A General, One-Pot Method for the Synthesis of Sulfinic Acids from Methyl Sulfones

Abstract

A simple and efficient method for converting methyl sulfones to sulfinic acids is described. The process involves alkylation with a benzylic halide, followed by in situ elimination of the resulting styrene in the presence of excess base to yield a sulfinic acid in a single reaction process. The usefulness of the alkylation-elimination sequence is demonstrated by generating a variety of sulfinic acids from methyl sulfones. Late stage functionalization and C-labeling of several biologically active methyl sulfones were accessed via sulfinate intermediates.

Late‐Stage 18O Labeling of Primary Sulfonamides via a Degradation–Reconstruction Pathway

“…This degradation-reconstruction approach afforded isolated yields of up to 96 %f or the stable isotopel abeled (SIL) sulfonamides, and was compatible with multiple marketed therapeutics, including celecoxib, on ag ram scale. The SIL products also exhibited no 18 O/ 16 Ob ack exchange under extreme conditions, further validating the utility of this green strategy for drug labeling for both in vitro and in vivo use. This procedure was also adapted to include pharmaceutically relevant methyl sulfones by using 13 CH 3 ,a ffording M + 5i sotopic enrichment, therebyi llustrating the broad utility of this methodology.…”

“…Our aim was to incorporate a ‐S 18 O 2 13 CH 3 labeled handle in order to provide a higher mass and more metabolically stable tracer than the ‐SO 2 CD 3 containing congeners. In order to access the desired sulfinate, we followed a sulfone demethylation strategy disclosed by Gauthier and Yoshikawa in 2016 . After obtaining the crude sulfinate intermediate from unlabeled 7 a , we employed our 18 O enrichment conditions, followed by treatment with 13 CH 3 I in DMF, to obtain isotopically enriched etoricoxib 8 a , a selective COX‐2 inhibitor, at a 55 % yield with a M+5 isotopic enrichment of 88 %.…”

“…[11] Compared to 2 H, 13 C, or 15 Ni sotopes, developing sulfonamides tracers with ad oubly-labeled oxygen-18 ( 18 O) sulfonyl would be af ar more efficient strategy for achieving the required mass differential of the SIL compound, due to the overall four-mass unit increase. Furthermore, the inherent chemical and metabolic stability of sulfonamides allows the doubly-labeled sulfonyl oxygenst ob e" locked" into tracer,t hereby eliminating any potential for degradation or 18 O/ 16 Ob ack-exchange of the labeled handle (vide infra). Inspired by the sulfonamide deamination work of Fier and Maloney, [12] we envisioned utiliz- ing the more reactive sulfinate to access an 18 O-labeled sulfinic acid intermediate, followed by subsequent SÀ 15 Nb ond reformation, to generate the desired doubly-labeled sulfonamide ( Figure 2B).…”

“…Furthermore, the inherent chemical and metabolic stability of sulfonamides allows the doubly-labeled sulfonyl oxygenst ob e" locked" into tracer,t hereby eliminating any potential for degradation or 18 O/ 16 Ob ack-exchange of the labeled handle (vide infra). Inspired by the sulfonamide deamination work of Fier and Maloney, [12] we envisioned utiliz- ing the more reactive sulfinate to access an 18 O-labeled sulfinic acid intermediate, followed by subsequent SÀ 15 Nb ond reformation, to generate the desired doubly-labeled sulfonamide ( Figure 2B). By incorporating 15 N, this approach would deliver an overall five mass unit increase and allow the use of the non-labeled parentc ompound as the starting material.…”

“…By incorporating 15 N, this approach would deliver an overall five mass unit increase and allow the use of the non-labeled parentc ompound as the starting material. Herein, we disclose this late-stage 18 Ol abellings trategy and illustrate the tolerance of this approach towards complex primary sulfonamides and methyl sulfones. Unlike carboxylic acid functional groups, [13] sulfonamides do not undergo direct 16 O/ 18 Oexchangeunder acidic or basic conditions ( Figure 3A).…”