Synthesis of Disulfanes from Organic Thiocyanates Mediated by Sodium in Silica Gel

Article abstract of DOI:10.1055/s-0035-1560368

We report an efficient procedure for the synthesis of symmetrical disulfanes from organic thiocyanates in the presence of sodium in silica gel at room temperature. By avoiding the use of foul-smelling thiols, the present protocol provides an attractive alternative to existing methods for the preparation of symmetrical disulfanes.

Full text of DOI:10.1055/s-0035-1560368

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, 409–411
letter
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C. K. Maurya et al.
Letter
Synlett
Synthesis of Disulfanes from Organic Thiocyanates Mediated by
Sodium in Silica Gel
Chandra Kant Maurya
Avik Mazumder
N
R
S
sodium in silica gel
THF, r.t.
R
C
S
R
S
Ajeet Kumar
13 examples
78–89%
R = alk, Bn
Pradeep Kumar Gupta*
Defence Research & Development Establishment (DRDE),
Jhansi Road, Gwalior (MP)-474002, India
pkgupta@drde.drdo.in
pr_14@rediffmail.com
Received: 12.08.2015
Accepted after revision: 05.10.2015
Published online: 09.11.2015
for the synthesis of symmetrical disulfanes from organic
thiocyanates in the presence of sodium in silica gel (Na_SG)
as the reducing agent (Scheme 1).
DOI: 10.1055/s-0035-1560368; Art ID: st-2015-d0633-l
Abstract We report an efficient procedure for the synthesis of sym-
metrical disulfanes from organic thiocyanates in the presence of sodi-
um in silica gel at room temperature. By avoiding the use of foul-smell-
ing thiols, the present protocol provides an attractive alternative to
existing methods for the preparation of symmetrical disulfanes.
N
R
S
Na_SG
R
C
S
R
S
THF, r.t.
R = alkyl, benzyl
Scheme 1 Conversion of organic thiocyanates into the corresponding
disulfanes in the presence of sodium encapsulated in silica gel (Na_SG)
Key words disulfides, reduction, thiocyanates, coupling, sodium
Alkali metals encapsulated in nanostructured porous
oxides, such as silica gel, are free-flowing black powders
that are more convenient and safer to handle than metallic
sodium.13 Sodium in silica gel can be easily handled in the
open air without loss of activity, and is safer to quench than
sodium. This reagent has shown its usefulness in a variety
of applications, including Birch reduction, ester reduction,
detosylation, desulfurization, cleavage of arylphosphines to
metal phosphides, and decarbamoylation of primary carba-
mates.14 The thiocyanates used in this study were synthe-
sized by the reaction of the corresponding alkyl halide with
potassium thiocyanate in refluxing propylene glycol.15
To optimize the conditions for our reaction,16 we chose
benzyl thiocyanate as the model substrate. Initially, we per-
formed the reactions in various organic solvents and we
found that the best results were obtained in tetrahydrofu-
ran with four equivalents of sodium in silica gel, which gave
an 85% yield of dibenzyl disulfide in one hour (Table 1, en-
try 1). The reaction was also fast in acetonitrile, but the
yield was somewhat lower (entry 2). In diethyl ether, the
reaction was sluggish (4 h) and gave a lower yield (entry 4).
Toluene was found to be inefficient for this reaction, giving
a 30% yield in four hours (entry 3), whereas no reaction oc-
curred in N,N-dimethylformamide (entry 5).
Disulfanes (R–S–S–R), often called organic disulfides,
have applications encompassing several areas of the syn-
thetic, biochemical, and agrochemical sciences.1 They have
been used as vulcanizing agents for rubbers or elastomers
to increase their tensile strength.2 Furthermore, the disul-
fane moiety occurs widely in a variety of small-molecule
natural products, pharmacologically active compounds,
and proteins.3 Cyclic and acyclic disulfanes are useful inter-
mediates in synthesis4 or in the preparation of adsorbed
monolayers.5 Consequently, owing to the versatility of di-
sulfanes, the search for efficient, mild, and inexpensive
methods for the preparation of these compounds remains
an important area of research. Conventionally, symmetrical
disulfanes are prepared by oxidation of thiols,6 a reaction
that often leads to concomitant formation of appreciable
amounts of trimers and polymers.7 As an alternate to the
use of foul-smelling thiols, organic thiocyanates have also
been reported as suitable substrates for preparation of di-
sulfanes by reductive dimerization in the presence of sever-
al reagents, including tetrathiomolybdate,8 polyionic resin
hydroxide,7 samarium(II) iodide,9 titanium(IV) chloride/sa-
marium,10 tetrabutylammonium fluoride,11 or Streptomyces
aureofaciens.12 In this context, we report a simple method
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 409–411

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C. K. Maurya et al.
Letter
Synlett
Table 1 Effect of the Reaction Medium on the Reductive Dimerization
of Benzyl Thiocyanate with Na_SG
Mechanistically (Scheme 2) the reaction might involve
generation of a nucleophilic thiolate anion by dissociative
electron transfer from sodium metal to the thiocyanate.18
The thiolate ion then participates in nucleophilic attack on
another thiocyanate molecule to displace the cyanide ion,
resulting in the formation of the disulfide product. The in-
volvement of a nucleophilic thiolate ion in the reaction is
supported by the observation that the reaction is sluggish
for benzyl thiocyanates bearing electron-withdrawing sub-
stituents on the phenyl ring, whereas it is promoted by the
presence of an electron-donating methoxy group on the
phenyl ring.
Entry
Solvent
Time (h)
Yield (%)
1
2
3
4
5
THF
1
1
4
4
4
85
80
35
70
–
MeCN
toluene
Et2O
DMF
a General reaction conditions: BnSCN (1.0 mmol), Na_SG (4.0 mmol), sol-
vent (5 mL).
e–
CN–
RCH2SCN
RCH2S •
RCH2S–
RCH2S•
+
+
+
+
On the basis of these results, we extended the method
to other thiocyanates (Table 2) and found that it was effec-
tive for the conversion of various alkyl or benzylic thiocya-
nates into the corresponding disulfanes. Good product
yields were obtained in short times with all the substrates
investigated. Furthermore, the reaction was found to toler-
ate a variety of functional groups, including ether and ester
linkages, halo groups, or triple bonds. However, the pres-
ence of a nitro group on the phenyl ring (entry 14) had a
marked effect on the reaction, and no disulfide product was
obtained with this substrate.
e–
RCH2S–
RCH2SSCH2R
CN–
RCH2SCN
+
Scheme 2 Proposed mechanism for the conversion of thiocyanates to
disulfanes in the presence of Na_SG
In conclusion, we have developed a protocol for the re-
ductive dimerization of organic thiocyanates to the corre-
sponding disulfanes with sodium in silica gel. The reaction
proceeds under mild conditions at room temperature to
give good product yields. It represents an attractive alterna-
tive to existing methods for the synthesis of symmetrical
disulfanes from the corresponding thiocyanates.
Table 2 Preparation of Symmetrical Disulfanes from Thiocyanate
Entry
Reactant
Product
Time
(min)
Yielda
(%)
1
2
BnSCN
(BnS)2
60
40
85b
84b
80
79
87
78
88
87
89
83
82
88
78
–
Acknowledgements
PrSCN
(PrS)2
The authors thank Dr. Lokendra Singh, Director, DRDE, Gwalior, and
Dr. D. K. Dubey, Head, Synthetic Chemistry Division, for their support
and encouragement.
3
BuSCN
(BuS)2
60
4
PhO(CH2)3SCN
PhS(CH2)2SCN
BzO(CH2)2SCN
2-ClC6H4CH2SCN
3-ClC6H4CH2SCN
3-BrC6H4CH2SCN
4-MeOC6H4CH2SCN
Ph(CH2)2SCN
3-FC6H4CH2SCN
HC≡C(CH2)2SCN
4-O2NC6H4CH2SCN
[PhO(CH2)3S]2
[PhS(CH2)2S]2
[BzO(CH2)2S]2
(2-ClC6H4CH2S)2
(3-ClC6H4CH2S)2
(3-BrC6H4CH2S)2
(4-MeOC6H4CH2S)2
[Ph(CH2)2S]2
(3-FC6H4CH2S)2
[HC≡C(CH2)2S]2
–
120
120
120
180
180
180
120
75
5
6
Supporting Information
7
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560368.
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References and Notes
(1) (a) Jocelyn, P. C. Biochemistry of the SH Group: The Occurrence,
Chemical Properties, Metabolism and Biological Function of Thiols
and Disulphides; Academic Press: London, 1972. (b) Bodzansky,
M. Principles of Peptide Synthesis; Springer: Berlin, 1984.
(c) Capozzi, G.; Madona, G. In The Chemistry of the Thiol Group;
Vol. II; Patai, S., Ed.; Chap. 17; Wiley: Chichester, 1974, 785.
(2) (a) Ramadas, K.; Srinivasan, N. Synth. Commun. 1995, 25, 227.
(b) Fisher, H. L. Ind. Eng. Chem. 1950, 42, 1978.
100
90
120
a Yield of isolated product.
b Identified by comparison of physical data with those of authentic samples
available commercially; other products were characterized by spectroscopic
analysis.17
(3) (a) Kishi, Y.; Nakatsuga, S.; Fukuyama, T.; Havel, M. J. Am. Chem.
Soc. 1973, 95, 6493. (b) Ito, S.; Ota, A.; Suhara, H.; Tabashi, K.;
Kawashima, Y. Chem. Pharm. Bull. 1993, 41, 1066.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 409–411

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C. K. Maurya et al.
Letter
Synlett
(4) (a) Tazaki, M.; Tagaki, M. Chem. Lett. 1979, 767. (b) Caserio, M.
C.; Fisher, C. L.; Kim, J. K. J. Org. Chem. 1985, 50, 4390. (c) Koval,
I. V. Russ. Chem. Rev. 1994, 63, 735. (d) Billard, T.; Langlois, B. R.
Tetrahedron Lett. 1996, 37, 6865.
H), 6.87–6.95 (m, 5 H), 7.25–7.29 (m, 5 H). 13C NMR (100 MHz,
CDCl3): δ = 28.76, 35.07, 65.65, 114.45, 120.71, 120.78, 129.40,
158.73. HRMS (ESI): m/z [M + Na]+ calcd for C18H22NaO2S2:
357.1061; found: 357.1063.
(5) (a) Nuzzo, R. G.; Allara, D. L. J. Am. Chem. Soc. 1983, 105, 4481.
(b) Biebuyck, H. A.; Bain, C. D.; Whitesides, G. M. Langmuir 1994,
10, 1825.
(6) (a) Witt, D. Synthesis 2008, 2491. (b) Mandal, B.; Basu, B. RSC
Adv. 2014, 4, 13854.
(7) Sengupta, D.; Basu, B. Tetrahedron Lett. 2013, 54, 2277.
(8) Prabhu, K. R.; Ramesha, A. R.; Chandrasekaran, S. J. Org. Chem.
1995, 60, 7142.
Bis[2-(phenylsulfanyl)ethyl] Disulfide (Table 2, Entry 5)
Oil; yield: 147 mg (87%). 1H NMR (400 MHz, CDCl3): δ = 2.75 (t,
J = 12 Hz, 4 H), 3.10 (t, J = 12 Hz, 4 H), 7.15–7.19 (m, 2 H), 7.21–
7.23 (m, 4 H), 7.27–7.29 (m, 4 H). 13C NMR (100 MHz, CDCl3): δ
= 33.13, 37.61, 126.54, 129.03, 129.86, 134.75. HRMS (ESI): m/z
[M + Na]+ calcd for C16H18NaS4: 361.0291; found: 361.0289.
Disulfanediylbis(ethane-2,1-diyl) Dibenzoate (Table 2, Entry
6)
(9) Jia, X.; Zhang, Y.; Zhou, X. Tetrahedron Lett. 1994, 35, 8833.
(10) Guo, H.; Zhan, Z.; Zhang, Y. Synth. Commun. 1997, 27, 2721.
(11) Burns, C. J.; Field, L. D.; Morgan, J.; Ridley, D. D.; Vignevich, V.
Tetrahedron Lett. 1999, 40, 6489.
(12) Fuska, J.; Šturdíkova, M.; Proksa, B. Lett. Appl. Microbiol. 1994,
19, 124.
Oil; yield: 141 mg (78%). 1H NMR (400 MHz, CDCl3): δ = 3.09 (t,
J = 6 Hz, 4 H), 4.60 (t, J = 6 Hz, 4 H), 7.43 (t, J = 6 Hz, 4 H), 7.55–
7.56 (d, J = 6 Hz, 2 H), 8.05 (t, J = 6 Hz, 4 H). 13C NMR (100 MHz,
CDCl3): δ = 37.42, 62.77, 128.41, 129.69, 129.87, 133.14, 166.35.
HRMS (ESI): m/z [M + Na]+ calcd for C18H18NaO4S2: 385.0647;
found: 385.0645.
(13) Dye, J. L.; Cram, K. D.; Urbin, S. A.; Redko, M. Y.; Jackson, J. E.;
Lefenfeld, M. J. Am. Chem. Soc. 2005, 127, 9338.
Bis(4-methoxybenzyl) Disulfide (Table 2, Entry 10)
Oil; yield: 127 mg (83%). 1H NMR (400 MHz, CDCl3): δ = 3.63 (s,
4 H), 3.83 (s, 6 H), 6.89 (d, J = 6 Hz, 4 H), 7.20 (d, J = 6 Hz, 4 H).
13C NMR (100 MHz, CDCl3): δ = 42.75, 55.25, 113.87, 129.38,
(14) (a) Costanzo, M. J.; Patel, M. N.; Petersen, K. A.; Vogt, P. F. Tetra-
hedron Lett. 2009, 50, 5463. (b) Nandi, P.; Redko, M. Y.; Petersen,
K.; Dye, J. L.; Lefenfeld, M.; Vogt, P. F.; Jackson, J. E. Org. Lett.
2008, 10, 5441. (c) Maurya, C. K.; Gupta, P. K. Tetrahedron Lett.
2015, 56, 2228.
130.49, 159.00. HRMS (ESI): m/z [M
16H18NaO2S2: 329.0748; found: 329.0745.
+
Na]+ calcd for
C
Bis(2-phenylethyl) Disulfide (Table 2, Entry 11)
Oil; yield: 112 mg (82%). 1H NMR (400 MHz, CDCl3): δ = 2.88
(dd, J = 6, 12 Hz, 4 H), 2.90 (dd, J = 6, 12 Hz, 4 H), 7.10–7.14 (m, 6
H), 7.20–7.23 (m, 4 H). 13C NMR (100 MHz, CDCl3): δ = 35.68,
40.16, 126.36, 128.47, 128.57, 139.98. HRMS (ESI): m/z [M +
Na]+ calcd for C16H18NaS2: 297.0850; found: 297.0852.
Bis(3-fluorobenzyl) Disulfide (Table 2, Entry 12)
(15) Kiasat, A. R.; Mehrjardi, M. F. Bull. Korean Chem. Soc. 2008, 29,
2346.
(16) Disulfanes (Table 2; Entries 1–14); General Procedure
An oven-dried three-neck flask, cooled under a flow of N2, was
charged with Na_SG (Stage 1, Sigma–Aldrich, Catalogue No.
660167; 4 mmol, 306 mg), and a solution of the appropriate
thiocyanate (1 mmol) in dry THF (5 mL) was added via syringe.
The solution was magnetically stirred until the starting mate-
rial was completely consumed. The reaction was then quenched
by careful addition of H2O (10 mL), and the mixture was filtered
and extracted with EtOAc (3 × 10 mL). The organic phases were
combined, dried (Na2SO4), filtered, and concentrated under
reduced pressure to give a crude product that was purified by
flash chromatography (silica gel; hexane–EtOAc). (CAUTION!
The reaction involves liberation of toxic cyanide ion. The
aqueous phase must be carefully treated with NaOCl solution
before disposal.).
Oil; yield: 124 mg (88%). 1H NMR (400 MHz, CDCl3): δ = 3.52 (s,
4 H), 6.89 (t, J = 6 Hz, 6 H), 6.94 (d, J = 12 Hz, 1 H), 7.1–7.23 (m, 1
H). 13C NMR (100 MHz, CDCl3): δ = 42.73, 114.37, 116.29,
125.01, 129.95, 130.00 139.80. HRMS (ESI): m/z [M + Na]+ calcd
for C14H12F2NaS2: 305.0348; found: 305.0349.
Bis(but-3-yn-1-yl) Disulfide (13)
Oil; yield: 66 mg (78%). 1H NMR (400 MHz, CDCl3): δ = 2.04 (s, 2
H), 2.60–2.63 (m, 4 H), 2.85 (t, J = 6 Hz, 4 H). 13C NMR (100 MHz,
CDCl3): δ = 18.98, 37.21, 69.87, 82.04. HRMS (ESI): m/z [M +
Na]+ calcd for C8H10NaS2: 193.0224; found: 193.0223.
(18) Hamed, E. M.; Doai, H.; McLaughlin, C. K.; Houmam, A. J. Am.
Chem. Soc. 2006, 128, 6595.
(17) Bis(3-phenoxypropyl) Disulfide (Table 2, Entry 4)
Oil; yield: 132 mg (79%). 1H NMR (400 MHz, CDCl3): δ = 2.18
(quin, J = 12 Hz, 4 H), 2.87 (t, J = 12 Hz, 4 H), 4.04 (t, J = 12 Hz, 4
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 409–411