One-Pot Synthesis of Organic Disulfides (Disulfanes) from Alkyl Halides Using Sodium Sulfide Trihydrate and Hexachloroethane or Carbon Tetrachloride in the Poly(ethylene glycol) (PEG-200)

Abstract

Symmetric disulfides are produced by treating their corresponding organic halides including benzylic, allylic, primary and secondary halides with Na₂S·3H₂O and C₂Cl₆ or CCl₄ in PEG-200 at room temperature in high yields.

Key words

disulfides - alkyl halides - sodium sulfide - C₂Cl₆ - CCl₄ - thiols

• References and Notes

• 1 Pattenden G, Shuker A. J. Chem. Soc., Perkin Trans. 1 1992; 1215
• 2a Inaba K. J. Biochem. 2009; 146: 591
• 2b Wedemeyer WJ, Welker E, Narayan M, Scheraga HA. Biochemistry 2000; 39: 4207
• 3 Lee KD, Saito G, Swanson JA. Adv. Drug Delivery Rev. 2003; 55: 199
• 4a Ramadas K, Srinivasan N. Synth. Commun. 1995; 25: 227
• 4b Fisher HL. Ind. Eng. Chem. 1950; 42: 1978
• 5a Dong Y. Sensor. Actuat. B: Chem. 2005; 108: 622
• 5b Shcherbakova I, Pozharskii AF. In Comprehensive Organic Functional Group Transformations II . Vol. 2. Katritzky AR, Taylor R, Ramsden C. Pergamon; Oxford: 2004: 210
• 5c Bulmanb Page PC, Wilkes RD, Reynolds D. In Comprehensive Organic Functional Group Transformations . Vol. 2. Katritzky AR, Meth-Cohn O, Rees CW. Pergamon; Oxford: 1995: 177-187
• 5d Sato R, Kimura T. In Science of Synthesis . Vol. 39. Kambe N, Drabowicz J, Molander GA. Thieme; Stuttgart, New York: 2007: 573-588 ; (also available online)
• 5e Witt D, Klajn R, Barski P, Grzybowski BA. Curr. Org. Chem. 2004; 8: 1763
• 6a Blanco GA, Baumgartner MT. Tetrahedron Lett. 2011; 52: 7061
• 6b Liu Y, Zhang Y, Hu C, Wan J.-P, Wen C. RSC Adv. 2014; 4: 35528
• 6c Taniguchi Y, Maruo M, Takaki K, Fujiwara Y. Tetrahedron Lett. 1994; 35: 7789
• 6d Koval IV. Russ. Chem. Rev. (Engl. Transl.) 1994; 63: 735
• 6e Shirani H, Janosik T. Synthesis 2007; 2690
• 6f Atkinson JG, Hamel P, Girard Y. Synthesis 1988; 480
• 7a Movassagh B, Sobhani S, Kheirdoush F, Fadaei Z. Synth. Commun. 2003; 33: 3103
• 7b Guo W, Chen J, Wu D, Ding J, Chen F, Wu H. Tetrahedron 2009; 65: 5240
• 7c Ranu BC, Mandal T. Can. J. Chem. 2006; 84: 762
• 7d Devan N, Sridhar PR, Prabhu KR, Chandrasekaran S. J. Org. Chem. 2002; 67: 9417
• 8a Movassagh B, Zakinezhad Y. Z. Naturforsch., B 2006; 61: 47
• 8b Ranu BC, Mandal T. Synlett 2004; 1239
• 8c Bartolozzi A, Foudoulakis HM, Cole BM. Synthesis 2008; 2023
• 8d Prabhu KR, Sivanand PS, Chandrasekaran S. Angew. Chem. Int. Ed. 2000; 39: 4316
• 9 Beletskaya I, Moberg C. Chem. Rev. 2006; 106: 2320
• 10a Kodama S, Nishinaka E, Nomoto A, Sonoda M, Ogawa A. Tetrahedron Lett. 2007; 48: 6312
• 10b Holmquist H, Carnahan J. J. Org. Chem. 1960; 25: 2240
• 10c Nishiyama Y, Kawamatsu H, Sonoda N. J. Org. Chem. 2005; 70: 2551
• 10d Kodama S, Nishinaka E, Nomoto A, Sonoda M, Ogawa A. Tetrahedron Lett. 2007; 48: 6312
• 11a Kondo T, Mitsudo T. Chem. Rev. 2000; 100: 3205
• 11b Yamagiwa N, Suto Y, Torisawa Y. Bioorg. Med. Chem. Lett. 2007; 17: 6197
• 11c Taniguchi N. Synlett 2008; 849
• 11d Sengupta D, Basu B. Tetrahedron Lett. 2013; 54: 2277
• 12a Witt D. Synthesis 2008; 2491
• 12b Mandal B, Basu B. RSC Adv. 2014; 4: 13854
• 13a Wang JX, Gao L, Huang D. Synth. Commun. 2002; 32: 963
• 13b Bandgar BP, Uppalla LS, Sadavarte VS. Tetrahedron Lett. 2001; 42: 6741
• 13c Kiasat AR, Mokhtari B, Kazemi F, Yousefi S, Javaherian M. J. Sulfur Chem. 2007; 28: 171
• 14a Hase TA, Perakyla H. Synth. Commun. 1982; 12: 947
• 14b Kamyshny A, Ekeltchlk I, Gun J, Lev O. Anal. Chem. 2006; 78: 2631
• 14c Weyerstahl P, Oldenburg T. Flavour Fragr. J. 1998; 13: 177
• 14d Krein EB, Aizenshtat Z. J. Org. Chem. 1993; 58: 6103
• 14e Gopalan AS, Jacobs HK. J. Chem. Soc., Perkin Trans. 1 1990; 1897
• 14f Sonavane SU, Chidambaram M, Almog J, Sasson Y. Tetrahedron Lett. 2007; 48: 6048
• 14g Schneider HB, Rager H. Monatsh. Chem. 1950; 81: 970
• 15 Bandgar BP, Uppalla LS, Sadavarte VS. Tetrahedron Lett. 2001; 42: 6741
• 16a Firouzabadi H, Iranpoor N, Abbasi M. Tetrahedron Lett. 2010; 51: 508
• 16b Firouzabadi H, Iranpoor N, Abbasi M. Bull. Chem. Soc. Jpn. 2010; 83: 698
• 16c Abbasi M, Mohammadizadeh MR, Taghavi ZK. J. Iran Chem. Soc. 2013; 10: 201
• 17a Ghosh S, Easwaran KR. K, Bhattacharya S. Tetrahedron Lett. 1996; 37: 5769
• 17b Sridhar PR, Prabhu KR, Chandrasekaran S. Eur. J. Org. Chem. 2004; 4809
• 17c Bhar D, Chandrasekaran S. Carbohydr. Res. 1997; 301: 221
• 17d Ilankumaran P, Prabhu KR, Chandrasekaran S. Synth. Commun. 1997; 27: 4031
• 18 Sinha S, Ilankumaran P, Chandrasekaran S. Tetrahedron 1999; 55: 14769
• 19 Prabhu KR, Ramesha AR, Chandrasekaran S. J. Org. Chem. 1995; 60: 7142
• 20 Devan N, Sridhar PR, Prabhu KR, Chandrasekaran S. J. Org. Chem. 2002; 67: 9417
• 21 Sureshkumar D, Gunasundari T, Ganesh V, Chandrasekaran S. J. Org. Chem. 2006; 72: 2106
• 22 Distler H. Angew. Chem. Int. Ed. 1967; 6: 544
• 23a Wang L, Li P, Zhou L. Tetrahedron Lett. 2002; 43: 8141
• 23b Wang L, Zhang Y. Tetrahedron 1999; 55: 10695
• 23c Li P, Wang L, Yang Y, Sun X, Wang M, Yan J. Heteroat. Chem. 2004; 15: 376
• 23d Liu Y, Zheng H, Xu D, Xu Z, Zhang Y. Synlett 2006; 2492
• 24 Milligan B, Swan JM. J. Chem. Soc. 1962; 2172
• 25 General Procedure: Na₂S·3H₂O (0.291 g, 2.2 mmol) was added to a magnetically stirred solution of an alkyl halide (2 mmol) and C₂Cl₆ or CCl₄ (1.5 mmol) in PEG-200 (2 mL) at r.t. The stirring was continued until the starting halide was completely consumed (30–150 min). Next, the reaction mixture was diluted with H₂O (1 mL) and extracted with EtOAc–hexane (1:1; 4 × 2 mL). The organic extracts were combined, concentrated and purified by chromatography on silica gel. The desired disulfides were produced in excellent yields (Table 1). Benzyl Disulfide (1): white crystals; mp 68–70 °C [Lit.^13c mp 69–70 °C]. ¹H NMR (400 MHz, CDCl₃): δ = 7.26–7.34 (m, 10 H), 3.61 (s, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 138.6, 130.7, 129.7, 128.7, 44.4. Anal. Calcd for C₁₄H₁₄S₂: C, 68.25; H, 5.73; S, 26.02. Found: C, 68.12; H, 5.69; S, 26.19. Bis(2-methylbenzyl) Disulfide (4): white crystals; mp 71–73 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.13–7.21 (m, 8 H), 3.67 (s, 4 H), 2.38 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 135.8, 134.0, 129.5, 129.4, 126.7, 124.9, 40.5, 18.2. Anal. Calcd for C₁₆H₁₈S₂: C, 70.02; H, 6.61; S, 23.37. Found: C, 69.94; H, 6.50; S, 23.56. Bis(3-methylbenzyl) Disulfide (5): yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.20–7.26 (m, 2 H), 7.04–7.14 (m, 6 H), 3.60 (s, 4 H), 2.36 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 137.1, 136.2, 129.1, 127.4, 127.2, 125.4, 42.3, 20.4. Anal. Calcd for C₁₆H₁₈S₂: C, 70.02; H, 6.61; S, 23.37. Found: C, 70.16; H, 6.52; S, 23.32. Bis(4-methylbenzyl) Disulfide (6): colorless oil. ¹H NMR (250 MHz, CDCl₃): δ = 7.05–7.33 (m, 8 H), 3.71 (s, 4 H), 2.21 (s, 6 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 137.6, 134.8, 129.8, 129.1, 43.1, 21.4. Anal. Calcd for C₁₆H₁₈S₂: C, 70.02; H, 6.61; S, 23.37. Found: C, 70.05; H, 6.49; S, 23.46. Bis(2-chlorobenzyl) disulfide (8): yellow crystals; mp70–72 °C [Lit.²⁷ mp 74 °C]. ¹H NMR (400 MHz, CDCl₃): δ = 7.19–730 (m, 2 H), 7.11–7.19 (m, 6 H), 3.70 (s, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 133.9, 133.1, 130.5, 128.8, 127.9, 125.7, 40.0. Anal. Calcd for C₁₄H₁₂Cl₂S₂: C, 53.34; H, 3.84; S, 20.34. Found: C, 53.21; H, 3.77; S, 20.42. n-Decyl Disulfide (13): colorless oil. ¹H NMR (250 MHz, CDCl₃): δ = 2.64 (t, J = 7.3 Hz, 4 H), 1.59–1.71 (m, 4 H), 1.21–1.35 (m, 28 H), 0.82 (t, J = 6.2 Hz, 6 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 39.2, 31.8, 29.6, 29.5, 29.3, 29.2, 29.0, 28.5, 22.8, 14.2. Anal. Calcd for C₂₀H₄₂S₂: C, 69.29; H, 12.21; S, 18.50. Found: C, 69.16; H, 12.26; S, 18.58. Cyclopentyl Disulfide (18): colorless oil. ¹H NMR (250 MHz, CDCl₃): δ = 3.39–3.45 (m, 2 H), 1.94–1.97 (m, 4 H), 1.51–1.69 (m, 12 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 50.7, 32.9, 24.7. Anal. Calcd for C₁₀H₁₈S₂: C, 59.35; H, 8.97; S, 31.68. Found: C, 59.51; H, 8.99; S, 31.50. Cyclohexyl Disulfide (19): colorless oil. ¹H NMR (250 MHz, CDCl₃): δ = 2.64–2.73 (m, 2 H), 1.99–2.06 (m, 4 H), 1.70–1.82 (m, 4 H), 1.52–1.64 (m, 2 H), 1.17–1.31 (m, 10 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 50.1, 32.7, 26.1, 25.7. Anal. Calcd for C₁₂H₂₂S₂: C, 62.55; H, 9.62; S, 27.83. Found: C, 62.40; H, 9.75; S, 27.85. Bis(3-hydroxypropyl)disulfide (21): colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 3.78 (t, J = 6.0 Hz, 4 H), 3.02–3.14 (m, 4 H), 2.82 (br s, 2 H), 2.00–2.08 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 60.9, 35.2, 31.5. Anal. Calcd for C₆H₁₄O₂S₂: C, 39.53; H, 7.74; S, 35.17. Found: C, 39.72; H, 7.89; S, 34.98.
• 26 Typical Scale-Up Procedure for the Preparation of n-Octyl Disulfide: Na₂S·3H₂O (4.365g, 33 mmol) was added to a magnetically stirred solution of n-octyl bromide (5.182 mL, 30 mmol) and CCl₄ (2.25 mL, 22.5 mmol) in PEG-200 (30 mL) at r.t. The starting halide was completely consumed within 90 min. Then, the mixture was diluted with H₂O (15 mL) and extracted with EtOAc–hexane (1:1; 4 × 15 mL). The upper layers were decanted, combined, and concentrated. The crude product was purified by silica gel chromatography using n-hexane as eluent to provide octyl disulfide in 88% yield (3.836 g) yield. n-Octyl Disulfide (12): colorless oil. ¹H NMR (250 MHz, CDCl₃): δ = 2.64 (t, J = 7.3 Hz, 4 H), 1.53–1.68 (m, 4 H), 1.27–1.36 (m, 20 H), 0.81 (t, J = 6.2 Hz, 6 H); ¹³C NMR (62.5 MHz, CDCl₃): δ = 39.2, 31.7, 29.4, 29.2, 29.1, 28.6, 22.7, 14.1. Anal. Calcd for C₁₆H₃₄S₂: C, 66.14; H, 11.79; S, 22.07. Found: C, 65.99; H, 11.81; S, 22.20.
• 27 Srivastava SK, Rastogi R, Rajaram P, Butcher RJ, Jasinski JP. Phosphorus, Sulfur, Silicon Relat. Elem. 2010; 185: 455