One-Pot Synthesis of Sulfonamides from Unactivated Acids and Amines via Aromatic Decarboxylative Halosulfonylation

Abstract

The coupling of carboxylic acids and amines to form amide linkages is the most commonly performed reaction in the pharmaceutical industry. Herein, we report a new strategy that merges these traditional amide coupling partners to generate sulfonamides, important amide bioisosteres. This method leverages copper ligand-to-metal charge transfer (LMCT) to convert aromatic acids to sulfonyl chlorides, followed by one-pot amination to form the corresponding sulfonamide. This process requires no prefunctionalization of the native acid or amine and extends to a diverse set of aryl, heteroaryl, and s-rich aliphatic substrates. Further, we extend this strategy to the synthesis of (hetero)aryl sulfonyl fluorides, which have found utility as “click” handles in chemical probes and programmable bifunctional reagents. Finally, we demonstrate the utility of these protocols in pharmaceutical analogue synthesis.

Photoredox‐Catalyzed Preparation of Sulfones Using Bis‐Piperidine Sulfur Dioxide – An Underutilized Reagent for SO2 Transfer

“…As an alternative to the harsh conditions of organometallic approaches to incorporate SO 2 , radical methods have gained attention in recent years [10][11][12][13] with the emergence photoredox catalysis, as a range of highly reactive species can be generated under mild conditions by the use of light and a photocatalyst. [14,15] Although several photochemical strategies to incorporate aryl (and other sp 2 ) radicals into SO 2 sources have been developed, [16][17][18][19][20][21][22][23][24][25]26,27] there are somewhat fewer examples of alkyl radicals being trapped by SO 2 , [28][29][30][31][32][33][34][35][36] and fewer still, established general methods that allows the incorporation of both substituents. [37][38][39][40] Those that do have limited scope due to the required use of UV light irradiation in their preparation.…”

Single-Electron-Transfer-Generated Aryl Sulfonyl Ammonium Salt: Metal-Free Photoredox-Catalyzed Modular Construction of Sulfonamides

“…Representative molecules include Dabrafenib (Figure A, I ), Sulpiride ( II ), Belinostat ( III ), Fosamprenavir ( IV ), and Sildenafil ( V ) . Given the preeminence of aryl sulfonamides, much effort has been devoted to the development of effective methods to access these frameworks (Figure B). , The common approach involves the condensation of an amine with aryl sulfonyl chloride; however, this method suffers from the limitations imposed by preservation of sulfonyl chloride and the limited functional group compatibility . Even though secondary and tertiary sulfonamides can be accessed through metal-catalyzed C–N cross-coupling reactions of primary sulfonamides with aryl halides or boronic acid, primary sulfonamides are still mainly derived from sulfonyl chloride.…”

Visible-Light-Induced Decarboxylative Aminosulfonylation of (Hetero)aryl Carboxylic Oxime Esters

“…Very recently, Wang reported aminosulfonylation reactions of presynthesized dibenzothiophenium, aryldiazonium, and diaryliodonium salts by synergetic photoredox and copper catalysis using DABSO as a SO 2 surrogate . Almost at the same time, MacMillan’s group demonstrated a method that enables decarboxylative halosulfonylation of aromatic acids to synthesize sulfonamides by a ligand-to-metal charge transfer (LMCT) process under 365 nm light with 20% copper catalyst and SO 2 gas (Scheme A) . To date, a mild, catalytic, direct method for decarboxylative aminosulfonylation of aryl carboxylic acids remains rare, despite carboxylic acids being abundant materials readily available from natural sources and industrial precursors.…”