Nucleophilic fluoromethylation of aldehydes with fluorobis(phenylsulfonyl)methane: the importance of strong Li-O coordination and fluorine substitution for C-C bond formation.

Recently, the selective introduction of fluorinated moieties into organic molecules with a-fluorinated carbanions has attracted substantial interest in organic synthesis, owing to the increasingly important applications of selectively fluorinated organics in life and materials sciences. In particular, a-fluoro(phenylsulfonyl)methane (FSM) derivatives, such as difluoromethyl phenyl sulfone (PhSO2CF2H), fluoromethyl phenyl sulfone (PhSO2CH2F), and fluorobis(phenylsulfonyl)methane (FBSM), have been extensively studied as excellent precursors of a-fluorinated carbanions for nucleophilic diand monofluoromethylations. In this context, FBSM, a reagent independently reported by Shibata et al. and our group in 2006, 4] has been widely recognized as a robust nucleophilic monofluoromethylating agent for many applications, including catalytic enantioselective monofluoromethylation reactions. However, although FBSM reacts with a great variety of electrophiles, its nucleophilic addition reaction with aldehydes still remains a challenge. Very recently, Shibata et al. reported that “FBSM failed to undergo nucleophilic addition to aldehydes regardless of the reaction conditions, leading instead to starting materials by a retro-type reaction”, and they also reasoned that “this behavior presumably results from the instability of the resulting b-hydroxy-a-fluorobis(phenylsulfonyl)methanes caused by the steric hindrance of the two phenylsulfonyl groups” (Scheme 1). Prompted by their report, herein we wish to disclose our remarkable success in the efficient nucleophilic addition of FBSM to aldehydes. Our study shows that both the strong Li–O coordination at low temperatures and fluorine substitution play very important roles in the successful nucleophilic addition of FBSM to aldehydes, which provides new intriguing insights into the nucleophilic fluoroalkylation reactions with a-fluorinated carbanions. The nucleophilic addition reaction of FBSM to aldehydes was tested by using benzaldehyde (1a) as a model substrate (Table 1). When lithium hexamethyldisilazide (LiHMDS)