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Investigations in selective fluorinations: Novel synthetic methodologies and material syntheses

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Investigations in selective fluorinations: Novel synthetic methodologies and material syntheses

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Content INVESTIGATIONS IN SELECTIVE FLUORINATIONS: NOVEL SYNTHETIC METHODOLOGIES AND MATERIAL SYNTHESES Copyright 2002 by Jinbo Hu A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements of the Degree DOCTOR OF PHILOSOPHY (CHEMISTRY) August 2002 Jinbo Hu Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. UMI Number: 3094336 Copyright 2002 by Hu, Jinbo All rights reserved. ® UMI UMI Microform 3094336 Copyright 2003 by ProQ uest Information and Learning Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United S tates Code. ProQ uest Information and Learning Com pany 300 North Z eeb Road P.O. Box 1346 Ann Arbor, Ml 48106-1346 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. UNIVERSITY OF SOUTHERN CALIFORNIA The Graduate School University Park LOS ANGELES, CALIFORNIA 900894695 This dissertation, w r itte n b y J in b o Hu Under th e direction o f h .is- D issertation Com m ittee, an d approved b y a ll its m em bers, has been p resen ted to an d accepted b y The Graduate School, in p a rtia l fulfillm en t o f requirem ents fo r th e degree o f DOCTOR OF PHILOSOPHY Dean o f Graduate Studies D ate Aui^ust^.6^ 2 QQ2 DISSER TA H O N COMMITTEE L Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. DEDICATION To my parents 11 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGEMENTS First of all, I would like to express my appreciation to my Ph.D. research advisor, Professor G. K. Surya Prakash for his tireless guidance and kind support throughout my whole graduate study. This dissertation would not have been possible without his guidance and support. Dr. Prakash is an ideal role model for me to follow in my life, both as a scientist and a human being. I also would like to thank Professor George A. Olah for his support and encouragement. His profound knowledge in both chemistry and philosophy has given me a lot of inspirations. I will try to follow his serious and honest attitude in science. I must acknowledge all members in the Olah-Prakash group for their support and help. It is my fortune to pursue my Ph.D. study in this big scientific family. Among these people are Dr. Robert A. Aniszfeld, Dr. Golam Rasul, Dr. Thomas Mathew, Dr. Imre Busci, Dr. Bela Torok, Dr. Juergen Simon, Dr. Sabine Shwaiger, Dr. Markus Etzkom, Dr. Masashi Tashiro, Dr. Hedeki Tashiro, Dr. Hiroshi Suzuki, Dr. Akihisa Saitoh, Dr. Marcia Greci, Dr. Konstantin Koltunov, Dr. Douglas Klump, Mihir Mandal, Chulsung Bae, Bo Yang, Ping Yang, Chiradeep Panja, Ryan Desousa, Kimberly MacGrath, Iris Cheung. Professor Thieo Hogen-Esch, Dr. William Warner are also appreciated for our collaboration in metal-free anionic polymerizations. Professor Mian Alauddin is thanked for our collaboration with the 1 8 F radiolabeling chemistry. Dr. Marshal iii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Smart is thanked for our cooperation in lithium-ion battery project. Professor Hogen- Esch, Professor Bau and Professor Petruska are all thanked for their service as my Ph.D. committee members. Professor William Weber is especially acknowledged for his introducing me into the silicon chemistry. I appreciate Professor Ping Lu and Mr. Guoping Cai for their numerous help and our friendship since my college time at Hangzhou. Dr. Diyun Huang, Joseph Mabry, lie Da, Rong Chen are also thanked for our discussion and their help in polymer characterization. Kevin Jin is thanked for his friendship and help in the X-ray structure characterization. I would also like to thank so many good friends in Loker Hydrocarbon Research Institute and Department of Chemistry for our friendship. I especially thank Ralph, David, Jessy, Carole for their kind support. Mr. Allan Kershaw is thanked for his technical help with the NMR and IR instruments. Last, but certainly not least, I would like to convey my deep appreciation to my parents. Their selfless support to me over the years is the most valuable gift in my life. I always regard my parents as the best parents in the world. IV Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS Dedication ii Acknowledgements iii List of Figures x List of Schemes xi List of Tables xvii Abstract xviii Chapter 1 Introduction - Selective Fluorinations...................................................1 1.1 Historical background...........................................................................2 1.2 Unique properties of fluorine atom and fluorinated compounds............................................................... 5 1.3 Selective fluorinations............................................................ 8 1.3.1 Selective introduction of fluorine atoms ..................................8 1.3.1.1 Nucleophihc fluorination ..................................................8 (a) Hydrogen fluoride (HF) and its derivatives .........................9 (b) Other fluoride reagents ..................................................... 11 (c) Nucleophilic deoxo-fluorination using SF4 and its derivatives ........................................ 13 1.3.1.2 Electrophilic fluorination .................................................. 14 (a) Elemental fluorine (F2) 14 (b) Xenon difluoride (XeFa) .................................................... 15 (c) O-F containing reagents .................................................... 16 (d) N-F containing reagents ................................................... 17 1.3.1.3 Combined fluorination (Oxidative fluorination) ............19 1.3.1.4 Electrochemical fluorination ...................................... 20 1.3.2 Selective introduction of organofluorine building blocks ...21 1.3.2.1 Nucleophilic introduction of organofluorine building blocks ......................................................... 21 (a) Fluorinated organometallic reagents ................................21 (b) Fluorinated organosilicon reagents .................................24 1.3.2.2 Electrophilic introduction of organofluorine building blocks .......................................... 26 (a) (Perfluoroalkyl)- and (polyfluoroalkyl)aryliodonium ..... 26 (b) (Trifluoromethyl)chalcogenium salts ............... 27 1.3.2.3 Selective introduction of organofluorine building v Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. blocks ...................... 28 1.1 Prospective ....................... 30 1.5 References ........................................................ 31 Chapter 2 Facile Preparation of Di- and Monofluoromethyl Ketones from Trifluoromethyl Ketones via Fluorinated Enol Silyl Ethers ...... ...36 2.1 Introduction ...................................................................................37 2.2 Results and Discussion .................................................................. 40 2.2.1 Preparation of difluoromethyl ketones from trifluoromethyl ketones 40 2.2.2 Effect of fluoride ion sources on desilylative hydrolysis 41 2.2.3 Preparation of monofluoromethyl ketones from difluoromethyl ketones 42 2.2.4 The Z/E isomers of 2-fluoroenol silyl ethers ............... 45 2.2.5 Mechanism ............... 46 2.3 Conclusion ..................................................................................... 47 2.4 Experimental Section ............................................................... 47 2.5 References ............................................................................... 69 Chapter 3 Preparation of 1 S F Labeled Trifluoromethyl Ketones and Other Halodifluoromethyl Ketones via Selective Halogenation of 2,2- Difluoro Enol Silyl Ethers ........................................................... 71 3.1 Introduction 72 3.2 Results and Discussion ...................................................................... 76 3.3 Conclusion .......................................................................................80 3.4 Experimental Section.............................................. ....84 3.5 References ..................................................................................... ...90 Chapter 4 Preparation of Trifluoromethyl- and Difluoromethylsilanes via an Unusual Magnesium Metal Mediated Reductive Tri- and Difluoromethylation of Chlorosilanes Using Tri- and Difluoromethyl Sulfides, Sulfoxides and Sulfones ...........................92 4.1 Introduction 93 4.2 Results and Discussion ...............................................................96 4.3 Conclusion ............................. 106 4.4 Experimental Section .................................................................. 106 4.5 References ....................................................................................... 122 vi Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 5 Alkoxide Induced Nucleophilic Tri- and Difluoromethylation Using Tri- and Difluoromethyl Sulfones or Sulfoxides .............125 5.1 Introduction .............................. 126 5.2 Results and Discussion .............................................. 129 5.2.1 Trifluoromethylation of aldehyde ............................................129 5.2.2 Trifluoromethylation of ketones ....... 134 5.2.3 Trifluoromethylation of methyl ester .........................137 5.2.4 Trifluoromethylation of disulfide .......................... 139 5.2.5 Trifluoromethylation of aryl iodide 140 5.2.6 Difluoromethylation of disulfide ..................................... 141 5.2.7 Difluoromethylation of aldehyde ............ 143 5.2.8 Methyl trifluoromethyl sulfone as the trifluoromethylating agent .................. 147 5.3 Conclusion ........................................................................ 147 5.4 Experimental Section ....................................................................148 5.5 References .............................. 153 Chapter 6 Synthesis of Partially Fluorinated Ethers by Alkylation of Fluorinated Alkoxides Generated from Fluoroacyl Halides and the Fluoride Ion ........................................................................ 156 6.1 Introduction ................................................... 157 6.2 Results and Discussion ......................................................................160 6.2.1 Dimethyl sulfate as the alkylating agent .............................. 160 6.2.2 Alkyl sulfonates as the alkylating agents.............................. 165 6.2.3 Attempted reactions with other electrophiles.......................167 6.2.4 Attempted synthesis of partially fluorinated polyether ......168 6.3 Conclusion ........................................................................................ 171 6.4 Experimental Section ................ 171 6.5 References ................................................................................... 185 Chapter 7 Synthesis of Fluorinated Carbonates, Carbamates and Some Polymeric Materials for Low Temperature Lithium-Ion Battery Applications ...................................................................... 189 7.1 Introduction ...................................................................................190 7.1.1 Partially fluorinated carbonates and carbamates................. 190 7.1.2 Polymeric materials for lithium-ion battery electrolytes ....192 7.2 Results and Discussion ....... 193 7.2.1 Partially fluorinated carbonates and carbamates .......... 193 7.2.2 Polymeric materials for lithium-ion battery electrolytes ...197 (a) Copolymer of ethylene glycol and dichlorodimethylsilane. .197 (b) Attempted synthesis of polysilane functionalized with ethylene glycol .................................................................... 203 vii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. (c) Attempted Synthesis of copolymer of ethylene glycol and boron trichloride ................................................................ 204 (d) Synthesis of four-armed star shaped poly(ethylene oxide) (PEO) 205 7.3 Conclusion ............ 207 7.4 Experimental Section..................................................................... 207 7.5 References .................................................................................. ...215 Chapter 8 Synthesis of Superacidic Fluorinated Sulfonic Acids ..................217 8.1 Introduction .................................................. 218 8.1.1 Superacids .......................................................................218 8.1.2 Perfluorinated alkanesulfonic acids ..............................219 8.1.3 Synthesis of trifhioromethanesulfonic acid (Triflic acid) ............ 219 8.1.4 Synthesis of Nafion-H .................................................... ...222 8.1.5 Synthesis of chlorodifluoromethanesulfonic acid...............223 8.1.6 Synthesis of polymer-supported fluorinated alkanesulfonic acid ....... 224 8.2 Results and Discussion ..................................................................226 8.2.1 Novel synthesis of chlorodifluoromethanesulfonic acid 8.2.2 Synthesis of phenyl difluoromethanesulfonic acid 8.2.3 Synthesis of 2-phenyl-1,1,2,2-tetrafluoroethanesulfonic acid 8.2.4 Attempted synthesis of polystyrene supported superacid via a- or /3- bromodifluoromethyl styrene as monomers 8.2.5 Attempted synthesis of TMS-CF2S03CH(CF3)2 8.3 Conclusion ....................................................................................243 8.4 Experimental Section 244 8.5 References ..................................................................... 257 Chapter 9 Metal-free Anionic Polymerization Using Organosilanes/ Tetramethylammonium Fluoride as New Initiating System ........260 9.1 Introduction ..................................................................... 261 9.2 Results and Discussion ............ 264 9.2.1 Synthesis of silanes ............................... 264 9.2.2 Choice of fluoride ............................... 266 9.2.3 Polymerizaton of MMA using PhsCSiMea/TMAF . as initiator ............................................................................ 267 9.2.4 Other initiators and monomers ............................................ 273 9.3 Conclusion ................................................ 273 9.4 Experimental Section ......................................... 274 9.5 References ..................................................... 279 viii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Bibliography Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF FIGURES Figure 2.1 1 9 F NMR of 2,2-difluoro-l-phenyl-1-trimethylsiloxyethene 2a 40 Figure 2.2 1 9 F NMR of 2-fliioro-l-phenyl-1-trimethylsiloxyethene 5a 43 Figure 3.1 The radioactivity measurement of the product mixture of 1 8 F labeled 1-naphthyl 2,2,2-Trifluoro-l ’-acetonaphthone (2o) by a TLC scanner with radioactivity sensor 79 Figure 4.1 1 9 F NMR (CDC13 , CFC13 int.) of a sample from the reaction mixture of 1 mmol trifluoromethyl phenyl sulfone (1 9 F NMR: 5 -78.99 ppm), 3 mmol Mg and 4 mmol TMSC1 in 5ml DMF at 0 °C for 30 min 97 Figure 5.1 1 9 F NMR study of the trifluoromethylation of benzaldehyde by PhS02 CF/BuOK 133 Figure 5.2 1 9 F NMR of 2,2-Difluoro-1,3 -diphenyl-1,3 -propanediol (32) with anti/syn = 97:3 146 Figure 7.1 Proposed Schematic of segmental motion assisted diffusion of Li+ ion in the ethylene glycol/dichlorodimethylsilane copolymer matrix 193 Figure 7.2 X-ray structure of 2,2,7,7-tetramethyl-l,3,6,8-tetraoxo-2,7- disilacyclodecane 10 200 Figure 7.3 Self ring opening polymerization (ROP) of 10 201 Figure 8.1 1 3 C and 1 9 F NMR spectra of CF2 C1S03 H 231 Figure 9.1 X-ray crystal structure of silane 2 265 Figure 9.2 SEC trace of PMMA from reaction mixture of run 269 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF SCHEMES Scheme 1.1 Swarts reaction 4 Scheme 1.2 Balz-Schiemann reaction 4 Scheme 1.3 Biological effects of fluorine atom and fluorine-containing groups 7 Scheme 1.4 Nucleophilic fluorination of alkene with HF 7 Scheme 1.4 Nucleophilic fluorination of alkene with HF 9 Scheme 1.5 Lewis acid catalyzed nucleophilic fluorination of alkene with HF 9 Scheme 1.6 Fluorination of o^a-trichlorotoluene with HF 10 Scheme 1.7 Applications of Olah reagent in fluorinations 1 1 Scheme 1.8 Spray-dried KF mediated nucleophilic fluorinations 12 Scheme 1.9 Applications of TASF, TBAT and TBTD in organic synthesis 13 Scheme 1.10 Nucleophilic deoxo-fluorinations with SF4 and DAST 14 Scheme 1.11 Electrophilic fluorinations with F2 15 Scheme 1.12 Electrophilic fluorinations with XeF2 16 Scheme 1.13 Electrophilic fluorinations with O-F containing reagents 17 Scheme 1.14 Structures ofN-F containing electrophilic fluorinating reagents 18 Scheme 1.15 Stereoselective fluorinations N-F containing reagents 19 Scheme 1.16 Combined fluorinations (oxidative fluorinations) 20 Scheme 1.17 Preparation of triflic acid by ECF 21 Scheme 1.18 Introduction of perfluoroalkyl groups into carbonyl compounds with fluorinated organometallic reagents 22 Scheme 1.19 Introduction of fluoro- alkenyl and alkynyl groups into electrophiles 22 Scheme 1.20 Decomposition of trifluoromethylated organometallic compounds 23 xi Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Scheme 1.21 Introduction of perfiuoroalkyl group with perfluoroalkylcopper reagents 23 Scheme 1.22 Reaction with fluorinated metal enolate 24 Scheme 1.23 Nucleophilic trifluoromethylation with TMS-CF3 25 Scheme 1.24 Nucleophilic difluoromethylation with PhMe2 SiCF2 H 26 Scheme 1.25 Introduction of perfiuoroalkyl and polyfluoroalkyl groups with (perfiuoroalkyl)- and (polyfluoroalkyl)aryliodonium 27 Scheme 1.26 Electrophilic trifluoromethylation with S-, Se-, or Te- (trifluoromethyl)dibenzochalcogenophenium salts 28 Scheme 1.27 Introduction of organofluorine building blocks with fluorine-containing radicals 29 Scheme 1.28 Introduction of organofluorine building blocks with fluorine-containing carbenes 30 Scheme 2.1 Proposed mechanism of transformation of 3->6 46 Scheme 3.1 The synthesis of I8 FDG 72 Scheme 3.2 Formation of stable hydrates or hemiacetals between TFMKs and protease/enzyme molecules 73 Scheme 3.3 Examples of TFMKs as protease inhibitors 74 Scheme 3.4 Selective halogenations of 2,2-difluoro silyl enol ethers (1) 76 Scheme 3.5 Proposed mechanism of selective halogenations 80 Scheme 4.1 Mechanistic considerations 95 Scheme 4.2 Preparation of phenyl trifluoromethyl sulfide (lc), sulfoxide (lb), sulfone (la) and difluoromethyl phenyl sulfide (lp), sulfone (li) 96 Scheme 4.3 Two possible pathways for the formation of 31 from 1 1 99 Scheme 4.4 Formation of 31 from lm or In 100 Scheme 4.5 Proposed mechanism 102 Scheme 4.6 Different reactivities of phenyl 2,2,2-trifluoroethyl sulfide, sulfoxide and sulfone under similar reaction conditions 103 Scheme 4.7 Possible catalytic pathway for the preparation of TMS-CF3 from CF3 H 105 xii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Scheme 4.8 Di- and trifluoromethylations with new silanes 3j and 3h 106 Scheme 5.1 Mechanistic considerations 129 Scheme 5.2 Trifluoromethylation ofPhCHO with la 130 Scheme 5.3 Proposed mechanism potassium fe/7-butoxide induced trifluoromethylation ofPhCHO 132 Scheme 5.4 Trifluoromethylation of benzophenone with la 135 Scheme 5.5 Trifluoromethylation of acetophenone with la 135 Scheme 5.6 Trifluoromethylation of methyl benzoate using la to give 2,2,2-trifluoro- acetophenone 138 Scheme 5.7 Trifluoromethylation ofPhSSPh with la 139 Scheme 5.8 Trifluoromethylation of iodobenzene with la 140 Scheme 5.9 Proposed mechanism for the difluoromethylation ofPhSSPh with lc 142 Scheme 5.10 Difluoormethylene dianion synthon 143 Scheme 5.11 Stahly’s difluoromethylation with lc 143 Scheme 5.12 Reaction of PhCHO (excess) and lc/‘ BuOK 144 Scheme 5.13 Proposed mechanism of distereoselective formation of 30 145 Scheme 5.14 Attempted trifluoromethyaltion with CH3SO2CF3 147 Scheme 6.1 Synthesis of fluoroalkyl ethers (2) 160 Scheme 6.2 Proposed mechanism for the formation of 2 from 1 161 Scheme 6.3 (a) C-0 and C-F Bond lengths from (Me2 N)3S+ CF3 0 ‘ X-ray crystal structure; (b) Negative hyperconjugation in fluorinated alkoxide (5) 164 Scheme 6.4 Synthesis of fluoroalkyl ethers (6) using alkyl sulfonates as alkylating Agents 165 Scheme 6.5 Proposed mechanism of formation of the methyl ether 2a via an alkylated diglyme oxonium ion 7 intermediate 167 Scheme 6.6 Attempted reactions of fluoroalkoxide 5 with other electrophiles 168 Scheme 6.7 Synthesis of polyether 11 169 xiii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Scheme 7.1 Synthesis of partially fluorinated carbonates and carbamates 194 Scheme 7.2 Different reactivities of carbamoyl chloride and chloroformate 195 Scheme 7.3 Synthesis of partially fluorinated carbamates 196 Scheme 7.4 Synthesis of bis(2,2,2-trifluoroethyl)carbonate 6 196 Scheme 7.5 Synthesis of ethylene glycol/dichlorodimethylsilane copolymer 9 198 Scheme 7.6 Possible structure for compound 10 198 Scheme 7.7 Formation of 5- and 10-member-ring products 199 Scheme 7.8 The formation of polymer 9 and cyclic compound 10 202 Scheme 7.9 Attempted formation of Si—F—Si bridge with cyclic compound 10 203 Scheme 7.10 Attempted synthesis of functionalized polysilane 12 204 Scheme 7.11 Attempted synthesis of copolymer 15 205 Scheme 7.12 Synthesis of four-arm star shape PEO 206 Scheme 8.1 Synthesis of triflic acid from (CF3S)2 Hg 220 Scheme 8.2 Synthesis of triflic acid from CF3 SC 1 220 Scheme 8.3 Synthesis of triflic acid from methyltrifluoromethyl sufide 221 Scheme 8.4 Synthesis of triflic acid from bis(trifluoromethyl) disulfide 221 Scheme 8.5 ECF synthesis of triflic acid 221 Scheme 8.6 Synthesis of Nafion 223 Scheme 8.7 Synthesis of chlorodifluoromethanesulfonic acid by Yagupol’skii and co-workers 224 Scheme 8.8 Dupont’s synthesis of PS supported -CF2S03 H 225 Scheme 8.9 Attempted preparation of CF2 C 1SC 1 from C 13 CSC1 226 Scheme 8.10 Synthesis of CC13 SC 1 from CS2 and Cl2 226 xiv Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Scheme 8.11 Attempted Swarts reactions 227 Scheme 8.12 Preparation of CF2 ClSNEt2 228 Scheme 8.13 Mechanistic explanation of the role of SbCl5 in halogen-exchange reaction 229 Scheme 8.14 New approach for the synthesis of CF2 C1S03 H 230 Scheme 8.15 Structure ofPhCF2S03 H and its PS supported analog 232 Scheme 8.16 BBr3 mediated benzylic F/Br exchange reactions 233 Scheme 8.17 Synthesis of PhCF2 S03 H 234 Scheme 8.18 The decomposition PhCF2S03 H 235 Scheme 8.19 Retro synthetic route of PhCF2 CF2 S03 H 236 Scheme 8.20 Attempted synthesis of PhCOCF2 Br using TMS-CF2 Br 236 Scheme 8.21 Synthesis of PhCOCF2 Br 237 Scheme 8.22 Synthesis of PhCF2 CF2 Br using DAST 237 Scheme 8.23 Synthesis of PhCF2 CF2 S03H 238 Scheme 8.24 Structures of designed polymer-supported -CF2S03 H 29 and 30 239 Scheme 8.25 Synthesis of /S-bromodifluoromethylstyrene 239 Scheme 8.26 Hydrolysis of 34 into cinnamic acid 240 Scheme 8.27 Synthesis of a-bromodifluoromethyl styrene 241 Scheme 8.28 Unusual formation of 1,3-diol 38 242 Scheme 8.29 Attempted synthesis of difluorinated methanesulfonates from trifluoromethanesulfonate 243 Scheme 9.1 Generation of anion [R40] from silane and fluoride 262 Scheme 9.2 Structures of silanes 1 - 4 264 Scheme 9.3 The effects of different fluoride sources 266 Scheme 9.3 Schematic illustration of the initiation and propagation processes 270 xv Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Scheme 9.5 Possible side reactions 272 x v i Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF TABLES Table 1.1 Some properties of fluorine and other elements 6 Table 2.1 Preparation of difluoromethyl ketones 3 from trifluoromethyl ketones 1 via difluoroenol silyl ethers 2 39 Table 2.2 The effect of fluoride ion sources on the desilylative hydrolysis 42 Table 2.3 Preparation of monofluoromethyl ketones 6 from difluoromethyl ketones 3 44 Table 2.4 The Z/E isomers of 2-fluoroenol silyl ethers 5 45 Table 3.1 Preparation ofhalogenated methyl ketones 2 through facile selective halogenations of 2,2-difluoroenol silyl ethers 1 78 Table 4.1 Preparation of trifluoromethylsilanes and difluoromethylsilanes through Mg° mediated reductive cleavage of C-S bond 98 Table 5.1 Trifluoromethylation ofbenzaldehyde by PhS02 CF3 induced by alkoxide or hydroxide 131 Table 5.2 Reaction of trifluoromethyl phenyl sulfone (la) or sulfoxide (lb) (2 equiv) with non-enolizable carbonyl compounds (1 equiv) and lBuOK (2.5 equiv) in DMF at - 50 °C ~ room temperature 136 Table 5.3 Difluoromethylation ofPhSSPh with lb 141 Table 5.4 Reaction ofPhCHO (excess) and lc/BuOK 144 Table 6.1 Preparation of fluoroethers 2 from fluorinated acyl chlorides 1, KF and dimethyl sulfate in diglyme 162 Table 6.2 Preparation of fluoroethers 6 from fluorinated acyl chlorides 1, KF and alkyl sulfonates in diglyme 166 Table 7.1 Synthesis of carbonates from chloroformate and alcohol 195 Table 9.1. Ph3 C' + NMe4 initiated anionic polymerization ofMMA in THF at - 78 °C 268 xvii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ABSTRACT In this dissertation, we have investigated selective fluorination chemistry that has led to novel synthetic methodologies and material syntheses. Chapter 1 reviews some historical background and recent developments in the selective fluorinations, i.e. the chemo- and stereoselective introductions of fluorine atoms or organofluorine building blocks. Difluoromethyl and monofluoromethyl ketones are potential protease and enzyme inhibitors, due to their ease of formation of stable tetrahedral hydrates or hemiacetals. In Chapter 2, we have explored the preparation of di- and monofluoromethyl ketones from trifluoromethyl ketones via fluorinated enol silyl ethers. Through magnesium mediated selective defluorination followed by hydrolysis, trifluoromethyl ketones are transformed into difluoromethyl ketones. The difluoromethyl ketones are further transformed into monofluoromethyl ketones through their respective monofluoroenol silyl ethers. A significant advantage of this methodology is that it uses only inexpensive and readily available reagents, and the reactions are mild and facile. In Chapter 3, we have investigated the electrophilic selective halogenations of 2,2-difluoroenol silyl ethers using bromine, iodine, fluorine, Selectfluor® as halogenating agents. The resulting bromodifluoromethyl or iododifluoromethyl ketones are useful intermediates for further elaboration to prepare other difluorinated •I Q species. The F labeled trifluoromethyl ketones were also prepared, which provides xviii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. a useful methodology to generate important new types of potential positron emission tomography (PET) imaging agents. In Chapter 4, we have developed an efficient method for the preparation of trifluoromethyl- and difluoromethylsilanes using magnesium metal mediated reductive tri- and difluoromethylation of chlorosilanes using tri- and difluoromethyl sulfides, sulfoxides, and sulfones. The byproduct of the process is diphenyl disulfide. Since phenyl trifluoromethyl sulfone, sulfoxide and sulfide are readily prepared from trifluoromethane (CF3H) and diphenyl disulfide, the method can be considered “pseudo-catalytic” for the preparation of (trifluoromethyl)trimethylsilane (TMS-CF3 ) from environmentally benign trifluoromethane. In Chapter 5, we have explored a novel potasium tert-butoxide induced trifluoromethylation of carbonyl compounds and disulfides by using phenyl trifluoromethyl sulfone (PI1SO2CF3, la ) or sulfoxide (PI1SOCF3, lb ) in high yields. Phenyl difluoromethyl ketone PI1SO2CF2H (lc) can also be used as “PI1SO2CF2"” or “CF2 2 ‘ ” synthon to react with different types of electrophiles. In Chapter 6, we have synthesized partially fluorinated ethers by alkylation of fluorinated alkoxides generated from fluoroacyl chlorides and potassium fluoride in diglyme. The success and different yields of the reaction are affected by two factors: one is the stability and nucleophilicity of the fluorinated alkoxide generated i n situ; and the other is the electrophilicity of different electrophiles, such as. alkylating agents. The new fluoroethers prepared appeared to be promising candidates for the lithium battery applications. xix Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. In Chapter 7, we have successfully carried out the synthesis of partially fluorinated carbonates, carbamates, and other polymeric materials such as ethylene glycol/dichlorodimethylsilane copolymer, four-arm star shaped PEO. These compounds and materials are good candidates as low temperature lithium-ion battery electrolytes or co-solvents. In Chapter 8, we successfully developed a new route for the synthesis of superacidic chlorodifluoromethanesulfonic acid. Syntheses of phenyl difluoromethanesulfonic acid (PI1CF2SO3H) and 2-phenyl-1,1,2,2- tetrafluoroethanesulfonic acid (PI1CF2CF2SO3H) were also carried out. It was found that the sodium salts of both acids are quite stable. However, the acids themselves are only stable in aqueous solution. In the pure form, both acids can readily undergo superacid catalyzed self-hydrolysis. In Chapter 9, we have developed a new methodology to generate a metal-free aninionic polymerization initiator, tetramethylammonium triphenylmethide (PI1 3 C' + NMe,}) in situ by the reaction of (triphenylmethyl)trimethylsilane and tetramethylammonium fluoride in THF at low temperature. Metal-free polymerization of MMA initiated by this initiator in THF at - 78 °C successfully produced quantitatively yields of high molecular weight PMMA with very narrow molecular weight distribution. The initiation process appeared to be slow while the polymerization process was rapid, which were consistent with the low initiator efficiencies (9 - 40 %) and narrow MW distributions. (Diphenylmethyl) xx Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. trimethylsilane /TMAF was also able to initiate MMA polymerization with a similar result. xxi Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 1 Introduction - Selective Fluorinations Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. In recent years, organofluorine chemistry has made a remarkable progress due to the extensive applications of fluorinated compounds and materials in materials science, medicinal and agrochemistry.1 '6 Fluorine chemistry is recognized as being totally different from chemistry of other halogens, since fluorine atom imparts special reactivities and properties to molecules. In this field, selective fluorinations, i.e. the chemo- and stereoselective introductions of fluorine atoms or organofluorine building blocks, are of most importance and challenge. Currently, many chemoselective fluorination methods are well documented, and relatively less is known on the highly stereoselective fluorinations. This chapter will review some historical background and recent developments in the field. 1.1 Historical background The name, fluorine was first coined as le fluor by French scientist Ampere in 1812 after its natural resource fluorspar. Fluorine exists in nature as fluoride forms, such as fluorite (CaF2 ), cryolite (Na3[AlF6]), and phosphorite (Ca5[F,Cl][P04]3). Fluorine is the most abundant halogen in Earth’s crust - the abundance of fluorine is as high as about five times that of chlorine. However, it is surprising that compounds containing carbon-fluorine bonds are not common in nature. Only twelve examples have been discovered, and how these compounds are biosynthesized is largely unknown. The South African plant dichapetalum cymosum (gifblaar) contains 2 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. potassium monofluoroacetate, an extremely toxic compound. A shrub occurring in Sierra Leone, dichapetalum toxicarium (ratsbane) contains 6 J-fluoro-oleic acid CH2F-(CH2)7CH=CH-(CH2)7COOH, which is also a poisonous compound. Recently, O’Hagan and co-workers7 discovered the first known fluorinase enzyme, which can catalyze carbon-fluorine bond formation between an organic substrate and fluoride ion. This work may provide a clue how the natural organofluorine compounds are biosynthesized. The fact that fluorite can react with sulfuric acid to generate an acid was known as early as in 17th century. The acid was commonly used for glass etching, although it was not well characterized until in the early 18th century. On the basis of the discovery of chlorine (1774) and iodine (1811), people began to consider the “etching acid” as a compound consisting of hydrogen and another new element fluorine. However, the isolation of elemental fluorine (F2) was still left as a major experimental challenge for almost a century, until French chemist Henri Moissan achieved success in 1886 by electrolyzing a melt mixture of potassium hydrogen difluoride (KHF2) and hydrogen fluoride (HF) at - 23 °C. This work led him to obtain the Nobel Prize in 1906. Moissan studied the reactions of fluorine to prepare simple alkyl fluorides,8 however, the method could not be used as a practical synthetic tool for organofluorine compounds due to the extremely high reactivity of element fluorine and the difficulties in handling it. One of the seminal methods of selective fluorinations is the nucleophilic fluorination of organic halides (halogen exchange) with antimony trifluoride (SbF3), 3 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. which was discovered by Belgium chemist F. Swarts in 1892.9 This reaction and other similar type of halogen exchange reactions are commonly called Swarts reaction (Scheme 1.1). Swarts reaction was further modified to synthesize a variety of oganofluorine compounds and was later improved to be an industrial process.1 0 R1 R 1 R2-C-C\ + SbF3 ► r 2-hD-F + SbF2Cl R3 R3 Scheme 1.1 Swarts reaction. Another important early finding in selective fluorination is the Balz-Schiemann reaction}1 This reaction is very useful to convert aromatic amines into fluoroaromatics through their diazonium salts (Scheme 1.2). / = \ 1)NaN02 lHCl / = \ A / = \ R - \J ~N H * 1 7 s ; ----- ~ Scheme 1.2 Balz-Schiemann reaction. 4 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Fluorine also had a major impact in the fields other than organic synthesis. Uranium (IV) fluoride was used in the United States during World War II for the enrichment of radioactive uranium-235 that was essential for the development of atomic bombs. Chlorofluorocarbons (CFCs) have been used as refrigerants for more than half century. In early 1960s, Olah and co-worker1 2 discovered the stable and long-lived tert- butyl carbocation by reacting tert-butyl fluoride with antimony pentafluoride at low temperature. The discovery of Teflon® (Poly(tetrafluoroethene)) has also led to remarkable progress in fluorine-containing materials and chemicals that has been utilized in everyday life all over the world. Non-stick frying pan is one of the many applications of Teflon in our life. Perfluoroalkanesulfonic acids (RfSCbH), especially triflic acid CF3SO3H, have been developed as strong acid catalysts and also for many other applications such as surfactants, lithium battery electrolytes (by using the lithium salts RfSOsLi). 5-Fluorouracil (5-FU) is well known for its effectiveness for the treatment of human breast cancer and several other types of malignancies. Another ubiquitous fluorine-containing product is the fluoride-added toothpaste, which has been used by most people for its anti-cavity property. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1.2 Unique properties of fluorine atom and fluorinated compounds Fluorine has three isotopes: the natural and stable isotope 1 9 F, and other two radioactive isotopes 1 8 F (half-life time of 110 min) and 1 7 F (half-life time of 1.08 min). 1 8 F has been used in positron emission tomography (PET) for medical applications. Due to its short half-life time, nF is less known. The fluorine- containing compounds and materials used in normal laboratory contain only stable and non-radioactive 1 9 F isotope. Fluorine is the most electronegative element with Pauling’s electronegativity value (EN) of 4.0, indicating the strong electron-withdrawing property of fluorine atom (Table 1.1). It has short van der Waal’s radius of 1.35 A, and the carbon- fluorine bond is extraordinarily strong (homolytic bond dissociation energy 116 kCal/mol). Table 1.1 Some properties of fluorine and other elements.2 Element EN (Pauling) T v (A ) (Pauling) r v (A ) (Bondi) BE(CH3 -X) (kCal/mol) c h 3 -x (A ) H 2-1 1.20 1.20 99 1.09 F 4.0 1.35 1.47 116 1.39 Cl 3.0 1.80 1.75 81 1.77 Br 2.8 1.95 1.85 68 1.93 0 (OH) 3.5 1.40 1.52 86 1.43 S (SH) 2.5 1.85 1.80 65 1.82 6 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Due to these unique properties of fluorine atom, organoflurine compounds thus usually have various useful properties such as highly oxidative, hydrolytic and thermal stability. Recently more and more of these compounds have been found to have biological effects like mimic, block, polar, lipophilic effects.2 For example, C-F bond is known to mimic C-H and C-0 bonds because of their similar bond lengths (scheme 1.3). Difluoromethylene group is known to be isosteric and isopolar to ethereal oxygen atom. Difluoromethyl group is isosteric and isopolar to hydroxyl group.1 3 mimic C F I •> c — H c — ° 1.38 A 1.10 A 1.43 A isosteric CF2 i *> O (ethereal) isopolar isosteric CF2H [ = = = = = = = > OH isopolar Scheme 1.3 Biological effects of fluorine atom and fluorine-containing groups. Perfluoroorganic compounds also have special properties2: they possess lower melting point than their hydrocarbon analogs; they are chemically and biologically inert; they are immicible with both water or organic solvents and stay by itself as a 7 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. fluorous phase. These compounds can readily dissolve gaseous species like molecular oxygen. Highly fluorinated polymers (likeTeflon®, Nafion®) have unique physical properties, such as high thermal stability, low dielectric constant, less moisture absorption, excellent weatherability, low flammability and low surface energy, and outstanding resistance to most chemicals. 1.3 Selective fluorinations The filed of selective fluorinations (chemo- or stereoselective) has blossomed since the early 1970s. Numerous selective fluorination methods abound in the literature, and they have been reviewed by several different authors.1 '6 In general, selective fluorinations can be divided in two categories: selective introduction of fluorine atoms and organofluorine building blocks. 1.3.1 Selective introduction of fluorine atoms Selective introduction of fluorine atoms include nucleophilic fluorination, electrophilic fluorination, combined fluorination (using combination of an electrophile and fluoride source), and electrochemical fluorination. 8 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1.3.1.1 Nucleophilic fluorination (a) Hydrogen fluoride (HF) and its derivatives The most common nucleophilic fluorinating reagent is hydrogen fluoride (HF). Anhydrous HF is a colorless liquid with a boiling point of 19.5 °C. HF is basically produced from fluorite (CaF2) and sulfuric acid, and is an important industrial material for various applications, such as fluorination, preparation of other derived fluorinating agents, acid catalysis,1 4 etching (semiconductor industry), and so on. HF can readily undergo addition reaction to a carbon-carbon double bond to give fluorinated alkane.1 5 The reaction typically proceeds to give Markovnikov-type product distributions (Scheme 1.4). For some less reactive olefins, the use of a Lewis acid catalyst like FeCT, SbF3/SbF5, or TaFs accelerates the addition reaction (Scheme 1.5).1 6 F HF Scheme 1.4 Nucleophilic fluorination of alkene with HF. .C l 89% Scheme 1.5 Lewis acid catalyzed nucleophilic fluorination of alkene with HF. 9 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. HF also readily reacts with acetylenes to give fluorinated olefins or difluorinated alkanes.1 7 It also readily reacts with a labile C-Cl bond to form 1 o corresponding C-F bond (scheme 1.6). < > C C 13 HF Scheme 1.6 Fluorination of a,a,a-trichlorotoluene with HF. HF-amine complexes have also been developed as less volatile and less corrosive alternative fluorinating reagents of HF, including HF/pyridine, HF/melamine, HF/NEt3, HF/BUNH2. The most well known HF-amine complex is (pyridinium poly (hydrogen fluoride) or PPHF (Olah reagent, HF/pyridine = 70:30 w/w, or ca. 9:1 molar ratio). It is a stable liquid and does not liberate HF even at 50 °C. It has been employed in various fluorinations,1 9 such as fluorination of alkenes and alkynes (hydrofluorination, halofluorination, nitrofluorination, fluorosulfenylation), fluorination of secondary and tertiary alcohols including glucose, transformation of amino, diazo, triazeno, and isocyano groups into fluorides, ring-opening fluorination, gem-di fluorination and trifluorination, transformation of C-H and C-X into C-F bonds, and oxidative and reductive fluorinations, among others. The Olah reagent has been commercialized, and its 10 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. various applications in fluorinations have been reviewed elsewhere.1 9 Scheme 1.7 2 0 2 1 demonstrates two examples of the applications of Olah reagent m fluorinations. BnOH2C OBn BnOH2 C OBn OBn OH PPHF (30:70) CH2CI2, r.t. OBn NH2 NaN02 F COOH PPHF (30:70) 0°C COOH Scheme 1.7 Applications of Olah reagent in fluorinations (b) Other fluoride reagents In contrast to corrosive and toxic HF, other fluoride reagents like KF, CsF, BmN+F (TBAF), Me4 N+F‘ (TMAF), Bu4N+ Ph3SiF2 ‘ (TBAT), (Me2 N)3S+ [F2SiMe3 ]' (TASF) and Ph4P+F‘ are inexpensive, stable, and thus attractive for manufacture and applications. Spray-dried KF has small KF particle size (10-15 nm) and it is less hygroscopic. Thus it is commonly used in various types of fluorinations, sometimes with the use of 18-crown-6 or a phase-transfer catalyst. Scheme 1.8 shows two examples of spray-dried KF mediated fluorinations. 11 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. spray-dried KF MeCN, reflux 82% CHO CHO spray-dried KF 18-Crown-6 / Pt^PBr 30 °C 74% Scheme 1.8 Spray-dried KF mediated nucleophilic fluorinations. KF derived regent potassium hydrogen fluoride (KHF2), which has also been used in the fluorinations of epoxy sugars.2 2 Tetraalkylammonium fluorides (I^N* F") are highly nucleophilic fluoride ion reagents soluble in organic solvents, among which Bu^tsT F‘ (TBAF) is most commonly used. However, TBAF exists in its stable form as a trihydrate, and the dehydration under vacuum will easily induce its decomposition via Hoffman- elimination.2 To avoid this elimination, other tetraalkylammonium fluoride like tetramethylammonium fluoride (TMAF) has been synthesized and commercialized as stable and anhydrous salt.2 3 Recently, reagents which provide a fluoride ion by an equilibrium in organic media have been prepared.24 These includes (Me2N)3S+ [F2SiMe3]‘ (TASF, R= Me, Et)2 5, Bu4N+ Ph3SiF2 ' (TBAT)26, and Bu4N+ Ph3SnF2 ' (TBTD)2 7 , and they are all useful reagents in organic synthesis (Scheme 1.9). 12 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. OSiMe3 O O H ( £ : Z = 0 : 100; + PhCHO TASF (Et) THF - 78 °C Ph 65 %, erythro:threo = 8 6 :14 OTs F MeCN, reflux TBAT 98% OSiMe3 O + PhCH2Br THF, 20 °C 6 h TBTD Ph 99 % Scheme 1.9 Applications of TASF, TBAT and TBTD in organic synthesis. Phosphonium analogs of the quaternary ammonium fluoride salts have also been prepared, and their reactivities are shown to be similar to the corresponding (c) Nucleophilic deoxo-fluorination using SF4 and its derivatives Oxygen-containing functional groups like hydroxyl, carbonyl, and carboxyl groups are readily converted into fluorine functional groups with sulfur tetrafluoride (SF4), or with its safer derivatives (diethylamino)sulfur trifluoride (DAST), (dimethylamino)sulfur trifluoride (methyl-DAST), morpholinosulfur trifluoride 7 8 ammonium salts. 13 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. (morph-DAST), and [bis(2-methoxyethyl)amino]sulfur trifluoride (Deoxo-fluor™). These compounds are commercially available and commonly used. Scheme 1.10 shows two examples of these transformations.2 We can see that the fluorination by DAST gave high yield of S^-type product (stereo-inversed). O MeO SF4 115 C OH O F . F 79% OMe DAST MeO o°c o o OMe 85% Scheme 1.10 Nucleophilic deoxo-fluorinations with SF4 and DAST. 1.3.1.2 Electrophilic fluorination Several electrophilic fluorinating reagents have been known, including elemental fluorine (F2), xenon difluoride (XeF2), reagents containing O-F bond, and reagents containing N-F bond. (a) Elemental fluorine (F2) Elemental fluorine is a traditional electrophilic fluorinating reagent, and its study can be derived from its first isolation by Moissan in 1886. Since the extremely 14 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. high reactivity of elemental fluorine (F2 reacts violently with most organic compounds), it is always diluted with inert gases like nitrogen or helium before use. Special protection, reaction apparatus and scrubbers are always required for fluorine gas reactions. Scheme 1.11 demonstrates the electrophilic fluorinations with fluorine gas.2 N H C O C F 3 F2/He C FC I3 83% OAc OAc AcO AcO 50% Scheme 1.11 Electrophilic fluorinations with F2 . (b) Xenon difluoride (XeFi) Xenon difluoride is a stable, colorless and commercially available crystalline reagent, and it can selectively convert a tertiary C-H bond of hydrocarbons into a C- F bond.29,30 Scheme 1.12 shows two examples of XeF2 mediated electrophilic fluorinations.3 1 ,3 2 15 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Me3SiO 77 % OAc OAc (4 : 1 ) Scheme 1.12 Electrophilic fluorinations with XeF2. (c) O-F containing reagents Electrophilic fluorinating regents containing O-F bonds include fluoroxytrifluoromethane (CF3OF), bis(fluoroxy)difluoromethane [CF2(OF)2], acetyl hypofluorite (CH3COOF), perchloryl fluoride (CIO3 F), and cesium fluorosulfate (CSSO4F), among others. It was proposed that the fluorination with these reagents involves fluorine radical intermediates (F ). Scheme 1.13 shows some examples of ' y these types of fluorination reactions. 16 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Ph' ,OSiMe3 CF3OF •70 °C OEt Ph COOEt 77% OHC > [CH 3COOF] OHC' CsS 0 4F / / ch 2ci2 23% Scheme 1.13 Electrophilic fluorinations with O-F containing reagents. (d) N-F containg reagents + 3 3 Electrophilic fluorinating reagents with N-F bonds include NF4 BF4 \ N- fluoropyridinium triflate and its derivatives,3 4 ]V-fluoro-1,4-diazabicyclo[2.2.2]- octane derivatives,34 and iV-fluorosulfonamides and -imides.3 6 ,3 7 The most well known reagent in this category is 1 -chloromethyl-4-fluoro-1,4- diazoniabicyclo[2 .2 .2]octane bis(tetrafluoroborate), which is commonly known as Selectfluor™. Scheme 1.14 shows the structures of some of these reagents. 17 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Scheme 1.14 Structures of N-F containing electrophilic fluorinating reagents. Recently, distereoselective and enantioselective fluorinations have attracted much interest for the synthesis of biologically active compounds.38-40 For instance, reagent 7-9 can be used to synthesize organofluorine compounds with high distereomeric or enantiomeric excesses (Scheme 1.15).2 Me 1) ld a 2)9 81 %, 80 % ee (i) 1 8 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Ph Me 1) LDA 2)7 (ii) Ph Me 88 %, 97 % de Scheme 1.15 Stereoselective fluorinations N-F containing reagents. 1.3.1.3 Combined fluorination (Oxidative fluorination) Besides nucleophilic and electrophilic fluorinations, there is another type of fluorination that combines an oxidant and a fluoride source. At first, the substrate is oxidized to generate an electrophilic (normally cationic) species, and it can be attacked by a fluoride to give desired product. These types of combined fluorinations include halofluorination, thiofluorination or selenofluorination, nitrofluorination, oxidative desulfurization- fluorination, and oxidative fluorination of amines. Scheme 1.16 gives some examples of these fluorination reactions.2 Br 2) AgF 95 % (Bromofluorination) F (Me2S + -SMe)BF4' SMe (Thiofluorination) 3HF/NEt3 CH2CI2, rt 90 % 19 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. PhSeBr, AgF C H 2C I 2 57% N 02+BF4" (2 mol) PPHF (30:70) 80% a a : SePh (S elenofluorination) (Nitrofluorination) CF NON HF/py (80 eq . HF) NIS (2.2 eq.) CH 2 CI2, -78°C to rt HF/py (60:40) N O + B F / 0 °C to rt CF3 (Oxidative Desulfurization -Fluorination) (Oxidative Fluorination of Amines) Scheme 1.16 Combined fluorinations (oxidative fluorinations). 1.3.1.4 Electrochemical fluorination (ECF) Electrochemical fluorinations are normally carried out in HF or its equivalent to convert hydrocarbons to highly fluorinated or even perfluorinated products. This method (especially the one in HF) is called Simons method.1 ’6 This method is still a very important tool for industrial manufacturing of fluorinated products, such as trifluoromethanesulfonic acid (Scheme 1.17).4 1 20 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Distill over 3 h f ao. KOH 100 % h2S0 4 CH3SO 2F .......... ► CF3SO2F — ...... » CF3SO3K CF3SO3H ECF, - 3 H2 Scheme 1.17 Preparation of triflic acid by ECF. 1.3.2 Selective introduction of organofluorine building blocks Fluorine-substituted building blocks like trifluoromethyl (CF3), difluoromethyl (CF2H) and perfluoro alkyl (Rf) group can also be selectively introduced into organic molecules, among which the chemo- and stereoselective trifluoromethylation is most important and extensively studied.42-45 The selective introduction of organofluorine building blocks are usually through nucleophilic, electrophilic and radical pathways. 1.3.2.1 Nucleophilic introduction of organofluorine building blocks (a) Fluorinated organometallic reagents The selective introduction of organofluorine building blocks, mainly perfluoroalkylation, was first achieved using organometallic reagents in 1960s. Various fluorinated organometallic reagent (normally prepared in situ) have been developed to introduce perfluoroalkyl groups into carbonyl compounds, such as organometallic reagents based on lithium, magnesium, zinc, calcium, manganese, and silver (Scheme 1.18) 46 21 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. R1 R + Rf-X M R2 Solvent -► R2 C — Rf OH R1= H, Alkyl, Aryl; R2= Alkyl, Aryl; Rf= C2F5; C3F7; etc. M= Zn, Mg, Mn, Ca, Ag, Li; Solvent= DMF, THF. Scheme 1.18 Introduction of perfluoroalkyl groups into carbonyl compounds with fluorinated organometallic reagents. Perfluorinated and partially fluorinated alkenylmetallic and alkynylmetallic reagents have also been known to introduce fluoro- alkenyl and alkynyl groups into electrophiles.2 Scheme 1.19 shows some examples of these transformations. 4 7 -4 9 N' n-C6F13l + H- .Et ‘H BuLi MeLi-LiBr BF-fOEt2 Et20 , -78°C THF, -110 °C F H F - c f 3 Et20 ► BrMg- EtMgBr n-C6F1 3 8 8 % : I - X F L i PhCHO Ph HO 90% -c f 3] acetone (i) (ii) HO 75% -CF3 (iii) Scheme 1.19 Introduction of fluoro- alkenyl and alkynyl groups into electrophiles. 22 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. However, such organometallic methodologies are not applicable to trifluoromethylation. The formation of difluorocarbene by a-elimination of metal fluoride is a serious side reaction (Scheme 1.20).46 CF3M 8 > » M F + :CF2 Scheme 1.20 Decomposition of trifluoromethylated organometallic compounds. Perfluoroalkylcopper reagents can be easily prepared from perfluoroalkyl iodides and copper metal, and they are known to be more stable than the corresponding lithium or magnesium reagents.5 0 ,5 1 They can react with iodoarenes to form perfluoroalkylated arenes (Scheme 1.21). The mechanism of these reactions involves oxidative addition/reductive elimination pathways, rather than simple addition-elimination pathway. » - c ,f ,5i ♦ 1 d m ^ o "*■ C 3 > “ " 'C7F,5 110-120 °C 70% Scheme 1.21 Introduction of perfluoroalkyl group with perfluoroalkylcopper reagents. Fluorinated metal enolates have also been used in aldol- or reformatsky- type of reactions. These reagents are commonly prepared in situ by reacting diluoro(halo) carbonyl compounds with reducing metals like zinc.2 In the presence of chlorotrimethylsilane (TMSC1), 2,2-dilfuoro silyl enol ether can be obtained as a 23 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. stable compound.5 2 Scheme 1.22 demonstrates one example of the reaction of fluorinated metal enolate.5 3 0 1 Br2FC O E t O H OH 2 Zn/EtjAICI + TH F, - 2 0 C P h X " Ph 2 P hC H O F C ° 2Et 79 % Scheme 1.22 Reaction with fluorinated metal enolate. (b) Fluorinated organosilicon reagents At present, fluoride induced polyfluoroalkylation (especially trifluoromethylation) with organosilicon reagents is considered a straightforward and reliable method and widely used.54 This methodology was first discovered and then systematically studied by Prakash, Olah and co-workers.5 4 b These methodologies are widely used.54a’ 5 5 Nucleophilic trifluoromethylation using (trifluoromethyl)trimethysilane (TMS- CF3, Prakash’s reagent, originally prepared by Ruppert5 6 ) is the most important reaction in this category. TMS-CF3 has known to transfer CF3 group into various types of substrates, including aldehydes, ketones, esters, lactones, a-keto esters, cyclic anhydrides, oxazolidinones, carboxylic acid halides, amides, imides, azirines, nitroso compounds, alkyl, allyl, aromatic and vinyl halides, sulfur-based electrophiles, organometallic compounds, aromatic compounds and organophosphorus compounds, and so on (see Scheme 1.23).5 4 a 24 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. RCCOOEt CF- TMS-CF N02 N-Me Cu (I) salt, KF, DMF CF- CF CF N— Me Scheme 1.23 Nucleophilic trifluoromethylation with TMS-CF3 . More recently, stereoselective trifluoromethylation using TMS-CF3 has also been developed.5 7 Compared with trifluoromethylation, less is known on the difluoromethylation using difluoromethyltrialkylsilane reagents.5 4 c,5 4 f Hagiwara and Fuchikami5 4 f have shown that (difluoromethyl)dimethylphenylsilane can efficiently transfer CF2 H group into carbonyl compounds at elevated temperatures (Scheme 1.24). 25 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. PhMe2SiCF2H + PhCHO KF (5 mol%) DMF, 100 °C OH Ph CF2H 8 2 % Scheme 1.24 Nucleophilic difluoromethylation with PhMe2SiCF2 H. 1.3.2.2 Electrophilic introduction of organofluorine building blocks Due to the opposite polarization of perfluoroalkyl halides (Rf7 '—X a + , X= Cl, Br, I), these compounds cannot undergo nucleophilic alkylation as non-fluorinated alkyl halides normally do. Electrophilic introduction of organofluorine building blocks (mainly perfluoroalkylation) are based on the perfluoroalkyl group-containing hypervalent reagents, such as (perfluoroalkyl)aryliodonium, (polyfluoroalkyl)- aryhodonium, and (perfluoroalkyl)chalcogen.2 This topic has been reviewed by T. Umemoto elsewhere.5 8 (a) (Perfluoroalkyl)- and (polyfluoroalkyl)aryliodonium5 8 It has been known that (Perfluoroalkyl)aryliodonium chlorides can transfer perfluoroalkyl and polyfluoroalkyl groups into various substrates, such as thiolates, selenolates, nitrates, thiocyanates, selenocyanates, and iV-methylanilines. (Perfluoroalkyl)aryliodonium triflates can react with thiols, carbanions, alkenes, alkynes, silyl enol ethers, and aromatics to give corresponding products. 26 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. (Polyfluoroalkyl)aryliodonium triflates can react with amines, lithium alkoxides, metal carboxylates, carbanions, enol silyl ethers, and electron-rich aromatics to afford corresponding polyfluoroalkyl substituted products. Scheme 1.25 shows some examples of these reactions. C3F7— I— Cl + a SNa DMF CH, n-C6F13 I OTf c h 3 RfH2C— I— OTf ^ _ nh2 "f s c 3f 7 81 % ,n-CeFi3 97% ^ . N H C H 2Rf 98% Scheme 1.25 Introduction of perfluoroalkyl and polyfluoroalkyl groups with (perfluoroalkyl)- and (polyfluoroalkyl)aryliodonium. (b) (Trifluoromethyl)chalcogenium salts In the past decade, electrophilic trifluoromethylation has been developed mainly by T. Umemoto and co-workers59,60 by using S-, Se-, or Te- 27 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. (trifluoromethyl)dibenzochalcogenophenimn salts. Scheme 1.26 shows the reaction between these salts with various nucleophiles.5 9 Ph 89% 65 % *^>Tf CF3 78% 90% CF Scheme 1.26 Electrophilic trifluoromethylation with S-, Se-, or Te- (trifluoromethyl)dibenzochalcogenophenium salts. 1.3.2.3 Selective introduction of organofluorine building blocks via fluorine- substituted radicals and carbenes Both fluorine-containing radicals6 0 ,6 1 and carbenes6 2 are useful intermediates for the introduction of fluorine-containing building blocks. The reviews of these chemistry have been well documented in the literature.60'6 2 2 8 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Fluorine-containing radicals6 0 ^ 1 are commonly derived from perfluoroalkyl halides, peroxides, trifluoroacetates and other precursors. Under heating or irradiation, these precursors readily undergo homolysis to generate radical species (Rf*) in situ, and the latter one can react with various substrates like alkene, arenas, heteroarenes, etc. Scheme 1.27 demonstrates some of these conversions. CF3I + H2C=CH2 --------------- ► CF3CH2CH2I + CF3(CH2CH2)nl 250 °C, 48 h 75 % hv, 108h 82% (C3 F7C 0 2)2 + \ — —----- ► O 98% CF3C 0 2H C l CF3 72% Scheme 1,27 Introduction of organofluorine building blocks with fluorine-containing radicals. Fluoriner-containing carbenes**1 are also commonly derived from bromodifluoromethane (CHFBra), dibromodifluoromethane (CF2 Br2) pentafluorocyclopropane or other precursors with the action of heat or chemical XeF2 C' ^ W ^ CI ........6 h^ , 2. r. 29 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. reagents. The in situ generated fluorocarbenes (:CFH or :CF2 ) can readily react with 2 alkenes to produce addition products. Scheme 1.28 shows these types of reactions. CF2Br2 + Ph Zn (l2) Ph THF, r.t. 84% Et2Zn CHFlo i".-"'1 [ EtZnCHFI 1 25-35 °C 91 % :h O ~ ^ V - 170-200 Cw F^C” “CF— CFo ...............— .CF2 3 2 - CF3C0F F F F 65% Scheme 1.28 Introduction of organofluorine building blocks with fluorine-containing carbenes. 1.4 Prospective Since organofluorine chemistry has a relatively short history and organofluorine compounds have unique and sometimes even unusual properties and reactivities, much needs to be explored in this field. With the dawn of the 21st century, new highly selective, technically safe and environmentally benign fluorination methods are expected to grow. Fluorine substituted compounds and 30 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. materials will find increasing use in various fields like material, medicinal, pharceutical, and agrochemistry. Fluorine is possible to be a high-tech element in the 21st century. 1.5 References 1. Hudlicky, Milos; Pavlath, A. E. Chemistry o f Organic Fluorine Compounds II: A Critical Review, ACS: Washing D.C., 1995. 2. Hiyama, T. Organofluorine Compounds: Chemistry and Applications, Springer: New York, 2000. 3. Olah, G. A.; Chambers, R. D.; Prakash, G. K. S. Synthetic Fluorine Chemistry, Wiley: New York, 1992. 4. Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine Chemistry: Principles and Commercial Applications, Plenum: New York, 1994. 5. Filler, R.; Kobayashi, Y.; Yagupolskii, L. M. ed. Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications, Elsevier: New York, 1993. 6. Chamber, R. D. Fluorine in Organic Chemistry, Wiley: New York, 1973. 7. Ritter, S. Chem. & Eng. News 80 (12), March 25,2002. 8. James, L. K. ed. Nobel Laureates in Chemistry 1901-1992, ACS/CHF: Washinton, D. C., 1993, pp 35. 9. Swarts, F. Bull. Acad. Royal Beige 1892, 24, 309. 10. Henne, A. L. Org. React., 1944, 2, 49. 31 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 11. (a) Roe, A. Org. React., 1949, 5, 193. (b) Flood, D. T. Org. Synth., Collective Vol. 1943, 2, 299. 12. (a) Olah, G. A., Conference Lecture at 9th Reaction Mechanism Conference, Brookhaven, New York, August 1962. (b) Olah, G. A. Angew. Chem. Int. Ed. Engl. 1963, 2, 629. (c) Olah, G. A. Angew. Chem. Int. Ed. Engl. 1973,12, 173. (d) Olah, G. A. Angew. Chem. Int. Ed. Engl. 1995, 34, 1393. 13. Yudin, K. Y.; Prakash, G. K. S.; Deffieux, D., Bradley M.; Bau, R.; Olah, G. A. J. Am. Chem. Soc. 1997,119,1572; and the references therein. 14. Olah, G. A.; Prakash, G. K. S.; Sommer, J. Superacids, Wiley: New York, 1985. 15. Grosse, A. V.; Linn, C. B. J. Org. Chem. 1939, 3, 26. 16. Feiring, A. E. J. Fluorine Chem. 1979,14, 7. 17. Feiring, A. E. Addition o f Hydrogen Fluoride, in Review Monograph (ref. 1), PP 54. 18. Tarrant, P.; Atlaway, J.; Lovelace, A. M. J. Am. Chem. Soc. 1954, 76, 2343. 19. Olah, G. A.; Li, X. Fluorination with Onium Poly(hydrogen fluorides): The Taming ofAnhydrous Hydrogen Fluoride fo r Synthesis, in ref. 3. 20. Szarek, W. A.; Grynkiewicz, G.; Doboszewski, B.; Hay, G. W. Chem. Lett. 1984, 1751. 21. Ayi, A. I.; Remli, M.; Guedj, R. J. Fluorine Chem. 1981,17, 565. 22. Wright, J. A.; Taylor, N. F.; Fox, J. J. J. Org. Chem. 1969, 34 ,2632. 23. Christe, K. O.; Wilson, W. W.; Wilson, R. D.; Bau, R.; Feng, J. J. Am. Chem. Soc. 1990,112, 7619. 24. Middleton, W. J. Org. Synth. 1986, 64, 221. 25. Noyori, R.; Nishida, I.; Sakata, J. J. Am. Chem. Soc. J981,103, 2106. 26. Pilcher, A. S.; Ammon, H. L.; DeShomg, P. J. Am. Chem.Soc. 1995,117, 5166. 27. Gingras, M. Tetrahedron Lett. 1991, 32, 7381. 32 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 28. (a) Gasser, O.; Schmidbaur, H. J. Am. Chem. Soc. 1975, 97, 6281. (b) Brown, S. J.; Clark, J. H. J. Chem. Soc., Chem. Comm., 1983, 1256. (c) Brown, S. J.; Clark, J. H.; Macquarrie, D. J. J. Chem. Soc., Dalton Trans., 1988,277. 29. (a) Zajc, B.; Zupan, M. Bull. Chem. Soc. Jpn. 1986, 59, 1659. (b) Tius, M. A. Tetrahedron, 1995, 51, 6605. 30. Zupan, M. J. Fluorine Chem. 1976, 8, 305. 31. (a) Marat, R. K.; Janzen, A. F. Can. J. Chem. 1977, 55, 3031. (b) Janzen, A. F.; Wang, P. M. C.; Lemire, A. E. J. Fluorine Chem. 1983, 22, 557. 32. Cantrell, G. L.; Filler, R. J. Fluorine Chem. 1985, 27, 35. 33. (a) Christe, K. O.; Schack, C. J.; Wilson, R. D. J. Fluorine Chem. 1976, 8, 541. (b) Schack, C. J.; Christe, K. O. J. Fluorine Chem. 1981,18, 363. 34. (a) Umemoto, T.; Tomita, K. Tetrahedron Lett. 1986, 27, 3271. (b) Umemoto, T.; Kawada, K.; Tomita, K. Tetrahedron Lett. 1986, 27, 4465. 35. Gilicinski, A. G.; Pez, G. P.; Syvret, R. G.; Lai, G. S. J. Fluorine Chem. 1992, 59, 157. 36. Barnette, W. E. J. Am. Chem. Soc. 1984,106, 452. 37. Differding, E.; Ruegg, G. M.; Lang, R. W. Tetrahedron Lett. 1991, 32, 1779. 38. Muniz, K. Angew. Chem. Int. Ed. 2001, 40, 1653-1656. 39. Shibata, N.; Suzuki, E.; Takeuchi, Y. J. Am. Chem. Soc. 2000, 122, 10728- 10729. 40. Cahard, D.; Audouard, C.; Plaquevent, J.-C.; Roques, N. Org. Lett. 2000, 2, 3699-3701. 41. (a) Trott, P. W.; Brice, T. J.; Guenthner, R. A.; Severson, W. A.; Coon, R. I.; LaZerte, J. D.; Nirschl, A. M.; Danielson, R. D.; Morin, D. E.; Pearlson, W. H., Abstracts, 126th National Meeting of the American Chemical Society, New York, 1954, p 42-M. (b) Brice, T. J.; Trott, P. W., US Patent, 1956, US 2,732,398. 42. McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555. 33 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 43. (a) Prakash, G. K. S.; Yudin, A. K. Chem. Review. 1997, 97, 757. (b) Prakash, G. K. S.; Mandal, M. J. Fluorine Chem. 2001,112, 123. (c) Prakash, G. K. S.; Krishnamuti; and Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393. (d) Krishnamurti, R.; Bellow D. R.; Prakash G. K. S. J. Org. Chem. 1991, 56, 984. 44. (a) Umemoto, T. Chem. Rev. 1996, 96, 1757. (b) Umemoto, T.; Ishihara, S. J. Am. Chem. Soc. 1993,115, 2156. (c) Umemoto, T.; Gotoh, Y. Bull. Chem. Soc. Jpn. 1987, 60, 3307. (d) Shreeve, J. M.; Yang, J.-J.; Kirchmeier, R. L. US Patent, US 6215021, 2001. 45. (a) Dolbier, W. R. Jr. Chem. Rev. 1996, 96, 1557. (b) Dolbier, W. R. Jr. Top. Curr. Chem. 1997,192, 97. 46. Prakash, G. K. S. Nucleophilic Perfluoroalkylation o f Organic Compounds Using Perfluoroalkyltrialkylsilanes, in ref. (3), pp 227, and the references therein. 47. Uno, H.; Okada, S.; Ono, T.; Shiraishi, Y.; Suzuki, H. J. Org. Chem. 1992, 57, 1504. 48. (a) Tillier, F.; Duffault, J.-M.; Baudry, M.; Sauvetre, R. J. Fluorine Chem. 1998, 91, 133. (b) Tillier, F.; Sauvetre, R. J. Fluorine Chem. 1996, 76, 79. (c) Sauvetre, R.; Normant, J. F. Tetrahedron Lett. 1981, 22, 957. 49. Drakesmith, F. G.; Stewart, O. J.; Tarrant, P. J. Org. Chem. 1968, 33, 280. 50. Mcloughlin, V. C. R.; Thrower, J. Tetrahedron 1969, 25, 5921. 51. Burton, D. J. Organometallics in Synthetic Organofluorine Chemistry, in ref (3), PP 205. 52. (a) Yamana, M.; Ishihara, T.; Ando, T. Tetrahedron Lett. 1983, 24, 507. (b) Jin, F.; Jiang, B.; Xu, Y. Tetrahedron Lett. 1992, 33, 1221. (c) Brigaud, T.; Doussot, P.; Portella, C. J. Chem. Soc., Chem. Commun. 1994, 2117. (d) Uneyama, K.; Maeda, K.; Kato, T.; Katagiri, T. Tetrahedron Lett. 1998, 39, 3741. (e) Amii, H.; Kobayashi, T.; Hatamoto, Y.; Uneyama, K. Chem. Commun. 1999, 1323. 53. Ishihara, T.; Matsuda, T.; hnura, K.; Matsui, H.; Yamanaka, H. Chem. Lett. 1994, 2167. 54. (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757. (b) Prakash, G. K. S.; Krishnamuti; and Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393. (c) Yudin, K. Y.; Prakash, G. K. S.; Deffieux, D., Bradley M.; Bau, R.; Olah, G. 34 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. A. J. Am. Chem. Soc. 1997, 119, 1572. (d) Krishnamurti, R.; Bellow D. R.; Prakash G. K. S. J. Org. Chem. 1991, 56, 984. (e) Broicher, V.; Geffken, D. Tetrahedron Lett. 1989, 30, 5243. (f) Hagiwara, T.; Fuchikami, T. Synlett 1995, 717. 55. Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613. 56. TMS-CF3 was first used by G. K. S. Prakash and co-workers as nucleophilic trifluoromethylating reagent, and thus this reagent is commonly called Prakash’s reagent. Other people also call TMS-CF3 as Ruppert’s reagent, considering that the compound itself was synthesized by Ruppert and co workers in 1984 although Ruppert did not use it as trifluoromethylating agent. See: Ruppert, I.; Schlich, K.; Volbach, W. Tetrahedron Lett. 1984, 25, 2195. 57. (a) Prakash, G. K. S.; Mandal, M. J. Fluorine Chem. 2001, 112, 123. (b) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem. Int. Ed. Engl. 2000, 40, 589-590. 58. Umemoto, T. Chem. Rev. 1996, 9 6 ,1757. 59. Umemoto, T.; Ishihara, S. J. Am. Chem. Soc. 1993,115, 2156. 60. Dolbier, W. R. Jr. Chem. Rev. 1996, 96, 1557. (b) Dolbier, W. R. Jr. Top. Curr. Chem. 1997,192, 97. 61. Sawada, H. Chem. Rev. 1996,9 6 ,1779. 62. Brahms, D. L. S.; Dailey, W. P. Chem. Rev. 1996, 96, 1585. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 2 Facile Preparation of Di- and Monofluoromethyl Ketones From Trifluoromethyl Ketones Via Fluorinated Enol Silyl Ethers Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2.1 Introduction Difluoromethyl and monofluoromethyl ketones are potential biologically active compounds of increasing interest. These compounds have found use as potential protease and enzyme inhibitors due to the unique properties of the 1 1 fluorinated methyl group. ' These compounds are commonly prepared either by Friedel-Crafts acylation,4’ 5 or by reaction between difluoro- or monofluoroacetic acid Z Q derivatives and organometallic reagents. " However, both difluoro- and monofluoroacetic acid derivatives are rather expensive, and the monofluoroacetic acid derivatives are highly toxic. Recently, several other approaches for the prepration of difluoromethyl ketones have been reported, such as using 1,1-difluoro- 2-lithioalkenes obtained from trifluoroethanol, 9 ,1 0 2,2-difluoroalkenylboranes from 2,2,2-trifluoroethyl tosylate,1 1 difluoroenol silyl ethers obtained through nucleophilic trifluoromethylation of acylsilanes with Ruppert’s reagent,1 2 difluoromethyl-p- ketophosphonate,1 3 and electrophilic fluorination of acetylenes.1 4 Enol silyl ethers react with electrophlic fluorinating agents such as trifluoromethyl hypofluorite, acetyl hypofluorite, elemental fluorine and Selectfluor® to provide monofluoromethyl ketones.1 5 ’1 8 Stereoselective monofluorinations of enol silyl ethers have been recently developed.1 9 '2 1 Diazoketones or a-halo ketones also react with HF to provide monofluoromethyl ketones.2 2 ,2 3 However, none of these methods 37 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. uses trifluoromethyl ketones as precursor to prepare di- and monofluoromethyl ketones through selective successive defluorinations. Trifluoromethyl ketones can be obtained from inexpensive trifluoroacetic acid derivatives.24’ 2 5 Recently we reported the direct preparation of trifluoromethyl ketones from carboxylic esters with (trifluoromethyl)trimethylsilane (TMS-CF3).2 6 The method has been further extended by Shreeve and coworkers with CsF catalyzed trifluoromethylation of esters.27 Uneyama and coworkers have elegantly shown magnesium metal promoted selective defluorination of trifluoromethyl ketones in the presence of chlorotrimethylsilane (TMSC1) to 2,2-difluoroenol silyl ethers.28 Such silyl ether intermediates have found use in synthesis of difluorinated compounds by aldol type chemistry.29'3 0 We now report the preparation of di- and monofluoromethyl ketones from trifluoromethyl ketones via fluorinated enol silyl ethers. Through magnesium mediated selective defluorination followed by hydrolysis, trifluoromethyl ketones are transformed into difluoromethyl ketones. The difluoromethyl ketones are further transformed into monofluoromethyl ketones through their respective monofluoroenol silyl ethers. A significant advantage of this methodology is that it uses only inexpensive and readily available reagents, and the reactions are mild and facile. 38 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 2.1 Preparation of difluoromethyl ketones 3 from trifluoromethyl ketones 1 via difluoroenol silyl ethers 2. 0 Mg/TMSCl JMSOx_ / F "F / H20" or H30 + 0 R ^ C F 3 THF or DMF ^F or " F " /D 20 " R CF2H (D) 1 0°C 2 3 Entry R Solvent3 Time[h]a hydro|ysls Product 3 Yield (%)c ______________________________________ method________________ ______________ O a Ph THF 1.0 TBAF/H20/THF P fr^C F H 83 CH3~ < Q ^ - THF 2.0 5M HCI CH3 h Q M : 81 2‘ i ° c f 2h Cm ( > THF 1.5 TBAF/H20/THF a _ / ~ Y ^ ° 80 c f 2h THF 2.0 3M HCI CF2H 87 g Br THF 2.0 3M HCI 0 - ~ ^ 0 92 s s c f 2h Ph THF 1.0 TBAT/D20/THF j? 88 Ph CF2D THF 1.5 3M HCI Br^ O ^ r F H 14d - > M e 3 Si"^Q ^ cF 2 H 65' r79 DMF 2.0 3M HCI CF2H 3 For the first step 1 -> 2 ; b for the second step 2— >3; c isolated yield; ddetermined by GCMS; determ ined by 19F NMR. 39 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2.2 Results and discussion 2.2.1 Preparation of difluoromethyl ketones from trifluoromethyl ketones Table 2.1 summarizes the reaction conditions and yields of the preparation of difluoromethyl ketones from trifluoromethyl ketones. Aromatic and heteroaromatic trifluoromethyl ketones la-e can be smoothly transformed into corresponding 2,2- dilfuoroenol silyl ethers in THF.28 These 2,2-difluoroenol silyl ethers are reasonably stable to be isolated and characterized. Figure 2.1 shows the 1 9 F NMR spectrum of 2,2-difluoro-1 -phenyl-1 -trimethylsiloxyethene 2a. Two doublets (coupling constant 2J f - f - 68 Hz) correspond to two different geminal fluorine atoms, which couple with each other. -112.16ppm, d, 2J f .f = 6 8 Hz -100.39ppm, d, 2J f _ f = 6 8 Hz -98 ■100 -104 -106 -108 •110 -112 -114 ppm Figure 2 .1 1 9 F NMR of 2,2-difluoro-1 -phenyl-1 -trimethylsiloxyethene 2a. 40 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. After hydrolysis, difluoromethyl ketones were obtained in good to excellent yields (see Table 2.1). The presence of either electron-withdrawing or electron- donating groups has little effect on the overall yields. By using tetrabutylammonium triphenyldifluorosilicate (TBAT) with D2O in THF, deuterium-labeled difluoromethyl ketone 3f was successfully obtained. Interestingly, chloroarene functionality in lc is compatible with the reaction conditions, while bromoarene group in lg is not; a silylated Barbier by-product is formed in major amounts. In the case of aliphatic trifluoromethyl ketone, more polar solvent DMF has to be used to facilitate the formation of difluoroenol silyl ether in moderate yield.2 8 2.2.2 Effect of fluoride ion sources on desilylative hydrolysis During our investigation on the hydrolysis of 2,2-difluoroenol silyl ethers 2, we found a dramatic effect of fluoride ion sources on the desilylative hydrolysis process. Silyl ether 2a was treated with KF, tetrabutylammonium fluoride (TBAF), benzyltrimethylammonium fluoride (BTAF), tetrabutylammonium triphenyldifluorosilicate (TBAT), respectively. As shown in Table 2.2, aqueous KF needs prolonged time and gives homo aldol condensation by-product 4a in significant amounts. TBAF and BTAF in wet THF give only small amounts of the aldol product. It turns out that TBAT in wet THF and dilute HCI (3~5M) are the ideal hydrolysis media. Both systems generate the desired 2,2-difluoromethyl ketone 3a (3f) cleanly without any adol by-product 4a. 41 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 2.2 The effect of fluoride ion sources on the desilylative hydrolysis. + 4a F H20 (D20 ) 2 a 3a (3f) Fluoride source Reaction time Temperature Yield (%)a (°C) 3a (3f) 4a KF / H20 48h r. t. 32 46 TBAF/ H20 / THF 15 min 0 83 -5 BnNMe3 F I H2 O/THF 15 min 0 82 -5 TBAT/D 20/THF 15 min 0 8 8 0 3M HCI (no fluoride) overnight r. t. 85 0 a Isolated yields based on trifluoroacetophenone used to prepare enol silyl ethers . 2.2.3 Preparation of monofluoromethyl ketones from difluoromethyl ketones We have also found that difluoromethyl ketones react with Mg/TMSCl system to produce isomeric 2-fluoroenol silyl ethers 5 in excellent yields {vide supra). Similar to 2,2-difluoroenol silyl ethers, these 2-monofluoroenol silyl ethers are easy to be isolated and characterized. Figure 2.2 shows the 1 9 F NMR spectrum of 2- fluoro-1 -phenyl-1 -trimethylsiloxyethene 5a. Two different doublets (2J f-h ~ 79.6 Hz, 76.4 Hz respectively) correspond to the fluorine atoms in Z- and E-isomers. 42 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Z-isomer: -158.94 ppm, d, 2JF .H =79.6 Hz E-isomer: -164.43 ppm, d, 2J F.H =79.4 Hz Z/E=2.2:1 Z-isomer E-isomer f.20 < 0 0 -156 -158 -160 ' ' -162 -164 -166 Figure 2.2 1 9 F NMR of 2-fluoro-l -phenyl-1 -trimethylsiloxyethene 5a. MesSiO. F c T “ Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2-Fluoroenol silyl ethers 5 can be easily hydrolyzed to the corresponding monofluoromethyl ketones. The reaction conditions and the yields are similar to the conversion from 1 to 3. The results are shown in Table 2.3. Table 2.3 Preparation of monofluoromethyl ketones 6 from difluoromethyl ketones 3. O Mg/TMSCI TMSO F "F / H20" or H30 + 0 A -------------- >=< F R CF2H THF or DMF R H or nF'* / D20 R \~~H (D) 3 ° ° C 5 6 ” Entry r Solvent® Time [ha hydrolysis Product 6 Yield (%)c method1 3 a Ph THF 1.0 TBAF/ H20/THF j? 89 Ph CFH2 CH3“ ( ~ ) " ^ THF 1-0 5M H C I cH3^ Q M : C = \ ,p CFH2 78 THF 2.0 TBAF/ H20/THF C I - A A f 80 C FH 2 THF 2.0 3M H CI Q i - THF 2.0 3M H CI < T A f ( S C CH3 ~ 0 ' ^ THF 1.0 TBAT/ D 20/THF V (/ ( 84 S— 0 CFH2 p CFHD g M e3S i-^ ~ ^ -j- THF 1.0 3M H C I Me3S i - ^ ^ - ^ ° CFH2 91 91 DMF 2.0 3M H CI ? 35d a For the first step 3 -»5; b for the second step 5 -»6 ; c isolated yield; ddetermined by 19F NMR. 44 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2.2.4 The Z/E isomers of 2-fluoroenoI silyl ethers 2-Fluoroenol silyl ethers 5 prepared from 3 are obtained as mixtures of Z- and E-isomers, as shown in Table 2.4. It is remarkable that aromatic and heteroaromatic ketones 3a-f all give isomers with a Z:E ratio about 2:1 (see Figure 2.2), while the aliphatic ketone 3g gives the opposite ratio (Z:E = 0.7:1). This is probably due to the steric as well as electronic effect of the different aryl and alkyl groups. Table 2.4 The Z/E isomers of 2-fluoroenol silyl ethers 5. Entry R 5 Z/E ratio3 Yield (%)a a Ph 2 .2:1 94 b CH 3 ~ " 0 ^ 2 .2:1 92 c “ - O r I ww 2 .0:1 96 d 2 .1:1 quantitative e Q - i - 2 .0:1 quantitative f Me3 Si--- 2 .2:1 94 g 0.72:1 50 determ ined by 19F NMRf31' 45 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2.2.5 Mechanism The mechanism of Mg promoted defluorination of difluoromethyl ketones is not clear. It is possible that the C-F bond cleavage is facilitated by a two-electron 28 transfer process as suggested by Uneyama in the case of trifluoromethyl ketones. As shown in Scheme 2.1, the first electron transfer from Mg species (Mg° or in situ generated Mg+ ) to ketone gives a ketyl species 8, which is further reduced to an anionic species 9 by the Mg species (Mg° or Mg4 ). After P-elimination,2 8,32 2- fluoroenol silyl ether 5 is formed which readily reacts with protic acid to generate 6. O "Mg" o* TMSCI OSiMe3 R ^ C F 2H 1e' r - ^ C F 2H R ^ C F 2H 3 7 8 1e‘ "Mg" OSiMe3 O "H+» { ^ ' SiMe3 HH ^ 'F 6 5 9 ( "Mg" = Mg° or Mg+ in situ generated form Mg°.) Scheme 2.1 Proposed mechanism of transformation of 3*^6. 46 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2.3 Conclusion In conclusion, Mg metal mediated reductive successive defluorinations provide an effective methodology to prepare difluoromethyl and monofluoromethyl ketones from readily available trifluoromethyl ketones. 2.4 Experimental Section 2.4.1 General Unless otherwise mentioned, all the other reagents were purchased from commercial sources. THF was distilled under nitrogen over sodium/benzophenone ketyl prior to use. DMF was distilled over calcium hydride. Except for a,a,a- trifluoroacetophenone, all the other trifluoromethyl ketones were simply prepared according to the reported procedures.25,26 Column chromatography was carried out using silca gel (60-200 mesh) and hexanes/ethyl acetate (commonly v/v=4:l). All Mg mediated defluorinaion reactions were carried out by Schlenk technique, and the reactions were monitored by 1 9 F NMR. All the fluorinated enol silyl ethers were directly hydrolyzed shortly after work-up and solvent removal.28 The ratios of Z/E isomers of 2-fluoroenol silyl ethers were determined from 1 9 F NMR.3 1 ^ 1 3 C and 1 9 F NMR spectra was recorded on Bruker AMX 500 and AM 360 NMR spectrometers. *H NMR chemical shifts were determined relative to internal (CH3)4Si (TMS) at 8 0.0 or to the signal of a residual protonated solvent: CDCI3 8 7.26. 1 3 C NMR chemical shifts were determined relative to internal TMS at 8 0.0 or 47 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. to the 1 3 C signal of solvent: CDCI3 8 77.0. CFCI3 (5 0.0) was used as the internal standard for 1 9 F NMR. Mass spectra were obtained on a Hewlett Packard 5890 Gas Chromatograph equipped with a Hewlett Packard 5971 Mass Selective Detector. 2.4.2 Preparation of trifluoromethyl ketones (I) 25,26 4’-Methyl-2,2,2-trifluoro-acetophenone (lb): p-Bromotoluene (9.5 g, 55 mmol) reacted with magnesium turnings (1.1 equiv.) in 50 ml dry ether to form corresponding Grignard reagent. The Grignard reagent was slowly added into 7.89 g ethyl trifluoroacetate (55 mmol) solution in 50 ml ether at -78 °C. The reaction mixture was stirred at -78 °C to room temperature for 4 h, and sequently quenched by a small amount of NH4CI aqueous solution. After the removal of solvent, the residue was stirred with 30 ml 5 M HCI overnight. The mixture was extracted with CH2CI2 (15 ml x 3), and the combined organic phase was washed with water. After drying over MgS04, filtration, and solvent removal, the cmde product was distilled to afford 5.0 g product 3b as colorless liquid, yield 48 %. *H NMR (500 MHz, CDCI3): 5= 2.44 (s, 3H), 7.32 (d, J= 8.3 Hz, 2H), 7.96 (d, J= 8.1 Hz, 2H); 1 3 C NMR (125 MHz, CDCI3): 8= 21.78, 116.76 (q, lJ(C, F)= 291.7 Hz), 129.77, 130.17 (q, J = 2.4 Hz), 130.75, 147.05, 180.05 (q, J= 35.3 Hz); 1 9 F NMR (470 MHz, CDCI3): 5= - 71.76. 48 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 4’-Chloro-2,2,2-trifluoroacetophenone (1 c): With a similar method as above. After the work up, the hydrolysis process needs harsher conditions (under reflux in 5 M HCI). Final separation by column chromatography (hexanes/ethyl acetate = 7/3) to afford 71 % yield of product lc as pale yellow solid, m.p. ~ 26 °C. NMR (500 MHz, CDC13 ): 5= 7.53 (d, J= 8.8 Hz, 2H), 8.02 (d, J= 8.8 Hz, 2H); 1 3 C NMR (125 MHz, CDCI3): 5= 116.51 (q, lJ(C, F)= 290.4 Hz), 128.21, 129.56, 131.42, 142.47, 179.44 (q, J= 35.9 Hz); 1 9 F NMR (470 MHz, CDC13 ): 6= -72.01. 2,2,2-Trifluoro-1 ’-acetonaphthone (Id): 1 -Bromonaphthalene (10 g, 48.3 mmol) was reacted with 1.05 equiv. 'BuLi in 60 ml ether at -78 °C, and into the resultant solution was added slowly 1.2 equiv. ethyl trifluoroacetate at -78 °C during 30 min period. The reaction mixture was stirred at -78 °C for another 1 h, and then warmed to room temperature. After similar work up and acid hydrolysis procedure as above, the crude product was distilled to give 8.51 g (79 % yield) product Id, b.p. 88-90 °C/1.1 Torr. *H NMR (500 MHz, CDC13 ): 6= 7.54 (t, J= 7.9 Hz, 1H), 7.60 (td,J = 7.8 H z,/ = 1.0 Hz, 1H), 7.69 (td, J = 7.8 Hz, J= 1.5 Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 8.12 (d, J= 8.3 Hz, 1H), 8.21 (dt, J= 7.3 Hz, J= 1.5 Hz, 1H), 8.87 (d, J = 8.8 Hz, 1H); l3C NMR (125 MHz, CDCI3): 8= 116.66 (q, V(C, F)= 293.6 Hz), 124.06, 125.13, 126.20, 127.07, 128.94, 129.45, 131.13, 131.69 (q, J = 3.7 Hz), 133.92,136.17, 182.22 (q, /= 33.7 Hz); 1 9 F NMR (470 MHz, CDC13 ): 8= -70.54. 49 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2,2,2-Trifluoro-2’-acetothienone (le): Use same method as preparation of lb. The Grignard reagent (prepared from 2-iodothiophene and Mg in ether) reacted with ethyl trifluoroacetate at -78 °C. Yield: 62 %. !H NMR (500 MHz, CDCI3): 5 - 7.26 (m, 1H), 7.92 (dm, 1H), 7.99 (m, 1H); 1 3 C NMR (125 MHz, CDCI3): 5= 116.38 (q, ^(C, F)= 291.4 Hz), 129.17, 131.47, 136.50 (q, J = 2.5 Hz), 138.08, 173.73 (q, J= 36.7 Hz); 1 9 F NMR (470 MHz, CDC13 ): 8= -72.91. 4’-Bromo-2,2,2-trifluoroacetophenone (lg): Using a similar method as in the preparation of Id. 1,4-Dibromobenzene reacted with n-BuLi in ether at -5 to -10 °C to generate jp-bromophenyl lithium, which further reacted with ethyl trifluoroacetate in ether at -78 °C. After work up and acid hydrolysis, 75 % yield of product lg was collected by distillation. *H NMR (500 MHz, CDC13 ): 8= 7.70 (d, 2H), 7.92 (d, 2H); 1 3 C NMR (125 MHz, CDC13 ): 8= 116.43(q), 128.54, 129.65, 131.30 (q), 132.50, 179.37 (q); 1 9 F NMR (470 MHz, CDC13 ): 8= -71.98. /i-Hexyl trifluoromethyl ketone (lh): Using a similar method as in the preparation of lb. The Grignard reagent (prepared from 1-bromohexane and Mg in ether) reacted with ethyl trifluoroacetate at -78 °C. Yield: 75 %. *H NMR (500 MHz, CDCI3): 8= 0.88 (t, 3H), 1.30 (m, 6H), 1.67 (m, 2H), 2.70 (t, 2H); 1 3 C NMR (125 MHz, CDCI3): 8= 13.91, 22.35, 22.39, 28.42, 31.37, 36.36, 115.61 (q, lJ(C, F)= 292 Hz), 191.64 (q, J= 34.8 Hz); 1 9 F NMR (470 MHz, CDCI3): 8= -79.85. 50 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2.4.3 Preparation of difluoromethyl ketones (3) from trifluoromethyl ketones (1) 2.2-Difluoro-l-phenyl-l-trimethylsiloxyethene (2a)28: To a dry 250 ml Schlenk flask was added magnesium turnings (1.45 g, 60 mmol), dry THF (120 ml) and chlorotrimethylsilane (TMSC1) (13.0 g, 120 mmol), and the flask was cooled down to 0 °C. 2,2,2-Trifluoroacetophenone la (5.2 g, 30 mmol) was added dropwise into the flask via a syringe. After addition, the reaction mixture was stirred for additional 1 h. The completion of the reaction was confirmed by 1 9 F NMR. The solvent and excess TMSC1 were removed under vacuum, and hexane (50 ml) was added to the residue. After the solid impurities was filtered off by suction filtration, the solvent was evaporated to afford 2a (6.8 g, 99% yield). *H NMR and GC-MS showed the purity was > 95%. *H NMR (500 MHz, CDCI3 ): 6= 0.60 (s, 9H), 7.38 (t, J=1.5 Hz, 1H), 7.47 (t, /=7.5 Hz, 2H), 7.61 (d, .7=8.8 Hz, 2H); 1 3 C NMR (125 MHz, CDCI3): 5= 0.02, 114.09 (q, 2 J(C, F)= 18.0 Hz), 125.84, 127.72, 128.25, 132.71, 154.87 (t, '/(C, F)= 286.8 Hz); 1 9 F NMR (470 MHz, CDC13 ): 8= -100.39 (d, V(F, F) = 68.0 Hz ), -112.16 (d, 2 /(F, F)= 68.0 Hz). GC-MS (70 eV) m/z (relative intensity): 228 (M+ , 79), 213 (2), 197 (1), 186 (5), 177 (60), 165 (1), 149 (1), 143 (1), 131 (5), 115 (9), 105 (36), 89 (45), 81 (29), 77 (75), 73 (100). 2.2-Difluoroacetophenone (3a): (i) Method A (3M HCI): 2,2-Difluoro-1 -phenyl-1 -trimethylsiloxyethene 2a (1.35 g) prepared from 2,2,2-trifluoroacetophenone la (1.04 g, 6 mmol) as above, 51 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. was stirred in 10 ml 3M HCI at room temperature overnight. The completion of the hydrolysis was confirmed by 1 9 F NMR. The reaction mixture was extracted with hexanes (10 ml x 3), and the combined organic phase was washed with brine. After drying over anhydrous MgSC> 4 and solvent removal, the crude product was further purified by silica gel column chromatography (hexanes/ethyl acetate = 4/1 (v/v)) to afford product 3a (0.80 g, 85% yield calculated from 2,2,2-trifluoroacetophenone) as colorless liquid, which froze in the refrigerator. *H NMR (360 MHz, CDCI3 ): 8= 6.30 (t, 2 7(H, F)=53.8Hz, 1H), 7.53 (t, 7=7.5 Hz, 2H), 7.67 (t, 7= 7.5 Hz, 1H), 8.08 (d, 7=7.4 Hz, 2H); 1 3 C NMR (90 MHz, CDC13 ): 8= 110.98 (t, V(C, F)= 253.7 Hz), 128.88, 129.50, 131.45, 134.83, 187.46 (t, 2 7(C, F)= 25.2 Hz); 1 9 F NMR (338 MHz, CDCI3 ): 8= -122.51 (d, 2 7(F, H)= 56.4 Hz, 2F); MS (70 eV), m/e (relative intensity): 156 (M+ , 43), 127 (10), 105 (100), 77(55), 51(16). (ii) Method B (TBAF): 2,2-Difluoro-1 -phenyl-1 -trimethylsiloxyethene 2a prepared from 2,2,2-trifluoroacetophenone la (3.12 g, 18 mmol) as above, was dissolved in THF (20 ml) and then was slowly added into tetrabutylammonium fluoride (TBAF-3H20, 20 mmol) solution in wet THF (20 ml) at 0 °C. The reaction mixture was stirred for 15 min, and the completion of the reaction was confirmed by 1 9 F NMR analysis. After removal of most of the THF solvent, hexanes (30 ml) were added and washed with water. The organic phase was dried over MgSC>4, and then the solvent was evaporated under vacuum. The crude product was distilled to afford 2.31 g product 3a (83% yield), b.p. 33-34°C/1.2 Torr. At the bottom of distillation flask, small amount of self-condensed by-product 4a was left as colorless sticky oil, 52 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. yield ~ 5%. Similarly, benzyltrimethylammonium fluoride (BTAF) was used as the fluoride ion source. Product 3a was obtained in 82% isolated yield, and ~5% by product 4a was also found. (iii) Method C (aqueous KF): 2,2-Difluoro-1 -phenyl-1 -trimethylsiloxyethene (2a, 6.6 g, 2.9 mmol) was stirred with KF (6.8 g 11.7 mmol) in H2O/THF (40 ml, v/v=l/l) at room temperature for 48 h. The reaction mixture was extracted with ether (20 ml x 3). After drying over MgSC>4, the organic solvent was removed. The residue was further purified by silica gel column chromatography (hexanes/CH2Cl2 = 1/1) to afford 2,2-Difluoroacetophenone 3a (1.42 g, 32%) and the self-condensed product 2,2-difluoro-2-(l’-hydroxy-l ’-phenyl-2’,2’-difluoroethyl) acetophenone 4a ( 2.06 g, 46% yield) as colorless sticky liquid. For 4a: *H NMR (500 MHz, CDCI3 ): 5= 4.24 (s, 1H), 6.40 (t, 1H), 7.40(m, 5H), 7.60 (m, 3H), 7.94 (d, 2H); 1 3 C NMR (125 MHz, CDCI3 ): 5= 78.01 (m, V(C, F)= 23.6 Hz), 113.90 (tt, J=249.1 Hz, J= 3.4 Hz), 114.97 (t, J= 268.1 Hz), 126.82, 128.44, 129.31, 130.28, 132.50, 134.75. 1 9 F NMR (470 MHz, CDCI3): 8= -105.90 (dt, J= 293.5 Hz, J= 9.2 Hz), -107.21 (dt, J= 293.5 Hz, J= 9.2 Hz), -129.19 (ddt, J= 290 Hz, J= 54.4 Hz, J= 9.2 Hz), -130.92 (ddt, J= 290 Hz, J= 54.4 Hz, J= 9.2 Hz). MS (70 eV), m/e (relative intensity): 311(M+-1, 0.3), 261(M+ - CF2H, 5), 225 (4), 156 (56), 127 (10), 105 (100), 77 (44), 51 (11). 2,2-DifIuoro-4’-methylacetophenone (3b): Under an argon atmosphere, to the mixture of 0.27 g (11 mmol) magnesium turnings and 2.4 g (22 mmol) 53 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. chlorotrimethylsilane (TMSC1) in 25 ml dry THF at 0 °C, was added 1.0 g (5.3 mmol) 4 -methyl-2,2,2-trifluoroacetophenone lb. Then the mixture was stirred at 0 °C for 2 h. THF and excess TMSC1 were removed under vacuum and to the residue was added 30 ml of hexanes. The solid was removed by suction filtration, and the filtrate was concentrated under vacuum to give about 1.4 g of the crude product 2b. To 2b was added 20 ml 5M HC1 and the mixture was stirred at room temperature overnight. Then the mixture was extracted successively with 20 ml ether thrice. Combined ether phase was further washed with 20 ml brine thrice, and then washed with 20 ml water. The organic phase was dried over anhydrous MgSCh and 0.85 g crude product was collected after removal of the solvent. The product was purified by silica gel column chromatography (hexanes/ethyl acetate (v/v=4:l)) to give 0.73 g 3b as a white solid, yield 81%. *H NMR (360 MHz, CDC13 ): 5= 2.45 (s, 3H), 6.26 (t, 2 /(H , F)=53.8Hz, 1H), 7.33 (d, J= 8 .0 Hz, 2H), 7.97 (d, J= 8.0 Hz, 2H); 1 3 C NMR (90 MHz, CDCI3): 5= 21.71, 111.03 (t, \/(C, F)= 253.4 Hz), 128.98, 129.59, 133.27, 146.15, 187.03 (t, 2 J{C, F)= 25.1 Hz); 1 9 F NMR (338 MHz, CDC13 ): 6= -122.62 (d, V(F, H)= 55.1 Hz, 2F). 4’-Chloro-2,2-difluoroacetophenone (3c): Under an argon atmosphere, to the mixture of 0.10 g (4.3 mmol) magnesium turnings and 0.93 g (8.6 mmol) chlorotrimethylsilane (TMSC1) in 12 ml dry THF at 0 °C, was added 0.45 g (2.15 mmol) 4 -chloro-2,2,2-trifluoroacetophenone lc. Then the mixture was stirred at 0 °C for 90 m. The completion of the reaction was monitored by 1 9 F NMR. THF and 54 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. excess TMSC1 were removed under vacuum and to the residue was added 15 ml hexanes. The solid was removed by suction filtration, and the filtrate was concentrated under vacuum to give the crude product 2c (1 9 F NMR: -99.6 ppm (d); - 111.3 ppm (d)). To 2c was added 10 ml THF, 5 ml water, and the mixture was cooled down to 0°C. Then 2.3 ml 1M TBAF in THF was added to the mixture, and stirred at 0°C to room temperature for 30 min. Then the mixture was extracted successively with 10 ml ether, thrice. Combined ether phase was further washed with 10 ml brine successively thrice, and then washed with 10 ml water. The organic phase was dried over anhydrous MgSC> 4 and 0.39 g crude product was collected after removal of the solvent. The product was purified by silica gel column chromatography (hexanes/ethyl acetate (v/v=10:l)) to give 0.33 g (80% yield) product 3c as colorless liquid. *H NMR (500 MHz, CDCI3): 5= 6.28 (t, 2 J(H, F)=53.5Hz, 1H), 7.49 (d, J =8.9 Hz, 2H), 8.01 (d, J= 8.5 Hz, 2H); 1 3 C NMR (125 MHz, CDCI3): 8= 111.27 (t, lJ(C, F)= 254.3 Hz), 129.34, 129.72 (t, 3 J(C, F)= 2.1 Hz), 130.96, 141.61, 186.53 (t, 2 J(C, F)= 25.9 Hz); 1 9 F NMR (470 MHz, CDC13 ): 8= -122.11 (d, 2 J{F, H)= 53.4 Hz, 2F). 2,2-Difluoro-l ’-acetonaphthone (3d): Under an argon atmosphere, to the mixture of 0.21 g (8.8 mmol) magnesium turnings and 1.94 g (17.9 mmol) chlorotrimethylsilane (TMSC1) in 25 ml dry THF at 0 °C, was added 1.0 g (4.5 mmol) 2,2,2-trifluoro-1 -acetonaphthone Id. Then the mixture was stirred at 0 q C for 2 h. The completion of the reaction was monitored by 1 9 F NMR. THF and excess 55 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TMSC1 were removed under vacuum and to the residue was added 15 ml of hexanes. The solid was removed by suction filtration, and the filtrate was condensed under vacuum to give 1.2 g crude product 2d (1 9 F NMR: -104.07 ppm (d); -114.06 ppm (d)). To 2d was added 15 ml 3 M HC1, and the mixture was stirred overnight. Then the mixture was extracted successively with 10 ml of ether, thrice. Combined ether phase was further washed with 10 ml saturated NaHCCb aqueous solution, and then with 10 ml brine. The organic phase was dried over anhydrous MgSCTj and solvent was removed under vacuum. Further purification by silica gel column chromatography (hexanes/ethyl acetate (v/v=4:l)) afforded 0.80 g (87% yield) of product 3d as a colorless crystalline solid. lH NMR (360 MHz, CDCfi): 5= 6.47 (t, V(H, F)=53.8Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.58 (t, J= 7.5 Hz, 1H), 7.67 (t, J= 7.8 Hz, 1H), 7.88 (d, J= 8.3 Hz, 1H), 8.07 (d, J= 8.3 Hz, 1H), 8.16 (dm, J= 7.5 Hz, 1H), 8.90 (d, 8.8 Hz, 1H); 1 3 C NMR (90 MHz, CDCI3): 5= 110.64 (t, V(C, F)= 254.9 Hz), 124.08, 125.24, 126.87, 128.74, 129.06, 131.10 (t, V(C, F)= 4.3 Hz), 133.87, 135.40, 189.52 (t, 2 J(C, F)= 23.8 Hz); l9F NMR (338 MHz, CDCI3): 6= - 121.18 (d, 2 J{F, H)= 52.0 Hz, 2F). 2,2-Difluoro-2’-acetothienone (3e): Under an argon atmosphere, to the mixture of 0.27 g (11.1 mmol) magnesium turnings and 2.41 g (22.2 mmol) chlorotrimethylsilane (TMSC1) in 25 ml dry THF at 0 °C, was added 1.0 g (5.56 mmol) 2,2,2-trifluoro-2’-acetothienone le. Then the mixture was stirred at 0 °C for 2 h. The completion of the reaction was monitored by 1 9 F NMR. THF and excess 56 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TMSC1 were removed under vacuum and to the residue was added 15 ml of hexanes. The solid was removed by suction filtration, and the filtrate was condensed under vacuum to give 1.33 g crude product 2e (1 9 F NMR: -102.7 ppm (d); -109.1 ppm (d)). To 2e was added 10 ml of 3 M HC1 and 5 ml of methanol, and the mixture was stirred overnight. Then the mixture was extracted successively with 10 ml of ether, thrice. Combined ether phase was further washed with 15 ml saturated NaHC03 aqueous solution, followed by with 10 ml of brine. The organic phase was dried over anhydrous MgSC> 4 and solvent was removed under vacuum. Further purification by silica gel column chromatography (hexanes/ethyl acetate (v/v=4:l)) afforded 0.83 g (92% yield) product 3e as a colorless liquid. * 1 1 NMR (360 MHz, CDCI3): 5= 6.24 (t, 2 J(H, F)=53.9Hz, 1H), 7.27 (m, 2H), 7.89 (m, 1H), 8.05 (m, 1H); 1 3 C NMR (90 MHz, CDCI3 ): 5= 110.69 (t, lJ(C, F)= 253.5 Hz), 128.87, 135.51, 136.75, 137.68 ((t, 3 /(C, F)= 2.5 Hz), 180.98 (t, 2 J(C, F)= 26.9 Hz); 1 9 F NMR (338 MHz, CDC13 ): 8= - 122.21 (d, 2 J(F, H)= 55.9 Hz, 2F). 2-Deutero-2,2-difluoroacetophenone (3f): 2,2-Difluoro-1 -phenyl-1 -trimethyl- siloxyethene 2a (crude, 140 mg) prepared from 2,2,2-trifluoroacetophenone (la) (106 mg, 0.61 mmol) as mentioned above, was dissolved in THF (2 ml) and then was slowly added into a solution of tetrabutylammonium triphenyidifluorosilicate (TBAT, 0.34 g, 0.63 mmol) in 2 ml THF / lml D2O at 0 °C. The reaction mixture was stirred for 15 min, and the completion of the reaction was confirmed by 1 9 F NMR. The reaction mixture was extracted with ether (10 ml x 3), and the combined 57 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ether phase was washed with brine twice. The organic phase was dried over MgSQ,*, and subsequently the solvent was evaporated under vacuum. Further purification by column chromatography (hexanes/ether = 100/4 (v/v)) afforded 84.2 mg (88% yield) of product 3f as a colorless liquid. *H NMR (500 MHz, CDCI3): 5= 7.54 (t, J — 8 .0 Hz, 2H), 7.68 (t, J= 7.5 Hz, 1H), 8.08 (d, J= 7.5 Hz, 2H); 1 3 C NMR (125 MHz, CDCI3): 6= 110.85 (tt, ^(C, F)= 252.4 Hz, X J{C, D)= 29.2 Hz), 128.94, 129.61 131.5 l(t, 3 J(C, F)= 1.7 Hz), 134.87, 187.57 (t, 2 J(C, F)= 25.5 Hz); 1 9 F NMR (470 MHz, CDCI3): 5= -123.10 (t, 2 J(F, D)= 7.6 Hz, 2F). 2,2-Difluoro-4’-trimethylsilylacetophenone (3g): Under an argon atmosphere, to the mixture of 0.19 g (7.9 mmol) magnesium turnings and 1.71 g (15.8 mmol) chlorotrimethylsilane (TMSC1) in 25 ml dry THF at 0 °C, was added 1.0 g (3.95 mmol) 2,2,2-trifluoro-4’-bromoacetophenone lg. Then the mixture was stirred at 0 °C for 90 min. The completion of the reaction was monitored by I9 F NMR. THF and excess TMSC1 were removed under vacuum and to the residue was added 15 ml of hexanes. The solid was removed by suction filtration, and the filtrate was condensed under vacuum to give a crude product. Both 1 9 F NMR and GC-MS spectra showed that the crude product mixture mainly contains three compounds: 2,2-Difluoro-l-(4’ -trimethylsilyl)phenyl-l-trimethyl-siloxyethene (~67%, I9 F NMR: - 99.9 ppm (d); -111.8 ppm (d); MS: m/s = 300 (M+ )), 2,2-Difluoro-l-(4 bromophenyl)-l-trimethyl-siloxyethene (~14%, 1 9 F NMR: -99.4 ppm (d); -111.1 ppm (d); MS: m/e = 306 (M*)); 2,2-Difluoro-l-phenyl-1-trimethyl-siloxyethene 2a (~8%, 58 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1 9 F NMR: -100.4 ppm (d); -112.2 ppm (d); MS: m/e = 228 (M+ ) . To the product mixture was added 5 ml of 3 M HC1, and the mixture was stirred overnight. Then the mixture was extracted successively with 10 ml of ether, thrice. Combined ether phase was further washed with 15 ml saturated NaHCC> 3 aqueous solution, and then with 10 ml brine. The organic phase was dried over anhydrous MgSC> 4 and the solvent was removed Under vacuum. Further purification by silica gel column chromatography (hexanes/ethyl acetate (v/v=4:l)) afforded 0.58 g (65% yield) product 2,2-Difluoro-4 ’ -trimethylsilylacetophenone 3g as a colorless liquid. *H NMR (360 MHz, CDC13 ): 8= 0.33 (s, 9H), 6.31 (t, 2 J{H, F)=53.5Hz, 1H), 7.70 (d, J -8 .3 Hz, 2H), 8.04 (d, J= 8.3 Hz, 2H); 1 3 C NMR (90 MHz, CDC13 ): 5= -1.54, 111.09 (t, 'J(C, F)= 253.6 Hz), 128.32 (t, V(C, F)= 2.8 Hz), 131.46, 133.74, 149.91, 187.72 (t, 2 J(C, F)= 25.0 Hz); 1 9 F NMR (338 MHz, CDC13 ): 8= -122.62 (d, 2 J(F, H)= 53.4 Hz, 2F). 2,2-Difluoromethyl «-hexyl ketone (3h): Under an argon atmosphere, to the mixture of 116.6 mg (4.8 mmol) magnesium turnings and 0.264 g (2.4 mmol) chlorotrimethylsilane (TMSC1) in 2.4 ml of dry DMF at -15 °C, was added 109.2 mg (0.6 mmol) 2,2,2-trifluoro-«-hexyl ketone Ih. Then the mixture was stirred at -15°C to room temperature for 3 h. The completion of the reaction was monitored by 1 9 F NMR. Volatile species were removed under vacuum and to the residue was added 15 ml of hexanes. The solid was removed by suction filtration, and the filtrate was 59 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. condensed under vacuum to give crude product 2h (-50 %, 1 9 F NMR: -107 ppm (d); -122 ppm (d)). To 2h was added 10 ml of 3 M HC1, and the mixture was stirred overnight. Then the mixture was extracted successively with 10 ml of ether, thrice. Combined ether phase was further washed with 15 ml of saturated NaHCC> 3 aqueous solution, and then with 10 ml of brine. The organic phase was dried over anhydrous MgS04 and solvent was removed under vacuum. 1 9 F NMR (with internal standard) showed that product 2,2-Difluoromethyl n-hexyl ketone (3h) was generated in 33% yield. 1 9 F NMR (338 MHz, CDC13 ): 5= -127.38 (d, 2 J(F, H)= 46.8 Hz, 2F). 2.4.4 Preparation of monofluoromethyl ketones (6 ) from difluoromethyl ketones (3) 2-Fluoro-l-phenyl-l-trimethyisiIoxyethene (5a): To a dry 100 ml Schlenk flask was added magnesium turnings (0.307 g, 12.8 mmol), dry THF (20 ml) and chlorotrimethylsilane (TMSC1) (2.78 g, 25.6 mmol), and the flask was cooled down to 0 °C. 2,2-Difluoroacetophenone 3a (1.0 g, 6.4 mmol) in 5 ml of THF was added dropwise into the flask via a syringe. After addition, the reaction mixture was stirred for additional 1 h. The completion of the reaction was confirmed by 1 9 F NMR. The solvent and excess TMSC1 were removed under vacuum, and hexane (30 ml) was added to the residue. After the solid impurities were filtered off by suction filtration, the solvent was evaporated to afford 2-Fluoro-l -phenyl-1 -trimethylsiloxyethene 5a (1.33 g, 99% yield). lH NMR and GC-MS showed the purity was > 96%, and it 60 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. contains Z/E isomers (Z/E = 2.2/1.0). Z-isomer: *H NMR (360 MHz, CDCI3): 5= 0.31 (s, 9H), 7.04 (d, 2 J{H, F)=78.2 Hz, 1H), 7.34-7.49 (m, 3H), 7.71 (d, J=7.8 Hz, 2H); 1 9 F NMR (338 MHz, CDC13 ): 5= -158.83 (d, V(F, H)= 79.4 Hz). E-isomer: *H NMR (360 MHz, CDC13 ): 6= 0.25 (s, 9H), 6.99 (d, 2 J{H, F)=79.6 Hz, 1H), 7.34-7.49 (m, 3H), 7.71 (d, .7=7.8 Hz, 2H); 1 9 F NMR (338 MHz, CDCI3): 6= -164.63 (d, 2 J{F, H)= 79.5 Hz). 2-Fluoroacetophenone (6 a): 2-Fluoro-1 -phenyl-1 -trimethylsiloxyethene 5a prepared from 2,2-difluoroacetophenone 3a (1.0 g, 6.4 mmol) as mentioned above, was dissolved in THF (10 ml) and then was slowly added into tetrabutylammonium fluoride (TBAF, 7.0 mmol) solution in THF (10 ml)/H20 (2 ml) at 0 °C. The reaction mixture was stirred for 30 min, and the completion of the reaction was confirmed by 1 9 F NMR. After removal of most of the THF solvent, hexanes (30 ml) were added and washed with water. The organic phase was dried over MgSC>4, and then the solvent was evaporated under vacuum. The crude product was distilled to afford 0.87 g crude product. Small scale bulb to bulb vacuum distillation afforded 0.78 g (89% yield calculated from 3a) product 6 a as a colorless liquid, which crystallizes in the refrigerator. :H NMR (360 MHz, CDCI3): 8= 5.51 (d, 2 J(H, F)=47.0 Hz, 2H), 7.46 (t, J =7.4 Hz, 2H), 7.60 (t, J= 7.4 Hz, 1H), 7.86 (d, J=1.4 Hz, 2H); 1 3 C NMR (90 MHz, CDCI3): 8= 83.38 (d, 7(C, F)= 183.2 Hz), 127.66(d, 3 /(C, F)= 2.5 Hz), 128.81, 133.48, 134.02, 193.31 (d, 2 J(C, F)= 15.9 Hz); 1 9 F NMR (338 MHz, CDCI3): 8= -231.69 (t, 2 J{F, H)= 47.0 Hz, IF). 61 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2-Fluoro-4’-methyl-acetophenone (6b): To the mixture of 28 mg (1.17 mmol) magnesium turnings and 260 mg (2.35 mmol) TMSC1 in 3 ml dry THF at 0 °C, was added 100 mg (0.588 mmol) 4 -methyl-2,2-difluoroacetophenone 3b under an argon atmosphere. Then the mixture was stirred at 0 °C for 1 h. THF and excess TMSC1 were removed under vacuum and to the residue was added 15 ml of hexanes. The solid was removed by suction filtration, and the filtrate was condensed under vacuum to give about 140 mg crude product 5b: 1 9 F NMR: -159.85 (Z-isomer, d, 2J f-h -83.6 Hz), -165.02 (E-isomer, d, 2J f-h -83.6 Hz), Z/E =2.2/1.0. To 5b was added 10 ml of 5M HC1 and the mixture was stirred at room temperature overnight. Then the mixture was saturated with NaCl and extracted successively with 10 ml of ether three times. Combined ether phase was further washed with 10 ml of brine twice, and the organic phase was dried over anhydrous MgSC>4. After removal of the solvent 89.6 mg crude product was collected. The product was purified by silica gel column chromatography (hexanes/ethyl acetate (v/v=4:l)) to give 69.8 mg 6b as a white solid, yield 78%. L H NMR (360 MHz, CDCI3): 5= 2.42 (s, 3H), 5.50 (d, 2 J(H, F)=47.5Hz, 2H), 7.29 (d, J =8.2 Hz, 2H), 7.79 (d, J= 8.2 Hz, 2H); 1 3 C NMR (90 MHz, CDCI3): 5= 21.77, 83.45 (d, X J(C, F)= 182.0 Hz), 127.91 (3 /(C, F)= 2.5 Hz), 129.56, 131.16, 145.16, 192.90 (d, 2 J(C, F)= 15.9 Hz); 1 9 F NMR (338 MHz, CDCI3): 5= -231.31(t, V(F, H)= 47.7 Hz, IF). 62 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 4’-Chloro-2-fluoroacetophenone (6c): To the mixture of 40 mg (1.67 mmol) magnesium turnings and 360 mg (3.32 mmol) TMSC1 in 6 ml dry THF at 0 °C, was added 150 mg (0.787 mmol) 4 -chloro-2,2-difluoroacetophenone 3c under an argon atmosphere. Then the mixture was stirred at 0 °C for 2 h. THF and excess TMSC1 were removed under vacuum and to the residue was added 20 ml of hexanes. The solid was removed by suction filtration, and the filtrate was condensed under vacuum to give the crude product 5c (96% NMR yield): 1 9 F NMR: -157.8 (Z-isomer, d, 2 Jf-h =76.3 Hz), -163.1 (E-isomer, d, 2/f - h =80.1Hz), Z/E =2.0/1.0. Compound 5c was then dissolved in THF (3 ml) and then was slowly added into tetrabutylammonium fluoride (TBAF, 1.0 mmol) solution in THF (1 ml)/H20 (0.1 ml) at -78 °C. The reaction mixture was stirred for 30 min at -78 °C and warmed to room temperature, and the completion of the reaction was confirmed by 1 9 F NMR. After removal of most of the THF solvent, hexanes (15 ml) were added and washed with brine. The organic phase was dried over MgSC>4, and then the solvent was evaporated under vacuum. The product was further purified by silica gel column chromatography (hexanes/ethyl acetate (v/v=l:l)) to give 107 mg 6c as a white solid, yield 80%. *H NMR (500 MHz, CDC13 ): 8= 5.48 (d, 2 /(H , F)=47.0Hz, 2H), 7.47 (d, .7=8.5 Hz, 2H), 7.85 (d, J= 8.5 Hz, 2H); 1 3 C NMR (125 MHz, CDC13 ): 5= 83.57 (d, lJ(C, F)= 183.1 Hz), 129.27, 129.40 (d, V(C, F)= 2.5 Hz), 132.07, 140.65, 192.48 (d, 2 C, F)= 16.1 Hz); 1 9 F NMR (470 MHz, CDC13 ): 8= -230.25 (t, V(F, H)= 46.7 Hz, IF). 63 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2-FLuoro-l ’-acetonaphthone (6d): To the mixture of 42 mg (1.7 mmol) magnesium turnings and 378 mg (3.5 mmol) TMSC1 in 4 ml dry THF at 0 °C, was added 180 mg (0.87 mmol) 2,2-Difluoro-l’-acetonaphthone 3d under an argon atmosphere. Then the mixture was stirred at 0 °C for 2 h. THF and excess TMSC1 were removed under vacuum and to the residue was added 15 ml of hexanes. The solid was removed by suction filtration, and the filtrate was condensed under vacuum to give crude product 5d (quantitative NMR yield): 1 9 F NMR: -154.26 (Z-isomer, d, Vf-h =76.5 Hz), -165.72 (E-isomer, d, 2 J F .H =76.5 Hz), Z/E =2.1/ 1.0 . To 5d was added 5 ml of 3M HC1 and the mixture was stirred at room temperature overnight. Then the mixture was saturated with NaCl and extracted successively with 10 ml ether three times. Combined ether phase was further washed with 10 ml brine twice, and the organic phase was dried over anhydrous MgSC>4. After removal of the solvent the crude product was collected. The product was purified by silica gel column chromatography (hexanes/ethyl acetate (v/v=4.T)) to give 137 mg 2-Fluoro-l ’ -acetonaphthone 6d as a white solid, yield 84%. jH NMR (360 MHz, CDC13 ): 6= 5.58 (d, 2 J{H, F)=47.4 Hz, 2H), 7.54 (t, J= 7.8 Hz, 1H), 7.64 (t, J= 7.5 Hz, 1H), 7.71 (t, J= 7.8 Hz, 1H), 7.82 (d, /= 7.5 Hz, 1H), 7.95 (d, J= 8.1 Hz, 1H), 8.10 (d, J= 8.1 Hz, 1H), 8.82 (d, J= 8.4 Hz, 1H); 1 3 C NMR (90 MHz, CDCI3 ): 5= 83.74 (d, lJ(C, F)= 184.8 Hz), 124.04, 125.21, 126.67, 128.02, 128.05, 128.40, 128.44, 133.79, 133.88, 196.81 (d, 2 /(C, F)= 17.1 Hz); 1 9 F NMR (338 MHz, CDCI3): 5= -225.78 (t, 2 /(F, H)= 45.9 Hz, IF). 64 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2-FIuoro-2’-acetothienone (6e): To the mixture of 144 mg (6.0 mmol) magnesium turnings and 1.3 g (12 mmol) TMSC1 in 10 ml dry THF at 0 °C, was added 486 mg (3.0 mmol) 2,2-Difluoro-2’-acetothienone 3e under an argon atmosphere. Then the mixture was stirred at 0 °C for 2 h. THF and excess TMSC1 were removed under vacuum and to the residue was added 15 ml of hexanes. The solid was removed by suction filtration, and the filtrate was condensed under vacuum to give the crude product 5e (quantitative NMR yield): 1 9 F NMR: -158.43 (Z-isomer, d, 2 J F-h =76.8 Hz), -161.02 (E-isomer, d, 2J F-h =76.8 Hz), Z/E =2.0/1.0. To 5e was added 5 ml 3M HC1 and the mixture was stirred at room temperature overnight. Then the mixture was saturated with NaCl and extracted successively with 10 ml of ether three times. Combined ether phase was further washed with 10 ml of brine twice, and the organic phase was dried over anhydrous MgSCk After removal of the solvent the crude product was collected. The product was purified by silica gel column chromatography (hexanes/ethyl acetate (v/v=4:l)) to give 421 mg 2-Fluoro- 2’-acetothienone 6e as a white solid, yield 95%. !H NMR (360 MHz, CDCI3): 8= 5.30 (d, 2 J{H, F)=47.5Hz, 2H), 7.12 (m, 1H), 7.69 (m, 1H), 7.79 (m, 1H); 1 3 C NMR (90 MHz, CDCI3 ): 8= 83.46 (d, */(C, F)= 184.4 Hz), 128.32, 132.93, 134.77, 139.55 ((d, V(C, F)= 2.4 Hz), 186.87 (d, 2 J(C, F)= 17.1 Hz); 1 9 F NMR (338 MHz, CDC13 ): 8= -227.99 (t, 2 J{F, H)= 45.9 Hz, IF). 2,2-Deuterofluoro-4’-methylacetophenone (61): Compound 5b (crude) prepared from 2,2-Difluoro-4’-methylacetophenone 3b (100 mg, 0.59 mmol) as 65 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. mentioned above, was dissolved in THF (2 ml) and then was slowly added into a solution o f tetrabutylammonium triphenyldifluorosilicate (TBAT, 0.19 g) in 2 ml of THF / 4 ml D2O at 0 °C. The reaction mixture was stirred for 15 min, and the completion of the reaction was confirmed by 1 9 F NMR. The reaction mixture was extracted with ether (10 ml x 3), and the combined ether phase was washed with brine twice. The organic phase was dried over MgSCX and then the solvent was removed under vacuum. Further purification by column chromatography (hexanes/ethyl acetate = 4/1 (v/v)) afforded 82 mg (91% yield) of product 6f as a white solid. *H NMR (360 MHz, CDC13 ): 8= 2.42 (s, 3H), 5.48 (dt, 2 J(H, F)=46.8Hz, , 2 J(H, D)= 2.5 Hz 1H), 7.29 (d, J -8 .1 Hz, 2H), 7.79 (d, 8.1 Hz, 2H); 1 3 C NMR (90 MHz, CDCI3): 5= 21.72, 83.13 (dt, ^(C, F)= 181.1 Hz, lJ(C, D)= 23.3 Hz), 127.90 (d, 3 J(C, F)= 2.5 Hz), 129.55, 131.16, 145.15, 193.01 (d, 2 J{C, F)= 16.0 Hz); 1 9 F NMR (338 MHz, CDC13 ): 8= -231.95 (dt, 2 J{F, H )- 45.8 Hz, V(F, D)= 7.6 Hz, IF). 2-Fluoro-4’-trimethylsilyIacetophenone (6g): To the mixture of 21 mg (0.87 mmol) magnesium turnings and 190 mg (1.75 mmol) TMSC1 in 3 ml dry THF at 0 °C, was added 100 mg (0.44 mmol) 2,2-Difluoro-2 ’ -trimethylsilylacetophenone 3g under an argon atmosphere. Then the mixture was stirred at 0 °C for 1 h. THF and excess TMSC1 were removed under vacuum and to the residue was added 15 ml of hexanes. The solid was removed by suction filtration, and the filtrate was condensed under vacuum to give 107 mg crude product Sg (94% NMR yield): 1 9 F NMR: - 66 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 158.63 (Z-isomer, d, 2 Jf-h =77.2 Hz), -163.24 (E-isomer, d, VF .H =79.8 Hz), Z/E = 2 .2/ 1.0 . To 5g was added 5 ml of 3M HC1 and the mixture was stirred at room temperature overnight. Then the mixture was saturated with NaCl and extracted successively with 10 ml of ether three times. Combined ether phase was further washed with 10 ml 10 % NaHCC> 3 solution and brine, respectively. The organic phase was dried over anhydrous MgSC>4. After removal of the solvent the crude product was collected. The product was purified by silica gel column chromatography (hexanes/ethyl acetate (v/v=4:l)) to give 83.5 mg 2-Fluoro-4 trimethylsilylacetophenone 6g as a white solid, yield 91%. !H NMR (360 MHz, CDC13 ): 8= 0.30 (s, 9H), 5.52 (d, 2 J(H, F)=47.3Hz, 2H), 7.65 (d, / = 8.3 Hz, 2H), 7.84 (d, J= 8.3 Hz, 2H); 1 3 C NMR (90 MHz, CDCI3): 8= -1.49, 83.47 (d, \/(C, F)= 181.7 Hz), 126.60, 133.59, 133.70, 148.75, 193.63 (d, V(C, F)= 15.2 Hz); 1 9 F NMR (338 MHz, CDCI3 ): 8= -231.60 (t, 2/(F, H)= 47.7 Hz, IF). GC-MS (70 eV) m/e (relative intensity): 210 (M+, 2), 195 (100), 177 (80), 149 (5), 134 (39), 119 (36), 105 (11), 91 (14), 77 (17), 73 (31), 67 (6), 53 (11). 2-Fluoromethyl w-hexyl ketone (6h): Under an argon atmosphere, to the mixture of 58.3 mg (2.4 mmol) magnesium turnings and 0.132 g (1.2 mmol) chlorotrimethylsilane (TMSC1) in 3 ml dry DMF at 0 °C, was added 50 mg (0.3 mmol) 2,2-difluoro-n-hexyl ketone 3h. Then the mixture was stirred at 0 °C to room temperature for 2 h. The completion of the reaction was monitored by 1 9 F NMR. 67 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Volatile species were removed under vacuum and to the residue was added 15 ml hexanes. The solid was removed by suction filtration, and the filtrate was condensed under vacuum to give the crude product 5h (-35 % NMR yield, 1 9 F NMR: -161.82 ppm (d, V f- h = 83.6 Hz); -173.40 ppm (d, 2 / F .H = 83.6 Hz)). To 5h was added 5 ml 3 M HC1, and the mixture was stirred overnight. Then the mixture was extracted successively with 10 ml of ether thrice. Combined ether phase was further washed with 15 ml saturated NaHCC> 3 aqueous solution, followed with 10 ml of brine. The organic phase was dried over anhydrous MgSC> 4 and solvent was removed under vacuum. 1 9 F NMR (with internal standard) showed the formation of product 2-Fluoromethyl n-hexyl ketone (6h) in 35% yield. 1 9 F NMR (338 MHz, CDC13 ): 8= -227.94 (t, 2 J{F, H)= 45.8 Hz, IF). 68 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2.5 References 1. Takahashi, L. H.; Radhakrishnan R.; Rosenfield, Jr. R. E.; Meyer, Jr., E. F. Biochemistry 1989, 28, 7610. 2. Morris, T. S.; Frormann, S.; Shechosky, S.; Lowe, C.; Lall, M. S.; Gauss Muller, V.; Purcell, R. H.; Emerson, S. U.; Vederas, J. C.; Malcolm, B. A. Bioorg. Med. Chem. 1997, 5, 797. 3. Imperiali, B.; Abeles, R. H. Biochemistry 1986,25, 3760. 4. Cohen, S.G.; Wolosinski, H. T.; Schener, P. J. J. Am. Chem. Soc. 1949, 71, 3439. 5. Bronnert, D. L. E.; Saunders, B. C. Tetrahedron 1965, 21, 3325. 6. Kitazume, T.; Asai, M.; Tsukamoto, T.; Yamazaki T. J. Fluorine Chem. 1992, 56,271. 7. Capriel, P.; Biusch, G. Tetrahedron 1979, 25, 2661. 8. Kitazume, T.; Asai, M.; Lin, J. T .; Yamazaki, T. J. Fluorine Chem. 1987,35 A ll. 9. Howarth, J. A.; Owton, W. M.; Percy, J. M.; Rock, M. H. Tetrahedron 1995, 37, 10289. 10. Howarth, J. A.; Owton, W. M.; Percy J. M. Chem. Comm. 1995, 757. 11. Ichikawa, J.; Sonoda, T.; Kobayashi, H. Tetrahedron Letters 1989, 30, 5437. 12. Brigaud, T.; Doussot, P.; Portella, C. Chem. Comm. 1994, 2117. 13. Piettre, S. R.; Girol, C.; Schelcher, C. G. Tetrahedron Letters 1996, 37, 4711. 14. Zupan, M.; Iskra, J.; Stavber, S. J. Org. Chem. 1995, 60,259. 15. Middleton, W. J.; Bingham, E. M. J. Am. Chem. Soc. 1980,102, 4845. 16. Rozen, S.; Bareket, Y.; Kol, M. J. Fluorine Chem. 1993, 61, 141. 69 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 17. Purrington, S. T.; Lazaridis, N. Y.; Bumgardner, C. L. Tetrahedron Lett. 1986, 27,2715. 18. Banks, R. E. J. Fluorine Chem. 1998, 87, 1. 19. Muniz, K. Angew. Chem. Int. Ed. 2001, 40, 1653. 20. Shibata, N.; Suzuki, E.; Takeuchi, Y. J. Am. Chem. Soc. 2000,122,10728. 21. Cahard, D.; Audouard, C.; Plaquevent, J.-C.; Roques, N. Org. Lett. 2000, 2, 3699. 22. Olah, G.; Kuhn, S. Chem. Ber. 1956, 864. 23. Olah, G. A.; Chambers, R. D.; Prakash, G. K. S. Synthetic Fluorine Chemistry 1992, Wiley-Interscience, p.196, and references therein. 24. Keumi, T.; Shimada M.; Takahashi, M.; Kitaj ama, H. Chem. Lett. 1990, 783. 25. Creary, X. J. Org. Chem. 1987, 52, 5026. 26. Wiedemann, J.; Heiner, T.; Mloston, G.; Prakash, G. K. S.; Olah, G. A. Angew. Chem. Int. Ed. 1998, 37, 820. 27. Singh, R. P.; Cao, G.; Kirchmeier, R. L.; Shreeve, J. M. J. Org. Chem. 1999, 64, 2873. 28. Amii, H.; Kobayashi, T.; Hatamoto, Y.; Uneyama, K. Chem. Commun. 1999, 1323. 29. Yamana, M.; Ishihara, T.; Ando, T. Tetrahedron Lett. 1983, 24, 507. 30. Jin, F.; Jiang, B.; Xu, Y. Tetrahedron Lett. 1992, 3 3 ,1221. 31. Uno, H.; Sakamoto,K.; Suzuki, H. Bull. Chem. Soc. Jpn. 1992, 65,218. 32. Lefebvre, O.; Brigaud, T.; Portella, C. J. Org. Chem. 2001, 6 6 ,1941. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 3 Preparation of 1 8 F Labeled Trifluoromethyl Ketones and Other Halodifluoromethyl Ketones via Selective Halogenations of 2,2-Difluoro Enol Silyl Ethers Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 3.1 Introduction Fluorine has three isotopes: the natural and stable isotope 1 9 F, radioisotopes 1 7 F (half-life time of 1.08 minutes) and 1 8 F (half-life time of 110 minutes).1 1 8 F labeled radiopharmaceuticals can be imaged in vivo by positron emission tomography (PET), and thus they are very useful for diagnosis of disease and for detecting metabolic parameters, especially in the field of oncology.2 Several types of 1 8 F labeled PET imaging agents have been developed, including 1 8 F labeled sugars,3 steroids,2 proteins and peptides.4 The first routinely accepted and widely used PET imaging agent is 2-deoxy-2-[1 8 F]fluoro-D-glucose (1 8 FDG), which was used for the quantitation of brain glucose metabolism in normal and abnormal brain tissue (its synthesis is shown in Scheme 3.1).5 AcO. A cO . OAc OAc 'OAc K 16^. K ryptofixR 2.2.2 OAc OAc OAc (K ryptofixR 2,2,2 =4,7,13,16,21,24- hexaoxa-1,10-diazabicyclo[8.8.8]- hexacosane) H 30 +, 120 °C 40 -55 % H O . O H OH OH Scheme 3.1 The synthesis of 1 S FDG. 72 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The traditional methods to incorporate fluorine atoms into organic molecules labeling reagents are fluorides (1 8 F"), such as 1 8 F labeled tertabutylammonium fluoride (TAB1 8 F), potassium fluoride (K1S F), among others. All electrophilic 1 8 F iodine to generate corresponding halogen fluorides, and the latter one have been used labeling methodology has to be quick, facile and efficient.2 Trifluoromethyl ketones (TFMKs) are potential biologically active compounds of increasing interest. These compounds have found use as potential protease and enzyme inhibitors due to the unique properties of the trifluoromethyl group, which helps the formation of hydrates or hemiacetals with target protease/enzyme molecules (Scheme 3.2).8 ,9 Scheme 3.3 shows some examples of TFMKs as protease inhibitors.8 are also used to prepare 1 8 F labeled compounds, including nucleophilic substitution, electrophilic substitution, and addition.6 The most commonly used nucleophilic 1 8 F labeling methods are normally based on 1 8 F2. Fluoride ion can react with bromine or for alkene halofluorination reactions.2,7 1 8 F is usually generated by cyclotron bombardment of appropriate molecules such as 2 0 Ne or 1 80 . Because the half-life of 1 8 F is under two hours, its cyclotron generation needs to be on-site and the fluorine H em ia ceta ls H yd rates Scheme 3.2 Formation of stable hydrates or hemiacetals between TFMKs and protease/enzyme molecules. 73 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ( target enzym e: fatty acid am ide hydrolase (FAAH)) (target enzym e: phospholipase Az (PLA2) ) C8H17S. CF, (target enzym e: insect juvenile hormone esterase) C F3 O 4 (target enzym e: acetyl cholinesterase) (target enzyme: cydooxygenase-2 (COX-2)) H2N, •NH Me-D-PheProHN" 6 o c f 3 (target enzyme: thrombin) (tar9 et enzym e: hum an cytomegalovirus) PhO' , - Y N Y -P t 0 o ^ c f3 (target enzyme: metallo-beta-lactam ase) BocHN' (target enzym e: re n in ) C l S 0 2NHC0 CONH. -CON CONH, CF, 10 (target enzyme: hum an leukocyte elastase (HLE)) Scheme 3.3 Examples of TFMKs as protease inhibitors. 74 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. However, 1 8 F labeled txifluoromethyl ketones are still unkown. As our continuing research efforts in fluorinated methyl ketones,9’1 0 we have been interested in the facile preparation of 1 8 F labeled fluorinated methyl ketones using fluorinated silyl enol ethers as precursors (see Chapter 1). This methodology may provide us a useful tool to prepare certain 1 8 F labeled TFMKs as lead compounds for PET clinical studies. Furthermore, little is known about the reactions between 2,2-difluoroenol silyl ethers and halogens (Br2, 12, F2, Selectfluor®, etc.) to prepare bromodifluoromethyl-, iododifluoromethyl- or trifluoromethyl ketones. To our best knowledge, only iodination of 2,2-difluoroenol silyl ether has been reported using iodine in moderate yield.1 1 ,1 2 Bromodifluoro- or idodifluoromethyl ketones are very useful intermediates for further elaborations. Burton and co-workers reported that, in the presence of tetrakis(triphenylphosphine) palladium [Pd(PPfi3)4], iododifluoromethyl ketones reacted with alkenes to produce a,a-difluoro-7-iodo ketones in high yields at room temp.1 2 We have shown that, bromodifluoromethyl phenyl ketones are useful precursors to synthesize 1 -phenyl-1,1,2,2-tetrafluoroethanesulfonic acid (see Chapter 8). Herein we wish to report our study on the preparation of 1 8 F Labeled trifluoromethyl ketones and other related bromodifluoro-, iododifluoromethyl ketones via selective halogenations of 2,2-difluoro enol silyl ethers. 75 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 3.2 Results and discussion 2,2-Difluoroenol silyl ethers1 3 1 were prepared via magnesium metal mediated reductive defluorination of trifluoromethyl ketones (see Chapter 2). Selective halogenations of 1 using bromine (Br2), iodine (I2), Selectfluor®, normal fluorine (1 9 F2) as well as 1 8 F labeled fluorine (1 8 F2) were carried out to prepare the corresponding halogenated methyl ketones (Scheme 3.4). Br 2 tmso. f R F 1 CH2 C I2, -78°C, 30 min CH2 C I2, -78° C ~r.t„ overnight Selectfluor ® CH3CN,-40 °C-r.t., 30 min _________ F2 CH3 GN, -45 °C or CFCI3 , -78°C 18r CH3 CN, -45 °C O U R CF2Br O y R CF2l O r A c f 3 o I I R CF3 o r^ c f218f Selectfluor' CH2C I (ti) 2 B F * ' F Scheme 3.4 Selective halogenations of 2,2-difluoro silyl enol ethers (1). 76 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The results of the reactions are listed in Table 1. The bromoniation reactions were facile in dichloromethane even at - 78 °C to produce bromodifluoromethyl ketones in excellent yields. The slow addition of bromine into the dichloromethane solution of 1 was similar to a titration process, since the completion of the reaction can be monitored by the persistence of the bromine color. However, due to the lower electrophilicity of iodine, the iodination reactions need longer reaction time and gave moderate yield of iododifluoromethyl ketones (Table 1). When Selectfluor® (F- TEDA-BF4, A-fhioro-A-chloromethyl-triethylenediamine bis(tetrafluoroborate) was applied as electrophilic fluorination reagent, the reaction proceeded quite efficiently in acetonitrile and gave almost quantitative yield of trifluoromethyl ketones. As a model reaction for 1 8 F labeling, normal fluorine (1 9 F2, 20 vol % in nitrogen) was also used as the fluorination source using acetonitrile or fluorotrichloromethane (Freon- 11) as solvent at low temperatures. The reactions were successful to give good yield of the corresponding trifluoromethyl ketones, which is consistent with the fluorination of non-fluorinated silyl enol ethers as reported by Purrington and co workers.1 4 The 1 8 F electrophilic fluorinations of 1 to form 1 8 F labeled trifluoromethyl ketones were also attempted. Due to the radioactivity of 1 8 F, the reaction was strictly performed inside a “hot cell” (fume hood with thick lead wall) with automated manipulators. The typical reaction was carried out as follows: at - 45 °C, into a small 77 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 3.1. Preparation of halogenated methyl ketones 2 through facile selective halogenations of 2,2-difluoroenol silyl ethers 1. Entry P rod uct 2 Y ield (%) N u cleo p h ile Ph , 0 CF2Br CF2Br 88 S electflu o r ® Ph S electflu o r P S electflu o r ® PF; S electflu o r ® 94' S e le c tflu o r ® 7 8 3 2 - 5 0 ' O Ph - 2 5 ' a Isolated yield; d e t e r m in e d b y 1 9 F; c ra d io ch em ica l yield; p rod u ct w a sp a rtia lly e v a p o r ta e d during th e so lv e n t rem o v a l p r o c e s s , s o th e radioactivity yield w a s lo w er th a n it sh o u ld b e. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. dry sealed vial containing acetonitrile solution of fluoroenol silyl ethers 1 (40 mg, to to excess amount compared with the amount of F2 used), was slowly introduced F2 which was generated via cyclotron bombardment of 1 8 C > 2. The reaction was then carefolly worked up and the yield was determined by radioactivity measurement of the product, concerning the natural loss due to the time pass (Figure 3.1). The 1 R radioactivity yields of F labeling reactions are lower than their non-radioactive fluorinations. This is mainly" due to the tiny reaction scale, which leads to the considerable by-product formation and product loss during to the work-up inside the “hot cell”. \M m m 7 . 0 e 3 6 . 9 e 3 5 . 0 e 3 4 . 9 e 3 3 . 9 e 3 2 .0 d m 0.0 0 3 0 1 0 0 1 3 0 2 0 0 m s Figure 3.1 The radioactivity measurement of the product mixture of 1 S F labeled 1-naphthyl 2,2,2-Trifluoro-r-acetonaphthone (2o) by a TLC scanner with radioactivity sensor. 79 - - product - . . 1 1 - 1 1 1 ' l A v / ' \ \ \ i . _ _ _ _ _ _ _ _/ . . . \ V-------------- - < .......... s - .....- 1 . ... * ... ........ ■ ’ M L. ...................t_ .. .... I -------------1-------------1------------T------- — 1-------------f T " .......... <" 1 1 ' m" \------------n ‘ 1" ' 1 ! t ' r r " 1 ' 1 " ' 1 i Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The 1 8 F labeled products were isolated with HPLC using acetonitril/water (70:30) as eluent solvent. The yields were also affected by the formation of hydrate of the trifluoromethyl ketone product (Fig. 3.1). The mechanism of these selective halogenation reactions is suggested as shown in Scheme 3.5. For the halogens, the reaction is proposed to proceed via a six- membered transition state (Eq. I). In the case of Selectfluor®, the reaction is assumed as be a typical electrophilic substitution process (eq. II). O + M e3SiX (X) (X = F, Br, I) F 2 B F 4- O R' (II) Scheme 3.5 Proposed mechanism of selective halogenations. 3.3 Conclusion In summary, electrophilic selective halogenations of 2,2-difluoroenol silyl ethers were successfully accomplished in good to excellent yields using bromine, 80 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. iodine, fluorine, Selectfluor® as halogenating agents. The resulting bromodifluoromethyl or iododifluoromethyl ketones are useful intermediates for further elaboration to prepare other difluorinated species. The 1 8 F labeled trifluoromethyl ketones were also prepared, which provides a useful methodology to 1 8 generate important new types PET imaging agents. Further investigation of F labeled TFMK lead compounds and other 1 8 F labled difluoro- and monofluoromethyl ketones are still underway in our labratories. 3.4 Experimental section General: Unless otherwise mentioned, all the other reagents were purchased from commercial sources. Dichloromethane and fluorotrichloromethane were distilled over CaFf?, and acetonitrile was distilled over P2O5 prior to use. Column chromatography was carried out using silca gel (60-200 mesh). All the 2,2- difluoroenol silyl ethers 1 were prepared from magnesium mediated defluorination of corresponding trifluoromethyl ketones. 1 H, 1 3 C, I9 F NMR spectra were recorded on Bruker AMX 500 and AM 360 NMR spectrometers. *H NMR chemical shifts were determined relative to internal (CH3)4Si (TMS) at 8 0.0 or to the signal of a residual protonated solvent: CDCI3 5 7.26. 1 3 C NMR chemical shifts were determined relative to internal TMS at 8 0.0 or to the 1 3 C signal of solvent: CDCI3 8 77.0. CFCI3 (5 0.0) was used as the internal standard for 1 9 F NMR. Mass spectra were obtained on a Hewlett Packard 5890 Gas Chromatograph equipped with a Hewlett Packard 5971 Mass Selective Detector. 81 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1 S F labeling experiments were carried out in USC PET Imaging Science Center at the Norris School of Medicine. All the 1 8 F related experiments were performed inside thick lead equipped fume hood (Hot Cell) with automated manupulators. The small clinic vials (5 cc) with rubber septa were used as reaction vessels. The Waters HPLC with analytical/preparative columns and UV-Radioactive detectors, was used to analyze and purify the 1 8 F labeled products. Acetonitrile/H20 (70/30) was used as eluent solvent for HPLC. 2-Bromo-2,2-difluoroacetophenone (2a): The 2,2-difluoro-1 -phenyl-1 - trimethylsiloxyethene la was prepared fresh from 2,2,2-trifluoroacetophenone as described in Chapter 1. The above prepared la (6.08 g, 26.7 mmol) was dissolved in 50 ml dry CH2CI2, and at -78 °C bromine was added via a syringe until the brown bromine color no longer breached. After stirring for another 30 min, the solvent in the reaction mixture was evaporated under vacuum, and the left over residue was extracted with CH2CI2. The organic phase was further washed with NaHCCE, brine and water subsequently. After drying over MgSCL and solvent removal, the crude product was purified by column chromatography (hexanes as eluent) to afford 5.33 g product 2-bromo-2,2- difluoroacetophenone 2a, yield 85 %. !H NMR (500 MHz, CDCI3, in ppm): 7.53 (t, J = 7.8 Hz, 2H); 7.68 (t, J = 7.8 Hz, 1H); 8.15 (d, J = 8.0 Hz, 2H). 1 3 C NMR (90 MHz, CDCI3 ): 5 113.56 (t, ‘/ C -F = 319.1 Hz); 128.87; 129.05; 130.61 (t, VC -f = 2.6 82 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Hz); 135.09; 181.32 (t, 2 JC .F = 26.0 Hz). 1 9 F NMR (476 MHz, CDC13 ): 5 -58.29. MS (70 eV): 234 (M+ ); 105 (PhCO+ ); 77 (Ph+ ). 2-Bromo-2,2-difluoro-4’-chloro-acetophenone (2b): Into a 10 ml dichloromethane solution of 2,2-difluoro-1 -(4 ’ -chloro-phenyl)-1 -trimethylsiloxy- ethene lb (200 mg, 0.76 mmol) at -78 °C, was added 0.12 g bromine (0.75 mmol). After warming up to room temperature, 10 ml of sodium sulfite (10 % aqueous solution) was added to remove excess bromine, followed by washing with 5 ml of brine. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by a rotary evaporator. The crude product was purified by a flash chromatography (hexanes as eluent) to give 180 mg product 2b as a white solid, yield 88 %. *H NMR (500 MHz, CDC13 , in ppm): 7.52 (d, J = 7.9 Hz, 2H); 8.09 (d, J = 8.0 Hz, 2H). 1 3 C NMR (90 MHz, CDC13 ): 5 113.28 (t, 'JC -f = 318.9 Hz); 127.39; 129.39 (t, 3 / C -f = 2.5 Hz); 142.03; 181.35 (t, Vc-f = 24.6 Hz). 1 9 F NMR (476 MHz, CDC13 ): 5 -58.61. 2-Bromo-2,2-difluoro-4’-trifluoromethyl-acetophenone (2c): The 2,2- difluoro- 1 -(4’-trifluoromethylphenyl)-1 -trimethylsiloxyethene lc was prepared from 2,2,2-trifluoro-4’-trifluoromethyl-acetophenone (0.6 g, 2.48 mmol), magnesium metal (0.12 g, 5 mmol), and chlorotrimethylsilane (1.08 g, 10 mmol) in 15 ml THF at 0 °C for 90 minutes (similar work-up as mentioned in Chapter 2) in quantitative yield. For lc: *H NMR (500 MHz, CDC13 , in ppm): 0.21 (s, 9H); 7.62 (m, 4H). 1 3 C 83 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. NMR (90 MHz, CDCI3 ): 6 0.09; 124.06 (q, ^c-f = 272.4 Hz); 125.28 (q, J = 4.2 Hz); 125.97 (q, J = 6.2 Hz); 155.20 (t, ^c-f =288.6 H z). 1 9 F NMR (476 MHz, CDC13 ): 6 - 63.18 (s, 3F); -97.50 (d, Z JF .F = 61.1 Hz); -109.50 (d, 2 JF .F = 61.1 Hz). The above prepared lc (100 mg, 0.34 mmol) was reacted with 1.1 eq. bromine in 10 ml dichloromethane at - 78 °C, followed by a similar work-up as before and flash chromatography using pentane as the eluent to give 89.6 mg of the product 2c, in 87 % yield. *H NMR: 6 7.80 (d, J = 8.7 Hz, 2H); 8.26 (d, J = 8.7 Hz, 2H). 1 3 C NMR: 8 113.18 (t, lJc.v = 318.2 Hz); 123.22 (q, X JC .V = 273.2 Hz); 125.95 (q, J = 4.2 Hz); 131.01 (t, J = 2.8 Hz); 131.96; 136.21 (q, J = 33.3 Hz); 180.54 (t, J = 27.7 Hz). 1 9 F NMR: 5 -59.22 (s, 2F); -63.96 (s, 3F). 2-Bromo-2,2-difluoro-/i-hexyl-acetophenone (2d): Similarly, 2,2-difluoro-1- n-hexyl-1 -trimethylsiloxyethene Id [1 9 F NMR: -107.17 ppm (d, 2 Jf-f = B6.7 Hz, IF); -121.54 ppm (d, 2 J f-f - 86.7 Hz, IF)] was reacted with bromine in dichloromethane at - 78 °C to give the product 2d in 90 % yield (determined by 1 9 F NMR, -65.30 ppm). 2-Bromo-2,2-difluoro-4’-methyl-acetophenone (2e): The 2,2-difluoro-l-(4’- methylphenyl)-1 -trimethylsiloxyethene le was prepared from 2,2,2-trifluoro-4’- methyl-acetophenone (1.0 g, 5.33 mmol), magnesium metal (0.27 g, 10.6 mmol), and chlorotrimethylsilane (2.46 g, 22.7 mmol) in 25 ml THF at 0 °C for 2 h (similar work-up as mentioned in Chapter 2). For le: *H NMR (500 MHz, CDCI3, in ppm): 84 permission of the copyright owner. Further reproduction prohibited without permission. 0.17 (s, 9H); 2.33 (s, 3H); 7.15 (d, J = 8.0 Hz, 2H); 7.37 (d, 2H, J = 8.5 Hz). 1 3 C NMR (90 MHz, C D C13 ): 5 -0.04; 21.11; 125.79; 125.85 (t, J = 3.0 Hz); 128.97; 133.36; 137.58 (t, J = 2.0 Hz); 154.73 (t, lJc.F =285.8 Hz). 1 9 F NMR (476 MHz, CDC13 ): 5 -101.2 (d, 2 Jf .f = 70.6 Hz); -112.8 (d, 2 JF .F = 70.6 Hz). The above prepared le (330 mg, 1.36 mmol) was reacted with 1.1 eq. bromine in 10 ml dichloromethane at - 78 °C, followed by similar work-up as before and flash chromatography using pentane as the eluent to give 300 mg product 2e, yield 88 %. JH NMR: 5 2.39 (s, 3H); 7.25 (d, J = 8.5 Hz, 2H); 7.98 (d, J = 8.0 Hz, 2H). 1 3 C NMR: 5 21.70; 113.64 (t, I / c- f = 318.4 Hz); 129.55; 130.65; 131.07; 146.54; 180.90 ( t , 2J C-F = 26.5 Hz). 1 9 F NMR: 8 -57.98. 2-Iodo-2,2-difluoro-4’-chloro-acetophenone (2f): Into a 10 ml of dichloromethane solution of 2,2-difluoro-1 -(4 ’ -chloro-phenyl)-1 - trimethylsiloxyethene If (200 mg, 0.76 mmol) at -78 °C, was added 0.19 g iodine (0.75 mmol). After warming up to room temperature, the reaction mixture was stirred overnight. Then 10 ml of sodium sulfite (10 % aqueous solution) was added to remove excess bromine, followed by washing with 5 ml of brine. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporator. The crude product was purified by a flash chromatography (pentane as the eluent) to give 137 mg of the product 2f as a white solid, yield 60 %. * H NMR (500 MHz, CDC13, in ppm): 7.51 (d, J = 8.9 Hz, 2H); 8.11 (d, J = 8.9 Hz, 2H). 1 3 C NMR (90 MHz, CDCI3 ): 5 95.13 (t, V C-f = 326.4 Hz); 126.67; 129.37; 85 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 132.18 (t, Vc-f = 3.4 Hz); 1412.85; 181.29 (t, VC - f = 23.6 Hz). 1 9 F NMR (476 MHz, CDCls): 8-55.16. 2-Iodo-2,2-difluoro-4’-methyl-acetophenone (2g): The 2,2-difluoro-l-(4’- methylphenyl)-1 -trimethylsiloxyethene lg (400 mg, 1.65 mmol) was reacted with iodine (461 mg, 1.81 mmol) in 10 ml of dichloromethane at - 78 °C for 30 minutes, and then the reaction mixture was stirred at room temperature overnight. After similar work-up as above, flash chromatography using pentane as the eluent afforded 190.5 mg product 2g, yield 39 %. *H NMR: 8 2.46 (s, 3H); 7.32 (d, J = 8.3 Hz, 2H); 8.07 (d, J = 8.3 Hz, 2H). 1 3 C NMR: 8 21.89; 95.79 (t, 7 C -f = 325.5 Hz); 125.78; 129.63; 130.98 (t, J = 2.5 Hz); 146.43; 182.04 (t, VC - F = 22.9 Hz). 1 9 F NMR: 8 - 54.41. Reaction between 2,2-difluoro-l-phenyl-1 -trimethylsiloxyethene (la) and Selectfluor®: Into a acetonitrile solution (20 ml) of Selectfluor® (1.0 g, 2.8 mmol) at - 78 °C, was added 2,2-difluoro-1 -phenyl-1 -trimethylsiloxyethene la (0.51 g, 2.2 mmol) in 5 ml of dichloromethane. Then the reaction mixture was allowed to warm up to 0 °C slowly over a period of 2 h. The reaction mixture was quenched by adding 15 ml of ice water and 20 ml of dichloromethane. The organic phase was separated, followed by drying over magnesium sulfate. After removal of the solvent, flash chromatography using ethyl acetate/hexanes (1:1) as eluent afforded 0.34 g 2,2,2- trifluoroactophenone 2h as the product, yield 89 %. *H NMR: 8 7.56 (t, J = 7.8 Hz, 86 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2H); 7.72 (t, 1H, J = 7.3 Hz); 8.08 (d, J - 8.1 Hz, 2H). 1 3 C NMR: 5 116.67 (q, lJC - F = 291.7 Hz); 129.06; 129.90; 130.06; 135.49; 181.05 (t, 2 JC - f = 35.2 Hz). 1 9 F NMR: 6-71.85. Reaction between 2,2-difluoro-l-(4,-chloro-phenyl)-l-trimethylsiloxy- ethene ( l i ) and Selectfluor®: Similar procedure as above. 2,2,2-trifluoro-4’-chloro- acetophenone 21 was isolated via flash column chromatography (hexanes: ethyl acetate = 7 : 3) in 90 % yield. *H NMR (500 MHz, CDC13 ): 5= 7.53 (d, J= 8.8 Hz, 2H), 8.02 (d, J= 8.8 Hz, 2H); 1 3 C NMR (125 MHz, CDC13 ): 8= 116.51 (q, V(C, F)= 290.4 Hz), 128.21, 129.56, 131.42, 142.47, 179.44 (q, J= 35.9 Hz); 1 9 F NMR (470 MHz, CDC13 ): 8= -72.01. Reaction between 2,2-difluoro-l-(4’-trifluoromethyl-phenyI)-l-trimethyI- siloxyethene (lj) and Selectfluor®: Similar procedure as above. 2,2,2-trifluoro-4’- trifluoromethyl-acetophenone 2j was isolated via distillation in 88 % yield. L H NMR: 8 7.82 (d, J = 8.3 Hz, 2H); 8.19 (t, 1H, J = 8.3 Hz). 1 3 C NMR: 8 116.43 (q, x Jc.f = 290.6 Hz); 117.06 (q, VC -f = 290.6 Hz); 126.17 (q, J = 3.5 Hz); 130.49; 132.63; 136.64 (q, V c- f = 32.9 Hz); 179.80 (q, 2 JC - f = 36.7 Hz). 1 9 F NMR: 8 -63.80; -71.99. Reaction between 2,2-difluoro-1 -«~hexyl-1 -trimethylsiloxyethene (lk) and Selectfluor®: Similar procedure as above, n-hexyl trifluoromethyl ketone 21 was isolated in 94 % yield (determined by 1 9 F NMR, 8 -79.85 ppm). 87 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reaction between 2,2-difluoro-l-(4’-methyl-phenyl)-l-trimethylsiloxy- ethene (11) and Selectfluor®: Similar procedure as above. 2,2,2-trifluoro-4’ -methyl- acetophenone 21 was isolated via flash chromatography (hexanes: ethyl acetate = 7 : 3 as eluent) in 87 % yield. ‘H NMR (500 MHz, CDC13 ): 5= 2.44 (s, 3H), 7.32 (d, J= 8.3 Hz, 2H), 7.96 (d, J= 8.1 Hz, 2H); 1 3 C NMR (125 MHz, CDC13 ): 5= 21.78,116.76 (q, lJ(C, F)= 291.7 Hz), 129.77,130.17 (q ,/= 2 .4 Hz), 130.75, 147.05,180.05 (q, J= 35.3 Hz); 1 9 F NMR (470 MHz, CDC13 ): 5= -71.76. Fluorination of 2,2-difluoro-l-phenyl-l-trimethylsiloxyl-ethene (In) with fluorine (F2): Into a 20 ml acetonitrile solution of 200 mg (0.88 mmol) of 2,2- difluoro- 1 -phenyl-1 -trimethylsiloxyl-ethene la at - 45 °C, was introduced excess F2/N2 (v/v = %). Then the reaction mixture was warmed to room temperature, and 5 ml of ice water was added. The mixture was extracted with ether (10 ml x 2 ), followed by drying over MgSC>4. After removal of the solvent, 209 mg crude trifluoroacetophenone was obtained, yield 83 % determined by 1 9 F NMR (-71.8 ppm). Fluorination of 2,2-difluoro-l-(2’-thienyI)-l-trimethylsiloxyl-ethene (In) with fluorine (F2): Into 20 ml fluorotrichloromethane solution of 150 mg (0.64 mmol) of 2,2-difluoro-1 -(2’-thienyl)-1 -trimethylsiloxyl-ethene In at - 78 °C, was introduced excess F2/N2 (v/v = l A). Then the reaction mixture was warmed to room 88 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. temperature, and 5 ml of ice water was added. The mixture was extracted with ether (10 ml x 2 ), followed by drying over MgSCL. After removal of the solvent, 141 mg crude 2,2-difluoro-2’-acetothienone 2n was obtained, yield 78 % determined by 1 9 F NMR (-72.97 ppm). 1 8 F labeled 2,2,2-trifluoro-l’-acetonaphthone (2o): The experiment was carried out inside a Hot Cell using automated manipulators. Into a 5 cc vial containing 40 mg (0.14 mmol) of 2,2-difluoro-1 -(1’ -naphthnyl)-1 -trimethylsiloxyl- ethene in 0.5 ml dry acetonitrile at - 45 °C, was passed through 60.5 mCi (12:44 pm) amount of 1 8 F2 (generated by cyclotron bombardment of 1 8 C > 2). The reaction mixture was warmed to room temperature for 10 min, and a silica gel TLC was developed using hexane/ethyl acetate (9:1) as solvent. Then the TLC was quickly monitored by a radioactive TLC scanner, which showed that product 2o was formed in about 50 % yield. The whole reaction mixture was injected into the preparative HPLC column using CH3CN/H2O (70:30) as eluent (flow rate 1.5 cc/min). The product (retention time: 11 min) was isolated by HPLC to give 6.7 mCi of radioactivity (13:39 pm). The radiochemical yield 6.7/(60.5* e'°'6 9 3 *1 /2 ) = 16 %, and the reaction yield 16 % *2 = 32 %. 1 8 F labeled 2,2,2-trifluoroacetonaphthone (2o): Similar procedure was used. Due to the volatility of the product, the rather lower radiochemical yield (25 %) was detected for this reaction. 89 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 3.5 References 1. Hiyama, T. Ed. Organofluorine Compounds: Chemistry and Applications, Springer: New York, 2000, p2. 2. Katzenellenbogen, J. A. Journal o f Fluorine Chemistry 2001,109,49. 3. (a) Tamaki, N. Nippon Naika Gakkai Zasshi 2000, 89, 145. (b) Helus, F.; Maier-Borst, W.; Oberdorfer, F. Dev. Nucl. Med. 1992, 22, 131. 4. (a) Okarvi, S. M. Eur. J. Nucl. Med. 2001, 28, 929. (b) Varagnolo, L.; Stokkel, M. P. M.; Mazzi, U.; Pauwels, E. K. J. Nucl. Med. Biol. 2000, 2 7 ,103. 5. Hudlicky, M.; Pavlath, A. E. Chemistry o f Organic Fluorine Compounds II: A Critical Review, ACS Monograph, American Chemical Society: Washington, D. C., 1995, pi 126. 6. Kilboum, M. R. Fluorine-18 Labeling o f Radiopharmaceuticals; National Academy Press: Washington, D. C., 1990. 7. Chi, D. Y.; Kiesewetter, D. O.; Katzenellenbogen, J. A.; Kilboum, M. R.; Welch, M. J. J. Fluorine Chem. 1986, 31, 99. 8. Kawase, M. J. Syn. Org. Chem. Jpn. 2001, 59, 755. 9. Wiedemann, J.; Heiner, T.; Mloston, G.; Prakash, G. K. S.; Olah, G. A. Angew. Chem. Int. Ed. 1998, 37, 820-821. 10. Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Fluorine Chem. 2001,112, 357. 11. Lin, G.; Liu, H.-C.; Wu, F.-C.; Chen, S.-J. J. Chin. Chem. Soc. (Teipei) 1994, 41, 103. 12. Qiu, Z.-M.; Burton, D. J. J. Org. Chem. 1995, 60, 5570. 13. (a) Yamana, M.; Ishihara, T.; Ando, T. Tetrahedron Lett. 1983, 24, 507. (b) Jin, F.; Jiang, B.; Xu, Y. Tetrahedron Lett. 1992, 33, 1221. (c) Brigaud, T.; Doussot, P.; Portella, C. J. Chem. Soc., Chem. Commun. 1994, 2117. (d) Uneyama, K.; Maeda, K.; Kato, T.; Katagiri, T. Tetrahedron Lett. 1998, 39, 3741. (e) Amii, H.; Kobayashi, T.; Hatamoto, Y.; Uneyama, K. Chem. Commun. 1999, 1323. 90 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 14. Purrington, S. T.; Lazaridis, N. V.; Bumgardner, C. L. Tetrahedron Lett. 1986, 2715. 91 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 4 Preparation of Trifluoromethyl- and Difluoromethylsilanes via an Unusual Magnesium Metal Mediated Reductive Tri- and D ifluorom ethylation of Chlorosilanes Using Tri- and Difluoromethyl Sulfides, Sulfoxides and Sulfones Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 4.1 Introduction The introduction o f the trifluoromethyl (CF3 ) and the difluoromethyl (CF2H) groups into organic molecules has gained increasing attention due to the potential use o f trifluoromethylated and difluoromethylated compounds in materials science, medicinal and agrochemistry. 1 Although there are few approaches to achieve this goal, the fluoride induced trifluoromethylation or difluoromethylation with organosilicon reagents (RfSiR.3 , Rf = CF3, CF2H) has been considered a straightforward and reliable m ethod.2 (Trifluoromethyl)trimethylsilane (TM S-CF3), first developed by us2b in 1989 as a nulceophilic trifluoromethylating reagent of choice under milder conditions, is widely used and also works very well w ith both non-enolizable as well as enolizable substrates. Recently developed nucleophilic trifluoromethylation methods are inefficient in the case o f enolizable systems. 3 TM S-CF3 was first prepared by Ruppert et al. in 1984,4 and since then several other procedures have been developed by us and others via both chemical and electrochemical methods during last two decades. 5 However, all o f these methods have some drawbacks. First o f all they all use bromotrifluoromethane (CFsBr) or iodotrifluoromethane (CF3 l)3a as a source for the trifluoromethyl group. Trifluoromethyl halides, particularly CFsBr, in general are ozone depleting and recently their manufacture and use are regulated. Second, these procedures need special apparatus and well-controlled reaction conditions, and the product yields vary widely. Finally, none o f the reported methods are amenable for the preparation of structurally diverse trifluoromethylsilanes. Compared w ith the trifluoromethylation, 93 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. little is known on the nucleophilic difluoromethylation.2f This is mainly due to the lack of general and efficient methods for the preparation of difluoromethylsilanes.6 We now wish to report now a new general and efficient method for the preparation of both trifluoromethylsilanes and difluoromethylsilanes, using an unusual magnesium metal mediated reductive tri- and difluoromethylation of various chlorosilanes. Magnesium metal promoted reactions through electron transfer processes have attracted increasing interest recently, such as C-F bond cleavage of 7 8 o trifluoromethyl ketones (Scheme 1, Eq. I), trifluoroacetates, trifluoromethylimines, />-bis(trifluoromethyl) benzene1 0 and difluoromethyl ketones,1 1 O-silylation of tertiary alcohols,1 2 cross coupling of carbonyl compounds with TMSC1,1 3 and C- acylation of aromatic a,(3-unsaturated carbonyl compounds.1 4 However, the magnesium metal mediated reduction of trifluoromethyl and difluoromethyl sulfones or sulfoxides is still not explored, and we felt that it may exhibit some different interesting aspects as related to the well known reductive C-F bond cleavage of tri- and difluoromethyl ketones.7 ,1 1 In the trifluoromethyl and difluoromethyl sulfones or sulfoxides, due to the strong electron withdrawing effect of CF3 and CF2 H groups, the bond between the pseudohalide and the sulfur atom is sufficiently polarized with the pseudohalide group bearing substantial negative charge. Thus, when the electrons are transferred from magnesium metal to the sulfones and sulfoxides, reductive cleavage of the C-S bond to generate anionic CF3' or CF2H' species was anticipated over the C-F bond cleavage (Scheme 4.1, Eq. II, III). Moreover, the phenyl trifluoromethyl sulfone la or the sulfoxide lb can also be conveniently 94 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. prepared from environmentally benign precursors such as trifluoromethane (CF3H) or trifluoroacetate (Scheme 4.2,1),1 5 and the difluoromethyl phenyl sulfone li can be obtained using known methods (Scheme 4.2, II).1 6 Furthermore, with these sulfones and sufoxides, the bond between sulfur and aromatic carbon is also hard to cleave resulting in the expected regioselective bond fission. With these considerations in mind we have embarked on the study of magnesium mediated reductive trifluoromethylation and difluromethylation of different chlorosilanes and have found a long sought after simple, efficient method for the preparation of diverse trifluoromethylsilanes and difluoromethylsilanes. ( X = F, H ) Scheme 4.1 Mechanistic considerations. 95 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CF3H + ■ PhSSPh + t-B U O K ^ ^ P h S C F 3^ 1 c %&?o (I) CF3COOK + PhSSPIr""1™ O PhSCF3 II J O 1 a MeOH H 20 2/H0Ac 9 CF2CIH + PhSNa--------------► PhSCF2H ► PhSCF2H (II) O 1 p 1i Scheme 4.2 Preparation of phenyl trifluoromethyl sulfide (lc), sulfoxide (lb), sulfone (la) and difluoromethyl phenyl sulfide (Ip), sulfone (II). 4.2 Results and Discussion 1 7 Reaction of sulfone la with 3 equivalents of maganesium metal and the chlorotriethylsilane in DMF solution at 0 °C gave exclusively (trifluoromethyl)triethylsilane, the only product detected by 1 9 F NMR. After work-up and purification, (trifhioromethyl)triethylsilane 3d was isolated in 95% yield. Diphenyl disulfide (PhSSPh) was also collected as a byproduct. TMS-CF3 was also prepared similarly in quantitative conversions (Fig. 4.1). 96 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. — ■- - - - - - - - - - - - - - 1 - - - - - - - - - - - - - - 1 - - - - - - - - - - - - - - 1- - - - - - - - - - - - - - i- - - - - - - - - - - - - - 1- - - - - - - - - - - - - - 1 - - - - - - - - - - - - - - 1- - - - - - - - - - - - - - 1 - - - - - - - - - - - - - - 1- - - - - - - - - - - - - - 1 - - - - - - - - - - - - - - 1 - - - - - - - - - - - - - - 1- - - - - - - - - - - - - - 1 - - - - - - - - - - - - - - 1- - - - - - - - - - - - - - »- - - - - - - - - - - - - - 1 - - - - - - - - - - - - - - 1 - - - - - - - - - - - - - - 1- - - - - - - - - - - - - - 1 - - - - - - - - - - - - - - 1 0 -50 -100 -150 ppm Figure 4.1 1 9 F NMR (CDC13 , CFC13 int.) o f a sample from the reaction mixture o f 1 mmol trifluoromethyl phenyl sulfone (1 9 F NMR: 5 -78.99 ppm), 3 mmol Mg and 4 mmol TMSC1 in 5ml DMF at 0 °C for 30 min. It is clear that the reaction produces TMS-CF3 as the only fluorine containing product (1 9 F NMR: 5 -67.16 ppm). The reaction works equally well for different type of chlorosilanes with tri- and difluoromethyl sulfones or sulfoxides (see Table 4.1). In the case of phenyl trifluoromethyl sulfide lc (entry c), the reaction was sluggish indicating that the fluoroalkyl carbon-sulfur bond is not efficient in accepting the electron from the Mg metal. This was also confirmed by the fact that for the sulfide lk , the Barbier product 3k was produced in high yield without the C-S bond cleavage. In the case of bromodifluoromethyl phenyl sulfone 11 (entry 1), 1,2-bis(trimethylsilyl)-1,1,2,2- tetrafluoroethane 31 was generated as the major product. This indicates that a Barbier-type coupling intermediate [PhS(0)2CF2CF2S(0)2Ph] 4 is presumably formed, which is subsequently transformed into 31 via a similar reductive fluoroalkylation process (see Scheme 4.3, Path A). 97 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 4.1. Preparation of trifluoromethylsilanes and difluoromethylsilanes through Mg° mediated reductive cleavage of C-S bond. / = \ < n) F + R2 — -S i— Cl N ' (O) x / R 3 R 1 \ - S / Mg DMF R2— Si . T . ' \ ■ F + P h S S P h entry sulfur com p ou n d 1 ch lorosilan e 2 tem p eratu re3 tim e (h)b product 3 y ield s (%)° a — 0 M e3SiCI 0 ° C ~ r t . 0 . 5 - 2 M e3 SiC F 3 1 0 0 (83) b < Q f - S - C F 3 M e3SiCI 0°C - r.t. 0 . 5 - 2 M e3 SiC F 3 1 0 0 (8 1 ) c d < Q ^ s - c f 3 O ^ I _CF3 — 0 M e3SiCI Et3SiCI r. t. 0 °C ~ r.t. 4 1.3 M e3 S iC F 3 Et3 SiC F 3 4 5 1 0 0 (9 5 ) e /_ _ \ 0 < L H ' C F 3 Et3SiCI r. t. 0 .5 Et3 SiC F 3 98 f \ _ j - ? r C F* — 0 1 o o o C O 3 C F3 7 5 (57) 9 ^ ^ - S - C F , ^ f c l r. t. 0 .5 c f 3 73 h C M " c f s — 0 (M e3 S i)3SiCI -4 0 °C ~ r.t. 0 .5 (M e3 Si)3 SiC F 3 8 5 (62) i ^ } “ F C F2 H — 0 M e3SiCI 0 °C 1.5 M e3 SiC F 2H 9 0 (76) j k / = r \ 0 \ _ / " ? ' C F2 H 0 \ _ J - S - C F 2 B r Et3SiCI S\/le3SiCl -4 0 °C - r.t. r.t. 3 1 . 0 Et3 S iC F 2H P h S C F 2 Si(C H 3 ) 3 5 9 (5 1 ) 8 6 (85) I r~ z~ \ 0 V > - | - C F 2 Br N — O M e3SiOI ( o O o 0 .5 M e3SiC F 2 C F 2 SiM e3 M e3SiC F 2 SiM e3 7 6 (5 5 ) 18 aThe reaction temperature control is crucial due to the exothermic nature of the reaction. Larger scale reaction normally needs lower temperature. bThe reaction time may vary according to the different reaction scales. cThe yields are determined by 1 9F N M R, and the data in parenthese are isolated yields. 98 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. o - S N a + C F 2 Br2 D ib e n z o -1 8 - crow n - 6 (c a t.) Et20 a />— S ~ C F 2Br m C P B A C H 2 CI2 \\ 0 1 1 M e3 S iC F 2 C F 2 S iM e 3 31 M g I TM SCI DMF O M e3 S iC F 2 C F 2 — S — O ~ . o //^S-C F .B r O 1 ! Mg / TM SCI /==\ o / \ n P ath A Path B h— S - C F 2 S iM e 3 V — 7 O 1 m Mg Mg Mg / TM SCI DMF O I I O / -i :-\ V j ^ m _ c f 2c f 2- s - \ J > v— 7 O O — // S C F 2 S iM e 3 0 6 •C F 2 S iM e3j 7 M e 3 S iC F 2 C F 2 S iM e 3 31 Schem e 4.3 Tw o possible pathways for the formation o f 31 from 11. It is also possible that an alternative Barbier type coupled intermediate lm is formed, which can generate the trimethylsilyldifluoromethyl radical species 7 that 99 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. homo-couples to produce 31. Likelihood of path B was supported by the fact that, under similar reaction conditions using Mg and TMSCI in DMF, both sulfone lm (PhS02CF2 SiMe3 ) and bissulfone In (PhSC^CFaC^SPh) readily produce compound 31 in good yields (Scheme 4.4). PhSCF2SiMe3 3k mCPBA O PhSCF2SiMe3 O 1m (I) PhSCF2H- O ll PhSCF2SiMe3 n z J 0 1m O O II ii PhSCF2SPh ii ii o o 1n NaOH H ,0 H20 Mg/TMSCI DMF PhSCF2SPh it O 70 % Me3SiCF2CF2SiMe3 3) 79% 2'“'2 O O II II PhSCF2SPh (II) it O O 1n 25 % Me3SiCF2SiMe3 (IT T ) 3m 8 % Scheme 4.4 Formation of 31 from lm or In. It should also be mentioned that the use of several reducing metals such as zinc, aluminum, indium, sodium and lithium were explored to replace magnesium as 100 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. the reducing agent, among which only zinc worked but only with low yield of the products (-30 %). Other reducing or electron-donating reagents, such as samarium iodide (Sm^) and tetrakis(dimethylamono)ethylene, were also investigated to no avail. Attempts to improve the reactivity of phenyl trifluoromethyl sulfide lc via electrochemistry using magnesium or zinc rod as the sacrificial anode, and platinum as the cathode in DMF, were also not successful. DMF is not the only solvent required for this reaction. Other solvents such as THF can also be used for the reaction, although it needs prolonged reaction time. This indicates there is no need to invoke CF37DMF adduct1 5 ® as the intermediate for these reactions. Concerning the mechanism, we propose that a single electron transfer from magnesium metal to sulfones or sulfoxides facilitate a reductive cleavage of the C-S bond to form anionic tri- and difluoromethyl species and a sulfur-containg radical species (see Scheme 4.5). The isolation of PhSSPh as a byproduct further confirms the possibility of the sulfur radical species. This mechanism is also supported by the fact that, when we used 2,2,2-trifluoroethyl phenyl sulfone [PhS(0)2CH2CF3] lo as the reactant with Mg and TMSCI under the similar reaction conditions, 1,1- difluoroethene was produced readily. Obviously, 1,1 -difluoroethene was obtained through the P-elimination of the fluoride (F‘) from the in situ generated anionic species (CF3CH2 ) from lo via a smilar mechanism as described above (Scheme 4.6). Scheme 6 also shows that in the case of 2,2,2-trifluoroethyl phenyl sulfone, sulfoxide and sulfide, the order of reactivity is sulfone > sufoxide > sulfide. 101 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. P h S S P h M g/TM SCI '-'iSxSi 11 2 R s / R Scheme 4.5 Proposed mechanism. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. o S N a + C F 3C H 2 I o l 94% O 04 o 86% C H 2C F 3 C H 2C F 3 - D M F, 3 5 ° C , 2h m C P B A ■ f V s - s - c h 2c f 3 95% C H 2CI2> 0 ° C , 1h H20 2 / H O A c 9 0 UC , 2 h 1 o y ' N o R e a c tio n M g/T M SC I D M F, R T • < a fte r 8 h r, 20 % c o n v e r s io n ' to C F 2= C H 2 a n d T M S F N O M e3S iC H 2C F 3 M 0 0 % c o n v e r s io n to C H 2= C F 2 a n d T M S F in 1 5 m in / t m s - c i . ------- V F ^.-E lim ination J © h ^ - ^ - f H F > = < + T M S -F H F 19; F NM R: - 8 1 .9 0 p p m , m - 1 5 8 p p m Scheme 4.6 Different reactivities of phenyl 2,2,2-trifluoroethyl sulfide, sulfoxide and sulfone under similar reaction conditions. It should be also mentioned that, methyl trifluoromethyl sulfone (CH 3 SO 2 CF 3) also reacts with magnesium metal and TMSC1 in DM F to produce TM S-CF 3 in moderate yields (~ 40 % over a period o f 20 hours at room temperature). However, 103 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. the reaction appears to be sluggish. This indicates that the aromatic ring conjugation in la is important to facilitate the initial electron transfer process. The reductive fluoroalkylation chemistry was also attempted with other electrophiles such as aldehydes, ketones, allyl bromide, benzyl chloride, or tributyltin chloride with no success. Even tributyl tin hydride and allyltrimethylsilane showed no reactivity. The reason for such a behavior is not clear. It is well known that the phenyl trifluoromethyl sulfone la and sulfoxide lb 1 8 can be readily prepared from trifluoromethane (manufactured from methane ) and diphenyl disulfide.1 9 Since in our fluoroalkylation process, diphenyl disulfide is produced as a reductive byproduct, the presently developed method provides a novel and useful “pseudo-catalytic” pathway for the production of (trifluoromethyl)silanes from trifluoromethane and chlorosilanes (see Scheme 4.7). 104 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. C H O cf3h TMS-CF. [0] PhSK + PhSSPh + PhSSPh BuOK S— C F - r D M F S—CF. DM F S—CF. [0] [0 ] Scheme 4.7 Possible catalytic pathway for the preparation of TMS-CF3 from CF3H. It should be mentioned that, some of these new silane compounds are very useful as CF3 or CF2H transfer reagent. Scheme 8 shows two examples of these applications: silane 2h transferred difluoromethyl group into benzaldehyde in 8 0 % yeld, and silane 2k transferred trifluoromethyl group via an CF3 Cu intermediate followed by oxidative addition. (1) KF (cat.) Et3 Si-CF2H + < 5, — CHO 3j DMF, 100°C 90 min (2) H30 + OH 80 % 105 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Phi, Cul, KF DMF, 80°C 71 % 3h Scheme 4.8 Di- and trifluoromethylations with new silanes 3j and 3h. 4.3 Conclusion In conclusion, we have developed a versatile new method for the preparation of a number of (trifluoromethyl)silanes and (difluoromethyl)silanes via a magnesium metal mediated reductive S-C bond cleavage process of trifluoromethyl and difluoromethyl sulfones, sulfoxides and sulfides. The method can be considered catalytic with respect to the sulfur compounds since the starting phenyl trifluoromethyl sulfones, sulfoxides and sulfides are themselves readily prepared using environmentally benign trifluoromethane and diphenyl disulfide. 4.4 Experimental section Unless otherwise mentioned, all the other reagents were purchased from commercial sources. Trifluoromethyl phenyl sulfone and sulfoxide were prepared General 106 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. from trifluoromethyl phenyl sulfide, which was obtained either from Aldrich or prepared from fluoroform and PhSSPh.1 5 Mg turnings were used without any special pretreatment. DMF was distilled over calcium hydride and stored over activated molecular sieves. All the reactions were carried out using Schlenk equipment, and the reactions were monitored by 1 9 F NMR periodically. !H, 1 3C, 1 9 F and 2 9 Si NMR spectra were recorded on 500 and 360 MHz superconducting NMR spectrometers. NMR chemical shifts were determined relative to internal (CHs^Si (TMS) at 8 0.0 or to the signal of a residual protonated solvent: CDCI3 8 7.26. 1 3 C NMR 1 T chemical shifts were determined relative to internal TMS at 8 0.0 or to the C signal of solvent: CDCI3 8 77.0. 1 9 F NMR chemical shifts were determined relative to internal CFCI3 at 8 0.0. 2 9 Si NMR chemical shifts were determined relative to internal TMS at 8 0.0. IR spectra were obtained on a Perkin-Elmer FTIR Spectrometer 2000. GC-MS were recorded on Hewlett Packard 5890 Gas Chromatograph with a Hewlett Packard 5971 Mass Selective Detector. High- resolution mass data of low boiling compounds were recorded on an Agilent 6890 GC chromatograph with micromass GCT (time of flight). Other high-resolution mass data were recorded on a VG 7070 high-resolution mass spectrometer. Preparation of sulfides, sulfoxides and sulfones Phenyl trifluoromethyl sulfide (lc)1 5 a : Into a 1 liter three-neck round bottom flask equipped with a dry ice condenser, a magnetic stirring bar and two rubber 107 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. septa, was added 85 g ( 0.39 mol) of diphenyl disulfide and 60 g (0.53 mol) of potassium tert-butoxide in 600 mL dry DMF. The reaction mixture was cooled down to -40 - -50 °C using dry ice /ethylene glycol/acetone bath, followed by bubbling of 70 g trifluoromethane via a needle slowly over a 4 h period. Then the flask was slowly warmed to room temperature over a period of 5 h, and the mixture was stirred overnight. Crude product PI1 SCF3 and DMF solvent were distilled out of reaction mixture under vacuum. Then the distillate was poured into 600 mL water, and extracted with ethyl acetate (200 mL x 2). The combined organic phase was washed with water and then dried over magnesium sulfate. Fractional distillation using a 30 cm long column gave 54.28 g of the product lc as a colorless liquid, yield 81 % based on diphenyl disulfide used. Boiling point: 55°C/30 mmHg. *H NMR (500 MHz, CDCI3 ): 6 7.40 (t, J - 7.8 Hz, 2H); 7.47 (t, J = 7.4 Hz, 1H); 7.65 (d, J = 7.8 Hz, 2H). 1 3 C NMR (125 MHz, CDC13 ): 5 124.4 (q); 127.7 (q, J = 309 Hz); 129.47; 130.81; 136.37. 1 9 F NMR (470 MHz, CDC13 ): 5 -43.3. Phenyl trifluoromethyl sufoxide (lb )1 5 d : Into the mixture of 7.8 g (45 mmol) of mCPBA in 170 mL dry CH2CI2 at 0 °C, was added 4.79 g (26.9 mmol) of phenyl trifluoromethyl sulfide lc. The reaction mixture was stirred at 0 °C for 5 h, and continued at room temperature for another 16 h. The white precipitate produced was filtered and the filtrate was evaporated to obtain a crude product that was purified by silica gel column chromatography (hexanes/ethyl acetate = 30/1) to give 3.0 g of product lb as a colorless liquid, yield 58 %. *H NMR (500 MHz, CDCI3): 6 7.63 (t, 108 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. J = 7.8 Hz, 2 H); 7.69 (t, J = 7.5 Hz, 1H); 7.81 (d, J = 7.9 Hz, 2H). 1 9 F NMR (470 MHz, CDCls): 8-75.1. Phenyl trifluoromethyl sulfone (la): The mixture of 5 g (28 mmol) phenyl trifluoromethyl sulfide lc and 30 mL 30 % aqueous hydrogen peroxide in 50 mL acetic acid, was heated at 90 °C for 21 h. After the reaction, 40 mL brine was added and the reaction mixture was extracted with dichloromethane (50 mL x 2). The combined organic phase was washed with cold 10 % NaOH aqueous solution twice, followed by washing with brine and water successively. Then the organic phase was dried over anhydrous MgSCL, and the solvent was removed to give the pure sulfone product la 5.28 g (yield: 90 %) as a colorless liquid. The compound can be used without further purification. 'H NMR (500 MHz, CDCI3 ): 8 7.69 (t, J = 7.7 Hz, 2 H); 7.86 (t, J = 7.6 Hz, 1H); 8.05 (d, J = 7.8 Hz, 2H). 1 9 F NMR (470 MHz, CDC13 ): 8-78.9. Phenyl difluoromethyl sulfide (Ip)1 6 : Under an argon atmosphere, into one liter three-neck flask equipped with a dry ice condenser, dropping funnel, a stirring bar and a rubber septum, was added 65 g (2.82 mol) of sodium pieces. At 0 °C and under argon bypass, 600 mL methanol was slowly added into the flask with caution. The mixture was stirred for another 8 h until all the sodium had dissolved, then 100 g (0.91 mol) PhSH was added at 0 °C. The reaction mixture was stirred at room temperature for 3 h and subsequently cooled down to - 25 °C. The 109 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. chlorodifluoromethane gas (102 g) was bubbled in slowly via a needle over a 7 h period, followed by brisk stirring overnight. The reaction mixture was quenched by the addition of 30 mL ice water, and most methanol solvent and the CH3OCF2 H byproduct were removed through fractional distillation. The residue was washed with 100 mL water, and extracted with dichloromethane (50 mL x3). Combined organic phase was washed with 5 % NaOH three times, and then washed with water (30 mL x 3). After drying over MgSCL, the organic mixture was fractionally distilled to afford 61.2 g product Ip as a colorless liquid, yield 42 %. *H NMR (500 MHz, CDCI3): 6 6.83 (t, J - 56.8 Hz, 1 H); 7.41 (m, 3H); 7.59 (d, J = 7.8 Hz, 2H). 1 9 F NMR (470 MHz, CDCI3): 6 -91.9 (d, J = 57.2 Hz). 1 3 C NMR (CDC13, in ppm): S 121.0 (td, J = 276.6 Hz, J = 3.1 Hz); 126.1 (t, J = 3.1 Hz); 129.4; 129.8; 135.3. Compound Ip can also be prepared by reacting PhSCF2SiMe3 (3k) with tetrabutylammonium fluoride (TBAF) in wet THF solution. Phenyl difluoromethyl sulfone (li): The mixture of 30 g (0.19 mol) of phenyl difluoromethyl sulfide Ip and 64 mL of 30 % aqueous hydrogen peroxide in 80 mL acetic acid, was heated at 90 °C for 20 h. After 150 mL aqueous brine solution was added, the reaction mixture was extracted with ether (60 mL x 3). The combined organic phase was washed with 10 % NaHCC> 3 aqueous solution (100 mL x 5), followed by washing with Na2SC> 3 aqueous solution (20 mL x 3) and water (20 mL x 3) successively. Then the organic phase was dried over anhydrous MgSCL, and the 110 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. solvent was removed to give pure product 36.22 g (yield 98 %) li as colorless liquid. The compound can be used without further purification. !H NMR (500 MHz, CDC13 ): 5 6.20 (t, J - 53.5 Hz, 1 H); 7.66 (t, J = 7.8 Hz, 2H); 7.81 (t, J = 7.6 Hz, 1H); 8.00 (d, J = 7.9 Hz, 2H). 1 9 F NMR (470 MHz, CDC13 ): 8 -122.2 (d, J - 53.4 Hz). Phenyl bromodifluoromethyl sulfide (lk)20: PhSNa (6.0 g, 45 mmol) was reacted with CF2 Br2 (22 g, 100 mmol) in 100 mL ether in the presence of 0.067 g dibenzo-18-crown-6 at room temperature. The reaction mixture was stirred for 15 h, followed by the addition of water. The separated ether phase was dried over MgSCL, and the solvent removed to give 5.84 g of the crude product. Further purification by fractional distillation afforded 5.01 g (yield 46 %) of product lk as a colorless liquid. *H NMR (360 MHz, CDCI3 ): 6 7.43 (t, J = 7.9 Hz, 2H); 7.51 (t, J = 7.8 Hz, 1H); 7.65 (d, J = 7.8 Hz, 2H). 1 9 F NMR (338 MHz, CDC13 ): 5 -22.6. Phenyl bromodifluoromethyl sulfone (ll)21: Phenyl bromodifluoromethyl sulfide lq (37.0 g, 0.15 mol) was mixed with mCPBA (4 eq.) in 500 mL dichloromethane at 0 °C. The mixture was stirred at room temperature over 30 h. The reaction mixture was washed with cold Na2SC> 3 solution (100 mL x 3). The organic phase was separated, washed with brine (100 mL x 3) and water (100 mL). After drying over MgSC> 4 and solvent removal, 42.1 g of product 11 was obtained 111 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. (quantitative conversion). *H NMR showed its purity to be > 98 %. *H NMR (360 MHz, CDCI3): 8 7.67 (t, J = 7.7 Hz, 2H); 7.84 (t, J - 7.8 Hz, 1H); 8.04 (d, J = 7.8 Hz, 2H). 1 9 F NMR (338 MHz, CDCI3 ): 8 -58.0. 2.2.2-TrifluoroethyI phenyl sulfide (lq)22: Into a DMF solution (260 mL) of PhSNa (23.76 g, 0.18 mol), was added CF3CH2I (31.5 g, 0.15 mol) drop-wise at room temperature. After addition, the reaction mixture was warmed up to 35 °C for 20 h. After ether (600 mL) was added, the reaction mixture was washed with 500 mL water. And the organic phase was washed with 200 mL NaHCCL aqueous solution and 100 mL water, dried over MgSCL, and the solvent was removed. The crude product was passed through a silica gel column (5 cm wide, 15 cm long) using pentane as eluent, 25.28 g of the product yielded (100 % conversion). Fractional distillation afforded 21.46 g of pure product lq as a colorless liquid, b.p. 39 - 40 °C/7 rnmHg. *H NMR (360 MHz, CDCI3): 8 3.42 (q, J = 9.5 Hz, 2H); 7.26 - 7.33 (m, 3H); 7.48 (d, J = 7.0 Hz, 2H). 1 3 C NMR (90 MHz, CDC13 ): 8 38.1 (q, J = 33.1 Hz); 125.4 (q, J = 276.8 Hz); 128.0; 129.2; 131.8; 133.7. 1 9 F NMR (338 MHz, CDCI3): 8 -66.8 (t, J = 9.6 Hz). 2.2.2-Trifluoroethyl phenyl sulfoxide (lr)23: Into 12 g (50-60 tech. purity) mCPBA dissolved in 200 mL dichloromethane, was added at 0 °C PhSCH2CF3 (10 g, 52 mmol) drop-wise. The reaction mixture was stirred at 0 °C for 2 h and then was 112 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. neutralized with cold N aH C 0 3 aqueous solution. The organic phase was washed w ith water, and then dried over MgSC>4 . After solvent removal, crude product lr (10.15 g) was obtained. Recrystallization from hexane afforded 8.46 g (78 % yield) o f pure crystalline product, m.p. 78-79 °C. *H NM R (360 MHz, CDCI3): 8 3.35-3.64 (m, 2H); 7.55 - 7.75 (m, 5H). 1 3 C N M R (90 MHz, CDC13): 8 61.3 (q); 123.1 (q); 123.9; 129.8; 132.2; 142.7. 1 9 F N M R (338 MHz, CDCI3): 8 -61.6 (t, J = 9.6 Hz). 2,2,2-Trifluoroethyl phenyl sulfone (lo): Compound lq (2 g) was oxidized with 10 mL 30 % H 2 O 2 in 15 m L acetic acid at 90 °C for 4h. After usual neutralization and work-up, 2 . 0 1 g product lo was obtained as a white solid, yield 8 6 %, m.p. 109-110 °C. *H NM R (360 MHz, CDCI3 ): 8 3.93 (q, 2H); 7.62 (t, 2H); 7.74 (t, 1H), 7.98 (d, 2H). 1 3 C N M R (90 MHz, CDC13): 5 58.4 (q, J = 30.5 Hz); 121.1 (q, J = 278.8 Hz); 128.5; 129.5; 134.8; 138.4. 1 9 F NM R (338 MHz, CDCI3): 5 -61.7 (t, J = 9.4 Hz). Bis(benzenesulfonyl)difluoromethane (In )24: A m ixture o f 600 m g (3.2 mmol) o f phenyl difluoromethyl sulfone (li), 6.0 m l CH 2 CI2 , 6.0 m L 50 % aqueous NaOH solution, and 120 mg (0.3 mmol) o f the phase transfer catalyst Aliquat 336® {CH3N[(CH 2 )7 CH 3 ]3 Cl}was stirred vigorously for 7 days. The reaction m ixture was poured into 20 mL 5 N HC1. After extraction w ith CH 2CI2 (10 m L x 3), the combined organic phase was dried over MgSC>4 and the solvent was evaporated. The 113 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. obtained crude product difluoro(phenylsulfonyl)methyl phenyl sulfide (PhS(0 )2CF2SPh, 1 9 F: a -78.9 ppm) was further oxidized with 10 mL 30 % H2O2 in 20 mL HOAc at 90 °C for 2 h. The reaction mixture was extracted with dichloromethane (20 mL x 3), and the combined organic phase was washed with NaHCC> 3 solution (30 mL x 3), Na2SC > 3 solution, brine consecutively. After drying over MgSCL, the solvent was evaporated to give 750 mg crude product. The product was passed through a short silica gel column (hexanes:ethyl acetate = 1:1), the resultant solid product was recrystallized from hexanes/ethyl acetate (1:1) to give pure product In 330 mg (yield 62 %), m.p. 112-113 °C. *H NMR (500 MHZ, CDCI3): 5 7.65 (t, 4H); 7.81 (t, 2H); 8.05 (d, 4H). 1 3 C NMR (125 MHz, CDCI3 ): 6 118.5 (t,J = 335.7 Hz); 129.5; 131.1; 132.9; 136.4. 1 9 F NMR (470 MHz, CDC13 ): 6 - 102.5 (t, J = 9.4 Hz). MS: 333 (M+ +l); 141; 125; 77; 51. Phenyl (trimethylsilyl)difluoromethyl sulfone (lm): Phenyl (trimethylsilyl)- difluoromethyl sulfide (3k) (2.0 g, 8.6 mmol) was oxidized with mCPBA (9.0 mmol) in 20 mL CH2CI2 initially at 0 °C, followed by stirring at room temperature overnight. After filtration, the filtrate was washed with Na2SC> 3 solution (10 mL x 3), NaHCC> 3 solution (10 mL x 2) and water sequentially. After drying over MgSCL and solvent removal, the crude product was distilled to afford 1.2 g (51 % yield) product lm as a colorless liquid, b.p.112 ~ 114 °C / 1 Torr. *H NMR (500 MHz, CDC13 ): 8 0.44 (s, 9H); 7.61 (t, 2H); 7.74 (t, 1H); 7.95 (d, 2H). 1 9 F NMR (470 MHz, CDC13 ): 8 114 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. -112.9. HRMS (DCI/NH3): m/z calculated for CioH1 8 F2 N 0 2 SSi (M+NH4 + ) 282.0795, found 282.0787. Methyl trifluoromethyl sulfone (Is)25: An Et2 0 solution of MeLi (18 mmol) was slowly added into a ether solution of triflic anhydride (17.7 mmol) at - 78 °C for 30 min. The mixture was further stirred for another 1 h at - 78 °C followed by warming to room temperature. The reaction mixture was washed with brine and water consecutively. After the organic phase was dried over M gS04, the product was isolated by fractional distillation to give 0.84 g product Is as colorless liquid, yield 32 %. 'H (360 MHz, CDCI3 ): a 3.13 (b, 3H). 1 9 F (338 MHz, CDC13 ): h -80.6. Preparation of trifluoromethyl and difluoromethylsilanes (Trifluoromethyl)trimethylsilane (3a): Into a 250 mL dry Schlenk flask under an argon atmosphere, was added 1.14 g Mg turnings (47.5 mmol) and 11.8 g TMSC1 (109 mmol) in 50 mL DMF at 0 °C. After stirring for 2 min, 4.62 g (23.8 mmol) of lb in 5 mL DMF was added slowly via a syringe. The reaction mixture was stirred at room temperature at 0 °C for 30 min, and then at room temperature for another 1.5 h until all the starting material was transformed into product 3a (monitored by 1 9 F NMR). All the low boiling fractions were collected under vacuum 115 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. into a trap (cooled in liquid nitrogen), warmed up to room temperature and then washed with ice water (50 mL x 3). After quick drying over activated molecular sieves, the organic mixture was fractionally distilled using a 30-cm long column to give 2.73 g (81 % yield) product 3a, b.p. 53 - 55 °C (lit. b.p. 55 - 55.5 °C).2 d *H NMR (360 MHz, CDC13 ): 5 0.25 (s, 9H, CH3 ). 1 3 C NMR (90 MHz, CDC13 ): 8 -5.3 (s, CH3 ); 131.7 (q, ' j C -F - 321.8 Hz, CF3 ). 1 9 F NMR (338 MHz, CDC13 ): 8 -67.2. Similarly, compound la was used to prepare 3a in 82 % isolated yield. Compound lc also could be used to prepare 3a, but the reaction was found to be sluggish. (Trifluoromethyl)triethylsilane (3d): Into a flame-dried Schlenk flask containing 1.03 g (43 mmol) magnesium turnings and 30 mL DMF under argon, was added 3.0 g (14 mmol) of trifluoromethyl phenyl sulfone la at 0 °C. After stirring for 5 minutes, 6.45 g (43 mmol) triethylsilyl chloride was added dropwise via syringe. The color of the reaction mixture slowly turned yellow. The progress of the reaction was monitored by 1 9 F periodically. After lh, the mixture was slowly warmed to room temperature over 20 minutes period and the reaction mixture was washed with 50 mL ice water. After removing the excess Mg, the solution was extracted with pentane (30 mL x 3). The pentane phase was washed carefully with cold 98% sulfuric acid (30 mL x 4) to remove most of the siloxane and silanol. Subsequently, the organic phase was washed with cold water (30 mL x 2), saturated aqueous NaHC03 solution (30 mL x 2), water (20 mL x 2) and dried over anhydrous 116 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. magnesium sulfate. The solvent was removed under vacuum (~100 Torr), and the resulting crude product also contains PhSSPh as a byproduct (characterized by both GC-MS and NMR). The crude product was carefully purified by small scale fractional distillation to give 2.48 g (95% yield) (trifluoromethyl)triethylsilane 3d, b.p. = 56 - 58 °C/60 Torr (lit. b.p. 52 - 54 °C/10 Torr).2 6 GC-MS showed its purity was higher than 96 %. *H NMR (500 MHz, CDC13 ): 6 0.79 (q, VH - h = 7.9 Hz, 6H); 1.04 (t, 3J h - h = 7.9 Hz, 9H). 1 3 C NMR (125 MHz, CDC13 ): 5 0.79 (s, CH2 ); 6.37 (s, CH3 ); 132.19 (q, 7 C -F = 323.5 Hz, CF3 ). 1 9 F NMR (470 MHz, CDC13 ): -61.30. 2 9Si NMR (99 MHz, CDC13 ): 6 7.74 (q, VS i- F = 32.0 Hz). GC-MS (m/z): 184 (M+ ), 155 (M-Et), 115(Et3Si+ ). (Trifluoromethyl)f-butyldimethylsilane (3f): Into a dry 250 mL Schlenk flask under an argon atmosphere, was added 5.14 g Mg turnings (214 mmol) and 32.3 g (214 mmol) t-butyldimethylsilyl chloride in 150 mL DMF at -30 °C. Subsequently, 15.0 g ( 71.4 mmol) of la in 10 mL DMF was added slowly via a syringe. The reaction mixture was stirred at room temperature at -30 °C for 1 h, and then at room temperature for another 2 h until all the starting material was consumed (1 9 F NMR showed that the conversion of 3f was 75 %). The reaction mixture was washed with ice water, followed by extraction with pentane (30 mL x 4 ). Combined pentane phase was further washed carefully with cold 98 % sulfuric acid (20 mL x 4) to remove most of the siloxane and silanol. Then the pentane phase was washed with cold NaHC03 aqueous solution three times until pH paper indicated neutral pH. The 117 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. pentane phase was dried over MgS04 and solvent evaporated to give a crude product that was fractionally distilled to give 7.46 g colorless liquid (95 °C/410 mmHg), which turned to a transparent crystalline solid at room temperature (m.p. 52 ~ 54 °C, sublimes), yield 57 %. ’H NMR (500 MHz, CDC13 ): 5 0.20 (s, 6H); 0.99 (s, 9H). 1 3 C NMR (125 MHz, CDC13 ): 5 -8.8; 16.0; 26.0; 132.0 (q, 7 C - f = 323.8 Hz, CF3 ). 1 9 F NMR (470 MHz, CDC13 ): 6 -61.8. 2 9Si NMR (99 MHz, CDC13 ): 5 8.4 (q, V S i-F = 32.8 Hz). GC-MS (m/z): 184 (M+ ), 127 (Wf-'Bu), 115 (M+ -CF3), 99 (M+-CF3-CH3 ), 57 (®u+ ). High-resolution GC-MS (El): m/z calculated for C7 HisF3 Si (M+ ) 184.0895, found 184.0943. Tris(trimethylsilyl)trifluoromethylsilane (3h): Procedure was similar as above examples: Into 2 g (83 mmol) Mg turnings and lg (4.76 mmol) la in 20 mL DMF at - 40 °C, was slowly added 3 g (10.6 mmol) tris(timethylsilyl)silyl chloride in 10 mL DMF. The reaction mixture was then stirred at - 40 °C for 1 h and between - 40 °C ~ - 20 °C for another 2 h, until all of la were consumed (monitored by 1 9 F NMR). The reaction mixture was washed with ice water, followed by extraction with pentane (20 mL x 4). The pentane phase was washed with cold 98 % sulfuric acid (10 mL x 3) to remove most of the siloxane and silanol, washed with cold NaHC03 aqueous solution three times until pH paper indicated neutral pH. After drying over MgSCL and solvent removal, the crude product was further purified by silica gel chromatography (pentane as eluent) to give 0.93 g (62 % yield) solid product 3h that sublimes at 50 °C/10 Torr. *H NMR (500 MHz, CDC13 ): 5 0.26 (s, 27 H). 1 3 C NMR 118 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. (125 MHz, CDCI3): 5 0.5 (s, CH3 ); 136.8 (q, ‘Jc-f =328.0 Hz, CF3 ). 1 9 F NMR (470 MHz, CDC13 ): 5 -41.4. 29Si NMR (99 MHz, CDC13 ): 8 -66.8 (q, V S i-F = 27.5 Hz, 1 Si); -12.5 (q, 3 / si-F = 4.6 Hz, 3Si). GC-MS (m/z): 316 (M*), 247 [(Me3Si)3Si+ ], 69 (CF3 + ). High-resolution GC-MS (E l): m/z calculated for CioH27p3 Si4 (M+ )316.1142, found 316.1110. (Difluoromethyl)trimethylsilane (3i): Into a mixture of 4.8 g (200 mmol) Mg turnings, 28.93 g (266 mmol) TMS Cl and 100 mL DMF at 0 °C, was added 12.80 g (66.7 mmol) difluoromethyl phenyl sulfone (li) in 10 mL DMF slowly. The reaction mixture was stirred at 0 °C for 90 min until 1 9 F NMR showed that all the li was consumed. All the low boiling species was separated out by bulb to bulb distillation, followed by washing with ice water (30 mL x 3) and drying over molecular sieve. Fractional distillation (using 30-cm long distillation column) afforded 4.96 g product, b.p. 52 °C (lit. b.p. 50 °C)2c, yield 76 %. *H NMR (360 MHz, CDC13 ): 8 0.15 (s, 9H); 5.82 (t, VH - f = 46.5 Hz, 1H). 1 3 C NMR (90 MHz, CDC13 ): 8 -5.4 (t, 3 JC . F- 2.8 Hz); 123.9 (t, lJc.F = 254.7 Hz). 1 9 F NMR (338 MHz, CDC13 ): 8 -140.1 (d, VF .H =46.8 Hz). (Difluoromethyl)triethylsilane (3j): Into a mixture of 5g (26 mmol) difluoromethyl phenyl sulfone (li), 1.9 g Mg turnings (78 mmol) and 150 mL DMF at - 40 °C, was slowly added 11.8 g (78 mmol) chlorotriethylsilane. The reaction mixture was then stirred at - 40 °C to 10 °C during a 4 h period until 1 9 F NMR 119 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. indicated all of li was consumed. Similar work-up as above and fractional distillation gave 2.2 g product 3j,2 7 b.p. 71 °C/56 mmHg, yield 51 %. * 1 1 NMR (500 MHz, CDC13 ): 8 0.72 (q, 3/ H - h = 8.0 Hz, 6H); 1.02 (t, V H -h = 8.0 Hz, 9H); 5.95 (t, V h-f = 46.0 Hz, 1H). ,3C NMR (125 MHz, CDC13 ): 6 0.6 (s, CH2 ); 6.7 (s, CH3 ); 124.3 (t, X JC -f = 254.8 Hz). 1 9 F NMR (470 MHz, CDCI3): 5 -137.6 (d, 2 J F-h = 45.8 Hz). 2 9Si NMR (99 MHz, CDCI3 ): 8 3.3 (t, 2 J si-f = 24.8 Hz). GC-MS {m /z): 166 (M+ ); 115 (Et3Si+ ); 51 (CF2 H+ ). 1,2-Bis(trimethylsilyl)-l ,1,2,2-tetrafluoroethane (31): Into a mixture of 0.42 g (17.5 mmol) of Mg turnings, 1.92 g (17.7 mmol) of TMSC1 and 10 mL DMF, was added 1.60 g (5.9 mmol) of bromodifluoromethyl phenyl sulfone 11. The reaction mixture was stirred at 0 °C for 30 min, and at room temperature for another 30 min until 1 9 F NMR showed all of 1 1 was consumed (the yield of 31 was 76 % and by product TMSCF2 TMS, 18 % by 1 9 F NMR analysis). The reaction mixture was washed with ice water followed by extraction with pentane (10 mL x 4). The pentane phase was washed with cold 98 % sulfuric acid (10 mL x 3) to remove most of the siloxane and silanol. Then the pentane solution was washed with cold NaHCCb aqueous solution three times until the pH paper indicated neutral pH. After drying over MgSCL and solvent removal, the crude product was further purified by fractional distillation and then recrystallization at -20 °C to give 0.40 g crystalline product 31, m.p. 40 ~ 42 °C, yield 55 %. *H NMR (500 MHz, CDCI3): 8 0.24 (s, 120 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 18H). 1 3 C NM R (125 MHz, CDC13 ): 5 -4.0 (m, CH3 ); 126.6 (tt, X JC -F = 265.0 Hz; 2 JC . F = 45.9 Hz). 1 9 F NM R (470 MHz, CDCI3): 6 -122.3. Compound 1 1 was also prepared by using PhS 0 2 CF 2 0 2 SPh or PI1SO 2 CF2 TMS as the starting material. Phenyl (trimethylsilyl)difluoromethyl sulfide (3k): Into a mixture o f 0.22 g (9.2 mmol) M g turnings, 1.99 g (18.3 mmol) o f TMSC1 and 20 m l DMF at room temperature, was added 1.1 g (4.6 mmol) bromodifluoromethyl phenyl sulfide lk. The reaction was stirred at room temperature for another 1 h. Excess TMSC1 was removed under vacuum ( - 1 0 mmHg). The residue was w ashed with ice water and then extracted with dichloromethane (20 mL x 3). The organic phase was further washed with brine and water successively, and dried over MgSCL. After solvent removal, the crude product was further purified by silica gel chromatography (pentane as eluent) to give 905 m g (85 % yield) product 3k as colorless liquid, b.p. 86-87 °C/4 Torr. ’H NM R (500 MHz, CDC13): 8 0.25 (s, 9H); 7.37 (m, 3H); 7.59 (d, 2H). 1 3 C NM R (125 MHz, CDCI3): 8 -4.2; 126.3 (t, 3 / C-f = 4.1 Hz); 128.8; 129.3; 134.0 (t, '/c-f = 300.1 Hz); 136.2. 1 9 F NM R (470 M Hz, CDC13): 8 -88.1 (s). 29Si N M R (99 M Hz, CDCI3): 7.7 (t, 2 JS ff = 31.28 Hz). IR (neat): 3064; 2965; 2904; 1884; 1585; 1475; 1441; 1414; 1307; 1255; 1076; 1025; 962; 884; 850; 825; 744; 703; 690; 631; 607; 496 cm '1 . GC-MS (m/z): 232 (M+), 109 (PhS+ ), 73 (Me3 Si+ ). HRMS (D E I): m/z calculated for C 1 0H 1 4F2SSi (M+ ) 232.0553, found 232.0545. 121 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 4.5 References 1. (a) Hiyama, T., Eds. Organofluorine compounds. Chemistry and Applications, Springer: New York, 2000. (b) Banks, R. E., Smart; B. E., Tatlow; J. C., Eds. Organofluorine Chemistry-Principles and Commercial Applications', Plenum Press: New York, 1994. (c) Welch, J. T.; Eshwarakrishman, S., Eds. Fluorine in Bioorganic Chemistry, Wiley: New York, 1991. (d) Liebman, J. F.; Greenberg, A.; Dolbier, W. R., Jr., Eds. Fluorine-Containing Molecules. Structure, Reactivity, Synthesis, and Applications', VCH: New York, 1988. 2. (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757. (b) Prakash, G. K. S.; Krishnamuti; and Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393. (c) Yudin, K. Y.; Prakash, G. K. S.; Deffieux, D., Bradley M.; Bau, R.; Olah, G. A. J. Am. Chem. Soc. 1997, 119, 1572. (d) Krishnamurti, R.; Bellow D. R.; Prakash G. K. S. J. Org. Chem. 1991, 56, 984. (e) Broicher, V.; Geffken, D. Tetrahedron Lett. 1989, 30, 5243. (f) Hagiwara, T.; Fuchikami, T. Synlett 1995, 717. 3. (a) Recently CF3I was also reported as a trifluoromethylating reagent: Ait- Mohand, S.; Takechi, N.; Medebielle, M.; Dolbier, W. Jr. Org. Lett. 2001, 3, 4271. (b) Motherwell, W. B.; Storey, L. Synlett 2002, 646. (c) Billard, T.; Langlois, B. R.; Blond, G. Eur. J. Org. Chem. 2001, 1467. (d) Billard, T.; Bruns, S.; Langlois, B. R. Org. Lett. 2000, 2, 2101. (e) Russell, J.; Roques, N. Tetrahedron 1998, 54, 13771. 4. Ruppert, I; Schlich, K.; Volbach, W. Tetrahedron Lett. 1984, 25, 2195. 5. (a) Pawelke, G. J. Fluorine Chem. 1989, 42, 429. (b) Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S. J. Org. Chem. 1991, 56, 984. (c) Aymard F.; Nedelec, J.-Y.; Perichon J. Tetrahedron Lett. 1994, 35, 8623. (d) Prakash, G. K. S.; Deffieux, D.; Yudin, A. K.; Olah, G. A. Synlett 1994, 1057. (e) Grobe, J.; Hegge, J. Synlett 1995, 641. 6. Although several different (difluoromethyl)silanes are documented in literature, their preparations give low yields or need high-cost precursors such as TMS- CF2CI. See reports: (a) Liu, E. K. S.; Lagow, R. J. J. Orgnomet. Chem. 1978, 145, 167. (b) Broicher, V.; Geffken, D. J. Orgnomet. Chem. 1990, 381, 315. (c) Buerger, EL; Moritz, P. J. Organomet. Chem. 1992, 427, 293. (d) Fuchikami, T.; Ojima, I. J. Organomet. Chem. 1981, 212,145. 122 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 7. (a) Amii, H.; Kobaiyashi, T.; Hatamoto, Y.; Uneyama, K. Chem.. Comm. 1999, 1323. 8. Amii, H.; Kobaiyashi, T.; Uneyama, K. Synthesis 2000, 2001. 9. Mae, M.; Amii, H.; Uneyama, K. Tetrahedron Lett. 2000, 41, 7893. 10. Amii, H.; Hatomoto, Y.; Seo, M.; Uneyama, K. J. Org. Chem. 2001, 66, 7216. 11. Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Fluorine Chem. 2001,112, 357-362. 12. Nishigachi, I.; Kita, Y.; Watanabe, M.; Ishino, Y.; Ohno, T.; Maekawa, H. Synlett 2000, 1025. 13. Ishino, Y.; Maekawa, H.; Takenchi, H.; Sukata, K.; Nishiguchi, I. Chem. Lett. 1995, 829. 14. Ohno, T.; Sakai, M.; Ishino, Y.; Shibata, T.; Maekawa, H.; Nishiguchi, I. Org. Lett. 2001, 3, 3439. 15. Trifluoromethyl phenyl sulfide, sulfoxide and sulphone are all commercially available. A number of reports on their preparation have been appeared in the literature. See recent ones: (a) Russell, J.; Roques, N. Tetrahedron 1998, 54, 13771. (b) Gerard, F.; Jean-Mannel, M.; Laurent, S.-J. Eur. Pat. Appl. 1996, EP 733614, 13 pp. (c) Chen, Q.-Y.; Duan, J.-X. Chem. Comm. 1993, 918. (d) Yang, J.-J.; Kirchmeier, R. L.; Shreeve, J. M. J. Org. Chem. 1998, 63, 2656. 16. (a) Hine, J.; Porter, J. J. Am. Chem. Soc. 1960, 82, 6178. (b) Hine, J.; Porter, J. J. Am. Chem. Soc. 1957, 79, 5493. (c) Stahly, G. P. J. Fluorine Chem. 1989, 43, 53. 17. Commercial magnesium turnings were used without special pretreatment. 18. Webster J. L.; Lerou, J. J. US Patent 5,446,218,1995. 19. PhS(0 )CF3 and PhS(0 )aCF3 can be obtained by oxidation of PI1 SCF3 which can be produced from CF3 H and PhSSPh. See ref. (15). 20. Li, X.; Jiang X.; Gong, Y.; Pan, H. HuaXue XueBao 1985, 43, 260. 21. Burton, D. J.; Weimers, D. M. J. Fluorine Chem. 1981,18, 573. 123 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 22. (a) Hine, J.; Ghirardelli, R. G. J. Org. Chem. 1958, 23, 1550. (b) Nakai, T. et al. J. Fluorine Chem. 1977, 9, 89. (c) Long, Z.-Y.; Chen, Q.-Y. J.Fluorine Chem. 1998, 91, 95. 23. Fuchigami, T.; Yamamoto, K.; Nakagawa, Y. J. Org. Chem. 1991, 56, 137. 24. Stahly, G. P. J. Fluorine Chem. 1989, 43, 53. 25. Yamamoto, T.; Watanabe, H. Jpn. Kokai Tokkyo Koho 2001, JP 2001039942. 26. Stably, G. P.; Bell, D. R. J. Org. Chem. 1989, 54, 2873. 27. Sukharev, V.; Zubkov, V. U.S. Patent, US 6365528,2002. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 5 Alkoxide Induced Nucleophilic Tri- and Difluoromethylation Using Tri- and Difluoromethyl Sulfones or Sulfoxides Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 5.1 Introduction In the last two decades, organofluorine compounds have attracted much attention due to their unique properties and unusual reactivities . 1 Among them, trifluoromethyl group (CF 3 ) containing molecules are o f particular importance for different applications in materials science, medicinal and agrochemistry. Although m any trifluoromethylation methods have been appeared in the literature including organometallic, 2 nucleophilic, 3 electrophilic4 and radical trifluoromethylations , 5 fluoride induced nucleophilic trifluoromethylation with (trifluoromethyl)trimethylsilane (TM S-CF 3 , Prakash or Ruppert reagent) has been considered a straightforward and reliable m ethod . 3 TM S-CF 3 was commonly prepared from ozone-depleting trifluoromethyl halides, and recently its environmentally benign preparation method has been developed by us (see Chapter 4). More recently, there has been some research interest in the trifluoromethylation using trifluoromethane (CF3 H) as trifluoromethylating precursor. CF 3H has low toxicity and is not ozone-depleting. It is a side-product o f the multi-step industrial synthesis o f Teflon ® . 6 The efficient production o f CF 3H has been disclosed via fluorination o f methane w ith hydrogen fluoride and chlorine . 7 Shono and co workers8 used electrochemically reduced 2-pyrrolidone to deprotonate CF 3H to generate the trifluoromethyl anion equivalent that reacts with aldehydes and ketones. Troupel et al. 9 also reported that cathodic reduction o f iodobenzene generates a 126 permission of the copyright owner. Further reproduction prohibited without permission. strong base, which deprotonates CF3H, inducing its addition to aldehydes. Thereafter, two research groups carried out extensive studies on the nucleophilic 6 10 trifluoromethylation using CF3H as a precursor. Normant and co-workers ’ have demonstrated the trifluoromethylation of aldehydes by CFsH/potassium dimsylate in DMF. They suggested that the CF37DMF adduct was the key intermediate for the trifluoromethylation. Roques, Langlois and co-workers1 1 reported the nucleophilic trifluoromethylation of carbonyl compounds and disulfides with CF3 H and different bases in DMF. CF3'/iV-Formylmorpholine adduct was also developed as a stable 1 0 reagents for trifluoromethylation of nonenolizable carbonyl compounds. Under similar consideration, Piperazino hemiaminal of trifluoroacetaldehyde was also used as a trifluoromethylating agent.1 3 However, these trifluoromethane derived methods have their drawbacks: first of all, trifluoromethane is a low-boiling gas (b.p. - 84 °C), thus its delivery and handling as a reagent in laboratory are not convenient; Second, these trifluoromethylations do not work well with enolizable carbonyl compounds. Trifluoromethyl iodide (CF3I) has also been successfully used as nucleophilic trifluoromethylating agent under the activation of electron-donating compound tetrakis(dimethylamino)ethylene (TDAE).1 4 a More recently, Motherwell and Storey1 4 b reported the nucleophilic trifluoromethylation using trifluoromethylacetophenone-Af Af-dimethyltrimethylsilylamine adduct. We previously reported a reductive tri- and difluoromethylation using tri- and difluorosulfides, sulfoxides and sulfones as trifluoromethyl (CF3) or difluoromethyl (CF2 H) group precursors (see Chapter 4). However, under the reductive condition 127 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. where magnesium metal was used, the reaction only worked with chlorosilanes, while the attempts to react with carbonyl compounds failed. We anticipated that by using a nucleophile such as alkoxide, the carbon-sulfur bond of trifluoromethyl phenyl sulfone la or sulfoxide lb will be cleaved to give a trifluoroanion CF3 " species which may undergo addition into carbonyl compounds (Scheme 5.1, A). The driving force of this substitution is the formation of strong S-0 bond (348 ~ 551 KJ/mol)1 5 and the high polarity of C-S bond of sulphone la or sulfoxide lb. The generation of pseudohalide CF3 ' species is somewhat similar to the reaction between benzenesulfonyl halide with alkoxide. Herein, we wish to report the first alkoxide induced nucleophilic trifluoromethylation and difluoromethylation of carbonyl compounds, disulfides and other electrophiles, using trifluoromethyl phenyl sulfone la (sulfoxide lb ) and difluoromethyl phenyl sulfone lc. The trifluoromethyl sulfone la or sulfoxide lb can be used as “CF3'” synthon, and difluoromethyl sulfone lc can be used as “PhS02CF2 '”, “CF2H‘” or “'CF2 '” synthon depending on the selective cleavage of ~CF2 -H and ~SQ2 -CF 2 bonds (Scheme 5.1, B). Since phenyl trifluoromethyl sulfone la or sulfoxide lb is a commercially available stable compound (b.p. 203 °C for la, b.p. 85~87°C/10 Torr for lb) which also can be conveniently produced from trifluoromethane,1 6 and difluoromethyl phenyl sulfone lc can be prepared using similar a method,1 7 this new methodology provides a very convenient tool for the environmentally benign and efficient tri- and difluoromethylations. 128 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. A: (even aq.NaOH) Scheme 5.1 Mechanistic considerations. 5.2 Results and discussion 5.2.1 Trifluoromethylation of aldehyde Potassium terf-butoxide fBuOK) was first used as nucleophile to attack the sulfur center of phenyl trifluoromethyl sulfone la to generate trifluoromethyl anion (scheme 1, A). Into the mixture of 0.68 mmol of la and 0.68 mmol of benzaldehyde 6 in 0.5 ml of DMF at - 50 °C, 2 ml DMF solution of 1.37 mmol 4 BuOK was slowly added. The reaction mixture was strried at - 50 °C for 1 h, and then warmed to room 129 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. temperature over period of 2h. 1 -Phenyl-2-trifluoromethyl-ethanol 7 was produced in 71 % yield (Scheme 5.2). O 0 PhS-CF3 (1a) ,lBuOK H O_____________ , DMF, - 50 °C OH CF. 7 Scheme 5.2 Trifluoromethylation of PhCHO with la. Shono and co-workers8 found that when they used CFsH/BuOK/DMF to react with benzaldehyde at - 50 °C, benzyl alcohol and benzoic acid were formed by the competing Cannizzaro reaction. Russell and Roques1 la repeated the reaction using excess CF3 H (9.5 eq.) and lBuOK (2.2 eq.) at - 50 °C, and 67 % yield of trifluoromethylated product 7 was formed and no benzyl alcohol was detected. They mentioned that the high reaction temperature with excess base could lead to Cannizzaro reaction and jeopardize the trifluoromethylation. In our reaction as shown in Scheme 5.2, only traces of benzoic acid and benzyl alcohol were detected by NMR. This implies that at low temperature the Cannizzaro reaction rate is much slower than the tert-butoxide induced trifluoromethylation process. When excess 130 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. benzaldehyde was introduced, the yield of the product 7 can be improved based on the amount of sulphone la used (Table 5.1, entry b). Table 5.1. Trifluoromethylation of benzaldehyde by PhS02 CF3 induced by alkoxide or hydroxide. Benzaldehyde Sulphone 1 a Alkoxide Solvent Temperature Time Yield3 (7 , %) a 1 eq. 1 eq. t-BuOK (2 eq.) DM F - 50 °C 1 h 71 b 3 eq. 1 eq. t-BuOK (2 eq.) DMF - 30 °C~r.t. 30 min 91 c 3 eq. 1 eq. MeONa (3 eq.) DM F - 30 °C~r.t. 3 h 30 d 3 eq. 1 eq. KOH (8 eq.) DM F r.t. 20 h 4 5 e 3 eq. 1 eq. t-BuOK (2 eq.) DMSO r.t.. 1 h 7 6 aYields were determined by 19F NMR based on the amount of 1 a used. Besides lBuOK, sodium methoxide (CEhONa) and potassium hydroxide (KOH) were tried as nucleophiles (table 1, entries c and d). Both of them worked but gave lower yields. There are several possible reasons: first of all, both sodium methoxide and KOH can not readily dissolve in DMF, which affects the reaction rate. Second, unlike potassium lBuOK, sodium methoxide may react with benzaldehyde via a Meerwein-Ponndorf-Verley reduction.1 8 Third, KOH has lower nucleophilicity than tBuOK, so the reaction rate can be slow. Here Cannizzaro reaction may still happen as a competing side-reaction, but it should not be a dominating factor to affect the yield since excess benzaldehyde is present.1 9 It is worth mentioning that DMF is not the only solvent for this reaction. Dimethyl sulfoxide (DMSO) was also used, and the reaction worked fairly well (Table 5.1, entry e). This indicates that the CFa'/DMF adduct may not be the 131 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. necessary intermediate for this new type of nucleophilic trifluoromethylation. However, the intermediate species 8 (in Scheme 5.3) may play an important role in the CF3 group transfer process. We also attempted to carry out the reaction by using catalytic amount of lBuOK (Scheme 5.3). We assumed that the generated CF3 containing alkoxide 9 might still react with sulfone la to facilitate further trifluoromethylation. However, when small amount of lBuOK was introduced, only a small amount of product 9 (and 7 after hydrolysis) was formed which can be monitored by 1 9 F NMR. Introduction of more lBuOK gave more product, excellent yield of 7 was achieved when excess £ BuOK was used (Fig. 5.1). P IY C F- 1 Ph' Ph- OH CF3 PIY Ph CF3 10 Scheme 5.3 Proposed mechanism potassium teri-butoxide induced trifluoromethylation of PhCHO. 132 permission of the copyright owner. Further reproduction prohibited without permission. A (0.6 mmol PhSQ2 CF3 + 1.2 mmol PhCHO in DMF) B (10 mol % *BuOK was added at - 30 °C, then stir for 30 min) I _______________ __________ A________ - T e ».2 -7 &.A - 7s. s -re.e .7 9 .0 .2 C (200 mol % *BuOK was added at - 30 °C, then stir for 30 min) Figure 5.1 1 9 F NMR study of the trifluoromethylation of benzaldehyde by PhS0 2CF3/tBu0 K, implying that stoichiometric amount of ‘ BuOK is required to complete the reaction in a short time, [singlet peak corresponds to PhS0 2 CF3 (- 78.9 ppm); doublet peak corresponds to the product 1 -phenyl-2-trifluoro-ethanol (d, - 78.6 ppm, 3JF .H = 7 Hz). 133 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The requirement of stoichiometric amount of potassium f-butoxide indicates that due to the strong electron-withdrawing effect of the CF3 group, the nucleophilicty of alkoxide 9 is much weaker than that of lBuQK, leading to its slow or no reaction toward sulfone la. Because of this kinetic reason (k2 « ki, see Scheme 3), this process can not be successful via a catalytic pathway at least in short reaction time. Excess amount of *BuOK (2 eq.) was found to be very helpful to accomplish the trifluoromethylation reaction with good yield of the product. There are several reasons and advantages. lBuOK reacts with water so readily that it may be partially hydrolyzed during storage and handling. Furthermore, excess lBuOK also removes the moisture in the solvent and reagents. More importantly, the excess ‘ BuOK in the reaction mixture eliminates the possibility of hydrolysis of CF3 ' to form CF3 H. It is known that CF3 H can be deprotonated by tBuOK and undergo trifluoromethylation of carbonyl compounds,9 ~u Thus, our current methodology is guaranteed to produce trifluoromethylated products in high yields. 5.2.2 Trilfuoromethylation of ketones Under the similar reaction condition, benzophenone 12 readily reacted with PhSC^CFs/BuOK in DMF to give trifluoromethylated product 13 in 86 % isolated yield (Scheme 5.4). 134 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 12 P h S 0 2CF3 (1a), *BuOK DMF - 40 °C ~ r.t., 2 h OH t 13 (86 %) Scheme 5.4 Trifluoromethylation of benzophenone with la. Since there is no Cannizarro reaction between benzophenone and lBuOK, this reaction can be carried out even at high temperatures. Due to lower reactivity of ketone compared with aldehydes, the reaction needs a little bit longer time (2 ~ 3 h) to complete. Enolizable ketone such as acetophenone 14 was used to react with la/BuOK under similar reaction conditions, and the yield of the trifluoromethylated product 15 was quite low (20 ~ 30 %, Scheme 5.5). O P h S 0 2CF3 (1a), lBuOK DMF -4 0 °C ~ r.t., 2 h 14 OH CH3 c f 3 15 (20-30 %) Scheme 5.5 Trifluoromethylation of acetophenone with la. 135 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 5.2 Reaction of trifluoromethyl phenyl sulfone (la) or sulfoxide (lb) (2 equiv) with non-enolizable carbonyl compounds (1 equiv) and *BuOK (2.5 equiv) in DMF at - 50 °C ~ room temperature. Entry Carbonyl T rifluoromethylating compound agent 19 FNMR Product Yield (%) (ppm) '1 MeO' HO CF3 1a 1a 1a 1a 1a 1a 1a I 10 1a 1b 1 b HO CF3 HO CF3 HO CF3 HO CF3 HQ CF3 -7 4 .5 -7 5 .1 -7 4 .7 - 7 4 .4 -7 5 .0 - 7 8 .5 - 7 8 .4 -7 6 .1 -7 4 .5 -7 8 .5 isolated yields. CFCI3 w as used as internal standard. 136 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 5.2 summarizes different examples of trifluoromethylation of various non-enolizable carbonyl compounds using trifluoromethyl phenyl sulfone la or sulfoxide lb. The typical reaction conditions are as follows: At - 50 °C, into the mixture of carbonyl compound (1 mmol) and la or lb (2 mmol) in 7 mL DMF, was added lBuOK (2.5 mmol) dissolved in 3 mL of DMF. The reaction mixture was stirred at - 50 °C for one hour, and then was stirred overnight at - 50 °C to room temperature. Corresponding trifluoromethylated carbinol products were isolated in good to excellent yields. It is remarkable that trifluoromethyl phenyl sulfoxide lb worked equally well as sulfone la (entries 9, 10 ). 5.2.3 Trifluoromethylation of methyl ester The reaction between trifluoromethyl anion (CF3 ') and carboxylic esters were previously reported to be quite poor.2 0 ,2 1 In 1998, Prakash and co-workers2 2 demonstrated that the fluoride induced trifluoromethylation of cayboxylic esters using TMS-CF3 in nonpolar solvents gave trifluoromethyl ketones in high yields. The method has been further extended by Shreeve and coworkers with CsF catalysis. Russell and Roques also reported the preparation of trifluoromethyl ketones from aromatic esters by using CFsH/base/DMF system.1 1 3 In our trifluoromethylation system, methyl benzoate 16 (1 eq.) reacted with la (1 eq./BuOK (1.5 eq.) in DMF to give hemiacetal species 17, which can be hydrolyzed into 2,2,2-trifluoroacetophenone 18 in 82 % yield (Scheme 5.6). 137 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The mechanism proposed is shown in Sheme 6. It turns out that the hemiacetal species 17 itself can not transform into the product 18 readily (path A). Actually the neutral hemicatal 19 can be isolated (1 9 F NMR: -84.7 ppm), which can be transformed into ketone 18 (1 9 F NMR: -71.8 ppm) under concentrated hydrochloric acid treatment (path B). \ / O I I c — och3 1) P hS 0 2CF3 / ‘BuOK, DMF -50 °C - r.t. 16 18 (82 %) P h -C -O C H , Ph_ _ 4 < ^ F3 P h™ C — OCH3 0*Bu 16 Scheme 5.6 Trifluoromethylation of methyl benzoate using la to give 2,2,2-trifluoro- acetophenone. 138 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 5.2.4 Trifluoromethylation of disulfide We were interested in determing whether the trifluoromethyl anion generated in our PI1 SO2CF3 / *BuOK system can readily react with disulfide to give trifluoromethyl sulfide in good yield. As shown in Scheme 5.7, PhS02CF3 (1 eq.) and *BuOK (2 eq.) reacted with diphenyl disulfide (20, 1.2 eq.) at - 30 °C to room temperature in 30 minutes to give quantitative conversion (87 % isolated) of phenyl trifluoromethyl sulfide 21 (1 9 F NMR: - 43.3 ppm). P h S 0 2CF3 / ‘BuOK Ph— S — S — Ph ------------------------------------ Ph— S — CF3 DMF, -30 °C ~ r.t. 20 21 87% Mechanism: Scheme 5.7 Trifluoromethylation of PhSSPh with la . We found that the trifluoromethylation of disulfide was even more facile than carbonyl compounds. Since there is no side reaction between disulfide and potassium tert-butoxide, the reaction is quite convenient to carry out. 139 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 5.2.5 Trifluoromethylation of aryl iodide Direct trifluoromethylation of alkyl or aryl halides has been known to be difficult.2 0 However, trifluoromethyl copper (CF3CU) was able to react with aryl iodide to produce trifluoromethylated aromatics via oxidative addition-reductive elimination pathway.2 4 CF3 Cu can be prepared in situ from copper(I) halide with CF3CdX2 4 or TMS-CF3 /F'.2 5 We attempted to generate CF3 Cu in situ using copper iodide (Cul) and la/BuOK, and then further react with iodobenzene 22 (Scheme 5.8). 22 23 2 6 % Scheme 5.8 Trifluoromethylation of iodobenzene with la. The yield of product 23 (1 9 F NMR: - 63.1 ppm) was quite low (26 %). This is mainly due to the competing reaction between Cul and 4 BuOK to form stable ^uOCu, which is an inert species towards the trifluoromethyl anion. 140 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 5.2.6 Difluoromethylation of disulfide Based on the study of trifluoromethylation by using PI1 SO2CF3 (la) or PI1 SOCF3 (lb)/‘ BuOK system, we also carried out the difluoromethylation via PI1 SO2CF2H (lc)/tBuOK as reagents. Diphenyl disulfide 20 was first tested for this reaction due to its high reactivity and less side-reactions. The results are shown in Table 5.3. Table 5.3 Difluoromethylation of PhSSPh with lb. o o o n . DMF 11 11 PhSCF2H + BuOK + PhSSPh ► PhSCF,SPh + PhSCF2SPh + PhSCF2H + PhSCF2H 11 * r.t. 11 * 11 0 0 O 1 c 22 24 25 26 1b Entry R e a c ta n t ratio R ea ctio n P ro d u c t y ie ld s 1b *BuOK 22 tim e 24 2 5 2 6 1b a 1 e q . 1 . 0 e q . 1 . 0 e q . 3 0 m in 7 6 % 0 % 5 % 1 9 % b 1 e q . 1 .5 e q . 1 . 0 e q . 5 0 m in h % | 3 % 6 % 0 % c 1 e q . 2 .5 e q . 2 . 0 e q . 1 4 h 6 4 % 2 2 % 1 4 % 0 % d 1 e q . 3 .0 e q . 2 . 0 e q . 4 h 41 % 4 4 % 1 4 % 0 % e 1 e q . 3 .5 e q . 2 . 0 e q . 4 h 0 % 8 4 % 1 6 % 0 % f 1 e q . 3 .5 e q . 2 .0 e q . 1 5 h 0 % 9 7 % 3 % 0 % g 1 e q . 4 .0 e q . 2 . 0 e q . 4 h 0 % 9 9 % | 0 % 0 % The yields were determined by F NMR with PhOCF3 as the internal standard. 141 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. As shown in Table 5.3, the reaction with sulfone lc has different aspects from sulfone la. Sulfone lc has acidic proton in CF2H group, which can be readily deprotonated by ‘BuOK to generate PI1SO2CF2" species 27(see Scheme 5.9). Species 27 can easily react with PhSSPh to give product 24 (1 9 F NMR: - 78 ppm), and compound 24 can again react with ‘ BuOK to generate PI1 SCF2' species 28. Species 28 reacts with PhSSPh to further produce disubstituted product 25 (1 9 F NMR: - 49 ppm). O , O II BuOK II PhSSPh PhS-CF^H ---------- ► PhS-CFp------------- ^ I I I I O O 1c 27 PhSSPh 1 1 PhSCF2SPh 25 Scheme 5.9 Proposed mechanism for the difluoromethylation of PhSSPh with lc. Thus, PI1SO2CF2 H (lc)/‘ BuOK system can be regarded as a “ CF2 2' ” equivalent. Due to the different reactivity of ~CF2 — H and ~S02— CF2 bonds under ‘ BuOK activation, the double anionic “CF22 ’ ” can be selectively used as demonstrated in Scheme 5.10. By controlling the amount of ‘BuOK added, high 142 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. yields of both mono-substituted product 24 (91 %, entry b in Table 5.2) and di substituted product 25 (99 %, entry e in Table 5.3) can be successfully obtained. O PhS-CF2H / 4 BuOK I ! O Scheme 5.10 Difluoormethylene dianion synthon. 5.2.7 Difluoromethylation of aldehyde In 1989, Stahly reported the nucleophilic addition to aldehydes by PI1 SO2CF2H lb in a two phase system (50 % aqueous sodium hydroxide, dichloromethane, Aliquate® 336) in 4 hours at room temperature to give difluoro(phenylsulfonyl)methyl substituted alcohols in excellent yields (Scheme 5.11). NaOH RCHO h2 0/ch2cC u o o on R-C-CF2H H 1c 27 29 30 I I I Scheme 5.11 Stahly’s difluoromethylation with lc. 143 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. However, in Stahly’s study, he did not observe any C-S bond cleavage under the aqueous NaOH condition, and only mono-substituted product 29 was isolated that was further transformed into difluoromethylated alcohol 30 under reductive cleavage (Na/EtOH). Obviously, aqueous NaOH is not nucleophilic enough to attack the sulfur atom of the sulfone lb to accomplish S— CF2~ bond cleavage. We carried out the reaction between benzaldehyde 6 and PI1SO2CF2H (lc/B uO K in DMF (Scheme 5.12). HO OH H PhS02CF2H (1 c)/ *BuOK DM F - 50 °C - r.t. OH 30 anti- (S,R- or R,S-) 19F NMR for anti- isomer: -120.9 ppm (dd,J= 11.4Hz, J=11.4 Hz, 2F) 1 9 , r f" V ^ C F 2 SPh U s 31 'F NMR: -104.4 ppm (dd, 1= 238 Hz, 2.8 Hz, IF) -119.8 ppm (dd, J= 238 Hz, 21.0 Hz, IF) Scheme 5.12 Reaction ofPhCHO (excess) and lc/BuOK. Table 5.4 Entry Reactant ratio Reaction Product yields 1 b ‘BuOK 6 time 30(anti-/syn-) 31 a 1 .0 eq. 3.0 eq. 2 .0 eq. 90 min 58 % (98:1) 41 % b 1 .0 eq. 4.0 eq. 3.0 eq. 8 h 92 % (97:1) 0 % The yields were determined by 1 9 F NMR with internal satndard. 144 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Similar as in section 5.2.6, PI1 SQ2CF2H can selectively react with benzaldehyde 6 to generate mono-substituted compound 31 (Table 5.4), which has been shown by Stahly in his aqueous NaOH conditions. Compound 31 can further react with another molecule of benzaldehyde to form di-substituted diol product 30 in excellent yield. Interestingly, the isolated product 30 was found to be highly disteroselective (anti/syn = 97:3, de = 94 %, see Fig. 5.2), which could be interpreted by the charge-charge repulsion effect during the second addition (Scheme 5.13). For the intermediate 32, anti- steroisomer is much more stable and preferred over the syn- isomer. To our knowledge, this may be the first example that high disteroselectivity can be obtained via an intramolecular charge effect rather than the traditional steric control (based on the Cram’s rule). o HO OH P h S 0 2CF2H (1 b y ‘BuOK 6 30 (82 % isolated) anti- (S,S- or R,R-) (1b)/*BuOK O' K+ 32 anti- (S,S- or R,R-) Scheme 5.13 Proposed mechanism of distereoselective formation of 30. 145 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Anti- Syn- tf.St 1 1.18 O H O H OH OH (R .R )- (S.S)- ► Anti- OH OH (R,S)- = (S,R)- Syn- Anti-1 Syn- = 97 : 3, de = 94 % Syn- d:57 0.41 -122 -123 -124 -125 ppm Figure 5.2 1 9 F NMR of 2,2-Difluoro-l,3-diphenyl-1,3-propanediol (32) with anti/syn = 97:3. 146 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 5.2.8 Methyl trifluoromethyl sulphone as the trifluoromethalting agent We also attempted other type of sulfones such as methyl trifluoromethyl sulfone (Id) as the trifluoromethylating agent (Scheme 5.14). When diphenyl disulfide was used as the model substrate, and reaction only gave very low yield of product (~ 2 %). This is probably due to the facile deprotonation of the methyl group by lBuOK, leading to other products. O DMF Ph— S— S— Ph + CH3 - S - C F 3 + lBuOK ---------------► Ph— S— CFo » -30 °C ~ r.t. 3 U 2 % v y / I O 'CH2- S - C F 3 ti o Scheme 5.14 Attempted trifluoromethyaltion with CH 3 SO 2 CF 3 . 5.3 Conclusion In summary, potasium fert-butoxide induced trifluoromethylation by using phenyl trifluoromethyl sulfone (PI1SQ2CF3, la) or sulfoxide (PI1SOCF3, lb ) enables 147 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. us to transfer CF 3 group into carbonyl compounds and disulfides in high yields. Phenyl difluoromethyl ketone PI1SO2 CF2H (lc ) can also be used as “PI1SO 2 CF 2 " ” or 'j “CF 2 synthon to react with different types o f electrophiles. Further investigation o f this novel type o f fluoroalkylation m ethodology is underway. 5.4 E x perim ental section G eneral: Unless otherwise mentioned, all other chemicals were purphased from commercial sources. Potassium /ert-tutoxide (95 %, Aldrich) was used as received. DM F was distilled over calcium hydride, and stored over activated m olecular sieve. Phenyl trifluoromethyl sulfone (la ) or sulfoxide (lb ) was prepared by the oxidation o f phenyl trifluoromethyl sulfide w ith hydrogen peroxide . 11 Phenyl difluoromethyl sulphone (lc ) and methyl trifluoromethyl sulfone (Id ) were prepared using known procedures. 1 2 ,2 6 ^ 1 3 C and 1 9 F N M R spectra w ere recorded on Bruker AM X 500 and AM 360 N M R spectrometers. ^ NM R chemical shifts w ere determined relative to internal (CH3 )4Si (TMS) at 8 0.0 or to the signal o f a residual protonated solvent: CDCI3 8 7.26. 1 3 C N M R chemical shifts were determined relative to internal TMS at 8 0.0 or to the 1 3 C signal o f solvent: CDCI3 8 7 7 .0 .1 9 F N M R chemical shifts were determined relative to internal CFCI3 at 5 0.0. The 1 9 F N M R yields w ere determined by the 148 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. integration of the corresponding product peaks with respect to PI1 OCF3 internal standard. Mass spectra were recorded on Hewlett Packard 5890 Gas Chromatograph with a Hewlett Packard 5971 Mass Selective Detector at 70 eV. Preparation of trifluoromethyl phenyl sulfone (la), sulfoxide (lb) and difluoromethyl phenyl sulfoxide (lc): see Chapter 4. Typical procedures for ‘BuOK induced trifluoromethylation or Difluoromethylation: The reaction was commonly carried out in a Schlenk flask under an argon atmosphere. Into 7 ml DMF solution of phenyl trifluoromethyl sulfone (la, 420 mg, 2 mmol) and 4-methylbenzophenone (196 mg, 1 mmol) at - 50 °C, was added 3 ml DMF solution of ‘ BuOK (280 mg, 2.5 mmol). The reaction flask was then sealed and the reaction mixture was then stirred from - 50 °C for lh, followed by stirring at - 50 °C to room temperature overnight. The reaction mixture was quenched with 10 ml of ice water, and extracted with ether (20 ml x 3). The combined ether phase was washed with saturated NH4CI aqueous solution, followed by washing with water. After drying over MgSC>4, the ether solvent was removed under vacuum. The crude product was further purified by column chromatography (hexanes/ether = 9/1) to give 225 mg of product, 4-methyl-a-phenyl-o (trifluoromethyl)benzenemethanol as a colorless oily liquid, yield 85 %. lH NMR 149 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. (CDC13, in ppm): a 3.01 (b, 1H); 7.35-7.38 (m, 6 H); 7.49-7.52 (m, 4H). 1 9 F NMR (CDCls, in ppm): - 74.5. MS: 252 (M+). a-Phenyl-Qf-(trifluoromethyl)benzenemethanol: oily liquid, 8 6 % yield. N M R (CDCI3 , in ppm): a 2.36 (s, 3H); 2.89 (s, 1H); 7.17-7.51 (m, 9H). 1 9 F NMR (CDCI3, in ppm): - 74.4. MS: 266 (M+). 4,4’-Dichloro-a-phenyl-a-(trifluoromethyl)benzenemethanol: pale yellow oily liquid, 74 % yield. N M R (CDCI3 , in ppm): a 2.95 (s, 1H); 7.34 (d, 4H); 7.40 (d, 4H). 1 9 F NM R (CDCI3 , in ppm): -75.1. MS: 320 (M+). 4-Nitro-ct-phenyl-a-(trifluoromethyl)benzenemethanol: pale yellow oily liquid, 83 % yield. lE NM R (CDC13, in ppm): o 3.15 (s, 1H); 7.37-8.23 (m, 9 H). 1 9 F N M R (CDCI3 , in ppm): - 74.7. MS: 297 (M+ ). 4-Methoxy-a-phenyl-a-(trifluoromethyl)benzenemethanol: oily liquid, 73% yield. 'H NM R (CDCI3, in ppm): a 2.80 (s, 1H); 3.81 (s, 3H); 6.87-7.49 (m, 9 H). 1 9 F NM R (CDCI3, in ppm): - 75.0. MS: 281 (M+-l). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1-Phenyl-2,2,2-trifluoroethanol: yellow oily liquid, 77 % yield. *H NMR (CDCI3, in ppm): o 2.86 (s, 1H); 5.01 (q, 3 JH -f = 6.3 Hz, 1H); 7.43 (m, 2H); 7.48 (m, 3H). 1 9 F (CDCI3, in ppm): - 78.5 (d, 3J H-f = 6.2 Hz). MS: 176 (M+ ). l-(2’-Naphthyl)-2,2,2-trifluoroethanol: yellow solid, 62 % yield. *H NMR (CDCI3, in ppm): a 2.76 (b, 1H); 5.19 (q, 3 J H -f = 6.7 Hz, 1H); 7.51-7.96 (m, 7H). 1 9 F (CDCI3, in ppm): - 78.4 (d, 3 JH -f = 6.7 Hz). MS: 226 (M+ ). 2-(Trifluoromethyl)-2-adamantanol: 82 % yield, white solid (sublimed). 'H NMR (CDCI3, in ppm): a 1.56-2.27 (m, 15H). 1 9 F (CDC1 3, in ppm): -76.1. MS: 220 (M"). 2,2,2-Trifluoroacetophenone: 82 % yield, colorless liquid. !H NMR (CDCI3, in ppm): a 7.53 (t, J = 8.0 Hz, 2H); 7.70 (t, J = 7.5 Hz, 1H); 8.06 (d, J = 8.0 Hz, 2 H). 1 9 F (CDCI3, in ppm): - 71.8. MS: 174 (M+ ). Phenyl trifluoromethyl sulfide: 87 % yield, colorless liquid. ]H NMR (CDCI3, in ppm): a 7.43 (t, J = 7.5 Hz, 2H); 7.50 (t, J = 7.5 Hz, 1H); 8.67 (d, J = 7.5 Hz, 2 H). 1 9 F (CDCI3, in ppm): - 43.2. 151 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. l , l ’-[(difluoromethylene)bis(thio)]bisbenzene: 85 % isolated yield. !H NMR (CDCI3, in ppm): a 7.36 (t, 4H); 7.50 (t, 2H); 7.59 (d, 4 H). 1 9 F (CDCI3 , in ppm): - 49.5. Bis(benzenesulfonyl)difluoromethane: *H NM R (CDCI3 , in ppm): 8 7.65 (t, 4H); 7.81 (t, 2H); 8.05 (d, 4H). 1 3 C N M R (CDC13, in ppm): 8 118.53 (t, J = 335.7 Hz); 129.52; 131.13; 132.91; 136.40. 1 9 F N M R (CDCI3 , in ppm): 8 -102.49 (t, J - 9.4 Hz). MS: 333 (M++ l); 141; 125; 77; 51. 2,2-D ifluoro-l,3-diphenyl-l,3-propanediol: white crystalline solid, yield 82 %, anti-/syn- ratio = 97/1 determined by 1 9 F NMR. For anti- isomer: *H NM R (actone-dg, in ppm): 5.27 (m, 4H); 7.28-7.50 (m, 10 H). 1 9 F (acetone-d 6 , in ppm): - 120.9 (dd, J = 11 Hz, J = 11 Hz, 2F). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 5.5 References 1. (a) Hiyama, T., Eds. Organofluorine compounds. Chemistry and Applications, Springer: New York, 2000. (b) Banks, R. E., Smart; B. E., Tatlow; J. C., Eds. Organofluorine Chemistry-Principles and Commercial Applications', Plenum Press: New York, 1994. (c) Welch, J. T.; Eshwarakrishman, S., Eds. Fluorine in Bioorganic Chemistry, Wiley: New York, 1991. (d) Liebman, J. F.; Greenberg, A.; Dolbier, W. R., Jr., Eds. Fluorine-Containing Molecules. Structure, Reactivity, Synthesis, and Applications', VCH: New York, 1988. 2. McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555. 3. (a) Prakash, G. K. S.; Yudin, A. K. Chem. Review. 1997, 97, 757. (b) Prakash, G. K. S.; Mandal, M. J. Fluorine Chem. 2001, 112, 123. (c) Prakash, G. K. S.; Krishnamuti; and Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393. (d) Krishnamurti, R.; Bellew D. R.; Prakash G. K. S. J. Org. Chem. 1991, 56, 984. 4. (a) Umemoto, T. Chem. Rev. 1996,9 6 ,1757. (b) Umemoto, T.; Ishihara, S. J. Am. Chem. Soc. 1993,115, 2156. (c) Umemoto, T.; Gotoh, Y. Bull. Chem. Soc. Jpn. 1987, 60, 3307. (d) Shreeve, J. M.; Yang, J.-J.; Kirchmeier, R. L. US Patent, US 6215021, 2001. 5. (a) Dolbier, W. R. Jr. Chem. Rev. 1996, 96, 1557. (b) Dolbier, W. R. Jr. Top. Curr. Chem. 1997,192, 97. 6. Folleas, B.; Marek, I.; Normant, J.-F.; Saint-Jalmes, L. Tetrahedron Lett. 1998, 39, 2973. 153 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 7. Webster J. L.; Lerou, J. J. US Patent 5,446,218,1995. 8. Shono, T.; Ishifume, M.; Okada, T.; Kashimura, S. J. Org. Chem. 1991,56,2. 9. Barhdadi, R.; Troupel, M.; Perichon, J. Chem. Comm. 1998,1251. 10. (a) Folleas, B.; Marek, I.; Normant, J.-F.; Saint-Jalmes, L. Tetrahedron 2000, 56, 275. 11. (a) Russell, J.; Roques, N. Tetrahedron 1998, 54, 13771. (b) Large, S.; Roques, N.; Langlois, B. R. J Org. Chem. 2000, 65, 8848. (c) Roques, N.; Russell, J.; Langlois, B.; Saint-Jalmes, L.; Large, S PCT Int. Appl. 1998, WO 9822435. (d) Roques, N.; Mispelaere, Tetrahedron 1999, 6411. 12. Billard, T. B.; Langlois, B. R. Org. Lett. 2000,2, 2101. 13. (a) Billard, T.; Langlois, B. R.; Blond, G. Eur. J. Org. Chem. 2001, 1467. (b) Billard, T.; Langlois, B. R. J. Org. Chem. 2002, 67, 997. 14. (a) Ait-Mohand, S.; Takechi, N.; Medebielle, M.; Dolbier, W. Jr. Org. Lett. 2001, 3 ,4271. (b) Motherwell, W. B.; Storey, L. J. Synlett 2002, 646. 15. Dean, J. A. Lange's Handbook o f Chemistry (14th Ed.), McGraw Hill: New York, 1992, p 4.34. 16. Trifluoromethyl phenyl sulfide, sulfoxide and sulphone are all commercially available. A number of reports on their preparation have been appeared in the literature. See: (a) Russell, J.; Roques, N. Tetrahedron 1998, 54, 13771. (b) Gerard, F.; Jean-Mannel, M.; Laurent, S.-J. Eur. Pat. Appl. 1996, EP 733614, 154 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 13 pp. (c) Chen, Q.-Y.; Duan, J.-X. Chem. Comm. 1993, 918. (d) Yang, J.-J.; Kirchmeier, R. L.; Shreeve, J. M. J. Org. Chem. 1998, 63,2656. 17. (a) Hine, J.; Porter, J. J. Am. Chem. Soc. 1960, 82, 6178. (b) Hine, J.; Porter, J. J. Am. Chem. Soc. 1957, 79, 5493. (c) Stahly, G. P. J. Fluorine Chem. 1989, 43, 53. 18. Hassner A.; Stumer, C. Organic Syntheses Based on Name Reactions and Unnamed Reactions, Pergamon: New York, 1994, pp 251. 19. Stahly, G. P. J. Fluorine Chem. 1989, 43, 53. 20. Prakash, G. K. S. in Synthetic Fluorine Chemistry, Edited by Olah, G. A.; Chamber, R. D.; Prakash, G. K. S., Wiley: New York, 1992. 21. Yokoyama, Y.; Mochida, K. SynLett 1997, 907. 22. Wiedemann, J.; Heiner, T.; Mloston, G.; Prakash, G. K. S.; Olah, G. A. Angew. Chem. Int. Ed. 1998, 37, 820-821. 23. Singh, R. P.; Cao, G.; Kirchmeier, R. L.; Shreeve, J. M. J. Org. Chem. 1999, 64,2873-2876. 24. Burton, D. J. in Synthetic Fluorine Chemistry, Edited by Olah, G. A.; Chamber, R. D.; Prakash, G. K. S., Wiley: New York, 1992, pp 212. 25. Urata, H.; Fuchikami, T. Tetrahedron Lett. 1991, 32, 91. 26. Yamamoto, T.; Watanabe, H. JP 2001-039942, 2001. 155 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 6 Synthesis of Partially Fluorinated Ethers by Alkylation of Fluorinated Alkoxides Generated from Fluoroacyl Halides and The Fluoride Ion Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 6.1 Introduction In general, carbon-fluorine bonds (C-F, -116 kcal/mol) are stronger than carbon-hydrogen bonds (C-H, -99 kcal/mol).1 However, not all organofluorine compounds are more stable than their non-fluorinated analogs, and sometimes they are even less stable. For instance, if a partially or fully fluorinated organic compounds contains acidic hydrogen at the /3 position, HF elimination is observed. This is the main reason that a-fluoro alcohols are thermally unstable and difficult to be synthesized or isolated.2 Formation of fluoromethanol (FCH2OH) from ethyl fluoroformate and from formyl fluoride was first reported by Olah and Pavlath in 1953, and Weinmayer4 in 1963 claimed that the formation of fluoromethanol (25- 30% in equilibrium) from a solution of paraformaldehyde in hydrogen fluoride. But both groups were unable to isolate and characterize the pure compound. Trifluoromethanol (CF3OH) has been prepared, purified and characterized from trifluoromethyl hypochlorite and hydrogen chloride by Kloter and Seppelt5 in 1979, but it decomposes readily above -20 °C. Stable protonated a-fluoro alcohols in condensed state or in crystalline state have been known, such as protonated fluoromethanol (FCH20H2+ ) by Olah and Mateescu,6 protonated heptafluoroisopropanol {(CF3 )2C(F)OH2+} by Minkwitz and Reinemann,7 and protonated trifluoromethanol (CF3 0H2+ ) by Christe and co-workers.8 However, to our knowledge, the only a-fluoro alcohol stable in a pure form at ambient temperature reported so far is heptafluorocyclobutanol (C4F7OH), which was 157 permission of the copyright owner. Further reproduction prohibited without permission. prepared from hexafluorocyclobutanone and hydrogen fluoride by Andreades and England9 in 1961. All these difficulties in the preparation and isolation of a-fluoro alcohols make them not practical as reagents for organic synthesis, especially as an a-fluoro alkoxide (RfO') synthon. a-fluoro alkoxides, particularly perfluoroalkoxides, have been reported for more than thirty years. The first preparations of reasonably stable, crystalline perfluoroalkoxides of alkali metals, i.e. RfOM (Rf= CF3, M=K, Rb or Cs; Rf= CF3, C2F5, C3F7 or perfluoroisopropyl group, M=Cs or Rb), were reported by Redwood and Willis1 0 in 1965 and 1966. Pittman,1 1 Evans1 2 and their coworkers also reported the formation of adducts between fluorinated ketones and metal fluorides in 1965 and 1968, respectively. Above room temperature (20 °C), these metal perfluoroalkoxides decompose into metal fluorides and acyl fluorides or ketones,1 0 which indicates their relatively lower nucleophilicity compared with their non- fluorinated alkoxide analogs. And in the following twenty years, only few synthetic applications of these perfluoroalkoxides have been explored, such as reactions with unsaturated acyl chloride,1 3 with allyl bromide,1 0 1 3 with olefin in the presence of a halogen,1 4 with epibromohydrin11 and fluoroolefm epoxides.1 5 Tris(dimethylamino)sulfonium trifluoromethoxide (TAS+ CF3O ) was also reported as a stable crystalline compound by Famham and co-workers in 1985,1 6 but its synthetic application has not been well investigated. In the last decade, partially fluorinated ethers, or so-called “hydrofluoroethers (HFE)”, have attracted an increasing interest as refrigerants especially in industry as 158 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. promising substitutes for ozone-depleting chlorofluorocarbons (CFCs). According to Montreal Protocol and its appended amendments, the production and use of CFCs must be discontinued.1 7 Partially fluorinated ethers (RfOR), as a class of compounds, are particularly spotlighted as promising replacements for CFCs not only because of their zero potential and low toxicity, but also because they exhibit excellent solvent properties—they can dissolve both hydrocarbon based and fluorocarbon based 1 R materials. These partially fluorinated ethers can be extensively used as detergents, solvents, lubricants, heat-transfer media, and so on.1 9 ,2 0 These fluoroethers can be synthesized by two categories of methods: methods of fluorinating an ether compound, and methods where the ether linkage is formed during a compound reacting with a fluorinated precursor.1 8 ,2 1 The latter methods are more popular, such as acid catalyzed alkylation of perfluoroacyl fluoride with alkyl fluoride,1 8 and alkylation of perfluorinated alkoxides prepared by the reaction of the corresponding perfluorinated acyl halide or perfluorinated ketone with an anhydrous metal fluoride | A AA *)A an anhydrous polar, aprotic solvent. ’ ' Since the acid catalyzed alkylation of 1 R perfluoroacyl fluorides normally gives low yields and complex isomerization, non- catalytic alkylation of perfluoroalkoxides shows the more attractive practical features for industrial applications. Although in the recent years there have been several disclosures on this methodology using different alkylating agents (such as alkyl fluorovinylalkyl ether,2 5 dimethyl sulfate1 9 and alkyl triflate2 6 ); gaseous short-chain perfluoroacyl halides are often used, and the results are only recorded in industrial patents without full characterization. 159 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Recently, we were interested in developing new types of fluorinated compounds as low temperature lithium battery electrolyte co-solvents. Partially fluorinated ethers are one of our prime candidates, since these compounds can increase the battery’s discharge capacity during charge/discharge cycle, by forming a stable coating on the surface of the negative electrode and suppressing the 77 7S degradation of the non-aqueous electrolyte. ’ Herein, we wish to report the synthesis of these partially fluorinated ethers by alkylating fluorinated alkoxides generated from short or long chain fluorinated acyl chloride and potassium fluoride. 6.2 Results and discussion 6.2.1 Dimethyl sulfate as the alkylating agent Dimethyl sulfate is a powerful alkylating agent and has been used for the methylation of almost every imaginable nucleophile.29 Using dimethyl sulfate as methylating agent, we successfully synthesized fluoroalkyl methyl ethers 2 (see Scheme 6.1). O 1) KF/dilyme i i RfC-CI RfCF2OCH3 2) Me2S0 4 1 2 Scheme 6.1 Synthesis of fluoroalkyl ethers (2). 160 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Fluorinated acyl chlorides 1 are the preferred precursors of 1,1- difluoroalkoxides, since fluoroacyl chlorides have higher boiling points than the corresponding fluoroacyl fluorides. During the reaction, fluoroacyl chloride can be fluorinated by KF to fluoroacyl fluoride 4 in situ,1 9 and the latter is easily transformed into fluoroalkoxide 5 (see scheme 6.2). Diglyme is the solvent of choice due to it’s high polarity and excellent solvation of the in situ generated fluorinated alkoxides 5. 19,25 © RfC-CI ( R ^ C I © RfC-F ( ?" RfC-F F Me2S0 4 Scheme 6.2 Proposed mechanism for the formation of 2 from 1. Typical reaction condition is as follows: perfluorooctanoyl chloride la (30 mmol) is reacted with anhydrous KF (90 mmol) in dry diglyme at 50 °C for 30 minutes, followed by a slow addition of dimethyl sulfate (60 mmol) at 70 °C. The reaction mixture was kept at 70 ~100 °C for another 1 hour, cooled to room temperature and stirred overnight. The ester by-product (RfCOOMe) can be removed 161 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. from ether product 2 simply by stirring the reaction mixture in a NaOH aqueous solution. After workup, perfluorooctyl methyl ether 2a can be isolated in 80% yield. Table 6.1 Preparation of fluoroethers 2 from fluorinated acyl chlorides 1, KF and dimethyl sulfate in diglyme. Reactants 1 Products 2 Yields (%)a n -C 7 F15COCI n-CaFi 7COCI /7-C9F19COCI CCIF2COCI <^^-c f 2co ci F F F F c io c y ; co ci F F n“C8F17OCH3 80 /7-C9F19OCH3 71 n-CioF2iOCH3 62 OCIF2CF2OCH3 48 ^ ~ ^ - C F 2CF2OCH3 23 CH3OCF2CF2CF2CF2CF2OCH3 50 a F—v\ / ^ C F 2OCH3 0 ( / - COCl < ^ J > - C F 2OCH3 0 o o II II C I-C -C -C I. CH3OCF2CF2OCH3 a All are isolated yields; methyl triflate was also tried as methylating reagent, but the reaction was not successful. 1 6 2 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. As shown in table 6.1, both short chain perfluoroacyl chlorodes (C i-G *)1 9 and long chain perfluoroacyl chlorides (Q~Cg) gave good yields of methylated products 2a~2c. For the other non-perfluorinated substrates Id and le, the reactions gave lower yields. For the substrates without fluorine atoms at the a-carbon to the carbonyl group (see lg and lh), the reaction did not work. These various yields of fluoroethers can be roughly explained by the stability and the nucleophilicity of each fluoroalkoxide 5 (RfCF20') generated in the reaction. Since these fluoroalkoxides exist in equilibrium with metal fluoride and fluoroacyl fluorides as shown in scheme 2, the weaker fluoroalkoxide would have a higher tendancy to decompose into the metal fluoride and acyl fluoride. Among these fluoroalkoxides 5, the trifluoromethoxide ion (i.e. Rf = F) is the most stable one, because the negative charge on the trifluoromethoxide ion rests formally on the oxygen atom, with sharing to some extent by the three fluoride atoms because of their greater electronegativity.1 0 When the Rf is changed to a perfluoroalkyl group, such as in la, lb and lc, the longer the perfluoroalkane chain makes the carbon atom connecting to CF2O' less electronegative, resulting in the lower stability of that alkoxide and then somewhat lower yields of the ethers. When Rf = Cl (Id), the ether yield is moderate; and when Rf - phenyl group (le), the yield of ether is much lower because the phenyl group has even weaker electron-withdrawing ability than the chlorine atom. In the case of lg-li, although these acyl chlorides can be transformed into corresponding acyl fluorides 4g-4i (detected by NM R), they failed to produce the ether product 2g, 2h or 2i indicating that these acyl fluorides 4g-4i are not further 163 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. fluorinated into alkoxides 5g-5i, probably due to their instability. Finally, it is also remarkable that the diacyl chloride I f can be transformed into the diether 2 f in good yield. (a) 'a ...,u\\F (Me2N)S+ C-O: 1.227 A C-F: 1.390-1.397 A O’ O O O | | | when | R f ^ l ^ F R f ^ l F R f ^ ^ F Rf=F Rf" P ^ F F F F F ® a 5b 5c 5d Scheme 6.3 (a) C-0 and C-F Bond lengths from (Me2 N)3 S+ CF3 0 ‘ X-ray crystal structure;1 6 3 (b) Negative hyperconjugation in fluorinated alkoxide (5). The relative stability and nucleophilicity of fluoroalkoxide 5 can also be explained by negative hyperconjugation (HCJ)30 as shown in Scheme 6.3. Farnham and coworkers have explained the structural parameters of (Me2N)3S+ CF3O' by HCJ. Their evidence for HCJ is that the X-ray structure shows the C-0 bond to be unusually short (1.227 A) and the C-F bond is extraordinarily long (1.390-1.397 164 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. A).1 6 a Thus we can derive that for the other fluorinated alkoxides (Rf ^F), strong electron-withdrawing property of Rf group may facilitate the HCJ between 5a, 5b and 5c, which stabilizes the corresponding alkoxides and increases their reactivity toward alkylating agent such as dimethyl sulfate. 6.2.2 Alkyl sulfonates as alkylating agents Besides dimethyl sulfate, we also attempted to use other strong alkylating agents to prepare partially fluorinated ethers, such as methyl trifluoromethanesulfonate (methyl triflate), ethyl triflate, hexyl triflate, methyl methanesulfonate (methyl mesylate) and methyl />-toluenesulfonate (methyl tosylate). The reaction conditions were similar to as previously studied reactions with dimethyl sulfate reactions (Scheme 6.4). The results are summarized in Table 6.2 . O 1) KF/dilyme n RfC-CI RfCF2OR 2) Alkyl sulfonate 1 6 Scheme 6.4 Synthesis of fluoroalkyl ethers (6 ) using alkyl sulfonates as alkylating agents. 165 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 6.2 Preparation of fluoroethers 6 from fluorinated acyl chlorides 1, KF and alkyl sulfonates in diglyme. Reactants 1 Alkyl sulfonate Products 6 Yields (%)a a n-C7 F15COCI CF3 SO3 CH3 n-C8 F1 7 OCH3 82 b n-C/F-jgCOCI Methyl mesylate /7-CgF’ )7 OCH3 29 c n-Cj F1 5 COCI Methyl tosylate n-C8 Fi7 OCH3 17 d n-C7 F15COCI CF3 S 0 3Et n-CgFi7 OCH2 CH3 n-C8 F1 7 OCH3 34 51 85 e n-C7F 1 5 COCI CF3 S 0 3 nC6 Hi3 n-C8 Fi7 OnC8 Hi3 n-C8 F1 7 OCH3 60 15 75 a All are isolated yields. The effect of different alkylating agents on the yields of ether product 6 can be clearly seen from Table 2 (entries a-c). Since the order of methylating ability is methyl triflate > methyl mesylate > methyl tosylate, the yields of methyl perfluorooctyl ether are in the same order. It is interesting note that in the case of ethylation and hexylation reactions using ethyl triflate and hexyl triflate, respectively (entries d and e), each reaction gives the methyl ether (n-CsFnOCHs) besides expected product (6d or 6e). The mechanism of formation of methyl ether is 166 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. proposed as shown in Scheme 6.5. At first, ethyl or hexyl triflate can react with diglyme solvent to form Meerwein-type3 1 oxonium ion 7, which can further methylate the fluorinated alkoxide to form 2a. diglyme \ / \ /— \ / +0 O O RfCF2OR 6 RfCF2OCH3 2a + R s /— \ / — \ / o o o R CF3 SO3 7 ( R = Ethyl, hexyl groups; Rf = C8F17. ) Scheme 6.5 Proposed mechanism of formation of the methyl ether 2a via an alkylated diglyme oxonium ion 7 intermediate. 6.2.3 Attempted reactions with other electrophiles We also attempted to react fluorinated alkoxide 5a with other electrophiles, such as methyl iodide, acetyl chloride, benzoyl chloride, triflic anhydride, allyl bromide, acryloyl chloride, methyl chloroformate, propyl chloroformate, and N,N- carbonyl diimidazole (Scheme 6.6). Unfortunately, all these reactions did not give 167 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. the expected products. This means that for the long chain perfluoroalkoxides 5, very strong electrophiles is necessary (Scheme 6.6). [RfCF20 'K +] 1 4 5 9 Rf - C7F15 E+ : c h 3i c h 3c o c i . PhCOCI Triflic anhydride CH2=CHCOCI CH2=CHCH2Br CH30C(0)CI PrOC(0)CI RfCF2OCH3 RfCF20C(0)CH 3 RfCF20C (0)Ph RfCF2OS(0)2CF3 RfCF2OC(0)CH=CH2 RfCF2OCH2CH=CH2 RfCF20C (0)0C H 3 RfCF2OC(0)OPr Carbonyl diimidazole RfCF2OC(0)OCF2Rf Scheme 6.6 Attempted reactions of fluoroalkoxide 5 with other electrophiles. 6.2.4 Attempted synthesis of partially fluorinated polyether With similar ether formation methodology methioned above, we tried to synthesize polyether 11 using ethylene glycol bistriflate 10 and hexafluoroglutaryl chloride If (Scheme 6.7). 168 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. o 0 (1) KF / diglym e n i i OCF2CF2CF2CF2CF2OCH2CH2- |- ci—c c f 2c f 2c f 2c - ci 10 11 Scheme 6.7 Synthesis of polyether 11. Hexafluorofluoroglutaryl chloride (3.6 mmol) is reacted with KF (21.6 mmol) in diglyme at 50 °C for 30 min, followed by addition of ethylene glycol bistriflate 10 out that the major products are some oligomeric compounds, and only around 5 % yield of relatively high molecular weight polymer was obtained as an oily liquid (average molecular weight = 1,413 according to SEC measurement using PEO as a standard). The above reaction is a typical A-R-A + B-R’-B type of step-reaction polymerization. For this type of polymerization it is well-known that monomer molecules are consumed rapidly without any concomitant large increase in molecular weight, which is totally different from chain-reaction polymerization. The low molecular weight of the product 11 may be also due to a side-reaction between ethylene ditriflate 10 and KF, or the Meerwein disproportion reaction between ethylene glycol bistriflate and diglyme solvent. These side reactions may upset the stoichiometric balance of monomers and then jeopardize the chain propagation (3.6 mmol) and the resulting reaction mixture was stirred at 70 °C for 20 h. It turns process. 32 169 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The Carother’s equation3 2 ,3 3 relates the average degree o f polymerization ( D P) to percent conversion of monomer: DP = 1 1 - p , in which p is the reaction conversion and it is defined as N0- N p = N o Here N is the total number of initial monomers, and No is the number of monomers after a given reaction period. In Table 1 we can see that the yield of 2f from If is 50 %, which means the yield of each ether linkage is (0.5)1 /2 = 71 %. Let’s assume the conversion (or yield) of ether linkage for each step in the polymerization reaction (Scheme 7) is similar as the formation of 2f from If. So we can approximately regard the reaction conversion p is 0.71, then the average degree of polymerization DP = 1 / (1 - 0.71) = 3.45. From this DP value, we can simply calculate the theoretical average molecular weight which is about 700. These kinds of low molecular weight oligomers are easy to dissolve in aqueous phase during work-up since they still have hydroxy or carboxylic acid functionality on their short chain end. This explains why finally we can only obtain small amount (5 %) of relatively high molecular weight polymer (Mw =1400). 170 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 6.3 Conclusion In conclusion, we have synthesized partially fluorinated ethers by alkylation of fluorinated alkoxides generated from fluoroacyl chlorides and potassium fluoride in diglyme. The success and different yields of the reaction are affected by two factors: one is the stability and nucleophilicity of the fluorinated alkoxide generated in situ; and the other is the electrophilicity of different electrophiles, such as alkylating agents. The new fluoroethers prepared appeared to be promising candidates for the lithium battery applications. 6.4 Experimental Section 6.4.1 General KF was dried at 300 °C under high vacuum for 10 hours and stored under argon. Diglyme was distilled over calcium hydride. Dimethyl sulfate was purchased from Aldrich chemical Co., and other fluoroacyl chlorides were purchased from Synquest laboratories, Inc. or prepared from the corresponding carboxylic acid with PC15 or SOCl2. *11 , 1 3 C and 1 9 F NMR spectra were recorded on Bruker AMX 500 and AM 360 NMR spectrometers. T H NMR chemical shifts were determined relative to internal (CH3)4Si (TMS) at 8 0.0 or to the signal of a residual protonated solvent: CDCI3 8 7.26. 1 3 C NMR chemical shifts were determined relative to internal TMS at 8 0.0 or to the 1 3 C signal of solvent: CDCI3 8 77.0. 1 9 F NMR chemical shifts were determined 171 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. relative to internal CFCI3 at 5 0.0. Infrared spectra were obtained on a Perkin-Elmer Spectrum 2000 FT-IR spectrophotometer. Mass spectra were recorded on Hewlett Packard 5890 Gas Chromatograph with a Hewlett Packard 5971 Mass Selective Detector at 70 eV. 6.4.2 Methyl perfluorooctyl ether (2a) In a 200 ml three-neck flask equipped with a dropping funnel, a magnetic stirring bar and condenser, was added 5.23 g of anhydrous KF (90 mmol) and 16 ml of freshly distilled diglyme under argon atmosphere. The temperature was raised to 50 °C, and 13.0 g perfluorooctanoyl chloride was added in slowly via dropping funnel over 30 minutes period. Then the temperature was raised to 70 °C and 7.57 g dimethyl sulfate (60 mmol) was dropped in slowly, and the reaction mixture was kept stirring at 70-100 °C for another 1 hour. The mixture was cooled and stirred overnight at room temperature. The volatile material (-25 g) was distilled into a liquid nitrogen trap by high vacuum, followed by washing with cold 10 % NaOH aqueous solution, brine and water respectively. After drying over anhydrous sodium sulfate, the crude product mixture was fractionally distilled. Totally 10.8 g (80% yield) of 2a was isolated as colorless liquid, b.p. 61 °C/26 mmHg. *H NMR(CDCl3, ppm): 8 3.73 (s, 3H); 1 3 C NMR(CDCl3,ppm): 5 51.25 (t, J = 7.7 Hz), 109.38-120.15 (m); 1 9 F NMR(CDC13 j ppm): 8 -81.49 (t, J = 9.2 Hz, 3F), -88.76 (m, 2F), -122.57 (m, 4F), -122.87 (m, 2F), -123.33 (m, 2F), -125.85 (m, 2F), -126.77 (m, 2F). IR (neat): 172 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2976, 1793,1460,1349,1206,1010, 879, 723, 704, 659, 561, 529 cm'1 . MS (relative intensity): 449 (0.7, M+ -l), 431 (30, M+- F), 381 (18), 331 (6), 281 (2), 231 (6), 181 (9), 169 (20), 131 (35), 119 (21), 100 (15), 81 (100), 59 (50). 6.4.3 Methyl perfluorononanoyl ether (2b) In a 50 ml three-neck flask equipped with a condenser, a stirring bar and two rubber septa, was added 2.41 g anhydrous KF (41 mmol) and 10 ml of dry diglyme under argon atmosphere. At 50 °C, 5.0 g perfluorononanoyl chloride (10 mmol) was added in slowly via a syringe. After 30 minutes at 50 °C, the temperature was raised to 70 °C slowly, followed by slow addition of 3.92 g dimethyl sulfate (30 mmol). The reaction mixture was stirred at 70 °C for 1 hour, then at 100 °C for another 1 hour. The reaction mixture was cooled, and stirred overnight at room temperature. The reaction mixture was mixed with 20 ml of ether and washed with cold 10% NaOH aqueous solution for 3 times. The ether layer was washed with brine and water 3 times, respectively. The ether phase was dried over magnesium sulfate. After filtration, the solvent was evaporated. The crude product was fractionally distilled and 3.66 g (71 %) of 2b was isolated, b.p. 80-81 °C/36 mmHg. *H NMR(CDC13 , ppm): 5 3.73 (s, 3H); 1 3 C NMR(CDCl3,ppm): 5 51.40 (t, J - 7.0 Hz); 105.28 - 122.00 (m); 1 9 F NMR(CDC13, ppm): 5 -81.54 (t, J = 9.3 Hz, 3F), -88.81 (m, 2F), -122.56 (m, 6F), -122.88 (m, 2F), -123.34 (m, 2F), -125.88 (m, 2F), -126.81 (m, 2F). MS (relative intensity): 481 (0.1, M+ - F), 463 (9), 413 (4), 281 (0.7), 231 (4), 181 (4), 169 (4), 151 (3), 131 (15), 119 (6), 100 (7), 81 (100), 69 (22), 51 (22). 173 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 6.4.4 Methyl perfluorodecanoyl ether (2c) In a 200 ml three-neck flask equipped with a stirring bar, a condenser and two rubber septa, was added 5.0 g of anhydrous KF (86 mmol) and 20 ml of dry diglyme under argon atmosphere. At 50 °C, 12.0 g perfluorononanoyl chloride (22 mmol) made from perfluorononanoic acid and thionyl chloride, was dissolved in 10 ml diglyme and added in reaction mixture slowly via a syringe. After 30 minutes at 50 °C, the temperature was raised up to 70 °C slowly, followed by the slow addition of 8.51 g dimethyl sulfate (66 mmol). The reaction mixture was stirred at 70 °C for 1 hour, then at 100 °C for another hour. The reaction mixture was cooled, and stirred overnight at room temperature. The reaction mixture was added in 20 ml of ether and washed with cold 10% NaOH aqueous solution for 3 times. The ether layer was washed with brine and water 3 times, respectively. The ether phase was dried over magnesium sulfate. After filtration, the solvent was evaporated. The crude product was fractionally distilled and 7.68 g of 2c (62%) was isolated, b.p. 84-85 °C/27 mmHg. * 1 1 NMR (acetone-d^ ppm): 8 3.83 (s, 3H); 1 3 C NMR(acetone-d6, ppm): 8 51.49 (t, J - 6.4 Hz); 106.14-123.16 (m); I9 F NMR(acetone-d6> ppm): 8 -81.29 (t, J = 9.2 Hz, 3F), -87.84 (m, 2F), -121.74 (m, 8F), -122.19 (m, 2F), -122.70 (m, 2F), - 125.32 (m, 2F), -126.28 (m, 2F). 6.4.5 2-Chloro-l ,1,2,2-tetrafluoroethyl methyl ether (2d) 174 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chlorodifluoroacetyl chloride (Id)3 4 : Chlorodifluoroacetic acid (100 g, 0.766 mol) reacts with 1.5 equiv. PCI5 (239 g) at 90-100 °C for 3h, and the product was distilled out to give 40.5 g (36 % yield) Id, b.p. 28-29 °C, I9 F NMR (CDCI3, ppm): 8 -63.30. It was re-distilled before use. 2-ChIoro-l,l,2,2-tetrafluoroethyI methyl ether (2d): In a 200 ml three-neck flask equipped with a dry ice condenser, a stirring bar and two rubber septa, was added 20.0 g of anhydrous KF (430 mmol) and 20 ml of dry diglyme under an argon atmosphere. At 50 °C, 6.0 g chlorodifluoroacetyl chloride (40 mmol) made from chlorodifluoroacetic acid and phosphorus pentachloride, was added into the reaction mixture slowly via a syringe. After 30 minutes at 50 °C, the temperature was raised to 70 °C slowly, followed by slow addition of 8.51 g dimethyl sulfate (66 mmol). Reaction mixture was kept at 70 °C for 1 hour and then cooled down to room temperature, followed by stirring overnight. 10 ml of 10% NaOH aqueous solution was added into the reaction mixture, and the volatile product was fractionally distilled. Totally 3.24 g (48%) 3d was isolated. JH NMR(CDCl3,ppm): 6 3.73 (s, 3H); 1 3 C NMR(CDCl3,ppm): 8 51.77 (t, J = 6.1 Hz), 117.18 (tt, 1 JC .F= 271.5 Hz, 2 JC -f= 34.2 Hz), 120.77 (tt, 1 JC .F= 299.1 Hz, 2JC -f ~ 45.2 Hz); 1 9 F NMR(CDC13 > ppm): 8 -73.11 (t, J = 3.0Hz, 2F), - 93.09 (t, 1=3.0 Hz, 2F). 175 permission of the copyright owner. Further reproduction prohibited without permission. 6.4.6 Methyl 2-phenyl-l ,1,2,2-tetrafluoroethyl ether (2e) 2-Phenyl-2,2-difluoroacetyl chloride (le)3 5 ,3 6 : At 0 °C, into 21.95 g (0.13 mol) methyl benzoylformate, was slowly added 25.85 g (0.16 mol) (diethylamino)sulfur trifluoride (DAST). The reaction mixture was stirred at 0 °C for 0.5 h and then at 40 °C for another 4 h. The reaction mixture was cooled to room temperature and poured into 50 ml of ice water, followed by extraction with 50 ml CH2CI2. The organic phase was washed with saturated NaHCC> 3 aqueous solution and water. After drying over MgSC> 4 and solvent removal, 22.9 g crude methyl 1,1-difluorobenzylformate as a wine-red liquid, yield 92 %. ]H NMR shows the purity to be above 96 %. *H NMRfCDCH ppm): 5 3.84 (s, 3H), 7.40 (m, 3H), 7.61 (d, 2H); 1 3 C NMR (CDC13 , ppm): 8 53.60, 113.41 (t), 125.42, 128.60,131.03,132.65 (t), 164.7; 1 9 F NMR(CDCl3> ppm): 5 - 104.25. Into 22.84 g (0.122 mol) methyl 1,1 -difluorobenzylformate was added 100 ml of 2.5 M aqueous NaOH solution and 60 ml of THF, then the mixture was refluxed for 4 h. The reaction mixture was cooled and extracted with 200 ml of ether. The aqueous phase was acidified with 5 % HC1 until pH paper test showed acidic. The aqueous phase was extracted with 100 ml ether twice, and the combined ether phase was dried over MgSO.*. After solvent removal, 18.05 g yellow liquid was obtained, into which 150 ml hexane was added. The hexane solution was stored in refrigerator -10 °C overnight, and 9.06 g Needle-like crystalline product 2-phenyl-2,2- 176 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. difluoroacetic acid, was isolated by suction filtraction, 9.06 g, yield 46 %. X H NMR(CDCl3,ppm): 5 7.55 (m, 3H), 7.62 (d, 2H), 10.08 (b, 1H); 1 3 C NMR (CDC13 ) ppm): 6 112.99 (t, J = 252.3 Hz), 125.52, 128.79, 131.43, 131.85 (t, J = 25.1 Hz), 169.25 (t, J = 36.1 Hz); 1 9 F NMR(CDCl3;ppm): 8 * 105.85. Into 9.31 g (54 mmol) of 2-phenyl-2,2-difluoroacetic acid was added 35 ml of thionyl chloride, and the mixture was refluxed for 10 h under argon. Fractional distillation gave 9.4 g 2-phenyl-2,2-difluoroacetyl chloride (le), yield 91 %, b.p. 67 °C/15 Torr. X H NMR(CDC13, ppm): 5 7.51 (t, 3H), 7.58 (t, 1H), 7.63 (d, 2H); 1 3 C NMR (CDC13 , ppm): 5 114.41 (t, J = 259.0 Hz), 125.95 (t, J = 6.0 Hz), 129.03, 130.02, (t, J = 26.1 Hz), 131.95, 167.31 (t, J = 50 Hz); 1 9 F NMR(CDCl3,ppm): 5 - 101.32. Methyl 2-phenyl-l,l? 2,2-tetrafluoroethyI ether (2e): In a 200 ml three-neck flask equipped with a stirring bar, a condenser and two rubber septa, was added 8.6 g of anhydrous KF (148 mmol) and 20 ml of dry diglyme under an argon atmosphere. At 50 °C, 8.5 g le (44 mmol) was added into the reaction mixture slowly via syringe. After 30 minutes at 50 °C, the temperature was raised up to 70 °C slowly, followed by slow addition of 11.25 g dimethyl sulfate (89 mmol). The reaction mixture was stirred at 70 °C for 1 hour, then at 100 °C for another 2 hours. The reaction mixture was cooled, and stirred overnight at room temperature. The reaction mixture was mixed with 20 ml of CH2CI2 and washed with 177 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. cold 10% NaOH aqueous solution trice. The organic layer was washed with brine and water trice, respectively. The organic phase was dried over magnesium sulfate and the solvent was evaporated off. After column chromatography using hexanes as eluent, 2.10 g (23%) of 2e was isolated as a corjorless liquid. !H (CDCI3, ppm): 8 3.61 (s, 3H), 7.45 (t, 2H), 7.51 (t, 1H), 7.59 (d, 2H); 1 3 C (CDQ3,ppm): 8 51.03 (t, J = 6.7 Hz), 119.24(tt, 1 J C-f = 271 Hz, 2JC-f = 36 Hz), 114.44 (tt, 'J c-f ^ 271 Hz, 2JC-f = 36 Hz), 130.86 (t, J=24.5Hz), 126.61 (t, J = 6.7 Hz), 128.18, 130.98; 1 9 F (CDCl3,ppm): 8 -93.81 (t, J = 4.9 Hz, 2F), -114.08 (t, J - 4.9 Hz). MS (relative intensity): 208 (27, M+ ), 189 (4, M+ - F), 177 (0.3, PhCF2CF2 + ), 127 (100, PhCF2 + ), 81 (21, CH3OCF2 + ), 77 (9, Ph+ ), 51 (4). 6.4.7 1,5-Dimethoxy-perfluoropentane (2f) In a 50 ml three-neck flask equipped with a dropping funnel, a magnetic stirring bar and a condenser, was added 6.22 g of anhydrous KF (107 mmol) and 10 ml of freshly distilled diglyme under an argon atmosphere. The temperature was raised to 50 °C, and 1.64 g (5.92 mmol) If was added in slowly via syringe. Then the temperature was raised to 70 °C and 3.78 g dimethyl sulfate (30 mmol) was dropped in slowly, and the reaction was kept stirred at 70-100 °C for another 1 hour. The reaction mixture was cooled and stirred overnight at room temperature. The reaction mixture was washed with 10% NaOH aqueous solution and extracted with CH2C12, and the organic phase was washed with brine and water, respectively. After drying 178 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. over magnesium sulfate, the solvent was evaporated. After fractional distillation, about 5 g crude product was isolated, which contains diglyme. The diglyme was removed by washing with water and extracted with diethyl ether 10 times. After drying and removal of the solvent, 0.92 g (50% yield) of 2f was isolated as a colorless liquid. *H (CDCI3 , ppm): 8 3.72 (s, 3H); 1 3 C (CDC1 3 , ppm): 8 51.44 (t, J = 6.8 Hz), 105.58-120.22 (m); 1 9 F (CDChppm): 8 -88.80 (t, J = 9.2 Hz, 4F), -123.36 (m, 2F), -126.01 (m, 4F). MS (relative intensity): 311 (0.07, M+ ), 293 (18), 243 (2), 231 (5), 197 (0.7), 181 (3), 169 (10), 131 (9), 119 (3), 112 (4), 100 (7), 81 (100, CH3OCF2 + ), 69 (10). 6.4.8 Methyl triflate as alkylating agent In a 50 ml three-neck flask equipped with a magnetic stirring bar and a condenser, was added 0.54 g (9.3 mmol) of anhydrous KF and 10 ml of freshly distilled diglyme under argon atmosphere. The temperature was raised to 50 °C, and 1.0 g (2.3 mmol) perfluorooctanoyl chloride was slowly added in via a syringe. Then the temperature was raised to 70 °C and 0.76 g methyl triflate (4.6 mmol) was added in via syringe, and the reaction was kept stirredat 70-100 °C for another 2 hours. The reaction mixture was cooled and stirred overnight at room temperature. The reaction mixture was stirred in cold 30 % NaOH aqueous solution (10 ml) for 30 min, followed by extraction with 15 ml ether twice. The ether phase was washed with brine and water respectively. After drying over anhydrous sodium sulfate, the crude 179 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. product mixture was fractionally distilled to afford 0.85 g (82% yield) of the product as a colorless liquid. 1 H, 1 3 C, 1 9 F NMR and MS spectra indicate the product to be Methyl perfluorooctyl ether 2a. The reaction conditions for the methyl mesylate and methyl tosylate as alkylating agents are similar, except that the reaction times are longer (-20 h). The isolated yields of 2a are 29 % and 17 % respectively. 6.4.9 Ethyl triflate as alkylating agent In a 100 ml three-neck flask equipped with a magnetic stirring bar and a condenser, was added 2.69 g (46.2 mmol) of anhydrous KF and 10 ml of freshly distilled diglyme under an argon atmosphere. The temperature was raised to 50 °C, and 5.0 g (11.6 mmol) perfluorooctanoyl chloride was slowly added in via a syringe. Then the temperature was raised to 70 °C and 2.06 g ethyl triflate (11.6 mmol) was added in via syringe, and the reaction was kept stirred at 70-100 °C for another 2 hours. Then another 5g of ethyl triflate (28 mmol) was added into the reaction mixture and stirred at 100 °C for another 2 h. The reaction mixture was cooled and stirred at room temperature. The reaction mixture was treated with cold 30 % NaOH aqueous solution (15 ml) for 30 min, followed by extraction with 15 ml ether thrice. The ether phase was washed with brine and water respectively. After drying over anhydrous sodium sulfate, the crude product mixture was fractionally distilled to afford 4.54 g (85% yield) of the product as a colorless liquid, b.p. 50-52 °C/17Torr. 180 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1 H, 1 9 F NMR and GCMS showed that it contains two compounds: ethyl perfluorooctyl ether 6d and methyl perfluorooctyl ether 2a. The ratio of 6d : 2a = 2: 3. For 6d, ca. 34 % yield. ’H NMR (CDCl3 ,ppm): 5 1.36 (t, 3H), 4.13 (q, 2H); 1 3 C NMR (CDC13 ) ppm): 8 14.54, 61.79 (t, J = 5.9 Hz), 104 -120 (m); 1 9 F NMR (CDC13 , ppm): 8 -81.47 (t, J = 9.2 Hz, 3F), -85.80 (m, 2F), -122.61 (m, 4F), -122.89 (m, 2F), - 123.40 (m, 2F), -125.86 (m, 2F), -126.77 (m, 2F). MS (relative intensity): 463 (7, M+ -l), 449 (13), 331 (4), 232 (7), 219 (13), 181 (15), 169 (36), 131 (55), 119 (34), 100 (33), 95 (40), 69 (100). For 2a, ca. 51 % yield. The characterization data are same as in section 6.4.2. 6.4.10 Hexyl triflate as the alkylating agent In a 200 ml three-neck flask equipped with a magnetic stirring bar and a condenser, was added 2.0 g (34 mmol) of anhydrous KF and 30 ml of freshly distilled diglyme under an argon atmosphere. The temperature was raised to 50 °C, and 5.0 g (11.6 mmol) perfluorooctanoyl chloride was slowly added in via a syringe. Then the temperature was raised to 70 °C and 4.06 g (17.4 mmol) of hexyl triflate was added in via syringe, and the reaction was kept stirred at 70-100 °C for another 2 hours. Then another 1.4 g (6 mmol) of hexyl triflate was added into the reaction mixture, and stirred at 90 °C overnight. The reaction mixture was cooled and stirred with cold 30 % NaOH aqueous solution (20 ml) for 30 min, followed by extraction with 15 ml ether thrice. The ether phase was washed with brine and water 181 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. respectively. After drying over anhydrous sodium sulfate and removal of the solvent, the crude product was further purified by silica gel column chromatography (hexanes as eluent) to afford 3.6 g (60 % yield) of hexyl perfluorooctyl ether 6e as a colorless liquid, and 0.78 g (15 % yield) 2a. For 6e, 'H NMR (CDCI3 , ppm): 8 0.90 (t, J= 6.6 Hz, 3H), 1.26-1.42 (m, 6H), 1.69 (m, 2H), 4.04 (t, J = 6.6 Hz, 2H); 1 3 C NMR (CDC13 , ppm): 5 13.78, 22.43, 25.06, 28.73, 31.17, 65.72 (t, J = 5.1 Hz), 108.63- 118.36 (m); 1 9 F NMR (CDC13 , ppm): 5 -81.26 (t, J = 9.5 Hz, 3F), -85.68 (2F), - 122.46 (b, 4F), -122.74 (b, 2F), -123.24 (b, 2F), -125.74 (b, 2F), -126.62 (b, 2F). MS (relative intensity): 475 (0.7), 449 (0.7), 231 (1), 219 (2), 181 (3), 169 (10), 131 (30), 119 (16), 100 (12), 85 (15), 69 (100), 55 (73). For 2a, the characterization data are same as in section 6.4.2. 6.4.11 Attempted reactions with other electrophiles The reaction conditions for other electrophiles, such as methyl iodide, acetyl chloride, benzoyl chloride, triflic anhydride, allyl bromide, acryloyl chloride, methyl chloroformate, propyl chloroformate, and N,N-carbonyl diimidazole, are silimiliar as in section 6.4.2. For some volatile substrates, dry ice condenser was used as in section 6.4.5. 182 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 6.4.12 Attempted synthesis of partially fluorinated polyether (11) Ethylene glycol bistriflate (10)3 7 : A mixture o f dry ethylene glycol (1 g, 16.1 mmol) and anhydrous pyridine (3 ml) in dry methylene chloride (30 ml), was added dropwise into an ice-cooled, stirred solution o f triflic anhydride (9.1 g, 32.2 mmol) in 20 m l o f methylene chloride under argon. The solution was stirred for an additional 2h, then washed with water (100 ml) and dried over MgSC>4 . After removal o f the solvent, 4.5 g product 10 was obtained as a pale yellow crystalline solid, yield 8 6 %. *H N M R (CDCI3 , ppm): 8 4.77 (s, CH2 -CH 2); 1 3 C NM R (CDCI3 , ppm): 8 71.72, 118.53 (q, J = 319.5 Hz); 1 9 F N M R (CDCl3 ,ppm): 8 -74.77 Fluorinated polyether (11): In a 100 ml three-neck round bottom flask, was added 1.26 g (21.7 mmol) o f dry KF and 10 m l o f dry diglyme. At 50 °C, 1.0 g hexafluoroglutaryl chloride (3.6 mmol) was added via a syringe, and the reaction mixture was stirred for 30 min. Then the temperature was raised to 70 °C and 1.18 g ethylene glycol bistriflate (3.6 mmol) was added into the reaction mixture. The reaction mixture was stirred at 70 °C for another 1 h and then at 100 °C overnight. The reaction mixture was cooled and stirred with 30 % NaOH aqueous solution (10 ml), and then extracted w ith 15 m l ether thrice. Combined ether phase was washed w ith w ater twice. After drying over M gS 0 4 and solvent removal, the crude product was treated w ith high vacuum for 1 0 183 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. h to give 0.12 g of oily liquid (~ 5 % yield). 1 9 F NMR (CDCI3, ppm): -85.8 (-OCF2-, 4F), -123.1 (m, 2F), -125.9 (m, 4F). Size Exclusion Chromatography measurement with PEO standard curve gave the average molecular weight Mw = 1,413; Mn = 1,316; Mw /Mn = 1.07. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 6.5 References 1. Hiyama, T. ed. Organofluorine Compounds: Chemistry and Applications, Springer-Verlag, New York, 2000, p 2. 2. (a) Banus, J.; Emeleus, H. J.; Haszeldine, R. N. J. Chem. Soc. 1951, 60. (b) Haszeldine, R. N.; Emeleus, H. J. Research 1948,1, 715. (c) Haszeldine, R. N.; Sharpe, A. G. Fluorine and Its Compounds, Methuen, London, 1951, p 92. (d) Pearlson, W. H. Fluorine Chemistry, Vol. 1, Pergamon Press, Elmsford, N.Y., 1950, p 483. (e) Lovelace, L. M.; Rausch, D. A.; Postelnek, W. Aliphatic Fluorine Compounds, Reinhold, New York, 1958, p 137. 3. Olah, G. A.; Pavlath, A. Acta Chim. Acad. Sci. Hung. 1953, 3, 203, 425. 4. Weinmayer, V. J. Org. Chem. 1963, 28, 492-494. 5. Kloter, G.; Seppelt, K. J. Am. Chem. Soc. 1979,101, 347-349. 6. Olah, G. A.; Mateescu, G. D. J. Am. Chem. Soc. 1971, 93, 781-782. 7. Minkwitz, R.; Reinemann, S. Z. Anorg. Allg. Chem. 1999, 625,121-125. 8. Christe, K. O., personal communication with Professors Olah and Prakash. 9. Andreades S.; England, D. C. J. Am. Chem. Soc. 1961, 83, 4670-4671. 10. (a) Redwood, M. E.; Willis, C. J. Can. J. Chem. 1965, 43, 1893-1898. (b) Redwood, M. E.; Willis, C. J. Can. J. Chem. 1965, 45, 389-395. 11. Pittman, A. G.; Sharp, D. L. J. Polym. Sci., Part B, 1965, 3, 379-381. 185 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 12. Evans, F. W.; Litt, M. H.; Weidler-Kubanek, A-M; Avonda, F. P. J. Org. Chem. 1968, 5 ,1837-1839. 13. Pittman, A. G.; Sharp, D. L.; Lundin, R. E. J Polym. Sci., Part A-l 1966, 4, 2637-2647. 14. Evans, F. W.; Litt, M. H.; Weidler-Kubanek, A-M; Avonda, F. P. J. Org. Chem. 1968, 5,1839-1844. 15. Knunyants, I. L.; Shokina, V. V.;. Tyuleneva, V. V; Razumeeva, T. N. Izv. Akad. Nauk SSSR, Ser. Khim. 1972, 5, 1133-1137. (English translation) 16. (a) Famham, W. B.; Smart, B. E.; Middleton, W. J.; Calabrese, J. C.; Dixon, D. A. J. Am. Chem. Soc. 1985,107, 4565-4567. (b) Famham, W. B.; Middleton, W .J. Eur. Pat. Appl. 1985, EP 164124. 17. Zurer, P. S. Chem. & Eng. News 1993, Nov. 15, p 12. 18. Lamanna, W. M.; Flynn, R. M.; Vitcak, D. R.; Qiu, Z.-M. PCTInt. Appl. 1999, WO 9947480. 19. Takata, N., Mochizuki, T., Fujimoto, E., Sekiya, A., Jpn. Kokai Tokkyo Koho, 1998, JP 10045651. 20. Dams, R. J.; Qiu, Z.-M.; Smolders, Robert, R. L.; Coppens, D. M.; Nagase, M. PCTInt. Appl., 1999, WO 9916809. 21. Sekya, A.; Ito, H.; Yamashita, S.; Mochizuki, J. Jpn. Kokai Tokkyo Koho 1994, JP 06293686. 22. Wasaki, T.; Takada, N.; Fujimoto, E.; Sekya, A. Jpn. Kokai Tokkyo Koho 1997, JP 09040594. 186 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 23. Goto, Y.; Yamashita, S.; Ito, H.; Suga, A.; Mochizuki, J.; Nagasaki, N.; Sekya, A., Jpn. Kokai Tokkyo Koho 1995, JP 07179386. 24. Ito, H.; Goto, Y.; Yamashita, S.; Suga, A.; Mochizuki, J.; Nagasaki, N.; Sekya, A., Jpn. Kokai Tokkyo Koho, 1996, JP 08034755. 25. Behr, F. E.; Cheburkov, Y. PCTInt. Appl. 1999, WO 9937598. 26. (a) Goto, Y.; Yamashita, S.; Ito, H.; Suga, A.; Mochizuki, J.; Nagasaki, N.; Sekya, A. Jpn. Kokai Tokkyo Koho 1995, JP 07179387. (b) Ito, H.; Goto, Y.; Yamashita, S.; Suga, A.; Mochizuki, J.; Nagasaki, N.; Sekya, A. Jpn. Kokai Tokkyo Koho 1996, JP 08034754. 27. Sakaguchi, T.; Fujimoto, H.; Oshita, R.; Watanabe, H.; Noma, T.; Nishio, A. Jpn. Kokai Tokkyo Koho 1999, JP 11329491. 28. Nakajima, T.; Dan, K.; Koh, M.; Ino, T.; Shimizu, T. J. Fluorine Chem. 2001, 111, 167-174. 29. (a) Paquette, L. A. ed. Encyclopedia o f Reagents fo r Organic Synthesis, John Wiley & Sons: New York, 1995, p 2132-2135. (b) Suter, C. M. The Organic Chemistry o f Sulfur, Wiley: New York, 1944, p 48-74. (c) Kaiser, E. T. The Organic Chemistry o f Sulfur, Plenum: New York, 1977, p 649. 30. See 16a and the references therein. 31. Hassner A.; Stumer C. Organic Syntheses Base on Named Reactions and Unnamed Reactions, Pergamon: New York, 1994, p 250 and references therein. 32. Stevens, M. P. Polymer Chemistry, Oxford: New York, 1999, p 12-15. 33. Carothers, W. H. J. Am. Chem. Soc. 1928, 51, 2548. 187 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 34. Corley, R. S.; Cohen, S. G.; Simon, M. S.; Wolosinski, H. T. J. Am. Chem. Soc. 1956, 78,2608. 35. Parisi, M. F.; Gattuso, G.; Notti, A.; Raymo, F. M. J. Org. Chem. 1995, 60, ■ 5174-5179. 36. Kitazume, T.; Tsukamoto T.; Yoshimura, K. Chem. Comm. 1994, 1355- 1356. 37. Salomon, M. F.; Salomon, R. G. J. Am. Chem. Soc. 1979,101,4290-4299. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 7 Synthesis of Fluorinated Carbonates, Carbamates, and Some Polymeric Materials for Low Temperature Lithium-ion Battery Applications Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 7.1 Introduction 7.1.1 Partially fluorinated carbonates and carbamates Recently, there has been increasing awareness of the need to use energy more efficiently, including the efficient storage of electricity. The development of advanced batteries is one of the major efforts in this area.1 In the last decade several different battery systems were found to have promising performance for the zero emission electric vehicles, such as nickel-metal hydride, sodium-sulfur, and lithium ion systems.2 Lithium-ion battery is considered to be the most promising system and its development is considerably supported.3 ,4 This is mainly due to the unique and attractive performance of lithium-ion battery: lithium is the lightest element that can be handled in an electrochemical process and it exhibits the highest oxidation potential of any element,4 which enables lithium-ion battery to have extraordinarily high energy density. Besides the above aspect, there are other interests in improving the performance of lithium-ion battery, such as the development of novel lithium-ion battery electrolytes that posses enhanced safety characteristics and low temperature property, while still being able to provide the desired stability and performance. Partially fluorinated compounds have received some attention as co-solvent for lithium-ion battery electrolytes. Partially fluorinated compounds have unique properties such as good solubility in both fluorous and hydrocarbon solvents, low flammability, low freezing point, and high anti-oxidation ability, among others. With 190 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. these special properties, partially fluorinated compounds are expected to improved high-rate charge/discharge cycle, safety characteristics in low temperature lithium ion batteries.5 ,6 Recently, it has been demonstrated that lithium can be intercalated within graphite in trifluoropropylene carbonate (3-trifluoromethyl-2,5-dioxa- 7 0 cyclopentan-1 -one). ' Fluoroesters have also been studied with the intent of improving the low temperature characteristics and suppress the dendrite formation on lithium anodes.1 0 ,1 1 Partially fluorinated ethers have also been applied in the lithium-ion battery applications, which impart greater safety aspects to lithium ion systems, as well as resulting in batteries with improved low temperature performance.1 2 With our collaborative work with Jet Propulsion Laboratory (JPL), we were interested in the synthesis and investigating partially fluorinated carbonates and carbamates as lithium-ion battery electrolyte co-solvents. It is expected that these partially fluorinated carbonates and carbamates solvents will possess more desirable physical properties imparted by the presence of the fluorine substituents, such as lower melting points, increased stability toward oxidation, and favorable solid electrolyte interphase (SEI) film forming characteristic on carbon. In addition, these solvents can also lead to the development of safer lithium-ion batteries, due to their low flammability. 191 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 7.1.2 Polymeric materials for lithium-ion battery electrolytes Since Wright and coworker’s discovery of ionic conductivity in alkali metal salt complexes of poly(ethylene oxide) (PEO) in 1973,1 3 polymeric materials have been used as battery electrolytes for more than two decades because they combine the advantages of solid-state electrochemistry with the ease of processing inherent to plastic materials.4,14 A number of contributions have been made to this field, particularly in the understanding of molecular and supramolecular architecture, which is important for the fast ion transport in polymer electrolytes.1 5 Some have assumed that the crystalline domains are responsible for ion transportation, with the ions moving along the PEO helices as the primary mechanism; while others believe that the amorphous phase alone gives rise to ion transport.4,16,1 7 So far the latter explanation has gained support. Several different types of polymer as lithium-ion battery electrolytes have been studied, such as PEO, polysiloxane with PEO side chains, poly(phosphazene) with PEO side chains, poly(p-phenylene) (PPP) with PEO chains, and so on.4 For these polymer electrolytes, a consequence of the correlation between the segmental motion of the host polymer and the efficiency of ion transport is the search for low glass transition temperature (Tg) materials, i.e., host polymers with softening temperatures as low as possible, with the hope to achieve high ion conductivity at ambient temperatures.4 As shown in Fig 1, the mobility of the Li cation is related to the motions of the complexing segments of the polymer chain. 192 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. We were interested in designing some low Tg and high conductive polymeric materials that can be used as ideal electrolytes for lithium ion batteries. Here we wish to describe the syntheses of ethylene glycol/dichlorodimethylsilane copolymer, star shaped PEO, and other types of materials. Fig 7.1 Proposed Schematic of segmental motion assisted diffusion of Li+ ion in the ethylene glycol/dichlorodimethylsilane copolymer matrix. 7.2 Results and discussion 7.2.1 Partially fluorinated carbonates and carbamates It is well known dialkyl carbonates are good candidates as lithium-ion battery electrolyte co-solvents due to their high dielectric constant. However, few of partially or perfluorinated carbonates are known. Fluorinated carbamates are even less known. Here we synthesized six partially fluorinated carbonates 1-6 and two carbamates 7-8, among which compounds 4, 5 and 8 are new compounds. 193 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. R O A ci Et20 -HCI O (R1 = -OR, -NR2) Scheme 7.1 Synthesis of partially fluorinated carbonates and carbamates. Carbonates 1-5 can be synthesized from the corresponding chloroformate and alcohol (see Scheme 7.1). Typical procedure is as follows: Into a mixture of 2,2,2- trifluoroethanol (137 mmol) and triethylamine (2 eq.) in 140 ml ether at 0 °C, was added slowly via a dropping funnel ethyl chloroformate (1 eq.) in 30 ml ether. After the addition, the reaction mixture was refluxed for another 2 h with vigorous stirring. After workup, the crude product was distilled to give carbonate 1 in 65 % yield. As shown in Table 7.1, carbonates 1-5 were prepared in good yields. However, when we attempted to use diethylcarbamoyl chloride and alcohol to synthesize carbamates 7 and 8 via same methodology, the reactions did not work (see Table 7.1). This indicates that the carbamoyl chloride is less reactive than chloroformate, which can be explained by the resonance stabilization of the carbonyl group (Scheme 7.2). 194 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 7.1 Synthesis of carbonates from chloroformate and alcohol. R product yield (%)a EtO CF3CH2 x c h 3c h 2o OCH2CF3 (1) 65 (99b) EtO (CF3)2CH CH3CH20^'0C H (C F 3)2 (2) 81 MeO c f 3c h 2 c h 3o OCH2CF3 (3) 73 MeO c f 3c h 2c h 2 CH30 '^ '0 C H 2CH2CF3 c h 3c h 2c h 2o OCH2CF3 A (4) 75 PrO c f 3c h 2 (5) 77 Et2N c f 3c h 2 X (CH3CH2)2N OCH2CF3 /N (7) 0 Et2N (c f 3)2ch (CH3CH2)2N OCH(CF3)2 (8 ) 0 “ Isolated yields in 10 g scales; isolated yield in 120 g scale. ■ X N Cl O n / N Cl 8 ci O 'Cl Scheme 7.2 Different reactivities of carbamoyl chloride and chloroformate. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. To solve this problem, we just simply transformed the alcohol to corresponding sodium alkoxide using sodium hydride or sodium metal, in order to enhance the nucleophilicity of the oxygen atom. By using this method, we successfully synthesized carbamates 7 and 8 in excellent yields (see Scheme 7.3). NaH or Na Et2NCOCI ROH - ..~ ...... ► RONa_ -____________► Et2NCOOR Et20 - NaCI -20 ~0°C R: -CH2CF3 7 91% -CH(CF3)2 8 92% Scheme 7.3 Synthesis of partially fluorinated carbamates. In the case bis(2,2,2-trifluoroethyl)carbonate 6, we had to use a different 1 R approach. In 1986, Smart et al. prepared this compound for fluorocarbanion study. They applied phosgene to react with 2,2,2-trifluoroethanol in the presence of pyridine in ether solution, and obtained product 6 in 88% yield. Instead of inconvenient and dangerous phosgene, we used N, N ’-carbonyl diimidazole as the phosgene equivalent reagent, and the reaction worked equally well (see Scheme 7.4). J * c f 3c h 2o h ♦ u CF*0H2cr OCH2CF3 (2 eq.) (1 eq.) - 71 % Scheme 7.4 Synthesis of bis(2,2,2-trifluoroethyl)carbonate 6. 196 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 7.2.2 Polymeric materials for lithium-ion battery electrolytes (a) Copolymer of ethylene glycol and dichlorodimethylsilane We attempted to synthesize ethylene glycol/dichlorodimethylsilane coplomer copolymer 9 via a condensation polymerization of two monomers: ethylene glycol and dichlorodimethylsilane (see Scheme 7.5). The reaction was carried out in THF as solvent. The reaction was facile, and the byproduct HC1 was generated which can be used as an indicator for the reaction progress. After the completion of the reaction, we got some oligomeric products as sticky liquid in almost quantitative yield. An attempt to remove low molecular species by vacuum distillation surprisingly gave us a crystalline compound 10 in 56 % yield (m.p. 57-59 °C) and 43% yield o f polymer 9 with molecular weight around 2000 and Tg = -128 °C. For the material 10, ^ NMR shows two singlets at 0.07 and 3.77 ppm with a relative integration 3:2. 1 3 C NMR shows two types of carbon atoms whose chemical shifts are -3.49 and 64.47 ppm, respectively. 2 9Si NMR shows it contains one type of silicon with chemical shift - 5.11 ppm. All these data indicate that compound 10 should have a cyclic structure (see Scheme 7.6). But the exact structure can not be determined based on NMR data alone. 197 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. n CH^ y C\ + .S i O H O H CH / \ C | T H F , 0 ° ~ 5 0 ° C n f H s - o O — S i— I c h 3 9 Scheme 7.5 Synthesis of ethylene glycol/dichlorodimethylsilane copolymer 9. We were interested in identifying the structure of cubic crystalline compound 10. Krieble and Burkhard1 9 reported the reaction between ethylene glycol and dichlorodimethylsilane in 1947. They did the reaction without any solvent and also obtained a crystalline compound and an oil-like polymer. Based on the elemental analysis and the ring strain consideration, they assumed that the crystalline compound 10 should have a 10-member-ring dimeric structure (see Scheme 7.6, structure b). After that, several other groups reported this reaction and argued about the structure of the crystalline compound they all observed. Some of them just quoted Krieble and Burkhard’s assumption1 9 and believed that it had a 10-member- r ~ A v \ ; h3 o H3C ^ / 0 S yCH3 h3 c Si Si / s ‘ h3 c o o ; CHs H 3° o °\ ,CH3 S i ^ C H 3 ,o n Scheme 7.6 Possible structure for compound 10 198 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 'jr\ ’ ja ring structure. In 1984, Cragg and Lane mentioned this compound in one review. From all the previously reported results, they concluded that 10-member-ring dimer formation is expected unless both the silicon and ethylene carbon atoms are fully substituted, as in the reaction between dichlorodimethylsilane and different pinacols, when 5-member-ring monomeric compounds will be formed. They also explained that this phenomenon is the consequence of the balance between a relatively straight angle in the Si-O-Si linkage and the steric effect of the R2, R3 group to the Si-O-C linkage (see Scheme 7.7). R2 H 3C . .C l X + R1 C l HO- HO- R 5-member-ring 10-member-ring ,3 Scheme 7.7 Formation of 5- and 10-member-ring products. 'y f s However, Hayes and Bowie opposed these reports by ion cyclotron resonance (ICR) study. They stated “it is reported that this compound exists as the dimer. The ICR shown is clearly that of the monomer (5-member-ring).” Kober and Ruhl2 7 also claimed that they prepared the 5-member-ring compound using organoarsenic precursor, based on the *H NMR and Mass Spectroscopy measurements. More recently, compound 10 was disclosed to be applied as a froth former in coal floatation.2 8 199 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Thus, although several groups have already noticed this crystalline compound 10 and all the reported melting point are almost same as ours (-57 °C), its exact structure is still not confirmed and actually is under argument in the literature. Since the NMR, elemental analysis, or other measurement such as ICR can not give the exact structural information, we have carried out the X-ray single crystal structure measurement. With quite low R value (3.4 %), the X-ray structure shows the structure of 10 to be the 10-member-ring, 2,2,7,7-tetramethyl-l,3,6,8-tetraoxo-2,7- disilacyclodecane (see Fig 7.2). C5 C7 Sis 03 04 C 6 ca cs Fig 7.2 X-ray structure of 2,2,7,7-tetramethyl-l,3,6,8-tetraoxo-2,7-disilacyclodecane 10. 200 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. It is interesting that compound 10 can slowly ungergo self ring-opening polymerization (ROP) even in a sealed flask under atmosphere to form oil-like polymer. This type of self ROP was demonstrated by 'H NMR spectra as shown in Fig 7.3. Pure compound 10 has only two clean singlets (0.07; 3.77 ppm) corresponding to four methyl roups and four methylene groups (Spectra A). After standing at room temperature for 30 days, both methyl and methylene groups are split into several peaks (see Spectra B), indicating ROP process leading to a linear polymer (if the polymer formed is cyclic, the methyl and methylene peaks should show two singlets). After 60 days, most of the compound 10 were transformed into polymer 9 via self ROP (see Spectra C). J JiA_ J jA L j l Oppm Fig 7.3 Self ring opening polymerization (ROP) of 10 [*H NMR (in CDCI3 )]. A: Pure compound 10; B: After standing at room temperature for 30 days; C: After standing at room temperature for 60 days. 201 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Another interesting phenomena is that under vacuum distillation condition (around 90°C/10 Torr), polymer 9 can be reverted into the cyclic compound 10 (see Scheme 7.8). The driving force of self ROP of 10 could be the strain force of its ring structure, and ROP process is very likely exothermic; while the ring closing process of polymer 9 may be driven by thermal molecular vibration energy as well as strong crystal lattice energy, and this process could be endothermic. 9 a: vacuum distillation or sublimation; b: standing at room temperature. Scheme 7.8 The formation of polymer 9 and cyclic compound 10. Based on the crown ether like structure of compound 10, we attempted to naked F' ion may participate in forming a Si—F— Si bridge, especially due to the strong Si-F bond energy (see Scheme 9). We dissolved compound 10 in dry THF, followed by adding dry LiF powder under argon atmosphere at room temperature. 10 a b OH OH THF or neat 0 - 60 °C I O O—Si C H 3 J n introduce LiF in the ring system. If the oxygen atoms coordinate with the Li+ ion, the 202 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 29 Unfortunately, the Si NMR showed that there was no interaction between 10 and LiF. Attempt to use NaF, KF, CsF, LiCl and LiF as LiF replacement also gave unsuccessful results. The reason probably is that the distance between two silicon atoms is too far (4.153 A) to bind F ion. H * % r V " 3 r 'N - c h 3 L iF THF r.t. O". h3c \ / Si---- / \ H 3 o : , ■ - - - o - \ / C H 3 • ' ........ .-Li ^ CH3 Scheme 7.9 Attempted formation of Si—F—Si bridge with cyclic compound 10. (b) Attempted synthesis of polysilane 11 functionalized with ethylene glycol At the same time, West’s group had reported the crystal structure of a perchlorinated polysilane 11 (see Scheme 7.10).29 We attempted to react 11 with ethylene glycol, hoping that structurally ordered product 12 can be formed. However, we only got rubber-like material which can only swell but can not dissolve in any common organic solvent. This indicates that a cross-linked polymer was formed (see Scheme 7.10). 203 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Li Ph. ,CI /Si n. Ph C l \ t h f {) Mg THF Ph Ph 1 I PfrSj Si-Ph Ph-Si— Si-Ph Ph Ph I hv, heat or even visible light I .■ ■ ■ ■ ■ ■ M il I . . . I I I . I .... ... ■■■■■t g l t1 •Si- i , 11 HCI(g)/ AICI3 cl'Si C l I -Si-CI PhH r ~ i OH OH -HCI Cl-Si— Si-CI C l C l 0 O 1 i -S i-S i 1 1 °L _ ? n i-Si- °ui _ i n 12 Cross-linked polymer Scheme 7.10 Attempted synthesis of functionalized polysilane 12. (c) Attempted Synthesis of copolymer of ethylene glycol and boron trichloride We also attempted to synthesize the copolymer of ethylene glycol and boron trichloride. However, the reaction could not give the expected cross-linked polymer, instead ethylene chloroboronate 13 and diethylene ethylene diborate 14 were produced in 72% and 11% yield respectively (Scheme 7.11).3 0 Gennari and coworkers have utilized compound 13 to prepare enolboronates, which are new practical synthons for regioselective aldol condensations.3 1 204 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. B -o!y O o - B O* v\> ‘ S - O 0 - B . / S _ < ^ b ' % P s 1 ^ l<n q 0 - 8 ° tj3 y . ° 7 r r ° - i ° v 0 . B ( p 7 b L - J B - 0 o_ / : 1 - s U t A vp • B - 0 ,O H J > / o V d O r- 9 n 0 ‘ <V° 0- -f fC °s /'-0- B . I A-o B ° c a/ 4 °i rc/°^\ > ? i o- * r ° \ °7/"<i'B n'\ L-fCb L° ^ b-o T7 f t — g _ 0__o ------- H B - O ^ * A 0 , , B . t f bci3 me OH 15 B I C l 13 o c h 2c h 2o -b ' 14 Scheme 7.11 Attempted synthesis of copolymer 15. (d) Synthesis of four-arm star shaped poly(ethylene oxide) (PEO) Star shape PEO may have unique physical properties such as low Tg and high conductivity, due to its high freedom of fragmental movement of the polymer “arms”. Four-arm star shape PEO can be synthesized by anionic polymerization of EO using potassium pentaerythritolate as an initiator (see Scheme 7.12).32 The polymerization was carried out in a dry and clean autoclave, the initiator and dry toluene solvent were added inside a glove box, and then the ethylene oxide was condensed inside autoclave through steel tubing. Then the reaction mixture was stirred at 75 °C for 20 hr. After cooling down, the reaction was quenched by adding 205 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. several drops of methanol. The polymer 16 was simply precipitated out in diethyl ether in almost quantitative yield. The molecular weight can be easily tuned by the ratio of EO monomer to initiator. The molecular weight distribution Mw/Mn normally is around 1.1-1.5. We also attempted to prepare star shaped poly(propylene oxide) using similar reaction conditions, but only small amount of low molecular oligomer was produced. C(CH2OH)4 - l K .:..°;TOH> K O v -OK o ( a )n H - 0 / KO \ ) K PhCH3, 75 °C H - (b) H + n— —n 16 H - H n/2 CH2N2, BF3-Et20 CH2CI2, 0°~RT H3C iO h , c - ° - V ^ O ,o— — o , n/2 17 c h 3 -C H 3 n/2 Scheme 7.12 Synthesis of four-arm star shape PEO. In order to fit the requirement of lithium-ion battery application, we also carried out the protection of the terminal hydroxyl groups on the polymer 16, simply using diazomethane as methylating agent (Scheme 12). 206 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 7.3 Conclusion In summary, we have successfully carried out the synthesis of partially fluorinated carbonates, carbamates, and other polymeric materials such as ethylene glycol/dichlorodimethylsilane copolymer, four-arm star shaped PEO. These compounds and materials are good candidates as low temperature lithium-ion battery electrolytes or co-solvents. 7.4 Experimental section 7.4.1 General Unless otherwise mentioned, all other reagents were purchased from commercial sources. Diethyl ether and THF were all distilled under nitrogen over sodium/benzophenone ketyl prior to use. Toluene was distilled over sodium. Column chromatography was carried out using silca gel (60-200 mesh). !H, 1 3 C and 1 9 F NMR spectra were recorded on Bruker AMX 500 and AM 360 NMR spectrometers. *H NMR chemical shifts were determined relative to internal (CH3 )4Si (TMS) at 8 0.0 or to the signal of a residual protonated solvent: CDCI3 8 7.26. 1 3 C NMR chemical shifts were determined relative to internal TMS at 8 0.0 or to the 1 3 C signal of solvent: CDCI3 8 77.0.1 9 F NMR chemical shifts were determined relative to internal CFCI3 at 8 0.0. IR spectra were obtained on a Perkin-Elmer FTIR Spectrum 2000. Mass spectra were obtained on a Hewlett Packard 5890 Gas 207 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chromatograph equipped with a Hewlett Packard 5971 Mass Selective Detector. Molecular weights were measured on a Size Exclusion Chromatograph with a standard curve. Glass transition temperature (Tg) was measured on a Perkin-Elmer Differential Scanning Calorimeter, DSC7 model. 7.4.2 Synthesis of partially fluorinated carbonates and carbamates Ethyl 2,2,2-trifluoroethyl carbonate (1): Under an argon atmosphere, into a 500 ml three neck round bottom flask equipped with a dropping funnel and a condenser, was added 10 ml (137 mmol) of 2,2,2-trifluoroethanol and 38 ml of EtsN in 140 ml dry ether. At 0 °C, 14.9 g (137 mmol) ethyl chloroformate in 30 ml ether was added slowly through a dropping funnel. After the addition, the reaction mixture was warmed up to room temperature, and kept under reflux for another 2 h. After cooling, the reaction mixture was washed with 150 ml of 10 % NH4CI aqueous solution. The aqueous phase was extracted with 50 ml ether again. The combined ether phase was washed with 100 ml of brine and 100 ml of water sequentially. After drying over MgSC>4, the organic mixture was fractionally distilled to give 15.35 g (yield 65%) product 1 as colorless liquid, b.p. 119-120 °C. *H NMR (CDCI3, in ppm): 8 1.35 (t, J = 7.4 Hz, 3H); 4.28 (q, J = 7.2 Hz, 2H); 4.51 (q, J = 8.3 Hz, 2H). 1 3 C NMR (CDCI3, in ppm): 8 13.47; 62.95 (q, 2JC -f = 37.2 Hz); 65.02; 122.72 (q, F = 277.3 Hz); 153.89. 1 9 F NMR (CDCI3, in ppm): 8 -74.91. 208 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The reaction was also carried out on a large scale (150 g), the isolated yield is 99%. Ethyl 1,1 » 1 j3,3»3-hexafluoro-2-propyl carbonate (2): Simliar procedure as the preparation of 1. Ethyl chloroformate (7.2 g, 66.5 mmol) was treated with 2,2,2- trifluoroethanol (11.2 g, 66.5 mmol) in 150 ml of ether in the presence of 18 ml of Et3 N to afford 12.9 g product 2, yield 81 %. B.P. 106-107 °C. *H NMR (CDC13, in ppm): 5 1.39 (t, J = 7.3 Hz, 3H); 4.37 (q, J = 7.3 Hz, 2H); 5.61 (m, J = 6.0 Hz, 1H). 1 3 C NMR (CDC13 , in ppm): 5 13.41; 66.59; 70.29 (m, 2JC -f = 34.9 Hz); 120.61 (q, ^c-f = 281.9 Hz); 153.10. 1 9 F NMR (CDC13, in ppm): 8 -74.18. Methyl 2,2,2-trifluoroethyl carbonate (3): Methyl chloroformate (11.34 g, 120 mmol) was treated with 2,2,2-trifluoroethanol (12.0 g, 120 mmol) in 100 ml of ether in the presence of 18 ml of Et3 N to afford 13.91 g product 3, yield 73 %. B.P. 27-30 °C/100 mmHg. *H NMR (CDC13, in ppm): 8 3.87 (s, 3H); 4.52 (q, J = 8.2 Hz, 2H). 1 3 C NMR (CDC13, in ppm): 8 55.85; 63.59 (q, 2JC -f = 36.5 Hz); 122.75 (q, 1 JC -f = 277.4 Hz); 154.78. 1 9 F NMR (CDC13 , in ppm): 8 -74.85. Methyl 3,3,3-trifluoropropyl carbonate (4): Methyl chloroformate (3.31 g, 35 mmol) was treated with 3,3,3-trifluoropropanol (4.0 g, 35 mmol) in 50 ml of ether in the presence of 5 ml of Et3 N to afford 4.5 g product 4, yield 75 %. B.P. 61-62 °C/10 mmHg. lH NMR (CDC13 , in ppm): 5 2.53 (m, 2H); 3.80 (s, 3H); 4.38 (q, J = 209 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 6.8 Hz, 2H). 1 3 C NMR (CDC13, in ppm): 8 33.71 (q, J= 29.2 Hz); 55.16; 61.06 (q, J - 3.7 Hz); 127.31 (q, J = 276.2 Hz); 155.54.1 9 F NMR (CDC13, in ppm): 8 -65.57. Propyl 2,2,2-trifluoroethyl carbonate (5): Propyl chloroformate (15.0 g, 122.4 mmol) was treated with 3,3,3-trifluoropropanol (12.24 g, 122.4 mmol) in 50 ml of ether in the presence of 17 ml Et3 N to afford 17.61 g product 5, yield 77 %. B.P. 72-74 °C/100 mmHg. *H NMR (CDC13 , in ppm): 8 0.98 (t, J = 7.4 Hz, 3H); 1.72 (m, J = 7.4 Hz, 2H); 4.18 (q, J = 6.8 Hz, 2H); 4.49 (q, J = 8.1 Hz, 2H). 1 3 C NMR (CDC13 , in ppm): 8 10.08; 21.95; 63.34 (q, J = 36.6 Hz); 70.91; 122.67 (q, J = 279.5 Hz); 154.14. 1 9 F NMR (CDC13 , in ppm): 8 -74.79. 2,2,2-Trifluoroethyl diethylcarbamate (6): Sodium 2,2,2-trifluoroethoxide (CF3CH20Na) prepared from 0.41 mmol CF3CH20H and 1 eq. NaH or sodium metal in dry ether in ether in -78 °C to room temperature under argon, was reacted with 13.56 g (0.1 mol) diethylcarbamyl chloride at 0 °C to room temperature. After similar workup as above, fractional distillation gave 18.17 g product 6, yield 91 %. B.P. 112-114 °C/174 mmHg. *H NMR (CDC13, in ppm): 8 1.15 (t, 2H); 3.30 (m, 4H); 4.49 (q, 6H). 1 3 C NMR (CDC13 , in ppm): 8 13.36; 13.95; 41.83; 42.68; 61.34 (q); 123.65 (q); 154.19. MS: 199 (M+ ). 1,1,1,3,3,3-Hexafluoro-2-propyl diethylcarbamate (7): Into a 250 ml three- neck round bottom flask equipped with a magnet stirring bar, a condenser and a 210 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. dropping funnel, was added 12.07 g (71.8 mmol) 1,1,1,3,3,3-heafluoro-2-propanol. Cooled down the flask to -78 °C and 886 mg small sodium metal slices were added into the flask under an argon atmosphere. With vigorous stirring, the reaction mixture was slowly warmed and the sodium metal reacted with alcohol smoothly. After all the sodium metal reacted, cooled down the reaction mixture to 0 °C, and 5.15 g (38 mmol) Et2 NCOCl was introduced slowly. An exothermic reaction ensued with the precipitation of NaCl salt. After another 2 h, the reaction mixture was quenched carefully with ice water and extracted with ether. The organic phase was further washed with water twice, and then dried over magnesium sulfate. After removal of ether solvent under vacuum, the crude product was fractionally distilled to give 9.35 g of product 7, b.p. 110 °C/204 mmHg, yield 92 %. *H NMR (CDCI3, in ppm): 8 1.18 (m, 6H); 3.35 (m, 4H); 5.70 (m, 1H). 1 3 C NMR (CDCI3, in ppm): 8 12.68; 13.37; 41.83; 41.87; 43.12; 67.90 (m); 120.86 (q); 152.21. MS: 267 (M+). Bis(2,2,2-trifluoroethyl)carbonate (8): Under an argon atmosphere, into the THF (100 ml) solution of carbonyl diimidazole (48.65 g, 0.3 mol), was added slowly CF3CH2OH (60 g, 0.6 mol). After the exothermic reaction faded, the reaction mixture was refluxed for another 15 h. After removal of the solvent under vacuum, the liquid crude product was distilled under high vacuum, followed by fractional distillation to give 42 g of product 8, b.p. 55-57 °C/100 mmHg, yield 71 %. JH NMR (CDCI3, in ppm): 8 4.58 (q, J = 8.5 Hz, 4H. 1 3 C NMR (CDC13 , in ppm): 8 64.17 (q, J - 37.5 Hz); 122.27 (q, J = 277.3 Hz); 153.14. 1 9 F NMR (CDCI3, in ppm): 8 -74.88. 211 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 7.4.3 Polymeric materials for lithium-ion battery electrolytes Copolymer of ethylene glycol and dichlorodimethylsilane (9): Into 12.4 g (200 mmol) ethylene glycol at 0 °C, was added drop-wise 25.8 g (200 mmmol) dichlorodimethylsilane. Immediately HC1 gas bubbling was observed. After the addition was finished, the reaction mixture was warmed to room temperature for 30 min. Then the mixture solution was heated to 50 °C for another 2 h until no HC1 gas evolution was observed. Vacuum distillation of the reacton mixture over 79 °C oil bath under 10 mmHg vucuum gave 13.32 g crystalline compound 10, m.p. 57-59 °C, yield 56 %. lE NMR (CDC13, in ppm): 5 0.11 (s, 12H); 3.78 (s, 8H). 1 3 C NMR (CDCls, in ppm): 5 -3.49; 64.67. 2 9 Si NMR (CDC13, in ppm): 8 -5.11. 10.3 g o f an oily liquid was left at the bottom of the flask which was identified as polymer 9, yield 43 %. *H NMR (CDC13 , in ppm): 6 0.11 (m, 6nH); 3.80 (m, 4nH). 2 9 Si NMR (CDC13 , in ppm): 8 -21.97. GPC analysis, Mw = 970-2250. DSC analysis: Tg = - 128.04 °C. X-ray single structure data for 10: Bond lengths [A] and angles Cdeg] for 1. 0 (1 )-S i(1 )-C (9) 105.36(10) Si(1)-0(2) 1.639(2) 0(2)-Si(1)-C (11) 104.07(10) Si(1)-0(1) 1.641(2) 0(1)-Si(1)-C (11) 109.32(10) Si(1)-C(9) 1.843(2) C(9)-Si(1)-C(11) 113,69(12) Si(1)-C(11) 1.848(2) 0 (4 )-S i(2 )-0 (3 ) 112.24(8) Si{2)-0(4) 1.637(2) 0(4)-Si(2)-C (10) 112.65(10) Si(25-0(3) 1.644(2) 0(3)-Si(2)-C (10) 105.43(10) Si(2)-C(10) 1.841(3) 0(4)-Si(2)-C (12) 103.74(11) Si(2)-C(12) 1.856(3) 0(3)-Si(2)-C (12) 108.84(10) 0 (1)-C(6) 1.424(3) C(10)-Si(2)-C(12) 114.07(12) 0(2)-C(7) 1.421(3) C (6)-0(1)-Si(1) 122.76(14) 0(3)-C(5) 1.424(3) C (7)-0(2)-Si(1) 127.98(14) 0(45-C(8) 1.424(3) C (5)-0(3)-Si(2) 122.46(14) C(5)-C(7) 1.504(3) C (8)-0(4)-Si(2) 128.11(14) C(6)-C(85 1.506(3) 0(3)-C(5)-C(7) 109.2(2) 0 (1 )-C(6)-C(8) 109.3(2) 0{2)-Si(1)-0(1> 112.49(8) 0{2)-C(7)-C(5) 112.6(2) 0(2)-Si(1)-C (9) 112.07(10) 0(4)-C(8)-C(6) 112.2(2) 212 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Synthesis of four-arm star shape poly(ethylene oxide) (PEO) (16)3 2 : The initiator potassium pentaerythritolate was prepared according to a known method, using KOH and pentaerythritol. The polymerization was carried out in a 250 ml dry and clean autoclave, the initiator (1.7 g) and dry toluene (150 ml) solvent were added inside a glove box, and then the ethylene oxide (47 g) was condensed inside autoclave at -78 °C through a steel tubing. Then the reaction mixture was stirred at 75 °C for 20 hr. After cooling down, the reaction was quenched by adding several drops of methanol. The polymer 16 (45 g, 96 % yield) was simply precipitated out in diethyl ether. SEC measurement with a standard PEO molecular weight distribution curve showed the Mn = 10,938, Mw/Mn = 1.56. 'H NMR (CDCI3, in ppm): 8 3.64. 1 3 C NMR (CDCI3, in ppm): 8 70.57. Tg = -65 °C, Tm = 54 °C. Methylation of polymer 16: A special glassware without ground glass or sharp joints. Into a 100 ml distillation flask connected with a dry ice condenser, was added a solution of 0.6 g of KOH in 1 ml of water, 3.5 ml of 2-(2- methoxyethoxy)ethanol and 3 ml of diethyl ether. The receiver flask was cooled to 0 °C. Then the reaction mixture was heated to 60 °C. As soon as the ether commenced to distil, a solution of 2.15 g DiazaldR (A-methyl-iV-nitrosotoluene-p-sulfonamide) in 13 ml of ether was added slowly through a syringe. After the addition of DiazaldR , another 10 ml of ether was added until the ditillate was colorless. The ethereal 213 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. solution of diazomethane in the receiver flask is in yellow color. It contains ca. 0.34 g (8.1 mmol) CH2 N2. Into a 100 ml round bottom flask without ground glass joint, was added 3.33 g of star shaped polymer 16 (Mw = 20,000) in 50 ml of dry dichloromethane at 0 °C, followed by addition of 5 drops of BF3-Et20 as catalyst. Subsequently, the freshly prepared diazomethane solution was slowly added, and the reaction mixture was stirred at room temperature for another 2 h. Most solvent was removed under vacuum, and the polymer was precipitated out in ether. After drying under vacuum overnight, methylated polymer 17 (2.81 g, 84 %) was obtained. * 1 3 NMR (CDCI3, in ppm): 5 3.65. 1 3 C NMR (CDC13, in ppm): 8 70.51. Tg = -61 °C, Tm = 53 °C. TGA analysis showed that it started to lose weight from 208 °C: lose 5 % at 286 °C, and lose 50 % at 365 °C. 214 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 7.4. References 1. (a) Vicent, C. A.; Scrosati, B. Modem Batteries: An Introduction to Electrochemical Power Sources (2n d Ed.), Arnold: London, 1997. (b) Gabano J.-P. Lithium Batteries, Academic Press: London, 1983. (c) Venkatasetty, H. V. Lithium Battery Technology, John Wiley & Sons: New York, 1984. 2. Sequeira, C. A.; Hooper A. Solid State Batteries, NATO ASI Series E, Vol. 101, Martinus Nijhoff, Dordrecht, The Netherland, 1985. 3. Krieger, J. Chem. Eng. News 1992,16, 17. 4. Meyer, W. H. Adv. Mater. 1998,10, 439. 5. Sakai, S.; Yamamoto, M. Eur. Pat. Appl. 1997, application number: EP 97- 107475. 6. Smart, M. C.; Ratnakumar, B. V.; Ryan, V. S.; Surampudi, S.; Prakash, G. K. S.; Hu, J., unpublished results. 7. Arai, J.; Katayama, H.; Akahoshi, H. Extended Abstracts o f the 4<fh ISE Meeting, 1998, Kitakyusyu, Japan, p. 642. 8. Inaba, M.; Kawatate, Y.; Funabiki, A.; Jeong, S.-K.; Abe, T.; Ogumi, Z. Electrochimica 1999, 45, 99. 9. Nagasubramanian, G. The 1999 Joint International Meeting o f the Electrochemical Society 1999, Abstract #334, Honolulu, Hawaii. 10. Shu, Z. X.; McMillan, R. S.; Murray, J. J.; Davidson, I. J. in Rechargeable Lithium and Lithium-ion Batteries, Magahed, S.; Barnett, B. M.; Xie, L.; Editors, 1994, PV 94-28, p. 431, The Electrochemical Society Proceedings Series, Pennington, NJ. 11. Shu, Z. X.; McMillan, R. S.; Murray, J. J.; Davidson, I. J. J. Electrochem. Soc. 1996,143, 2230. 12. Besenhard, J. O.; Werner, K. V.; Winter, M., US Patent, 1999, US 5,916,708. 13. Fenton, D. E.; Parker, J. M.; Wright, P. V. Polymer 1973,14, 589. 14. Armand, M.; Duclot, M. French Patent 78 329 76,1978. 15. Armand, M. B. Solid State Ionics 1994, 69, 309. 215 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 16. Berthier, C.; Gorecki, W.; Minier, M.; Armand, M. B.; Chabagno, J. M.; Rigaud, P. Solid State Ionics 1983,11, 91. 17. Gadjourova, Z.; Andreev, Y. G.; Tunstall, D. P.; Bruce, P. G. Nature 2001, 412, 520. 18. Krespan, C. G.; Smart, B. E. J. Org. Chem, 1986, 51, 320. 19. Krieble, R. H.; Burkhard, C. A. J. Am. Chem. Soc. 1947, 69, 2689. 20. Fridland, D. V.; Lebedev, E. P.; Reikhsfeld, V. O. Zh. Obshch. Khim. 1976, 46, 326. 21. Lebedev, E. P.; Fedorov, A. D.; Reikhsfeld, V. O. Zakirova, L. Z. Zh. Obshch. Khim. 1975, 45,2645. 22. Andrianov, K. A.; Dzhashiashvili, T. K.; Astakhin, V. V.; Shumakova, G. N. Zh. Obshch. Khim. 1967, 37, 928. 23. Voronkov, M. G.; Romadan, Y. P. Khim. Geterotsikl. Soedin 1966, 6, 879. 24. Andrianov, K. A.; Dzhashiashvili, T. K.; Astakhin, V. V.; Shumakova, G. N. Izv. Akad. Nauk. USSR. Ser. Khim 1966,12, 2229. 25. Cragg, R. H.; Lane, R. D. J. Organomet. Chem. 1984, 26 7 ,1. 26. Hayes, R. N.; Bowie, J. H. J. Chem. Soc. Pekin Trans. II 1984, 7,1167. 27. Kober, F.; Ruhl, W. J. J. Organomet. Chem. 1975,101, 57. 28. Petukhhov, V. N.; Rakhmankulov, D. L.; Musavirov, R.; Larionov, V. I.; Bresler, I. G. USSR Patent 1988, SU 1,430,110. 29. Koe, J. R.; Powell, D. R.; Buffy, J. J.; Hayase, S.; West, R. Angew. Chem., Int. Ed. 1998,37,1441. 30. Blau, J. A.; Gerrard, W.; Lappert, M. F. J. Am. Chem. Soc. 1957, 4116. 31. German, C.; Colombo, L.; Poli, G. Tetrahedron Lett. 1984, 25, 2279. 32. (a) One Canadian company Polymersource commerized four-arm star shape PEO. See webpage: www.polvmersource.com. (b) Zhu, K. J.; Song, B.; Yang, S. J. Polymer Sci. Part A 1989, 27, 2151. 216 permission of the copyright owner. Further reproduction prohibited without permission. Chapter 8 Synthesis of Superacidic Fluorinated Sulfonic Acids Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 8.1 Introduction 8.1.1 Superacids In the past forty years, the chemistry o f superacids, a term first coined by Conant and Hall in 1927,1 has been extensively developed m ainly by Olah and • » 0 Gillespie. For a Bronsted acid, the arbitrary definition given by Gillespie is that any protonic acid stronger than 100 % sulfuric acid is considered as a superacid, i.e., any Bronsted acid whose Hammett’s thermodynamic acidity function3 H0 < -12 can be called superacid. Olah, Prakash, and Sommer suggested that any Lewis acid stronger than anhydrous aluminum trichloride (AICI3 ) should be considered as a Lewis superacid.2 0 Common Bronsted superacids include fluorosufonic acid (FSO3 H, H 0 = -15.1), perchloric acid (HCIO4, H0 = -13.0), triflic acid (CF3SO3H, H0 = -14.1) and pentafluoroethanesulfonic acid (CF3CF2SO3 H, H0 = -14.0), etc.; and common Lewis superacids include antimony pentafluoride (SbF5 ), arsenic pentafluoride (AsF5 ), Tantalum pentafluoride (TaFs), Niobium pentafluoride (NbFs), boron tris(trifluoromethanesulfonate) [(CF3S03)3 B], and so on.2 c Quantitative measurements of relative Lewis acidities cannot be readily obtained, as it always depends on the nature of the Lewis base and involved steric (among other) interactions. Recently Christe4 suggested a quantitative scale for Lewis acidity based on the fluoride ion affinity pF. Since O lah’s pioneering studies on carbocations in extremely acidic non- aqueous solutions, 5 superacids have been extensively applied in all different areas o f 218 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. chemistry, including the isomerization of hydrocarbons, alkylation and acylation of aromatic and aliphatic compounds, polymerization, among others.2 0 8.1.2 Perfluorinated alkanesulfonic acids As one type of Bronsted superacids, perfluorinated alkanesulfonic acids are very useful industrially as both acid catalysts and surfactants. The strong electron- withdrawing effect of perfluoroalkyl groups increase the stability of the perfluoroalkanesufonate anion (RfSCV) and thus enhance the acidity of these acids. The combination of hydrophilic sulfonate group and lipophilic perfluoroalkane chain makes these compounds suitable for use as surfactants. Commonly used perfluoroalkanesulfonic acid catalysts include trifhioromethanesulfonic acid (triflic acid, CF3SO3 H),6 perfluorinated resinsulfonic acid (Nafion-H®),7’ 8 Nafion/Silica nanocomposites,9 etc. These fluorinated sulfonic acids are stronger acid catalysts than other non-fluorinated acids, such as sulfonated cross-linked polystyrene type resin (Dowex® and Amberlyst®)1 0 and zeolites.1 1 8.1.3 Synthesis of trifhioromethanesulfonic acid (Triflic acid) 1 2 * The first preparation of triflic acid was reported by Haszeldine and Kidd in 1954 by oxidation of bis(trifhioromethylthio)mercury with aqueous hydrogen peroxide (Scheme 8.1). 219 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. c s Hg 35% H2 O 2 hv CF3 SSCF3 ■ (CF3 S)2 Hg ^ CF 3S 0 3 H ^ 2 0 CF3' BaC0 3 (aq.) CF3 SO 3 H --------------------- (CF3 S 0 3)2Ba H2SO4 Scheme 8.1 Synthesis of triflic acid from (CF3S)2Hg. In 1955, the same group reported an alternative route to triflic acid via trifluoromethanesufenyl chloride (Scheme 8.2).1 3 p. Cl H o 15% NaOH CF3 SSCF3 — 2 ^ CF3 SCI 2’ 2 CF3 S 0 2CI ► CF3 S 0 3Na CF3 SO 3 H — H2SO- dry at 100 °C under vacuum Scheme 8.2 Synthesis of triflic acid from CF3SC1. Methyltrifluoromethyl sufide can also be used as another intermediate for the synthesis of triflic acid (Scheme 8.3).1 4 220 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. DMSO CF3I + NaSCH3 + CH3SSCH3 — — 5— CF3SCH3 (85 % ) 105 C CF3 I + CH3 SSCH3 CF3 SCH3 (92 % ) K M n04(or H 20 2) [O] _______ CF3SCH3 u r,a - ► CF3SO2CH3-------------------------- ►CF1SO3 H0Ac NaOCI, then OH 3 3 or aq. KMn04 Scheme 8.3 Synthesis of triflic acid from methyltrifluoromethyl sufide. Direct oxidation of Bis(trifluoromethyl) disulfide to triflic acid has also been disclosed (Scheme 8.4).1 5 0 CF0SSCF3 ► CF3SO3H 3 50 % H 2 0 2 in Oleum Scheme 8.4 Synthesis of triflic acid from bis(trifluoromethyl) disulfide. However, the current industrial manufacturing process for pure triflic acid is the electrochemical fluorination (ECF) of methanesulfonic halides, which was first disclosed by Trott, Brice and co-workers in 1954 (Scheme 8.5).1 6 Distill over 3 HF aq. KOH 100 % h2S0 4 CH3 S 0 2F ----------- ► CF3 S 0 2F-------------- ► CF3 SO 3 K ► CF3 SO 3 H ECF, - 3 H 2 Scheme 8.5 ECF synthesis of triflic acid. 221 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Other approaches to synthesize triflic acid are also known. When sodium trimethylsilanolate was used as an initiator, (trifluoromethyl)trimethylsilane (TMS- CF3) reacts with SO2 to give sodium trifluoromethanesulfinate, which was oxidized 1 7 into triflic acid in 30 % overall yield. 8.1.4 Synthesis of Nafion-H Intrigued by the idea of executing reactions on solid phases with functional 1 8 polymer supports, solid supported perfluorinated alkanesulfonic acid (solid superacid) was also developed. Nafion1 9 brand resins is a copolymer of perfluorinated epoxide and vinylsulfonic acid, -which was commercialized by DuPont 'J C i as membrane materials in electrochemical processes, fuel cells and batteries. Commercial Dupont Nafion 501, frequently used in superacid catalytic reactions, contains ~ 0.01 to 5 mequi/gram of sufonic acid groups. (F2C-CF2)x-(CF2-CF)y-(0CF2-CF)m -0CF2-CF2-S03lC+ or (F2C-CF2)x-(CF2-CF)y-(OCF2-CF)m -OCF-CF3 s o 3tc + 1 x/y = 2-50; m=l The syntheses of Nafion resins with the above structure involve either o polymerizing the corresponding perfluorinated vinyl compounds, or copolymenzmg the corresponding perfluorinated vinyl ethers 2 with tetrafluoroethylene and / or Q perfluoro-a-olefms (Scheme 8.6). 222 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. FpC—CFo F2C=CF2 + S 0 3 ---------► I I — ------- ► F-02S-CF2-C0-F o —s o 2 .Q m / \ _ ... __ 4 f F3 M , — _f f 3 ' N a2 c ° 3' A ^ F2C=CF-0-(CF2-CF-0)m -CF2-CF2-S 0 2-F f2c =c f2 -------: ---- ► v w ( C F 2-CF2)n -CF2-C F '^ ' copoymerize > H y 0(CF2-CF-0)m -CF2-CF2-S 0 2-X CF3 , 3 x = F, Nafion-F or resin KOH „ = -*► ^ ^ " V n ^ ' C F p S O i K 4 x ’ N a f i o n "K ^ 2 3rx 5 x = OH, Nafion-H Scheme 8.6 Synthesis of Nafion. 8.1.5 Synthesis of chlorodifluoromethanesuifonic acid (CICF2SO3H) As one analog o f triflic acid, chlorodifluoromethanesufonic acid (CICF 2 SO 3H) 6 is also a superscid but it is not that well known. The first preparation o f CICF2 SO 3H was reported by Yagupol’skii and co-workers2 1 via a tedious pathway (Scheme 8.7). But they did not give the any spectroscopic data o f 6 . Sweeney and coworkers also disclosed the preparation o f 6 by the reaction o f CI2 CHSH with HOF over CuCh-K Cl in low yield. N ippon Petrochemicals Company 2 3 disclosed the usage o f acid 6 as an acid catalyst in the dimerization o f styrenes into polycyclic aromatic hydrocarbons. Sanyo Electric Company 2 4 disclosed the application o f ClCF2S03‘Li+ as lithium battery electrolyte, and claimed its advantage over conventional CF 3 S0 3 'Li+ by preventing passivation o f the anodes and improving the 223 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. low-temperature discharge performance of the batteries. However, both companies did not disclose the method for the preparation of the acid 6. More recently, Smertenko and coworkers2 5 claimed the preparation of 6 via electrochemical oxidation of sulfodifluoroactetic acid (HOSO2CF2CO2H) in the presence of chlorine (CI2). But the detailed procedures are not available. O o S 0 3 F2C—CF2 1 1 h 20 1 1 F2C-CF2 ------- ► I I --------F-C-CF2-S 0 2-F -----------► H0-C-CF2-S 0 2-F O—S02 ~ Cl-C-CF2-S 0 2-F — ^ » Cl-CF2-S 0 2-F B a (O H )2 ^ (ciCF2S 0 3)2Ba h2s o 4 ; — ► c i c f 2s o 3h 6 Scheme 8.7 Synthesis of chlorodifluoromethanesulfonic acid by Yagupol’skii and co-workers.2 1 In this chapter, we wish to report the new approach to the synthesis of chlorodifluoromethanesulfonic acid 6 via Swarts reaction. 8.1.6 Synthesis of polymer-supported fluorinated alkanesulfonic acid (Polymer—CF2SO3H) Besides Nafion®-H, few is known about the polymer supported superacidic fluorinated alkanesufonic acid (Polymer-CF2S03H). Recently, DuPont Company2 6 disclosed the synthesis of polystyrene supported tetrafluoroethanesulfonate (PS- 224 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. OCF2CF2SO3XO using an ether linkage (Scheme 8.8, A). However, when they transformed the lithium sulfonate into free sulfonic acid, the acid decomposed readily (Scheme 8.8, B).2 7 A: Br^ O “ ° H Br—^ ~ ^ - O N a BrCp2CF2Br >■ Br—^ ^ - O C F 2CF2Br Na2S204/NaHC03 / = \ 9 Cl2 / H2Q • Br— OCF2CF2SONa B r ^ } ~ O C F 2CF2f c . — — H L Ijg ?. Br—^ ^ - O C F 2CF2S-OLi CH2=CH2 / = \ j ? . (NH4)2s 2o 8 ■'Pd(0^2;base' r \ _ / - O C F 2CF2S^OU--------------► OCF 2CF 2SO3U B: / = \ 9 h + / = \ 9 4 > - O C F 2CF2S-OLi ----------------I >-O C F2CF2S-OH (Decomposed!) O O Scheme 8.8 Dupont’s synthesis of PS supported -CF2 S03 H. We have been interested in the development of novel types of polymer supported fluoroalkanesufonic acid. In this chapter, we will report our attempt in this project. 225 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 8.2 Results and discussion 8.2.1 Novel Synthesis of chlorodifluoromethanesulfonic acid (CICF2SO3H) 6 Our first synthetic strategy to prepare acid 6 was to synthesize intermediate compound chlorodifluoromethanesulfenyl chloride (CICF2SCI) 7 from perchloromethyl mercaptan (CI3CSCI) 8 by Swarts28 reaction (Scheme 8.9). SbF3 / SbCI5(cat.) C I 3 CSCI — ■ 8 * CF2 CISCI Swarts reaction Scheme 8.9 Attempted preparation of CF2 C 1SC 1 from CI3CSCI. Perchloromethyl mercaptan 8 was first synthesized by Rathke2 9 in 1870 by reacting CS2 with Cl2 (contains 0.2 % I2 ) in 15 % yield. This methodology have been modified and improved several times,3 0 among which the best one is the chlorination of CS2 in aqueous hydrochloric acid or sulfuric acid with up to 90 % yield (Scheme 8.10).3 1 This method was also used by us to prepare the precursor compound 8. H + CS2 5CI2 4H20 ----------- ► CCI3 SCI + H 2 S 0 4 + 6 H C I Scheme 8.10 Synthesis of CCI3SCI from CS2 and Cl2 . 226 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Then, halogen exchange (Swarts) reaction was attempted to prepare CF2CISCI from CCI3SCI. Unfortunately, under Swarts reaction conditions both perchloromethyl mercaptan and trichloromethanesulfonyl chloride 9 could not give the expected chlorodifluormethylsufenyl(sulfonyl) chloride (Scheme 8.11). SbF3 / SbCI5(cat.) ™ CI3CSCI --------- ----------- — — --------► CFoCISCI (I) r.t. - 70 °C X CI3CSCI O CI3CSCI it O Scheme 8.11 Attempted Swarts reactions. Yarovenko and coworkers also found that C-S bond was broken during the reaction of perchloromethyl mercaptan with metal fluoride. It was noticed in 1936 and 1937 that, in the reaction of CS2 with HF/CI2 or with SbFa/SbCls, the C-S bonds were broken and fluoromethanes were formed.3 3 Then we modified the approach developed by Yarovenko and coworkers3 4 to avoid the C-S bond cleavage under Swarts reaction conditions, using the N,N-diethyl trichloromethanesulfenamide 10 as the precursor (Scheme 8.12). This reaction worked quite well except the reaction was very sensitive to reaction temperature and heating time. 227 SbF3 / HF ., ------------ — ----------------------- CF2CISCI (II) -1 0 C ~ r.t. 2 SbF3 / SbCI5(cat.) > \ 1 ? ^ CF2CISCI (HI) 70 °C X ^ Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CClaSCI fr~ - CCl3SNEt2 HNEt2 SbF3/SbCI5 (cat.) CF2CISNEt2 11 (51 %) 67°C, 90 min (91 %) Scheme 8.12 Preparation of CF2 ClSNEt2 . N,N-diethyl trichloromethanesulfenamide 10 was prepared simply from perchloromethyl mercaptan 8 and diethylamine in 91 % yield. The Swarts reaction was carried out without solvent using SI3 F3 as the fluorinating agent in the presence of catalytic amount of SbCls. Reaction temperature (67-70 °C) and time (1.5 - 2 h) are the optimized reaction conditions for this halogen exchange reaction. After decanting form the black tar-like byproduct, product 11 can be isolated via vacuum distillation in 44 - 51 % yield. This is better than Yarovenko and coworkers’s original report in which their best yields were around 21 - 24 %. The success of this reaction is also dependent on the amount of SbCls added into the reaction mixture at 67 °C to initiate the exothermic reaction. We found 5-10 (mol)% of SbCls was necessary to efficiently activate this halogen exchange reaction. Without SbCls or with trace amount of SbCls the reaction yield was extremely poor. The role of SbCls in this reaction is shown as in Scheme 8.13. 228 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Scheme 8.13 Mechanistic explanation of the role of SbCl5 in halogen-exchange reaction. Since antimony trifluoride (SbF3 ) has one non-bonded lone-pair electrons, they repulse the lone-pair electrons of chlorine atoms in chlorinated compounds resulting sluggish fluorination (Scheme 8.13,1). When strong Lewis acid SbCh is added, its coordination with SbF3 can diminish antimony’s lone-pair electron interaction with chlorine atoms, and thus increasing the fluorinating ability of SbF3 (Scheme 8.13, II). Similar explanation was made by Yagupol'skii and coworkers34 for the fluorination ofbenzylic C-Cl bonds into the corresponding C-F bonds. N,N-Diethyl chlorodifluoromethanesulfenamide 11 was further oxidized by 30 % aqueous hydrogen peroxide (H2O2) in acetic acid at 90-100 °C, which produced 229 permission of the copyright owner. Further reproduction prohibited without permission. N,N-diethyl chlorodifluoromethanesulfonamide 12. Compound 12 can further be hydrolyzed into chlorodifluoromethanesulfonic acid 6 (scheme 8.14). Acid 6 was neutralized by NaOH to form sodium chlorodifluorosulfonate 13, which can be easily dried under vacuum at 120 °C. Dried salt 13 was mixed with 98 % sulfuric acid and then distilled under vacuum to produce good quality CF2CISO3 H as colorless fuming liquid. Fig 8.1 shows its 1 3 C and I9 F NMR spectra. CF2CISNEt2 11 H20 2 / HOAc 90 °C O CF2CiSNEt2 O 12 H ,0 + CF2CIS03H (a) NaOH 98 % H2S 0 4 CF2CIS03Na ^ CF2ClS03H (b) Dry 13 distill Total yield from 11: 45 % Scheme 8.14 New approach for the synthesis of CF2 C1S03 H. 230 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. A: 1 3 C NMR (62 MHz; DMSO-d6; TMS int.) 150 100 50 ppm B: 1 9 F NMR (338 MHz; DMSO-de; CFCI3 int.) -10 — I— i - -50 - e o -20 -30 -40 -70 ppm Fig 8.1 1 3 C and 1 9 F NMR spectra of CF2 C1S03 H. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 8.2.2 Synthesis of phenyl difluoromethanesulfonic acid (PI1CF2SO 3H) 15 We were interested in development of polymer supported solid super acid Polymer-CF2S03H 14 as fuel cell proton conducting membrane material (Scheme 8.15). First of all, we decided to synthesize the model compound phenyl difluoromethanesulfonic acid 15 to test its physical and chemical properties (Scheme 8.15). Acid 15 was first synthesized in our group3 4 in 1991 using ct,a,a~ trifluorotoluene as precursor. We modified these procedures and carried out the synthesis of model compound 15. 1 1 1 Y c f 2s o 3h Y c f 2s o 3h 14 15 Schem e 8.15 Structure o f PhCF2S 0 3 H and its PS supported analog. First, we prepared a-bromo-a,a-difluorotoluene 16 by halogen exchange reaction between PI1 CF3 and BBr3 (Scheme 8.16). It turns out that this reaction could produce a,a,a-bromodifluoro-, dibromofluoro- and tribromotoluenes under different 232 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. reaction conditions. Compound PhCF2 Br (16) was isolated in 43 % yield by reacting 10 eq. of PI1 CF3 with 1 eq. BBr3 at refluxing temperature for 2h. BBr-j condition a,b,c CF2Br 16 CFBr2 CBr3 + I + 17 18 conditon a: b: c: 43% 14% trace(0.3%) 24% trace 48% 92% Condition a: neat, PhCF3 / BBr3 = 10/1, reflux for 2 hr followed by standing overnight at r.t. b: CH2CI2 as solvent, PhCF3 / BBr3 = 3/1, the reaction was run for 5 days at r.t. c: CCi4 as solvent, PhCF3 / BBr3 = 1/1.1, at r.t. for 32 h. Scheme 8.16 BBr3 mediated benzylic F/Br exchange reactions. Sulfinatodehalogenation3 6 ,3 7 of a-bromo-a,a-difluorotoluene 16 using sodium dithionite (Na2S204) under basic condition gave phenyl difluoromethanesulfinic acid sodium salt (PhCF2S02T N fa + ) 19 (Scheme 8.17). Simple oxidation of 19 by 30 % aqueous H20 2 generated sodium phenyl-difluoromethanesufonate (PhCF2S03_ Na+ ) 20. The crude salt 20 was dried under vacumm and it is a stable compound. The aqueous solution of 20 was ion-exchanged with acid resin Amberlyst® column, and the acid form PhCF2S03H 15 was produced. The acid 15 was stable in aqueous solution. However, when we tried to remove most water to obtain its pure form at 233 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 60-70 °C / 0.1 mmHg, it readily evolved gaseous compounds and decomposed. The product we isolated from its decomposition residue was benzoic acid. Other attempts to isolate pure PI1 CF2SO3 H by vacuum distilling mixture of salt 20 and 98 % sulfuric acid gave similar decomposition product (Scheme 8.18). CF2Br 2 NaSo04 2 NaHC03 16 H20 / CH3CN 80°C CF2S 0 2‘Na+ H20 2 19 CF2S03 "Na+ 20 Amberlyst CF2S 0 3H 15 Scheme 8.17 Synthesis of PhCF2 S03 H. 234 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. c f 2s o 3h COOH remove H20 60-70 °C/0.1 Torr (stable in H20 ) CF2S 0 3Na COOH (stable, dry solid) A 98 % H2S 0 4 Vac. Distill Scheme 8.18 The decomposition PhCF2 S03 H. This decomposition reaction is probably an acid catalyzed hydrolysis process. The good stability of PI1 CF2SO3H in water solution indicates that the hydrolysis reaction is dependent on the acidity rather than the amount of water. Due to the leveling effect of water, the acidity of PI1 CF2SO3 H was decreased in water solution which can not catalyze the hydrolysis efficiently. When most water was removed, the superacidity of PhCF2S03H self-catalyzes its own decomposition. Another reason is the labile benzylic C-F bond in this acid 15, which was confirmed by the fact that, when we treated PI1 CF3 with triflic acid, it readily hydrolyzed into benzoic acid. 235 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 8.2.3 Synthesis of 2-phenyI-l,l,2,2-tetrafluoroethanesulfonic acid 21 (PhCF2 CF2 S03 H) Based on the unsuccessful isolation o f pure PI1CF 2 SO 3H, we thought o f another model compound, 2 -phenyl-1 , 1 ,2 ,2 -tetrafluoroethanesulfonic acid 2 1 and carried out its synthesis. Since there is one additional -C F 2- group intervening the -C F 2 SO 3H moiety, it was presumed that the benzylic C-F bonds in this acid would be more stable. The retro synthetic route is shown in Scheme 8.19. 21 23 Scheme 8.19 Retro synthetic route of PhCF2 CF2S03 H. The attempted synthesis o f compound 23 w ith fluoride induced 38 bromodifluoromethylation o f methyl benzoyate using M e 3 SiCF 2 Br reagent, however, failed (Scheme 8.20). o 24 OCH3 TMS-CF2Br / TBAF (cat.) PhCH3 or Pentane -78 °C - r.t. O 23 Scheme 8.20 Attempted synthesis of PhCOCF2 Br using TMS-CF2 Br. 236 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The magnesium metal mediated defluorination3 9 of 2,2,2,- trifluoroacetophenone provided us an efficient way to prepare compound 23 from inexpensive PhCOCF3 in high yield (Scheme 8.21). The difluoro silyl enol ether 25 was conveniently prepared, followed by bromination with bromine. The bromination reaction was facile even at -78 °C, and the reaction proceeded smoothly. O OSiMe3 9 Mg/TMSCI ^ Y ^ C F 2 Br2 { ^ / X GF2Br I 11 — m— I 11 ———— ■—— —— ■ 1 1J THF, 0 °C CH2CI2 v ,! s v ^ -78 °C~r.t. 26 25 23 (78 % for 2 steps) Scheme 8.21 Synthesis of PhCOCF2Br. Deoxofluorination of 2-Bromo-2,2-difluoroacetophenone 23 readily gave 2- bromo-1,1,2,2-tetrafluoroethylbenzene 22 (Scheme 8.22). Diethylaminosulfur trifluoride (DAST)4 0 was used as deoxofluorinating agent. O U CF2CF2Br ^ Y ^ C F 2Br _______DAST_______ ^ CHCI3, reflux 58% 23 22 Scheme 8.22 Synthesis of PhCF2CF2 Br using DAST. 237 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. By similar approach as the preparation of PhCF2S03H, compound 22 was transformed into the unkown acid PI1CF2CF2SO3H 21 (Scheme 8.23). However, although acid 21 was stable in aqueous solution, it readily decomposed when all the free water was removed. Similarly, when stable salt PhCF2CF2S C > 3Na was mixed in 98 % sulfuric acid follwed by vacuum distillation, decomposition happened rapidly. Obviously, superacid catalyzed hydrolysis was brisk similar to that of PI1CF2SO3H {vide infra). CF2CF2S 0 3H 6 21 Scheme 8.23 Synthesis of PhCF2 CF2 S03H. Both acid 15 and 21 were also treated with LiOH and transformed into corresponding lithium salts. These lithium sulfonates can be dried and are reasonably stable. They can serve as potential candidates as lithium battery electrolytes. CF2CF2Br 2 NaS ^ CF2CF2S 0 2'Na+ CF2CF2S 0 3-Na+ 2 N aH ^03 ( i 5^ h 2 ° 2 Amberlyst h2o / c h 3cn * Kj KJ ------------- * 80°C 22 27 28 238 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 8.2.4 Attempted synthesis of polystyrene supported superacid via a- or j8- bromodifluoromethyl styrene as monomer We attempted the synthesis of polystyrene with a fluorinated methanesulfonic acid group in PS backbone at a- or /3- position (Scheme 8.24). CF 0 SO3 H 6 29 Scheme 8.24 Structures of designed polymer-supported -CF2 S03 H 29 and 30. 30 jS-bromodifluoromethylstyrene 34 was prepared through known procedures (Scheme 8.25).4 1 H O . J cf 2 sec-BuLi 1) PhCHO CF2=CH2 ------------- ► CF2=CHLi------------------► -100 °C 2) H 3 0 + CF2Br 1) SOBr2 2) H 20 * 31 32 33 34 Scheme 8.25 Synthesis of jS-bromodifluoromethylstyrene. 239 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. However, the polymerization of monomer 34 was not successful. The failure can be rationalized as follows: first, compound 34 is a 1,2-disubstituted olefin, which is difficult to polymerize; second, the allylic C-Br bond is very labile to most radical or anionic polymerization conditions. As a matter of fact, when we tried the homopolymerization of 34 under emulsion polymersion condition using potassium persulfate as an initiator, cinnamic acid was produced in high yield (Scheme 8.26). Other attempts to use AEBN or BPO as initiator in dry solvents were not successful either. Since the double bond in 34 is sensitive in the sulfinatodehalogenation reaction conditions,3 6 ’ 3 7 our attempts to transform 34 into PhCH=CH-CF2S02Na was not successful. K 2S20 8 (2 % ) COOH 34 35 Scheme 8.26 Hydrolysis of 34 into cinnamic acid. 240 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Unkown compound a-bromodifluoromethyl styrene 36 was also synthesized from previously prepared PhCOCF2Br 23 via Wittig reaction or dehydration (Scheme 8.27). Same as compound 34, the allylic C-Br bond in monomer 36 is very sensitive to radical polymerization conditions. When compound 36 was subjected to polymerization in benzene at 80 °C using 5 % BPO or AD3N as initiator, debromination reaction take place to generate 1,1-difluoro olefin product. We also tried BF3-OEt2 complex as the cationic initiator, but the polymerization did not happen either. Sulfinatodehalogenation reaction on 36 was failed due to the sensitivity of double bond. It is interesting that when we prepared the intermediate 37 via the reaction of PhCOCF2Br and CF^MgBr, we isolated a crystalline byproduct 38, which is an 241 HO CH3 Ph^XFaBr 37 PhCOCF2Br 36 Scheme 8.27 Synthesis of a-bromodifluoromethyl styrene. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. unknown compound (Scheme 8.28). The formation of 31 is probably through the intermediate 39 generated via halogen-metal exchange (Scheme 8.28, B). O 1) CH3MgBr HO CH3 BrF2C » ^ " C F a B r THF P h " t : F 2Br + Ph'^'V " " ^ 2 • F -78 °C~r.t. OH CH3 2) H30 + 37 38 (65 %) (-15% ) CH3M gB r/ H30 + BrMgO OH3 BrF2C BrMg9 X 3 PhCOCF2Br L - c f P h ^ C F 2MgBr ► Ph^\ 2 I ^ OMgBr C H 3 39 40 Scheme 8.28 Unusual formation of 1,3-diol 38. 8.2.5 Attempted synthesis of TMS-CF2S03 CH(CF3 )2 41 We were also interested in developing -C F2S 0 3 H transferring agents. Compound TMS-CF2S03 CH(CF3 )2 41 was designed to fit this objective. However, the synthesis of 41 is quite challenging. Based on the high stability of ester 242 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. compound CF3S03CH(CF3)2 42, we attempted to prepare 41 from 42 through halogen-exchange reactions (Scheme 8.29). Both BBr3 and BCI3 could not facilitate F-Br or F-Cl exchange reaction on 42, and only starting material 42 was recovered. When we tried to use Mg metal and TMSC1 to react with 42, the reaction turned out to be very messy and numerous CF3- containing products were formed with low selectivity. When we tried PI1 SOCF3 as starting material instead of 42, a new type of chemistry was discovered (See Chapter 4). O I I - s — Cl Br F - (CF3)2CHOH it^N O O I I -S -O C H (C F 3)2 o o I I -S -O C H (C F 3)2 o 42 C l b ci3 o Mg / TMSCI O „ -S -O C H (C F 3)2 r--^>— s —o c h (c f 3)2 t m s § F o 41 Scheme 8.29 Attempted synthesis of difluorinated methanesulfonates from trifluoromethanesulfonate. 8.3 Conclusion In summary, we successfully developed a new route for the synthesis of superacidic chlorodifluoromethanesulfonic acid. Syntheses of phenyl 243 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. difluoromethanesulfonic acid (PI1CF2SO3H) and 2-phenyl-1,1,2,2- tetrafluoroethanesulfonic acid (PhCFaCFaSOaH) were also carried out. It was found that the sodium salts of both acids are quite stable. However, the acids themselves are only stable in aqueous solution. In the pure form, both acids can readily undergo superacid catalyzed self hydrolysis. Syntheses of polystyrene with -CF2SO3 H group at a- or /S - position on PS backbone were also attempted. But they were not successful, due to the high sensitivity of these two monomer precursors during polymerization or sulfinatodehalogenation process. 8.5 Experimental section 8.5.1 General Unless otherwise mentioned, all the other reagents were purchased from commercial sources. Diethyl ether and THF were all distilled under nitrogen over sodium/benzophenone ketyl prior to use. Toluene was distilled over sodium. Column chromatography was carried out using silca gel (60-200 mesh). 'H, 1 3 C, 1 9 F spectra were recorded on Bruker AMX 500 and AM 360 NMR 1 13 spectrometers. (Q H ^Si (TMS) was used as an internal standard for H and C NMR, CFCI3 was used as internal standard for 1 9 F NMR. For some cases, CDCI3 was used as the internal standard for NMR (7.26 ppm) and 1 3 C NMR (77 ppm). IR spectra were obtained on a Perkin-Elmer FTIR Spectrometer 2000. Mass spectra 244 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. were obtained on a Hewlett Packard 5890 Gas Chromatograph equipped with a Hewlett Packard 5971 Mass Selective Detector at 70 eV. 8.5.2 Synthesis of chlorodifluoromethanesulfonic acid (6) Perchloromethyl mercaptan (8)3 1 : Into a 1 liter three-neck round bottom flask equipped with a magnetic stirrer, a condenser and two septa, was added 440 ml CS2, 280 ml of water, and 200 ml of 37 % HC1. The flask was cooled to 0 °C, and chlorine gas was bubbled into the reaction mixture slowly. The chlorine bubbling rate was controlled carefully to avoid chlorine to permeate outside. The reaction was processed for 2 days, and totally 438 g (1.23 mol) chlorine gas was consumed. The organic phase was isolated, washed 3 times with brine and dried over MgSCV The CS2 solvent was removed under vacuum and 144 g crude product 8 was collected, yield 63 %. After fractional distillation, 131.9 g (57 %) pure product 8 was obtained as a colorless liquid, b.p. 144-145 °C. 1 3 C NMR (62 MHz, CDC13 , in ppm): 8 97.49. N,N-Diethyl trichloromethanesulfenamide (10)32: At 0 °C, into a mixture of 50 ml of ether and 56.5 ml (546 mmol) of diethylamine, was slowly added 50.74 g (273 mmol) of perchloromethyl mercaptan 8 in 35 ml of ether through a dropping funnel. After addition was completed, the reaction mixture was stirred for another 1 h at room temperature. Then 50 ml of 10 % HC1 was added, and the organic phase was separated. The aqueous phase was further extracted with 20 ml of ether. Combined ether phase was washed with 10 % NaHCCb solution, and then with 30 ml 245 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. of water. After drying over CaCl2, the solvent was removed under vacuum. The crude product was distilled to afford 55.12 g (91 % yield) of product 10 as a colorless liquid, b.p. 78 °C/12.9 mmHg. *H NMR (360 MHz, CDC13, in ppm): 5 1.24 (t, 3 J H-h = 7 Hz, 6H); 3.34 (m, 3 J H -h = 7 Hz, 2H); 3.59 (m, 3 J H-h = 7 Hz, 2H). 1 3 C NMR (62 MHz, CDCI3, in ppm): 8 14.37; 51.92; 104.46. MS (70 eV): 223 [M+ (36C1)]; 223 [M+ (35C1)]; 188 [(M-35C1)+ ]; 186 [(M-36C1)+ ]; 104 [(SNEt2)+ ]. N,N-Diethyl chlorodifluoromethanesulfenamide (11): Under an argon atmosphere, into a 500 ml three neck round bottom flask equipped with a condenser and two septa, was added 54.5 g (245 mmol) of 10 and 32.85 g (184 mmol) of SbF3. The reaction mixture was heated up to 67 °C with stirring, and 2 g (6.7 mmol) of SbCls was added in via syringe. The exothermic reaction ensued immediately, and the color of reaction mixture turned brown. The reaction mixture was stirred for another 1.5 h, and then was cooled down to room temperature. The upper liquid layer was decanted out, and black tar at the bottom of flask was washed with ether (25 ml x 4). The combined organic phase was vacuum distilled to give 23.85 g (51 %) of product 11 as a colorless liquid, b.p. 57-59 °C/50 mmHg. (Caution: the compound 11 must be distilled under vacuum; one attempt to distill under atomospheric pressure caused explosion!). *H NMR (360 MHz, CDCI3, in ppm): 8 1.16 (t, 3 / h-h - 7 Hz, 6H); 3.15 (b, 4H). 1 3 C NMR (62 MHz, CDCI3, in ppm): 8 13.74; 52.48; 133.76 (t, Vc-f = 336.7 Hz). 1 9 F NMR (338 MHz, CDCI3, in ppm): 8 -35.57. MS (70 eV): 191 [M+ (3 7C1 )]; 189 [M+ (35C1 )]; 104 [(SNEt2)+ j; 85 [(CF2 3 5C1 )+]. 246 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chlorodifluoromethanesulfonic acid (6): Into a solution of 20.79 g (110 mmol) of 11 in glacial acetic acid (100 ml) at 75 ~ 85 °C, was added dropwise 100 ml of 30 % H2O2. Then the reaction mixture was heated at 90 °C for another 2 h. The reaction progress was monitored by 1 9 F NMR: at beginning 11 was transformed into N,N-diethyl chlorodifluoromethanesulfonamide 12 (1 9 F: -77 ppm), and then 12 was further hydrolyzed into chlorodifluoromethanesulfonic acid 6 (1 9 F: -63 ppm). Then most water and acetic acid was distilled out from reaction mixture using a 17 cm column, and to the residue 16 ml 50 % aqueous NaOH solution was added to neutralize the acids, as indicated by pH paper. After water was removed, the sodium salt 13 was dried at 120 °C / 0.1 mmHg. To the dried salt 13, 50 ml of 98 % H2SO4 was added, and the mixture was stirred vigorously at 100 °C for 2h, followed by careful fractional istillation to afford 8.19 g (45 % yield) acid 6 as a colorless fuming liquid, b.p. 104 °C / 7 mmHg. 1 3 C NMR (62 MHz, DMSO-d6, in ppm): 8 125.96 (t, Vc-f = 330 Hz). ,9F NMR (338 MHz, DMSO-d6, in ppm): 8 -62.36. 8.5.3 Synthesis of phenyl difluoromethanesulfonic acid (15, PI1CF2SO3H) a-Bromo-a,a-difluorotoIuene (16): Under an argon atmosphere, into a 1 liter three-neck round bottom flask equipped with a condenser and two septa,, was added 146.1 g (1 mol) of PI1 CF3 and then slowly was added 25.05 g (0.1 mol) of BBr3 at room temperature. Slowly the reaction mixture became warm and gaseous BF3 247 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. started bubbling out. The color of the mixture turned to yellow initially and abmber- like. After 1 h, the effervescence ceased and the mixture started to cool down. The mixture was refluxed for another 2 h, followed by stirring at room temperature overnight. Then the reaction mixture was poured into 100 ml of ice water, and extracted with CH2CI2 (50 ml x 3). The combined organic phase was washed with 30 ml of water, and then was dried over CaC^. After evaporating solvents, 48.44 g of amber color liquid was collected as the crude product, which was distilled to give 26.71 g (43 % yield) of product 16 as a colorless liquid, b.p. 54 °C/20 Torr. ). !H NMR (360 MHz, CDCI3, in ppm): 5 7.45 (m, 3H); 7.59 (m, 2H). 1 3 C NMR (62 MHz, CDCI3, in ppm): 8 118.41 (t, ^c-f = 303.9 Hz); 124.29 (t, 3 J C .F = 5.5 Hz); 128.62; 131.24; 138.15 (t, 2 JC .F = 23.3 Hz). 1 9 F NMR (338 MHz, CDC13, in ppm): 5 -44.01. MS (70 eV): 189 [(PhCFBr)+ ]; 127 [(PhCF2 )+ ]; 108 [(PhCF)+ ]; 77 (Ph+ ). a,a-Dibromo-a-fluorotoluene (17) (0.12 g, 0.3 % yield) was also obtained as a high boiling liquid. *H NMR (360 MHz, CDCI3, in ppm): 7.46 (m, 3H); 7.72 (m, 2H). 13C NMR (62 MHz, CDCI3, in ppm): 8 90.65 (d, VC -f = 316.0 Hz); 124.05 (d, 3 J C -F = 7.3 Hz); 128.35; 130.37 (d, 2 JC .F = 33.5 Hz); 144.71. 1 9 F NMR (338 MHz, CDCI3, in ppm): -53.82. a,a,Of-Tribromotoluene (18) (7.76 g, 24 % yield) was obtained as a white solid. *H NMR (360 MHz, CDC13 , in ppm): 8 7.34 (m, 3H); 8.02 (d, 2H). 1 3 C NMR (62 MHz, CDCI3, in ppm): 8 36.32; 126.45; 128.03; 130.09; 146.90. 248 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Phenyl difluoromethanesulfonic acid (15): Into a mixture of 135 ml of water, 90 ml of CH3CN, 25.66 g (305 mmol) of NaHC03 and 31.61 g (153 mmol) of PhCF2Br at room temperature, was added 53.2 g (305 mmol) of Na2S304 under argon atmosphere. The reaction mixture was heated to 80 °C for 12 h. After cooling down, the reaction mixture was filtered, and the solid residue was washed with hot CH3CN/H20 (9:1). The combined filtrate was vacuum distilled to remove water and organic solvents to give off-white solid product, which was further washed with 10 ml of hexane and 10 ml petroleum ether. Then the solid was dried at 80 °C under high vacuum to afford 75 g of crude sodium 1 -phenyl-1,1 -difluoromethanesulfinate 1 9 .1 9 F NMR (338 MHz, D20 , in ppm): -112.75. Then the salt 19 was dissolved in 100 ml of water, and 30 ml of 50 % H2O2 was added dropwise at 0 °C. After the exothermic reaction faded, the mixture was stirred at room temperature for another 2 h. After removal of water and excess H2O2 under vucuum, the residue salt was washed by CH2CI2 and pet ether. The resulting solid was dried at 80 °C / 0.1 mmHg to give 84 g of product sodium 1-phenyl-1,1- difluoromethanesufonate 20, *H NMR [360 MHz, D2O, D2O (4.67 ppm) as internal standard]: 7.44 (t, J = 7.9 Hz, 2H); 7.51 (t, J = 7.9 Hz, 1H); 7.59 (d, J = 7.9 Hz, 2H). 1 9 F NMR (338 MHz, D20 , in ppm): -102.52. Solid 20 was dissolved in 100 ml of H2O, and then was passed through a Amberlyst® acid resin column (15 mm x 410 mm). The free water (~ 80 ml) was evaporated from resulting solution to give a condensed aqueous solution of phenyl difluoromethanesulfonic acid 15. *H NMR (360 MHz, D2O, TMS int.): 7.58 (t, J = 249 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 7.9 Hz, 2H); 7.66 (t, J = 7.9 Hz, 1H); 7.73 (d, J = 7.9 Hz, 2H). 1 3 C NMR (62 MHz, D20 , in ppm): 8 117.05 (t, VC .F = 274.7 Hz); 123.43 (t, 3 J C-f = 6.0 Hz); 125.41; 127.00 (t, 2 / C-f = 23.0 Hz); 128.50. 1 9 F NMR (338 MHz, D20 , in ppm): -102.55. Attempted purification of acid (15): The condensed solution of 15 prepared above (3.0 g) was vacuum distilled over a 70 °C in an oil bath under 0.1 mmHg vacuum. After all the water distilled out, the gummy solid residue immediately decomposed to give some white crystalline solid with a melting point 122-123 °C. The solid turns out to be benzoic acid. *H NMR (360 MHz, CDCI3, in ppm): 8 7.50 (t, 2H); 7.64 (t, 1H); 8.17 (d, 2H). 1 3 C NMR (62 MHz, CDCI3, in ppm): 8 128.42; 129.25; 130.15; 133.74; 172.19. 8.5.4 Synthesis of 2-phenyl-l ,1,2,2-tetrafluoromethanesuIfonic acid (21, PhCF2 CF2 S 0 3 H) 2-Bromo-2,2-difluoroacetophenone (23): Into the mixture of magnesium turnings (1.28 g, 53.3 mmol) and TMSC1 (11.6 g, 106.9 mmol) in 150 ml of THF at 0 °C, was slowly added under argon atmosphere PI1 COCF3 (4.65 g, 26.7 mmol). The reaction mixture was stirred at 0 °C for 4 h. After removal of the solvent and excess TMSC1 under vacuum, 50 ml of hexane was added. Solid species was removed via vacuum filtration, and the filtrate was cocentrated to give 25.18 g crude product 25. lK NMR (500 MHz, CDCI3): 8= 0.60 (s, 9H), 7.38 (t, /= 7.5 Hz, 1H), 7.47 (t, J= 7.5 250 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Hz, 2H), 7.61 (d, J= 8 .8 Hz, 2H); 1 3 C NMR (125 MHz, CDC13 ): 5= 0.02, 114.09 (q, 2 J(C, F)= 18.0 Hz), 125.84, 127.72, 128.25, 132.71, 154.87 (t, V(C, F)= 286.8 Hz); 1 9 F NMR (470 MHz, CDCI3): 6- -100.39 (d, 2 J(F, F) = 68.0 Hz ), -112.16 (d, V(F, F)= 68.0 Hz). MS (70 eV) m/z (relative intensity): 228 (M+, 79), 213 (2), 197 (1), 186 (5), 177 (60), 165 (1), 149 (1), 143 (1), 131 (5), 115 (9), 105 (36), 89 (45), 81 (29), 77 (75), 73 (100). The above prepared 23 was dissolved in 100 ml of dry CH2CI2, and at -78 °C bromine was added via a syringe until the brown color no longer disappeared. After stirring for another 30 min, the solvent was evaporated under vacuum, and the residue was washed and extracted with CH2CI2. The organic phase was further washed with NaHCC>3, brine and water sequentially. After drying over MgSC>4, the solvent was removed to give 21.40 g crude product 23, yield 83 % calculated from PI1 COCF3. The crude product was further purified by fractional distillation to afford 20.03 g product 23 as a colorless liquid, b.p. 99 ~ 101 °C/15 mmHg, yield 78 % based on PhCOCF3 used. *H NMR (500 MHz, CDC13 , in ppm): 7.53 (t, J = 7.8 Hz, 2H); 7.68 (t, J - 7.8 Hz, 1H); 8.15 (d, J = 8.0 Hz, 2H). 1 3 C NMR (90 MHz, CDC13 ): 8 113.56 (t, I / c -f = 319.1 Hz); 128.87; 129.05; 130.61 (t, 3/ C-f = 2.6 Hz); 135.09; 181.32 (t, 2 JC -f = 26.0 Hz). 1 9 F NMR (476 MHz, CDC13 ): 5 -58.29. MS (70 eV): 234 (M+ ); 105 (PhCO*); 77 (Ph+ ). 2-Bromo-l,l»2,2-tetrafluoroethylbenzene (22): Under an argon atmosphere, into 9.40 g (40 mmol) 23 in 60 ml of dry chloroform was added 9.76 g (60 mmol) of 251 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. DAST. The reaction mixture was then refluxed for 34 h. After cooling down to room temperature, the mixture was poured into ice water, and then the organic phase was further washed with NaHCCb, brine and water successively. After drying over MgSC> 4 and solvent removal, 8.84 g crude product 22 was obtained as a yellow liquid. Further purification by silica gel chromatography using hexane as the eluent gave 5.84 g pure compound 22 as a colorless liquid, yield 58 %. *H NMR (500 MHz, CDCI3, in ppm): 7.47 (t, J = 7.7 Hz, 2H); 7.55 (t, J = 7.5 Hz, 1H); 7.60 (d, J = 7.6 Hz, 2H). 1 3 C NMR (90 MHz, CDC13 ): 5 114.93 (tt, lJc.F = 255.0 Hz, VC -f = 31.3 Hz); 117.66 (tt, VC -f = 312.8 Hz, VC -f = 44.7 Hz); 127.06 (t, 3 JC .F = 6.2 Hz); 128.51; 128.71, 131.72. 1 9 F NMR (476 MHz, CDCI3 ): 8 -65.34 (t, V F - f = 4.8 Hz); -108.60 (t, 3 JF - f = 4.8 Hz). MS (70 eV): 256 (M+ ); 177 (PhCF2CF2 + ); 127 (PhCF2 + ); 77 (Ph4 ). 2-Phenyl-l,1,2,2-tetrafluoroethanesulfonic acid (21): Under an argon atmosphere, 4.0 g (15.5 mmol) of 22 was mixed with 3.9 g (46 mmol) of NaHCCh, 8.1 g (46 mmol) Na2S2C > 4 in 12 ml of CH3CN and 20 ml of H20 , and the reaction mixture was refluxed for 20 h. After cooling down, the reaction mixture was filtered and the filtrate was condensed under vacuum to give 17.38 g of crude product sodium 2-phenyl-1,1,2,2-tetrafluoroethanesulfinate 27. Solid compound was further washed with 5 ml CH2C12 and then dried at 80 °C/0.1 torr to give a dry salt 10.75 g. lH NMR [360 MHz, D2 0 , D2 0 (4.67 ppm) as internal standard]: 7.43 (t, 2H); 7.49 (t, 1H); 7.52 (d, 2H). 1 9 F NMR (476 MHz, D20): 5 -109.85; -129.68. 252 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The above prepared solid 21 was dissolved in 15 ml of H2O, cooled down to 0 °C and 5.3 ml 30 % H2O2 was added dropwise. The reaction mixture was stirred for another 4 h. After filtration of reaction mixture, the resultant filtrate was concentrated to give 8.23 g solid, which was dried at 80 °C under high vacuum to give 8.04 g of dry crude sodium 2-phenyl-1,1,2,2-tetrafluoroethanesulfonate 28. ]H NMR [360 MHz, D2O, D2O (4.67 ppm) as internal standard]: 7.39 (t, J = 7.9 Hz, 2H); 7.46 (t, J = 7.9 Hz, 1H); 7.51 (d, J = 7.9 Hz, 2H). 1 9 F NMR (476 MHz, D20): 8 -107.85;-114.05. Above prepared solid 28 (2 g) was dissolved in 20 ml of water, and was passed through a Amberlyst® acid resin column (10 mm x 150 mm). The resulting amber colored solution was concentrated by evaporating water under high vacuum at room temperature to give 2.28 g concentrated acid 21. J H NMR (500 MHz, D2O, in ppm): 8 7.48 (t, J = 7.9 Hz, 2H); 7.56 (t, J = 7.9 Hz, 1H); 7.61 (d, J = 7.9 Hz, 2H). 1 3 C NMR (90 MHz, DMSO-d6, in ppm): 5 115.61 (tt, Vc-f = 287.2 Hz, 2 JC -f = 37 Hz); 117.62 (tt, !/ C -f = 253 Hz, 2 JC .f = 31 Hz); 127.88 (t, V C - f = 6.4 Hz); 129.63; 132.07 (t, V c- f = 25 Hz); 132.55. 1 9 F NMR (338 MHz, DMSO-d6 , in ppm): 8 -106.54; - 113.98. Attempted purification of acid (21): The condensed solution of 21 prepared above (1.0 g) was vacuum distilled over a 55-60 °C oil bath under 0.1 mmHg vacuum. After most water distilled out, the gummy solid residue was immediately 253 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. decomposed to evolve gaseous compounds (maybe HF and SO3). 1 9 F NMR of the dark liquid residue showed only one peak at - 110.0 ppm. 8.5.5 Others /S-bromodifluoromethylstyrene (34)40: Into a 100 ml 1.3 M sec-BuLi in cyclohexane (130 mmol) in mixed solvent (200 ml THF and 100 ml ether) at -110 °C, was bubbled in 19 g (290 mmol) of CF2=CH2, and the reaction mixture was stirred at -100 °C for another 30 min followed by addition of 10.6 g (100 mmol) benzaldehyde. The mixture was slowly warmed up to -78 °C in 30 min, and then to 0 °C for another 30 min. Then the mixture was washed with cold IN sulfuric acid, and the organic phase was separated and further washed with NaHC03 aqueous solution and brine, followd by drying over MgSC>4. GCMS analysis showed it contained PhC(OH)H=CH-CF2 33 as the major product, MS: 234 (M+ +l); 232 (M+ -l); 213; 188; 153; 133; 127; 114; 102; 88; 75. 1 9 F NMR: -88.22 (d, 2JF -f = 42.8 Hz, IF); - 89.22 (dd, 2Jf.f = 42.8 Hz, 3 Jf-h = 24.4 Hz). Compound 33 was very unstable in its pure state. To the crude compound 33 in 100 ml of THF/Et20 at -100 °C, was added 10.1 ml thionyl bromide (130 mmol). The reaction mixture was stirred at -100 °C for 1 h, then warmed to room temperature and poured into ice water. The separated organic phase was washed with NaHC03 solution, brine and water successively. After drying over MgSC>4, GCMS showed the GC yield of product 34 was 55 %. MS: 232 (M+ ); 254 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 188; 153; 133; 127; 114; 102; 88. 1 9 F NMR: -44.50 ppm. The compound 34 is quite difficult to purify due to its sensitivity to silica gel, light, and heat. of-bromodifluoromethylstyrene (36): At -78 °C, 10 g (42.5 mmol) of PhCOCF2Br was treated with 1.1 eq. of Ph3P=CH2 prepared from PPh3 Me+1' and n- BuLi in THF, to give 4.3 g (42 % yield) of 36 as colorless liquid after column chromatography using hexane as the eluent. Compound 36 was also very sensitive to light. !H NMR (360 MHz, CDC13 , in ppm): 8 5.55 (m, 1H); 5.90 (b, 1H); 7.41 (m, 3H); 7.48 (m, 2H). 1 9 F NMR (90 MHz, CDC13, in ppm): 5 -46.61. MS (70 eV): 234 (M++1); 232 (M+ -l); 153; 133; 103; 77. 1-Phenyl-l-bromodifluoromethyl-ethanoI (37): Into 23 g (97.8 mmol) of PhCOCF2 Br in 100 ml of THF at -78 °C, was added 1.0 eq. of CH3 MgBr (33 ml 3 M in ether) slowly. Then the reaction mixture was stirred vigorously from -78 °C to r.t. for 1.5 h. After usual work-up, fractional distillation gave 16 g product 37 as a colorless liquid. *H NMR (500 MHz, CDC13 , in ppm): 8 1.83 (t, J = 1.1 Hz, 3H); 2.59 (s, 1H); 7.39 (m, 3H); 7.60 (m, 2H). 1 9 F NMR (476 MHz, CDC13 , in ppm): 5 - 57.51. MS (70 eV): 252 (M+ + 1); 237; 121; 77. Some crystalline by-product 38 (5.5 g) was also isolated. lH NMR (500 MHz, CDC13, in ppm): 8 1.70 (t, J = 2 Hz, 3H); 3.04 (s, 1H); 5.50 (s, 1H); 6.9~7.2 (m, 10H). 1 9 F NMR (476 MHz, CDC13, in ppm): 8 -50.93 (ddd, J = 158.3 Hz, J = 53.4 Hz, J = 3.8 Hz, IF); -56.75 (ddd, J = 152.6 Hz, J = 19.1 Hz, J = 7.6 Hz, IF); -106.6 255 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. (dd, J = 265.1 Hz, J = 19.1 Hz); -112.7 (ddd, J = 265.1 Hz, I = 53.4 Hz, J = 7.6 Hz). MS (70 eV): 408 (M+ +l); 406 (M+ -l); 326; 309; 289; 277; 259; 197; 121; 105; 77; 57. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 8.5 References 1. Hall, N. F.; Conant, J. B. J. Am. Chem. Soc. 1927, 49, 3047. 2. (a) Olah, G. A. Chem. & Eng. News 1967, March 27, 45, 76. (b) Olah, G. A. Science 1970, 168, 1298. (c) Olah, G. A.; Prakash, G. K. S.; Sommer, J. Superacids, Wiley-Interscience: New York, 1984. (d) Gillespie, R. J. Acc. Chem. Res. 1968,1, 202. (e) Gillespie, R. J. Can. Chem. Educ. 1969, 4, 9. 3. Hammett, L. P. Physical Organic Chemistry, McGraw-Hill: New York, 1940. 4. Christe, K. O. J. Fluorine Chem. 2000,101, 151. 5. (a) Olah, G. A., Conference Lecture at 9th Reaction Mechanism Conference, Brookhaven, New York, August 1962. (b) Olah, G. A. Angew. Chem. Int. Ed. Engl. 1963, 2, 629. (c) Olah, G. A. Angew. Chem. Int. Ed. Engl. 1973,12, 173. (d) Olah, G. A. Angew. Chem. Int. Ed. Engl. 1995, 34, 1393. 6. For review: Howells, R. D.; Me Cown, J. D. Chem. Rev. 1977, 77, 69. 7. Nafion is a registered trademark of DuPont Company, U.S.A. 8. For review: Olah, G. A.; Prakash, G. K. S. Iyer, P. S. Synthesis 1986, 513, and references therein. 9. Sun, Q.; Harmer, M. A.; Fameth, W. E. Chem. Commun. 1996, 1201. 10. Him, S.-K.; Chung, M.-J.; Park, K.-Y. Ind. Eng. Chem. Res. 1 988, 27, 41. 11. Poutsma, M. L. in Zeolite Chemistry and Catalysis (Ed. Rabo, J. A.), Chapter 8, ACS Monographs 171, American Chemical Society, Washington D. C., 1976. 12. Haszeldine, R. N.; Kidd, J. M. J. Chem. Soc. 1954, 4228. 13. Haszeldine, R. N.; Kidd, J. M. J. Chem. Soc. 1955, 2901. 14. (a) Haszeldine, R. N.; Hewitson, B.; Higginbottom, B.; Rigby R. B.; Tipping, A. E. Chem. Commun. 1972, 249. (b) Ward, R. B. J. Org. Chem. 1965, 30, 3009. 15. Bielefeldt, D.; Marhold, A. US Patent, 1991, US 5,059,711; Ger. Offen., 1988, DE 3,712,318. 257 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 16. (a) Trott, P. W.; Brice, T. J.; Guenthner, R. A.; Severson, W. A.; Coon, R. I.; LaZerte, J. D.; Nirschl, A. M.; Danielson, R. D.; Morin, D. E.; Pearlson, W. H., Abstracts, 126 National Meeting of the American Chemical Society, New York, 1954, p 42-M. (b) Brice, T. J.; Trott, P. W„ US Patent, 1956, US 2,732,398. 17. Prakash, G. K. S. in Synthetic Fluorine Chemistry, Ed. by Olah, G. A.; Chamber, R. D.; Prakash, G. K. S., John Wiley & Sons: New York, 1992, pp 241-242. 18. Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149. 19. (a) Conolly, D. J.; Gresham, W. F. US Patent 1966, US 3,282,875 (DuPont), (b) England, D. C. US Patent 1958, US 2,852,554 (DuPont). 20. Eisenberg, A.; Yeager, H. L., Ed., Perfluorinated Ionomer Memberanes, ACS Symposium Series, 1982, 180, ACS, Washington D. C. 21. Volkov, N. D.; Nazaretian, V. P.; Yagupol’skii, L. M. Synthesis 1979, 972. 22. Sweeney, R. F.; Peterson, J. O.; Sukomick, B.; Berenbaum, M. B.; Nychka, H. R.; Eibeck, R. E. Can. Patent 1981, CA 1,093,581. 23. Nippon Petrochemical CO., Ltd., Japan, Jpn. Kokai. Tokkyo. Koho. 1980, JP 55,057,524. 24. Furukawa, S.; Yoshimura, S.; Takahashi, M. (Sanyo Electric Co., Ltd., Japan). Jpn. Kokai Tokkyo Koho 1990, JP 02306544. 25. Smertenko, E. A.; Volkov, N. D.; Datsenko, S. D.; Ignat'ev, N. V. Theor. Exp. Chem. 2000, 35,231. Chemical Abstract: CAN 132: 129 167. 26. Doyle, C. M.; Fiering, A. E.; Choi, S. K . PCTInt. Appl. 1999, WO 9,967,304. 27. Feiring, A. E.; Wonchoba, E. R. J. Fluorine Chem. 2000,105, 129. 28. (a) Swarts, F. Bull. Acad. Royal Beige. 1892, 24, 309. (b) Hassner, A.; Stumer, C. Organic Syntheses Based on Name Reactions and Unnamed Reactions', Pergamon: New York; 1994, p 377. 29. (a) Rathke, B. Ber. 1870, 3, 859. (b) Dyson, G. M. Organic Syntheses', Wiley: New York, 1932; Collet.Vol. I, p 506. 258 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 30. Helfrich, O. B.; Emmet Reid, E. J. Am. Chem. Soc. 1921, 43, 591; and the references therein. 31. Grayson, J. I. Organic Process & Research Development 1997,1, 240. 32. Yarovenko, N. N.; Motomyl, S. P.; Vasil’eva A. S.; Gershzon, T. P. Zh. Obshch. Khim. 1959, 29, 2163. (J. General Chem. 1959, 29, 2129.) 33. Cited in reference (30): US Patent 1936, US 2,000,932. British Patent 1937, Patent number 454,577. 34. Yagupol'skii, L. M.; Kondratenko, N. V.; Popov, V. I. Zh. Org. Khim. 1977, 13, 613. (English Transl.: J.Org. Chem. USSR 1977,13, 561. 35. Bellew, D. R. Studies in Organofluorine Chemistry (Ph.D. dissertation), 1991, University of Southern California; p51. 36. Huang, B. N.; Huang, W. Y.; Hu, C. M. Acta Chimica Sinica 1981, 39, 481. 37. Liu, J. T.; Liu, H. J. Chin. Chem. Lett. 2000,11, 189. 38. Yudin, K. Y.; Prakash, G. K. S.; Deffieux, D.; Bradley, M.; Bau, R.; Olah, G. A .J. Am. Chem. Soc. 1997,119, 1572. 39. See Chapter 2 and 3 and the references therein. 40. (a) Markovskii, L. N.; Pashinnik, V. E.; Kirsanov, A. V. Synthesis 1973, 787. (b) Middleton, W. J. J. Org. Chem. 1975, 40, 574. (c) Middleton, W. J. US Patent, 1975, US 3,914,265; US 3,888,924. 41. (a) Tillier, F.; Duffault, J.-M.; Baudry, M.; Sauvetre, R. J. Fluorine Chem. 1998, 91, 133. (b) Tillier, F.; Sauvetre, R. J. Fluorine Chem. 1996, 76, 79. (c) Sauvetre, R.; Normant, J. F. Tetrahedron Lett. 1981, 22, 957. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 9 Metal-Free Anionic Polymerization Using Organosilane/Tetramethylammonium Fluoride as New Initiating System Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 9.1 Introduction Metal-free anionic polymerization of a-activated olefins such as acrylates, methacrylates and acrylonitrile has been one of the recent exciting developments in polymer chemistry.1 '9 In 1983 Webster and co-workers1 at Du Pont reported a first metal-free living polymerization (so-called “group transfer polymerization”, GTP) of methacrylic esters at room temperature using silyl ketene acetal/catalytic fluorides as initiators. Thereafter, Reetz and co-workers used, for the first time, ammonium 0 ^ d thiolates, metal-free carbon or nitrogen nucleophiles ’ as initiators for the controlled anionic polymerization of methyl or n-butyl acrylates. Sivaram and others5 developed several other functional metal-free initiators consisting of tetrabutylammonium salts of oxazoline-functionalized malonates, diethylphenylmalonate, fluorene, and 9-ethylfluorene for the polymerization of alkyl acrylates. Pietzonka and Seebach5 used the P4-te/t-butyl-phosphazene salt of ethyl acetate for the polymerization of methyl methacrylate (MMA) in THF. Using similar method, Bomer and Heitz7 have demonstrated the complexity of the polymerization of n-butyl acrylate using P4-tert-butylphosphazene base/methyl isobutyrate initiating o system. Hogen-Esch and co-workers have shown a living polymerization of methacrylates using the tetraphenylphosphonium counterion at ambient temperatures in THF. It was found that this polymerization involves a phosphor ylide as a dormant species.9 2 6 1 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Furthermore, in the case of using tetrabutyiammonium5 d ’ 1 0 or tetrahexylammonium1 1 as counterion, the anionic polymerization of alkyl (meth)acrylates proceeds with incomplete conversion, low initiator efficiency and/or broad molecular weight distribution. The carbanion generation through the reaction between tetrasubstituted silane and fluoride has been known for more than twenty years.1 2 ' 1 3 In 1989, Prakash and co-workers1 4 reported the first nucleophilic trifluoromethylation using (trifhioromethyl)trimethylsilane (TMS-CF3 ) with catalytic amount o f fluoride, and currently this methodology has been extensively applied in synthesizing biologically active compounds and functional materials.1 5 It is generally believed that the generation of carbanion from silane and fluoride is via an anionic pentacovalent silicon species, which further undergo one polarized (R4)C-Si bond to release one anion and one trialkylsilyl fluoride (Scheme 9.1). Obviously, the formation of strong Si-F bond (540 kJ/mol1 6 ) is the driving force for this transformation. R! R 2 / R3 Si R4 R- .Si R 0 R R4© + R2 - 7 r 3 Si— F (R1, R2, R3 = alkyl groups, R,= Ph, CF3, Ph3C, Ph2CH, etc.) Scheme 9.1 Generation of anion [R4 D ] from silane and fluoride. 262 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. However, to our best knowledge, little is known about the organosilane /fluoride as initiating system for anionic polymerization. Eryama and co-workers1 7 disclosed disilane(polysilane)/Bu4 NF as initiating system for anionic polymerization of MMA in THF at 25 °C, but the molecular weight distribution (MWD) was quite broad (Mw /Mn = 2.03, Mw = 61,500). Ballard and co-workers1 8 also reported the use of benzyltrimethylsilane/ButNF (TBAF) as initiator for polymerization of MMA at room temperature, and they claimed that the benzyl anion (PhCH2‘) generated from the reaction between PhCH2SiMe3 and TBAF was the active initiator. They also found that the molecular weight of PMMA at a given concentration of silane i o compound was inversely proportional to the concentration of TBAF. However, more details of the polymerization such as MWD and initiator efficiency were not presented. Herein, we wish to report the (triphenylmethyl)trimethylsilane /tetramethylammonium fluoride initiated anionic polymerization of MMA. We will present evidence indicating that, this initiating system is capable of producing very high molecular weight PMMA (up to 96,000) with very narrow MWD (1.04). The use of other organosilanes as well as the mechanism of the initiation/propagation process will also be discussed. 263 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 9.2 Results and Discussion 9.2.1 Synthesis of silanes Silanes 1 - 4 were proposed as corresponding anionic initiator precursors (Scheme 9.2). (Triphenylmethyl)trimethylsilane 1 was prepared from the reaction between trityl lithium or Grignard reagent with chlorotrimethylsilane.1 9 9 0 9 1 (Diphenylmethyl)trimethylsilane 2 and (pentafluorophenyl)trimethylsilane 3 were synthesized using similar methods. (Trifluoromethyl)trimethylsilane 4 was commercially available, and it was also synthesized via a novel methodology developed by us (see Chapter 4). Scheme 9.2 Structures of silanes 1-4. 264 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. In order to verify the high polarity of the C—SiMes bonds in these silanes which leads to C-Si cleavage to generate carbanion species when a fluoride attacks silicon atom, we tried to characterize the structures of these silanes by X-ray acrystallography. Among above four silanes, only compound 2 gave a good single crystal. From its X-ray structure (Fig 9.1), the C—SiMe3 bond is extraordinarily long (1.91 A), compared with usual C-Si bond length of 1.87 A.1 6 Fig 9.1 X-ray crystal structure of silane 2 265 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 9.2.2 Choice of fluoride First of all, w e used (triphenylmethyl)trimethylsilane 1 as a model compound and scanned several fluoride precursors to generate tritryl anion (Scheme 9.3). Tetrabutylammonium fluoride (TBAF) reacted with 1 readily to form deep red trityl anion solution. However, since each TBAF molecule commonly contains three molecular water molecules (”Bu4NF-3H20), the trityl anion was quickly quenched by those water molecules and deep red color disappeared in about 10 seconds at - 78 °C. All attempts to remove water from TBAF crystalline solid resulted in 00 decomposition due to the Hoffman elimination on the butyl group. THF - 78 °C - -20 °C + Me3SiF 1 (deep red) (a) n Bu4N + F (TBAF) (b) CsF (c) nBu4N+ [Ph3SnF2 ]' (d) (Me2N)3S+ [Me3SiF2]' (TASF) (e) Me4N+ F' (TMAF) Scheme 9.3 The effects of different fluoride sources. 266 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Anhydrous cesium fluoride (CsF) was used but the reaction did not proceed even at room temperature. T etrabutylammonium difluorotiiphenylstannate ”Bu4N+[Ph3SnF2]" was prepared,2 3 but its reaction with 1 was not successful. Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TASF) was also attempted and it reacted with 1 very rapidly, but the disadvantage of TASF was its reaction with glass. Finally it turns out that tetramethylammonium fluoride (TMAF) is the fluoride reagent of choice. TMAF is the only tetraalkylammonium fluoride, which can be isolated in anhydrous form (water content < 0.06 wt %), and it is a very strong Lewis base as well as a strong nucleophile2 2 Although TMAF did not react with 1 readily in THF at -78 °C due to its poor solubility at this temperature, the reaction was very successful to generate deep red tetramethylammonium triphenylmethide (Ph3C‘ + NMe4) when we raised the temperature to - 20 °C or higher. The deep red solution can stand for hours even at 25 °C with very slow decomposition. This prompted us to use organosilane/TMAF as initiating system for metal-free anionic polymerization. 9.2.3 Polymerization of MMA using PI13CSiMea/TMAT as initiator The polymerizations of MMA using Ph3CSiMe3/Me4 NF (PI1 3 C" + NMe4 ) as initiator were carried out using high vacuum (10" 5 Torr) techniques using breakseals.2 4 The typical polymerization procedure is as follows: high vacuum dried 267 permission of the copyright owner. Further reproduction prohibited without permission. silane 1 and TMAF were reacted each other in extremely dry THF at - 20 °C over a period of around 30 minutes to give a deep red PI1 3C + NMe4 solution. After cooling to - 78 °C, carefully purified MMA monomer in THF was added dropwise over periods varying from 20 seconds to 10 minutes. Polymerization was then terminated by degassed methanol. Table 9.1 summarizes several different runs of polymerizations. Table 9.1. Ph3 C + NMe4 initiated anionic polymerization of MMA in THF at - 78 °Ca Run Yield (%)b Mn (Calc)0 Mn (SEC) Mn (NMR)d PDI f 85 12,100 92,900 - 1.30 0.13 2f > 9 5 4,100 35,700 - 1.09 0.11 3 > 95 8,600 96,000 - 1.04 0.09 4 > 9 5 13,200 57,300 - 1.07 0.23 5 > 95 4,700 11,900 12,000 1.09 0.40 6 h > 95 3,200 16,100 16,300 1.07 0.20 f > 95 4,200 7,100 7,400 4.07 - 8 j > 95 7,300 75,000 - 1.26 0.10 a [MMA] = 0.1 M, [Ph3CSiMe3] varies, VT H F = 30 ml, initiator generation: at -20 °C for 30 min. b Percent yield, determined gravimetrically. cMn (Calc) = [MMA]/[Ph3CSiMe3]. dNMR Mn determined from ratio of aromatic signals o f initiator group [Ph3C] to methyl ester signals. e Initiator efficiency = Mn(Calc) / Mn(SEC). f Initiator generation temperature was 25 °C. 8 Me4NF used was momentarily exposed to air. h MMA solution was added dropwise over 10 minutes.1 Initiator generation time was 10 minutes.31 mM [Ph2CHSiMe3] was used in place o f Ph3CSiMe3. 268 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. In all cases except runs 1 and 7, narrow MWDs (PDI < 1.1) were obtained, and monomer conversions were almost quantitative. Fig 9.2 shows the narrow MWD of run (PDI = 1.04). The relative wide MWD in run 1 most likely correlates with a brief exposure of the highly hydroscopic TMAF to the atmosphere. And the relative wide broad MWD of run 7 indicates that the enough time for initiator [PI1 3 C + NMe4] generation was necessary. It is remarkable that even when MMA was added dropwise over a period of 10 minutes (run 6), PMMA with narrow polydispersity (PDI = 1.07) was also obtained. Fig 9.2 SEC trace of PMMA (crude) from reaction mixture of run 3. 269 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The narrow polydispersity and high molecular weight of PMMA (especially runs 3 and 4) are particularly interesting. The exact mechanism of this unusual polymerization process is not clear. We envision this as a result offast initiation and more rapid polymerization processes (ki < k2) (Scheme 9.4). Since both initiation and polymerization processes consume monomer competitively with high reaction rate (although ki < k^), the monomer was converted immediately into polymer with narrow polydispersity when it was added in dropwise. The overall polymerization is like a “living” system. P h 3C S iM e 3 + M e4 N +F ------------------► P h 3C ' +N M e 4 + M e 3S iF 00 P h 3C" +N M e 4 *N I o / P h 3C N M e 4 ! (ii) o, C 00C H 3 coocHa Scheme 9.3 Schematic illustration o f the initiation and propagation processes. 270 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The assumption of relatively slower initiation was supported by the fact that, the persistence of the deep red color of the PI1 3C' + NMe4 initiator for at least 5 minutes after addition of MMA monomer (Table 9.1, run 6 ).5 d ’ 2 5 Since the polymerization was always leaving initiation process far behind, the added monomer was “eaten up” by the polymerization process before it can react with all of the initiators. Thus some “hungry” initiators were left inside the reaction system, which explains the persistence of red color as well as low initiation efficiency (9 - 40 %). Other factors such as small amounts of moisture in TMAF, slow generation of PI1 3 C" + NMe 4 from Ph 3 SiMe 3 and TMAF, and spontaneous degradation of PI1 3 C + NM e 4 before MMA monomer was added, may not be the main leads for the low initiator efficiencies. Even at 25 °C in THF in the absence of MMA, the red color of PI1 3 C' 4 NMe4 was found to persist for 2 - 4 hours before complete initiator decomposition. The residue from the decomposition experiment was mainly found to be PI1 3C-CH 3 , small amount of PI1 3 CH and volatile MesN. No Ph 3 CSiMe 3 (1) were found to be left, which means that the initiator generation from 1/TMAF was complete. The formation of PI1 3 CH (~ 10 mol %) was possibly from protonation of the trityl anion by either residual water associated with TAMF, or by the proton from tetramehtylammonium, thereby generating the nitrogen ylide (Scheme 9.5). However, the resulting Stevens rearrangement of the nitrogen ylide is expected to generate dimethylethylamine that was not detected. At the beginning we assumed the nitrogen ylide may intiate the polymerization of MMA, but it turns out this not the major pathway. Proton NMR integration of the aromatic peaks of initiator (PI1 3 C) 271 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. and the methyl groups of PMMA gave number average MWs that is in good agreement with that determined by SEC (Table 9.1). B' + H-CH2-N+ (CH3)3 ► BH + *CH2-N+(CH3)3 ^ -CH3 r > CH2-N+(CH3)2 --------------► CH3CH2N(CH3)2 (II) Nu' H3C (j l +(CH3)3 ---------- ► Nu-CH3 + NMe3 (III) (B, Nu = Ph3C' or PMMA') Scheme 9.5 Possible side reactions. Furthermore, the narrow polydispersities of the PMMA indicated that PMMA anion protonation or methylation did not appear to be a factor, at least on the very short time sacle fo the polymerization. The isolation of NMe3 and PI1 3 CCH3 from the decomposition residue indicated the methylation of trityl anion by tetramethylammonium cation (Scheme 9.5, III). However, this reaction seems to be slow and not to be a factor to disturb the polymerization, judging by the long time existence of red color of PI1 3C + NMe4 and the narrow molecular weight distribution. The broad MWD of run 7 indicated that enough time for complete generation of PI1 3C' + NMe4 initiator is necessary, otherwise the unreacted Ph3CSiMe3 is expected to lead to the trimethylsilylation of the PMMA anion and thus terminate the polymerization.2 6 272 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The relatively slow initiation and formation of PMMA with narrow MWD in high yield indicates the rapid polymerization process, which consumes the MMA monomer in a short time. This conclusion is consistent with other reports. Johann and Muller27 reported an extremely rapid polymerization of MMA in the presence of large organic cations or cryptated Li or Na cation, with polymerization half lives on the order of 10"1 second. Phosphor ylide, BudST [CPhaOi-CsHn)]’, (n-CeH^+N* ' CPI13, or n - 'CPI13 initiated polymerizations of MMA have also been known with a rapid polymerization rate.9a,5d’10,11 9.2.4 Other initiators and monomers Under similar conditions, PI12HC" + NMe4 generated from PhjHCSiMes 2 and TMAF was also able to initiate MMA to give PMMA with slightly wide molecular weight distribution (Table 9.1, run 8 ). TMS-CF3/TMAF initiated MMA polymerization only gave 5 % of high molecular weight PMMA due to the dominant trilfuoromethylation on the ester group of MMA.28 C6F5-TMS/TMAF was able to successfully initiate 2 -vinylpyridine once, but with poor yield. 9.3 Conclusion In summary, tetramethylammonium triphenylmethide (PI13C' + NMe4) was generated in situ by the reaction of (triphenyhnethyl)trimethylsilane and 273 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. tetramethylammonium fluoride in THF at low temperature. Metal-free polymerization of MMA initiated by this initiator in THF at - 78 °C successfully produced quantitatively yields of high molecular weight PMMA with very narrow molecular weight distribution. The initiation process appeared to be slow while the polymerization process was rapid, which were consistent with the low initiator efficiencies (9 - 40 %) and narrow MW distributions. (Diphenylmethyl) trimethylsilane /TMAF was also able to initiate MMA polymerization with a similar result. TMS-CF3 and C^Fs-TMS were also attempted to initiate MMA or 2-VP, but only gave poor results. 9.4 Experimental Section Materials and instrumentations: Unless otherwise mentioned, all the other reagents were purchased from commercial sources. Tetramethylammonium fluoride (TMAF) (Aldrich, 97 %) was handled inside a glove box, and dried under vacuum ( 10'5 Torr) overnight before use. THF was stored over Na/K alloy and distilled over PI1 3CK prior to use. Methyl methacrylate (MMA) was purified by distillation first over CaH2, then over 2 ml (1 mmol) of trioctylaluminum (Al(Oct)3, Aldrich, 25 wt. % in hexanes), followed by dilution with 90 ml of purified THF (distilled from PI1 3CK). Column chromatography was carried out using silca gel (60-200 mesh). 274 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1 H, 1 3C, 1 9 F and NMR spectra were recorded on Bruker AMX 500, AM 360, or AC-250 NMR spectrometers. (CH3 )4Si (IMS) was used as an internal standard for *H and 1 3 C NMR, CFCI3 was used as the internal standard for 1 9 F NMR. For some cases, CDCI3 was used as internal standard for *H NMR (7.26 ppm) and 1 3 C NMR (77 ppm). IR spectra were obtained on a Perkin-Elmer FTIR Spectrometer 2000. Mass spectra were obtained on a Hewlett Packard 5890 Gas Chromatograph equipped with a Hewlett Packard 5971 Mass Selective Detector at 70 eV. Size exclusion chromatography (SEC) measurements were carried out using THF as the eluent at a flow rate of 1.0 ml/min, using a LC system consisting of a Waters 510 HPLC pump, Waters 410 refractive detector, and a U6K injector. Two Waters “Unltrastyragel” columns (500 and 104 anstrom) caliberated with PMMA standards (Polysciences, Inc.) were used with a linear separation range of 800 - 350,000 Daltons. SEC analysis was carried out on the crude product (not the precipitated polymer) that may contain low molecular weight oligomers. (Triphenylmethyl)trimethylsilane19 (1): To a 100 ml Schlenk flask containing 2.67 g (10.9 mmol) of Ph3CH in 30 ml of dry THF under argon, was slowly added via syringe 4.36 ml (2.5 M in hexane, 10.9 mmol) of ”BuLi at 0 °C. After addition, the reaction mixture was warmed up to room temperature and stirred for another 1 hour. Subsequently, 1.5 g (13.8 mmol) TMSC1 was added slowly and the reaction mixture was stirred at room temperature overnight. 30 ml of ether was added and the organic phase was washed with ice water, saturated NaHCCh aqueous solution, and 275 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. water sequentially. After drying over anhydrous MgSC>4, the solvent was removed in vacuo to give 3.52 g crude product as a white solid. Further purification by column chromatography (silica 70-200 micron, pentane as eluent) afforded 2.44 g (71 %) of product 1 as a white solid, m.p. 166-167 °C. JH (CDCI3, ppm): 8 0.15 (s, 9H); 7.05 (d, J = 6.8 Hz, 6H); 7.17 (t, J= 7.3 Hz, 3 H); 7.25 (t, J= 7.4 Hz, 6H). 1 3 C (CDC13, ppm): 5 1.68; 53.60; 125.35; 127.86; 130.06; 146.70. MS: 316 (M+ ); 301; 243; 197; 165; 139;115. (DiphenyJmethyl)trimethylsilane19 (2): To a 250 ml Schlenk flask containing 5.03 g (29.9 mmol) of PI1 2 CH2 in 40 ml of dry THF under argon, was slowly added via syringe 12.4 ml (2.5 M in hexane, 31.0 mmol) of "BuLi at 0 °C. After addition, the reaction mixture was warmed to room temperature and stirred for another 1 hour. Subsequently, 5.43 g (50.0 mmol) TMSC1 was added slowly and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then quenched with 20 ml of aqueous NaHCC> 3 solution, followed by extraction with 40 ml ether. The organic phase was washed with brine and water succesively. After drying over anhydrous MgSCX, the solvent was removed in vacuo to give 7.28 g crude product. The crude product was recrystallized from ether to afford 6.48 g of pure crystalline product 2, yield 90 %. Melting point: 75-76 °C. *H (CDCI3, ppm): 8 0.03 (s, 9H); 3.51 (s, 1H); 7.12-7.24 (m, 10H). 1 3 C (CDC13, ppm): 8 -1.70; 46.10; 125.04; 128.26; 128.71; 142.88. GCMS: 240 (M+); 225; 197; 165; 152; 121; 105; 89; 73. This compound was also characterized by X-ray crystallography (Fig 1). 276 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Tetrabutylammonium difluorotriphenylstannate23: Into a 100 ml flask containing 4.78 g (12.95 mmol) tirphenyltin fluoride in 100 ml of dichloromethane, was added 4.08 g (12.95 mmol) of TBAF-3H20 in 50 ml dichloromethane. The reaction mixture was stirred for 30 min at room temperature. After filtration, the solvent was evaporated to give 8.69 g crude product, which was recrystallized from CH2C12/Et2 0 (1:1) to give 7.09 g (87 %) of crystalline product, m.p. 187-188.5 °C. lH NMR (CDCI3, in ppm): 8 0.90 (t, 12H); 1.16 (m, 16 H); 2.57 (t, 8H); 7.27 (m, 9H); 8.12 (d, 6H). Typical polymerization procedure: The polymerizations were carried out with high vacuum and breakseal techniques.2 4 Silane 1 (30 mg, 1.0 x 10'4 moles) was dissolved in 25 ml of THF at room temperature and the solution was cooled to - 78 °C. Then 18 mg TMAF solid (2.0 x 10'4 moles) was added from a breakseal and the mixture was stirred for 5 minutes with no appearance of color. One minute after warming to - 20 °C bath, a faint reddish color of the tiphenylmethyl anion appeared that intensified over the next 30 minutes. The reaction mixture was then cooled to - 78 °C for 5 minutes with no visible disappearance or change of color, indicating the lack of anion termination. To the mixture maintained at - 20 °C was added dopwise MMA monomer (1 g, 1 x 10'2 moles) in 10 ml of THF over a period of about 20 seconds, with little or no detectable change in color intensity. Polymerization was terminated by adding several drops of degassed methanol into the flask. Small 277 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. amount of reaction mixture was taken for SEC measurement. The rest of the mixture was poured into 300 ml of methanol, followed by filtration and drying to give ~ 1.0 g PMMA. 278 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 9.5 References 1. Webster, O. W.; Hertler, W. R.; Sogah, D. Y.; Famham, W. B.; RajanBabu, T. V. J. Am. Chem. Soc. 1983,105, 5706. 2. Reetz, M. T.; Ostarek, R. J. Chem. Soc., Chem. Commun. 1988, 213. 3. (a) Reetz, M. T. Angew. Chem. 1988,100, 1026. (b) Reetz, M. T.; Knauf, T.; Minet, U.; Bingel, C. Angew. Chem. 1988,100, 1422. 4. Reetz, M. T.; Hutte, S.; Goddard, R.; Minet, U. J. Chem. Soc., Chem. Commun. 1995, 275. 5. (a) Sivaram, S.; Dhal, P. K.; Kashikar, S. P.; Khisti, R. S.; Shinde, B. M.; Baskaran, D. Macromolecules 1991, 24, 1698. (b) Raj, D. J. A.; Wadgaonkar, P. P.; Sivaram, S. 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Creator Hu, Jinbo (author)

Core Title Investigations in selective fluorinations: Novel synthetic methodologies and material syntheses

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Advisor Prakash, G.K. Surya (committee chair), Olah, George A. (committee member), Petruska, John (committee member)

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