Efficient Difluoromethylation of sp3 Carbon Nucleophiles by Bromodifluoromethylation Reagents with Organic Bases

Introduction of a difluoromethyl (CF2H) unit into organic molecules is of specific interest in medicinal chemistry and chemical biology, as compounds with a CF2H moiety can act as an isostere to molecules having a methanol (CH2OH) unit with improved lipophilicity. Among several strategies for the synthesis of CF2H compounds available, a late-stage difluoromethylation using easy-to-handle reagents under mild conditions is principally advantageous for the synthesis of complex molecules. 9f] Transferring a CF2H group from a reagent to a target molecule is key for the reaction, and the reagents are classified according to their nucleophilic, radical, or electrophilic character. Electrophilic difluoromethylation through difluorocarbene species has attracted considerable attention, and several methods have been reported. j, l] Although the difluoromethylation of heteroatom-centered nucleophiles such as oxygen, sulfur and nitrogen nucleophiles is well studied, j, l] mild and efficient difluoromethylation methods for carbon-centered nucleophiles are relatively scarce. k–m,12d] In 2007, Prakash and co-workers developed a new electrophilic difluoromethylating reagent, S-(difluoromethyl)diarylsulfonium tetrafluoroborate. This reagent is effective for the introduction of a CF2H group into a wide range of heteroatom-centered nucleophiles, but it failed to transfer to carbon nucleophiles. Besides, they point out the drawback of S-(difluoromethyl)diarylsulfonium tetrafluoroborate being its slow decomposition over time even at low temperatures. Lately, Prakash group designed a novel electrophilic difluoromethylating protocol employing in situ prepared N,N-dimethyl-S-difluoromethyl-S-phenylsulfoximinium salt as a robust electrophilic difluoromethylating reagent. The reagent has exhibited good reactivity toward a broad scope of nucleophiles (N, P, S, and O nucleophiles), but no example was shown for carbon nucleophiles. N-Tosyl-S-difluoromethyl-S-phenylsulfoximine, which was developed as a difluorocarbene precursor by Hu and co-workers in 2009, is effective for transferring a CF2H group to both heteroatom and carbon nucleophiles. However, for carbon nucleophiles, only a limited number of phenylacetylene derivatives was examined as substrates for difluoromethylation. As part of our research program towards the enantioselective synthesis of biologically attractive fluoro-organic compounds, we required electrophilic difluoromethylation reagents reactive enough for sp carbon nucleophiles, which provide the CF2H compounds with an asymmetric carbon center. In 2010, Xiao et al. for the first time reported symmetrical S-(bromodifluoromethyl)diphenylsulfonium salts. Recently, we reported the efficient synthesis of a series of unsymmetrical S-(bromodifluoromethyl)diarylsulfonium salts 1 which are effective for electrophilic bromodifluoromethylation (CF2Br) of terminal alkynes in response to nBuLi. We disclose herein that the same regents 1 can be used as electrophilic difluoromethylation reagents for sp carbon nucleophiles mediated by organic bases (Scheme 1). Al-