Selective Nucleophilic Fluoroalkylations Facilitated by Removable Activation Groups

Abstract

Selective incorporation of fluorine atoms or fluorine-containingmoieties into organic molecules has become a routine and powerfulstrategy in drug design and new functional-material development.Nucleophilic fluoroalkylation, typically involving the transferof a fluorinated carbanion or carbanion equivalent to an electrophile,is one of the most important and frequently used methods to synthesizefluorinated organic molecules. In this Account, we introduce somerecent achievements in the field of nucleophilic di- and monofluoroalkylationchemistry with functionalized fluoroalkylation reagents. In particular,the effect of fluorine substitution on the reactivity of carbanionsis discussed, and several strategies for improving nucleophilicfluoroalkylations are proposed and successfully applied in variousnew nucleophilic fluoroalkylation reactions. It was found that attachinga removable activation group (such as the phenylsulfonyl group)to a fluorinated carbanion is an important approach to improve thelatter's reactivity. 1 Introduction 2 The Fluorine Effect in Nucleophilic Fluoroalkylation Reactions 2.1 Unique Properties of Fluorinated Carbanions 2.2 Factors Influencing the Reactivity of Fluorinated Carbanionstowards the Electrophiles 2.3 Possible Strategies to Improve the Nucleophilic Fluoroalkylations 3 Nucleophilic Di- and Monofluoroalkylation Reactions 3.1 Nucleophilic Difluoromethylation with PhSO 2 CF 2 Hand Related Reagents 3.2 Transformations of (Phenylsulfonyl)difluoromethylated Compounds 3.3 Nucleophilic Difluoromethylation with TMSCF 2 SPhand Related Reagents 3.4 Nucleophilic Phosphoryldifluoromethylation Reactions 3.5 Nucleophilic Monofluoromethylation with PhSO 2 CH 2 F Reagent 3.6 Nucleophilic Monofluoromethylation with α-FunctionalizedFluoro(phenylsulfonyl)methanes 3.7 Synthesis of Fluorinated Alkenes with Fluorinated Sulfoximinesand Heteroaryl Sulfones 3.8 Catalytic Asymmetric Fluoroalkylation Reactions 4 Concluding Remarks