Recent Applications of Hexamethyldisilathiane (TMS₂S) in Organic Synthesis

Abstract

Key words

hexamethyldisilathiane - bis(trimethylsilyl) sulfide - S1 source

Dr Damien Hazelard (right) obtained his PhD in 2005 under the supervision of Dr A. Fadel (Paris-Sud University). In 2006, he performed a postdoctoral training in the field of organocatalysis in the group of Prof. Y. Hayashi at the Tokyo University of Science. Then he joined the group of Prof. F. Colobert to work on total synthesis at the University of Strasbourg. He was appointed in 2010 as assistant professor at the same university in the group of Prof. P. Compain. In July 2019, he defended his habilitation (‘Habilitation à Diriger des Recherches’). His main research interests are the development of new synthetic methodologies for the synthesis of glycomimetics. Philippe Compain (left) gained his engineering degree from CPE Lyon. In 1998, he was awarded the Dina Surdin Prize by the French Chemical Society for his PhD research on alkaloid synthesis (UCBL, Lyon). After a postdoctoral stay at Montreal with Prof. Hanessian, he was appointed as a Chargé de Recherche at CNRS (ICOA, Orléans). In 2008, he accepted a full professorship at the University of Strasbourg. His research interests span from synthetic methodologies to glycomimetics of therapeutic interest. Prof. Compain is a fellow of the Royal Society of Chemistry and an honorary member of the Institut Universitaire de France (IUF). He is currently president of the ‘Groupe Français des Glycosciences’ (GFG, the French network in glycosciences).

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.

Table 1 Recent Applications of Hexamethyldisilathiane (TMS₂S)

(A) Nucleophilic substitution of alkylbromides:[8] [9] [10] [11] • access to thiols under mild conditions • broad synthetic scope
(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)
(C) Ring opening of aziridines:[16] • access to enantioenriched 1,2-mercaptoamines • metal-free • high regioselectivity
(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
(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
(F) Copper-catalyzed coupling reactions of aryl iodides:[21] • synthesis of diaryl sulfides • double C–S bond formation • high functional group tolerance
(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
(H) Copper-catalyzed synthesis of isothiochromenes and benzo[b]thiophenes:[23] • selective 6-endo-dig cyclization • mechanistic studies
(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
(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.

Conflict of Interest

The authors declare no conflict of interest.

• 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

For selected reviews, see:
• 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

For recent examples, see:
• 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

See for examples:
• 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

For recent examples, see:
• 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

See also:
• 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

Publication History

Received: 14 April 2023

Accepted after revision: 15 May 2023

Article published online:
05 June 2023