Facile C–S Bond Cleavage of Aryl Sulfoxides Promoted by Brønsted Acid

Dedicated with respect and admiration to Prof. Barry M. Trost, a founding member of Science of Synthesis, on the occasion of the 20th anniversary of Science of Synthesis.

‡ These authors contributed equally to this work

Abstract

A method for the Brønsted acid promoted desulfination of aryl sulfoxides is presented. In the presence of a thiol, electron-rich sulfoxides undergo C–S bond cleavage to give the corresponding protodesulfinated arenes and disulfides.

Sulfoxides are versatile reagents in organic synthesis. Besides their widespread use as ligands[1] and chiral auxiliaries,[2] sulfoxides have found application as directing groups.[3] In particular, we and others have shown that aromatic sulfoxides are especially useful for functionalization at the ortho-position.[4] More recently, the functionalization of meta-[5] and para-positions[6] in aromatic sulfoxides has also been achieved. Importantly, the chiral information encoded on the tetrahedral sulfur can be harnessed to control new stereocenters on carbon through chirality transfer.[7a] [b]

While cross-coupling and other methods enable the post-reaction conversion of sulfur residues,[8] their substitution by a simple hydrogen atom is a commonly performed reaction. Amongst the different sulfur-based functional groups, several undergo facile C–S or heteroatom–S bond cleavage under acidic conditions. Examples include the desulfonylation of aromatic sulfonic acids[9] in strongly acidic media or the removal of Ellman’s auxiliary with hydrochloric acid (Scheme [1, a]).[10] Interestingly, indolylsulfides can also be cleaved when dissolved in TFA in the presence of a thiol, as has been shown by Girard and co-workers (Scheme [1, b]).[11] The removal of sulfoxides, however, commonly requires hydrogenation with the pyrophoric Raney-nickel[12] or sulfoxide–lithium exchange with organolithium reagents such as t-BuLi.[13]

We have recently discovered that certain sulfoxides can be cleaved under mildly acidic conditions. Herein, we present the preliminary results of our investigations towards an acid-catalyzed desulfination reaction (Scheme [1, c]).

We started our investigations using sulfoxide 1a as our standard substrate and employing triflic acid as the protic catalyst (Table [1]). Dichloromethane proved to be the best solvent at a concentration of 0.2 M and a catalyst loading of 50 mol% was required to achieve full conversion after 12 hours. Triflimide showed comparable results. Importantly, an external nucleophilic thiol was found to promote the process in agreement with the previous results of Girard.[11]

Table 1 Optimization of the Desulfination Reaction Conditions

Entry	Deviation from general conditions	Conversion
1	MeOH	0%
2	acetone	0%
3	Et2O	0%
4	HFIP	traces
5	CH2Cl2 (0.5 M)	traces
6	Tf2NH (80 mol%), 20 h	100%
7	standard conditions	100% (67%)a

^a Isolated yield in parentheses.

We then went on to explore the generality of this protocol with a range of sulfoxides (Scheme [2]). o,o-Disubstituted derivatives were readily cleaved under the optimized reaction conditions, while less hindered sulfoxide 1c showed no conversion. This indicates that steric hindrance greatly facilitates the reaction. Heteroaromatic sulfoxides 1d–g also underwent the reaction smoothly, whereas less electron-rich derivative 1h bearing a Ts-protecting group was fully recovered after the reaction. Benzothiophene 1i required an elevated temperature, showing only traces of the desulfinated product at room temperature. In the case of methoxythiophene derivative 1j, the product was found to be unstable under the reaction conditions, with only a small amount of isolated protodesulfinated material being obtained. The reaction with cyclic sulfoxide 1k led to quantitative formation of a sulfide, the product of reduction.

Our mechanistic proposal is outlined in Scheme [3]. Addition of a Brønsted acid to a sulfoxide presumably leads to association with the highly polarized sulfoxide oxygen.[14] Alternatively, protonation on the electron-rich arene would generate a short-lived intermediate 4, which would rapidly be intercepted by the nucleophilic thiol generating the product 2 and one equivalent of thiosulfinate 5. The thiosulfinate formed in this process is not stable under the reaction conditions and further reacts to give a mixture of symmetrical and unsymmetrical disulfides as the only detectable byproducts.[15]

In summary, we have developed a convenient method for the desulfination of electron-rich aryl sulfoxides promoted by a Brønsted acid.[16] [17]

• References and Notes

• 1a Jia T, Wang M, Liao J. Top. Curr. Chem. 2019; 377: 1
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• 1b Trost B, Rao M. Angew. Chem. Int. Ed. 2015; 54: 5026
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• 1c Sipos G, Drinkel EE, Dorta R. Chem. Soc. Rev. 2015; 44: 3834
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• 1d Otocka S, Kwiatkowska M, Madalińska L, Kiełbasiński P. Chem. Rev. 2017; 117: 4147
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• 2a Frey J, Jerhaoui S, Choppin S, Wencel-Delord J, Colobert F. ACS Catal. 2018; 8: 2805
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• 2b Aitken HR. M, Furkert DP, Hubert JG, Wood JM, Brimble MA. Org. Biomol. Chem. 2013; 11: 5147
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• 2c Motohashi S, Nagase K, Nakakita T, Matsuo T, Yoshida Y, Kawakubo T, Miura M, Toriyama M, Barybin MV. J. Org. Chem. 2011; 76: 3922
  CrossrefPubMedSearch in Google Scholar
• 3a Tang K.-X, Wang C.-M, Gao T.-H, Chen L, Fan L, Sun L.-P. Adv. Synth. Catal. 2019; 361: 26
  CrossrefSearch in Google Scholar
• 3b Pulis AP, Procter DJ. Angew. Chem. Int. Ed. 2016; 55: 9842
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• 4a Kaiser D, Klose I, Oost R, Neuhaus J, Maulide N. Chem. Rev. 2019; 119: 8701
  CrossrefPubMedSearch in Google Scholar
• 4b Yanagi T, Nogi K, Yorimitsu H. Tetrahedron Lett. 2018; 59: 2951
  CrossrefSearch in Google Scholar
• 5 Maryasin B, Kaldre D, Galaverna R, Klose I, Ruider S, Drescher M, Kählig H, González L, Eberlin M, Jurberg I, Maulide N. Chem. Sci. 2018; 9: 4124
  CrossrefPubMedSearch in Google Scholar
• 6 Yanagi T, Nogi K, Yorimitsu H. Chem. Eur. J. 2020; 26: 783
  CrossrefPubMedSearch in Google Scholar
• 7a Kaldre D, Maryasin B, Kaiser D, Gajsek O, Gonzalez L, Maulide N. Angew. Chem Int. Ed. 2017; 56: 2212
  CrossrefPubMedSearch in Google Scholar
• 7b Kaldre D, Klose I, Maulide N. Science 2018; 361: 664
  CrossrefPubMedSearch in Google Scholar
• 8 Otsuka S, Nogi K, Yorimitsu H. Top. Curr. Chem. 2018; 376: 13
  CrossrefPubMedSearch in Google Scholar
• 9a Lindner O, Rodefeld L. In Ullmann’s Encyclopedia of Industrial Chemistry . Wiley-VCH; Weinheim: 2010: 269
  Search in Google Scholar
• 9b Grundmann C. In Houben-Weyl Methods of Organic Chemistry, 4th ed., Vol. 5/2b. Blome H, Clar E, Fiege H, Garratt PJ, Grundmann C, Gundermann K.-D, Padeken H.-G, Pauson PL, Voelter W, Zander M, Zeller K.-P. Georg Thieme Verlag; Stuttgart: 1981. 354
  Search in Google Scholar
• 9c For acid-promoted C–S bond cleavage in sulfoximines, see: Wiezorek S, Lamers P, Bolm C. Chem. Soc. Rev. 2019; 48: 5408
  CrossrefPubMedSearch in Google Scholar
• 10a Cogan DA, Ellman JA. J. Am. Chem. Soc. 1999; 121: 268
  CrossrefSearch in Google Scholar
• 10b Kochi T, Tang TP, Ellman JA. J. Am. Chem. Soc. 2003; 125: 11276
  CrossrefPubMedSearch in Google Scholar
• 11 Hamel P, Zajac N, Atkinson JG, Girard Y. J. Org. Chem. 1994; 59: 6372
  CrossrefSearch in Google Scholar

For representative examples of sulfoxide removal in total synthesis using Raney-nickel, see:
• 12a Klein LL. J. Am. Chem. Soc. 1985; 107: 2573
  CrossrefSearch in Google Scholar
• 12b Ohshima T, Xu Y, Takita R, Shimizu S, Zhong D, Shibasaki M. J. Am. Chem. Soc. 2002; 124: 14546
  CrossrefPubMedSearch in Google Scholar
• 12c Carreño MC, Des Mazery R, Urbano A, Colobert F, Solladié G. Org. Lett. 2004; 6: 297
  CrossrefPubMedSearch in Google Scholar

For representative examples of sulfoxide removal in total synthesis using t-BuLi, see:
• 13a Mastranzo VM, Yuste F, Ortiz B, Sánchez-Obregón R, Toscano RA, García Ruano JL. J. Org. Chem. 2011; 76: 5036
  CrossrefPubMedSearch in Google Scholar
• 13b Takiguchi H, Ohmori K, Suzuki K. Chem. Lett. 2011; 40: 1069
  CrossrefSearch in Google Scholar
• 13c Vakiti JR, Ghosh S. Tetrahedron Lett. 2014; 55: 6438
  CrossrefSearch in Google Scholar
• 14 Pons A, Michalland J, Zawodny W, Chen Y, Tona V, Maulide N. Angew. Chem. Int. Ed. 2019; 58: 17303
  CrossrefPubMedSearch in Google Scholar
• 15a Singh PK, Field L, Sweetman BJ. J. Org. Chem. 1988; 53: 2608
  CrossrefSearch in Google Scholar
• 15b Schöberl A, Gräfje H. Justus Liebigs Ann. Chem. 1958; 617: 71
  CrossrefSearch in Google Scholar
• 16 Protodesulfination; General Procedure To a solution of the sulfoxide (0.2 mmol, 1.0 equiv) and 1-octanethiol (0.8 mmol, 4.0 equiv) in CH₂Cl₂ (0.2 M) in a vial, trifluoromethanesulfonic acid (0.1 mmol, 0.5 equiv) was added and the mixture was stirred for 12 h at 23 °C. The reaction was quenched by the addition of solid NaHCO₃, stirred at 23 °C for 10 min, filtered and extracted with CH₂Cl₂. The resulting organic phase was dried over MgSO₄ and concentrated under reduced pressure to give a crude product that was purified by column chromatography (heptane/ethyl acetate).
• 17 1,3,5-Trimethoxy-2-(methylsulfinyl)benzene (1b) IR (neat): 2943, 1582, 1465, 1458, 1436, 1412, 1340, 1230, 1208, 1187, 1162, 1125, 1086, 1026 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 6.12 (s, 2 H), 3.88 (s, 6 H), 3.84 (s, 3 H), 3.04 (s, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 164.7, 161.3, 111.5, 91.3, 56.3, 55.7, 38.0. HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₀H₁₄O₄SNa: 253.0505; found: 253.0512.

• References and Notes

• 1a Jia T, Wang M, Liao J. Top. Curr. Chem. 2019; 377: 1
  CrossrefPubMedSearch in Google Scholar
• 1b Trost B, Rao M. Angew. Chem. Int. Ed. 2015; 54: 5026
  CrossrefPubMedSearch in Google Scholar
• 1c Sipos G, Drinkel EE, Dorta R. Chem. Soc. Rev. 2015; 44: 3834
  CrossrefPubMedSearch in Google Scholar
• 1d Otocka S, Kwiatkowska M, Madalińska L, Kiełbasiński P. Chem. Rev. 2017; 117: 4147
  CrossrefPubMedSearch in Google Scholar
• 2a Frey J, Jerhaoui S, Choppin S, Wencel-Delord J, Colobert F. ACS Catal. 2018; 8: 2805
  CrossrefSearch in Google Scholar
• 2b Aitken HR. M, Furkert DP, Hubert JG, Wood JM, Brimble MA. Org. Biomol. Chem. 2013; 11: 5147
  CrossrefPubMedSearch in Google Scholar
• 2c Motohashi S, Nagase K, Nakakita T, Matsuo T, Yoshida Y, Kawakubo T, Miura M, Toriyama M, Barybin MV. J. Org. Chem. 2011; 76: 3922
  CrossrefPubMedSearch in Google Scholar
• 3a Tang K.-X, Wang C.-M, Gao T.-H, Chen L, Fan L, Sun L.-P. Adv. Synth. Catal. 2019; 361: 26
  CrossrefSearch in Google Scholar
• 3b Pulis AP, Procter DJ. Angew. Chem. Int. Ed. 2016; 55: 9842
  CrossrefPubMedSearch in Google Scholar
• 4a Kaiser D, Klose I, Oost R, Neuhaus J, Maulide N. Chem. Rev. 2019; 119: 8701
  CrossrefPubMedSearch in Google Scholar
• 4b Yanagi T, Nogi K, Yorimitsu H. Tetrahedron Lett. 2018; 59: 2951
  CrossrefSearch in Google Scholar
• 5 Maryasin B, Kaldre D, Galaverna R, Klose I, Ruider S, Drescher M, Kählig H, González L, Eberlin M, Jurberg I, Maulide N. Chem. Sci. 2018; 9: 4124
  CrossrefPubMedSearch in Google Scholar
• 6 Yanagi T, Nogi K, Yorimitsu H. Chem. Eur. J. 2020; 26: 783
  CrossrefPubMedSearch in Google Scholar
• 7a Kaldre D, Maryasin B, Kaiser D, Gajsek O, Gonzalez L, Maulide N. Angew. Chem Int. Ed. 2017; 56: 2212
  CrossrefPubMedSearch in Google Scholar
• 7b Kaldre D, Klose I, Maulide N. Science 2018; 361: 664
  CrossrefPubMedSearch in Google Scholar
• 8 Otsuka S, Nogi K, Yorimitsu H. Top. Curr. Chem. 2018; 376: 13
  CrossrefPubMedSearch in Google Scholar
• 9a Lindner O, Rodefeld L. In Ullmann’s Encyclopedia of Industrial Chemistry . Wiley-VCH; Weinheim: 2010: 269
  Search in Google Scholar
• 9b Grundmann C. In Houben-Weyl Methods of Organic Chemistry, 4th ed., Vol. 5/2b. Blome H, Clar E, Fiege H, Garratt PJ, Grundmann C, Gundermann K.-D, Padeken H.-G, Pauson PL, Voelter W, Zander M, Zeller K.-P. Georg Thieme Verlag; Stuttgart: 1981. 354
  Search in Google Scholar
• 9c For acid-promoted C–S bond cleavage in sulfoximines, see: Wiezorek S, Lamers P, Bolm C. Chem. Soc. Rev. 2019; 48: 5408
  CrossrefPubMedSearch in Google Scholar
• 10a Cogan DA, Ellman JA. J. Am. Chem. Soc. 1999; 121: 268
  CrossrefSearch in Google Scholar
• 10b Kochi T, Tang TP, Ellman JA. J. Am. Chem. Soc. 2003; 125: 11276
  CrossrefPubMedSearch in Google Scholar
• 11 Hamel P, Zajac N, Atkinson JG, Girard Y. J. Org. Chem. 1994; 59: 6372
  CrossrefSearch in Google Scholar

For representative examples of sulfoxide removal in total synthesis using Raney-nickel, see:
• 12a Klein LL. J. Am. Chem. Soc. 1985; 107: 2573
  CrossrefSearch in Google Scholar
• 12b Ohshima T, Xu Y, Takita R, Shimizu S, Zhong D, Shibasaki M. J. Am. Chem. Soc. 2002; 124: 14546
  CrossrefPubMedSearch in Google Scholar
• 12c Carreño MC, Des Mazery R, Urbano A, Colobert F, Solladié G. Org. Lett. 2004; 6: 297
  CrossrefPubMedSearch in Google Scholar

For representative examples of sulfoxide removal in total synthesis using t-BuLi, see:
• 13a Mastranzo VM, Yuste F, Ortiz B, Sánchez-Obregón R, Toscano RA, García Ruano JL. J. Org. Chem. 2011; 76: 5036
  CrossrefPubMedSearch in Google Scholar
• 13b Takiguchi H, Ohmori K, Suzuki K. Chem. Lett. 2011; 40: 1069
  CrossrefSearch in Google Scholar
• 13c Vakiti JR, Ghosh S. Tetrahedron Lett. 2014; 55: 6438
  CrossrefSearch in Google Scholar
• 14 Pons A, Michalland J, Zawodny W, Chen Y, Tona V, Maulide N. Angew. Chem. Int. Ed. 2019; 58: 17303
  CrossrefPubMedSearch in Google Scholar
• 15a Singh PK, Field L, Sweetman BJ. J. Org. Chem. 1988; 53: 2608
  CrossrefSearch in Google Scholar
• 15b Schöberl A, Gräfje H. Justus Liebigs Ann. Chem. 1958; 617: 71
  CrossrefSearch in Google Scholar
• 16 Protodesulfination; General Procedure To a solution of the sulfoxide (0.2 mmol, 1.0 equiv) and 1-octanethiol (0.8 mmol, 4.0 equiv) in CH₂Cl₂ (0.2 M) in a vial, trifluoromethanesulfonic acid (0.1 mmol, 0.5 equiv) was added and the mixture was stirred for 12 h at 23 °C. The reaction was quenched by the addition of solid NaHCO₃, stirred at 23 °C for 10 min, filtered and extracted with CH₂Cl₂. The resulting organic phase was dried over MgSO₄ and concentrated under reduced pressure to give a crude product that was purified by column chromatography (heptane/ethyl acetate).
• 17 1,3,5-Trimethoxy-2-(methylsulfinyl)benzene (1b) IR (neat): 2943, 1582, 1465, 1458, 1436, 1412, 1340, 1230, 1208, 1187, 1162, 1125, 1086, 1026 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 6.12 (s, 2 H), 3.88 (s, 6 H), 3.84 (s, 3 H), 3.04 (s, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 164.7, 161.3, 111.5, 91.3, 56.3, 55.7, 38.0. HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₀H₁₄O₄SNa: 253.0505; found: 253.0512.

• Supplementary Material