Abstract
Sulfonamides have played a defining role in the history of drug development and continue to be prevalent today. In particular, primary sulfonamides are common in marketed drugs. Here we describe the direct synthesis of these valuable compounds from organometallic reagents and a novel sulfinylamine reagent, t-BuONSO. A variety of (hetero)aryl and alkyl Grignard and organolithium reagents perform well in the reaction, providing primary sulfonamides in good to excellent yields in a convenient one-step process.
Highlights
Sulfonamides have played a defining role in the history of drug development and continue to be prevalent today
The first sulfonamide drug, the antibacterial Prontosil,[2] contains an aryl-SO2NH2 unit (Figure 1). They have found use in treatments for epilepsy (Acetazolamide),[3] high blood pressure (Hydrochlorothiazide),[4] arthritis (Celecoxib),[5] and glaucoma (Methazolamide).[6]. They remain popular to this day; sulfonamides are present as active pharmaceutical ingredients (APIs) in 16 out of 200 (8%) of the best-selling small molecule drugs of 2018.7
An NHC-catalyzed deamination of primary sulfonamides to sulfinates has recently been developed by chemists at Merck, allowing them to act as precursors to sulfones, sulfonic acids, and other sulfonamides,[12] as well as enabling isotopic labeling.[13]
Summary
Sulfonamides have played a defining role in the history of drug development and continue to be prevalent today. The classical synthesis of primary sulfonamides involves the reaction of activated sulfonyl electrophiles, usually sulfonyl chlorides, with ammonia, or an ammonia surrogate with a subsequent deprotection step (Scheme 1a).
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