Practical Synthesis of 4‐Fluoro‐2‐(methylthio)benzylamine and the Corresponding Sulfone and Sulfonamide

Abstract

Practical syntheses of 4‐fluoro‐2‐(methylthio)benzylamine 1 and the corresponding 2‐methylsulfonyl analog 2 are reported. The methylthio moiety was introduced regioselectively by two methods. In the first method, metallation of 4‐fluoro‐2‐bromobenzoic acid, followed by treatment with dimethyl disulfide resulted in an easily isolated intermediate, which was suitable for further elaboration to the benzylamine 1. In the second method, selective nucleophilic aromatic substitution of 2,4‐difluorobenzonitrile with methanethiolate was explored, and a mechanistic rationale was offered for solvent effects on regioselectivity. Optimized conditions furnished the key 4‐fluoro‐2‐(methylthio)benzonitrile for further functionalization to the 2‐methylsulfonyl‐4‐fluorobenzylamine 2. In addition, the analogous sulfonamide 3 was prepared in a straightforward manner from 5‐fluoro‐2‐methylbenzenesulfonyl chloride.

Keywords:

• lithiation
• nucleophilic aromatic substitution
• sulfonamide
• sulfone
• thiol

Acknowledgments

The authors thank Charles W. Ross and Art Coddington for high‐resolution mass spectrometry analysis and Steven Pitzenberger and Sandor Varga for NMR determinations. Thanks are also extended to Peter D. Williams and Donnette D. Staas for helpful discussion and Joseph P. Vacca and Steven D. Young for their support.