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DOI: 10.1055/s-0040-1720071
Recent Applications of Hexamethyldisilathiane (TMS2S) in Organic Synthesis
Abstract
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Hexamethyldisilathiane (TMS2S), also named bis(trimethylsilyl) sulfide, (CAS: 3385-94-2), was reported for the first time in the early 1950’s.[1] This liquid compound (bp 160 °C) was prepared by the reaction between iodotrimethylsilane and silver sulfide. Alternatively, bis(trimethylsilyl) sulfide has been also prepared by the addition of disodium sulfide on chlorotrimethylsilane.[1] [2] TMS2S is nowadays commercially available (ca. 28 €/g).[3] This reagent can be viewed as a S1 source of sulfide that is less toxic, less flammable, and easier to handle than gaseous hydrogen sulfide (H2S). On contact with water, TMS2S releases H2S and should be stored in a cold and dry place in an oxygen-free atmosphere. TMS2S is used as a sulfur transfer agent for the synthesis of alkyl sulfides, thioaldehydes, or thioketones but also as a reducing agent.[4] TMS2S is also employed in the synthesis of inorganic–organic hybrid clusters[5] or phosphinidene sulfide compounds.[6] It is noteworthy that the number of publications describing the use of TMS2S has steadily increased since the 1950’s to reach an average of 65 publications per year from 2015 to 2022.[7] This Spotlight article highlights the versatility of TMS2S as a S1 source of sulfides and its recent applications in organic synthesis.
In 1999, Hu and Fox reported a trimethylsilylthioxy dehalogenation reaction for the synthesis of functionalized thiols (Table [1], A).[8] In this process, tetrabutylammonium trimethylsilylthiolate (Me3SiS–Bu4N+), generated in situ from TMS2S and tetrabutylammonium fluoride (TBAF), reacts with bromoalkanes to give the corresponding thiols without the formation of disulfide side products,[8] [9] even though exceptions exist.[10,11] This chemoselectivity may be explained by mild reaction conditions (i. e., short reaction time, low temperature).[8] TMS2S enables also the formation of thiolactones by way of indium-catalyzed nucleophilic ring opening of 5-aryl-lactones (Table [1], B)[12] [13] Two mechanistic pathways have been proposed for this reaction. The first one is based on the attack of TMS2S at the benzylic position of the indium-activated lactone followed by intramolecular cyclization.[14] In a second possible pathway, TMS2S attacks the lactone carbonyl group. The formation of the thiolactone ring would then proceed by way of intramolecular nucleophilic substitution at the benzylic position. Following related studies on epoxide ring-opening reactions,[15] Capperucci et al. showed that aziridines can be converted into 1,2-mercaptoamines in the presence of TMS2S and TBAF (Table [1], C).[16] TMS2S has also found application in glycochemistry as a nucleophile. In 2011, Zhu et al. reported an efficient method for the synthesis of α-glycosyl thiols through TMS2S ring opening of 1,6-anhydrosugars[17] in the presence of TMSOTf.[18] A few years later, it was discovered by serendipity that this process could be extended to the synthesis of dithioacetal-α,α-diglycosides by adding a ketone or an aldehyde to the reaction media (Table [1], D).[19] TMS2S ring opening of 1,6 anhydrosugars has been also applied to the expeditious synthesis of 1-thiotrehalose derivatives (Table [1], E).[20] As a metabolically stable analogue of trehalose, this thiodisaccharide and its derivatives are potential fungicides and insecticides.[20] In the highly convergent approach designed, the commercially available 1,6-anhydrosugar starting material serves both as a glycosyl donor and as a direct precursor of the glycosyl acceptor. The modification of the initial thiolation protocol[18] led to the one-step synthesis of the 1-thiotrahalose skeleton in 56% yield.
(A) Nucleophilic substitution of alkylbromides:[8] [9] [10] [11] • access to thiols under mild conditions • broad synthetic scope |
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(B) Nucleophilic substitution of 5-aryl-lactones:[12] [13] • access to thiolactones from lactones • moderate to high yields with γ-lactones • low yields with δ-lactones • mechanistic proofs (inversion of configuration) |
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(C) Ring opening of aziridines:[16] • access to enantioenriched 1,2-mercaptoamines • metal-free • high regioselectivity |
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(D) Ring opening of 1,6-anhydrosugars in the presence of carbonyl compounds:[19] • access to dithioacetal-α,α-diglycosides • high α-stereoselectivity • one-pot formation of three covalent bonds |
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(E) Double thioglycosylation:[20] • one-pot synthesis of protected 1-thiotrehalose • 2-step synthesis of 1-thiotrehalose • no need to prepare a glycosyl donor and acceptor |
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(F) Copper-catalyzed coupling reactions of aryl iodides:[21] • synthesis of diaryl sulfides • double C–S bond formation • high functional group tolerance |
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(G) Copper-catalyzed coupling reactions of aryl iodides in the presence of esters:[22] • synthesis of aryl alkyl sulfides • double C–S bond formation • high functional group tolerance |
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(H) Copper-catalyzed synthesis of isothiochromenes and benzo[b]thiophenes:[23] • selective 6-endo-dig cyclization • mechanistic studies |
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(I) Generation of thioaldehydes using ionic liquids:[24] • mild conditions • in situ formation of thioaldehydes • one-pot synthesis of 3,6-dihydro-2H-thiopyrans from aryl aldehydes |
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(J) TMS2S-promoted cleavage of sulfur–sulfur bond in aromatic disilathianes:[26] • one-pot synthesis of alkyl aryl sulfides • alkyl carboxylates used as alkylation reagents • TMS2S not acting as a S1 source but as a promoter of the S–S bond cleavage |
Cu-catalyzed coupling reactions of aryl iodide and TMS2S afford symmetrical diaryl sulfides in moderate to excellent yields (Table [1], F).[21] Alkyl aryl sulfides can be obtained via the same catalytic process in the presence of alkyl benzoates (Table [1], G).[22] TMS2S has been also used as a sulfur source in the copper-catalyzed synthesis of isothiochromenes and benzo[b]thiophenes via intramolecular endo-selective hydrothiolation of alkynes (Table [1], H).[23] The TMS2S-based thionation[4] of aryl aldehydes in ionic liquid leads to the in situ formation of thials and to 3,6-dihydro-2H-thiopyran derivatives by Diels–Alder trapping with 2,3-dimethylbutadiene (Table [1], I).[24] In contrast, the same process applied to alkyl aldehydes provides the corresponding 1,3,5-trithianes.[25] TMS2S promotes the cleavage of S–S bond in aromatic disulfides enabling the synthesis of the corresponding alkyl aryl sulfides through reaction of in situ generated thiosilanes with alkyl carboxylates (Table [1], J).[26] The scope of this reaction has been extended to the synthesis of alkyl aryl selenides from diaryl diselenides.[26]
In summary, TMS2S has found broad applications as a S1 source in the synthesis of sulfur-containing compounds, from useful building blocks to aromatic heterocycles and thioglycosides. The recent finding that hexamethyldisilathiane can also promote the cleavage of S–S or Se–Se bonds suggests that the synthetic potential of this reagent has not yet been fully uncovered.
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Conflict of Interest
The authors declare no conflict of interest.
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References and Notes
- 1a Eaborn C. Nature 1950; 165: 1686
- 1b Eaborn C. J. Chem. Soc. 1950; 165: 3077
- 1c So J.-H, Boudjouk P, Hong HH, Weber WP. Inorg. Synth. 1992; 29: 30
- 2 For others methods for the preparation of TMS2S, see: Curphey TJ. Phosphorus, Sulfur, Silicon Relat. Elem. 2001; 173: 123
- 3 Sigma-Aldrich (accessed March 16, 2023): https://www.sigmaaldrich.com/FR/en/product/aldrich/283134
- 4a Matulenko MA, Degl’Innocenti A, Capperucci A. Bis(trimethylsilyl) sulfide . In Encyclopedia of Reagents for Organic Synthesis . Paquette L. Wiley; New York: 2007
- 4b Degl’Innocenti A, Capperucci A, Castagnoli G, Malesci I. Synlett 2005; 1965
- 4c Degl’Innocenti A, Capperucci A, Nocentini T, Castagnoli G, Malesci I, Cerreti A. Phosphorus, Sulfur, Silicon Relat. Elem. 2005; 180: 1247
- 5a Rojas-León I, Christmann J, Schwan S, Ziese F, Sanna S, Mollenhauer D, Rosemann NW, Dehnen S. Adv. Mater. 2022; 34: 2203351
- 5b Liu LJ, Zhang JW, Asas M, Whang Z.-Y, Zhang S.-Q, Mak TC. W. Chem. Commun. 2021; 57: 5586
- 6a Sato Y, Nishimura M, Kawaguchi S, Nomoto A, Ogawa A. Chem. Eur. J. 2019; 25: 6797
- 6b Graham CM. E, Pritchard TE, Boyle PD, Valjus J, Tuononen HM, Ragogna PJ. Angew. Chem. Int. Ed. 2017; 56: 6236
- 6c Graham CM. E, Macdonald CL. B, Boyle PD, Wisner JA, Ragogna PJ. Chem. Eur. J. 2018; 24: 743
- 7 Search run on Scifinder March 16, 2023.
- 8 Hu J, Fox MA. J. Org. Chem. 1999; 64: 4959
- 9a Jayaraman J, Ganapathy AS, Thanikachalam V, Palanivel J, Sekar P. J. Phys. Org. Chem. 2018; 31: e3796
- 9b Kong R, Xiao Z, Xie F, Jiang J, Ding L. New J. Chem. 2017; 41: 2895
- 9c Kothur RR, Patel BA, Cragg PJ. Chem. Commun. 2017; 53: 9078
- 9d Wójcik MM, Wróbel J, Jańczuk ZZ, Mieczkowski J, Górecka E, Choi J, Cho M, Pociecha D. Chem. Eur. J. 2017; 23: 8912
- 9e Rahman ML, Biswas TK, Sarkar SM, Yusoff MM, Yuvaraj AR, Kumar S. J. Colloid Interface Sci. 2016; 478: 384
- 9f Sun J, Li W, Xiao L, Yu G, Shi J. RSC Adv. 2016; 6: 62200
- 9g Olshansky JH, Ding TX, Lee YV, Leone SR, Alivisatos AP. J. Am. Chem. Soc. 2015; 137: 15567
- 9h Liu Y, Najafabadi BK, Fard MA, Corrigan JF. Angew. Chem. Int. Ed. 2015; 54: 4832
- 10 Kizling M, Dzwonek M, Nowak A, Tymecki L, Stolarczyk K, Więckowska A, Bilewicz B. Nanomaterials 2020; 10: 1434
- 11a Reddy PV. G, Lin Y.-W, Chang H.-T. ARKIVOC 2007; (xvi): 113
- 11b Gopidas KR, Whitesell JK, Fox MA. J. Am. Chem. Soc. 2003; 125: 14168
- 12 Ogiwara Y, Takano K, Horikawa S, Sakai N. Molecules 2018; 23: 1339
- 13 Nie Z, Chiou M.-F, Cui J, Qu Y, Zhu X, Jian W, Xiong H, Li Y, Bao H. Angew. Chem. Int. Ed. 2022; 61: e202202077
- 14 Sakai N, Horikawa S, Ogiwara Y. Synthesis 2018; 50: 565
- 15 Degl’Innocenti A, Capperucci A, Cerreti A, Pollicino S, Scapecchi S, Malesci I, Castagnoli G. Synlett 2005; 3063
- 16a Tanini D, Borgogni C, Capperucci A. New J. Chem. 2019; 43: 6388
- 16b Tanini D, Barchielli G, Benelli F, Degl’Innocenti A, Capperucci A. Phosphorus, Sulfur, Silicon Relat. Elem. 2015; 190: 1265
- 17 For a review on ring opening of 1,6-anhydrosugars, see: Hazelard D, Compain P. Eur. J. Org. Chem. 2021; 3501
- 18 Zhu X, Dere RT, Jiang J, Zhang L, Wang X. J. Org. Chem. 2011; 76: 10187
- 19 Céspedes DávilaM. F, Schneider JP, Godard A, Hazelard D, Compain P. Molecules 2018; 23: 914
- 20 Tardieu D, Céspedes DávilaM. F, Hazelard D, Compain P. Synthesis 2018; 50: 3927
- 21 Ogiwara Y, Maeda H, Sakai N. Synlett 2018; 19: 655
- 22 Sakai N, Maeda H, Ogiwara Y. Synthesis 2019; 51: 2323
- 23 Nakajima T, Takeuchi R, Oomori K, Ishida K, Ogiwara Y, Sakai N. Synthesis 2023; 55: 779
- 24 Tanini D, Angeli A, Capperucci A. Phosphorus, Sulfur, Silicon Relat. Elem. 2016; 191: 156
- 25 Tanini D, Trapani F, Capperucci A. J. Sulfur Chem. 2020; 41: 635
- 26 Nakajima T, Takano K, Maeda H, Ogiwara Y, Sakai N. Chem. Asian J. 2021; 16: 4103
For selected reviews, see:
For recent examples, see:
See for examples:
For recent examples, see:
See also:
Corresponding Authors
Publication History
Received: 14 April 2023
Accepted after revision: 15 May 2023
Article published online:
05 June 2023
© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by/4.0/)
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References and Notes
- 1a Eaborn C. Nature 1950; 165: 1686
- 1b Eaborn C. J. Chem. Soc. 1950; 165: 3077
- 1c So J.-H, Boudjouk P, Hong HH, Weber WP. Inorg. Synth. 1992; 29: 30
- 2 For others methods for the preparation of TMS2S, see: Curphey TJ. Phosphorus, Sulfur, Silicon Relat. Elem. 2001; 173: 123
- 3 Sigma-Aldrich (accessed March 16, 2023): https://www.sigmaaldrich.com/FR/en/product/aldrich/283134
- 4a Matulenko MA, Degl’Innocenti A, Capperucci A. Bis(trimethylsilyl) sulfide . In Encyclopedia of Reagents for Organic Synthesis . Paquette L. Wiley; New York: 2007
- 4b Degl’Innocenti A, Capperucci A, Castagnoli G, Malesci I. Synlett 2005; 1965
- 4c Degl’Innocenti A, Capperucci A, Nocentini T, Castagnoli G, Malesci I, Cerreti A. Phosphorus, Sulfur, Silicon Relat. Elem. 2005; 180: 1247
- 5a Rojas-León I, Christmann J, Schwan S, Ziese F, Sanna S, Mollenhauer D, Rosemann NW, Dehnen S. Adv. Mater. 2022; 34: 2203351
- 5b Liu LJ, Zhang JW, Asas M, Whang Z.-Y, Zhang S.-Q, Mak TC. W. Chem. Commun. 2021; 57: 5586
- 6a Sato Y, Nishimura M, Kawaguchi S, Nomoto A, Ogawa A. Chem. Eur. J. 2019; 25: 6797
- 6b Graham CM. E, Pritchard TE, Boyle PD, Valjus J, Tuononen HM, Ragogna PJ. Angew. Chem. Int. Ed. 2017; 56: 6236
- 6c Graham CM. E, Macdonald CL. B, Boyle PD, Wisner JA, Ragogna PJ. Chem. Eur. J. 2018; 24: 743
- 7 Search run on Scifinder March 16, 2023.
- 8 Hu J, Fox MA. J. Org. Chem. 1999; 64: 4959
- 9a Jayaraman J, Ganapathy AS, Thanikachalam V, Palanivel J, Sekar P. J. Phys. Org. Chem. 2018; 31: e3796
- 9b Kong R, Xiao Z, Xie F, Jiang J, Ding L. New J. Chem. 2017; 41: 2895
- 9c Kothur RR, Patel BA, Cragg PJ. Chem. Commun. 2017; 53: 9078
- 9d Wójcik MM, Wróbel J, Jańczuk ZZ, Mieczkowski J, Górecka E, Choi J, Cho M, Pociecha D. Chem. Eur. J. 2017; 23: 8912
- 9e Rahman ML, Biswas TK, Sarkar SM, Yusoff MM, Yuvaraj AR, Kumar S. J. Colloid Interface Sci. 2016; 478: 384
- 9f Sun J, Li W, Xiao L, Yu G, Shi J. RSC Adv. 2016; 6: 62200
- 9g Olshansky JH, Ding TX, Lee YV, Leone SR, Alivisatos AP. J. Am. Chem. Soc. 2015; 137: 15567
- 9h Liu Y, Najafabadi BK, Fard MA, Corrigan JF. Angew. Chem. Int. Ed. 2015; 54: 4832
- 10 Kizling M, Dzwonek M, Nowak A, Tymecki L, Stolarczyk K, Więckowska A, Bilewicz B. Nanomaterials 2020; 10: 1434
- 11a Reddy PV. G, Lin Y.-W, Chang H.-T. ARKIVOC 2007; (xvi): 113
- 11b Gopidas KR, Whitesell JK, Fox MA. J. Am. Chem. Soc. 2003; 125: 14168
- 12 Ogiwara Y, Takano K, Horikawa S, Sakai N. Molecules 2018; 23: 1339
- 13 Nie Z, Chiou M.-F, Cui J, Qu Y, Zhu X, Jian W, Xiong H, Li Y, Bao H. Angew. Chem. Int. Ed. 2022; 61: e202202077
- 14 Sakai N, Horikawa S, Ogiwara Y. Synthesis 2018; 50: 565
- 15 Degl’Innocenti A, Capperucci A, Cerreti A, Pollicino S, Scapecchi S, Malesci I, Castagnoli G. Synlett 2005; 3063
- 16a Tanini D, Borgogni C, Capperucci A. New J. Chem. 2019; 43: 6388
- 16b Tanini D, Barchielli G, Benelli F, Degl’Innocenti A, Capperucci A. Phosphorus, Sulfur, Silicon Relat. Elem. 2015; 190: 1265
- 17 For a review on ring opening of 1,6-anhydrosugars, see: Hazelard D, Compain P. Eur. J. Org. Chem. 2021; 3501
- 18 Zhu X, Dere RT, Jiang J, Zhang L, Wang X. J. Org. Chem. 2011; 76: 10187
- 19 Céspedes DávilaM. F, Schneider JP, Godard A, Hazelard D, Compain P. Molecules 2018; 23: 914
- 20 Tardieu D, Céspedes DávilaM. F, Hazelard D, Compain P. Synthesis 2018; 50: 3927
- 21 Ogiwara Y, Maeda H, Sakai N. Synlett 2018; 19: 655
- 22 Sakai N, Maeda H, Ogiwara Y. Synthesis 2019; 51: 2323
- 23 Nakajima T, Takeuchi R, Oomori K, Ishida K, Ogiwara Y, Sakai N. Synthesis 2023; 55: 779
- 24 Tanini D, Angeli A, Capperucci A. Phosphorus, Sulfur, Silicon Relat. Elem. 2016; 191: 156
- 25 Tanini D, Trapani F, Capperucci A. J. Sulfur Chem. 2020; 41: 635
- 26 Nakajima T, Takano K, Maeda H, Ogiwara Y, Sakai N. Chem. Asian J. 2021; 16: 4103
For selected reviews, see:
For recent examples, see:
See for examples:
For recent examples, see:
See also: