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

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87 Chapter Three elimination product. This is strong evidence that the �-allyl species had formed, as there would be no other pathway for this elimination product to be formed. . Figure 3.6 Formation of (133) Due to the broad 1 H NMR spectrum obtained the reaction was repeated, with equimolar amounts of (74) and Pd(PPh3)4 and stirred at – 78 ºC for 8 hours (entry 11). A yellow precipitate was formed, the reaction solvent removed and the product dried in vacuo. Analysis of the precipitate, by 1 H and 19 F NMR spectroscopy, confirmed that the starting material was no longer present. However, due to the intensity of the triphenylphosphine groups in the spectra, it was difficult to fully assign the product peaks. Although, it was clearly evident that the elimination product (133) had formed once again. The reaction solvent was also analysed and exhibited a very broad peak at -168.4 ppm in the 19 F NMR spectrum. Due to the difficulties in isolating the �-allyl species, which were clearly forming, the same reaction conditions which had been employed to synthesise the chloro-bridged palladium allyl complexes were used with 2-(2-fluorobut-3-enyl)isoindoline-1,3-dione (74) (entry 9). After stirring equimolar quantities of (74) and Pd(dba)2 in DMSO at room temperature for 4 hours, the mixture was worked up as described previously and dried over magnesium sulphate, filtered and the solvent removed in vacuo. The yellowish product was analysed by 1 H and 19 F NMR spectroscopy and once more no direct evidence of the desired �-allyl complex was observed. Rather, the presence of 2-(buta-1,3-dienyl)isoindoline-1,3-dione (133) was confirmed. Therefore, it can be inferred that although the �-allyl complex must have formed, due to the presence of fluoride the elimination product was obtained. It also means that if a fluoro-bridged palladium complex is forming it is not sufficiently stable to be isolated and characterised in the same manner as the chloro-bridged palladium complexes described earlier.
88 Chapter Three Therefore, from the range of different reaction conditions tested it is evident that in the reactions conducted in toluene at -78 ºC with Pd(PPh3)4, the substrate clearly undergoes oxidative addition to Pd(0), as demonstrated by the formation of the elimination product in entries 13 and 14. Whilst those reactions conducted with Pd(dba)2 (both at low and elevated temperatures) were unsuccessful, affording only the starting allylic fluoride. 3.2.2.2 Activation of Allylic Fluoride with Pd(0) in the presence of a nucleophile- Trapping the Allyl Pd Intermediate During this time, work was published by Gouverneur et. al. which also examined the oxidative addition of Pd(0) to allylic fluorides. [34] Whereas the work in this thesis focussed on isolation of the �-allyl palladium species, Gouverneur et al. concentrated on the formation of the �-allyl species in situ and its subsequent reaction with a nucleophile such as dimethyl malonate, in order to quantify the reactivity of fluoride as a leaving group in comparison with OAc, OBz and OCO2Me. It was reported that NMR experiments were conducted in order to monitor the reaction and observe the changes occurring. In light of the scoping experiments discussed previously, this methodology was utilised in the reaction of (74) with 20 mol % Pd(dba)2 and 2 equivalents of PPh3 in anhydrous CDCl3. The reaction mixture was stirred for 1 minute under nitrogen before transferring a small aliquot to a Young’s NMR tube. The progress of the reaction was then monitored by 1 H, 19 F{ 1 H}, and 31 P{ 1 H} NMR spectroscopy (see Tables 6.1 and 6.2 in Chapter 6). Initially only the allylic fluoride (74), PPh3 and dba were evident in the 1 H NMR spectrum, though a new small broad peak was observed at – 157.9 ppm in the 19 F NMR spectrum. Over time, (74) (see Figure 3.7 for initial spectra ) began to disappear from both the 1 H and 19 F NMR spectra and peaks became apparent that were attributable to the desired �-allyl species (132) (3.0, 3.8, 4.1 and 4.5 ppm) and the elimination product (133) (5.1, 5.3, 6.3 and 6.8 ppm) (see Figure 3.8). The initially small peak at -157.9 ppm in the 19 F NMR spectrum grew becoming a very large broad peak and the allylic fluoride peak at -184.7 ppm was barely visible (see Figure 3.9). Electrospray mass spectrometry of the reaction mixture confirmed formation of the allylpalladium cationic complex (132) with a strong signal for the cation at m/z 830.
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Synthesis and Comparison of the Rea
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Acknowledgements Firstly, I would l
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2.2.2.1.1 Synthesis of 1-(Benzyloxy
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6.2.12 Preparation of 2-(4-trimethy
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6.4.12 Experimental Data for Dimeth
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AgF ap Bn Bz CsF d DAST dba DCM DME
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Chapter one
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2 Chapter One potentially explosive
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4 Chapter One ortho-biphenyl trifla
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6 Chapter One 2,10 (3,3-dichlorocam
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8 Chapter One both enantiomers were
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10 Chapter One poor to moderate ena
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Scheme 1.10 Fluorination of (17) 12
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14 Chapter One fluorine donors, Lew
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1.3 Enantioselective Nucleophilic F
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Scheme 1.16 Fluorination of (32) 18
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20 Chapter One (iii) SN2’ type su
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22 Chapter One cytotoxicity in the
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24 Chapter One Manabe and Ishikawa
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Scheme 1.25 Synthesis of (41)-(44)
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Figure 1.12 �-fluorinated NSAIDs
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1.6 Thesis Outline 30 Chapter One T
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32 Chapter One [26] M. Abdul-Ghani,
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[79] M. Schlosser, D. Michael, Z.-W
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2.1 Introduction 2 Synthesis of All
Page 51 and 52: 37 Chapter Two In dehydroxyfluorina
Page 53 and 54: Scheme 2.6 Fluorination with IF5/Et
Page 55 and 56: 41 Chapter Two desired allylic fluo
Page 57 and 58: 43 Chapter Two c) Formation of a su
Page 59 and 60: Scheme 2.14 Reaction of cis-3-methy
Page 61 and 62: Substrate (60) (61) (62) (63) R = O
Page 63 and 64: Alcohol Product Yield (%) Table 2.7
Page 65 and 66: 51 Chapter Two completion. This ena
Page 67 and 68: 53 Chapter Two Chapter Three. Follo
Page 69 and 70: 55 Chapter Two Two allyl alcohols w
Page 71 and 72: 57 Chapter Two The conversion of (8
Page 73 and 74: Starting substrate (88) (89) (90) (
Page 75 and 76: Starting substrate (99) (76) (77) (
Page 77 and 78: 63 Chapter Two Both (105) and (104)
Page 79 and 80: Scheme 2.25 Mechanistic pathway for
Page 81 and 82: 2.3 Conclusions 67 Chapter Two The
Page 83 and 84: [28] D. F. Taber, J. Am. Chem. Soc.
Page 85 and 86: Chapter THRee
Page 87 and 88: 72 Chapter Three Kurosawa reacted a
Page 89 and 90: 74 Chapter Three These results demo
Page 91 and 92: 76 Chapter Three More recently, wor
Page 93 and 94: 3.2 Results and Discussion 3.2.1 Re
Page 95 and 96: 80 Chapter Three Starting substrate
Page 97 and 98: 82 Chapter Three Figure 3.4 Crystal
Page 99 and 100: Scheme 3.12 Oxidative addition of 1
Page 101: 86 Chapter Three when the reaction
Page 105 and 106: -140 -140 -140 -140 -140 -150 -150
Page 107 and 108: 92 Chapter Three monitored for 80 m
Page 109 and 110: 3.4 References [1] W. T. Dent, R. L
Page 111 and 112: Chapter Four
Page 113 and 114: 97 Chapter Four nucleophilic substi
Page 115 and 116: 99 Chapter Four Further reactions w
Page 117 and 118: Figure 4.3 Structure of co-product
Page 119 and 120: 4.2.2 Reactions of palladium cation
Page 121 and 122: 105 Chapter Four substituents on th
Page 123 and 124: 107 Chapter Four The desired produc
Page 125 and 126: 109 Chapter Four The reaction of (1
Page 127 and 128: 111 Chapter Four were both reacted
Page 129 and 130: [28] D. Landini, A. Maia, A. Rampol
Page 131 and 132: 5.1 Introduction 5 Synthesis and Re
Page 133 and 134: 116 Chapter Five The first enantios
Page 135 and 136: 118 Chapter Five Gem(difluoroallyl)
Page 137 and 138: 120 Chapter Five benzaldehyde, 3-br
Page 139 and 140: Starting Substrate (76) (77) (78) (
Page 141 and 142: Starting Substrate Product Yield (%
Page 143 and 144: 5.2.4 Synthesis of Allylic Difluori
Page 145 and 146: 5.2.5 Metal-mediated synthesis of 3
Page 147 and 148: 130 Chapter Five process. [40] Unfo
Page 149 and 150: 132 Chapter Five compounds were pur
Page 151 and 152: 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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