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Development of sulfone-based nucleophilic fluoromethylating reagents and related methodologies
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Development of sulfone-based nucleophilic fluoromethylating reagents and related methodologies
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Development of Sulfone-Based Nucleophilic Fluoromethylating Reagents and Related Methodologies by Nan Shao ________________________________________ A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (CHEMISTRY) May 2013 Copyright 2013 Nan Shao ii DEDICATION To My Parents and Xi Wang iii ACKNOWLEDGEMENTS I would like to express my gratitude to Professor G. K. Surya Prakash for the opportunity that he gave me to work in his group at USC. I am grateful to him for his endless support, encouragement and guidance throughout my entire PhD study. This dissertation wouldn’t have been possible without his advice and motivation. I would also like to thank Prof. George A. Olah for his constant inspiration, advice and encouragement, and especially for his profound knowledge in both chemistry and philosophy. I would like to thank my PhD program guidance committee members Professor Kathering Shing, Professor Thieo E. Hogen-Esch and Professor Richard Brutchy for their guidance and helpful discussions. I would like to thank Dr. Thomas Mathew for his help and guidance in my research program. He has been someone I could turn to help and advice regarding many things. I am most grateful to Dr. Fang Wang whom I have worked with on several projects. The scientific discussion and the lab experience that he shared with me helped me to establish myself as a chemist. In addition, I like to acknowledge Dr. Sujith Chacko who taught me many lab techniques when I joined in our laboratory. I would like to extend my gratitude to Professor Gulam Rasul for his support in computational chemistry. I would like to thank Professor Chuanfa Ni at SIOC for his help and guidance on my projects. I would also like to thank Professor Ralf Haiges for solving all the crystal structures in this thesis. Many heartful thanks to my colleague, Ms. Zhe Zhang, for collaborating our project in chapter 5. I would also express my appreciation to Dr. Clement Do, Dr. Habiba iv Vaghoo, Dr. Timothy Stewart, Mr. Laxman Gurung and Mr. Socrates Munoz-Perez for part of my projects we collaborated. I am very grateful to Dr. Robert Aniszfeld for constant support throughout the research program. In addition, I am thankful to Dr. Alain Goeppert for his help and cooperation. There are many other remarkable individuals in Olah-Prakash group who provided support and guidance during my graduate studies. In this regard, I would like to thank Dr. Attila Papp, Dr. Patrice Batamack, Dr. Parag Jog, Dr. Miklos Czaun, Dr. Farzaneh Paknia, Dr. Bo Yang, Dr. Akhisa Saitoh, Mr. Anton Shakmin, Mr. Arjun Narayanan, Mr. Dean Glass, Ms. Hang Zhang, Ms. Hema Krishnan, Mr. John-Paul Jones, Ms. Jotheeswari Kothandaraman, Mr. Marc Iuliucci, Mr. Sankarganesh Krishnamoorthy and Ms. Xu Liu. I would also take this opportunity to express my appreciation to my former colleagues to provided support and assistance during my graduate studies. Among these people are Dr. Rehana Ismail, Dr. Chiradeep Panja, Dr. Somesh Kumar, Dr. Aditya Kullkarni, Dr. Inessa Bychinskaya, Dr. Mikhail Zibinsky, Dr. Kevin Glinton, Dr. Sergio Meth, Dr. Frederick Krause and Dr. Ying Wang. My appreciation must include all staff members of the chemistry department and Loker Hydrocarbon Institute, especially Ralph, Jessy, David, Carole, Michele, Heather and Katie for their kind support. All this wouldn’t have been possible without the support of my wife, Xi Wang, who always gives me endless encouragement and inspiration. I feel extremely lucky to be with her. Finally, I have to express my deepest appreciation to my parents for all things they have done for me. v TABLE OF CONTENTS DEDICATION ii ACKNOWLEDGEMENTS iii LIST OF FIGURES viii LIST OF TABLES x LIST OF SCHEMES xi ABSTRACT xii 1 Chapter 1: Introduction 1 1.1 Chapter 1: Introduction to Fluorine Chemistry 1 1.1.1 General Overview of Fluorine Chemistry and its Applications 1 1.1.2 Fluorination Methods and Fluorinating Reagents 5 1.1.3 Fluoroalkylation Methods and Fluoroalkylating Reagents 8 1.2 Chapter 1: Aim and Scope of Present Work 11 1.3 Chapter 1: References 13 2 Chapter 2: Efficient Nucleophilic Monofluoro-methylation of Alkyl Halides Using α- Fluorobis(phenylsulfonyl)methane 16 2.1 Chapter 2: Introduction 16 2.2 Chapter 2: Results and Discussion 18 2.3 Chapter 2: Conclusion 22 2.4 Chapter 2: Experimental 23 2.4.1 Typical Procedure for Preparation of Monofluorobisphenylsulfonyl Alkanes 23 2.4.2 Typical Procedure for Reductive Monodesulfonylation of Fluorobis(phenylsulfonyl) Derivatives 26 2.4.3 Typical Procedure for Reductive Desulfonylation of Fluorobis(phenylsulfonyl) Derivatives 30 2.5 Chapter 2: Representative Spectra 33 2.6 Chapter 2: References 51 3 Chapter 3: NMR and Computational Study of a Persistent α- Fluorocarbanion (FCA) and its Analogues 53 3.1 Chapter 3: Introduction 53 vi 3.2 Chapter: Results and Discussion 56 3.3 Chapter 3: Conclusion 68 3.4 Chapter 3: Experimental 69 3.4.1 Procedure for Preparation of α-Fluorocarbanion (II-N) Crystal 69 3.4.2 Typical Procedure for the Preparation of α-Fluorocarbanion in DMSO Solution 71 3.4.3 Typical Procedure for Preparation of Tetra-n-butylammonium- HBSM Anion Solution 72 3.4.4 DFT Calculated Structures and Energies of α-Fluorocarbanion 72 3.5 Chapter 3: Representative Spectra 75 3.6 Chapter 3: References 84 4 Chapter 4: Large Scale Preparation of α-Fluorobis(phenylsulfonyl)methane (FBSM) 86 4.1 Chapter 4: Introduction 86 4.2 Chapter 4: Results and Discussion 89 4.3 Chapter 4: Conclusion 92 4.4 Chapter 4: Experimental 92 4.4.1 Typical Procedure for Preparation of Chloromethyl Phenyl Sulfide 93 4.4.2 Typical Procedure for Preparation of Fluoromethyl Phenyl Sulfide 94 4.4.3 Typical Procedure for Preparation of Fluoromethyl Phenyl Sulfone 94 4.4.4 Typical Procedure for Preparation of Benzenesulfonyl Fluoride 96 4.4.5 Typical Procedure for Preparation of α- Fluorobis(phenylsulfonyl)methane (FBSM) 96 4.5 Chapter 4: Representative Spectra 100 4.6 Chapter 4: References 105 5 Chapter 5: Facile Synthesis of α-Monofluoromethyl Alcohols: Nucleophilic Monofluoromethylation of Aldehydes Using TMSCF(SO 2 Ph) 2 107 5.1 Chapter: Introduction 107 5.2 Chapter 5: Results and Discussion 109 5.3 Chapter 5: Conclusion 117 5.4 Chapter 5: Experimental 118 5.4.1 Typical Procedure for Preparation of α-Trimethylsilyl-α- fluorobis(phenylsulfonyl)methane (TFBSM) 118 5.4.2 Typical Procedure for the Addition Reaction of TFBSM to Aldehydes and Benzophenone 119 5.4.3 Typical Procedure of Preparation of 3e from Reductive Desulfonylation 123 vii 5.4.4 Typical Procedure of Preparation of 4e from Reductive Desulfonylation 124 5.5 Chapter 5: Representative Spectra 126 5.6 Chapter 5: References 138 6 Chapter 6: Stereoselective Organocatalytic Conjugate Addition of α-Fluoro- α-nitro(phenylsulfonyl)methane to α-Nitroolefins: Mechanistic Studies and Synthetic Applications 140 6.1 Chapter 6: Introduction 140 6.2 Chapter 6: Results and Discussion 146 6.3 Chapter 6: Conclusion 158 6.4 Chapter 6: Experimental 159 6.4.1 Typical Procedure for Catalytic Enatioselective Conjugate Addition of α-Fluoro-α-nitro(phenylsulfonyl)methane (FNSM) to Nitroolefins 159 6.4.2 Typical Procedure of NMR and Chiral HPLC Kinetic Analysis for Catalytic Enatioselective Conjugate Addition of FNSM to Nitroolefins 160 6.4.3 Determination of Thermodynamic Parameters for Catalytic Enatioselective Conjugate Addition of FNSM to Nitroolefins 160 6.5 Chapter 6: Representative Spectra 162 6.6 Chapter 6: References 165 BIBLIOGRAPHY 167 viii LIST OF FIGURES Figure 1.1 Examples of fluorine-containing drugs 4 Figure 1.2 Examples of nucleophilic fluorinating reagents 7 Figure 1.3 Examples of electrophilic fluorinating reagents 8 Figure 1.4 Examples of CF 2 H and CH 2 F containing drugs 10 Figure 3.1 The Coulombic repulsion of α-monofluorocarbanions caused by α-fluorine atom 55 Figure 3.2 Bis(phenylsulfonyl)methide ion and its derivatives 55 Figure 3.3 X-ray crystal structures of bis(phenylsulfonyl)methide (I-N) and α-fluorobis(phenylsulfonyl)methide (II-N) anions with tetra- butylammonium counter cations 59 Figure 3.4 Gas phase proton affinities (ionization energy-electronegativity profile) of α-fluorocarbanion (FCA) and the related carbanions 63 Figure 3.5 Calculated 13 C NMR chemical shifts of α-C in I-V and the corresponding neutral molecules 66 Figure 3.6 Orbital representation of FBSM anion based on molecular orbital (MO) theory and bond theory 67 Figure 3.7 B3LYP/6-311+G(2d,p) calculated structure of 1 and 2 74 Figure 5.1 Crystal structures of various fluoromethyl silane reagents and their computed structures at the B3LYP/6-311+G(d,p) level 115 Figure 6.1 Dexamethasone and fluticasone propionate 141 Figure 6.2 Reaction rate constants for different amount of catalyst loadings 150 Figure 6.3 Catalyst loadings vs rate in toluene at 0 o C 151 Figure 6.4 Normalized Eyring plot (10 mol% IId, in toluene) 152 Figure 6.5 Eyring plot (10 mol% IId, in CDCl 3 ) 153 Figure 6.6 Expanded catalyst list 154 ix Figure 6.7 Eyring plot (10 mol% IX, in toluene) 154 Figure 6.8 Suggested reaction pathways by chiral bifunctional organocatalyst 156 Figure 6.9 Interconversion between (R)-FNSM and (S)-FNSM 157 Figure 6.10 The conformational profile of N1,N1-dimethylcyclohexane-1,2- diamine framework 158 x LIST OF TABLES Table 2.1 Nucleophilic monofluoromethylation of alkyl halides using FBSM 19 Table 2.2 Reductive monodesulfonylation using Mg/HOAc/NaOAc system 21 Table 2.3 Synthesis of monofluoromethylalkanes using the Mg/MeOH system 22 Table 3.1 NMR Chemical shifts of carbanions I and II in combination with various cations. 61 Table 3.2 Structural parameters (bond order, bond lengths, and charges) associated with disulfonylmethide anions 65 Table 5.1 Optimization of the addition reaction of TFBSM with benzaldehyde 111 Table 5.2. Monofluoromethylation of aldehydes with TFBSM 113 Table 5.3 Investigation of Si-C F bond strength in various fluoromethyl silane reagents 116 Table 6.1 Catalyst screening of asymmetric conjugate addition reaction of FNSM to nitroolefins 145 Table 6.2 Temperature effects on reactions of FNSM with nitroolefin 147 Table 6.3 Data sample for kinetic analysis of reaction of FNSM to nitroolefins 149 Table 6.4 Thermodynamics and kinetics of addition FNSM to 2a with IId in toluene 152 xi LIST OF SCHEMES Scheme 3.1 Nucleophilic monofluoromethylation reactions of an electrophile by fluoro(phenylsulfonyl)methane derivatives 54 Scheme 3.2 Preparation of α-fluorobis(phenylsulfonyl)methide ion (II) under different conditions 57 Scheme 4.1 Synthetic applications for α-fluorobis(phenylsulfonyl)methane (FBSM) 87 Scheme 4.2 Synthesis of FBSM from bis(phenylsulfonyl)methane 88 Scheme 4.3 Synthesis of FBSM via C-S bond forming strategy 89 Scheme 4.4 Preparative scale total synthesis of FBSM 91 Scheme 5.1 Nucleophilic addition of monofluoromethylating reagents to aldehydes 108 Scheme 5.2 Self-quenching monofluoromethylation of aldehydes with TFBSM 109 Scheme 5.3 Preparation of α-Trimethylsilyl-α-fluorobis(phenylsulfonyl)methane (TFBSM) 110 Scheme 5.4 Synthesis of 2-fluoro-1-(naphthalen-1-yl)ethanol via reductive desulfonation of 2e 114 Scheme 6.1 Examples of enantioselective synthesis of fluorinated molecules 142 Scheme 6.2 Bifunctional organocatalysts of the asymmetric conjugate addition between FNSM and nitroolefins 144 Scheme 6.3 Calculation of Eyring plot and determination of reaction enthalpy, entropy, free Gibbs energy and other thermodynamic constants 161 xii Abstract This dissertation focuses the development of new methodologies for nucleophilic fluoromethylation and selective desulfonylation. It also describes the large-scale synthesis of sulfone-based nucleophilic fluoromethylating reagents. In addition, the stereoselective construction of fluorine bearing chiral carbon centers has also been explored. Chapter 1 makes a general overview of organofluorine chemistry. It is mostly focused on the applications of organofluorine compounds and developments of the methodologies of fluorination and fluoroalkylation. Chapter 2 describes an efficient fluoromethylation protocol by using α- fluorobis(phenylsulfonyl)methane as the fluoromethylating reagent. This type of reaction is found to be very effective on primary and secondary halides under mild reaction conditions and the corresponding products can undergo reductive desulfonylation selectively. Chapter 3 discusses the result of NMR and computational study of a persistent α- fluorocarbanion. Unlike its non-fluorinated species, α-fluorocarbanion possesses its unique properties in NMR and X-ray crystallographic studies which is also supported by high level calculation. Chapter 4 includes the practically efficient large-scale synthesis of α- fluorobis(phenylsulfonyl)methane (FBSM). This improved six-step method affords FBSM with high yield and purity without any sophisticated purification process. xiii Chapter 5 describes the facile synthesis of α-monofluoromethyl alcohols using α- trimethylsilyl-α-fluorobis(phenylsulfonyl)methane (TFBSM) as a fluoromethylating reagent. Functioning as both a pronucleophile and a Lewis acid, the reagent allows the one-step addition of the FBSM anion toward various aldehydes via a self-quenching mechanism. Chapter 6 explores stereoselective organocatalytic conjugate addition of α-fluoro- α-nitro(phenylsulfonyl)methane (FNSM) to α-nitroolefins. It also includes the kinetic study and the theoretical calculation of the organocatalytic reaction along with investigation of the reaction mechanism. 1 1 Chapter 1: Introduction 1.1 Chapter 1: Introduction to Fluorine Chemistry 1.1.1 General Overview of Fluorine Chemistry and its Applications Fluorine being the most electronegative element has become unique and useful in various fields of our life. It has a small van der Waal’s radius of 1.47Å, which is smaller than the radius of oxygen (1.52 Å) and larger than the radius of hydrogen (1.20 Å). 1 Even though free elemental fluorine has been found in nature, fluoride ion (F - ) is widely disseminated in nature as minerals. The most abundant fluorine sources are fluorspar (CaF 2 ) and cryolite (Na 3 AlF 6 ). 2 Fluorine gas (F 2 ) is a greenish yellow gas, melts at -219.6 °C and boils at -188.1°C. The very first synthesis of F 2 was achieved by Henri Moissan in 1886 using an electrochemical apparatus and its chemical synthesis was reported by Christe in 1986, 3 exactly100 year after Moissan’s success. The field of fluorine chemistry has developed relatively slowly mainly because of the extraordinary reactivity of F 2 and difficulties in handling it. During the World War II, the requirements for novel materials with unique properties gave great impetus and remarkable progress to research in fluorine chemistry. Later in the 20th century, with the development of novel, efficient, selective and safe fluorinating or fluoroalkylating reagents, the field of organofluorine chemistry started to bring in a lot of scientists’ interests and many applications in the use of organofluorine compounds from material to medicine have been reported. Nowadays, fluorinated compounds are in huge demand not only in conventional industries such as polymer and agrochemical industries, but also play a very important role in pharmaceutical industry, medicinal chemistry research, semiconductor industry and many 2 other fields. Fluoropolymers are found to have huge impact in the fields of polymer and lubricant industries. They are now still one of the major applications of organofluorine compounds. The representative poly(tetrafluoroethylene) (PTFE) 4 is chemically stable against many reactive reagents, such as fluorine gas, uranium hexafluoride, molten alkali metal hydroxides, and hot mineral acids over a wide working temperature range. 5 In addition to fluoropolymers, there are many other applications of fluorochemicals in the other areas. Gases such as CF 4 , CClF 3 , CH 3 F, C 2 F 6 and C 3 F 8 are widely used in the plasma-etching technique during the process of manufacture of microchips and other electronic products. 6, 7 In the liquid crystal display technology, applying fluoroaromatics is considered to improve multiple properties compared to their non-fluorinated analogues. 8, 9, 10 Fluorinated herbicides and insecticides have also acquired increasingly attention in agrochemical industry for crop protection. 11, 12 More recently, the biggest impact of organofluorine chemistry is in the diverse applications of fluorinated compounds in pharmaceutical and biomedical research areas. 13 This is based on the following reasons. The similarity in atomic size to hydrogen makes fluorine a candidate to replace hydrogen. For example, fluorinated hydrocarbons, such as difluoromethyl group, can mimic carbonyl group with respect to steric requirements at the enzyme receptor sites. 14 The replacement of hydrogen by fluorine at or near an active site usually causes inhibition of the metabolism. Even though the geometry of the fluorinated compounds has little difference compared to their fluorine-free substituted structures, in most cases, the electronic effect differs significantly. The strong inductive effect of fluorine influences the reactivity and stability of many functional groups. The 3 lipid solubility is greatly increased by the substitution of hydrogen with fluorine. Therefore, it enhances the rates of absorption and transport of drugs in vivo. 1,15 In many cases, non-toxic, physically and chemically inert perfluorocarbon-based fluids can dissolve molecular oxygen and can thus be used as temporary blood substitutes. 16 Fluorinated drugs were first introduced in 1957. 17 Studies showed that over 150 fluorine-containing drugs had come to market and these drugs occupied 20% of total pharmaceuticals. 17 Billions of dollars are spent for top selling fluorinated drugs such as Lipitor, Prozac and Cyprobay (Figure 1.1) and there is no doubt that more fluorinated drug candidates are coming on the way. The huge profitable market also promotes great interest in the research of fluorine-containing small molecule based drugs, as well as fundamental studies in biochemistry and organofluorine chemistry. Currently, fluorinated organic compounds are used as anticancer, antiviral agents, cardiovascular drugs, anesthetics, central nervous system agents, antibiotics, anti-inflammatory drugs, anti- diabetics, and hypolipidemic agents. Therefore, developing novel methodologies for introducing fluorine to various organic molecules has become more and more important in fluorine chemistry. 4 Figure 1.1 Examples of fluorine-containing drugs In medicinal diagnostics, artificial isotope fluorine-18 ( 18 F) substituted organics are particularly important for imaging purposes using positron emission tomography (PET), which is a high resolution tool for the survey of living tissue. 18 18 F labeled organics must be prepared and used immediately in PET applications because of the short half-life (109.9 min) of 18 F. By imaging the brain of the patients, PET has been successfully utilized to study the metabolism of diseases such as Parkinson’s and F 3 C O H N HCl Prozac N H O N COO - OH OH F Lipitor 1/2 Ca 2+ HCl N HN F N O OH O Ciprobay 5 Alzheimer’s diseases. 19 Fluorous chemistry 1, 20 offers a new scope in carrying out reactions safely in economically and environmentally benign solvents that can be recycled. There are many limitations for the normal work-up procedure in conventional syntheses, which include length of time, formation of side products, use of excess solvents and loss of expensive catalysts. Fluorous solvents and reagents, which possess favorable properties such as temperature dependent miscibility with hydrocarbons, non-toxicity, and chemical inertness, are highly beneficial in solving these problems. 21, 22 There has been a growing interest by applying fluorinated reagents in green chemistry. 1.1.2 Fluorination Methods and Fluorinating Reagents Elemental fluorine was the first fluorinating agent and used to form the strongest single bond to carbon (dissociation energy of C-F: 485 kJ mol -1 ). 1 By passing F 2 (diluted with N 2 ) through cooling n-hexane, 2-fluorohexane can be produced in good quantities. 2 Direct reaction of fluorine with alkane and alkene is normally conducted at very low temperature with a mixture of F 2 and inert gases; however, low selectivity and extreme reaction conditions restricted its application. Halogen fluorides such as chlorine trifluoride and chlorine monofluoride were also used as fluorinating agents; however, their low reactivity and uncontrollable side reaction limited their application either. 23 Since then, a large number of fluorinating agents have been developed to selectively introduce fluorine into organic compounds. One of the basic chemicals in fluorochemical industry is hydrogen fluoride. Before 1960s, a great number of reactions and protocols have been reported on HF addition agent to alkenes and alkynes as well as fluorine substitution of other halogens and oxygenated functions. In the presence of SbCl 5 , 6 hydrogen fluoride reacts with carbon tetrachloride to give a 90% yield of difluorodichloromethane. 2 It used to be an important industrial process for producing the refrigerant, Freon 12 (difluorodichloromethane), although Freon products are prohibited worldwide now. Another industrial application was developed in the electrochemistry field: when current is passed through organic compounds in liquid hydrofluoric acid, perfluorinated compounds are generated. 2 However, hydrogen fluoride (bp 19.5 °C) is one of the most hazardous agents used in chemical industry, even more toxic than elemental fluorine itself. Pyridinium polyhydrogen fluoride, known as the Olah’s reagent, 24, 25, 26 was successfully introduced and because of its lower vapor pressure, handling it is much simpler. Olah’s reagent is effective for the nucleophilic fluorination of a wide range of organic compounds. Following Olah’s reagent, diethylaminosulfur trifluoride (DAST), 2,2-difluoro-1,3- dimethylimidazolidine (DFI), and bis(2-methoxyethyl) aminosulfur trifluoride (Deoxofluor) (Figure 1.2) were also developed for safe handling. They have been used extensively for the nucleophilic introduction of a fluorine moiety into various organic molecules. 1 7 Figure 1.2 Examples of nucleophilic fluorinating reagents Electrophilic fluorination is another convenient fluorination method for the synthesis of fluororganics. One of the first electrophilic fluorination reagent applied in industrial scale production was perchloryl fluoride FClO 3 , 27 a gas that was used in the manufacture of fluoropharmaceuticals, in particular fluorine-containing steroids. Later, xenon difluoride (XeF 2 ), nitrogen oxyfluorides (NOF, and NO 2 F), and other hypofluorides were also used as efficient electrophilic fluorinating reagents. 28 A new group of electrophilic fluorinating reagents so called ‘N-F reagents’ was synthesized in the late 1980s. 29 Compared with the previous generation of ‘F + ’ reagents, they are mostly stable, non-explosive and non-toxic solids. N-fluorobenzenesulfonimide (NFSI), 1- Chloromethyl-4-fluorodiazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®), and N,N-difluoro-2,2'-bipyridinium bis(tetrafluoroborate) (Synfluor®) (Figure 1.3) are the most commonly used N-F reagents and all these compounds are commercially available. 1,30,31 They are the powerful fluorinating sources to make various fluorine- N SF 3 N N F F O N O SF 3 DAST DFI Dexofluor 70% HF + 30% N Olah's Reagent (an ionic liquid) 8 containing molecules including other fluorinating reagents. Figure 1.3 Examples of electrophilic fluorinating reagents 1.1.3 Fluoroalkylation Methods and Fluoroalkylating Reagents Fluoroalkylation plays an important role in the synthesis of complex organofluorine compounds. Straightforward and reliable procedures for the introduction of fluoroalkyl groups are highly desirable because of the unique physical, chemical and biological properties of fluorinated organics. Nucleophilic fluoroalkylating reagents such as trifluoromethyl mercury, cadmium, copper, and other metal reagents were used to introduce trifluoromethyl group to various molecules despite their low stability. 32 Fluoromethylating agents such as FSO 2 CF 2 COOCH 3 33 , trifluoromethane (CF 3 H) 34 , trifluoromethyl iodide (CF 3 I), etc. 35,36 have also been widely utilized as effective reagents. Relatively nontoxic, stable, and easy to handle trifluoromethylating reagents and their analogues have been explored systematically and extensively during the last twenty years. Me 3 SiCF 3 (TMS-CF 3 ) has been successfully developed as the most effective and widely used nucleophilic trifluoromethylating reagent in many synthetic applications. 37,38 It is also known as the Ruppert-Prakash reagent. The properties of these silylated species make them convenient reagents for introducing trifluoromethyl group into various functional groups such as aldehydes, ketones, esters, organohalides, sulfur-based PhO 2 S N SO 2 Ph F N N F F ( BF 4 ) 2 N N F Cl ( BF 4 ) 2 NFSI Selectfluor Synfluor R R 9 electrophiles, and organotin compounds. Prakash and coworkers also reported the generation of stereoselective trifluoromethyl chiral amines, which are potential intermediates in pharmaceutical chemistry. 39, 40 Umemoto and coworkers reported the synthesis of trifluoromethyl dibenzothiophenium salts as the electrophilic trifluoromethylating reagents for successful “CF 3 + ” transfer to various N, O, S, C, and P nucleophiles. 41 Togni and coworkers also reported the similar methodology to transfer trifluoromethyl group to various nucleophiles by using hypervalent iodine (III)-CF 3 as the electrophilic trifluoromethylating reagent. 42 Designing difluoromethyl and monofluoromethyl containing chemicals has significant importance in pharmaceutical arena; study shows that these types of compounds lead to many biological benefits such as the enhancement of metabolic stability, bioavailability, lipophilicity, and membrane permeability. 17 The difluoromethyl group (CF 2 H) can act as a lipophilic hydrogen bond donor such as a hydroxyl group 43 and compounds with a monofluoromethyl (CH 2 F) demonstrate drug activity. 44 For instance, Pantoprazole (Figure 1.4) is a proton pump inhibitor drug to treat erosion and ulceration of the esophagus caused by gastroesophageal reflux disease; Afloqualone (Figure 1.4) is a nicotinic antagonist used as a myorelaxant; Fluticasone propionate (Figure 1.4) is widely used against the inflammatory diseases and to alleviate pain related to certain cancers. 45, 46 10 Figure 1.4 Examples of CF 2 H and CH 2 F containing drugs Difluoromethyl metal (Cd, Zn and Cu) reagents and difluoromethylsilylated compounds are two common categories for selective nucleophilic difluoromethylations, which can transfer difluoromethyl anion “CF 2 H − ” to electrophiles like aldehydes and ketones. 47 Prakash and coworkers reported a protocol to use difluoromethyl phenyl sulfone (PhSO 2 CF 2 H) to convert alkyl halides, aldehydes, ketones, esters and other substrates to their corresponding difluoromethyl compounds. 48,49,50 In this case, the O HF 2 C N H N S N MeO OMe O Pantoprazole N N O CH 2 F H 2 N Afloqualone Me O F F HO O S CH 2 F O O Fluticasone propionate 11 phenylsulfonyl group worked as a suitable electron withdrawing moiety that can be easily removed in the presence of reductive metals such as Mg in methanol or acetic acid. Monofluoromethylation reactions have been studied much less than the well- known trifluoromethylation reactions. In 2006, Hu and coworkers reported the efficient monofluoromethylation of imines using fluoromethyl phenyl sulfone (PhSO 2 CH 2 F) and the reactions resulted in high stereoselectivity. 51 Another novel reagent, fluorobis(phenylsulfonyl)methane (FBSM), was synthesized independently by Hu and Shibata it the same year, which can transfer CH 2 F group to epoxides and α,β- unsaturated ketones, respectively. 47 1.2 Chapter 1: Aim and Scope of Present Work As discussed, fluorinated molecules demonstrate their unique properties in life sciences and material chemistry. About one fifth of pharmaceutical drugs available today in the market are fluorinated drugs. Therefore, many scientists are intrigued to study organofluorine chemistry due to its growing value. As a result of the increasing demand in pharmaceutical industry, efficient fluoroalkylating reagents and improved methodologies are always desired. Development of new synthetic methodologies for the fluoroalkylation reactions and the exploration of their biological properties and therapeutic activities of fluorinated drugs are in high demand. Although the methods for trifluoromethylation and difluoromethylation reactions have been well studied, more efforts are needed for the development of easy and convenient monofluoromethylation methodologies. The major goal of my research was to develop the novel nucleophilic 12 monofluoromethylations for general applications. Multiple monofluoromethylating reagents were introduced and their corresponding monofluoromethylation methodologies were developed. The reaction mechanisms and the key reaction intermediates have also been examined for the better understanding of the nature of the process of monofluoromethylation. The third objective of this work was to develop an optimal procedure fit for the large-scale synthesis of FBSM, which could be useful in industrial applications. 13 1.3 Chapter 1: References 1 Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Wiley-VCH, Weinheim, Germany, 2004. 2 Banks, R. E.; Sharp, D. W. A.; Tatlow, J. C. Fluorine, the first hundred years (1886-1986), Elsevier Sequoia, USA, 1986. 3 Christe, K. O. Inorg. Chem. 1986, 25, 3721. 4 Plunkett, R. J. US Patent 2,230,654, 1941. 5 Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine Chemistry: Principles and Commercial Applications; Plenum Press, New York, 1994. 6 Baasner, B.; Hagemann, H.; Tatlaw, J. C. Applications: polymers in Houben- Weyl: Organo-Fluorine Compounds Vol E, Georg Thieme Verlag, Stuttgart, 2000. 7 Allgood, C. Adv. Mater. 1998, 10, 1239. 8 Kirsch, P.; Bremer, M. Angew. Chem. Int. Ed. 2000, 39, 4216. 9 Kirsch, P.; Reiffenrath, V.; Bremer, M. Synlett 1999, 389. 10 Hiyama, T. Organofluorine Compounds: Chemistry and Applications, Springer, Berlin, 2000. 11 Hartley, D. The Argrochemicals Handbook 2nd ed., The Royal Society of Chemistry, London, 1987. 12 Maienfisch, P.; Hall, R. G. Chimia 2004, 58, 93. 13 Ismail, F. M. D. J. Fluorine Chem. 2002, 118, 27. 14 Berkowitz, D. B.; Bose, M. J. Fluorine Chem. 2001, 112, 13. 15 Selig, H.; Holloway, J. H. Topics in Current Chemistry, Boschke, Springer, Berlin, 1984. 16 Riess, J. G. New J. Chem. 1995, 19, 891. 17 Muller, K; Faeh, C; Diederich, F. Science 2007, 317, 1881. 18 Le Bars, D. J. Fluorine Chem. 2006, 127, 1488. 14 19 Coenen, H. H.; Franken, K.; Kling, P.; Stocklin, G. Appl. Radiat. Isot. 1988. 39, 1243. 20 Horavath, I. T. Acc. Chem. Res. 1998, 31, 641. 21 Fish, R. H. Chem. Eur. J. 1999, 5, 1677. 22 Hope, E. G.; Stuart, A. M. J. Fluorine Chem. 1999, 100, 75. 23 Musgrave, W. K. R. Advan. Fluorine Chem. 1960, 1, 1. 24 Olah, G. A.; Nojima, M.; Kerekes, I. Synthesis. 1973, 779. 25 Olah, G. A.; Nojima, M.; Kerekes, I. Synthesis. 1973, 780. 26 Olah, G. A.; Vankar, Y. D.; Nojima, M.; Kerekes, I.; Olah, J. A. J. Org. Chem. 1979, 44, 3872. 27 Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.; Wong, C. Angew. Chem. Int. Ed. 2005, 44, 192. 28 Singh, R. P.; Shreeve, J. M. Acc. Chem. Res. 2004, 37, 31. 29 Umemoto, T.; Kawada, K.; Tomita, K. Tetrahedron Lett. 1986, 27, 4465. 30 Resnati, G.; DesMarteau, D. D. J. Org. Chem. 1991, 56, 4925. 31 DesMarteau, D. D.; Xu, Z.-Q.; Witz, M. J. Org. Chem. 1992, 112, 8563. 32 Burton, D. J.; Yang, Z.-Y. Tetrahedron 1992, 48, 189. 33 Chen, Q.-Y. J. Fluorine Chem. 1995, 72, 241. 34 Langlois, B. R.; Vidal, T. Tetrahedron. 2000, 56, 7613. 35 Medebielle, M.; Dolbier, W. R. Jr. J. Fluorine Chem. 2008, 129, 930. 36 Ma, J.-A.; Cahard, D. Chem. Rev. 2004, 104, 6119. 37 Ruppert, I.; Schlich, K.; Volbach, W. Tetrahedron Lett. 1984, 25, 2195. 38 Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757. 39 Prakash, G. K. S.; Mandal, M.; Olah, G. A. Org. Lett. 2001, 3, 2847. 40 Prakash, G. K. S.; Mandal, M. J. Am. Chem. Soc. 2002, 124, 6538. 41 Umemoto, T. Chem. Rev. 1996, 96, 1757. 15 42 Koller, R.; Stanek, K.; Stolz, D.; Aardoom, R.; Niedermann, K.; Togni, A. Angew. Chem. Int. Ed. 2009, 48, 6324. 43 Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60, 1626. 44 Prakash, G. K. S.; Ledneczki, I.; Chacko, S.; Olah, G. A. Org. Lett. 2008, 10, 557. 45 Begue, J.-P.; Bonnet-Delpon, D. Biooganic and Mecicinal Chemistry of Fluorine, Wiley, Hoboken, 2008. 46 Karagas, M. R.; Cushing, G. L.; Greeberg, E. R. Jr.; Mott, L. A.; Spencer, S. K.; Nierenberg, D. W. Br. J. Cancer. 2001, 85, 683. 47 Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465. 48 Prakash, G. K. S.; Hu, J.; Mathew, T.; Olah, G. A. Angew. Chem. Int. Ed. 2003, 42, 5216. 49 Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. Org. Lett. 2004, 6, 4315. 50 Prakash, G, K, S.; Hu, J.; Wang, Y.; Olah, G. A. Eur. J. Org. Chem. 2005, 2218. 51 Li, Y.; Ni, C.; Liu, J.; Zheng, J.; Zhang, L.; Zhu, L.; Hu, J. Org. Lett. 2006, 8, 1693. 16 2 Chapter 2: Efficient Nucleophilic Monofluoro- methylation of Alkyl Halides Using α- Fluorobis(phenylsulfonyl)methane 2.1 Chapter 2: Introduction Monofluoromethylation is an important protocol in organic synthesis with great significance to life sciences because fluoromethylated compounds have huge impact in biological systems and in medicinal chemistry. 1 , 2 For example, 7α-(fluoromethyl) dihydrotestosterone, 3 3-fluoro-5-(2-(2-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile, 4 and 6-(fluoromethyl)purine 5 are few examples of monofluoromethyl analogues of biologically important compounds synthesized. Sevoflurane, a fast acting volatile monofluoromethyl anesthetic, is found to have fast uptake and elimination properties and currently widely used in the United States pharmaceutical market. 6 , 7 Fluoromethyl histidine is found to be stable against the action of histamine decarboxylase, an enzyme inhibits the formation of histamine, which has a crucial role in gastric ulcers. 8 Fluoromethyl dehydroornithine, fluoromethyl gamma amino butyric acid, and fluoromethyl glyoxal have been synthesized and used in various biological systems. 8 However, the introduction of a monofluoromethyl group into organic molecules has attracted much less interest than the well-known trifluoromethylation reactions. Extensive research has been directed towards the facile introduction of a monofluoromethyl group into various organic molecules. Olah first reported the electrophilic monofluoromethylation by using fluoromethanol in 1953. 9 After that, the applications of using fluoromethyl halides, fluoromethyl triflates, chlorofluoromethane and others as monofluoromethylating reagents have been also reported during the past 17 decades. 10, 11, 12, 13 Fluoromethyl phenyl sulfone and magnesium benzyl fluoromalonates were also used for nucleophilic monofluoromethylation. 14 , 15 , 16 α-Fluorobis (phenylsulfonyl)methane (FBSM) has been developed as one of the versatile, efficient, and stable nucleophilic monofluoromethylating reagents. FBSM was used as the pronucleophile, which is a synthetic equivalent of monofluoromethide species. The presence of the electron withdrawing phenylsulfonyl group was very effective in stabilizing the α-fluorocarbanion during the nucleophilic reaction. 17 Hu, Shibata, and Prakash independently reported the use of FBSM as a pronucleophile to build fluoromethyl group into different substrates, and the developed methodologies worked efficiently for a variety of functional groups such as epoxides, 2 allylic acetates, 18 alcohols 1 and for the 1,4-addition reactions to various Michael acceptors. 19 FBSM can also be further converted to TMSCF(SO 2 Ph) 2 and (PhSO 2 ) 2 CFI, which have been employed as monofluoromethylating reagents. 20, 21 Nucleophilic substitution reactions of primary halides have been widely studied and it has been covered mostly in the organic chemistry history. Prakash and coworkers reported nucleophilic difluoromethylation of alkyl halides using difluoromethyl phenyl sulfone. 22 Potassium tert-butoxide was used as a base to deprotonate the PhSO 2 CHF 2 and excellent yields were achieved. Herein, an efficient method for the preparation of monofluoromethyl compounds from FBSM and primary halides under mild conditions is discussed. The protocol for selective desulfonylation for the corresponding products is also disclosed. 18 2.2 Chapter 2: Results and Discussion The reactions of α-fluorobis(phenylsulfonyl)methane (FBSM) and primary halides such as alkyl iodides and alkyl bromides were found to produce the corresponding monofluorobis(phenylsulfonyl) derivatives under mild reaction conditions. The reaction was carried out at room temperature in air, by mixing one equivalent of FBSM, one equivalent of alkyl halides and two equivalent of potassium carbonate in DMF. The progress of the reaction was monitored by 19 F NMR spectroscopy. Primary alkyl iodides and bromides were found to react faster and give the products in excellent yields, while the yield was moderate in the case of secondary alkyl halides despite the reaction turned sluggish. (Table 2.1) The primary chloride substituents also gave the desired product in very low yields, but when a catalytic amount of NaI was added in the reaction, the reaction rate increased and the product yield improved (Table 2.1). The selection of the base for the nucleophilic substitution reaction of primary halides is to match the softness of the nucleophile with that of the electrophilic center. Instead of using strong bases, it is found that using mild basic systems such as potassium carbonate in DMF or cesium carbonate in stoichiometric amounts in acetonitrile, the soft carbanion from FBSM can be generated and readily participate in the nucleophilic substitution at room temperature. Thus, excellent to moderate yields were achieved under moderate reaction conditions without using strong bases and applying low temperature conditions. 19 Table 2.1 Nucleophilic monofluoromethylation of alkyl halides using FBSM The above products were further subjected to reductive desulfonylation reaction for the replacement of sulfone group with hydrogen, which is one of the major synthetic transformations for the sulfone-based compounds. Previous studies have developed numerous reducing agents, including metal amalgams, samarium iodide, sodium dithionite, hydrides in the presence of transition metal catalysts, and tributyl tin hydride (under free radical conditions). 23, 24, 25 Geminal bis-sulfones are widely used in organic syntheses, as two sulfonyl groups possess strong electron withdrawing nature and these compounds can be easily deprotonated and used in various nucleophilic substitution reactions and in cyclization reactions as well. Falck and coworkers reported the use of lithium naphthalenide in THF as well as samarium iodide for the reductive Entry Starting Materail Product Yield (%) 1 2 3 4 5 6 7 8 9 10 Ph(CH 2 ) 3 I Ph(CH 2 ) 4 I CH 3 (CH 2 ) 6 I CH 3 (CH 2 ) 5 I PhCH 2 Br PhCH 2 CH 2 Br CH 3 CHICH 3 CH 3 CHBr(CH 2 ) 2 CH 3 CH 3 (CH 2 ) 6 Cl PhCH 2 Cl Ph(CH 2 ) 3 CF(SO 2 Ph) 2 Ph(CH 2 ) 4 CF(SO 2 Ph) 2 CH 3 (CH 2 ) 6 CF(SO 2 Ph) 2 CH 3 (CH 2 ) 5 CF(SO 2 Ph) 2 PhCH 2 CF(SO 2 Ph) 2 PhCH 2 CH 2 CF(SO 2 Ph) 2 CH 3 CHCF(SO 2 Ph) 2 CH 3 CH 3 CHCF(SO 2 Ph) 2 (CH 2 ) 2 CH 3 CH 3 (CH 2 ) 6 CF(SO 2 Ph) 2 PhCH 2 CF(SO 2 Ph) 2 1a 1b 1c 1d 1e 1f 1g 1h 1c 1e 83 85 90 81 87 82 60 40 20 60 R-X R-CF(SO 2 Ph) 2 1 K 2 CO 3 , DMF (PhSO 2 ) 2 CHF a b c d a b c d Reacton is carried out at room temperature, isolated yield, No NaI used in the reaction, in the presence of catalytic amount of NaI 20 monodesulfonylation of geminal bis-sulfones. 26, 27 Tuttle and coworkers reported the use of neutral organic super-electron-donor (S.E.D) reagent for the synthesis of monosulfones from gem-disulfones. 28 However, successful stepwise desulfonylation or selective desulfonylation is still challenging. The goal is to find a protocol to selectively reduce the fluorine substituted disulfone compounds using environmentally friendly and economical reagents. A Mg/HOAc/NaOAc based buffered system was developed for the reductive desulfonylation of the gem-disulfones. Interestingly, the reaction resulted in the selective reduction of one phenylsulfonyl group. The reaction of reductive monodesulfonylation was carried out at room temperature, by mixing metal Mg and compounds (Table 2.1) in HOAc/NaOAc buffer and the corresponding products were isolated in moderate to excellent yields. (Table 2.2) Hu and coworkers have also used a similar system to desulfonylate difluoromethyl phenyl sulfonyl derivatives. 29, 30 21 Table 2.2 Reductive monodesulfonylation using Mg/HOAc/NaOAc system The complete reductive desulfonylation of fluorobis(phenylsulfonyl)alkanes was carried out at 0 o C with Mg/CH 3 OH system. The reductive fluoromethylated products were isolated in excellent to moderate yields. The reductive Mg/CH 3 OH system is a well- established reductive desulfonylating protocol, and has been widely used in organic synthesis. 1, 23, 31 It has been successfully developed for the reductive desulfonylation of disulfones for the synthesis of monofluoromethyl substituted compounds. During the reaction, monodesulfonylated products were not observed and only completely desulfonylated products were afforded, which are listed in Table 2.3. Entry Starting Materail Product Yield (%) 1 2 3 4 5 6 CH 3 (CH 2 ) 5 CF(SO 2 Ph) 2 CH 3 (CH 2 ) 6 CF(SO 2 Ph) 2 PhCH 2 CF(SO 2 Ph) 2 PhCH 2 CH 2 CF(SO 2 Ph) 2 Ph(CH 2 ) 3 CF(SO 2 Ph) 2 Ph(CH 2 ) 4 CF(SO 2 Ph) 2 2a 2b 2c 2d 2e 2f 70 65 63 65 60 62 R-CFSO 2 Ph 2 Mg, DMF HOAc, NaOAc a b a b Reacton is carried out at room temperature, isolated yield. R-CF(SO 2 Ph) 2 CH 3 (CH 2 ) 5 CHFSO 2 Ph CH 3 (CH 2 ) 6 CHFSO 2 Ph PhCH 2 CHFSO 2 Ph PhCH 2 CH 2 CHFSO 2 Ph Ph(CH 2 ) 3 CHFSO 2 Ph Ph(CH 2 ) 4 CHFSO 2 Ph H 22 Table 2.3 Synthesis of monofluoromethylalkanes using the Mg/MeOH system. 2.3 Chapter 2: Conclusion In conclusion, an efficient methodology for the nucleophilic substitution of alkyl halides using α-fluorobis(phenylsulfonyl)methane (FBSM) have been developed. By applying carefully tuned reductive desulfonylating systems, we were able to perform selective desulfonylation reaction to afford both fluoro(phenylsulfonyl)alkanes and monofluoromethyl alkanes, respectively. This practical synthetic methodology possesses many advantages, including cost efficacy, simplicity, and has great potential for easy access to many novel monofluoromethylated molecules for various applications. Entry Starting Materail Product Yield (%) 1 2 3 4 5 6 PhCH 2 CH 2 CF(SO 2 Ph) 2 Ph(CH 2 ) 3 CF(SO 2 Ph) 2 Ph(CH 2 ) 4 CF(SO 2 Ph) 2 Ph(CH 2 ) 5 CF(SO 2 Ph) 2 PhO(CH 2 ) 3 CF(SO 2 Ph) 2 PhO(CH 2 ) 4 CF(SO 2 Ph) 2 3a 3b 3c 3d 3e 3f 71 48 56 75 83 77 R-CH 2 F 3 a a isolated yield R-CF(SO 2 Ph) 2 Mg, MeOH, 0 o C PhCH 2 CH 2 CH 2 F Ph(CH 2 ) 3 CH 2 F Ph(CH 2 ) 4 CH 2 F Ph(CH 2 ) 5 CH 2 F PhO(CH 2 ) 3 CH 2 F PhO(CH 2 ) 4 CH 2 F 23 2.4 Chapter 2: Experimental Unless otherwise mentioned, all reagents were purchased from commercial sources. Dichloromethane and acetonitrile were used as received from Aldrich (water content < 50 ppm). 1 H, 13 C and 19 F NMR spectra were recorded on Varian Mercury-400 NMR spectrometer. 1 H-NMR chemical shifts were determined relative to internal (CH 3 ) 4 Si (TMS) at δ 0.00. 13 C-NMR chemical shifts were determined relative to the 13 C signal of the solvent: CDCl 3 (77.16 ppm). CFCl 3 was used as internal standard for 19 F NMR. High resolution mass spectra were recorded in EI + or FAB + mode on a high resolution mass spectrometer at the Mass Spectrometry facility, University of Arizona. 2.4.1 Typical Procedure for Preparation of Monofluorobisphenylsulfonyl Alkanes To a solution of fluorobis(phenylsulfonyl)methane (0.16 mmol, 1 equivalent) and primary alkyl halide (0.16 mmol, 1 equivalent) in DMF (2 mL) was added potassium carbonate (0.36 mmol, 0.050 g) at room temperature and the reaction was monitored by 19 F NMR. Aqueous work up followed by extraction with dichloromethane (3 x 15 mL) afforded the crude product. The pure product was obtained by performing column chromatography (eluent: 30% ethyl acetate in hexane). 1-Fluoro-1,1-bis(phenylsulfonyl)-4-phenyl-butane (1a) White solid. 1 H NMR (CDCl 3 ): δ 1.95 (m, 2H), 2.22 (m, 2H), 2.50 (t, J = 7.1 Hz, 2H), 7.00 (m, 2H), 7.16 (m, 3H), 7.42 (m, 4H), 7.61 (m, 2H), 7.75 (m, 4H). 13 C NMR SO 2 Ph SO 2 Ph F 24 (CDCl 3 ): δ 23.9 (d, J = 6.6 Hz), 29.8 (d, J = 18.2 Hz), 35.3, 115.3 (d, J = 266 Hz), 126.1, 128.4, 128.5, 128.9, 130.7, 135.0, 135.1, 140.3. 19 F NMR (CDCl 3 ): δ -141.9 (t, J = 15.8 Hz, 1F). HRMS (FAB): m/zalcd for C 22 H 21 O 4 FS 2 (M+H + ) 433.0944, found 433.0949. 1-Fluoro-1,1-bis(phenylsulfonyl)-5-phenyl-pentane (1b) White solid. 1 H NMR (CDCl 3 ): δ 1.41 (m, 2H), 1.54 (m, 2H), 2.27 (m, 2H), 2.40 (t, J = 7.5 Hz, 2H), 6.98 (m, 2H), 7.05 (m, 1H), 7.14 (m, 2H), 7.38 (m, 4H), 7.55 (m, 2H), 7.75 (m, 4H). 13 C NMR (CDCl 3 ): δ 21.9 (d, J = 6.2 Hz), 30.0 (d, J = 18.2 Hz), 31.4, 35.1, 115.5 (d, J = 267 Hz), 125.7, 128.19, 128.20, 128.9, 130.5, 135.0, 135.1, 141.6. 19 F NMR (CDCl 3 ): δ -142.7 (t, J = 16.6 Hz, 1F). HRMS (FAB): m/z calcd for C 23 H 23 O 4 FS 2 (M+H + ) 447.1100, found 447.1113. 1-Fluoro-1,1-bis(phenylsulfonyl)-octane (1c) White solid. 1 H NMR (CDCl 3 ): δ 0.86 (t, J = 6.8 Hz, 3H), 1.20 (m, 10H), 2.33 (m, 2H), 7.56 (m, 4H), 7.72 (m, 2H), 7.92 (m, 4H). 13 C NMR (CDCl 3 ): δ 14.0, 22.3 (d, J = 6.2 Hz), 22.5, 28.6, 29.7, 30.3 (d, J = 18.2 Hz), 31.5, 115.7 (d, J = 267 Hz), 129.0, 130.7, 135.1, 135.3. 19 F NMR (CDCl 3 ): δ -142.4 (t, J = 16.3 Hz, 1F). HRMS (FAB): m/z calcd for C 20 H 25 O 4 FS 2 (M+H + ) 413.1257, found 413.1256. SO 2 Ph SO 2 Ph F SO 2 Ph SO 2 Ph F 25 1-Fluoro-1,1-bis(phenylsulfonyl)-heptane (1d) White solid. 1 H NMR (CDCl 3 ): δ 0.85 (t, J = 6.9 Hz, 3H), 1.21 (m, 6H), 1.60 (m, 2H), 2.33 (m, 2H), 7.56 (m, 4H), 7.72 (m, 2H), 7.92 (m, 4H). 13 C NMR (CDCl 3 ): δ 13.8, 22.3, 23.1, 29.4, 30.3 (d, J = 18.2 Hz), 31.1, 115.8 (d, J = 267 Hz), 129.0, 130.7, 135.1, 135.3. 19 F NMR (CDCl 3 ): δ -142.9 (t, J = 16.6 Hz, 1F). HRMS (FAB): m/z calcd for C 19 H 23 O 4 FS 2 (M+H + ) 399.1100, found 399.1082. 1-Fluoro-1,1-bis(phenylsulfonyl)-2-phenyl-ethane (1e) 1 H NMR (CDCl 3 ): δ 3.85 (d, J = 22.3 Hz, 2H), 7.06 (m, 2H), 7.13 (m, 2H), 7.19 (m, 1H), 7.45 (m, 4H), 7.64 (m, 2H), 7.75 (m, 4H). 13 C NMR (CDCl 3 ): δ 35.0 (d, J = 17.3 Hz), 115.5 (d, J = 270 Hz), 127.7, 128.2, 128.7, 130.0, 130.6, 131.1, 134.9, 135.3. 19 F NMR (CDCl 3 ): δ -142.3 (t, J = 22.2 Hz, 1F). HRMS (FAB): m/z calcd for C 20 H 17 O 4 FS 2 (M+H + ) 405.0631, found 405.0631 1-Fluoro-1,1-bis(phenylsulfonyl)-2-methyl-propane (1g) SO 2 Ph SO 2 Ph F SO 2 Ph SO 2 Ph F SO 2 Ph SO 2 Ph F 26 1 H NMR (CDCl 3 ): δ 1.43 (dd, J = 7.1, 1.6 Hz, 6H), 2.70 (m, 1H), 7.51 (m, 4H), 7.69 (m, 2H), 7.86 (m, 4H). 13 C NMR (CDCl 3 ): δ 16.8 (d, J = 6.9 Hz), 33.3 (d, J = 17.3 Hz), 117.4 (d, J = 265 Hz), 128.8, 130.8, 134.9, 136.2. 19 F NMR (CDCl 3 ): δ -133.3 (br s, 1F). HRMS (EI): m/z calcd for C 16 H 17 O 4 FS 2 (M+H + ) 356.0537, found 356.0552. 1-Fluoro-1,1-bis(phenylsulfonyl)-2-methyl-pentane (1h) 1 H NMR (CDCl 3 ): δ 0.86 (t, J = 7.3 Hz, 3H), 1.11 (m, 1H), 1.41 (dd, J = 7.0, 1.5 Hz, 3H), 1.47 (m, 1H), 1.67 (m, 1H), 2.02 (m, 1H), 2.47 (m, 1H), 7.51 (m, 4H), 7.68 (m, 2H), 7.86 (m, 4H). 13 C NMR (CDCl 3 ): δ 13.68 (d, J = 7.5 Hz), 13.69, 21.3, 32.0 (d, J = 5.5 Hz), 38.2 (d, J = 16.4 Hz), 117.5 (d, J = 266 Hz), 128.75, 128.77, 130.79, 130.81, 134.84, 134.87, 136.12, 136.24. 19 F NMR (CDCl 3 ): δ -132.8 (br s, 1F). HRMS (FAB): m/z calcd for C 18 H 21 O 4 FS 2 (M+H + ) 385.0944, found 385.0953. 2.4.2 Typical Procedure for Reductive Monodesulfonylation of Fluorobis(phenylsulfonyl) Derivatives 29 Under argon atmosphere, 4 mL of HOAc/NaOAc (1:1) buffer solution (8 mol/L) was added into a Schlenk flask containing 1d (398 mg, 1.0 mmol) in 3 mL DMF at room temperature. Excess activated Mg turnings was added in portions. The reaction mixture was stirred at room temperature and the reaction completion was monitored 19 F NMR spectroscopy. 30 mL water was added into the reaction mixture followed by extraction with dichloromethane (3 × 15 mL). The combined organic layers were collected, washed with saturated NaHCO 3 solution and brine, dried over MgSO 4 and the solvent was SO 2 Ph SO 2 Ph F 27 removed under reduced pressure. The crude product was purified by flash chromatography (eluent: 10% ethyl acetate in hexane), to provide the pure product 2a (181 mg, 70 % yield). 1-Fluoro-1-phenylsulfonyl-heptane (2a) Colorless oil. 1 H NMR (CDCl 3 ): δ 0.79 (t, J = 6.7 Hz, 3H), 1.20 (m, 6H), 1.44 (m, 2H), 1.79 (m, 1H), 2.06 (m, 1H), 5.02 (ddd, J = 48.7, 10.0, 2.7 Hz, 1H), 7.55 (br t, J = 7.8 Hz, 2H), 7.63 (br t, J = 7.7 Hz, 1H), 7.86 (br d, J = 7.7 Hz, 2H). 13 C NMR (CDCl 3 ): δ 13.9, 22.4, 24.3 (d, J = 2.1 Hz), 27.4 (d, J = 19.4 Hz), 28.5, 31.2, 102.7 (d, J = 219 Hz), 129.19, 129.43, 134.5, 135.3. 19 F NMR (CDCl 3 ): δ -179.3 (ddd, J = 48.8, 37.7, 14.9 Hz, 1F). HRMS (FAB): m/z calcd for C 13 H 20 O 2 FS (M+H + ) 259.1168, found 259.1173. 1-Fluoro-1-phenylsulfonyl-octane (2b) Colorless oil. 1 H NMR (CDCl 3 ): δ 0.85 (t, J = 6.9 Hz, 3H), 1.27 (m, 8H), 1.51 (m, 2H), 1.86 (m, 1H), 2.10 (m, 1H), 5.08 (ddd, J = 48.7, 10.1, 2.8 Hz, 1H), 7.58 (br t, J = 7.6 Hz, 2H), 7.69 (br t, J = 7.5 Hz, 1H), 7.92 (br d, J = 7.9 Hz, 2H). 13 C NMR (CDCl 3 ): δ 13.9, 22.5, 24.4 (d, J = 2.2 Hz), 27.4 (d, J = 19.4 Hz), 28.77, 28.82, 31.5, 102.7 (d, J = 219 Hz), 129.2, 129.4, 134.4, 135.3. 19 F NMR (CDCl 3 ): δ -179.3 (ddd, J = 48.7, 37.8, 14.9 Hz, 1F). HRMS (FAB): m/z calcd for C 14 H 22 O 2 FS (M+H + ) 273.1325, found 273.1319. SO 2 Ph F SO 2 Ph SO 2 Ph F 28 1-Fluoro-1-phenylsulfonyl-2-phenyl-ethane (2c) White solid. 1 H NMR (CDCl 3 ): δ 3.08 (m, 1H), 3.43 (ddd, J = 40.5, 14.9, 2.0 Hz, 1H), 5.16 (ddd, J = 48.6, 10.6, 2.1 Hz, 1H), 7.2 (br t, J = 7.1 Hz, 2H), 7.21 (m, 3H), 7.52 (br t, J = 7.9 Hz, 2H), 7.64 (m, 1H), 7.90 (br d, J = 7.2 Hz, 2H). 13 C NMR (CDCl 3 ): δ 33.7 (d, J = 19.4 Hz), 102.6 (d, J = 222 Hz), 127.5, 128.8, 129.32, 129.33, 129.5, 133.7, 134.7, 135.1. 19 F NMR (CDCl 3 ): δ -178.1 (ddd, J = 48.7, 40.6, 16.1 Hz, 1F). HRMS (FAB): m/z calcd for C 14 H 14 O 2 FS (M+H + ) 265.0699, found 265.0706. 1-Fluoro-1-phenylsulfonyl-3-phenyl-propane (2d) White solid. 1 H NMR (CDCl 3 ): δ 2.15 (m, 1H), 2.38 (m, 1H), 2.70 (m, 1H), 2.86 (m, 1H), 4.97 (dddd, , J = 48.4, 10.1, 2.8, 1.0 Hz), 7.12 (m, 2H), 7.17 (m, 1H), 7.23 (m, 2H), 7.52 (m, 2H), 7.64 (m, 1H), 7.85 (br d, J = 7.7 Hz, 2H). 13 C NMR (CDCl 3 ): δ 29.1 (d, J = 19.5 Hz), 30.2 (d, J = 2.8 Hz), 101.6 (d, J = 219 Hz), 126.6, 128.5, 128.7, 129.3, 129.5, 134.6, 135.2, 139.0. 19 F NMR (CDCl 3 ): δ -180.7 (ddd, J = 48.5, 36.7, 13.5 Hz, 1F). HRMS (FAB): m/z calcd for C 15 H 16 O 2 FS (M+H + ) 279.0855, found 279.0859. SO 2 Ph F SO 2 Ph F 29 1-Fluoro-1-phenylsulfonyl-4-phenyl-butane (2e) White solid. 1 H NMR (CDCl 3 ): δ 1.75-2.25 (m, 4H), 2.65 (t, J = 7.4 Hz, 2H), 5.08 (ddd, J = 48.6, 9.4, 3.0 Hz, 1H), 7.14 (m, 2H), 7.17 (m, 1H), 7.26 (m, 2H), 7.56 (m, 2H), 7.68 (m, 1H), 7.90 (br d, J = 7.5 Hz, 2H). 13 C NMR (CDCl 3 ): δ 26.2 (d, J = 2.3 Hz), 27.0 (d, J = 19.5 Hz), 35.1, 102.5 (d, J = 2195 Hz), 126.1, 128.27, 128.41, 129.21, 129.42, 134.5, 135.2, 140.8. 19 F NMR (CDCl 3 ): δ -179.1 (ddd, J = 48.6, 36.5, 14.4 Hz, 1F). HRMS (FAB): m/z calcd for C 16 H 18 O 2 FS (M+H + ) 293.1012, found 293,1015. 1-Fluoro-1-phenylsulfonyl-5-phenyl-pentane (2f) White solid. 1 H NMR (CDCl 3 ): δ 1.41-1.64 (m, 4H), 1.84 (m, 1H), 2.09 (m, 1H), 2.54 (t, J = 7.4 Hz, 2H), 5.00 (ddd, J = 48.7, 10.0, 2.9 Hz, 1H), 7.05-7.12 (m, 3H), 7.19 (m, 2H), 7.51 (m, 2H), 7.63 (m, 1H), 7.85 (br d, J = 7.3 Hz, 2H). 13 C NMR (CDCl 3 ): δ 24.1 (d, J = 2.2 Hz), 27.3 (d, J = 19.5 Hz), 30.7, 35.4, 102.7 (d, J = 219 Hz), 125.8, 128.29, 128.32, 129.24, 129.47, 134.5, 135.3, 141.7. 19 F NMR (CDCl 3 ): δ -179.2 (ddd, J = 48.8, 37.5, 14.9 Hz, 1F). HRMS (FAB): m/z calcd for C 17 H 20 O 2 FS (M+H + ) 307.1168, found 307.1166. SO 2 Ph F SO 2 Ph F 30 2.4.3 Typical Procedure for Reductive Desulfonylation of Fluorobis(phenylsulfonyl) Derivatives 1 Under argon atmosphere, excess activated Mg turnings were added into a Schlenk flask containing 1a (432 mg, 1.0 mmol) in 5 mL anhydrous methanol at 0 o C. The reaction mixture was stirred at 0 o C and the completion of the reaction was monitored by 19 F NMR. Fresh Mg turnings were added after 2 h to ensure the complete conversion. The reaction mixture was filtered, washed with dilute HCl and water followed by extraction with dichloromethane (3 × 15 mL). The combined organic layers were collected and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (eluent: 10% ethyl acetate in hexane), to provide the pure product 3b (73 mg, 48 % yield). (3-Fluoropropyl)benzene (3a) Colorless oil. 1 H NMR (CDCl 3 ): δ 2.02 (m, 2H), 2.75 (t, J = 7.5 Hz, 2H), 4.46 (dt, J = 47.2, 6.0 Hz, 2H), 7.21 (m, 3H), 7.30 (m, 2H). 13 C NMR (CDCl 3 ): δ 31.29(d, J = 5.4 Hz), 32.02 (d, J = 19.8 Hz), 83.12 (d, J = 164 Hz), 126.0, 126.1, 128.43. 128.46. 128.50, 141.1. 19 F NMR (CDCl 3 ): δ -220.5 (tt, J = 47.2 Hz, J = 25.4 Hz, 1F). HRMS (EI): m/z calcd for C 9 H 11 F (M + ) 138.0845, found 138.0839. F 31 (4-Fluorobutyl)benzene (3b) Colorless oil. 1 H NMR (CDCl 3 ): δ 1.68 (m, 4H), 2.59 (t, J = 7.3 Hz, 2H), 4.38 (dt, J = 47.4, 5.90 Hz, 2H), 7.11 (m, 3H), 7.21 (m, 2H). 13 C NMR (CDCl 3 ): δ 27.0 (d, J = 5.1 Hz), 29.9 (d, J = 19.6 Hz), 84.0 (d, J = 164 Hz), 125.8, 128.32, 128.38, 142.0. 19 F NMR (CDCl 3 ): δ -218.4 (tt, J = 47.4 Hz, J = 25.5 Hz, 1F). HRMS (EI): m/z calcd for C 10 H 13 F (M + ) 152.1001, found 152.0996. (5-Fluoropentyl)benzene (3c) Colorless oil. 1 H NMR (CDCl 3 ): δ 1.38 (m, 2H), 1.60 (m, 2H), 1.66 (m, 2H), 2.56 (t, J = 7.6 Hz, 2H), 4.37 (dt, J = 47.3, 6.2 Hz, 2H), 7.11 (m, 3H), 7.21 (m, 2H). 13 C NMR (CDCl 3 ): δ 24.8 (d, J = 5.5 Hz), 30.3 (d, J = 19.4 Hz), 31.1, 35.8, 84.1 (d, J = 164 Hz), 125.7, 128.27, 128.36, 142.4. 19 F NMR (CDCl 3 ): δ -218.1 (tt, J = 47.4 Hz, J = 25.0 Hz, 1F). HRMS (EI): m/z calcd for C 11 H 15 F (M + ) 166.1158, found 166.1145. (6-Fluorohexyl)benzene (3d) F F F 32 Colorless oil. 1 H NMR (CDCl 3 ): δ 1.39 (m, 4H), 1.63 (m, 4H), 2.61 (t, J = 7.6 Hz, 2H), 4.42 (dt, J = 47.4, 6.1 Hz, 2H), 7.18 (m, 3H), 7.27 (m, 2H). 13 C NMR (CDCl 3 ): δ 25.0 (d, J = 5.5 Hz), 28.8, 30.3 (d, J = 19.4 Hz), 31.3, 35.8, 84.1 (d, J = 164 Hz), 125.6, 128.23, 128.36, 142.6. 19 F NMR (CDCl 3 ): δ -217.6 (tt, J = 47.2 Hz, J = 25.2 Hz, 1F). HRMS (EI): m/z calcd for C 12 H 17 F (M + ) 180.1314, found 180.1302. (4-Fluorobutoxy)benzene (3e) Colorless oil. 1 H NMR (CDCl 3 ): δ 1.25 (m, 2H), 1.92 (m, 2H), 4.01 (t, J = 5.8 Hz, 2H), 4.53 (dt, J = 47.3, 5.7 Hz, 2H), 6.91 (m, 3H), 7.29 (m, 2H). 13 C NMR (CDCl 3 ): δ 25.2 (d, J = 5.1 Hz), 27.2 (d, J = 19.9 Hz), 67.0, 83.8 (d, J = 164.6 Hz), 114.3, 120.6, 129.4, 158.8. 19 F NMR (CDCl 3 ): δ -219.0 (tt, J = 47.3 Hz, J = 25.4 Hz, 1F). HRMS (EI): m/z calcd for C 10 H 13 OF (M + ) 168.0950, found 168.0946. (5-Fluoropentoxy)benzene (3f) Colorless oil. 1 H NMR (CDCl 3 ): δ 1.58 (m, 2H), 1.79 (m, 4H), 3.94 (t, J = 6.3 Hz, 2H), 4.45 (dt, J = 47.4, 6.0 Hz, 2H), 6.90 (m, 3H), 7.26 (m, 2H). 13 C NMR (CDCl 3 ): δ 21.9 (d, J = 5.4 Hz), 28.8, 30.1 (d, J = 19.6 Hz), 67.4, 83.8 (d, J = 164.5 Hz), 114.4, 120.5, 129.4, 158.9. 19 F NMR (CDCl 3 ): δ -218.4 (tt, J = 47.3 Hz, J = 25.1 Hz, 1F). HRMS (EI): m/z calcd for C 11 H 15 OF (M + ) 182.1107, found 182.1101. F O F O 33 2.5 Chapter 2: Representative Spectra 1 H NMR spectrum of 1a 34 19 F NMR spectrum of 1a 35 13 C NMR spectrum of 1a 36 1 H NMR spectrum of 1d 37 19 F NMR spectrum of 1d 38 13 C NMR spectrum of 1d 39 1 H NMR spectrum of 2a 40 19 F NMR spectrum of 2a 41 13 C NMR spectrum of 2a 42 1 H NMR spectrum of 2d 43 19 F NMR spectrum of 2d 44 13 C NMR spectrum of 2d 45 1 H NMR spectrum of 3a 46 19 F NMR spectrum of 3a 47 13 C NMR spectrum of 3a 48 1 H NMR spectrum of 3e 49 19 F NMR spectrum of 3e 50 13 C NMR spectrum of 3e 51 2.6 Chapter 2: References 1 Prakash, G. K. S.; Chacko, S.; Alconcel, S.; Stewart, T.; Mathew, T.; Olah, G. A. Angew. Chem. Int. Ed. 2007, 46, 4933. 2 Li, Y.; Ni, C.; Liu, J.; Zhang, L.; Zhang, J.; Zhu, L.; Hu, J. Org. Lett. 2006, 8, 1693. 3 Parent, E. E.; Carlson, K. E.; Katzenellenbogen, J. A. J. Org. Chem. 2007, 72, 5546. 4 Simeon, F. G.; Brown, A. K.; Zoghbi, S. S.; Patterson, V. M.; Innis, R. B.; Pike, V. W. J. Med. Chem. 2007, 50, 3256. 5 Silhar, P.; Pohl, R.; Votruba, I.; Hocek, M. Org.Biomol.Chem. 2005, 3, 3001. 6 Brown Jr. B. R.; Frink, E. J. Can. J. Anaesth 1992, 39, 207. 7 Kira, T.; Harata, N.; Sakata, T.; Akaike, N. Neuroscience 1998, 85, 383. 8 Welch, J. T. Tetrahedron 1987, 43, 3123. 9 Olah, G. A.; Pavlath, A. Acta Chim. Acad. Sci. Hung. 1953, 3, 425. 10 Gerus, I. I.; Kolomeistsev, A. A.; Kolychev, M. I.; Kukhar, V. P. J. Fluorine Chem. 2000, 105, 31. 11 Zhang, M.-R.; Ogawa, M.; Furutsuka, K.; Yoshida, Y.; Suzuki, K. J. Fluorine Chem. 2004, 125, 1879. 12 Zheng, L.; Berridge, M. S. Appl. Radiat. Isotopes 2000, 52, 55. 13 Zhang, W.; Zhu, L.; Hu, J. Tetrahedron 2007, 63, 10569. 14 Li, Y.; Hu, J. Angew. Chem. Int. Ed. 2005, 44, 5882. 15 Li, Y.; Ni, C.; Liu, J.; Zhang, L.; Zheng, J.; Zhu, L.; Hu, J. Org. Lett. 2006, 8, 1693. 16 Liu, J; Li, Y.; Hu, J. J. Org. Chem. 2007, 72, 3119. 17 Prakash, G. K. S.; Wang, F.; Shao, N.; Mathew, T.; Rasul, G.; Haiges, R.; Stewart, T.; Olah, G. A. Angew. Chem. Int. Ed. 2009, 48, 5358. 18 Fukuzumi, T.; Shibata, N.; Sugiura, M.; Yasui, H.; Nakamura, S.; Toru, T. Angew. Chem. Int. Ed. 2006, 118, 5095. 52 19 Prakash, G. K. S.; Zhao, X.; Chacko, S.; Wang, F.; Vaghoo, H.; Olah, G. A. Beilstein J. Org. Chem. 2008, 4, 17. 20 Prakash, G. K. S.; Shao, N.; Zhang, Z.; Ni, C.; Wang, F.; Haiges, R.; Olah, G. A. J. Fluorine Chem. 2012, 133, 27. 21 Prakash, G. K. S.; Ledneczki, I.; Chacko, S.; Ravi, S.; Olah, G. A. J. Fluorine Chem. 2008, 129, 1036. 22 Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. Org. Lett. 2004, 6, 4315. 23 Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon Press: Oxford, England, 1993. 24 Najera, C.; Yus, M. Tetrahedron 1999, 55, 10547. 25 Magnus, P. D. Tetrahedron 1977, 33, 2019. 26 Chandrasekhar, S.; Yu, J.; Falck, J. R. Tetrahedron Letters 1994, 35, 5441. 27 Yu, J.; Cho, H.-S.; Chandrasekhar, S.; Falck, J. R. Tetrahedron Letters 1994, 35, 5437. 28 Schoenebeck, F.; Murphy, J. A.; Zhou, S.; Uenoyama, Y.; Miclo, Y.; Tuttle, T. J. Am. Chem. Soc. 2007, 129, 13368. 29 Ni, C.; Hu, J. Tetrahedron Letters 2005, 46, 8273. 30 Liu, J.; Ni, C.; Wang, F.; Hu, J. Tetrahedron Letters 2008, 49, 1605. 31 Brown, A. C.; Caprino, L. A. J. Org. Chem. 1985, 50, 1749. 53 3 Chapter 3: NMR and Computational Study of a Persistent α-Fluorocarbanion (FCA) and its Analogues 3.1 Chapter 3: Introduction Fluorine-containing chemicals demonstrate unique physicochemical and biological properties and great potential in pharmaceutical research, This has provided impetus for fundamental studies and development of the synthetic methodologies for selective fluorinations and fluoroalkylations. 1,2,3,4,5,6 Nucleophilic monofluoromethylation reactions have been mainly used as one of the important synthetic strategies for efficient introduction of monofluoromethyl building blocks into complex molecules. 7,8 Recently, fluoro(phenylsulfonyl)methane derivatives have been extensively studied as efficient monofluoromethyl pronucleophiles in numerous reactions. 9,10,11 (Scheme 3.1) 54 Scheme 3.1 Nucleophilic monofluoromethylation reactions of an electrophile by fluoro(phenylsulfonyl)methane derivatives It is worth noting that these nucleophilic monofluoromethylation reactions involve α-monofluorocarbanions as key intermediates. Interestingly, a number of computational studies have shown that α-monofluorocarbanions are thermodynamically, sterically and electronically different from their non-fluorinated analogues due to the electronic effects of the fluorine atom. 12 α-Fluorocarbanions are known to be pyramidal, even though the corresponding parent non-fluorinated carbanions assume a planar structure. 12,13,14,15,16,17 The α-fluorine atom, intuitively, could stabilize the carbanions via its remarkably strong electron withdrawing effect. However, repulsion force from non-bonded 2p electron pair (Figure F H R SO 2 Ph + E = Electrophile Base -H F R SO 2 Ph E F E SO 2 Ph SO 2 Ph O R 1 R 2 R 3 R 1 SO 2 Ph SO 2 Ph R 3 OH R 2 F n-BuLi, BF 3 -Et 2 O Cl O H PhSO 2 CH 2 F + n-BuLi THF, -78 o C Cl OH C SO 2 Ph F H + F H SO 2 Ph SO 2 Ph F H NO 2 SO 2 Ph Ar O Ar + chiral catalyst Toluene, -20 o C O 2 N O SO 2 Ph F Ar Ar 55 3.1) makes the fluorine less stabilizing than chlorine, bromine, or some other electron withdrawing groups. (Figure 3.2) 18 Figure 3.1 The Coulombic repulsion of α-monofluorocarbanions caused by α-fluorine atom Figure 3.2 Bis(phenylsulfonyl)methide ion and its derivatives In many cases, this property of the α-fluorine atom leads to the destabilization of the α-carbanions and α-elimination of a fluoride ion takes place to form complex by- products through carbenoid intermediates. 18, 19 , 20 Consequently, the experimental investigation for the structural study of FCAs is still a challenge. Till the present study, F R 1 R 2 R 1 R 2 F Coulombic Repulsion I II III IV PhSO 2 SO 2 Ph H PhSO 2 SO 2 Ph F PhSO 2 SO 2 Ph OMe PhSO 2 SO 2 Ph Cl PhSO 2 SO 2 Ph Br V C 4 F 9 SO 2 SO 2 C 4 F 9 Br VI S S F O O O O S H O S O O O S Cl O S O O O S Br O S O O O S S O O O O O CH 3 I II III IV V 56 α-monofluorocarbanions were not identified and characterized, despite the reports of many computational studies on fluorine-bearing carbanions. Recently, α-fluorobis(phenylsulfonyl)methane (FBSM) has been successfully used in nucleophilic monofluoromethylations of various substrates and has been found to be a superior reagent compared with PhSO 2 CH 2 F. Hu et al. pointed out that the additional phenylsulfonyl group not only stabilizes the formed carbanion, but also increases the nucleophilicity of the fluorinated carbanion by its good softening ability. 10 The strong stabilizing effect of the two electron withdrawing phenylsulfonyl groups was found in the non-fluorinated analogue (Figure 3.2, carbanion I). Carbanion I was readily prepared and found to be thermally stable by Henderson and others. 21 The potassium salts of IV and V were isolated by Dubenko et al. and bis(perfluoroalkylsulfonyl) carbanion VI was also prepared as a fairly stable crystal. 22, 23 Based on the above studies, it is necessary to discover a method to synthesize the fluorine-bearing carbanion II and study its stability behavior under suitable conditions. In this chapter, the NMR, X-ray structural characterization and the computational studies of the persistent FBSM anion and its hydrogen, methoxy, bromo and chloro substituted analogues are reported. The synthetic and mechanistic study of monofluoromethylation reactions is discussed as well. 3.2 Chapter: Results and Discussion The very first observation of α-fluorobis(phenylsulfonyl)methide ion II was from an attempt of utilization FBSM to benzaldehyde with t-BuOK as a mild base. During that reaction, a new singlet peak at about -202 ppm was observed in the 19 F NMR spectrum of 57 the reaction mixture. After the work up, FBSM and the aldehyde starting materials were recovered, also suggesting that FBSM carbanion could be formed as a rather stable intermediate. Hu and coworkers reported that FBSM could be added to aldehydes using LiHMDS as the base. 24 Scheme 3.2 Preparation of α-fluorobis(phenylsulfonyl)methide ion (II) under different conditions FBSM was treated with strong metallic bases such as t-BuOK or n-BuLi in order to generate II complex with the corresponding counter cations. When FBSM was mixed with t-BuOK in anhydrous DMF, the doublet 19 F signal transformed into a sharp singlet at -202 ppm in the 19 F NMR spectrum indicating the deprotonation of FBSM. The 1 H NMR signal of the acidic CH proton at 6.1 ppm also disappeared. Similar results were also observed using other metallic bases. However, thus generated FBSM salts were found to be unstable in the solid state under ambient conditions, thereby restricting their isolation in solid crystalline form (Scheme 3.2). One possible cause of defluorination is the strong C−F···M + interactions, which lead to the generation of stable metallic fluorides. 25 n-Bu 4 N + K + II-K b II-N c II-Na a PhO 2 S n-BuLi a Not stable in solid state. b Not isolated. c Stable at ambient temperature for up to few weeks under inert conditions. II-Li a n-Bu 4 N + OH - t-BuOK MeONa DMF, r.t. THF, r.t. F SO 2 Ph H THF, r.t. DMF, r.t. Li + Na + (PhSO 2 ) 2 CF - (PhSO 2 ) 2 CF - (PhSO 2 ) 2 CF - (PhSO 2 ) 2 CF - 58 We thus chose tetra-alkyl ammonium hydroxide, a non-metallic base, because of its diminished interaction with the fluoride, greater commercial availability, and structural variability. Finally, reaction of FBSM with tetra-butylammonium hydroxide resulted in the formation of the ionic salt II-N and it was found to be stable in the solid state for up to few weeks under inert conditions. The complex II-N was crystallized from THF/toluene/hexane solvent mixture as fine cubes. 26 59 Figure 3.3 X-ray crystal structures of bis(phenylsulfonyl)methide (I-N) and α- fluorobis(phenylsulfonyl)methide (II-N) anions with tetra-butylammonium counter cations 60 X-ray crystallographic studies clearly illustrated that the fluorinated ion complex II-N was significantly different from its non-substituted and brominated analogues in its electronic as well as stereochemical nature. A planar structure was adopted by both I and VI, whereas II-N had a pyramidal structure. As the most remarkable structural character of II-N, the critical pyramidalization angle (Φ) of II-N around carbanion center was found to be 49.9 o . Given the fact that the pyramidalization angle (Φ) of a standard tetrahedron structure was 60 o , it was apparent that II-N was strongly sp 3 hybridized (pyramidalized) rather than sp 2 hybridized. On the other hand, the C17-F1 distance of 1.409 Å was considerably longer than the typical C sp3 -F bond distance in fluorohydrocarbons (1.32-1.38 Å as in CH 3 F, CH 2 F 2 , CF 3 H and CF 4 ). Remarkably, this C-F bond distance even has slightly overcome the “upper limit” of C-F bond distance (1.408 Å). 27 The C-Br bond of VI, 1.884 Å, was much shorter compared with the regular C-Br bond which is approximately 1.95~1.98 Å. It was also important to note that the structure of II-N, besides the two differences noted above, was essentially consistent with the properties of α-sulfonyl carbanions described by Gais and co-workers. 28 For instance, the average S-C17 bond distance (1.713 Å) was noticeably shorter than the corresponding one in sulfone whereas the S-O bonds of the anion have slightly longer distances. Furthermore, 1 H, 19 F and 13 C NMR spectroscopic data of II with different counter ions (II-Li, II-Na, and II-N) in d 6 -DMSO were very similar in the liquid phase. (Table 3.1) 61 Table 3.1 NMR Chemical shifts of carbanions I and II in combination with various cations As expected, the 19 F NMR data demonstrated an upfield shift of ~30 ppm accounting for the additional shielding effect on the fluorine atom caused by the increased electron density at the anionic carbon atom. The essentially identical 19 F chemical shifts for all the salts (II-Li, II-Na, and II-N) clearly indicated the absence of strong interactions between the cations (Li + , Na + , n-Bu 4 N + ) and the FBSM anion in high dielectric DMSO solvent. More interestingly, the carbanionic signals of II in the 13 C NMR spectrum unexpectedly showed a downfield shift by 22.7 ppm compared to FBSM. However, about 8 ppm upfield shift in 19 F NMR spectrum was observed for the α-carbon of the non-fluorinated anion I-N compared to that of bis(phenylsulfonyl)methane (HBSM). In order to understand the observed properties of II, computational studies on the anions I-V were carried out. This included optimizing conformations, ionization energies and their charge densities. A diagram of gas phase proton affinities of these anions (I-V) is illustrated in Figure 3.4. By defining the heats of formation of the corresponding neutral molecules as 0.0 kcal/mol, it was found that the gas phase deprotonation became o-H m-H p-H δ H (ppm) δ α-F /δ α-H (ppm) Compound II-N II-Na II-Li II-H (FBSM) δ c (ppm) I-H (HBSM) I-N 5.94 7.87-7.89 7.60-7.64 7.73-7.77 71.8 -171.9 7.93-7.95 7.71-7.75 7.86-7.90 104.4 -202.5 7.15-7.17 7.04-7.08 7.19-7.23 127.2 -202.8 7.17 7.04-7.08 7.21-7.23 127.1 -202.3 7.16-7.18 7.04-7.08 7.19-7.23 127.2 3.65 63.8 Two multiplets at 7.30-7.34 (2H) and 7.70-7.74 (3H) 62 more difficult as the electronegativity of the substituent increases (anion II-V). The diagram showed that Cl and Br could stabilize the anion, however, OCH 3 and F substituents destabilized the anion. It was also discovered that the “cis-pyramidal” conformation (II-b), which agrees well with the X-ray determined geometry, is 2.1 kcal/mol more stable than the “cis-planar” conformation (II-a) at the B3LYP/6- 311+G(2d,p)//B3LYP/6-311+G(2d,p)+ZPE level. Although the trans-planar structure II-c was found to be the most stable conformation of II, there was only 0.9 kcal/mol difference compared with the experimentally observed conformation II-b. In contrast, the trans-planar structures were favored when the substituent atom X was H, Cl or Br. It was of interest to find that the methoxy substituent diminished the energetic gap between the pyramidal conformation and the planar conformation to only 0.2 kcal/mol. In other words, the methoxy group was the “critical” threshold substitute in making the pyramidal conformation as an energetically preferred structure. 63 Figure 3.4 Gas phase proton affinities (ionization energy-electronegativity profile) of α- fluorocarbanion (FCA) and the related carbanions The computational studies on partial atomic charges (Q), bond distances and pyramidalization angles (Table 3.2) have demonstrated the structural and electronic effects of the substituents on the geometry of the anion and the stereochemistry of the products derived from the anion. First of all, the opposite partial charges on the central carbon (C x ) and the substituent exhibited the existence of Coulombic attractions when X is H, Cl, and Br, whereas the negative partial charges on both C x and the substituent X undoubtedly caused repulsions when the anion was substituted with F or OCH 3 groups. A 335.1 O 2 S SO 2 H Ph Ph O 2 S SO 2 H Ph Ph 334.3 332.7 0.0 O 2 S SO 2 Cl Ph Ph O 2 S SO 2 Cl Ph Ph 331.9 330.1 0.0 O 2 S SO 2 Br Ph Ph O 2 S SO 2 Br Ph Ph 329.4 330.8 0.0 O 2 S SO 2 OCH 3 Ph Ph 0.0 O 2 S SO 2 OCH 3 Ph Ph O 2 S SO 2 F Ph Ph O 2 S SO 2 F Ph Ph O 2 S SO 2 F Ph Ph 336.0 338.1 0.0 ~ ~ 2.20 3.98 3.16 3.44 2.96 X=F X=OCH 3 X=Cl X=Br X=H PhSO 2 SO 2 Ph X H 335.4 335.6 a b c Ionization Energy (Kcal/mol) Electronegativity (Pauling Scale) I V IV III II 64 trend that F and OCH 3 showed more negative charge densities than Cl and Br which reveals the important role played by the electronegativity of the substituents in the electronic properties of the anions. It is of importance to mention that the anions are greatly stabilized by the oxygen atoms on sulfonyl groups, although the α-substituents X also considerably affect structures of the anion. This is also strongly supported by two facts: (a) each oxygen atom bears more than 0.5 negative charges and the NAO bond order study showed partial single bond character of the S-O bonds in all structures; (b) the calculated bond distances agreed extremely well with the experimentally determined results. 65 Table 3.2 Structural parameters (bond order, bond lengths, and charges) associated with disulfonylmethide anions Consistent with the X-ray crystallographic data, the calculated C x -X bond distances in I, IV-VI were also significantly shorter than the standard C x -X bond distances, which can be rationalized by the Coulombic attractions. In contrast, the computational C-F bond distance values were found to be considerably longer than the regular C-F bond distances observed in analogous organic compounds. The above computational result was also consistent with the data obtained from X-ray crystallographic analysis. In addition, the extremely low C-F bond orders of both II-b (0.633) and II-c (0.644) theoretically supported the above-mentioned properties of C-F S-O S-C x X-C x Φ ( ο ) Ph S C x S Ph O O O O X (X-C x ) standard [b] Q O Q S Q Cx Q X X Bond Distance (A) o Mulliken Charge F [e] H OCH 3 Cl Br F [f] 1.466 1.690 1.077 1.088-1.099 -0.561 +0.696 -0.240 +0.097 0.0 1.461 1.713 1.921 1.951-1.983 -0.541 +0.646 +0.093 -0.105 0.0 1.461 1.712 1.761 1.783-1.858 -0.536 +0.476 +0.354 -0.084 0.0 1.464 1.715 1.389 1.405-1.458 -0.522 +0.963 -0.326 -0.310 (O) 18.8 1.458 1.731 1.400 1.312-1.408 -0.529 +0.994 -0.066 -0.295 43.3 1.461 1.699 1.381 -0.533 +0.707 -0.107 -0.256 0.0 F [g] 1.438 1.713 1.409 - - - - 49.8 [a] Natural bond order. [b] Bond distances in similar C sp3 -X structures are used as the standard. [c] Experimental data. [d] X-ray diffraction data of (CF 3 SO 2 ) 2 CBr - , taken from ref. 23. [e] cis-Pyramidal conformation. [f] trans-Planar conformation. [g] Experimental data. H [c] 1.448 1.664 0.949 1.088-1.099 - - - - 0.0 Br [d] 1.435 1.670 1.884 1.951-1.983 - - - - 0.0 -0.103 (OCH 3 ) 1.312-1.408 1.312-1.408 Bond Order [a] X-C x 0.811 0.765 1.023 0.772 0.633 0.644 - - - 66 bonds in FCAs and explain the defluorination observed in the solid state. The measured chemical shift deviation was in good agreement with the calculated values in the gas phase (I-H to I-N and II-H to II-N). Except in the case of FBSM, all carbanionic carbons showed clear upfield shifts. Calculations showed a gradual increase in chemical shift deviation (from the neutral to the carbanionic carbon) with increase in electronegativity of the substituents [Br (-24 ppm) < Cl (-18 ppm) < OCH 3 (-12 ppm) < F (+14 ppm), Figure 3.5]. Probably, electronegativity of the substituent plays a major role. Gradual decline in the pyramidalization angles from 49.9 o to 0.0 o with decrease in electronegativity (F > OCH 3 > Cl > Br) clearly showed the gradual transition in hybridization of the C x from sp 3 to typical sp 2 . Figure 3.5 Calculated 13 C NMR chemical shifts of α-C in I-V and the corresponding neutral molecules δ (ppm) 139 118 88 84 75 130 125 108 106 89 Anionic C Neutral C F OCH 3 Br Cl H Substituents 67 S S X O O O O Ph Ph - S S Ph Ph O O O O X S S Ph Ph O O O O X H S S Ph Ph O O O O X S Ph Ph O O O X S O PhO 2 S SO 2 Ph CH 3 O PhO 2 S PhO 2 S O CH 3 111.3 o 86.6 o PhO2S PhO 2 S F PhO 2 S PhO 2 S F -2.1 kcal/mol II-a II-b II-b-HOMO II-c-HOMO II Ph S S Ph F O O O O Ph S S Ph F O O O O + II-b-HOMO-33 II-b-HOMO-14 SimpleBondTheory MO Theory Resonance 2pof C x 2pofF π−π interaction small lobe Figure 3.6 Orbital representation of FBSM anion based on molecular orbital (MO) theory and bond theory Based on these results, a detailed picture of the structure features of FBSM anion can be well illustrated (Figure 3.6). In terms of MO theory, maximum orbital overlap occur among the 2p orbital on C x and the two 3p orbitals on S atoms since all three orbitals are parallel to each other. Although one of the 2p orbitals on the fluorine and the 2p orbital on C x are in the same plane, the maximum overlap is not possible because the two orbitals are not parallel. Similarly, there are also four 2p orbitals on the two oxygen atoms interacting with the 3p orbitals on S. The sum of these combinations forms π-type MOs, and the bonding orbital is illustrated as II-b-HOMO-33 (Figure 3.6). Moreover, 68 the II-b-HOMO-14 shows the overlap between the two π orbitals on the phenyl groups, which may partially cancel out the destabilization caused by the additional steric repulsion in the cis conformation. The structure of II-b can be explained by simple bond theory as well. To “localize” the lone pairs on the fluorine atom and their relation to the anionic sp 3 orbital on C x , the anion III (Figure 3.1) is used as a model structure since the positions of the lone pairs on oxygen can be determined by viewing at the direction of the O-CH 3 bond. According to the calculation, the O-CH 3 bond is roughly periplanar to the anionic sp 3 orbital on C x which means the two lone pairs on oxygen are gauche to the sp 3 orbital. Consequently, the lone pairs on FBSM anion II-b is supposed to have a similar conformation shown above. It is apparent that the planar structure causes more electronic repulsion due to the fact that the two lobes of the 2p orbital strongly interact with all three lone pairs on F. Nevertheless, in the pyramidal structure II-b, there are only two of the pairs having similar repulsion. To some extent, this explanation can be supported by the MO theory results as well (note that the two lobes of 2p orbital in II-b-HOMO have slightly different size where as the two lobes of the 2p orbital in II-c-HOMO have the same size). The anion II-b can be described as a resonance hybrid of the various resonance structures (Figure 3.6), which rationalizes many properties exhibited by the anion. 3.3 Chapter 3: Conclusion In conclusion, based on the X-ray crystal structures of FBSM anion and its non- fluorinated analogue, the critical role of electron-withdrawing substituents in modulating the properties of bis(phenylsulfonyl)methide anions and consequent pyramidalization have been revealed. High level theoretical calculations at the B3LYP/6- 69 311+G(2d,p)//B3LYP/6-311+G(2d,p)+ZPE level is further supported by X-ray crystallographic studies of the α-fluorobis(phenylsulfonyl)methide salt. 3.4 Chapter 3: Experimental Unless otherwise mentioned, all the chemicals were purchased from commercial sources. α-Fluoro(bisphenylsulfonyl)methane (FBSM) was prepared following the literature procedures. 10 The DriSolv ® solvents were purchased from EMD TM and used without further purification. Silica gel chromatography was performed to isolate the products using 60-200 mesh silica gel (from silicycle) with hexane-dichloromethane solvent system as eluent. 1 H, 13 C, and 19 F spectra were recorded on 400 MHz Varian NMR spectrometer. 1 H NMR chemical shifts were determined relative to residual solvent peak of DMSO-d 6 (at 2.50 ppm) or THF-d 8 (at 1. 72 ppm and 3.58 ppm). 13 C NMR shifts were determined relative to the solvent peak of DMSO-d 6 (at 39.5 ppm) or THF-d 8 (at 25.3 ppm and 67.4 ppm). 19 F NMR chemical shifts were determined relative to internal standard CFCl 3 at 0.00 ppm. Mass spectra were recorded on a high resolution mass spectrometer, in the EI + , FAB + or ESI mode. 3.4.1 Procedure for Preparation of α-Fluorocarbanion (II-N) Crystal 26 FBSM (157 mg, 0.5 mmol) was dissolved in anhydrous THF (1 mL) in a Schlenk flask under argon atmosphere. Tetra-n-butylammonium hydroxide (1 M in MeOH, 0.5 mL) was added to the solution dropwise at room temperature and the reaction mixture was stirred for 20 min. After evaporating the solvents and water under vacuum, the resulting salt was redissolved in 1:1 mixture of anhydrous THF and toluene (3 mL) and the solution was quickly transferred into a vial using a syringe. Anhydrous hexane (0.5 70 mL) was added to this solution and stored at room temperature under argon atmosphere to allow evaporation of the solvents. Fine crystalline solid (light yellow) was formed after majority of the solvent evaporated. HBSM anion crystal (I-N) was prepared by the similar procedure. 26 α-Fluoro-bis(phenylsulfonyl)methane (FBSM, II-H) White solid, 1 H NMR (DMSO-d 6 ): δ 7.46 (d, J = 42.5 Hz, 1H), 7.71-7.75 (m, 4H), 7.86- 7.90 (m, 2H), 7.93-7.95 (m, 4H). 13 C NMR (DMSO-d 6 ): δ 104.4 (d, J CF = 255 Hz), 129.70, 129.80, 135.3, 136.0. 19 F NMR (DMSO-d 6 ): δ -171.9 (d, J = 42.5 Hz, 1F). α-Fluoro-bis(phenylsulfonyl)methane n-tetrabutylammonium salt (II-N) Colorless crystals, 95% yield. NMR spectra have been recorded in both THF-d 8 and DMSO-d 6 as solvents. 1 H NMR (THF-d 8 ): δ 0.95 (t, J = 7.2 Hz, 12H), 1.39 (h, J = 7.2 Hz, 8H), 1.63-1.69 (m, 8H), 3.32-3.37 (m, 8H), 6.90 (t, J = 7.6 Hz, 4H), 7.06 (t, J = 7.6 Hz, 2H), 7.21 (d, J = 7.6 Hz, 4H). 13 C NMR (THF-d 8 ): δ 14.2, 20.5, 26.4, 59.3, 126.8, 128.1, 128.5 (d, J CF = 274 Hz), 129.6, 144.0. 19 F NMR (THF-d 8 ): δ -202.0 (s, 1F). HRMS (ESI): SO 2 Ph PhO 2 S H F PhO 2 S SHO 2 Ph F N(CH 2 CH 2 CH 2 CH 3 ) 4 71 m/z Calcd. for C 13 H 10 FO 4 S 2 - [(PhSO 2 ) 2 CF - ]: 313.0005, Found: 313.0014, Calcd. for C 16 H 36 N + (n-Bu 4 N + ): 242.2842, Found: 242.2843. 1 H NMR (DMSO-d 6 ): δ 0.92 (t, J = 7.2 Hz, 12H), 1.30 (h, J = 7.2 Hz, 8H), 1.56 (m, 8H), 3.15-3.19 (m, 8H), 7.04-7.08 (m, 4H), 7.16-7.23 (m, 6H). 13 C NMR (DMSO-d 6 ): δ 13.5, 19.2, 23.1, 57.5, 125.3, 127.0 (d, J CF = 273 Hz), 127.7, 129.5, 142.1. 19 F NMR (DMSO- d 6 ): δ -202.3 (s, 1F). 3.4.2 Typical Procedure for the Preparation of α-Fluorocarbanion in DMSO Solution FBSM (157 mg, 0.5 mmol) was dissolved in anhydrous THF (1 mL) in a Schlenk flask under argon atmosphere. The base (tetra-butylammonium hydroxide, n-BuLi, or sodium methoxide in MeOH, 0.5 mmol) was added to the solution dropwise at room temperature (for lithium salt, n-BuLi was added at -40 o C) and the reaction mixture was stirred for 20 min. After evaporating volatile solvents and water under vacuum, the resulting salt was redissolved in DMSO-d 6 . The solution was carefully transferred in to a pre-dried NMR tube using a syringe. α-Fluorobis(phenylsulfonyl)methane lithium salt (II-Li) 1 H NMR (DMSO-d 6 ): δ 7.04-7.08 (m, 4H), 7.15-7.17 (m, 4H), 7.19-7.23 (m, 2H). 13 C NMR (DMSO-d 6 ): δ 125.4, 127.2 (d, J CF = 273 Hz), 127.8, 129.68, 142.0. 19 F NMR (DMSO-d 6 ): δ -202.5 (s, 1F). PhO 2 S SO 2 Ph F Li 72 α-Fluorobis(phenylsulfonyl)methane sodium salt (II-Na) 1 H NMR (DMSO-d 6 ): δ 7.04-7.08 (m, 4H), 7.17 (m, 4H), 7.21-7.23 (m, 2H). 13 C NMR (DMSO-d 6 ): δ 125.4, 127.0 (d, J CF = 273 Hz), 127.8, 129.69, 141.9. 19 F NMR (DMSO- d 6 ): δ -202.8 (s, 1F). 3.4.3 Typical Procedure for Preparation of Tetra-n-butylammonium-HBSM Anion Solution HBSM (148 mg, 0.5 mmol) was dissolved in anhydrous THF (1 mL) in a Schlenk flask under argon atmosphere. The base (tetra-n-butylammonium hydroxide, or sodium methoxide in MeOH, 0.5 mmol) was added to the solution dropwise at room temperature (for lithium salt, n-BuLi was added at -40 o C) and the reaction mixture was stirred for 20 min. After evaporating volatile solvents and water under vacuum, the resulting salt was redissolved in DMSO-d 6 . The solution was carefully transferred in to a pre-dried NMR tube using a syringe. 3.4.4 DFT Calculated Structures and Energies of α-Fluorocarbanion Calculations were performed using the Gaussian 03 program. 29 The geometry optimizations were performed at the B3LYP/6-31G(d) level. Vibrational frequencies at the B3LYP/6-31G(d)//B3LYP/6-31G(d) level were used to characterize stationary points as minima (number of imaginary frequency (NIMAG) = 0) and to evaluate zero point vibrational energies (ZPE) which were scaled by a factor of 0.96. 30 For B3LYP/6-31G(d) structures further geometry optimizations were carried out at the B3LYP/6-311+G(2d,p) PhO 2 S SO 2 Ph F Na 73 level. Final energies were computed at the B3LYP/6-311+G(2d,p)//B3LYP/6- 311+G(2d,p) + ZPE level. Pyramidal structure 1 was found to be a minimum on the potential energy surface of α-fluorocarbanion at the B3LYP/6-31G(d) and B3LYP/6-311+G(2d,p) level of calculations (Figure 3.7). The B3LYP/6-311+G(2d,p) calculated C-F, C1-S1 and C1-S2 distances of 1 are 1.401 Å, 1.732 Å and 1.731 Å, respectively, agree extremely well with the X-ray determined bond distances of 1.408 Å 1.717 Å and 1.708 Å. Both calculated and X-ray structures were found to be very close to C s symmetrical. The critical pyramidalization angle 3 (Φ) of 1 around carbanion center was computed to be 39.7 o also agrees very well with that of the experimental value of 46.2 o . Isomeric non-pyramidal structure 2 was also found to be a minimum at the both B3LYP/6-31G(d) and B3LYP/6-311+G(2d,p) level of calculations (Figure 3.7). In contrast to structure 1, the pyramidalization angle (Φ) around carbanion center of the computed structure of 2 was found to be exactly zero. The structure 2 is only 0.9 kcal/mole more stable than structure 1 at the B3LYP/6-311+G(2d,p)//B3LYP/6- 311+G(2d,p) + ZPE level. However, structure 2 was not observed experimentally. The geometry of 1 was optimized by constraining the pyramidalization angle (Φ) to 0.0 o (i.e. planar carbanion center). It is important to mention that the planar structure without constrain converted into more stable pyramidal structure 1 upon optimization without any activation barrier. As expected the planar structure was computed to be 2.1 kcal/mole less stable than structure 1 at the B3LYP/6-311+G(2d,p)//B3LYP/6- 311+G(2d,p) + ZPE level. 74 1, C 1 2, C 2 Figure 3.7 B3LYP/6-311+G(2d,p) calculated structure of 1 and 2. 75 3.5 Chapter 3: Representative Spectra 1 H NMR Spectrum of FBSM 76 19 F NMR Spectrum of FBSM 77 13 C NMR Spectrum of FBSM 78 1 H NMR Spectrum of II-Li in DMSO 79 19 F NMR Spectrum of II-Li in DMSO 80 13 C NMR Spectrum of II-Li in DMSO 81 1 H NMR Spectrum of II-N in DMSO 82 19 F NMR Spectrum of II-N in DMSO 83 13 C NMR Spectrum of II-N in DMSO 84 3.6 Chapter 3: References 1 Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Wiley-VCH, Weinheim, Germany, 2004. 2 Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. 3 Smart, B. E. J. Fluorine Chem. 2001, 109, 3. 4 Filler, R.; Kobayashi, Y.; Yagupolskii, L. M. Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications, Elsevier, Amsterdam, 1993. 5 Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine Chemistry: Principles and commercial applications, Plenum, New York, 1994. 6 Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. 7 Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757. 8 Prakash, G. K. S.; Hu, J. Acc. Chem. Res. 2007, 40, 921. 9 Liu, J.; Ni, C.; Li, Y.; Zhang, L.; Wang, G.; Hu, J. Tetrahedron Lett. 2006, 47, 6753. 10 Ni, C.; Li, Y.; Hu, J. J. Org. Chem. 2006, 71, 6829. 11 Prakash, G. K. S.; Wang, F.; Stewart, T.; Mathew, T.; Olah, G. A. Proc. Natl. Acad. Sci. 2009, 106, 4090. 12 Uneyama. K. Organofluorine Chemistry, Blackwell, Oxford, 2006. 13 Lorand, J. P.; Urban, J.; Overs, J.; Ahmed, Q. A. J. Org. Chem. 1969, 34, 4176. 14 Castejon, H. J.; Wiberg, K. B. J. Org. Chem. 1998, 63, 3937. 15 Dixon, D. A.; Fukunaga, T.; Smart, B. E. J. Am. Chem. Soc. 1986, 108, 4027. 16 Farnham, W. B.; Dixon, D. A.; Calabrese, J. C. J. Am. Chem. Soc. 1988, 110, 2607. 17 Qian, C.-P.; Nakai, T.; Dixon, D. A.; Smart, B. E. J. Am. Chem. Soc. 1990, 112, 4602. 18 Adolph, H. G.; Kamlet, M. J. Am. Chem. Soc. 1966, 88, 4761. 19 Hine, J.; Mahone, L. G.; Liotta, C. L. J. Am. Chem. Soc. 1967, 89, 5911. 85 20 Faigl, F.; Marzi, E.; Schlosser, M. Chem. Eur. J. 2000, 6, 771. 21 MacDougall, D. J.; Kennedy, A. R.; Noll, B. C.; Henderson, K. W. J. Chem. Soc., Dalton Trans. 2005, 2084. 22 Dubenko, R. G.; Nelpyuev, V. M.; Pel’kis, D. S. Zh. Org. Khim. 1968, 4, 324. 23 Ochiai, M.; Tada, N.; Murai, K.; Gota, S.; Shiro, M. J. Am. Chem. Soc. 2006, 128, 9608. 24 Shen, X.; Zhang, L.; Zhao, Y.; Zhu, L.; Li, G.; Hu, J. Angew. Chem. Int. Ed. 2011, 50, 2588. 25 Takemura, H.; Nakashima, S.; Kon, N.; Yasutake, M.; Shinmyozu, T.; Inazu, T. J. Am. Chem. Soc. 2001, 123, 9293. 26 Prakash, G. K. S.; Wang, F.; Shao, N.; Mathew, T.; Rasul, G.; Haiges, R.; Stewart, T.; Olah, G. A. Angew. Chem. Int. Ed. 2009, 48, 5358. 27 Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A. G.; Taylor, R. J. Chem. Soc. Perkin Trans. 2 1987, 12, S1. 28 Raabe, G.; H. Gais, J.; Fleischhauer, J. J. Am. Chem. Soc. 1996, 118, 4622. 29 Gaussian 03, Revision C.02, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; and Pople, J. A.; Gaussian, Inc., Wallingford CT, 2004. 30 Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502. 86 4 Chapter 4: Large Scale Preparation of α- Fluorobis(phenylsulfonyl)methane (FBSM) 4.1 Chapter 4: Introduction Fluorine-containing organics are of substantial interest in pharmaceutics, biochemistry and material science due to their unique properties. 1, 2 The incorporation of fluorinated motifs using various fluoroalkylating reagents is particularly important because of their synthetic advantages. 3,4 Among these fluoroalkylating reagents, α- fluorobis(phenylsulfonyl)methane (FBSM) has been developed as a versatile and efficient nucleophilic monofluoromethylating reagent. FBSM acts as an effective carbon acid due to the presence of the two electron withdrawing phenylsulfonyl groups, and undergo facile deprotonation under suitable basic conditions leading to the formation of corresponding persistent α-fluorocarbanion as effective reaction intermediate (see previous chapter 3). 5 Number of reactions have been achieved by using this sulfur-based nucleophilic monofluoromethylating reagent. Ring opening of epoxides and aziridines, 6 the allylic monofluoromethylation reaction, 7 the Mitsunobo reaction, 8 conjugate addition reaction, 9 the Mannich reaction, 10 the aldol reaction, 11 are a few among many other reactions recently studied. (Scheme 4.1) 12 87 Scheme 4.1 Synthetic applications for α-fluorobis(phenylsulfonyl)methane (FBSM) Notably, the selective and effective protocol for the reductive removal of sulfonyl groups allows the introduction of the CH 2 F motif using FBSM, more efficiently than the application of many other monofluoromethylating reagents. In addition, FBSM can be further converted to TMSCF(SO 2 Ph) 2 and (PhSO 2 ) 2 CFI, which have also been later utilized as novel monofluoromethylating reagents. 13, 14 O R 1 R 2 R 3 R 1 SO 2 Ph SO 2 Ph R 3 OH R 2 R R R R R R F OAc CH 2 F SO 2 Ph F PhO 2 S R 1 R 2 OH R 1 R 2 PhO 2 S SO 2 Ph F R 1 R 2 CH 2 F R SO 2 Ph NHBoc R NHBoc F SO 2 Ph SO 2 Ph R CH 2 F NHBoc R X R CF(SO 2 Ph) 2 R X R SO 2 Ph F R 1 R 2 O R 1 R 2 O PhO 2 S F SO 2 Ph R H O R CF(SO 2 Ph) 2 OH FBSM, n-BuLi, BF 3 -Et 2 O FBSM, Cs 2 CO 3 [Pd(C 3 H 5 )Cl] 2 (2.5 mol%) (S)-PHOX (5 mol%) Mg, MeOH FBSM, Ph 3 P, DIAD Mg, MeOH FBSM, CsOH-H 2 O charal phase transfer catalyst Mg, MeOH FBSM, Base FBSM, Base FBSM chiral catalyst (1) FBSM, LiHMDS (2) CF 3 CO 2 H 88 On the other hand, the synthetic approaches towards FBSM in high yield had been rather limited because the original synthetic pathway of FBSM only afforded moderate yield due to some practical difficulties. (Scheme 4.2) The original preparation of FBSM requires expensive starting materials and fluorinating reagent that affords difluoro- bis(phenylsulfonyl)methane as a by-product and can only be removed by chromatographic separation. 15, 16 So the preparation scale of original FBSM synthesis has been limited to gram level, the price of FBSM on the market is about 80 USD per gram. 17 Scheme 4.2 Synthesis of FBSM from bis(phenylsulfonyl)methane Lately, Hu et al. reported the synthesis of FBSM by the treatment of fluoromethyl phenyl sulfone with methyl benzenesulfinate followed by the oxidation using m- chloroperoxybenzoic acid (mCPBA) in high selectivity and excellent yield. 18 Later, Prakash and coworkers reported another efficient approach for the preparation of FBSM using PhSO 2 CH 2 F and PhSO 2 F as the starting materials. 19 (Scheme 4.3) This type of synthetic route used the C-S bond forming strategy instead of the conventional C-F bond forming strategy towards the FBSM synthesis. Inspired by their early studies, it is necessary to improve and simplify the whole synthesis of FBSM as well as its purification process. The aim is to increase the production scale, avoid using hazardous and expensive fluorine source, improve the selectivity and overall yield, and simplify the work up procedures. S Ph S O O O O Ph F FBSM (1) base (2) Selectfluor S Ph S O O O O Ph byproduct F F + S S Ph Ph O O O O H H scale < 2 g 89 Scheme 4.3 Synthesis of FBSM via C-S bond forming strategy 4.2 Chapter 4: Results and Discussion Even though FBSM has been employed as an efficient nucleophilic monofluoromethylating reagent, 12 due to its high cost and inconvenient preparation methods, the availability of FBSM in the market is still very limited. 15,16 Up to now, only two registered companies have FBSM as its commercial product and unit price of FBSM is relatively high. In order to expand the applications of FBSM, it is necessary to improve and simplify the preparation method as well as to reduce the overall cost for the production of FBSM. Here, a six step total synthesis of FBSM with high yield was proposed and FBSM was synthesized not only from inexpensive starting materials but using a non-hazardous fluorine source, KF. (Scheme 4.4) Initially, thioanisole was selected as the starting material for the synthesis of chloromethyl phenyl sulfide. SO 2 Cl 2 was used as the chlorination reagent and dichloromethane was used as solvent, both of which are inexpensive and readily available. The isolated yield of the product in the first step was above 93% with very high purity after the vacuum fractional distillation. S Ph S O O O O Ph F FBSM PhSO 2 CH 2 F S Ph OMe O (1 )LiHMDS (2) mCPBA + PhSO 2 CH 2 F + PhSO 2 F (1) KHMDS (2) HCl S Ph S O O O O Ph F FBSM 90 In the second step, dry potassium fluoride was employed as the sole fluorinating reagent to promote the fluoride/chloride (F/Cl) exchange. The work up procedure of PhSCH 2 F was also straightforward as the first step, which only required the removal of CH 3 CN solvent as the key work up procedure resulting in excellent yield. PhSCH 2 F was dissolved in CH 3 OH/H 2 O mixture and oxidized by Oxone to yield PhSO 2 CH 2 F over 4 h in the third step. The reaction mixture was initially placed in an ice bath then slowly warmed to room temperature. Methanol was removed by rotary evaporation and the insoluble inorganic precipitate was removed by filtration and washed by CH 2 Cl 2 . The combined liquid was extracted with CH 2 Cl 2 , and PhSO 2 CH 2 F was prepared by the extraction of the aqueous layer, filtration, concentration, and recrystallization in 92% overall yield. All of above did not involve any chromatographic separation techniques. PhSO 2 F was synthesized from PhSO 2 Cl with the F/Cl exchange using KF salt in the fourth step. The inexpensive KF was used in this synthesis twice as the fluorinating agent. Although PhSO 2 F is available with small quantities in the current chemical market, PhSO 2 Cl still has its advantage for the inexpensive unit price, so it is necessary to add this step to reduce the total cost for the synthesis of FBSM. 91 Scheme 4.4 Preparative scale total synthesis of FBSM A ‘C-S bond forming strategy’ 19 was applied in the fifth and sixth step. KHMDS was readily prepared from KH and HMDS and used immediately. Two equivalent base was used since the first equivalent was required to deprotonate PhSO 2 CH 2 F to make fluoro(phenylsulfonyl)methide anion (PhSO 2 CHF - ) and the extra amount was consumed during the facile formation of FBSM anion. FBSM was synthesized by mixing the anion and PhSO 2 F under -78 °C before quenching the reaction mixture with HCl in the last step. The product was isolated in high purity by extraction technique since all the byproducts were either water soluble or volatile. High purity and high yield of FBSM was obtained via two recrystallization steps. The newly developed synthetic strategy S CH 3 + SO 2 Cl 2 CH 2 Cl 2 reflux, 2 hr S CH 2 Cl S CH 2 Cl + KF 18-crown-6, CH 3 CN reflux, 120 hr S CH 2 F S CH 2 F + Oxone CH 3 OH / H 2 O 4 hr S CH 2 F O O S Cl O O + KF 18-crown-6, CH 3 CN 24 hr S F O O S CH 2 F O O + S F O O KHMDS THF, -78 o C HCl FBSM Step 1: Step 2: Step 3: Step 4: Step 5 & 6: 93% 95% 92% 78% 95% $ 31 / mol $ 60 / mol $ 5.8 / mol $ 25 / mol $ 11 / mol $ 5.8 / mol 92 successfully avoided tedious separation processes such as column chromatography and utilization of any expensive or low efficient reagents. 4.3 Chapter 4: Conclusion A practical and high yield synthesis of FBSM was developed. Instead of applying ‘C-F bond forming strategy’, the ‘C-S bond forming strategy’ synthetic protocol affords FBSM with excellent yield and high purity without chromatographic purification processes. Compared to the conventional synthetic method of FBSM, the improved designed synthetic approach greatly increases the yield and the scalability of the product, simplifies the separation procedures and reduces its overall production total cost. 4.4 Chapter 4: Experimental Unless otherwise mentioned, all reagents were purchased from commercial sources. Dichloromethane and acetonitrile were used as received from Aldrich (water content < 50 ppm). 1 H, 13 C and 19 F-NMR spectra were recorded on Varian Mercury-400 NMR spectrometer. 1 H-NMR chemical shifts were determined relative to internal (CH 3 ) 4 Si (TMS) at 0.00. 13 C-NMR chemical shifts were determined relative to the 13 C signal of the solvent: CDCl 3 (77.16 ppm). CFCl 3 was used as internal standard for 19 F- NMR. High resolution mass spectra were recorded in EI+ or FAB+ mode on a high resolution mass spectrometer at the Mass Spectrometry facility, University of Arizona. 93 4.4.1 Typical Procedure for Preparation of Chloromethyl Phenyl Sulfide A 500-mL three-necked round-bottomed flask equipped with a magnetic stir bar (37.5 x 10 mm, octagonal) is charged with thioanisole (35.2 mL, 0.30 mol) and anhydrous methylene chloride (230 mL), added sequentially via syringe. The flask is fitted with two rubber septa and a reflux condenser. To quench the HCl (g) generated through the chlorination, a Tygon ® tube is affixed to the top of the condenser, and the end of the tubing is submerged in an Erlenmeyer flask containing 500 mL of 2M aqueous NaOH. The reaction is placed under a positive pressure of nitrogen via a needle connected to a nitrogen vacuum manifold, then heated to reflux in an oil bath while stirring (50 °C, bath temp). When the reaction reaches a steady reflux, a solution of sulfuryl chloride (24.1 mL, 0.33 mol, 1.1 equiv) in methylene chloride (70 mL) is added over 1 h via cannula. The reaction is kept under reflux for 2 h, removed from the oil bath and allowed to cool to room temperature. The reaction mixture is then carefully diluted with water (100 mL) and transferred to a 500-mL separatory funnel. The organic phase is separated and then washed with water (3 x 75 mL) and brine (50 mL) to give a pale pink translucent solution that is dried over magnesium sulfate (15 g, 15 min). The drying agent is removed by filtration and the filtrate is concentrated by rotary evaporation (23 °C, 2 mmHg) to give the crude product as an oil (44.30 g, 93%). The product is further purified using fractional vacuum distillation at (0.2–0.3 mm Hg). A small amount of starting material is collected in the first fraction (60–63 °C at distillation head; 110 °C bath temp) and this is followed by the product (87–91 °C at the distillation head; 140 °C bath temp). The distilled product (25.37 g, 53.3%) was determined to be pure enough for the following reactions (>99.7% by 1 H NMR). Additional fractions from the distillation 94 contained product (14.48 g, 30.4%) that was deemed insufficiently pure (95.0% by 1 H NMR) for use in the present sequence of reactions. 4.4.2 Typical Procedure for Preparation of Fluoromethyl Phenyl Sulfide 20 An oven-dried (140 °C for 12 h) 100-mL round-bottomed flask equipped with a magnetic stir bar (25 x 8 mm, octagonal) is charged with spray-dried potassium fluoride (8.80 g, 152 mmol, 2.0 equiv) and 18-crown-6 (2.01 g, 7.6 mmol, 0.1 equiv). The flask is sealed with a rubber septum into which is inserted a syringe needle attached to a nitrogen/ vacuum line. The flask is evacuated and refilled with nitrogen 3 times. Anhydrous acetonitrile (50 mL) and chloromethyl phenyl sulfide (10.2 mL, 12.10 g, 76.0 mmol, 1.0 equiv) are added successively to the flask by syringe. A reflux condenser fitted with a nitrogen inlet adaptor is quickly attached and the apparatus is flushed with nitrogen three times. The stirred reaction mixture is heated to reflux in an oil bath (102–103 °C, bath temp) for 120 h. The reaction mixture is then cooled in an ice bath (0 °C, bath temp), diluted with ice water (50 mL), and transferred to a 250 mL separatory funnel. The mixture is extracted with methylene chloride (4 x 25 mL). The combined organic layer is washed with water (30 mL), dried over magnesium sulfate (ca. 10 g, 15 min), and filtered. The solvent is removed on a rotary evaporator (23 °C bath temp, 2 mmHg) to give crude fluoromethyl phenyl sulfide as a brownish oil (10.04–10.25 g, 93–95%) that is directly subjected to oxidation for the next step. 4.4.3 Typical Procedure for Preparation of Fluoromethyl Phenyl Sulfone 21 To a 1-L round-bottomed flask equipped with a magnetic stir bar (50 x 8 mm, octagonal) is added Oxone ® (116.80 g, 190 mmol KHSO 5 , 2.6 equiv) and distilled water 95 (175 mL). The flask is capped loosely with a septum and placed in an ice bath. The septum is replaced with an addition funnel and a solution of crude fluoromethyl phenyl sulfide (10.20 g, 72 mmol, 1.0 equiv) in methanol (175 mL) is added dropwise over ca. 1 h. The reaction mixture is allowed to slowly warm to room temperature and stirred for an additional 12 h. Methanol is removed via rotary evaporation (45 °C bath temp, 2 mm Hg). The resulting residue contains a large amount of insoluble white precipitate, which is removed by filtration through a Büchner funnel. The funnel is rinsed with methylene chloride (2 x 30 mL) and the filtrate is transferred to a 250-mL separatory funnel. After organic layer separation, the aqueous layer is further extracted with methylene chloride (5 × 30 mL). The organic layers are combined, washed with water, dried over magnesium sulfate (ca. 10 g, 15 min), filtered, and concentrated to ca. 40 mL of a pale yellow solution. The solution is filtered through a plug of silica gel (230–400 mesh, 100 mL), which is further washed with methylene chloride (ca. 250 mL) to give a clear solution. The filtrate is concentrated via rotary evaporation (23 °C, 2 mmHg) and then placed under vacuum (room temperature, ca. 0.2–0.3 mmHg, 15–30 min) to result in a clear or slightly yellowish oil, which slowly solidifies at room temperature under vacuum. The solid is stirred with hot hexanes (ca. 50 mL, 60~65 °C) for 20 min, which forms two layers. Upon cooling to 0 °C in an ice bath, the bottom layer gradually crystallizes to yield colorless crystals over 15 min, which are collected by filtration on a Büchner funnel and washed with cold (0 °C) hexanes (2 x 10 mL) to afford fluoromethyl phenyl sulfone (10.99–12.18 g, 83–92%). 96 4.4.4 Typical Procedure for Preparation of Benzenesulfonyl Fluoride 22 A 500-mL round-bottomed flask equipped with a magnetic stirring bar (50 mm x 8 mm, octagonal) is charged with benzenesulfonyl chloride (39.0 mL, 53.90 g, 0.3 mol, 1.0 equiv), potassium fluoride (22.70 g, 0.39 mol, 1.3 equiv) and 18-crown-6 (3.96 g, 15 mmol, 0.05 equiv). The flask is then sealed with a rubber septum and connected via a syringe needle to nitrogen/vacuum line. The flask is evacuated/flushed with nitrogen three times, then acetonitrile (300 mL) is added via syringe and the mixture is stirred at room temperature for 24 h. The reaction mixture is then diluted with water (150 mL) and transferred to a 1L separatory funnel and extracted with diethyl ether (3 x 75 mL). The combined organic layer is washed with brine (30 mL) and dried over magnesium sulfate (15 g, 15 min). The drying agent is removed by filtration and the solvent is removed by rotary evaporation (23 °C, 2 mm Hg) to give a clear low-viscosity liquid. This product is dissolved in hexanes (50 mL) and washed with HCl solution (1 N, 5 x 20 mL) to remove residual 18-crown-6. The organic phase is dried over magnesium sulfate (15 g, 15 min), the drying agent is removed by filtration and the filtrate is concentrated by rotary evaporation (23 °C, 2 mm Hg) and then further under high vacuum (room temp, 0.2–0.3 mm Hg) to give benzenesulfonyl fluoride (28.2 mL, 37.50 g, 78 % yield). 4.4.5 Typical Procedure for Preparation of α-Fluorobis(phenylsulfonyl)methane (FBSM) An oven-dried (140 °C, 12 h) 250-mL round-bottomed flask, equipped with a magnetic stir bar (25 x 8 mm, octagonal), is charged with potassium hydride (21.80 g, 30% wt in oil, 163 mmol, 2.7 equiv), sealed with a rubber septum and connected through a syringe needle to a nitrogen/ vacuum line. The flask is evacuated and purged with 97 nitrogen three times and then placed in an ice bath. Excess oil is removed as follows. Anhydrous hexanes (20 mL) are added to the flask via syringe. The mixture is gently stirred for 10 min and allowed to stand unstirred for another 10 min before the removal of the hexanes-oil solution with a syringe. The hexanes-oil solution is added dropwise to an isopropyl alcohol solution. This washing procedure is repeated two more times. Anhydrous THF (130 mL) is then added. Hexamethyldisilazane (40.9 mL, 31.5 g, 195 mmol, 3.2 equiv) is then added portion-wise to the stirred solution via syringe over a period of 20–30 min. The hydrogen evolution ceases within 15 min after the addition. The ice bath is removed and the reaction mixture is allowed to stand without stirring for 30 min at room temperature before use. An oven dried (140 °C, 12 h) 500-mL round-bottomed flask equipped with a magnetic stir bar (37.5 x 8 mm, octagonal) is charged with fluoromethyl phenyl sulfone (10.66 g, 61.2 mmol, 1.0 equiv). The flask is sealed with a rubber septum and connected through a syringe needle to a nitrogen/vacuum line. The flask is evacuated and purged with nitrogen three times. Benzenesulfonyl fluoride (7.37 mL, 9.80 g, 61.2 mmol, 1.0 equiv) and anhydrous tetrahydrofuran (40 mL) are added successively via syringe. The flask is cooled in a dry ice-acetone bath (–78 °C) and the stirred contents are treated with the KHMDS solution in tetrahydrofuran prepared above, which is added dropwise via cannula over 30 min. During the course of the addition, the reaction mixture becomes brownish, cloudy, and viscous. After 30 min at –78 °C, the reaction mixture is quenched by transfer via cannula over 30 min to another 500-mL round-bottomed flask maintained under a nitrogen atmosphere containing a stirred solution of 4M HCl (185 mL). The resultant mixture appears as a single opaque layer and is extracted with methylene 98 chloride in a 500 mL separatory funnel (5 × 60 mL). The combined organic layer is washed with brine (50 mL), dried over magnesium sulfate (ca. 15 g, 15 min), and filtered. The filtrate is concentrated via rotary evaporation (23 °C bath temp, 2 mm Hg) and further dried under vacuum (room temperature, ca. 0.2–0.3 mm Hg) to afford crude α- fluorobis(phenylsulfonyl)methane (FBSM) as a colorless solid (18.28 g, 95%). Examination by 1 H NMR and 19 F NMR spectroscopy shows the crude FBSM product to be satisfactory for most preparative purposes (>98% purity). Crude FBSM product can be further purified by recrystallization in methylene chloride and hexanes as follows. The crude product is placed in a 250-mL round-bottomed flask equipped with a stir bar and a reflux condenser. Methylene chloride (35 mL) is added and the mixture is heated under reflux to dissolve the product. Hexanes (ca. 30 mL) are slowly added portion-wise through the top of the condenser, while maintaining the reflux. The solution is slowly cooled to room temperature. The solution is then transferred to a refrigerator set to 5 °C and held for 2 h. The resulting white precipitate is collected on a Büchner funnel, rinsed with 25 mL cold methylene chloride/hexanes (1:1, v/v; 0 °C) and allowed to air dry on the funnel for 15 min and then placed on a vacuum line for 15 min (rt, 0.2– 0.3 mmHg) to render 14.04 g of FBSM. The mother liquor is further concentrated to approximately one-half volume. An additional 20 mL of cold hexanes (0 °C) is then added causing the solution to become cloudy. After 15 minutes without stirring, an additional 2.51 g of FBSM is isolated by the above mentioned procedure (combined yield 16.55 g, 85%). 99 Fluoromethyl phenyl sulfone Mp 51–52 °C; 1 H NMR (500 MHz, CDCl 3 ) δ: 5.16 (d, J = 47 Hz, 2 H), 7.62 (t, J = 8.3 Hz, 2 H), 7.74 (tt, J = 7.4, 1.2 Hz, 1 H), 7.96 (d, J = 7.3 Hz, 2 H). 13 C NMR (125 MHz, CDCl 3 ) δ: 92.0 (d, J = 217.5 Hz), 129.0, 129.6, 134.9. 19 F NMR (500 MHz, CDCl 3 ) δ: – 210.0 (td, J = 50.0, 2.25 Hz); IR (KBr) 3013 (w), 2950 (w), 1587 (w), 1447 (s), 1343 (s), 1314 (s), 1220 (m), 1155 (s), 1053 (s), 937 (m), 790 (s), 751 (s), 683 (s), 556 (s), 527 (s) cm -1 ; Anal. Calcd for C 7 H 7 FO 2 S: C, 48.27; H, 4.05. Found: C, 48.28; H, 3.89. The spectral data are in agreement with the reported values. 2 α-Fluorobis(phenylsulfonyl)methane Mp 106.5–107.0 °C. 1 H NMR (500 MHz, CDCl 3 ) δ: 5.81 (d, J = 45.7 Hz, 1 H), 7.60 (t, J = 7.8 Hz, 4 H), 7.76 (t, J = 7.2 Hz, 2 H), 7.98 (d, J = 7.9 Hz, 4 H). 13 C NMR (125 MHz, CDCl 3 ) δ: 105.6 (d, J = 264 Hz), 129.6, 130.2, 135.3, 135.8. 19 F NMR (500 MHz, CDCl 3 ) δ: –167.4 (d, J = 48.6 Hz); IR (KBr) 3096 (w), 3071 (w), 2955 (m), 1581 (m), 1450 (s), 1358 (s), 1172 (s), 1077 (s), 797 (s), 683 (s), 533 (s), 520 (s) cm -1 ; HRMS for (C 13 H 11 FO 4 S 2 )Na + : Calcd 336.997500; Found 336.997129. Anal. Calcd for C 13 H 11 FO 4 S 2 : C, 49.67; H, 3.53. Found: C, 49.39; H, 3.45. The spectral data are in agreement with the reported values. 7,8 S F O O PhO 2 S SO 2 Ph H F 100 4.5 Chapter 4: Representative Spectra 1 H NMR spectrum of PhSO 2 CH 2 F 101 19 F NMR spectrum of PhSO 2 CH 2 F 102 13 C NMR spectrum of PhSO 2 CH 2 F 103 1 H NMR spectrum of FBSM 104 19 F NMR spectrum of FBSM 105 4.6 Chapter 4: References 1 Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Wiley-VCH, Weinheim, Germany, 2004. 2 Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. 3 Prakash, G. K. S.; Mandal, M. J. Fluorine Chem. 2001, 112, 123. 4 Hu, J. J. Fluorine Chem. 2009, 130, 1130. 5 Prakash, G. K. S.; Wang, F.; Shao, N.; Mathew, T.; Rasul, G.; Haiges, R.; Stewart, T.; Olah, G. A. Angew. Chem. Int. Ed. 2009, 48, 5358. 6 Ni, C.; Li, Y.; Hu, J. J. Org. Chem. 2006, 71, 6829. 7 Fukuzumi, T.; Shibata, N.; Sugiura, M.; Yasui, H.; Nakamura, S.; Toru, T. Angew. Chem. Int. Ed. 2006, 45, 4973. 8 Prakash, G. K. S.; Chacko, S.; Alconcel, S.; Stewart, T.; Mathew, T.; Olah, G. A. Angew. Chem. Int. Ed. 2007, 46, 4933. 9 Prakash, G. K. S.; Zhao, X.; Chacko, S.; Wang, F.; Vaghoo, H.; Olah, G. A. Beilstein J. Org. Chem. 2008, 4, 17. 10 Mizuta, S.; Shibata, N.; Goto, Y.; Furukawa, T.; Nakamura, S.; Toru, T. J. Am. Chem. Soc. 2007, 129, 6394. 11 Shen, X.; Zhang, L.; Zhao, Y.; Zhu, L.; Li, G.; Hu, J. Angew. Chem. Int. Ed. 2011, 50, 2588. 12 Ni, C.; Hu, J. Synlett 2011, 770. 13 Prakash, G. K. S.; Shao, N.; Zhang, Z.; Ni, C.; Wang, F.; Haiges, R.; Olah, G. A. J. Fluorine Chem. 2012, 133, 27. 14 Prakash, G. K. S.; Ledneczki, I.; Chacko, S.; Ravi, S.; Olah, G. A. J. Fluorine Chem. 2008, 129, 1036. 15 Ni, C.; Li, Y.; Hu, J. J. Org. Chem. 2006, 71, 6829. 16 Fukuzumi, T.; Shibata, N.; Sugiura, M.; Yasui, H.; Nakamura, S.; Toru, T. Angew. Chem. Int. Ed. 2006, 45, 4973. 106 17 SciFinder Search Results, 2013. 18 Ni, C.; Zhang, L.; Hu, J. J. Org. Chem. 2009, 74, 3767. 19 Prakash, G. K. S.; Wang, F.; Ni, C.; Thomas, T. J.; Olah, G. A. J. Fluorine Chem. 2010, 131, 1007. 20 More, K. M.; Wemple, J. Synthesis 1977, 791 21 McCarthy J. R.; Matthews, D. P.; Paolini J. P. Org. Synth. 1995, 72, 209. 22 Lee, I; Shim, C. S.; Chung, S. Y.; Kim, H. Y.; Lee, H. W. J. Chem. Soc., Perkin Trans. II 1988, 1919. 107 5 Chapter 5: Facile Synthesis of α-Monofluoromethyl Alcohols: Nucleophilic Monofluoromethylation of Aldehydes Using TMSCF(SO 2 Ph) 2 5.1 Chapter: Introduction Introduction of fluoromethyl substituted groups into organic molecules has become very important because of the enormous potential of fluoro-organics in many science fields. 1 , 2 , 3 , 4 Fluoromethyl groups are particularly important because their mimicking ability to represent themselves as the methyl or hydroxymethyl groups and numerous compounds containing fluoromethyl groups have shown much significance in biological studies. To fulfill this synthetic demand, fluorinated methyl phenyl sulfone derivatives, such as difluoromethyl phenyl sulfone (PhSO 2 CF 2 H), fluoromethyl phenyl sulfone (PhSO 2 CH 2 F), and α-fluorobis(phenylsulfonyl)methane (FBSM), have been extensively and successfully employed in various reactions as versatile fluoromethylating reagents. 5, 6, 7 Among the reagents mentioned above, α-fluorobis(phenylsulfonyl)methane (FBSM) has become a robust monofluoromethylating reagent and been utilized in many different transformations, 8, 9, 10, 11, 12, 13 which are otherwise very difficult to achieve. In spite of these successful applications, the addition of the FBSM anion to aldehydes was considered a challenge. Shibata et al. have previously claimed that regardless of the reaction conditions, such an addition was not possible because of the instability of the β- hydroxy-α-fluorobis(phenylsulfonyl)methane and its reversal to starting material. 14 PhSO 2 CH 2 F was found to undergo monofluoromethylation reaction with aromatic substituted aldehydes. 15 Then, a complex pronucleophile molecule, 2-fluoro-1,3- benzodithiole-1,1,3,3-tetraoxide (FBDT) was also synthesized and introduced as an 108 alternative for the nucleophilic addition to aldehydes. 14 However, Hu and coworkers recently reported that FBSM anion could be added to aldehydes using LiHMDS as the base below -78 o C. 16 The reaction intermediate, lithium carbinolates (Scheme 5.1), which can be stabilized through strong interactions between Li and O, were then in situ quenched with Brønsted acids such as trifluoroacetic acid at even lower temperature, to afford the corresponding alcohols. 16 Scheme 5.1 Nucleophilic addition of monofluoromethylating reagents to aldehydes In this chapter, α-trimethylsilyl-α-fluorobis(phenylsulfonyl)methane (TFBSM), TMSCF(SO 2 Ph) 2 , is introduced as a novel monofluoromethylating reagent, and the method to capture the FBSM anion-aldehyde adducts (carbinolates) through a reaction with Lewis acids is described. (Scheme 5.2) The one-pot methodology for addition reaction between the FBSM anion and aldehydes is also disclosed. This type of reactions Cl O H PhSO 2 CH 2 F + n-BuLi THF, -78 o C Cl OH C SO 2 Ph F H SO 2 Ph PhO 2 S F + R H O R H HO SO 2 Ph F SO 2 Ph H + Quenching with a Bronsted Acid LiHMDS -78 o C -94 o C R O S S F Li Ph O O O O Ph Monofluorination of Aldehydes with PhSO 2 CFH 2 S O 2 O 2 S F + R H O DABCO Toluene, r.t., 1 d R OH O 2 S SO 2 F Monofluorination of Aldehydes with FBDT Monofluorination of Aldehydes with FBSM 109 can be achieved under a self-quenching mechanism. During the reaction, TFBSM was used and served as both a pronucleophile and a Lewis acid. 17, 18, 19, 20 Scheme 5.2 Self-quenching monofluoromethylation of aldehydes with TFBSM 5.2 Chapter 5: Results and Discussion The starting material for the synthesis of TFBSM was FBSM, which is readily obtained on large scale (see previous chapter 4). 21, 22 After an extensive screening of various reaction conditions, the preparation of TFBSM was carried out at 0 o C, by slowly adding FBSM into a suspension of NaH in THF. After stirring the reaction mixture containing FBSM anion for 30 minutes, TMSCl was added into the reaction mixture and the reaction was continued for additional 1 h. Pure needle shape crystals of TFBSM were collected after the work up and crystallization with an overall yield of 43%. (Scheme 5.3) TFBSM was found to be not stable in air and can only be stored in a glove box under argon for several months. The decomposition of TFBSM occurred within a few days to afford FBSM in the presence of moisture or in CDCl 3 solution, which contains some protic acid impurities. Comparing to TMSCF 3 (the Ruppert-Prakash reagent) and [(phenylsulfonyl)difluoromethyl]trimethylsilane (TMSCF 2 SO 2 Ph), which are substantially inert toward aqueous HCl solution, instant hydrolysis of TFBSM was observed when concentrated aq. HCl (12 mol/L) was added, indicating the exceptional lability of the Si-C F bond. R H O R H TMSO SO 2 Ph F SO 2 Ph F - SO 2 Ph SO 2 Ph F TMS PhO 2 S SO 2 Ph F TMS 110 Scheme 5.3 Preparation of α-Trimethylsilyl-α-fluorobis (phenylsulfonyl)methane (TFBSM) The initial trial for the reaction of TFBSM to benzaldehyde was performed by employing THF as a solvent and tetra-n-butylammonium difluorotriphenylsilicate (TBAT) as an initiator. As expected, β-fluoro silyl ether was formed as the desired product, however, in only 22% yield (Entry 1, Table 5.1). After that, multiple reaction parameters such as initiators, solvents, temperatures, and proportions of substrates were tested in order to reach the best reaction condition and to enhance the efficacy of the protocol. The reaction screening data are shown in Table 5.1 and the yield improved to 99% under optimized reaction conditions. The yields of Entries 1-5 were very low, and it can be rationalized as the competitive protonation of FBSM anion due to the presence of moisture in the reaction system. Applying an excess amount of TFBSM can, therefore, compensate the consumption of the pronucleophile. After we modified the proportions of the substrates, the yields were significantly improved (Entries 1-5 and 6-9, Table 5.1). In addition, CsF was found to be the best initiator of all Lewis bases we selected (Entries 1- 9, Table 5.1). Solvent effects were also studied (Entries 9, 11-13, Table 5.1), which showed THF as the most efficient solvent medium in this case. While addition sequences of reagents were critical (Entries 8 and 10, Table 5.1), yields did not decrease, when the reaction time was shortened to 4 h (Entries 14, Table 5.1). In particular, performing the reaction at room temperature resulted in a decrease in yield to 75%. The optimized reaction between TFBSM and aldehyde was carried out below 0 o C by mixing 2 Ph S S Ph O O O O 2) TMSCl (2.0 eq.), 0 o C 43% Ph S S Ph O O O O F TMS TFBSM 1) NaH (1.5 eq.), THF, 0 o C F H 111 equivalent TFBSM, 1 equivalent aldehyde and 20% CsF as initiator in THF. The progress of the reaction was monitored via 19 F NMR till completion. Final product was purified via silica gel column chromatography. Table 5.1 Optimization of the addition reaction of TFBSM with benzaldehyde With optimized reaction conditions established, various aldehydes were tested and used to explore the scope of this protocol (Table 5.2). The reaction was found to be applicable to aromatic aldehydes bearing both electron-withdrawing and electron- S F Ph O O S Ph O O TMS + Ph H O temperature, time initiator, solvent Ph H TMSO SO 2 Ph F SO 2 Ph Entry 1a TFBSM/1a/Initiator 2a Temp. ( o C) Initiator Solvent Yield (%) c Time (h) 1 a 2 a 3 a 4 a 5 a 6 a 7 a 8 a TBAT TBAF d Me 3 N + O - KF CsF THF THF THF THF THF 2/1/0.05 1/2/0.05 1/2/0.20 1/2/0.20 1/2/0.20 TBAT THF 1/2/0.05 0 ~ rt 12 0 ~ rt 0 ~ rt 0 ~ rt 0 ~ rt 0 ~ rt 12 12 12 12 12 66 22 0 34 38 31 Me 3 N + O - KF CsF THF THF THF 0 ~ rt 0 ~ rt 0 ~ rt 12 12 12 71 78 99 2/1/0.20 2/1/0.20 2/1/0.20 9 a KF THF 0 ~ rt 12 0 2/1/0.20 10 b CsF Et 2 O 0 ~ rt 12 25 2/1/0.20 11 a CsF DMF 0 ~ rt 12 0 2/1/0.20 12 a CsF Toluene 0 ~ rt 12 54 2/1/0.20 13 a CsF THF 0 4 99 2/1/0.30 14 a CsF THF rt 4 75 2/1/0.20 15 a a Fluoride source in THF was added to a mixture of TFBSM and 1a in THF. b TFBSM in THF was added to a mixture of KF and 1a in THF. c 19 F NMR yields. d A TBAF solution in THF (1M) containing 5 wt% H 2 O was used. 112 donating groups (Entries 1-5, Table 5.2). While 2,4,6-trimethoxyl benzaldehyde (1d) underwent the reaction smoothly and gave the corresponding product in high yield (Entry 4, Table 5.2), the addition reaction was completely impeded in the case of 2,4-dimethyl benzaldehyde (1f), probably due to more effective steric demand of the methyl groups (Entry 6, Table 5.2). The protocol was also suitable to α,β-unsaturated aldehyde (cinnamaldehyde) (1g), which exclusively gave 1,2-adduct (2g) in 80% yield (Entry 7, Table 5.2). The method was also compatible for aliphatic aldehyde 1h, however, afforded the corresponding carbinol 2h in a lower yield (Entry 8, Table 5.2). Similar to the addition reaction to aromatic aldehydes, the steric encumbrance of aliphatic aldehydes can considerably affect the outcome of the reaction. As demonstrated, pivalaldehyde (1i) was unable to participate in the addition reaction (Entry 9, Table 5.2). It is worth noting that the attempt to add TFBSM to benzophenone was unsuccessful under similar reaction conditions, indicating the limitation of the present protocol (Entry 10, Table 5.2). Since fluoromethyl phenyl sulfone (PhSO 2 CH 2 F) readily underwent addition reaction with various ketones, 23 the low reactivity of the FBSM anion toward ketones can be probably attributed to steric effects. 113 Table 5.2. Monofluoromethylation of aldehydes with TFBSM S F Ph O O S Ph O O TMS + R H O THF, rt, 4h CsF (20 mol%) R H TMSO SO 2 Ph F SO 2 Ph Entry 1 (1 eq.) 2 Product Yield (%) a 1 1a 2a 99/81 TFBSM (2 eq.) PhCHO 2 1b 2b 93/90 CHO 3 1c 2c 99/86 OMe CHO 4 1d 2d 97/87 Me CHO Me 5 1e 2e 96/83 6 1f 2f 0/0 CHO O 2 N 7 1g 2g 88/80 CHO F 8 1h 2h 64/54 Ph CHO 9 1i 2i 0/0 tBu CHO a 19 F NMR yield/Isolated yield. 10 1j 2j 0/0 OMe MeO Ph CHO Ph O Ph Carbonyl Compounds Ph H TMSO SO 2 Ph F SO 2 Ph OTMS SO 2 Ph F SO 2 Ph F OTMS SO 2 Ph F SO 2 Ph O 2 N OTMS SO 2 Ph F SO 2 Ph MeO OMe OMe OTMS SO 2 Ph F SO 2 Ph OTMS SO 2 Ph F SO 2 Ph Me Me OTMS SO 2 Ph F SO 2 Ph Ph OTMS SO 2 Ph F SO 2 Ph Ph OTMS SO 2 Ph F SO 2 Ph tBu OTMS SO 2 Ph F SO 2 Ph Ph Ph 114 To demonstrate the synthetic utility of the present protocol, β-fluoro silyl ether (2e) was subjected to the reductive Mg/acetic acid desulfonylation system. As described in Scheme 5.3, the corresponding monosulfones (3e) were generated in 74% yield as a mixture of two diastereomers under the reaction conditions. Further desulfonylation of 3e was achieved using Na/Hg/MeOH system to form β-monofluorinated alcohol 4e in 48% yield. Importantly, the rate of the desilylation of 2e was slower than that of its desulfonylation in Mg/acetic acid system, thereby permitting the desulfonylation without significant decomposition of 2e. In comparison, rapid degradation of 2e was found to be inevitable under Mg/MeOH reductive conditions. Scheme 5.4 Synthesis of 2-fluoro-1-(naphthalen-1-yl)ethanol via reductive desulfonation of 2e It was also important to explore the nature of Si-C F bonds in these fluoromethylating reagents. As mentioned before, the Si-C F bond in TFBSM was found to be rather labile compared with those in TMSCF 3 and PhSO 2 CF 2 TMS. The previously reported crystal structure of TMSCF 3 (4) has showed an elongated Si-C F bond (1.944 Å) TMSO SO 2 Ph F SO 2 Ph 2e Mg/AcOH 74 % HO F 4e TMSO SO 2 Ph F 3e Na/Hg MeOH 48 % 115 compared with other Si-C H bond in the same molecule (bond distances range from 1.848- 1.862 Å) (Figure 5.1 and Table 5.3). 24 Crystal structures of [(phenylsulfonyl) difluoromethyl]trimethylsilane (TMSCF 2 SO 2 Ph, 5) and TFBSM were obtained herein, which demonstrated even longer Si-C F bonds of 1.957 Å and 1.994 Å, respectively (Figure 5.1 and Table 5.3). This result presumably suggests a gradual decrease in the strengths of Si-C F bonds from TMSCF 3 to TFBSM. Figure 5.1 Crystal structures of various fluoromethyl silane reagents and their computed structures at the B3LYP/6-311+G(d,p) level To achieve a quantitative assessment of Si-C F bond strengths in these reagents, systematic theoretical calculations on 4, 5, and TFBSM were carried out at the B3LYP/6- 311+G(d,p) level. 25, 26 As depicted in Fig 5.1, optimized geometries of these molecules highly resemble their structures in the solid state. Consistent with the tendency observed in crystal structures, the Si-C F bond distance order of TFBSM>TMSCF 2 SO 2 Ph>TMSCF 3 is followed (Column 2, Table 5.3). Wiberg bond indices 27 of Si-C F bonds were computed 116 to reveal the weakness of the Si-C F bond in TFBSM, which was shown to be only 77% of the value of the TMS-CH 3 bond. 28 A more accurate evaluation of bond strengths was achieved on the basis of free energy changes (ΔG) of hypothesized reactions between silane reagents and a fluoride anion (Eq. 1, Table 5.3). For all three reagents, the Si-C F bond cleavage was thermodynamically favorable both in the gas phase and in THF solution. Among these reagents, the Si-C F bond in TFBSM was found to be particularly labile (57.1 kcal/mol and 37.8 kcal/mol weaker than 4 and 5 in the gas phase, respectively). Such a bond strength order can also be experimentally supported by methanolysis rates of these reagents as TFBSM>TMSCF 2 SO 2 Ph >TMSCF 3 (Eq. 2 and Column 7, Table 5.3). Table 5.3. Investigation of Si-C F bond strength in various fluoromethyl silane reagents To rationalize the remarkably elongated Si-C F bonds in TFBSM, we further computed Si-C F bond distances in TMSCF 2 H, TMSCH 2 F, and TMSCH 3 at the B3LYP/6- 311+G(d,p) level. Clear trends were observed through a systematic structural variation R TMS + F - R - + TMSF TMSCF 3 PhSO 2 CF 2 TMS (PhSO 2 )CFTMS + ΔG ΔG gas a (kcal/mol) ΔG THF a,c (kcal/mol) -28.0 -46.7 -65.8 -3.8 -12.7 -29.7 k dec. d (Lmol -1 s -1 ) Wiberg Bond Indices (Si-CF n ) a,b 0.7564 (91%) 0.7085 (85%) 0.6457 (77%) Exp./Cal. Si-CF n Bond Distances (A) 1.1x10 -5 2.6x10 -5 Ins. Dec. 1.943/1.953 1.957/1.971 1.994/2.010 R TMS + CD 3 OD R-D + TMSOCD 3 k dec. Eq. 1 Eq. 2 a Computed at the B3LYP/6-311+G(d,p) level. b Compared with the Wiberg bond index of 0.8339 in tetramethylsilane. c The effect of THF solvent was treated implicitly using the standard PCM method of Gaussian03. d Determined via 19 F NMR a 0.1 M solution of the corresponding reagent at 298 K. o TMSCH 3 TMSCFH 2 TMSCF 2 H +13.6 +3.9 -9.6 +37.8 +26.5 +13.5 0.8339 (100%) 0.8120 (97%) 0.7895 (95%) - - - -/1.891 -/1.913 -/1.936 R TMS NBO Charge on Si +1.493 +1.545 +1.618 +1.563 +1.518 +1.497 R TMS R - + TMS + Eq. 3 117 from TMSCH 3 to TFBSM. As shown in Table 5.3, the increase in bond distances and the decrease in Wiberg bond indices can be seen from TMSCH 3 to TFBSM, indicating a gradual weakening of the Si-C F bonds. In particular, by comparing the Si-C F bond distances of TMSCH 2 F<TMSCF 3 <TFBSM, the exceptionally long Si-C F bond distance in TFBSM is unlikely to result from the removal of the fluorine substituent. Simply, it can be understood as the prevailing stabilizing effect of the phenylsulfonyl group over fluorine on the carbanions, which leads to more contribution from ionic resonance structures (comparing the NBO charges on Si atoms in Column 3 in Table 5.3, and Eq. 3, Table 5.3). 29 5.3 Chapter 5: Conclusion In conclusion, α-trimethylsilyl-α-fluorobis(phenylsulfonyl)methane (TFBSM) has been successfully synthesized and utilized as a viable nucleophilic monofluoromethylating reagent for aldehydes. Functioning as both a pronucleophile and a Lewis acid, the reagent allowed the one-step addition of the FBSM anion toward various aldehydes via a self-quenching mechanism. Undergoing a reductive desulfonylation reaction, the silyl ether adduct can be further converted to β-fluorinated alcohol, which, however, was not feasible from the corresponding β-bis(phenylsulfonyl)- β-fluoro-alcohol. Mechanistic studies revealed the remarkably weak nature of the Si-C F bond in TFBSM, which facilitated the facile cleavage of the Si-C F bond. 118 5.4 Chapter 5: Experimental Unless otherwise mentioned, all chemicals were purchased from commercial sources. THF was freshly distilled over Na before use. The NMR spectra were recorded on 400 MHz and 500 MHz superconducting NMR spectrometers, respectively. All the unknown compounds have been fully characterized by NMR spectroscopy and high resolution MS analysis, whereas structures of all known products were confirmed by comparison of their 1 H NMR and 19 F NMR spectra with reported data. 1 H NMR chemical shifts (δ) were determined relative to internal (CH 3 ) 4 Si at δ 0.0 or to the signal of a residual solvent in CDCl 3 (at δ 7.26). 13 C NMR chemical shifts were determined relative to internal (CH 3 ) 4 Si at δ 0.0 or to the 13 C signal of CDCl 3 at δ 77.16. 19 F NMR chemical shifts were determined relative to CFCl 3 at δ 0.0 as internal standard. 5.4.1 Typical Procedure for Preparation of α-Trimethylsilyl-α- fluorobis(phenylsulfonyl)methane (TFBSM) To a suspension of NaH (216 mg, 9 mmol) in THF (11 mL) was slowly added a solution of FBSM (1.88 g, 6 mmol) in THF (11 mL) at 0 ° C. The reaction mixture was stirred at the same temperature for 30 min, and TMSCl (1.52 mL, 12 mmol, freshly distilled) was added dropwise to the reaction mixture. The reaction mixture was further stirred for 1 h and transferred into a 25 mL syringe through a needle. The suspension was then passed through a 25 mm GD/X Whatman syringe filter (0.45 µm GMF, heated in an oven at 90 ° C for 1 h before use) into a Schlenk tube under Ar. Anhydrous hexanes (20 mL) was carefully added onto the top of the solution. Agitation of the THF layer should be avoided, so that a two-layer system can be formed. The Schlenk tube was subsequently stored in a freezer (-20 ° C) for 24-48 h until a large amount of colorless 119 needles was formed (a small amount of cloudy precipitate may be formed as well). The solvents were then removed from the tube via a syringe under Ar. The crystals were rinsed with anhydrous hexanes (10 mL×2), which were also removed via a syringe. The product was dried under vacuum at room temperature and then stored in a glove box (997 mg, 43%). α-Trimethylsilyl-α-fluorobis(phenylsulfonyl)methane (TFBSM) 1 H NMR (C 6 D 6 ): δ 0.70 (d, J = 0.7 Hz, 9H), 6.45-6.48 (m, 4H), 6.67-6.70 (m, 2H), 7.35- 7.37 (m, 4H). 19 F NMR (C 6 D 6 ): δ -157.0 (s, 1F). 13 C NMR (C 6 D 6 ): δ -0.43 (d, J = 2.4 Hz) 121.0 (d, J = 268.3 Hz), 128.4, 128.5, 130.2 (d, J = 1.9 Hz), 133.6. Satisfactory HRMS data could not be obtained due to the extreme lability of the compound. 5.4.2 Typical Procedure for the Addition Reaction of TFBSM to Aldehydes and Benzophenone To a solution of benzaldehyde (1a, 20.2 mg, 0.19 mmol) and TFBSM (147 mg, 0.38 mmol, 2 eq.) in anhydrous THF (0.5 mL) was quickly added a suspension of CsF (6 mg, 0.04 mmol, 20 mol%) in anhydrous THF (0.5 mL) under argon at 0 ° C. The progress of the reaction was monitored via 19 F NMR spectroscopy, which showed the completion of the reaction after stirring for 4 h. The solvent was evaporated under vacuum. The resulting crude product was purified via silica gel column chromatography using ethyl acetate and hexanes as eluents Ph S S Ph O O O O F TMS 120 (2-Fluoro-1-phenyl-2,2-bis(phenylsulfonyl)ethoxy)trimethylsilane (2a) 1 H NMR (CDCl 3 ): δ 0.10 (s, 9H), 5.92 (d, J = 7.8 Hz, 1H), 7.14-7.27 (m, 5H), 7.35-7.39 (m, 2H), 7.53-7.56 (m, 2H), 7.56-7.60 (m, 1H), 7.64-7.66 (m, 2H), 7.68-7.71(m, 1H), 7.98-8.00 (m, 2H). 19 F NMR (CDCl 3 ): δ -132.3 (d, J = 7.8 Hz, 1F). 13 C NMR (CDCl 3 ): δ 0.2, 73.7 (d, J = 23.1 Hz), 114.4 (d, J = 270.7 Hz), 127.8, 128.3 (d, J = 2.4 Hz), 128.4, 128.7, 128.8, 131.0 (d, J = 1.6 Hz), 131.4 (d, J = 1.8 Hz), 134.4, 135.0, 135.6 (d, J = 1.4 Hz), 136.5, 138.2. HRMS: calcd for C 23 H 24 F 2 NaO 5 S 2 Si + 535.0695 (M+Na + ), found: 535.0692. M.p. 113-115 °C. (2-Fluoro-1-(4-fluorophenyl)-2,2-bis(phenylsulfonyl)ethoxy)trimethylsilane (2b) 1 H NMR (CDCl 3 ): δ 0.08 (s, 9H), 5.89 (d, J = 8.2 Hz, 1H), 6.86-6.90 (m, 2H), 7.15-7.18 (m, 2H), 7.38-7.42 (m, 2H), 7.52-7.56 (m, 2H), 7.56-7.61 (m, 1H), 7.66-7.72 (m, 3H), 7.95-7.97 (m, 2H). 19 F NMR (CDCl 3 ): δ -113.3 (m, 1F), -132.52 (d, J = 8.1 Hz, 1F). 13 C NMR (CDCl 3 ): δ 0.1, 73.3 (d, J = 23.0 Hz), 114.3 (d, J = 270.4 Hz), 114.7, 114.9, 128.5, 128.8, 130.2 (dd, J = 8.4 Hz, J = 2.5 Hz), 131.0 (dd, J = 30.0 Hz, J = 1.8 Hz), 131.4 (dd, J = 3.2 Hz, J = 1.8 Hz), 134.6, 135.0, 136.6, 138.1, 163.0 (d, J = 247.8 Hz). HRMS: calcd for C 23 H 24 F 2 NaO 5 S 2 Si + 535.0695 (M+Na + ), found: 535.0692. M.p. 130-132 °C. Ph H TMSO SO 2 Ph F SO 2 Ph OTMS SO 2 Ph F SO 2 Ph F 121 (2-Fluoro-1-(4-nitrophenyl)-2,2-bis(phenylsulfonyl)ethoxy)trimethylsilane (2c) 1 H NMR (CDCl 3 ): δ 0.09 (s, 9H), 6.00 (d, J = 7.0 Hz, 1H), 7.40-7.44 (m, 4H), 7.54-7.58 (m, 2H), 7.63-7.67 (m, 1H), 7.70-7.74 (m, 3H), 7.94-7.96 (m, 2H), 8.07-8.10 (m, 2H). 19 F NMR (CDCl 3 ): δ -132.5 (d, J = 7.0 Hz, 1F). 13 C NMR (CDCl 3 ): δ 0.1, 73.2 (d, J = 22.7 Hz), 113.8 (d, J = 270.3 Hz), 122.8, 128.6, 129.0, 129.3 (d, J = 2.7 Hz), 131.1 (d, J = 1.6 Hz), 131.2 (d, J = 1.8 Hz), 135.0, 135.3, 136.1, 137.6, 143.1 (d, J = 2.1 Hz), 148.1. HRMS: calcd for C 23 H 25 FNO 7 S 2 Si + 538.0820 (M+H + ), found: 538.0827. M.p. 126-127 °C. (2-Fluoro-2,2-bis(phenylsulfonyl)-1-(2,4,6-trimethoxyphenyl) ethoxy)trimethylsilane (2d) 1 H NMR (CDCl 3 ): δ 0.00 (s, 9H), 3.47 (br s, 3H), 3.89 (s, 3H), 4.04 (br s, 3H), 5.75 (br s, 1H), 6.17(br s, 1H), 6.77 (d, J = 27.5 Hz, 1H), 7.39-7.44 (m, 2H), 7.59-7.67 (m, 5H), 7.76-7.80 (m, 1H), 8.15-8.17 (m, 2H). 19 F NMR (CDCl 3 ): δ -143.8 (d, J = 27.5 Hz, 1F). 13 C NMR (CDCl 3 ): δ 0.1, 54.9, 55.3, 56.3, 64.4 (d, J = 16.8 Hz), 89.9, 91.0, 106.4, 118.2 (d, J = 291.3 Hz), 128.0, 128.5, 130.0 (d, J = 1.8 Hz), 130.9 (d, J = 1.4 Hz), 133.8, 134.2, 137.9, 139.1, 162.4. HRMS: calcd for C 23 H 24 FNO 8 S 2 + 511.0891 (M-TMS+H + ), found: 511.0886. M.p. (dec.) 142-143 °C. OTMS SO 2 Ph F SO 2 Ph O 2 N OTMS SO 2 Ph F SO 2 Ph MeO OMe OMe 122 (2-Fluoro-1-(naphthalen-1-yl)-2,2-bis(phenylsulfonyl)ethoxy)trimethylsilane (2e) 1 H NMR (CDCl 3 ): δ 0.11 (s, 9H), 6.80 (br s, 1H), 7.21-7.25 (m, 1H), 7.33-7.37 (m, 3H), 7.41-7.47 (m, 4H), 7.51-7.59 (m, 1H), 7.67-7.79 (m, 5H), 7.92-7.96 (m, 3H). 19 F NMR (CDCl 3 ): δ -132.0 (br s, 1F) (Two rotamers were observed in 19 F NMR spectrum. The major rotamer appeared as a broad singlet, wheares the minor one, partially overlapped with the major isomer, was shown to be a doublet at -132.1 ppm). 13 C NMR (CDCl 3 ): δ 0.2, 69.9 (br s), 115.7 (d, J = 274.1 Hz), 123.3, 124.8, 125.5, 126.4, 128.0, 128.5, 128.7, 128.8, 129.7, 131.0, 131.2, 131.5, 131.7, 133.3, 134.4, 135.0, 136.1, 138.6. HRMS: calcd for C 27 H 27 FNaO 5 S 2 Si + 565.0945 (M+Na + ), found: 565.0945. M.p. 154-155 °C. (E)-((1-Fluoro-4-phenyl-1,1-bis(phenylsulfonyl) but-3-en-2-yl)oxy)trimethylsilane (2g) 1 H NMR (CDCl 3 ): δ 0.00 (s, 9H), 5.37 (dd, J = 7.9 Hz, J = 4.9 Hz, 1H), 6.58-6.67 (m, 2H), 7.30-7.38 (m, 1H), 7.38-7.45 (m, 2H), 7.48-7.50 (m, 2H), 7.52-7.58 (m, 2H), 7.59- 7.67 (m, 2H), 7.68-7.74 (m, 1H), 7.74-7.82 (m, 1H), 7.93-7.96 (m, 1H), 8.13-8.16 (m, 2H). 19 F NMR (CDCl 3 ): δ -136.87 (d, J = 7.9 Hz, 1F). 13 C NMR (CDCl 3 ): δ 0.1, 73.7 (d, J = 21.0 Hz), 114.1 (d, J = 269.5 Hz), 123.7 (d, J = 4.4 Hz), 127.2, 128.4, 128.5, 128.6, 128.7, 131.3 (d, J = 1.5 Hz), 131.8 (d, J = 1.5 Hz), 134.8, 134.9 (d, J = 1.5 Hz), 135.1, OTMS SO 2 Ph F SO 2 Ph OTMS SO 2 Ph F SO 2 Ph Ph 123 136.2, 137.0, 137.9. HRMS: calcd for C 25 H 27 FNaO 5 S 2 Si + 541.0945 (M+Na + ), found: 541.0955. M.p. 135-136 °C. ((1-Fluoro-4-phenyl-1,1-bis(phenylsulfonyl)butan-2-yl)oxy)trimethylsilane (2h) 1 H NMR (CDCl 3 ): δ 0.00 (s, 9H), 2.57-2.72 (m, 1H), 2.75-2.83 (m, 1H), 2.86-2.97 (m, 1H), 3.00-3.12 (m, 1H), 2.71 (ddd, J = 10.2 Hz, J = 8.3 Hz, J = 1.9 Hz, 1H), 7.41-7.46 (m, 3H), 7.50-7.54 (m, 2H), 7.63-7.74 (m, 4H), 7.83-7.92 (m, 2H), 8.06-8.11 (m, 4H). 19 F NMR (CDCl 3 ): δ -135.34 (d, J = 8.3 Hz, 1F). 13 C NMR (CDCl 3 ): δ 0.1, 33.0 (d, J = 0.6 Hz), 33.5 (d, J = 3.2 Hz), 73.3 (d, J = 17.0 Hz), 114.7 (d, J = 266.3 Hz), 126.3, 128.6(1), 128.6(5), 128.7(9), 128.8(0), 131.4 (d, J = 1.4 Hz), 131.6 (d, J = 1.8 Hz), 134.8, 135.2, 136.3, 138.2, 140.8. HRMS: calcd for C 22 H 21 FNaO 5 S 2 + 471.0707 (M-TMS+Na + ), found: 471.0705. M.p. 137-140 °C. 5.4.3 Typical Procedure of Preparation of 3e from Reductive Desulfonylation To a solution of 2e (456 mg, 0.84 mmol) in acetic acid and DMF (1:1 v:v, 8 mL) was added Mg turnings (408 mg, 16.8 mmol, 20 equiv.) all at once. The reaction mixture was stirred at 0 °C for 4 h (monitored by 19 F NMR spectroscopy until the completion of the reaction). The resulting slurry was diluted with 20 mL water and washed with hexanes/ethyl acetate (1:1, 25×3 mL). The organic solution was then washed with water (20×2 mL) and dried over MgSO 4 . The solvent was removed under vacuum. The crude product was purified via silica gel column chromatography using ethyl acetate and OTMS SO 2 Ph F SO 2 Ph Ph 124 hexanes as eluent to obtain 3e as a white solid (two separated diastereomers, combined weight 207 mg, 74%). 2-Fluoro-1-(naphthalen-1-yl)-2-(phenylsulfonyl)ethanol (3e) 1 H NMR (CDCl 3 ): δ 5.29 (dd, J = 46.5, 8.8 Hz, 1H), 6.07-6.09 (m, 1H), 7.47-7.52 (m, 3H), 7.62-7.66 (m, 2H), 7.74-7.78 (m, 2H), 7.84-7.87 (m, 2H), 7.91-7.94 (m, 1H), 8.02- 8.05 (m, 2H). 19 F NMR (CDCl 3 ): δ -176.0 (d, J = 46.6 Hz, 1F). HRMS: calcd for C 18 H 15 FNaO 3 S + 353.0618 (M+Na + ), found: 353.0617. 1 H NMR (CDCl 3 ): δ 5.28 (dd, J = 46.1, 0.8 Hz, 1H), 6.51-6.57 (m, 1H), 7.50-7.55 (m, 2H), 7.59-7.62 (m, 3H), 7.71-7.74 (m, 1H), 7.83-7.86 (m, 2H), 7.90-7.92 (m, 1H), 8.00- 8.03 (m, 3H). 19 F NMR (CDCl 3 ): δ -196.3 (dd, J = 46.1, 23.4 Hz, 1F). HRMS: calcd for C 18 H 15 FNaO 3 S + 353.0618 (M+Na + ), found: 353.0622. 5.4.4 Typical Procedure of Preparation of 4e from Reductive Desulfonylation Under N 2 atmosphere, into a Schlenk flask containing 3e (207 mg, 0.62 mmol) and Na 2 HPO 4 (528 mg, 3.72 mmol, 6 equiv.) in anhydrous methanol (8 mL) at -20 o C, was added Na/Hg amalgam (10 wt% Na in Hg, net sodium content 90 mg, 3.72 mmol). The reaction mixture was stirred at -20 o C to 0 o C for 7h. The liquid phase was decanted, and the solid residue was washed with Et 2 O. The solid was then treated with elemental sulfur powder. The solvents were removed under vacuum, and 25 mL brine was added before extraction with Et 2 O (20×3 mL). The combined ether phase was dried over TMSO SO 2 Ph F 125 MgSO 4 , and the ether was removed to afford the crude product. The crude product was further purified via silica gel column chromatography using ethyl acetate and hexanes as eluent. 4e was obtained as a white solid (57 mg, 48%). 2-Fluoro-1-(naphthalen-1-yl)ethanol (4e) 1 H NMR (CDCl 3 ): δ 2.84-2.98 (m, 1H), 4.54 (ddd, J = 48.7, 9.8, 8.4 Hz, 1H), 4.71 (ddd, J = 48.6, 9.8, 2.8 Hz, 1H), 5.82 (ddt, J = 14.3, 8.4, 2.8 Hz, 1H), 7.76-7.72 (m, 4H), 7.83 (d, J = 8.2 Hz, 1H), 7.92-7.87 (m, 1H), 8.04 (d, J = 8.2 Hz, 1H). 13 C NMR (CDCl 3 ): δ 70.0 (d, J = 20.0 Hz), 87.0 (d, J = 174.8 Hz), 122.5, 124.3 (d, J = 1.3 Hz), 125.6, 125.9, 126.6, 129.0, 129.2, 130.5, 133.7 (d, J = 8.7 Hz), 133.8. 19 F NMR (CDCl 3 ): δ -221.3 (ddt, J = 48.6, 14.3, 4.9 Hz). HRMS: calcd for C 12 H 11 OF + 190.0794 (M + ), found: 190.0793. M.p. 96-99 °C. HO F 126 5.5 Chapter 5: Representative Spectra 1 H NMR spectrum of TFBSM 127 19 F NMR spectrum of TFBSM 128 1 H NMR spectrum of 2a 129 19 F NMR spectrum of 2a 130 13 C NMR spectrum of 2a 131 1 H NMR spectrum of 2e 132 19 F NMR spectrum of 2e 133 13 C NMR spectrum of 2e 134 1 H NMR spectrum of 3e 135 19 F NMR spectrum of 3e 136 1 H NMR spectrum of 4e 137 19 F NMR spectrum of 4e 138 5.6 Chapter 5: References 1 Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Wiley-VCH, Weinheim, Germany, 2004. 2 Uneyama, K. Organofluorine Chemistry, Blackwell, Oxford, 2006. 3 Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. 4 Muller, K; Faeh, C; Diederich, F. Science 2007, 317, 1881. 5 Prakash, G. K. S.; Hu, J. Acc. Chem. Res. 2007, 40, 921. 6 Hu, J. J. Fluorine Chem. 2009, 130, 1130. 7 Ni, C.; Hu, J. Synlett 2011, 770. 8 Ni, C.; Li, Y.; Hu, J. J. Org. Chem. 2006, 71, 6829. 9 Fukuzumi, T.; Shibata, N.; Sugiura, M.; Yasui, H.; Nakamura, S.; Toru, T. Angew. Chem. Int. Ed. 2006, 45, 4973. 10 Prakash, G. K. S.; Chacko, S.; Alconcel, S.; Stewart, T.; Mathew, T.; Olah, G. A. Angew. Chem. Int. Ed. 2007, 46, 4933. 11 Mizuta, S.; Shibata, N.; Goto, Y.; Furukawa, T.; Nakamura, S.; Toru, T. J. Am. Chem. Soc. 2007, 129, 6394. 12 Ni, C.; Zhang, L.; Hu, J. J. Org. Chem. 2008, 73, 5699 13 Prakash, G. K. S.; Zhao, X.; Chacko, S.; Wang, F.; Vaghoo, H.; Olah, G. A. Beilstein J. Org. Chem. 2008, 4, 17. 14 Furukawa, T.; Goto, Y.; Kawazoe, J.; Tokunaga, E.; Nakamura, S.; Yang, Y.; Du, H.; Kakehi, A.; Shiro, M.; Shibata, N. Angew. Chem. Int. Ed. 2010, 49, 1642. 15 Liu, J.; Ni, C.; Li, Y.; Zhang, L.; Wang, G.; Hu, J. Tetrahedron Lett. 2006, 47, 6753. 16 Shen, X.; Zhang, L.; Zhao, Y.; Zhu, L.; Li, G.; Hu, J. Angew. Chem. Int. Ed. 2011, 50, 2588. 17 Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc.1989, 111, 393. 18 Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757. 139 19 Ni, C.; Hu, J. Tetrahedron Lett. 2005, 46, 8273. 20 Liu, J.; Ni, C.; Wang, F.; Hu, J. Tetrahedron Lett. 2008, 49, 1605. 21 Prakash, G. K. S.; Wang, F.; Ni, C.; Thomas, T. J.; Olah, G. A. J. Fluorine Chem. 2010, 131, 1007. 22 Prakash, G. K. S.; Shao, N.; Wang, F.; Ni, C. Organic Syntheses 2013, 90, 130. 23 Inbasekaran, M.; Peet, N. P.; McCarthy, J. R.; LeTourneau, M. E. J. Chem. Soc., Chem. Commun. 1985, 678. 24 Olejniczak, A.; Katrusiak, A.; Vij, A. J. Fluorine Chem. 2008, 129, 1090. 25 Gaussian 03, Revision C.02, Frisch, M. J. Gaussian, Inc., Wallingford CT, 2004 26 Klatte, K.; Christen, D.; Merke, I.; Stahl, W.; Oberhammer, H. J. Phy. Chem. A 2005, 109, 8438. 27 Wiberg, K. B. Tetrahedron 1968, 24, 1083. 28 The present Wiberg bond indices of TMSCF3 and TMSCF2H are significantly higher than the previously reported values (0.436 and 0.220, respectively), which were obtained using the PM3 method. Hagiwara, T.; Fuchikami, T. Synlett 1995, 717. 29 Prakash, G. K. S.; Wang, F.; Shao, N.; Mathew, T.; Rasul, G.; Haiges, R.; Stewart, T.; Olah, G. A. Angew. Chem. Int. Ed. 2009, 48, 5358. 140 6 Chapter 6: Stereoselective Organocatalytic Conjugate Addition of α-Fluoro-α-nitro(phenylsulfonyl)methane to α-Nitroolefins: Mechanistic Studies and Synthetic Applications 6.1 Chapter 6: Introduction As mentioned before, fluoro-organics have been found to possess unique chemophysical and biological properties. 1, 2, 3 Many fluoro-organics, especially chiral molecules, have been widely used in medicinal chemistry, materials science and other important fields. In medicinal chemistry, the replacement of hydrogen, oxygen or hydroxyl group with fluorine or fluorine substituted group could result in significantly different physiological properties. 4 For example, anti-cancer agents such as dexamethasone and fluticasone propionate show better results than their non-fluorinated analogues. 5 (Figure 6.1) As of now, fluorinated drugs occupy around 20% of total pharmaceuticals in the market. 3 Therefore, the asymmetric synthesis of fluorinated molecules, mainly for the construction of the fluorine onto stereogenic carbon center, has attracted increasing attention. 6, 7 On the other hand, the construction of chiral fluorine containing molecules is considered a difficult task even though asymmetric synthesis of organics in catalytic fashion has been developed exceptionally well over the past few decades. 8 There are two strategies to introduce a chiral fluorinated carbon center: one is to directly construct a chiral carbon center by asymmetric fluorination; the second strategy is to form a C-C bond with a fluorine-bearing carbon atom, which has been extensively employed for the construction of fluorinated stereogenic centers in various applications. 9, 10, 11, 12, 13 141 O O OH HO H F CH 3 H S O O HO H F CH 3 H OH Dexamethasone F F O O Fluticasone propionate Figure 6.1 Dexamethasone and fluticasone propionate Organocatalysis emerges as a powerful tool in asymmetric synthesis as well as in green chemistry since it avoids the use of hazardous metal catalysts. 14, 15, 16, 17 In this field, aryl sulfone-based reagents have been employed for various types of organocatalyzed reactions, 18 , 19 since sulfonyl groups are highly electron withdrawing resulting in significant enhancement of the carbon acidity of the reagent. 20 Another advantage is that these sulfone-based compounds can lead to a wide range of enantiomerically available building blocks by removing the sulfone functionality through desulfonylation protocols. 21 In particular, the construction of chiral carbon-fluorine centers with aryl sulfones by using organocatalyst is of great interest. 22, 23 Shibata et al. previously showed the enantioselective reaction of α- fluorobis(phenylsulfonyl)methane (FBSM) with N-Boc-protected imines to generate α- amido sulfones. 24 Fluoromethylated products in low to high yields were synthesized after desulfonylation. FBSM was also used for fluoromethyl transfer to α,β-unsaturated aldehydes to obtain the corresponding 1,4-addition products in good to excellent yields and with high enantioselectivity. 25, 26, 27 Hu and coworkers reported the enantioselective organocatalyzed 1,2-addtion of α,α-difluoro(phenylsulfonyl)methane to aromatic 142 aldehydes under phase transfer conditions. 28 Prakash et al. showed a highly efficient 1,4- addition of racemic α-fluoro-α-nitro(phenylsulfonyl)methane (FNSM) to chalcones. 9 Using cinchona-based catalysts, corresponding fluorine-containing products were synthesized in high yields with excellent stereoselectivity. (Scheme 6.1) SO 2 Ph PhO 2 S F + R SO 2 Ph NHBoc R NHBoc F SO 2 Ph SO 2 Ph Catalyst (5 mol%) CsOH CH 2 Cl 2 Catalyst SO 2 Ph PhO 2 S F + R CHO Catalyst (20 mol%) toluene R CHO F SO 2 Ph PhO 2 S N Bn H N OH Cl N H Ph OTMS N H Ph OTBS or Ph Ph PhSO 2 CHF 2 + Ar O Catalyst (10 mol%) KOH toluene Ar OH CF 2 SO 2 Ph * N H N OH Br F 3 C SO 2 Ph O 2 N F Ar Ar' O + Catalyst (10 mol%) toluene PhO 2 S O Ar' Ar F NO 2 N H N OCH 3 NH NH S CF 3 F 3 C Scheme 6.1 Examples of enantioselective synthesis of fluorinated molecules The main concept discussed in this chapter is the stereoselective carbon-carbon bond formation between nitroalkanes and nitroolefins via hydrogen bonding mediated organocatalysis. Numerous cinchona-based bifunctional catalyst candidates were 143 previously screened for the organocatalyzed conjugate addition of FNSM to nitroolefins as in our current efforts to establish the fluorinated carbon center. 29 (Scheme 6.2) Other reaction parameters such as reaction media were also carefully adjusted in order to obtain the optimal reaction conditions. The reaction underwent smoothly to afford Michael addition product with excellent yields (>99%) in most cases, and the best enantioselectivity (57% ee.) was observed when IId was applied as the catalyst. 29 (Table 6.1) A number of nitroolefins with different functionalities were also investigated and the method was found to be widely acceptable for nitroolefins containing either electron- withdrawing or electron-donating substituted groups. 29 144 Ia Ib Ic Id N OH N N OH N N OH N H OMe OMe N OH N H OMe N NHR N IIa, IIIa N NHR N N NHR N H OMe OMe N NHR N H OMe IIb, IIIb NH S F 3 C F 3 C IIc, IIIc IId, IIId IIa-IId, R = HIIIa-IIId, R = N NH N OMe N H S N NH N OMe N H S F F IV V VI CF 3 N NH N OMe N H O CF 3 HN Ph NH Ph S HN S Me 2 N O O CF 3 CF 3 NH 2 N H N NMe 2 N H S N H N NMe 2 VII VIII NH 2 NH 2 IX H N HN S Me 2 N CF 3 CF 3 X XI N H CF 3 CF 3 S NO 2 Ph O O F Ph NO 2 cat. 10 mol % PhSO 2 Ph Toluene + Rac F O 2 N NO 2 12h H PhSO 2 H F O 2 N NO 2 Ph + FNSM Scheme 6.2 Bifunctional organocatalysts of the asymmetric conjugate addition between FNSM and nitroolefins 29 145 Table 6.1 Catalyst screening of asymmetric conjugate addition reaction of FNSM to nitroolefins Entry Catalyst Yield% a d.r. b ee% c 1 2 3 4 5 6 7 8 >99 38:62 8 >99 41:59 9 >99 40:60 8 >99 28:72 7 >99 >99 >99 22 10 34:66 0 >99 26:74 57 Id IIa IIb IIc IId Ic 9 IIIa 3 22:78 96 a. 19 F NMR yield; b. Determined by 19 F NMR; c. Determined by chiral HPLC; d. Defluorination of V was observed; e. 5 mol% catalyst was used. (3a') Ia Ib 10 11 12 13 14 15 16 17 95 22:78 -5 91 20:80 4 95 23:77 6 97 26:74 14 97 96 >99 24:76 25 21:79 -15 28:72 5 >99 19:81 23 VII VIII IIId 18 IX e 46 15:85 94 IIIb IIIc IV V d VI 19 >99 44:56 37 X 20 XI 31 43:57 94 S NO 2 Ph O O F Ph NO 2 cat. 10 mol % PhSO 2 Ph 1.5 eq Toluene + 1.0 eq Rac 1 2a 3a F O 2 N NO 2 (3a:3a') 38:62 37:63 12h H PhSO 2 H 3a' F O 2 N NO 2 Ph + In this chapter, an extensive and systematic study of this synthetic methodology for the asymmetric organocatalyst-mediated conjugate addition of FNSM to nitroolefins 146 is disclosed. The kinetic study, theoretical calculations along with the investigation of the reaction mechanism are also included. 6.2 Chapter 6: Results and Discussion Previous study 29 on the conjugate addition of FNSM to nitroolefins showed that the catalyst IId led to the highest enantioselectivity observed. In the presence of catalytic amount of IId, solvents have significant impact on the enantioselectivity and the diastereoselectivity of the reaction without any noticeable variation in the yields. Extensive studies included various catalyst loadings and different proportions of the substances. 30 In general, the optimal molar ratio of FNSM, β-nitrostyrene (2a) and IId were found to be 1 : 1.5 0.1. Further investigation for the addition reaction at different temperature was carried on with IId in toluene, CDCl 3 and CH 2 Cl 2 as the solvent medium. (Table 6.2) The reaction temperatures spanned from -70 o C up to 100 o C. There were no positive improvements for the stereoselectivity even by lowering the temperature since ee% range of the major diastereomer 3a’ was from 18 to 55. 147 Table 6.2 Temperature effects on reactions of FNSM with nitroolefin PhSO 2 Ph 3a F O 2 N NO 2 H PhSO 2 H 3a' F O 2 N NO 2 Ph + Entry d.r. a (3a:3a') ee% b (3a) S NO 2 Ph O O F Ph NO 2 IId 10 mol % Solvent, Temp. + Rac 1 2a Temp. (K) toluene ee% b (3a') Temp. ( o C) 1 203 -70 35:65 18 27 2 223 -50 35:65 5 27 3 253 -20 25:75 - 35 4 273 0 25:75 3 45 5 298 25 25:75 16 55 7 333 60 27:73 11 44 8 353 80 27:73 10 39 6 313 40 27:73 12 50 9 373 100 27:73 2 30 a. Determined by 19F NMR; b. Determined by chiral HPLC Entry d.r. a (3a:3a') ee% b (3a) Temp. (K) ee% b (3a') Temp. ( o C) 1 203 -70 65:35 0 20 2 223 -50 60:40 4 18 3 253 -20 61:39 - 36 4 273 0 63:37 2 33 5 298 25 63:37 2 40 CDCl 3 Entry d.r. a (3a:3a') ee% b (3a) Temp. (K) ee% b (3a') Temp. ( o C) 1 203 -70 53:47 - - 2 223 -50 53:47 0 26 3 253 -20 47:53 1 26 4 273 0 45:55 2 24 5 298 25 46:54 3 28 CH 2 Cl 2 148 After an extensive and thorough investigation of various reaction conditions, the enantioselectivity of the product such as 3a’ could not go higher than 57% ee indicating only moderate stereoselectivity. Next, we focused on the experimental and theoretical investigation to understand the mechanistic aspects of organocatalytic protocol of FNSM addition to a nitroolefin. 19 F nuclear magnetic resonance (NMR) spectroscopy was utilized in the experimental mechanistic study to evaluate the conversion of the starting material (FNSM) to products (3a and 3a’) versus reaction time. A series of 19 F NMR monitored experiments were conducted in order to analyze the kinetic nature for the organocatalytic conjugate addition between FNSM and 2. Different molar ratios of FNSM and 2 (4:1, 2:1, 1:1, 1:2, 1:4) were first utilized in the study and the addition reaction promoted by 10% IId was found to exhibit a first order dependence on both reactants. 31 Reaction rate law of catalyst IId was determined in the NMR kinetic analysis with equal molar amount (0.05 mmol : 0.05 mmol) of starting materials. The catalyst loadings were from 2% to 20% and all reactions were performed at 0 o C in 0.6 mL toluene. The reaction was monitored by 19 F NMR and conversions of FNSM were recorded at each time points. Table 6.3 shows as an example for conversion recorded with each time point along with other data points needed for further calculation such as the concentration of the starting material and its reciprocal value when 5 mol% (0.0025 mmol) of IId was initially added to the reaction mixture. 149 Table 6.3 Data sample for kinetic analysis of reaction of FNSM to nitroolefins S NO 2 Ph O O F Ph NO 2 catalyst PhSO 2 Ph + FNSM 2 3 F O 2 N NO 2 H PhSO 2 H 3' F O 2 N NO 2 Ph + solvent temperature 0.1 mmol 0.1 mmol Catalyst loading 5% IId 0.6 mL toluene 0 o C = 273K time conversion Conc of SM 1/[SM] (s) (%) (M) (1/M) 180 3.38 0.08048 12.4248 300 5.48 0.07874 12.7008 600 9.51 0.07538 13.2664 900 13.08 0.07240 13.8113 1200 16.16 0.06984 14.3187 1800 21.36 0.06551 15.2655 As shown in Figure 6.2, first order rate law was also applied for all the cases of IId at 0 o C with different catalyst loadings since linear fit values of R 2 were all in good ranges. (Figure 6.2) The calculated reaction rate constant (k) increased linearly with the catalyst loading amount when other reaction parameters, such as the proportion of starting materials, reaction temperature, solvent media and solvent volume remained constant. (Figure 6.3) However, chiral HPLC tests indicated that enantiomeric excess slightly decreased when more than 15 mol% of catalyst IId was added. 31 Additional catalyst loading tests were performed with different solvent medium (CD 3 Cl, CH 2 Cl 2 ) at different reaction temperatures. Similar rate law was found in all cases, which indicated that catalyst IId obeyed first order rate law in the organocatalytic reaction of FNSM addition to a nitroolefin. 150 S NO 2 Ph O O F Ph NO 2 catalyst PhSO 2 Ph + FNSM 2 3 F O 2 N NO 2 H PhSO 2 H 3' F O 2 N NO 2 Ph + 0.6 mL toluene 0 o C 0.1 mmol 0.1 mmol y = 6.2614E-04x + 1.2109E+01 R² = 9.8607E-01 0 2 4 6 8 10 12 14 16 0 500 1000 1500 2000 2500 3000 conc of SM (M -1 ) time (s) 2% IId y = 1.7474E-03x + 1.2181E+01 R² = 9.9732E-01 0 5 10 15 20 25 0 500 1000 1500 2000 conc of SM (M -1 ) time (s) 5% IId 10% 15% 20% IId IId IId y = 5.1791E-03x + 1.2282E+01 R² = 9.9944E-01 0 5 10 15 20 25 0 500 1000 1500 2000 conc of SM (M -1 ) time (s) y = 3.9034E-03x + 1.2842E+01 R² = 9.9370E-01 0 5 10 15 20 25 30 0 1000 2000 3000 4000 conc of SM (M -1 ) time (s) y = 7.8061E-03x + 1.2319E+01 R² = 9.9829E-01 0 5 10 15 20 25 0 500 1000 1500 conc of SM (M -1 ) time (s) catalyst loading 2% 5% 10% 15% 20% rate constant 6.26 1.75 3.90 5.18 7.86 x10 x10 x10 x10 x10 -4 -3 -3 -3 -3 R 2 0.986 0.997 0.994 0.999 0.998 Figure 6.2 Reaction rate constants for different amount of catalyst loadings 151 y = 0.0387x - 0.0002 R² = 0.99052 0.00E+00 2.00E-03 4.00E-03 6.00E-03 8.00E-03 1.00E-02 1.20E-02 1.40E-02 0% 5% 10% 15% 20% 25% 30% 35% Rate Cat Loading Cat Loading vs Rate Figure 6.3 Catalyst loadings vs rate in toluene at 0 o C A series of NMR experiments along with chiral HPLC characterizations were performed in order to discover the relationship among the reaction temperatures, solvent media, reaction rate constants, and enantiomeric ratios (er). As shown in Figure 6.4, two types of results were recorded and calculated using the Eyring plot: 1) ln(k/T) vs 1/T: In the first case, two opposite trends were observed. The ln(k/T) increased linearly to reach the local maximum at 20 o C (1/T = 1/293 K -1 ); then decreased linearly. In other words, ln(k/T) increased linearly between the temperature interval [-60 o C, 20 o C] and decreased linearly in the [20 o C, 80 o C] range. 2) ln(er) vs 1/T: A similar plot was observed in the second case in which ln(er) increased linearly from [-60 o C, 20 o C] and decreased linearly from [20 o C, 80 o C]. The calculated reaction enthalpy (ΔH), entropy (ΔS), free Gibbs energy (ΔG) and other thermodynamic constants are listed in Table 6.4. In particular, the ΔG was found to be significantly impacted by the ΔS (entropy controlled) over a large temperature range, implying that the ground states of the current reaction involve a combination of various structures. 152 3a 3a' PhO 2 S NO 2 F Ph NO 2 IId (10 mol%) Toluene, temp. + FNSM 2a 12h + 1 equiv. 1 equiv. Figure 6.4 Normalized Eyring plot (10 mol% IId, in toluene) Table 6.4 Thermodynamics and kinetics of addition FNSM to 2a with IId in toluene r = k[cat] 1 [FNSM] 1 [olefin] 1 ΔH ΔS ΔΔH ΔΔS 293-323 K 216-293 K -4.72 kcal/mol +3.13 kcal/mol -86 cal/(mol K) -59 cal/(mol K) -1.23 kcal/mol +1.78 kcal/mol -2.1 cal/(mol K) +8.5 cal/(mol K) ΔG +(20.2~22.7) kcal/mol +(15.9~20.4) kcal/mol ΔΔG -(0.55~0.61) kcal/mol -(0.06~0.71) kcal/mol 3a 3a' PhO 2 S NO 2 F Ph NO 2 IId (10 mol%) Toluene, temp. + FNSM 2a 12h + 1 equiv. 1 equiv. 153 We also explored the kinetics of the reaction in CDCl 3 (ln(er) vs 1/T). Unlike the other cases, results indicated that ln(er) decreased linearly from -60 o C to 20 o C and increased linearly from 20 o C to 80 o C. (Figure 6.5) 3a 3a' PhO 2 S NO 2 F Ph NO 2 IId (10 mol%) CDCl 3 , temp. + FNSM 2a 12h + 1 equiv. 1 equiv. Figure 6.5 Eyring plot (10 mol% IId, in CDCl 3 ) Intrigued by above mentioned results, it was necessary to reinvestigate and add more catalysts (Figure 6.6) into the mechanistic analysis in order to compare the result of IId. Toluene was selected as a solvent in these reactions based on previous screening result and for overall consistency. 154 HN Ph NH Ph S HN S Me 2 N O O CF 3 CF 3 IX N NH 2 CH 3 CH 3 VIII H N HN S Me 2 N CF 3 CF 3 NH 2 NH 2 XII XIII NHCH 3 NHCH 3 XIV Figure 6.6 Expanded catalyst list 3a 3a' PhO 2 S NO 2 F Ph NO 2 IX (10 mol%) Toluene, temp. + FNSM 2a 12h + 1 equiv. 1 equiv. Figure 6.7 Eyring plot (10 mol% IX, in toluene) Interestingly, the adduct was obtained with very low er value when catalysts VIII, XII, XIII, and XIV were employed. However, when catalyst IX was used in the mechanism study, there was only one simple trend obtained from the ln(er) vs 1/T diagram (Figure 6.7): ln(er) decreased linearly as 1/T increased; in other words, ln(er) 155 increased as temperature raised in the same fashion. This suggested that there was one mechanism working in the IX catalytic reaction during the tested temperature region. (Figure 6.7) On the other hand, there could be more than one mechanism operating over different temperature ranges with regard to IId, correspondingly. In addition, solvent played a special role in this type of reaction, which led to contradicting Eyring plot results. (Figure 6.4, Figure 6.5) Kinetic study revealed that the present reaction proceeds under various mechanistic pathways at different temperatures. Papai and coworkers 32 investigated the mechanism of enantioselective Michael addition of acetylacetone to a nitroolefin catalyzed by a thiourea-based chiral bifunctional organocatalyst (Figure 6.8). Two distinct reaction pathways have been suggested toward the formation of the Michael product (Figure 6.8). In particular, reaction intermediates were stabilized via extensive H-bonded network in the transition states. The C 1 symmetry geometry of the catalyst possibly led to different stereoisomers, which also had impacts of the enantioselectivity of the Michael adduct 3a’. 156 N N ∗ ∗ C 2 Symmetry N N ∗ ∗ C 1 Symmetry N N N + O - O Ar H N + S F O Ph O O - H O N N H N + S F O Ph O O - H O N O O Two Possible Reaction Pathways Resembling the Previously Proposed Transition States on Thio-based Bifunctional Organocatalytic Reaction by Papai et. al. N S N Ar N + H H H N O - O Ar O O Energetically Favorable TS v.s. N S N Ar N + H H H Energetically Unfavorable TS v.s. N + O - O Ar O O Ar Possible Reaction Pathways on Michael Addition of FNSM to Nitroolefin via Bifunctional Organocatalytic Routes Figure 6.8 Suggested reaction pathways by chiral bifunctional organocatalyst Such low stereoselectivity of the organocatalytic Michael addition of FNSM to nitroolefin was initially attributed to the relatively high inversion barriers between the R- and S-FNSM anions or enolate-like species, which possibly impede the dynamic kinetic resolution process which has been discussed on the asymmetric conjugate addition of racemic FNSM to chalcone. 9 Nonetheless, the high-level quantum mechanics study (at the B3LYP/6-311+G(2d,p) level) has revealed that there are two possible pathways for 157 the interconversion between R- and S-FNSM: 1) 6.4 kcal/mol transition energy in gas phase through enolic pathway; 2) 5.7 kcal/mol barrier through anionic pathway between R-anion and S-FNSM indicating a rapid equilibrium of the two anions under reaction conditions. 29 (Figure 6.9) Figure 6.9 Interconversion between (R)-FNSM and (S)-FNSM The conformational flexibility of the catalyst could also influence the result in the observed low stereoselectivity. This was presumably due to the lack of conformational order in the transition state structures of the catalyst. Computational and NMR spectroscopic studies showed that the conformations of cinchona alkaloid scaffolds 158 possessed less thermodynamic and kinetic stability than the N1,N1-dimethylcyclohexane- 1,2-diamine framework, which, however, led to less stereoselectivity. 31 (Figure 6.10) N N CH 3 CH 3 H H +0.37 N N CH 3 CH 3 H H +0.0 N H H N H 3 C CH 3 N N H H CH 3 CH 3 +5.87 +4.52 +7.24 N H H H 3 C CH 3 +8.66 N N H H H 3 C CH 3 N H H N H H +14.15 +2.99 N N CH 3 CH 3 H H N H H N H 3 C CH 3 +10.79 E (kcal/mol) Conformational Profile at the B3LYP/6-31G+(2d,p) level The 3 J a-b has been measured to be 10.1 Hz in CDCl 3 indicating an ideal trans-geometry, which is highly consistent with the computational study. NMe 2 NH 2 H a H b Figure 6.10 The conformational profile of N1,N1- dimethylcyclohexane-1,2-diamine framework 6.3 Chapter 6: Conclusion In conclusion, we have made a detailed investigation on the conjugate addition of FNSM to nitroolefins mediated by organocatalysts via hydrogen bonding interactions. In spite of our extensive investigation for adjusting reaction condition parameters accordingly, only low to moderate stereoselectivities were achieved. The mechanistic study has revealed that the reaction de facto undergoes by several pathways at different temperatures. 159 6.4 Chapter 6: Experimental Unless otherwise mentioned, all other reagents were purchased from commercial sources. Catalysts I-XIV were prepared according to the reported procedure. 9 Column chromatography was performed using silica gel (60-200 mesh). Analytical thin-layer chromatography (TLC) was performed on precoated, glass-backed silica gel. 1 H, 13 C and 19 F NMR spectra were recorded on 400 MHz Varian NMR spectrometer. 1 H NMR chemical shifts were determined relative to (CH 3 ) 4 Si (TMS) as the internal standard at δ 0.0 or to the signal of a residual protonated solvent CDCl 3 as the internal standard at δ 7.26. 13 C NMR chemical shifts were determined relative to TMS as the internal standard at δ 0.0 or to the 13 C signal of solvent CDCl 3 as the internal standard at δ 77.16. 19 F NMR chemical shifts were determined relative to CFCl 3 as the internal standard at δ 0.0. HPLC analysis was carried out on ChiralCel OD-H or ChiralPak AD-H columns. 6.4.1 Typical Procedure for Catalytic Enantioselective Conjugate Addition of α- Fluoro-α-nitro(phenylsulfonyl)methane (FNSM) to Nitroolefins S NO 2 Ph O O F Ph NO 2 IId 10 mol % PhSO 2 Ph 1.5 eq Toluene + 1.0 eq F O 2 N NO 2 H PhSO 2 H F O 2 N NO 2 Ph + To a solution of α-fluoro-α-nitro(phenylsulfonyl)methane (21.9 mg, 0.1 mmol, 1 equivalent) and β-nitrostyrene (0.15 mmol, 1.5 equivalent) in toluene (0.5 mL), catalyst IId was added (3.2 mg 0.01 mmol, 10 mol%) in one load. The reaction mixture was monitored by 19 F NMR for conversion and diastereoselectivity, and purified by flash column chromatography to produce the title product in good to excellent yield. 160 6.4.2 Typical Procedure of NMR and Chiral HPLC Kinetic Analysis for Catalytic Enantioselective Conjugate Addition of FNSM to Nitroolefins To a solution of FNSM (10.95 mg, 0.05 mmol, 1 equivalent) and β-nitrostyrene (7.45 mg, 0.05 mmol, 1 equivalent) in toluene (0.6 mL), catalyst IId was added (1.6 mg 0.005 mmol, 10 mol%) in one load and transferred to a NMR tube immediately. The conversion of FNSM was monitored by 19 F NMR spectroscopy at VT mode and recorded at each time point. Completed reaction mixture was subjected to flash column chromatography to afford purified set of diastereomer compounds 3a and 3a’. Then enatiomeric ratio was determined by the chiral HPLC method. 6.4.3 Determination of Thermodynamic Parameters for Catalytic Enantioselective Conjugate Addition of FNSM to Nitroolefins 31 The calculated reaction enthalpy (ΔH), entropy (ΔS), free Gibbs energy (ΔG) and other thermodynamic constants listed in Table 6.4 were defined and determined by the following method. (Scheme 6.3) 161 r = k [cat] 1 [FNSM] 1 [nitroolefin] 1 k 1 /k 2 = er (major diastereomers) (k 1 +k 2 )/(k 3 +k 4 ) = dr (major: minor) k total = k 1 (1 + 1/er) x (1 + 1/dr) ln(k total /T) = ln[k 1 (1 + 1/er) x (1 + 1/dr)] = lnk 1 + ln[(1 + 1/er) x (1 + 1/dr) = ΔH 1 /RT + ΔS 1 /R + ln(k b /h) Eyring Plot ln(k/T) = (-ΔH/R)x(1/T)+ln(k B /h) + ΔS/R ln(k B /h) = 23.76 J/mol R = 1.985 cal/mol S NO 2 Ph O O F Ph NO 2 catalyst PhSO 2 Ph + FNSM 2 3 F O 2 N NO 2 H PhSO 2 H 3' F O 2 N NO 2 Ph + sovlent Scheme 6.3 Calculation of Eyring plot and determination of reaction enthalpy, entropy, free Gibbs energy and other thermodynamic constants 162 6.5 Chapter 6: Representative Spectra HPLC spectrum of 3a 163 HPLC spectrum of 3a’ 164 NMR kinetic analysis profile ( 19 F NMR spectrum) 165 6.6 Chapter 6: References 1 Hiyama, T. Organofluorine Compounds: Chemistry and Applications; Springer, Heidelberg, 2000. 2 Banks, R. E.; Smart, B. E.; Tatlow, J. C. 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Abstract (if available)
Abstract
This dissertation focuses the development of new methodologies for nucleophilic fluoromethylation and selective desulfonylation. It also describes the large-scale synthesis of sulfone-based nucleophilic fluoromethylating reagents. In addition, the stereoselective construction of fluorine bearing chiral carbon centers has also been explored. ❧ Chapter 1 makes a general overview of organofluorine chemistry. It is mostly focused on the applications of organofluorine compounds and developments of the methodologies of fluorination and fluoroalkylation. ❧ Chapter 2 describes an efficient fluoromethylation protocol by using α- fluorobis(phenylsulfonyl)methane as the fluoromethylating reagent. This type of reaction is found to be very effective on primary and secondary halides under mild reaction conditions and the corresponding products can undergo reductive desulfonylation selectively. ❧ Chapter 3 discusses the result of NMR and computational study of a persistent α-fluorocarbanion. Unlike its non-fluorinated species, α-fluorocarbanion possesses its unique properties in NMR and X-ray crystallographic studies which is also supported by high level calculation. ❧ Chapter 4 includes the practically efficient large-scale synthesis of α- fluorobis(phenylsulfonyl)methane (FBSM). This improved six-step method affords FBSM with high yield and purity without any sophisticated purification process. ❧ Chapter 5 describes the facile synthesis of α-monofluoromethyl alcohols using α-trimethylsilyl-α-fluorobis(phenylsulfonyl)methane (TFBSM) as a fluoromethylating reagent. Functioning as both a pronucleophile and a Lewis acid, the reagent allows the one-step addition of the FBSM anion toward various aldehydes via a self-quenching mechanism. ❧ Chapter 6 explores stereoselective organocatalytic conjugate addition of α-fluoro-α-nitro(phenylsulfonyl)methane (FNSM) to α-nitroolefins. It also includes the kinetic study and the theoretical calculation of the organocatalytic reaction along with investigation of the reaction mechanism.
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Creator
Shao, Nan
(author)
Core Title
Development of sulfone-based nucleophilic fluoromethylating reagents and related methodologies
School
College of Letters, Arts and Sciences
Degree
Doctor of Philosophy
Degree Program
Chemistry
Publication Date
04/23/2013
Defense Date
03/18/2013
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carbanion,desulfonylation,fluoroalkylation,fluoromethylation,nucleophilic,OAI-PMH Harvest,organofluorine chemistry
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English
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Prakash, G. K. Surya (
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), Olah, George A. (
committee member
), Shing, Katherine (
committee member
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nathanshao@live.com,nshao@usc.edu
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Tags
carbanion
desulfonylation
fluoroalkylation
fluoromethylation
nucleophilic
organofluorine chemistry