Rapid Transformation of Alkyl Halides into Symmetrical Disulfides Using Sodium Sulfide and Carbon Disulfide

Abstract

An efficient one-pot reaction has been developed for the preparation of symmetrical disulfide derivatives directly from alkyl halides by reaction with a combination of sodium sulfide and carbon disulfide without requirement for any catalyst.

Key words

alkyl halides - carbohydrates - disulfides - sodium sulfide - carbon disulfide

Organic disulfides are an important class of compounds that have applications in organic synthesis,[1] biological studies,[2] drug delivery,[3] and the polymer industry.[4] Stabilization of protein structure due to the formation of disulfide bridges is common in biological systems[5] and ligation through the formation of disulfide linkage is often used in the functionalization of proteins.[6] Several bioactive molecules contain disulfide bonds as active pharmacophores.[7] Disulfide compounds are used as vulcanizing agents for rubber.[8]

Several reports have appeared on the preparation of disulfides by the oxidation of thiols using a variety of reagents,[9] electrochemical oxidation[10] and enzymatic reaction.[11] They have also been prepared from thiol acetates using clayfen under solvent-free conditions.[12] Alkyl halides could be considered as lower odor alternatives of thiols for the preparation of disulfide derivatives. The preparation of disulfides starting from alkyl halides using sodium sulfide in the presence of a phase-transfer catalyst[13] and hexachloroethane, carbon tetrachloride or thiourea in PEG medium has been reported.[14] In addition, disulfides have been prepared from alcohols,[15] thiocyanates,[16] epoxides,[17] aziridines,[18] and S-alkylthiosulfates (Bunte salts).[19] Despite their synthetic utilities, the above mentioned approaches suffer from shortcomings, which include the use of malodorous thiols, requirement of special reaction conditions, hazardous reagents, extended reaction times, high temperatures, unsatisfactory yield and limited substrate scope. In the search for efficient reaction conditions for the preparation of symmetrical disulfides, we have explored the reaction of alkyl halides with a combination of sodium sulfide (Na₂S·9H₂O) and carbon disulfide (CS₂) (Scheme [1]). Recently, we have used the combination of Na₂S·9H₂O and CS₂ as a surrogate of hydrogen sulfide for the formation of glycosyl thiol derivatives.[20] During the preparation of glycosyl thiols it was observed that variation of the ratio of Na₂S·9H₂O and CS₂ as well as the presence of substituents on the sugar ring led to the formation of disulfide derivatives. In fact, sodium sulfide has been used to react with alkyl halides to produce symmetrical sulfides in the presence of a phase-transfer catalyst.[13] To our satisfaction, we found that the disulfide derivatives were formed almost instantly by mixing the substrates and the reagent system without formation of symmetrical thioethers as by-products. In this communication, we present the fast, efficient preparation of symmetrical disulfide derivatives directly from alkyl halides in excellent yield.

Scheme 1 Synthesis of symmetrical disulfides from alkyl halides using a combination of sodium sulfide and carbon disulfide at room temperature

Table 1 Reaction of Benzyl Bromide with Na₂S·9H₂O and CS₂ in Different Solvents at Room Temperature

Entry	Na2S·9H2O (equiv)	CS2 (equiv)	Solvent	Time (min)	Yield (%)
1	1.0	1.0	DMF	2	96
2	1.0	0.5	DMF	10	55
3	0.5	1.0	DMF	10	65
4	1.5	1.5	DMF	2	96
5	1.0	1.0	DMSO	2	95
6	1.0	1.0	THF	30	68
7	1.0	1.0	CH3CN	60	70
8	1.0	1.0	CH2Cl2	120	48
9	1.0	1.0	CH3OH	10	64
10	1.0	1.0	H2O	720	52
11	–	1.0	DMF	720	–
12	1.0	–	DMF	720	20

In initial experiments, benzyl bromide was added to a varied stoichiometric combination Na₂S·9H₂O and CS₂ in DMF at room temperature. It was observed that treatment of benzyl bromide (1.0 mmol) with a combination of Na₂S·9H₂O (1.0 mmol) and CS₂ (1.0 mmol) in DMF at room temperature instantaneously furnished dibenzyl disulfide 7 in 96% yield. Reduction of the quantity of either Na₂S·9H₂O or CS₂ resulted in the formation of product 7 in poor yield due to the formation of thioether derivatives. However, increasing the quantity of the reagents did not improve the yield significantly. The reaction did not take place in the absence of either Na₂S·9H₂O or CS₂ (Table [1]). Notably, the reaction does not require any metallic or phase-transfer catalyst. Commonly used solvents such as CH₂Cl₂, THF, CH₃CN, DMF, DMSO, CH₃OH, and H₂O were screened for their suitability to carry out the reaction. Excellent yields of 7 were obtained by carrying out the reaction in DMF and DMSO due to the high solubility of the reagents compared with other solvents (Table [1]). However, DMF was considered as the preferred solvent due to the drawbacks associated with DMSO such as high boiling point, unpleasant odor and scope for formation of by-products. Although earlier Na₂S·9H₂O-mediated thiolation reactions were carried out in water or CH₃OH at high temperature or in the presence of a phase-transfer catalyst, under these conditions a satisfactory yield of the product was not obtained; presumably due to the loss of carbon disulfide at high temperature. Following the optimization studies, a series of symmetrical disulfide derivatives was prepared in excellent yield (Table [2]).[23] The reaction conditions were also successfully applied for the preparation of the O-glycosylated alkyl disulfide derivatives. The functional groups present in the sugar moieties were compatible with the reaction conditions. A variety of alkyl halides were used for the preparation of disulfide derivatives. The reaction is exceptionally fast and disulfide derivatives were obtained exclusively within 2–5 min. The reaction has been successfully applied for a scaled-up (20 g) preparation of dibenzyl disulfide (7) in excellent yield (Table [2]). All products were unambiguously characterized by spectroscopic analysis.[24]

Table 2 Preparation of Disulfides from Alkyl Halides using Na₂S·9H₂O (1.0 mmol) and CS₂ (1.0 mmol) in DMF at Room Temperature

Entry	Alkyl halide	R	Product	Time (min)	Yield (%)a	M.p. (°C)	Ref.
1	propyl bromide	propyl	1	2	88	syrup	[14a]
2	butyl bromide	butyl	2	2	90	syrup	[13]
3	2-propyl bromide	2-propyl	3	2	86	syrup	[14a]
4	allyl bromide	allyl	4	2	95	syrup	[13]
5	prenyl bromide	prenyl	5	2	95	syrup	[14a]
6	dodecyl bromide	dodecyl	6	5	92	syrup	[15b]
7	benzyl bromide	benzyl	7	2	96 (95)b	69–70	[14a]
8	4-methoxybenzyl chloride	4-methoxybenzyl	8	4	95	88–90	[14a]
9	2-naphthyl methyl bromide	2-naphthylmethyl	9	5	90	85–86	[13b]
10			10	2	95	syrup	[12]
11			11	5	90	syrup	–
12			12	5	86	syrup	–
13			13	5	85	syrup	–
14			14	5	90	91–92	[21]
15			15	5	92	syrup	[22]

^a Isolated yield.

^b Scale up preparation.

A plausible mechanistic pathway is presented in Scheme [2]. Presumably, the reaction of Na₂S·9H₂O and CS₂ generates a carbonotrithioate ion in situ, which displaces the halide ion in the alkyl halide by nucleophilic substitution to furnish an alkyl thiolate ion after regenerating CS₂. Finally, oxidative condensation of alkyl thiolates results in the formation of the symmetrical disulfide.

Scheme 2 Plausible mechanism for the formation of symmetrical disulfides

In summary, an exceptionally fast reaction has been developed for the direct preparation of symmetrical disulfide derivatives in excellent yield from alkyl and glycosylalkyl halides by using a combination of Na₂S·9H₂O and CS₂.[23] This clean, catalyst-free reaction is suitable for scale-up. By applying these reaction conditions, a diverse range of disulfide derivatives of non-commercial thiols can also be prepared in excellent yield.

Acknowledgment

I.B. thanks CSIR, New Delhi for providing a Senior Research Fellowship. This work was supported by SERB, New Delhi (Project No. EMR/2015/000282).

• References

• 1a Karchmer JH. The Analytical Chemistry of Sulfur and Its Compounds . Wiley; New York: 1972
• 1b Oae S. Organic Sulfur Chemistry: Structure and Mechanism . CRC Press; Boca Raton, FL: 1991
• 1c Johnson JR. Bruce WF. Dutcher JD. J. Am. Chem. Soc. 1943; 65: 2005
• 2a Bodanszky M. Principles of Peptide Synthesis . Springer; Berlin: 1984. Chap. 4, 119-157
• 2b Patai S. Chemistry of the Thiol Groups . Wiley & Sons; New York: 1974: 785
• 3a Saito G. Swanson JA. Lee KD. Adv. Drug Delivery Rev. 2003; 55: 199
• 3b Lee MH. Sessler JL. Kim JS. Acc. Chem. Res. 2015; 48: 2935
• 4a Graf TA. Yoo J. Brummett AB. Lin R. Wohlgenannt M. Quinn D. Bowden NB. Macromolecules 2012; 45: 8193
• 4b Gyarmati B. Némethy Á. Szilágui Eur. Polym. J. 2013; 49: 1268
• 4c Zelikin AN. Quinn JF. Caruso F. Biomacromolecules 2006; 7: 27
• 5a Trivedi MV. Laurence JS. Siahaan TJ. Curr. Protein Pept. Sci. 2009; 10: 614
• 5b Oka OB. V. Bulleid NJ. Biochim. Biophys. Acta, Mol. Cell Res. 2013; 1833: 2425
• 6a Marshall CJ. Agarwal N. Kalia J. Grosskopf VA. McGrath NA. Abbott NL. Raines RT. Shusta EV. Bioconjugate Chem. 2013; 24: 1634
• 6b van Vught R. Pieters RJ. Breukink E. Comput. Struct. Biotechnol. J. 2014; 9: e201402001
• 7a Góngora-benitez M. Tulla-Puche J. Albericio F. Chem. Rev. 2014; 114: 901
• 7b Brady RM. Baell JB. Norton RS. Mar. Drugs 2013; 11: 2293
• 8a Adhikari B. De D. Maiti S. Prog. Polym. Sci. 2000; 25: 909
• 8b Sonavane SU. Chidambaram M. Almog J. Sasson Y. Tetrahedron Lett. 2007; 48: 6048
• 9a Iranpoor N. Firouzabadi H. Pourali AR. Tetrahedron 2002; 58: 5179
• 9b Silveira CC. Mendes SR. Tetrahedron Lett. 2007; 48: 7469
• 9c Akdag A. Webb T. Worley SD. Tetrahedron Lett. 2006; 47: 3509
• 9d Olah GA. Arvanaghi M. Vankar YD. Synthesis 1979; 721
• 9e Mckillop A. Koyuncu D. Krief A. Dumont W. Renier P. Trabelsi M. Tetrahedron Lett. 1990; 31: 5007
• 9f Fujihara H. Mima H. Ikemori M. Furukawa N. J. Am. Chem. Soc. 1991; 113: 6337
• 9g Kirihara M. Okubo K. Uchiyama T. Kato Y. Ochiai Y. Matsushita S. Hatano A. Kanamori K. Chem. Pharm. Bull. 2004; 52: 625
• 9h Ali MH. McDermott M. Tetrahedron Lett. 2002; 43: 6271
• 9i Iranpoor N. Zeynizadeh B. Synthesis 1999; 49
• 9j Sato T. Otera J. Nozaki H. Tetrahedron Lett. 1990; 31: 3591
• 9k Misra AK. Agnihotri G. Synth. Commun. 2004; 34: 1079
• 9l Kirihara M. Asai Y. Ogawa S. Noguchi T. Hatano A. Hirai Y. Synthesis 2007; 3286
• 9m Hosseinpoor F. Golchoubian H. Catal. Lett. 2006; 111: 165
• 9n Lenardao EJ. Lara RG. Silva MS. Raquel G. Jacob RG. Perin G. Tetrahedron Lett. 2007; 48: 7668
• 9o Firouzabadi H. Mottghinejad E. Seddighi M. Synthesis 1989; 378
• 10 Sergio LS. Pardini VL. Viertler H. Synth. Commun. 1990; 20: 393
• 11 Rao KR. Kumar HM. S. Bioorg. Med. Chem. Lett. 1991; 1: 507
• 12 Meshram HM. Tetrahedron Lett. 1993; 34: 2521
• 13a Sonavane SU. Chidambaram M. Almog J. Sasson Y. Tetrahedron Lett. 2007; 48: 6048
• 13b Wang J.-X. Cui W. Hu Y. Synth. Commun. 1995; 25: 3573
• 14a Abbasi M. Mohammadizadeh MR. Moosavi H. Saeedi N. Synlett 2015; 26: 1185
• 14b Firouzabadi H. Iranpoor N. Abbasi M. Tetrahedron Lett. 2010; 51: 508
• 15a Sinha S. Ilankumaran P. Chandrasekaran S. Tetrahedron 1999; 55: 14769
• 15b Iranpoor N. Firouzabadi H. Khalili D. Tetrahedron Lett. 2012; 53: 6913
• 16 Prabhu KR. Ramesha AR. Chandrasekaran S. J. Org. Chem. 1995; 60: 7142
• 17 Devan N. Sridhar PR. Prabhu KR. Chandrasekaran S. J. Org. Chem. 2002; 67: 9417
• 18 Sureshkumar D. Gunasundari T. Ganesh V. Chandrasekaran S. J. Org. Chem. 2006; 72: 2106
• 19a Liu Y. Zheng H. Xu D. Xu Z. Zhang Y. Synlett 2006; 2492
• 19b Wang L. Zhang Y. Tetrahedron 1999; 55: 10695
• 20 Jana M. Misra AK. J. Org. Chem. 2013; 78: 2680
• 21 Liu C.-Y. Chen H.-L. Ko C.-M. Chen C.-T. Tetrahedron 2011; 67: 872
• 22 Adinolfi M. Capasso D. Gaetano SD. Iadonisi A. Leone L. Pastore A. Org. Biomol. Chem. 2011; 9: 6278
• 23 Typical experimental procedure for the preparation of symmetrical dialkyl disulfides: To a solution of Na₂S·9H₂O (1.0 mmol) in DMF (2 mL) was added CS₂ (1.0 mmol) at room temperature. The alkyl halide (1.0 mmol) was added to the dark-red reaction mixture at room temperature with vigorous stirring. The color of the reaction mixture changed from red to yellow. The reaction mixture was stirred for the appropriate time (Table 2), then poured into water and extracted with Et₂O (2 × 25 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified over SiO₂ using hexane–EtOAc (15:1) as eluant to give the pure dialkyl disulfide derivative (Table 2)
• 24 Spectroscopic data of novel products:Di[2-O-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)ethyl] Disulfide (11): Yield: 733 mg (90%); Colorless oil; ¹H NMR (500 MHz, CDCl₃): δ = 5.18 (t, J = 7.5 Hz, 2 H), 5.08 (t, J = 9.5 Hz, 2 H), 4.97 (m, 2 H), 4.55 (d, J = 9.0 Hz, 2 H), 4.26 (dd, J = 4.5, 8.0 Hz, 2 H), 4.14–3.95 (m, 4 H), 3.89–3.60 (m, 4 H), 2.96–2.71 (m, 4 H), 2.09, 2.06, 2.02, 2.00 (4 × s, 24 H); ¹³C NMR (125 MHz, CDCl₃): δ = 170.2 (2 C), 169.9 (2 C), 169.0 (2 C), 168.9 (2 C), 100.7 (2 C), 72.7 (2 C), 72.6 (2 C), 71.8 (2 C), 69.6 (4 C), 67.6 (2 C), 61.7 (2 C), 38.3 (2 C), 20.5 (8 C); HRMS (ESI): m/z [M+Na]⁺ calcd. for C₃₂H₄₆O₂₀S₂: 837.1922; found: 837.1916.Di[2-O-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl)ethyl] Disulfide (12): Yield: 700 mg (86%); Colorless oil; ¹H NMR (500 MHz, CDCl₃): δ = 5.39-5.31 (m, 2 H), 5.20–5.13 (m, 2 H), 5.05–4.95 (m, 2 H), 4.50 (d, J = 8.0 Hz, 2 H), 4.19–4.09 (m, 4 H), 4.05–3.89 (m, 2 H), 3.81–3.61 (m, 2 H), 2.91–2.71 (m, 4 H), 2.16, 2.07, 2.05, 1.98 (4 × s, 24 H); ¹³C NMR (125 MHz, CDCl₃): δ = 170.1 (2 C), 170.0 (2 C), 169.9 (2 C), 169.2 (2 C), 101.4 (2 C), 70.8 (4 C), 70.7 (2 C), 68.7 (4 C), 66.9 (2 C), 61.1 (2 C), 20.7 (8 C); HRMS (ESI): m/z [M+Na]⁺ calcd. for C₃₂H₄₆O₂₀S₂: 837.1922; found: 837.1917.Di-[2-O-(2,3,4-tri-O-acetyl-α-l-rhamnopyranosyl)ethyl] Disulfide (13): Yield: 594 mg (85%); Colorless oil; ¹H NMR (500 MHz, CDCl₃): δ = 5.31–5.19 (m, 4 H), 5.05 (t, J = 9.5 Hz, 2 H), 4.76 (s, 2 H), 3.98–3.88 (m, 2 H), 3.85–3.69 (m, 4 H), 2.98–2.81 (m, 4 H), 2.15, 2.08, 1.98 (3 × s, 18 H), 1.22 (d, J = 6.0 Hz, 6 H); ¹³C NMR (125 MHz, CDCl₃): δ = 169.9 (2 C), 169.8 (2 C), 169.7 (2 C), 97.5 (2 C), 70.9 (2 C), 70.6 (2 C), 69.7 (2 C), 69.0 (2 C), 66.6 (2 C), 66.3 (2 C), 38.2 (2 C), 20.8 (6 C), 17.4 (2 C); HRMS (ESI): m/z [M+Na]⁺ calcd. for C₂₈H₄₂O₁₆S₂: 721.1812; found: 721.1806