliminary investigations ······························································································· 51
2.3 Cyclobutene formation in PtCl -catalyzed cycloisomerization of heteroatom-tethered
2
1,6-enynes ····························································································································· 53
2.3.1 The solvent screening ······························································································· 53
2.3.2 The role of amide solvent ························································································· 55
2.3.3 Determination the structure of cyclobutene 3··························································· 56
2.3.3.1 1H NMR and 13C NMR of cyclobutene 3 ·························································· 56
2.3.3.2 NOESY of cyclobutene 3 ··················································································· 56
2.3.3.3 X-ray diffraction of the cyclobutene 3 ······························································· 57
2.4 Scope of the Pt-Catalyzed Cycloisomerization of Hetero- atom-Tethered 1,6-Enynes ·· 58
2.4.1 Cycloisomerization of N-tethered enynes with disubstitution α to nitrogen atom ··· 58
2.4.2 Cycloisomerization of N-tethered enynes with monosubstitution at the propargylic
or allylic position ··············································································································· 62
2.4.3 Cycloisomerization of N-tethered enynes without substitution at the propargylic
carbon atom ······················································································································· 65
2.4.4 Cycloisomerization of O-tethered enynes with disubstitution α to nitrogen atom ··· 68
2.4.5 Attempted Cycloisomerization of carbon-tethered enynes ······································· 71
2.5 Studies on the reaction mechanism ················································································· 72
2.5.1 Insights on the role of DMA as a ligand ··································································· 72
2.5.2 Proposal of mechanism for the formation of cyclobutene ········································ 75
2.5.3 Deuterium labeling experiments ··············································································· 75
Conclusion ································································································································ 78

Chapter III A New Approach to the Bicyclo[2.1.0]pentane Framework through the
Ruthenium-Catalyzed Cyclopropanation of Cyclobutenes with Tertiary Propargylic
Carboxylates ··························································································································· 79
3.1 The bicyclo[2.1.0]pentane framework: synthetic methods and synthetic utility ············ 80
3.1.1. Syntheses from 2,3-diazabicyclo[2.2.1]hept-2-enes················································ 80
3.1.2. Syntheses from cyclobutenes and carbene precursors ············································· 81
3.1.3. Synthetic utility of bicyclic [2.1.0] structures ························································· 82
3.2 Presentation and purpose of the project ·········································································· 84
3.2 Preliminary studies ·········································································································· 86
3.2.1 Cyclopropanation of model substrate 32 ·································································· 86
VI
3.2.2 Determination of the structure of tricyclic compound 86 ········································ 86
3.2.2.1 1H NMR and 13C NMR of 86 ············································································· 86
3.2.2.2 NOESY of 86 ····································································································· 87
3.3 Scope of the Ruthenium-Catalyzed Cyclopropanation of Cyclobutenes with Tertiary
Propargylic Carboxylates ······································································································ 88
3.3.1 Ruthenium-Catalyzed Cyclopropanation of Cyclobutenes ······································ 88
3.3.2 Ruthenium-Catalyzed cyclopropanation of cyclobutene 14 with various propargylic
carboxylates ······················································································································· 91
3.3.3 Substituents effects on the ruthenium-catalyzed cyclopropanation of cyclobutenes 93
3.3.3.1 Cyclobutene monosubstituted at sp2 carbon atom 107 ······································ 93
3.3.3.2 Cyclobutene monosubstituted at sp3 carbon atom 113 ······································ 93
3.3.3.3 Disubstituted cyclobutenes 114 and 117 ···························································· 95
3.3.3.4 Sterically congested cyclobutene 122 ································································ 96
Conclusion ···························································································································· 98
General Conclusion ················································································································ 99

Experimental Section ··········································································································· 102
I. Preparation of 1,6-enynes. ······························································································· 104
II. PtCl -catalyzed enyne cycloisomerizations ···································································· 134
2
III. Deuterium labeling experiments ··················································································· 147
IV. Preparation of tertiary propargyl carboxylates ······························································ 151
V. Preparation of cyclobutenes 107, 113, 117 and 122 ······················································· 154
VI. CpRuCl(PPh ) -catalyzed cyclopropanation of cyclobutenes ······································ 159
3 2

VII
General Introduction
In our laboratory, we are interested in novel transition metal catalyzed reactions based on the
atom economy principle,1 such as addition, cycloaddition and cycloisomerization reactions.
In this manuscript we present a two-steps atom-economic synthesis of bicyclo[2.1.0]pentanes
through the sequential Pt-catalyzed cycloisomerization of heteroatom-tethered 1,6-enynes and
Ru-catalyzed cyclopropanation of cyclobutenes with tertiary propargyl acetates. The
manuscript contains three chapters and an experimental part.

Chapter I. This chapter is a bibliographical survey summarizing the main results of metal
catalyzed [2+2] cycloaddtions for the synthesis of cyclobutenes. The reactions are presented
according to the metal catalyst.

Chapter II. This chapter provides the deep and thorough study of cyclobutene formation in
Pt-catalyzed cycloisomerizations of heteroatom-tethered 1,6-enynes. It is shown that the
presence of alkyl substituent(s) at propargyl position and the use of weakly coordinating
solvents such as DMA are the key elements favoring the formation of cyclobutenes.

Chapter III. Presented herein is the development of a new approach to
bicyclo[2.1.0]pentanes through the ruthenium-catalyzed cyclopropanation of cyclobutenes
with tertiary propargylic carboxylates. It provides a safe method which avoid the use of
hazardous carbene precursors to generate functionalized bicyclo[2.1.0]pentane frameworks in
high yields under mild conditions.

1 a) Trost, B. M. Science 1991, 254, 1471-1477. b) Trost, B. M. Angew. Chem. Int. Ed. 1995, 34, 259-281.
2