Organosulfur functionalities are ubiquitous in nature, pharmaceuticals, agrochemicals, materials and flavourants. Historically, these moieties were introduced almost exclusively using ionic chemistry; however, radical-based methods for the installation of sulfur-based functional groups have recently come to the fore. These radical methods have enabled their late-stage introduction into complex molecules, avoiding the need to preserve labile organosulfur moieties through multistep synthetic sequences. Here, we discuss homolytic C–S bond-forming processes, with a particular emphasis on radical substitution approaches to sulfide, disulfide and sulfinyl products, and the use of sulfur dioxide and its surrogates to build sulfonyl products. We also highlight the mechanistic considerations that we hope will guide further development of radical-based strategies compatible with the various organosulfur moieties that feature in modern chemistry.
This is a preview of subscription content, access via your institution
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Ilardi, E. A., Vitaku, E. & Njardarson, J. T. Data-mining for sulfur and fluorine: an evaluation of pharmaceuticals to reveal opportunities for drug design and discovery. J. Med. Chem. 57, 2832–2842 (2014).
Devendar, P. & Yang, G. F. Sulfur-containing agrochemicals. Top. Curr. Chem. 375, 1–44 (2017).
Wang, N., Saidhareddy, P. & Jiang, X. Construction of sulfur-containing moieties in the total synthesis of natural products. Nat. Prod. Rep. 37, 246–275 (2020).
Worthington, M. J. H., Kucera, R. L. & Chalker, J. M. Green chemistry and polymers made from sulfur. Green. Chem. 19, 2748–2761 (2017).
Wang, M. & Jiang, X. Prospects and challenges in organosulfur chemistry. ACS Sustain. Chem. Eng. 10, 671–677 (2022).
Scott, K. A. & Njardarson, J. T. Analysis of US FDA-approved drugs containing sulfur atoms. Top. Curr. Chem. 376, 5 (2018).
Zhao, C., Rakesh, K. P., Ravidar, L., Fang, W. Y. & Qin, H. L. Pharmaceutical and medicinal significance of sulfur (SVI)-containing motifs for drug discovery: a critical review. Eur. J. Med. Chem. 162, 679–734 (2019).
Voss, J. History of nineteenth-century organosulfur chemistry. J. Sulfur. Chem. 30, 167–207 (2009).
Nguyen, T. B. Recent advances in organic reactions involving elemental sulfur. Adv. Synth. Catal. 359, 1066–1130 (2017).
Aida, F. & Oyaizu, K. Emerging organosulfonium electrophiles as unique reagents for carbonsulfur bond formation: prospects in synthetic chemistry of organosulfur compounds. Chem. Lett. 45, 102–109 (2016).
Ravindra, V. & Kupwade, A. Concise review on synthesis of sulfoxides and sulfones with special reference to oxidation of sulfides. J. Chem. Rev. 1, 99–113 (2019).
Kondo, T. & Mitsudo, T. A. Metal-catalyzed carbon–sulfur bond formation. Chem. Rev. 100, 3205–3220 (2000).
Correa, A., Mancheño, O. G. & Bolm, C. Iron–catalysed carbon–heteroatom and heteroatom–heteroatom bond forming processes. Chem. Soc. Rev. 37, 1108–1117 (2008).
Beletskaya, I. P. & Ananikov, V. P. Transition-metal-catalyzed C–S, C–Se, and C–Te bond formation via cross-coupling and atom-economic addition reactions. Chem. Rev. 111, 1596–1636 (2011).
Lee, C. F., Liu, Y. C. & Badsara, S. S. Transition-metal-catalyzed C–S bond coupling reaction. Chem. Asian J. 9, 706–722 (2014).
Liu, H. & Jiang, X. Transfer of sulfur: from simple to diverse. Chem. Asian J. 8, 2546–2563 (2013).
Liang, S., Shaaban, S., Liu, N. W., Hofman, K. & Manolikakes, G. Recent advances in the synthesis of C–S bonds via metal-catalyzed or -mediated functionalization of C–H bonds. Adv. Organomet. Chem. 69, 135–207 (2018).
Huang, S., Wang, M. & Jiang, X. Ni-catalyzed C–S bond construction and cleavage. Chem. Soc. Rev. 51, 8351–8377 (2022).
Munir, I. et al. Synthetic applications and methodology development of Chan–Lam coupling: a review. Mol. Divers. 23, 215–259 (2019).
Qiao, J. X. & Lam, P. Y. S. Copper-promoted carbon-heteroatom bond cross-coupling with boronic acids and derivatives. Synthesis 2011, 829–856 (2011).
Sanjeeva Rao, K. & Wu, T. S. Chan–Lam coupling reactions: synthesis of heterocycles. Tetrahedron 68, 7735–7754 (2012).
Zhao, X., Dimitrijević, E. & Dong, V. M. Palladium-catalyzed C–H bond functionalization with arylsulfonyl chlorides. J. Am. Chem. Soc. 131, 3466–3467 (2009).
Beletskaya, I. P. & Ananikov, V. P. Transition-metal-catalyzed C–S, C–Se, and C–Te bond formations via cross-coupling and atom-economic addition reactions. Achievements and challenges. Chem. Rev. 122, 16110–16293 (2022).
Yang, D., Yan, Q., Zhu, E., Lv, J. & He, W. M. Carbon–sulfur bond formation via photochemical strategies: an efficient method for the synthesis of sulfur-containing compounds. Chin. Chem. Lett. 33, 1798–1816 (2022).
Crich, D. & Quintero, L. Radical chemistry associated with the thiocarbonyl group. Chem. Rev. 89, 1413–1432 (1989).
Barton, D. H. R., Crich, D. & Motherwell, W. B. New and improved methods for the radical decarboxylation of acids. J. Chem. Soc. Chem. Commun. https://doi.org/10.1039/C39830000939 (1983).
Barton, D. H. R., Crich, D. & Motherwell, W. B. The invention of new radical chain reactions. Part VIII. Radical chemistry of thiohydroxamic esters; a new method for the generation of carbon radicals from carboxylic acids. Tetrahedron 41, 3901–3924 (1985).
Barton, D. H. R., Crich, D. & Motherwell, W. B. A practical alternative to the hunsdiecker reaction. Tetrahedron Lett. 24, 4979–4982 (1983).
Zard, S. Z. & Barton, D. On the trail of xanthates: some new chemistry from an old functional group. Angew. Chem. Int. Edn 36, 672–685 (1997).
Barton, D. H. R. & Crich, D. A new method for the radical deoxygenation of tertiary alcohols. J. Chem. Soc. Chem. Commun. https://doi.org/10.1039/C39840000774 (1984).
Delduc, P., Tailhan, C. & Zard, S. Z. A convenient source of alkyl and acyl radicals. J. Chem. Soc. Chem. Commun. https://doi.org/10.1039/C39880000308 (1988).
Barton, D. H. R., Bridon, D. & Zard, S. Z. New decarboxylative chalcogenation of aliphatic and alicyclic carboxylic acids. Tetrahedron Lett. 25, 5777–5780 (1984).
McCombie, S. W., Motherwell, W. B. & Tozer, M. J. The Barton–McCombie reaction. Org. React. 77, 161–432 (2012).
Crespi, S. & Fagnoni, M. Generation of alkyl radicals: from the tyranny of tin to the photon democracy. Chem. Rev. 120, 9790–9833 (2020).
Corce, V., Ollivier, C. & Fensterbank, L. Boron, silicon, nitrogen and sulfur-based contemporary precursors for the generation of alkyl radicals by single electron transfer and their synthetic utilization. Chem. Soc. Rev. 51, 1470–1510 (2022).
Bell, J. D. & Murphy, J. A. Recent advances in visible light-activated radical coupling reactions triggered by (i) ruthenium, (ii) iridium and (iii) organic photoredox agents. Chem. Soc. Rev. 50, 9540–9685 (2021).
Yan, M., Lo, J. C., Edwards, J. T. & Baran, P. S. Radicals: reactive intermediates with translational potential. J. Am. Chem. Soc. 138, 12692–12714 (2016).
Huang, H., Steiniger, K. A. & Lambert, T. H. Electrophotocatalysis: combining light and electricity to catalyze reactions. J. Am. Chem. Soc. 144, 12567–12583 (2022).
Shaw, M. H., Twilton, J. & MacMillan, D. W. Photoredox catalysis in organic chemistry. J. Org. Chem. 81, 6898–6926 (2016).
Studer, A. & Curran, D. P. Catalysis of radical reactions: a radical chemistry perspective. Angew. Chem. Int. Edn 128, 58–106 (2016).
Amri, N. & Wirth, T. Recent advances in the electrochemical synthesis of organosulfur compounds. Chem. Rec. 21, 2526–2537 (2021).
Hoyle, C. E. & Bowman, C. N. Thiol-ene click chemistry. Angew. Chem. Int. Edn 49, 1540–1573 (2010).
Ahangarpour, M., Kavianinia, I., Harris, P. W. R. & Brimble, M. A. Photo-induced radical thiol–ene chemistry: a versatile toolbox for peptide-based drug design. Chem. Soc. Rev. 50, 898–944 (2021).
Lowe, A. B. Thiol-ene ‘click’ reactions and recent applications in polymer and materials synthesis. Polym. Chem. 1, 17–36 (2010).
Leifert, D. & Studer, A. The persistent radical effect in organic synthesis. Angew. Chem. Int. Edn 59, 74–108 (2020).
Liu, B., Lim, C. H. & Miyake, G. M. Visible-light-promoted C–S cross-coupling via intermolecular charge transfer. J. Am. Chem. Soc. 139, 13616–13619 (2017). This paper discloses a visible-light-promoted, catalyst-free radical cross-coupling reaction between aryl halides and thiolates enabled by the formation of an EDA complex; several examples of EDA-mediated radical cross-couplings have since followed.
Nandy, A., Kazi, I., Guha, S. & Sekar, G. Visible-light-driven halogen-bond-assisted direct synthesis of heteroaryl thioethers using transition-metal-free one-pot C–I bond formation/C–S cross-coupling reaction. J. Org. Chem. 86, 2570–2581 (2021).
Sundaravelu, N., Nandy, A. & Sekar, G. Visible light mediated photocatalyst free C–S cross coupling: domino synthesis of thiochromane derivatives via photoinduced electron transfer. Org. Lett. 23, 3115–3119 (2021).
Piedra, H. F. & Plaza, M. Photochemical halogen-bonding assisted generation of vinyl and sulfur-centered radicals: stereoselective catalyst-free C(sp2)–S bond forming reactions. Chem. Sci. 14, 650–657 (2022).
Li, T. et al. A photoexcited halogen-bonded EDA complex of the thiophenolate anion with iodobenzene for C(sp3)–H activation and thiolation. Chem. Sci. 12, 15655–15661 (2021).
Uchikura, T., Hara, Y., Tsubono, K. & Akiyama, T. Visible-light-driven C–S bond formation based on electron donor-acceptor excitation and hydrogen atom transfer combined system. ACS Org. Inorg. Au 1, 23–28 (2021).
Luo, Y.-R. Comprehensive Handbook Of Chemical Bond Energies (CRC Press, 2007).
Blanksby, S. J. & Ellison, G. B. Bond dissociation energies of organic molecules. Acc. Chem. Res. 36, 255–263 (2003).
Scaiano, J. C. & Stewart, L. C. Phenyl radical kinetics. J. Am. Chem. Soc. 105, 3609–3614 (1983).
Huang, C. et al. Direct allylic C(sp3)−H and vinylic C(sp2)−H thiolation with hydrogen evolution by quantum dots and visible light. Angew. Chem. Int. Edn 60, 11779–11783 (2021).
Vara, B. A. et al. Scalable thioarylation of unprotected peptides and biomolecules under Ni/photoredox catalysis. Chem. Sci. 9, 336–344 (2018).
Uyeda, C., Tan, Y., Fu, G. C. & Peters, J. C. A new family of nucleophiles for photoinduced, copper-catalyzed cross-couplings via single-electron transfer: reactions of thiols with aryl halides under mild conditions (0 °C). J. Am. Chem. Soc. 135, 9548–9552 (2013).
Oderinde, M. S., Frenette, M., Robbins, D. W., Aquila, B. & Johannes, J. W. Photoredox mediated nickel catalyzed cross-coupling of thiols with aryl and heteroaryl iodides via thiyl radicals. J. Am. Chem. Soc. 138, 1760–1763 (2016).
Jerry, M. Advanced Organic Chemistry Reactions, Mechanisms And Structure (John Wiley & Sons, 1985).
Ingold, K. U. & Roberts, B. P. Free-Radical Substitution Reactions. Bimolecular Homolytic Substitutions (SH2 Reactions) At Saturated Multivalent Atoms (John Wiley & Sons, 1971).
Walton, J. C. Homolytic substitution: a molecular ménage à trois. Acc. Chem. Res. 31, 99–107 (1998).
Derek, H. R. B., Dominique, B. & Zard, S. The invention of new radical chain reactions. Part XIII. High yielding decarboxylative chalcogenation of aliphatic and alicyclic acids. Heterocycles 25, 449–462 (1987).
Curran, D. P., Martin-Esker, A. A., Ko, S. B. & Newcomb, M. Rate constants for chalcogen group transfers in bimolecular substitution reactions with primary alkyl radicals. J. Org. Chem. 58, 4691–4695 (1993).
Hoffman, M. Z. & Hayon, E. Pulse radiolysis study of sulfhydryl compounds in aqueous solution. J. Am. Chem. Soc. 94, 7950–7957 (1972).
Madej, E., Folkes, L. K., Wardman, P., Czapski, G. & Goldstein, S. Thiyl radicals react with nitric oxide to form S-nitrosothiols with rate constants near the diffusion-controlled limit. Free Radic. Biol. Med. 44, 2013–2018 (2008).
Dénès, F., Pichowicz, M., Povie, G. & Renaud, P. Thiyl radicals in organic synthesis. Chem. Rev. 114, 2587–2693 (2014).
Tang, R. Y., Xie, Y. X., Xie, Y. L., Xiang, J. N. & Li, J. H. TBHP-mediated oxidative thiolation of an sp3 C–H bond adjacent to a nitrogen atom in an amide. Chem. Commun. 47, 12867–12869 (2011).
Guo, S. R., He, W. M., Xiang, J. N. & Yuan, Y. Q. Palladium-catalyzed thiolation of alkanes and ethers with arylsulfonyl hydrazides. Chem. Commun. 50, 8578–8581 (2014).
Li, Y., Zhu, F., Wang, Z. & Wu, X. F. Synthesis of thioethers and thioesters with alkyl arylsulfinates as the sulfenylation agent under metal-free conditions. Chem. Asian J. 11, 3503–3507 (2016).
Zhao, J., Fang, H., Han, J., Pan, Y. & Li, G. Metal-free preparation of cycloalkyl aryl sulfides via di-tert-butyl peroxide-promoted oxidative C(sp3)–H bond thiolation of cycloalkanes. Adv. Synth. Catal. 356, 2719–2724 (2014).
Du, B., Jin, B. & Sun, P. Syntheses of sulfides and selenides through direct oxidative functionalization of C(sp3)–H bond. Org. Lett. 16, 3032–3035 (2014).
Xiao, Z. et al. Visible-light induced decarboxylative coupling of redox-active esters with disulfides to construct C–S bonds. Chem. Commun. 56, 4164–4167 (2020).
Shi, Q., Li, P., Zhang, Y. & Wang, L. Visible light-induced tandem oxidative cyclization of 2-alkynylanilines with disulfides (diselenides) to 3-sulfenyl- and 3-selenylindoles under transition metal-free and photocatalyst-free conditions. Org. Chem. Front. 4, 1322–1330 (2017).
Smaligo, A. J. & Kwon, O. Dealkenylative thiylation of C(sp3)–C(sp2) bonds. Org. Lett. 21, 8592–8597 (2019).
Li, Z. et al. Manganese-mediated reductive functionalization of activated aliphatic acids and primary amines. Nat. Commun. 11, 5036 (2020).
Jin, Y., Yang, H. & Fu, H. An N-(acetoxy)phthalimide motif as a visible-light pro-photosensitizer in photoredox decarboxylative arylthiation. Chem. Commun. 52, 12909–12912 (2016).
Loh, Y. Y. et al. Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds. Science 358, 1182–1187 (2017).
Musacchio, A. J. et al. Catalytic intermolecular hydroaminations of unactivated olefins with secondary alkyl amines. Science 355, 727–730 (2017).
Panferova, L. I., Zubkov, M. O., Kokorekin, V. A., Levin, V. V. & Dilman, A. D. Using the thiyl radical for aliphatic hydrogen-atom transfer: thiolation of unactivated C−H bonds. Angew. Chem. Int. Edn 60, 2849–2854 (2021). This paper reported the the first synthetic application of a thiyl radical for unactivated C−H bond thiolation, in which an electron-deficient diaryldisulfide serves as both the sulfurating reagent and source of H-atom abstractor.
Zubkov, M. O., Kosobokov, M. D., Levin, V. V. & Dilman, A. D. Photocatalyzed decarboxylative thiolation of carboxylic acids enabled by fluorinated disulfide. Org. Lett. 24, 2354–2358 (2022).
Gadde, K. et al. Thiosulfonylation of unactivated alkenes with visible-light organic photocatalysis. ACS Catal. 10, 8765–8779 (2020).
Luo, Y.-R. Handbook Of Bond Dissociation Energies In Organic Compounds (CRC Press, 2003).
Li, J. et al. Visible-light-promoted cross-coupling reactions of 4-alkyl-1,4-dihydropyridines with thiosulfonate or selenium sulfonate: a unified approach to sulfides, selenides, and sulfoxides. Org. Lett. 22, 4908–4913 (2020).
Dong, Y. et al. Organophotoredox-catalyzed formation of alkyl–aryl and –alkyl C–S/Se bonds from coupling of redox-active esters with thio/selenosulfonates. Org. Lett. 22, 9562–9567 (2020).
Fazekas, T. J. et al. Diversification of aliphatic C–H bonds in small molecules and polyolefins through radical chain transfer. Science 375, 545–550 (2022).
Quiclet-Sire, B. & Zard, S. Z. Some aspects of the radical chemistry of xanthates. Chimia 66, 404–412 (2012).
Czaplyski, W. L., Na, C. G. & Alexanian, E. J. C–H xanthylation: a synthetic platform for alkane functionalization. J. Am. Chem. Soc. 138, 13854–13857 (2016). This paper presents a visible-light-enabled C–H xanthylation using a N-xanthylamide as the radical-trapping reagent for C−S bond formation, with the resulting amidyl radical being responsible for aliphatic C–H bond activation.
Quinn, R. K. et al. Site-selective aliphatic C–H chlorination using N-chloroamides enables a synthesis of chlorolissoclimide. J. Am. Chem. Soc. 138, 696–702 (2016).
Schmidt, V. A., Quinn, R. K., Brusoe, A. T. & Alexanian, E. J. Site-selective aliphatic C–H bromination using N-bromoamides and visible light. J. Am. Chem. Soc. 136, 14389–14392 (2014).
Williamson, J. B., Czaplyski, W. L., Alexanian, E. J. & Leibfarth, F. A. Regioselective C−H xanthylation as a platform for polyolefin functionalization. Angew. Chem. Int. Edn 57, 6261–6265 (2018).
Williamson, J. B. et al. Chemo- and regioselective functionalization of isotactic polypropylene: a mechanistic and structure–property study. J. Am. Chem. Soc. 141, 12815–12823 (2019).
Na, C. G., Ravelli, D. & Alexanian, E. J. Direct decarboxylative functionalization of carboxylic acids via O–H hydrogen atom transfer. J. Am. Chem. Soc. 142, 44–49 (2020).
Na, C. G. & Alexanian, E. J. A general approach to site-specific, intramolecular C−H functionalization using dithiocarbamates. Angew. Chem. Int. Edn 57, 13106–13109 (2018).
Morcillo, S. P. et al. Photoinduced remote functionalization of amides and amines using electrophilic nitrogen radicals. Angew. Chem. Int. Edn 57, 12945–12949 (2018).
Mukherjee, S., Patra, T. & Glorius, F. Cooperative catalysis: a strategy to synthesize trifluoromethyl-thioesters from aldehydes. ACS Catal. 8, 5842–5846 (2018).
Mukherjee, S., Maji, B., Tlahuext-Aca, A. & Glorius, F. Visible-light-promoted activation of unactivated C(sp3)–H bonds and their selective trifluoromethylthiolation. J. Am. Chem. Soc. 138, 16200–16203 (2016).
Candish, L., Pitzer, L., Gómez-Suárez, A. & Glorius, F. Visible light-promoted decarboxylative di- and trifluoromethylthiolation of alkyl carboxylic acids. Chem. Eur. J. 22, 4753–4756 (2016).
Liang, R. B. et al. External oxidant-free and selective thiofunctionalization of alkenes enabled by photoredox-neutral catalysis. Org. Chem. Front. 9, 4536–4541 (2022).
Harris, J. F. Free-radical reactions of fluoroalkanesulfenyl halides. II. Free-radical reactions of trifluoromethanesulfenyl chloride with alkanes. J. Org. Chem. 31, 931–935 (1966).
Mokrosz, M. J. Syntheses with unsaturated nitriles. Part VII. Trifluoromethanesulfenylation of ylidenemalononitrile dimers. J. Fluor. Chem. 34, 201–207 (1986).
Wu, H. et al. Direct trifluoromethylthiolation of unactivated C(sp3)–H using silver(I) trifluoromethanethiolate and potassium persulfate. Angew. Chem. Int. Edn 54, 4070–4074 (2015).
Guo, S., Zhang, X. & Tang, P. Silver-mediated oxidative aliphatic C–H trifluoromethylthiolation. Angew. Chem. Int. Edn 54, 4065–4069 (2015).
Park, C. M. et al. 9-Fluorenylmethyl (Fm) disulfides: biomimetic precursors for persulfides. Org. Lett. 18, 904–907 (2016).
Xiao, X., Feng, M. & Jiang, X. New design of a disulfurating reagent: facile and straightforward pathway to unsymmetrical disulfanes by copper-catalyzed oxidative cross-coupling. Angew. Chem. Int. Edn 55, 14121–14125 (2016).
Xiao, X., Xue, J. & Jiang, X. Polysulfurating reagent design for unsymmetrical polysulfide construction. Nat. Commun. 9, 2191 (2018).
Dai, Z., Xiao, X. & Jiang, X. Nucleophilic disulfurating reagents for unsymmetrical disulfides construction via copper-catalyzed oxidative cross coupling. Tetrahedron 73, 3702–3706 (2017).
Gao, W. C., Liu, J. & Jiang, X. Phthalimide-based-SSCF3 reagent for enantioselective dithiotrifluoromethylation. Org. Chem. Front. 8, 1275–1279 (2021).
Xue, J. & Jiang, X. Unsymmetrical polysulfidation via designed bilateral disulfurating reagents. Nat. Commun. 11, 4170 (2020).
Gao, W. C., Tian, J., Shang, Y. Z. & Jiang, X. Steric and stereoscopic disulfide construction for cross-linkage via N-dithiophthalimides. Chem. Sci. 11, 3903–3908 (2020).
Zou, J. et al. Phthalimide-carried disulfur transfer to synthesize unsymmetrical disulfanes via copper catalysis. ACS Catal. 9, 11426–11430 (2019).
Ong, C. L., Titinchi, S., Juan, J. C. & Khaligh, N. G. An overview of recent advances in the synthesis of organic unsymmetrical disulfides. Helv. Chim. Acta 104, e2100053 (2021).
Chauvin, J. P. R. et al. Polysulfide-1-oxides react with peroxyl radicals as quickly as hindered phenolic antioxidants and do so by a surprising concerted homolytic substitution. Chem. Sci. 7, 6347 (2016).
Chauvin, J. P. R., Griesser, M. & Pratt, D. A. Hydropersulfides: H-atom transfer agents par excellence. J. Am. Chem. Soc. 139, 6484–6493 (2017).
Chauvin, J. P. R., Griesser, M. & Pratt, D. A. The antioxidant activity of polysulfides: it’s radical! Chem. Sci. 10, 4999–5010 (2019).
Wu, Z. & Pratt, D. A. Radical substitution provides a unique route to disulfides. J. Am. Chem. Soc. 142, 10284–10290 (2020). The first report on radical substitution to yield disulfides, demonstrating that tetrasulfides undergo rapid homolytic substitution and the resultant perthiyl radicals dimerize to yield more tetrasulfide.
Chen, S. et al. Sandmeyer-type reductive disulfuration of anilines. Org. Lett. 23, 7428–7433 (2021).
Zhang, J. & Studer, A. Decatungstate-catalyzed radical disulfuration through direct C–H functionalization for the preparation of unsymmetrical disulfides. Nat. Commun. 13, 3886 (2022). Tetrasulfides are used along with decatungstate photocatalysis for the disulfuration of sp3 and aldehydic C–H bonds.
Wu, Z. & Pratt, D. A. A divergent strategy for site-selective radical disulfuration of carboxylic acids with trisulfide-1,1-dioxides. Angew. Chem. Int. Edn 60, 15598–15605 (2021). Using trisulfide-1,1-dioxides as disulfuraing reagents, the authors develop a visible-light-photocatalysed direct disulfuration of carboxylic acids, as well as the first C−H disulfuration.
Noble, A. & MacMillan, D. W. C. Photoredox α-vinylation of α-amino acids and N-aryl amines. J. Am. Chem. Soc. 136, 11602–11605 (2014).
Xia, Y., Wang, L. & Studer, A. Site-selective remote radical C−H functionalization of unactivated C−H bonds in amides using sulfone reagents. Angew. Chem. Int. Edn 57, 12940–12944 (2018).
Moutrille, C. & Zard, S. Z. A new, practical access to amidyl radicals. Chem. Commun. https://doi.org/10.1039/b405545d (2004).
Gui, Y., Qiu, L., Li, Y., Li, H. & Dong, S. Internal activation of peptidyl prolyl thioesters in native chemical ligation. J. Am. Chem. Soc. 138, 4890–4899 (2016).
Liu, N. W., Liang, S. & Manolikakes, G. Recent advances in the synthesis of sulfones. Synthesis 48, 1939–1973 (2016).
Liang, S., Hofman, K., Friedrich, M. & Manolikakes, G. Recent advances in the synthesis and direct application of sulfinate salts. Eur. J. Org. Chem. 2020, 4664–4676 (2020).
Shaaban, S., Liang, S., Liu, N. W. & Manolikakes, G. Synthesis of sulfones via selective C–H functionalization. Org. Biomol. Chem. 15, 1947–1955 (2017).
Liu, J. & Zheng, L. Recent Advances In Transition-metal-mediated Chelation-assisted Sulfonylation Of Unactivated C−H Bonds Vol. 361, 1710–1732 (John Wiley & Sons, 2019).
Qiu, G., Zhou, K. & Wu, J. Recent advances in the sulfonylation of C–H bonds with the insertion of sulfur dioxide. Chem. Commun. 54, 12561–12569 (2018).
Matavos-Aramyan, S., Soukhakian, S. & Jazebizadeh, M. H. Selected methods for the synthesis of sulfoxides and sulfones with emphasis on oxidative protocols. Phosph. Sulfur Silicon Relat. Elem. 195, 181–193 (2020).
McGrath, A. J., Garrett, G. E., Valgimigli, L. & Pratt, D. A. The redox chemistry of sulfenic acids. J. Am. Chem. Soc. 132, 16759–16761 (2010).
Ishii, A., Kashiura, S., Oshida, H. & Nakayama, J. First isolation of eclipsed vic-disulfoxide: 7,8-dithiabicyclo[4.2.1]nona-2,4-diene 7-exo,8-exo-dioxide. Org. Lett. 6, 2623–2626 (2004).
Nguyen, V. D. et al. Decarboxylative sulfinylation enables a direct, metal-free access to sulfoxides from carboxylic acids. Angew. Chem. Int. Edn 61, e202210525 (2022). Larionov and co-workers developed a direct decarboxylative sulfinylation employing radical substitution on a sulfinyl sulfone formed in situ from sulfinates and a acyl chloride, thereby enabling the construction of sulfoxides directly from carboxylic acids.
Griesser, M., Chauvin, J. P. R. & Pratt, D. A. The hydrogen atom transfer reactivity of sulfinic acids. Chem. Sci. 9, 7218–7229 (2018).
Farng, L. P. O. & Kice, J. L. Substitution reactions of alkanesulfonyl derivatives: direct substitution vs. elimination–addition mechanisms in substitution reactions of alkyl α-disulfones. J. Am. Chem. Soc. 103, 1137–1145 (1981).
Suzuki, H. & Abe, H. Copper-assisted displacement reaction of nonactivated lodoarenes with arenesulfinates. Convenient alternative synthesis of unsymmetrical diaryl sulfones. Tetrahedron Lett. 36, 6239–6242 (1995).
Gund, S. H., Shelkar, R. S. & Nagarkar, J. M. Copper catalyzed synthesis of unsymmetrical diaryl sulfones from an arenediazonium salt and sodium p-toluenesulfinate. RSC Adv. 5, 62926–62930 (2015).
Zhang, K., Xu, X. H. & Qing, F. L. Copper-promoted trifluoromethanesulfonylation and trifluoromethylation of arenediazonium tetrafluoroborates with NaSO2CF3. J. Org. Chem. 80, 7658–7665 (2015).
He, J. et al. Catalytic decarboxylative radical sulfonylation. Chem 6, 1149–1159 (2020). Li and co-workers demonstrated decarboxylative sulfonylation by merging copper and photoredox catalysis; the reaction produces sulfones directly from carboxylic acids and organosulfinates at room temperature under redox-neutral conditions.
Zhang, S. et al. Photocatalyzed site-selective C(sp3)–H sulfonylation of toluene derivatives and cycloalkanes with inorganic sulfinates. Chin. J. Catal. 43, 564–570 (2022).
Chen, Y. et al. Photoredox generation of sulfonyl radicals and coupling with electron deficient olefins. Org. Lett. 22, 5746–5748 (2020).
Dong, D. Q. et al. Recent progress in sulfonylation via radical reaction with sodium sulfinates, sulfinic acids, sulfonyl chlorides or sulfonyl hydrazides. Chem. Sel. 5, 13103–13134 (2020).
Chatgilialoglu, C. et al. Kinetic studies on the formation of sulfonyl radicals and their addition to carbon–carbon multiple bonds. J. Phys. Chem. A 116, 7623–7628 (2012).
Freeman, F. & Keindl, M. C. Sulfinyl, α-sulfinyl, sulfonyl, and α-sulfonyl radicals. Sulfur. Rep. 4, 231–298 (1985).
Horowitz, A. Radiolytic decomposition of methanesulfonyl chloride in liquid cyclohexane. A kinetic determination of the bond dissociation energies D(Me‐SO2) and D(c‐C6H11‐SO2). Int. J. Chem. Kin. 8, 709–723 (1976).
Dos Passos Gomes, G., Wimmer, A., Smith, J. M., König, B. & Alabugin, I. V. CO2 or SO2: should it stay, or should it go? J. Org. Chem. 84, 6232–6243 (2019).
Reed, C. F. Method of halogenating compounds and product resulting therefrom. US patent 2046090A (1936).
Meerwein, H. et al. Untersuchungen über aromatische Diazoverbindungen, II. Verfahren zur Herstellung Aromatischer Sulfonsäurechloride, Eine Neue Modifikation der Sandmeyerschen Reaktion. Chem. Ber. 90, 841–852 (1957).
Ye, S., Li, X., Xie, W. & Wu, J. Photoinduced sulfonylation reactions through the insertion of sulfur dioxide. Eur. J. Org. Chem. 2020, 1274–1287 (2020).
Hofman, K., Liu, N. W. & Manolikakes, G. Radicals and sulfur dioxide: a versatile combination for the construction of sulfonyl-containing molecules. Chem. Eur. J. 24, 11852–11863 (2018).
Zeng, D., Wang, M., Deng, W. P. & Jiang, X. The same oxygenation-state introduction of hypervalent sulfur under transition-metal-free conditions. Org. Chem. Front. 7, 3956–3966 (2020).
Chen, S., Li, Y., Wang, M. & Jiang, X. General sulfone construction via sulfur dioxide surrogate control. Green Chem. 22, 322–326 (2020).
Blum, S. P., Hofman, K., Manolikakes, G. & Waldvogel, S. R. Advances in photochemical and electrochemical incorporation of sulfur dioxide for the synthesis of value-added compounds. Chem. Commun. 57, 8236–8249 (2021).
Emmett, E. J. & Willis, M. C. The development and application of sulfur dioxide surrogates in synthetic organic chemistry. Asian J. Org. Chem. 4, 602–611 (2015).
Liu, G., Fan, C. & Wu, J. Fixation of sulfur dioxide into small molecules. Org. Biomol. Chem. 13, 1592–1599 (2015).
Nguyen, B., Emmett, E. J. & Willis, M. C. Palladium-catalyzed aminosulfonylation of aryl halides. J. Am. Chem. Soc. 132, 16372–16373 (2010).
Andrews, J. A. & Willis, M. C. DABSO — a reagent to revolutionize organosulfur chemistry. Synthesis 54, 1695–1707 (2022).
Zheng, D., An, Y., Li, Z. & Wu, J. Metal-free aminosulfonylation of aryldiazonium tetrafluoroborates with DABCO⋅(SO2)2 and hydrazines. Angew. Chem. Int. Edn 53, 2451–2454 (2014). Aryl N-aminosulfonamides are prepared by coupling aryldiazonium tetrafluoroborates, DABSO, and hydrazines, first demonstrating the utility of SO2 surrogates for trapping carbon-centred radicals in the synthesis of sulfonyl compounds.
Liu, T. et al. Photocatalytic reaction of potassium alkyltrifluoroborates and sulfur dioxide with alkenes. Org. Lett. 20, 3605–3608 (2018).
Andrews, J. A., Pantaine, L. R. E., Palmer, C. F., Poole, D. L. & Willis, M. C. Sulfinates from amines: a radical approach to alkyl sulfonyl derivatives via donor–acceptor activation of pyridinium salts. Org. Lett. 23, 8488–8493 (2021).
Wang, X., Li, H., Qiu, G. & Wu, J. Substituted Hantzsch esters as radical reservoirs with the insertion of sulfur dioxide under photoredox catalysis. Chem. Commun. 55, 2062–2065 (2019).
Wang, X., Yang, M., Xie, W., Fan, X. & Wu, J. Photoredox-catalyzed hydrosulfonylation reaction of electron-deficient alkenes with substituted Hantzsch esters and sulfur dioxide. Chem. Commun. 55, 6010–6013 (2019).
Xiang, Y., Li, Y., Kuang, Y. & Wu, J. Vicinal difluoroalkylation and aminosulfonylation of alkynes under photoinduced conditions. Chem. Eur. J. 23, 1032–1035 (2017).
Li, Y., Xiang, Y., Li, Z. & Wu, J. Direct vicinal difunctionalization of alkynes through trifluoromethylation and aminosulfonylation via insertion of sulfur dioxide under catalyst-free conditions. Org. Chem. Front. 3, 1493–1497 (2016).
Liu, Y. et al. Zinc-mediated intermolecular reductive radical fluoroalkylsulfination of unsaturated carbon–carbon bonds with fluoroalkyl bromides and sulfur dioxide. Chem. Eur. J. 25, 1824–1828 (2019).
Mao, R., Yuan, Z., Li, Y. & Wu, J. N-radical-initiated cyclization through insertion of sulfur dioxide under photoinduced catalyst-free conditions. Chem. Eur. J. 23, 8176–8179 (2017).
Zhang, J., Yang, M., Liu, J. B., He, F. S. & Wu, J. A copper-catalyzed insertion of sulfur dioxide via radical coupling. Chem. Commun. 56, 3225–3228 (2020).
Tu, X., Huang, J., Xie, W., Zhu, T. & Wu, J. Generation of (E)-β-sulfonyl enamines from sulfur dioxide via a radical process. Org. Chem. Front. 8, 1789–1794 (2021).
Nguyen, V. D., Trevino, R., Greco, S. G., Arman, H. D. & Larionov, O. V. Tricomponent decarboxysulfonylative cross-coupling facilitates direct construction of aryl sulfones and reveals a mechanistic dualism in the acridine/copper photocatalytic system. ACS Catal. 12, 8729–8739 (2022).
Nguyen, V. T. et al. Functional group divergence and the structural basis of acridine photocatalysis revealed by direct decarboxysulfonylation. Chem. Sci. 13, 4170–4179 (2022).
Ye, S., Zheng, D., Wu, J. & Qiu, G. Photoredox-catalyzed sulfonylation of alkyl iodides, sulfur dioxide, and electron-deficient alkenes. Chem. Commun. 55, 2214–2217 (2019).
Nguyen, V. T. et al. Photocatalytic decarboxylative amidosulfonation enables direct transformation of carboxylic acids to sulfonamides. Chem. Sci. 12, 6429–6436 (2021).
Li, Y., Mao, R. & Wu, J. N-radical initiated aminosulfonylation of unactivated C(sp3)–H bond through insertion of sulfur dioxide. Org. Lett. 19, 4472–4475 (2017).
Chen, Z. D. et al. Catalytic decarboxylative fluorosulfonylation enabled by energy-transfer-mediated photocatalysis. Org. Lett. 24, 2474–2478 (2022).
Jia, X., Kramer, S., Skrydstrup, T. & Lian, Z. Design and applications of a SO2 surrogate in palladium‐catalyzed direct aminosulfonylation between aryl iodides and amines. Angew. Chem. Int. Edn 60, 7353–7359 (2021).
Raasch, M. S. Annelations with tetrachlorothiophene 1,1-dioxide. J. Org. Chem. 45, 856–867 (1980).
Wang, X., Kuang, Y., Ye, S. & Wu, J. Photoredox-catalyzed synthesis of sulfones through deaminative insertion of sulfur dioxide. Chem. Commun. 55, 14962–14964 (2019).
Qiu, G., Zhou, K., Gao, L. & Wu, J. Insertion of sulfur dioxide via a radical process: an efficient route to sulfonyl compounds. Org. Chem. Front. 5, 691–705 (2018).
Qiu, G., Lai, L., Cheng, J. & Wu, J. Recent advances in the sulfonylation of alkenes with the insertion of sulfur dioxide via radical reactions. Chem. Commun. 54, 10405–10414 (2018).
Yi, J. T. et al. Copper-catalyzed direct decarboxylative fluorosulfonylation of aliphatic carboxylic acids. Chem. Commun. 58, 9409–9412 (2022).
Wang, H., Bellotti, P., Zhang, X., Paulisch, T. O. & Glorius, F. A base-controlled switch of SO2 reincorporation in photocatalyzed radical difunctionalization of alkenes. Chem 7, 3412–3424 (2021).
Sarver, P. J., Bissonnette, N. B. & Macmillan, D. W. C. Decatungstate-catalyzed C(sp3)–H sulfinylation: rapid access to diverse organosulfur functionality. J. Am. Chem. Soc. 143, 9737–9743 (2021).
Benefice-Malouet, S., Blancou, H., Calas, P. & Commeyras, A. Synthese d’acides perfluoroalcane carboxylique et sulfinique par reduction electrochimique d’iodures de perfluoroalkyle sur cathode en fibres de carbone dans le solvant N,N-dimethylformamide. Application a la synthese de perfluoro α,ω diacides. J. Fluor. Chem. 39, 125–140 (1988).
Jin, S. et al. Photoinduced C(sp3)–H sulfination empowers the direct and chemoselective introduction of the sulfonyl group. Chem. Sci. 12, 13914–13921 (2021). Larionov and co-workers demonstrate the installation of the sulfonyl group using sodium metabisulfite, which under UV irradiation generates 3SO2, which can abstract H atoms from unreactive aliphatic substrates to generate carbon-centred radicals that react with SO2.
Ma, S. & Ma, Z. Na2S2O4-promoted radical addition reaction of perfluoroalkyl iodides with allenes and the Pd(0)-catalyzed stereoselective Sonogashira coupling reaction of addition products with propargyl alcohol. Synlett 8, 1263–1265 (2006).
Li, Y., Liu, T., Qiu, G. & Wu, J. Catalyst-free sulfonylation of (hetero)aryl iodides with sodium dithionite. Adv. Synth. Catal. 361, 1154–1159 (2019).
Li, Y., Chen, S., Wang, M. & Jiang, X. Sodium dithionite-mediated decarboxylative sulfonylation: facile access to tertiary sulfones. Angew. Chem. Int. Edn 59, 8907–8911 (2020).
Ye, S., Li, Y., Wu, J. & Li, Z. Thiourea dioxide as a source of sulfonyl groups: photoredox generation of sulfones and sulfonamides from heteroaryl/aryl halides. Chem. Commun. 55, 2489–2492 (2019).
Protti, S. & Fagnoni, M. Recent advances in light-induced selenylation. ACS Org. Inorg. Au 2, 455–463 (2022).
Voronkov, M. G. & Deryagina, E. N. Thermal reactions of thiyl radicals. Russ. Chem. Rev. 59, 778–791 (1990).
Beckwith, A. L. J. & Pigou, P. E. Relative reactivities of various sulfides, selenides and halides towards SH2 attack by tributyltin radicals. Aust. J. Chem. 39, 77–87 (1985).
Mukhopadhyay, S. & Bell, A. T. Direct sulfonation of methane to methanesulfonic acid by sulfur trioxide catalyzed by cerium(IV) sulfate in the presence of molecular oxygen. Adv. Synth. Catal. 346, 913–916 (2004).
Huie, R. E. & Neta, P. Chemical behavior of SO3- and SO5- radicals in aqueous solutions. J. Phys. Chem. 88, 5665–5669 (1984).
Huang, Y., Li, J., Chen, H., He, Z. & Zeng, Q. Recent progress on the synthesis of chiral sulfones. Chem. Rec. 21, 1216–1239 (2021).
Wojaczyńska, E. & Wojaczyński, J. Modern stereoselective synthesis of chiral sulfinyl compounds. Chem. Rev. 120, 4578–4611 (2020).
Clayden, J. & MacLellan, P. Asymmetric synthesis of tertiary thiols and thioethers. Beilstein J. Org. Chem. 7, 582–595 (2011).
Nagib, D. A. Asymmetric catalysis in radical chemistry. Chem. Rev. 122, 15989–15992 (2022).
Cao, S., Hong, W., Ye, Z. & Gong, L. Photocatalytic three-component asymmetric sulfonylation via direct C(sp3)–H functionalization. Nat. Commun. 12, 2377 (2021).
Luo, Q., Mao, R., Zhu, Y. & Wang, Y. Photoredox-catalyzed generation of sulfamyl radicals: sulfonamidation of enol silyl ether with chlorosulfonamide. J. Org. Chem. 84, 13897–13907 (2019).
Hell, S. M. et al. Silyl radical-mediated activation of sulfamoyl chlorides enables direct access to aliphatic sulfonamides from alkenes. J. Am. Chem. Soc. 142, 720–725 (2020).
Li, Z. et al. CF3SO2Na as a bifunctional reagent: electrochemical trifluoromethylation of alkenes accompanied by SO2 insertion to access trifluoromethylated cyclic N-sulfonylimines. Angew. Chem. Int. Edn 59, 7266–7270 (2020).
Zhang, Z. X., Bell, C., Ding, M. & Willis, M. C. Modular two-step route to sulfondiimidamides. J. Am. Chem. Soc. 144, 11851–11858 (2022).
Zhang, Z. X. & Willis, M. C. Sulfondiimidamides as new functional groups for synthetic and medicinal chemistry. Chem 8, 1137–1146 (2022).
Ding, M., Zhang, Z. X., Davies, T. Q. & Willis, M. C. A Silyl sulfinylamine reagent enables the modular synthesis of sulfonimidamides via primary sulfinamides. Org. Lett. 24, 1711–1715 (2022).
Lo, P. K. T. & Willis, M. C. Nickel(II)-catalyzed addition of aryl and heteroaryl boroxines to the sulfinylamine reagent TrNSO: the catalytic synthesis of sulfinamides, sulfonimidamides, and primary sulfonamides. J. Am. Chem. Soc. 143, 15576–15581 (2021).
Li, L. et al. Photoredox alkylation of sulfinylamine enables the synthesis of highly functionalized sulfinamides and S(VI) derivatives. ACS Catal. 12, 15334–15340 (2022).
Bremerich, M., Conrads, C. M., Langletz, T. & Bolm, C. Additions to N-sulfinylamines as an approach for the metal-free synthesis of sulfonimidamides: O-benzotriazolyl sulfonimidates as activated intermediates. Angew. Chem. Int. Edn 58, 19014–19020 (2019).
This work was supported by the Natural Sciences and Engineering Research Council of Canada (RGPIN-2022-05058).
The authors declare no competing interests.
Peer review information
Nature Reviews Chemistry thanks Wei Wang and the other, anonymous, reviewers for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Wu, Z., Pratt, D.A. Radical approaches to C–S bonds. Nat Rev Chem 7, 573–589 (2023). https://doi.org/10.1038/s41570-023-00505-x