Selective Nucleophilic Fluoroalkylations Facilitated by Removable Activation Groups

Abstract

Selective incorporation of fluorine atoms or fluorine-containing moieties into organic molecules has become a routine and powerful strategy in drug design and new functional-material development. Nucleophilic fluoroalkylation, typically involving the transfer of a fluorinated carbanion or carbanion equivalent to an electrophile, is one of the most important and frequently used methods to synthesize fluorinated organic molecules. In this Account, we introduce some recent achievements in the field of nucleophilic di- and monofluoroalkylation chemistry with functionalized fluoroalkylation reagents. In particular, the effect of fluorine substitution on the reactivity of carbanions is discussed, and several strategies for improving nucleophilic fluoroalkylations are proposed and successfully applied in various new nucleophilic fluoroalkylation reactions. It was found that attaching a removable activation group (such as the phenylsulfonyl group) to a fluorinated carbanion is an important approach to improve the latter’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 Carbanions towards the Electrophiles

2.3 Possible Strategies to Improve the Nucleophilic Fluoroalkylations

3 Nucleophilic Di- and Monofluoroalkylation Reactions

3.1 Nucleophilic Difluoromethylation with PhSO₂CF₂H and Related Reagents

3.2 Transformations of (Phenylsulfonyl)difluoromethylated Compounds

3.3 Nucleophilic Difluoromethylation with TMSCF₂SPh and Related Reagents

3.4 Nucleophilic Phosphoryldifluoromethylation Reactions

3.5 Nucleophilic Monofluoromethylation with PhSO₂CH₂F Reagent

3.6 Nucleophilic Monofluoromethylation with α-Functionalized Fluoro(phenylsulfonyl)methanes

3.7 Synthesis of Fluorinated Alkenes with Fluorinated Sulfoximines and Heteroaryl Sulfones

3.8 Catalytic Asymmetric Fluoroalkylation Reactions

4 Concluding Remarks

Key words

fluorine - nucleophilic fluoroalkylation - activation group - sulfone - fluorine effect

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A SciFinder search (October, 2010) revealed >4,000,000 structures containing at least one C-F bond and >7,200,000 structures containing at least one C-X (X = F, Cl, Br, I) bond.