Sulfur functional groups

Sulfur is among the most versatile elements in medicinal chemistry, present in approximately 25% of all FDA-approved small molecules and appearing across at least fourteen distinct functional group classes: sulfonamides, thioethers, sulfoxides, sulfones, sulfonyl fluorides, sulfamides, disulfides, sulfonylguanidines, and sulfates, among others. This diversity arises directly from sulfur's ability to exist in oxidation states from −2 to +6, each providing distinct physicochemical and binding properties. The sulfonamide group, with its planar sulfonyl geometry and strong hydrogen bond donor capacity, is one of the most widely exploited pharmacophores in drug design, acting as a bioisostere for the carboxylic acid while conferring greater metabolic stability and improved crystallinity. Thioethers and sulfoxides contribute to lipophilicity and metabolic profile modulation, while sulfones introduce polarity and can serve as hydrogen bond acceptors within hydrophobic pockets. The cysteine-reactive thiol and electrophilic sulfonyl fluoride groups are exploited in targeted covalent inhibitor design, engaging active-site residues with tuned reactivity for selective and durable target engagement. The broad chemical range of sulfur functional groups, combined with the element's distinct contribution to binding geometry and electronic properties, makes it a uniquely productive area for medicinal chemistry exploration.

Some FDA-approved drugs that illustrate the pharmacological utility of distinct sulfur functional groups include Sotagliflozin (Inpefa, Lexicon Pharmaceuticals), the first dual SGLT1 and SGLT2 inhibitor, which was approved in May 2023 for the reduction of cardiovascular death, hospitalisation for heart failure, and urgent heart failure visits. It incorporates a methylthio (thioether) group at the anomeric C-1 position of its glucose-derived ring, replacing the oxygen atom present in all other SGLT inhibitors. This C-glycoside architecture, enabled by the C-S bond, confers resistance to hydrolytic cleavage and allows the compound to reach the intestinal SGLT1 transporter intact, distinguishing it mechanistically from all SGLT2-selective agents. Revumenib (Revuforj, Syndax Pharmaceuticals), the first-in-class menin inhibitor FDA-approved in November 2024 for relapsed or refractory acute leukaemia with a KMT2A translocation, incorporates an ethylsulfonamide group on a trans-cyclohexyl ring as a key pharmacophoric element, where the sulfonamide NH acts as a hydrogen bond donor that contributes to the binding interaction within the menin protein interface. The planar sulfonyl geometry and defined sp³-rich cyclohexyl presentation of the sulfonamide in revumenib illustrate how sulfonamide building blocks can be deployed not only in classical enzyme active site targeting but in the disruption of protein-protein interactions, a mechanistically distinct and increasingly important application of the group in oncology drug discovery.

In organic synthesis, sulfur functional groups participate in a rich array of named reactions spanning multiple oxidation states. The Pummerer rearrangement converts sulfoxides to alpha-acyloxy thioethers via reactive sulfonium intermediates, providing access to versatile alpha-functionalised carbonyl equivalents. The Ramberg-Backlund reaction converts alpha-halosulfones to alkenes with extrusion of sulfur dioxide under basic conditions, offering a powerful ring-contraction and C-C bond-forming strategy. The Corey-Chaykovsky reaction exploits sulfonium ylides derived from dimethylsulfonium methylide for the synthesis of epoxides and cyclopropanes from carbonyl compounds. The Mislow-Evans rearrangement enables [2,3]-sigmatropic rearrangement of allylic sulfoxides to allylic alcohols, and the Johnson-Swern oxidation uses dimethylsulfoxide as the terminal oxidant for mild conversion of primary and secondary alcohols to aldehydes and ketones under oxalyl chloride activation. The formation of sulfonamides from amines and sulfonyl chlorides, and the synthesis of sulfones via oxidation of sulfides, are among the most routinely applied transformations in pharmaceutical synthesis.

Emerging synthetic techniques are significantly expanding access to sulfur-containing drug scaffolds. In photochemistry, visible-light photoredox catalysis has enabled practical thiol-ene and thiol-yne radical additions, producing thioethers and vinyl sulfides from thiols and unsaturated substrates under mild, operationally simple conditions with excellent regioselectivity. Photoredox-mediated sulfonylation, using sulfonyl chlorides or sodium sulfinates as sulfonyl radical precursors, enables direct C(sp2)-S and C(sp3)-S bond formation on arenes and drug-like heterocycles without transition-metal catalysts. Desulfurative photoredox strategies exploit thioethers and xanthates as radical precursors through photo-induced C-S bond homolysis, generating carbon radicals for downstream C-C and C-heteroatom coupling. Electrochemically, anodic oxidation of thioethers provides a scalable, stoichiometric-oxidant-free route to sulfoxides and sulfones with selectivity governed by the applied potential; this approach has been demonstrated at kilogram scale as a practical green alternative to classical mCPBA oxidation routes in pharmaceutical manufacturing. Electrochemical sulfonamide synthesis from thiols and amines, and electrochemical C-S bond formation via sulfonyl hydrazides, provide further atom-economical routes to sulfonamide-containing drug candidates.

Our catalogue of sulfur building blocks encompasses sulfonamides, sulfones, sulfoxides, thioethers, thiols, and a diverse range of sulfur-containing heterocycles.