New synthesis of unsymmetrical dithia compounds

摘要

J. CHEM. SOC. PERKIN TRANS. I 1995 238 1 New synthesis of unsymmetrical dithia compounds Keith Smith * and Michael Tzimas Department of Chemistry, University of Wales Swansea, Singleton Park, Swansea SA2 8PP, UK 1,2-Dithiacycloalkanes undergo nucleophilic ring-opening with organolithium reagents; the intermediates can be treated with electrophiles to provide unsymmetrical dithia compounds in high yields. Organic thiols, sulfides and disulfides are important because of their physiological activity,' their auxiliary roles in a number of modern synthetic methods,2 and their potential use in electronic and other modern materials. Therefore, there is considerable interest in the development of novel syntheses of such compound^.^ As part of our more general interests in sulfur compounds 'and in lithiations we have introduced processes for the elaboration of arenethiols by directed lithiation 'and for the incorporation of a thiol equivalent into heterocyclic compounds by reaction of tetraisopropylthiuram disulfide with appropriate lithiated heterocycles. This last reaction is a specific example of the well-established cleavage of an organic disulfide by an organometallic reagent to yield an unsym-metrical sulfide eqn.(1).9 RLi + RSSR (1)-RSR + RSLi In principle, application of this reaction to cyclic disulfides could provide potential access to unsymmetrical dithia compounds eqn. (2), but there are no such reactions in the literature. A possible complication is that a free metal thiolate formed in the initial step can react rapidly with further cyclic disulfide to produce oligomeric materials eqn.(3)J lo which could then give rise to symmetrical compounds eqn. (4). It was therefore not clear whether the desired unsymmetrical compounds could be obtained selectively. However, we now report that reactions of 1,2-dithiacycloalkanes with organo- lithium reagents followed by trapping of the intermediates with certain electrophiles can indeed give unsymmetrical dithia compounds in high yields eqn. (2). RT, 12h 1.2-Dithiacycloalkanes of ring sizes from 5 to 12 are easily syn thesised by oxidative cyclisation of the readily available dithiols.' ' The literature method,'* with only minor modific- ations of concentration and purification procedure, was applied in the synthesis of 1J-dithiane and I ,2-dithiacyclooctane eqn.(5).These compounds tended to undergo oligomerisation on I,. triethylamine HS(CH3nSH CHCI3 prolonged storage, so they were used relatively soon after purification. The dithianes were treated first with an organolithium and then with an alkyl or acyl halide to give the corresponding products in good yield (see Table 1). As the results in Table 1 show, the reaction was successful with a range of different organolithium reagents and with acetyl halides and primary alkyl halides as electrophiles, but alkylation did not take place under these conditions with tertiary alkyl halides which, after work-up, led instead to the corresponding thiols.This work shows that the reaction of eqn. (2) is a fast and convenient way to synthesise a range of dithia compounds in high yields. Although the investigation was limited to dithiane and dithiacyclooctane, smaller and larger ring sizes and rings containing additional heteroatoms l2 or fused to aromatic or alicyclic rings I3*l4 have been reported in the literature. This leads to possibilities for the synthesis of other unsymmetrical dithia compounds eqn. (6), X = a heteroatom or a ring system. /bsol; i RLi (CH2)n (CH2)n -R-S-(CHamp;-X-(CH2),,-S-R (6)ii R'Br 'X' Experimental General procedure The dithiacycloalkane was dissolved in dry THF and the solution cooled to -78 "C. An equimolar amount of organo-lithium compound in hexane or diethyl ether was added to the solution and the mixture stirred for 30 min; it was then allowed to warm to room temperature before addition of an equimolar amount of the electrophile.The mixture was stirred at ambient temperature overnight after which it was washed with water, dried, concentrated under reduced pressure and purified by bulb-to-bulb distillation. The products and yields obtained are those shown in Table 1. Acknowledgements We thank NIPA Laboratories for financial support to M. T., the EPSRC for a grant to provide the NMR equip-ment used in this study and the EPSRC Mass Spectrometry Centre in Swansea for running the mass spectra. We also thank Dr C. Brown and Mr K. Payne of NIPA for their contributions.2382 J. CHEM. SOC. PERKIN TRANS. 1 1995 Table 1 Products synthesised according to eqn. (2) RLi Disulfide EX Product Yield ()a MeLi 1,2-Dithiane Me1 MeS(CH,),SMe 86 MeLi 1,2-Dithiane MeBr MeS(CH,),SMe 55 MeLi I ,2-Dithiane BuBr MeS(CH,),SBu 74 BuLi 1,2-Dithiane EtBr BuS(CH,),SEt 97 BuLi 1,2-Dithiane BuBr BuS(CH,),SBu 87 Bu'Li 1,2-Dithiane BuBr Bu'S(CH,),SBu 98 Bu'Li 1,2-Dithiane Bu'Br Bu'S(CH,),SH 77 BuLi 1,2-Dithiane PhCH,Br BuS(CH 2)4SCH ,Ph 78 BuLi 1,2-Dithiane AcCl BuS(CH 2)4SA~ 80 PhLi 1,2-Dithiane BuBr PhS(CH,),SBu 77 PhLi 1,2-Dithiane PhCH,Br PhS(CH2)4SCH,Ph 98 Ph Li 1,2-Dithiane AcBr PhS(CH,),SAc 71 MeLi 1,2-Dithiacyclooctane Me1 MeS(CH,),SMe 67 BuLi BuLi BuLi BuLi 1,2-Dithiacyclooctane 1,2-Dithiacyclooctane 1,2-Dithiacyclooctane 1,2-Dithiacyclooctane BuBr PhCH,Br AcBr C,H, 5Br BuS(CH,),SBu BuS(CH,),SCH,Ph BuS(CH,),SAc BuS(CH2)6SC7H15 85 82 86 69 a Yield of isolated, purified product.All the products were confirmed by spectroscopic and analytical data. References S. C. Mitchell and R. M. Nickson, Surfur Reports, 1993, 13, 161; K. T. Douglas, Acc. Chem. Res., 1986, 19, 186; A. L. Fluharty, The Chemistry ofthe Thiol Group, ed. S. Patai, John Wiley and Sons, New York, 1974, Part 2, p. 589 and references therein; T. C. Bruice and S. J. Benkovic, Bioorganic Mechanisms, Benjamin, New York, 1966, vol. I, p. 259. 2 B. M. Trost, Acc. Chem. Rex, 1978, 11, 453; W. K. Musker, Acc. Chem.Rex, 1980,13,200; E. Vedejs, Ace. Chem. Rex, 1984,17,358; T. Y. Luh, Acc. Chem. Res., 1991,24,257. 3 F. Ogura, T. Otsubo and Y. Aso, Sulfur Reports, 1992, 11, 439; G. Schukat, A. M. Richter and E. Tanghanel, Sulfur Reports, 1987, 7, 155. 4 E. 1. Miranda, M. J. Diaz, I. Rosado and J. A. Soderquist, Tetrahedron Lett., 1994, 35, 3221; P. C. Bulman Page, S. S. Klair, M. P. Brown, C. S. Smith, S. J. Maginn and S. Mulley, Tetrahedron, 1992,48,5933. 5 See, for example: K. Smith, A. Small and M. G. Hutchings, Synlett, 1991, 485; C. M. Lindsay, K. Smith, I. Matthews, W. W. Lam, M. J. Musmar, G. E. Martin, A. F. Hoffschwelle,V. M. Lynch and S. M. Simonsen, Sulfur Lett., 1992,15,68; K. Smith, C. M. Lindsay, I. K. Morris, I. Matthews and G. J.Pritchard, Sulfur Lett., 1994, 17, 197. 6 See, for example: K. Smith and G. J. Pritchard, Angew. Chem., Int. Ed. Engl., 1990,29,282; K. Smith and D. Hou, J. Chem. Soc., Perkin Trans. I, 1995, 185. 7 K. Smith, C. M. Lindsay and G. J. Pritchard, J. Am. Chem. Soc., 1989,111,665. 8 K. Smith, D. Anderson and I. Matthews, Sulfur Lett., 1995, 18,79. 9 B. J. Wakefield, The Chemistry of Organolithium Compounds, Pergamon Press, Oxford, 1974, pp. 192, 214; A. J. Parker and N. Kharasch, Chem. Rev., 1959, 59, 583; M. S. Kharasch and 0. Reinmuth, Grignard Reactions of Non-metallic Substances, ed. S. Oea, Plenum Press, New York, 1977, p. 356. 10 A. Fawa, A. Illiceto and E. Camera, J. Am. Chem. Soc., 1957, 79, 833. 11 M. Ravenscroft, R. M. G. Roberts and J. G. Tillett, J, Chem. Soc., Perkin Trans. 2, 1982, 1569; J. G. Affleck and G. Dougherty, J. Org. Chem., 1950, 15, 865; R. H. Cragg and A. F. Weston, Tetrahedron Lett., 1973, 9, 655; D. N. Harpp, S. J. Bodzay, T. Aida and T. H. Chan, Tetrahedron Lett., 1986, 27, 441; L. Field and R. B. Barbee, J. Org. Chem., 1969,34, 36. 12 M. H. Goodrow and W. K. Musker, Synthesis, 1981,457. 13 P. Dhar, N. Chidambaram and S. Chandrasekaran, J. Org. Chem., 1992,57,1699. 14 J. Houk and G. M. Whitesides, Tetrahedron, 1989,45,91. Paper 5/04965B Received 26th Jury 1995 Accepted 26th Jury 1995