Synthesis and Comparison of the Reactivity of Allyl Fluorides and ...

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Synthesis and Comparison of the Reactivity of Allyl Fluorides and Allyl Chlorides Kirandeep Rakkar Abstract A small library of novel allylic fluorides were synthesised via a two-step process, involving the cross-metathesis of allyltrimethylsilane with varying olefinic partners, followed by fluorodesilylation of the corresponding allylsilane with Selectfluor. Their structures were determined by NMR spectroscopy and mass spectrometry. The analogous novel allylic chlorides were also formed and successfully separated from their rearranged products by column chromatography and characterised fully by NMR spectrometry and mass spectroscopy. A series of novel Pd(II) chloride-bridged dimers were synthesised from the corresponding allylic chlorides and purified by column chromatography. Their structures were determined by NMR spectroscopy, mass spectrometry and single crystal X-ray crystallography. New palladium cationic complexes were synthesised from their preceding allylic fluorides by reaction with Pd(dba)2 and PPh3 in CDCl3, but not isolated. Their structures were determined by NMR spectroscopy and mass spectrometry. It was observed that the allylic chloride, 2-chlorobut-3-enyl benzoate and allylic fluoride, 2-fluorobut-3-enyl benzoate both oxidatively added to Pd(0) in the same manner. However, with 2-(2-fluorobut-3enyl)isoindoline-1,3-dione, although the cationic species was formed, due to the electronwithdrawing property of the nitro group, the protons alpha to nitrogen were susceptible to elimination by fluoride acting as a base to form 2-(buta-1,3-dienyl)isoindoline-1,3-dione. The novel Pd(II) chloride-bridged dimers and the palladium cationic complexes on reaction with the sodium salt of dimethyl malonate afforded nucleophilically substituted products in moderate yields. However, it was also found that the substituents on allyl substrates influenced the site of nucleophilic attack. In contrast, reactions with a variety of sources of fluoride were unsuccessful. A series of related allylic difluorides were also synthesised by reaction of 2,2-difluoro but- 3-en-1-ol in DCM solution with derivatised benzoyl chlorides. Attempts to activate these difluoroallyl compounds with Pd(dba)2 and Pd(PPh3)4 were unsuccessful. However, the reaction of 3-bromo-3,3-difluoropropene with Pd(PPh3)4 formed the corresponding novel �allyl complex and was identified by mass spectrometry. i
Acknowledgements Firstly, I would like to thank my family for their love and support over the many years I have been at the University of Leicester, especially my brother Rohit, whose help in sorting all of my stacks of spectra over the course of the Ph.D. has been invaluable! I also wish to thank my partner John, whose unwavering belief in me has helped me continue through the many problems inherent in a Ph.D. Next, I would like to thank my supervisor Prof. Eric Hope for his help, support and enthusiasm throughout the three years. I would also like to thank Dr Alison Stuart, for her help with random NMR questions. I give thanks to everyone I have had the pleasure of knowing and working with whilst I have been at the University of Leicester, with special thanks to Dr Carla Jones, Michal Fornalczyk, Becky Williams, Alex Goddard and Ann Beresford. I give a huge thank you to Dr Daniel Duncan for proofreading my thesis and his continued friendship. I would also like to thank Kerry Willis, Raminder Shergill and Chris Whyte for helping me take my mind off work occasionally with trips to the pub and quizzing. I would like to thank Toni Wilkes, Benjamin Ho and Pradeep Chenna for their contributions to Chapter Five. I would also like to thank Dr Graham Eaton, Dr Gerry Griffiths and Kuldip Singh for all their technical support over the years. Finally, I must also thank the University of Leicester and EPSRC for funding throughout my Ph.D. ii
Page 1: Synthesis and Comparison of the Rea
Page 5 and 6: 2.2.2.1.1 Synthesis of 1-(Benzyloxy
Page 7 and 8: 6.2.12 Preparation of 2-(4-trimethy
Page 9 and 10: 6.4.12 Experimental Data for Dimeth
Page 11 and 12: AgF ap Bn Bz CsF d DAST dba DCM DME
Page 13 and 14: Chapter one
Page 15 and 16: 2 Chapter One potentially explosive
Page 17 and 18: 4 Chapter One ortho-biphenyl trifla
Page 19 and 20: 6 Chapter One 2,10 (3,3-dichlorocam
Page 21 and 22: 8 Chapter One both enantiomers were
Page 23 and 24: 10 Chapter One poor to moderate ena
Page 25 and 26: Scheme 1.10 Fluorination of (17) 12
Page 27 and 28: 14 Chapter One fluorine donors, Lew
Page 29 and 30: 1.3 Enantioselective Nucleophilic F
Page 31 and 32: Scheme 1.16 Fluorination of (32) 18
Page 33 and 34: 20 Chapter One (iii) SN2’ type su
Page 35 and 36: 22 Chapter One cytotoxicity in the
Page 37 and 38: 24 Chapter One Manabe and Ishikawa
Page 39 and 40: Scheme 1.25 Synthesis of (41)-(44)
Page 41 and 42: Figure 1.12 �-fluorinated NSAIDs
Page 43 and 44: 1.6 Thesis Outline 30 Chapter One T
Page 45 and 46: 32 Chapter One [26] M. Abdul-Ghani,
Page 47 and 48: [79] M. Schlosser, D. Michael, Z.-W
Page 49 and 50: 2.1 Introduction 2 Synthesis of All
Page 51 and 52: 37 Chapter Two In dehydroxyfluorina
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Scheme 2.6 Fluorination with IF5/Et
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41 Chapter Two desired allylic fluo
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43 Chapter Two c) Formation of a su
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Scheme 2.14 Reaction of cis-3-methy
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Substrate (60) (61) (62) (63) R = O
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Alcohol Product Yield (%) Table 2.7
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51 Chapter Two completion. This ena
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53 Chapter Two Chapter Three. Follo
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55 Chapter Two Two allyl alcohols w
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57 Chapter Two The conversion of (8
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Starting substrate (88) (89) (90) (
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Starting substrate (99) (76) (77) (
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63 Chapter Two Both (105) and (104)
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Scheme 2.25 Mechanistic pathway for
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2.3 Conclusions 67 Chapter Two The
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[28] D. F. Taber, J. Am. Chem. Soc.
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Chapter THRee
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72 Chapter Three Kurosawa reacted a
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74 Chapter Three These results demo
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76 Chapter Three More recently, wor
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3.2 Results and Discussion 3.2.1 Re
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80 Chapter Three Starting substrate
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82 Chapter Three Figure 3.4 Crystal
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Scheme 3.12 Oxidative addition of 1
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86 Chapter Three when the reaction
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88 Chapter Three Therefore, from th
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-140 -140 -140 -140 -140 -150 -150
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92 Chapter Three monitored for 80 m
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3.4 References [1] W. T. Dent, R. L
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Chapter Four
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97 Chapter Four nucleophilic substi
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99 Chapter Four Further reactions w
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Figure 4.3 Structure of co-product
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4.2.2 Reactions of palladium cation
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105 Chapter Four substituents on th
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107 Chapter Four The desired produc
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109 Chapter Four The reaction of (1
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111 Chapter Four were both reacted
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[28] D. Landini, A. Maia, A. Rampol
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5.1 Introduction 5 Synthesis and Re
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116 Chapter Five The first enantios
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118 Chapter Five Gem(difluoroallyl)
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120 Chapter Five benzaldehyde, 3-br
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Starting Substrate (76) (77) (78) (
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Starting Substrate Product Yield (%
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5.2.4 Synthesis of Allylic Difluori
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5.2.5 Metal-mediated synthesis of 3
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130 Chapter Five process. [40] Unfo
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132 Chapter Five compounds were pur
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134 Chapter Five [30] H. L. Sham, N
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6.1 General Experimental Procedures
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6.2 Experimental Details for Chapte
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139 Chapter Six (1 g, 0.75 cm 3 , 6
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6.2.7 Preparation of allyl 4-(trifl
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6.2.10 Preparation of (3-[1,3]Dioxa
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145 Chapter Six reaction mixture wa
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147 Chapter Six mg, 1.1 mmol), ally
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149 Chapter Six 260.3 Hz, ArCF), 16
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6.2.22 Preparation of 2-fluorobut-3
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6.2.25 Preparation of 2-fluorobut-3
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6.2.28 Preparation of 2-hydroxybut-
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157 Chapter Six 1 JCF = 253.5 Hz, A
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159 Chapter Six drying under high v
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6.2.37 Preparation of 2-chlorobut-3
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6.2.40 Preparation of 2-chlorobut-3
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6.3.2 Preparation of Bis[�-chloro
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167 Chapter Six 6.3.5 Preparation o
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169 Chapter Six 4 JHH = 1.2 Hz, ArH
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Time (minutes) 4 11 18 25 Table 6.2
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Time (minutes) 19 F{ 1 H} (ppm) Tim
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175 Chapter Six suspension of sodiu
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177 Chapter Six Hz, Ha), 5.19 (1H,
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6.4.9 Preparation of Dimethyl 2-(4-
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181 Chapter Six 6.4.13 Preparation
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6.5 Experimental Details for Chapte
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185 Chapter Six CHCH2), 133.9 (d, 3
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187 Chapter Six 6.5.6 Preparation o
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189 Chapter Six (5 mg, 0.27 mmol) a
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191 Chapter Six (d, 1 JCF = 255.0 H
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193 Chapter Six layer separated and
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195 Chapter Six Hz, 4 JHF = 3.2 Hz,
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Appendix
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II Appendix Second generation Grubb
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IV Appendix mixture was stirred at
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VI Appendix stirred at room tempera
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VIII Appendix The organic phase was
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X Appendix A6 Crystal data and stru
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XII Appendix A8 Crystal data and st
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XIV Appendix A10 Crystal data and s
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A12 Lecture Courses Attended XVI Ap
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A14 Conferences Attended RSC Organi
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