H. Firouzabadi et al. / Tetrahedron Letters 51 (2010) 508–509
509
Table 1
References and notes
One-pot transformation of alkyl halides into their corresponding symmetric disulfides
1. (a) Bodanszky, M. Principles of Peptide Synthesis; Springer: Berlin, 1984. Chapter
4; (b) Johnson, J. R.; Bruce, W. F.; Dutcher, J. D. J. Am. Chem. Soc. 1943, 65, 2005–
2009.
2. Sonavane, S. U.; Chidambaram, M.; Almog, J.; Sasson, Y. Tetrahedron Lett. 2007,
48, 6048–6050.
S
Na2CO3, MnO2
H2N
NH2
RX
+
RSSR
wet PEG, 30-35 °C
3. (a) Sudharsanam, R.; Chandrasekaran, S.; Das, P. K. J. Mater. Chem. 2002, 12,
2904–2908; (b) Haas, U.; Thalacker, C.; Adams, J.; Fuhrmann, J.; Riethmuller, S.;
Beginn, U.; Ziener, U.; Moller, M.; Dobrawa, R.; Wurthner, F. J. Mater. Chem.
2003, 13, 767–772.
4. (a) Shirani, H.; Janosik, T. Synthesis 2007, 2690–2698; (b) Atkinson, J. G.; Hamel,
P.; Yves Girard, Y. Synthesis 1988, 480–481.
5. (a) Movassagh, B.; Zakinezhad, Y. Z. Naturforsch. 2006, 61b, 47–49; (b) Ranu, B.
C.; Mandal, T. Synlett 2004, 1239–1242; (c) Bartolozzi, A.; Foudoulakis, H. M.;
Cole, B. M. Synthesis 2008, 2023–2032; (d) Prabhu, K. R.; Sivanand, P. S.;
Chandrasekaran, S. Angew. Chem., Int. Ed. 2000, 39, 4316–4319.
6. Movassagh, B.; Sobhani, S.; Kheirdoush, F.; Fadaei, Z. Synth. Commun. 2003, 33,
3103–3108.
7. Kodama, S.; Nishinaka, E.; Nomoto, A.; Sonoda, M.; Ogawa, A. Tetrahedron Lett.
2007, 48, 6312–6317.
8. (a) Kondo, T.; Mitsudo, T. Chem. Rev. 2000, 100, 3205–3220; (b) Yamagiwa, N.;
Suto, Y.; Torisawa, Y. Bioorg. Med. Chem. Lett. 2007, 17, 6197–6201; (c)
Taniguchi, N. Synlett 2008, 849–852.
9. (a) Kirihara, M.; Asai, Y.; Ogawa, S.; Noguchi, T.; Hatano, A.; Hirai, Y. Synthesis
2007, 3286–3289; (b) Golchoubian, H.; Hosseinpoor, F. Catal. Commun. 2007, 8,
697–700; (c) Kirihara, M.; Okubo, K.; Uchiyama, T.; Kato, Y.; Ochiai, Y.;
Matsushita, S.; Hatano, A.; Kanamori, K. Chem. Pharm. Bull. 2004, 52, 625–627;
(d) Silveira, C. C.; Mendes, S. R. Tetrahedron Lett. 2007, 48, 7469–7471; (e)
Lenardao, E. J.; Lara, R. G.; Silva, M. S.; Raquel, G.; Jacob, R. G.; Perin, G.
Tetrahedron Lett. 2007, 48, 7668–7670; (f) Ali, M. H.; McDermott, M.
Tetrahedron Lett. 2002, 43, 6271–6273; (g) Akdag, A.; Webb, T.; Worley, S. D.
Tetrahedron Lett. 2006, 47, 3509–3510; (h) Iranpoor, N.; Zeynizadeh, B.
Synthesis 1999, 49–50; (i) Firouzabadi, H.; Abbassi, M.; Karimi, B. Synth.
Commun. 1999, 29, 2527–2531; (j) Iranpoor, N.; Firouzabadi, H.; Pourali, A. R.
Tetrahedron 2002, 58, 5179–5184.
10. Witt, D. Synthesis 2008, 2491–2509. and references cited therein.
11. (a) Hase, T. A.; Perakyla, H. Synth. Commun. 1982, 12, 947–950; (b) Wang, J.-X.;
Gao, L.; Huang, D. Synth. Commun. 2002, 32, 963–969; (c) Gladysz, J. A.; Wong,
V. K.; Jick, B. S. Tetrahedron 1979, 35, 2329–2335; (d) Wang, J.-X.; Cui, W.; Hu,
Y. Synth. Commun. 1995, 25, 3573–3581; (e) Srivatava, P. K.; Chandra, R.; Gupta,
M. B. Curr. Sci. 1982, 51, 692–695.
Entry Alkyl halide
Producta
Time (h) Isolated
yield (%)
1
2
3
4
5
6
7
8
9
n-Decyl iodide
(n-C10H21S–)2
(n-C8H17S–)2
(n-C8H17S–)2
(n-C4H9S–)2
(n-C4H9S–)2
(n-C3H7S–)2
12
10
12
3.5
5
3
3.5
3
85
86
86b
85
87
86
80
87
85
88
n-Octyl iodide
n-Octyl bromide
n-Butyl iodide
n-Butyl bromide
n-Propyl iodide
Ethyl bromide
Allyl bromide
Allyl chloride
3-Chloro-2-methyl-
propene
(C2H5S–)2
(CH2@CHCH2S–)2
(CH2@CHCH2S–)2
(CH2@C(CH3)CH2S–)2
5
5
10
11
12
13
Benzyl bromide
Benzyl chloride
4-Methylbenzyl
chloride
(PhCH2S–)2
(PhCH2S–)2
(4-CH3C6H4CH2S–)2
2.5
4
3
86
86
84
14
4-Bromobenzyl
chloride
(4-BrC6H4CH2S–)2
6
83
15
16
17
18
19
(2-Bromoethyl)benzene (PhCH2CH2S–)2
9
87
82
85
77
65
Cyclohexyl bromide
Cyclopentyl bromide
iso-Propyl bromide
tert-Butyl bromide
(cyclohexyl-S–)2
(cyclopentyl-S–)2
[(CH3)2CHS–]2
[(CH3)3CS–]2
36
30
36
72
All products were identified from their 1H NMR and 13C NMR spectra and ele-
mental analyses.
The reaction was applied for the large-scale operation using 40 mmol of n-octyl
bromide.
a
b
applied for the preparation of different symmetric disulfides using
MnO2.16 The results are shown in Table 1.
12. Bandgar, B. P.; Uppalla, L. S.; Sadavarte, V. S. Tetrahedron Lett. 2001, 42, 6741–
6743.
Using this method, primary, allylic, and benzylic halides were
easily transformed into their corresponding disulfides in good to
excellent yields (Table 1, entries 1–15). We also extended our stud-
ies for the preparation of more sterically hindered disulfides.
Cyclopentyl, cyclohexyl, iso-propyl, and tert-butyl disulfides were
prepared from their corresponding organic bromides in high yields
within 30–72 h (Table 1, entries 16–19).
This protocol was easily applicable to scale-up. For example, the
direct conversion of n-octyl bromide into its corresponding sym-
metric disulfide on several gram-scale was carried out successfully
(Table 1, entry 3).17
In conclusion, we have described a novel one-pot odorless pro-
cess for the formation of disulfides from alkyl halides. This method
is conducted under mild conditions and is suitable for scale-up. As
structurally diverse organic halides are readily available and their
synthesis is much easier than the corresponding thiols, the prepa-
ration of structurally diverse disulfides becomes more practical
using this protocol.
13. Emerson, D. W.; Bennett, B. L.; Steinberg, S. M. Synth. Commun. 2005, 35, 631–
638.
14. Chen, J.; Spear, S. K.; Huddleston, J. G.; Rogers, R. D. Green Chem. 2005,
7, 64–82.
15. (a) Firouzabadi, H.; Ghaderi, E. Tetrahedron Lett. 1978, 19, 839–840; (b)
Firouzabadi, H.; Mostafavipoor, Z. Bull. Chem. Soc. Jpn. 1983, 56, 914–917.
16. General procedure: To a solution of thiourea (3 mmol) in PEG 200 (2 mL) were
added an alkyl halide (2 mmol), H2O (0.15 mL), MnO2 (2 mmol), and Na2CO3
(3 mmol). The mixture was stirred magnetically at 30–35 °C. The progress of
the reaction was monitored by TLC or GC until the alkyl halide was consumed.
After completion of the reaction, the mixture was extracted with low-boiling
petroleum ether (5 Â 2 mL). The organic layers were decanted, combined, dried
over Na2SO4, filtered, and concentrated to yield the crude product, which was
further purified by silica gel chromatography using low-boiling petroleum
ether as an eluent to provide the desired product in 65–88% yields.
17. Typical scale-up procedure for the conversion of n-octyl bromide into its
corresponding symmetrical disulfide: To a solution of thiourea (60 mmol,
4.57 g), n-octyl bromide (40 mmol, 7.72 g), H2O (3 mL) in PEG-200 (60 mL),
MnO2 (40 mmol, 3.48 g), and Na2CO3 (60 mmol, 6.36 g) were added. The
mixture was stirred at 30–35 °C. The progress of the reaction was monitored by
GC until the alkyl bromide was consumed (12 h). The mixture was extracted
with low-boiling petroleum ether (5 Â 15 mL). The organic layers were
combined, dried over Na2SO4, filtered, and concentrated to yield the crude
product, which was further purified by silica gel chromatography using low-
boiling petroleum ether as an eluent to provide the desired product in 86%
(5.00 g) yield. 1,2-Dioctyl disulfide: Colorless oil; 1H NMR (250 MHz, CDCl3) d
2.61 (t, J = 7.3 Hz, 4H), 1.66–1.54 (m, 4H), 1.30–1.21 (m, 20H), 0.84–0.79 (m,
6H); 13C NMR (62.5 MHz, CDCl3) d 39.2, 31.8, 29.2, 29.2, 29.1, 28.5, 22.6, 14.1;
Anal. Calcd for C16H34S2: C, 66.14; H, 11.79; S, 22.07. Found: C, 66.21; H, 11.71;
S, 22.08.
Acknowledgment
We gratefully acknowledge the support of this study by Shiraz
University Research Council.