Iodine-mediated thioetherification of alcohols with disulfides or NaSh under microwave irradiation

Article abstract of DOI:10.1002/cjoc.201200723

An efficient and novel method for the thioetherification of an alcohol with disulfides or NaSH under microwave irradiation is presented. In the presence of iodine, a variety of alcohols were smoothly S-alkylated with disulfides or NaSH to give the corresponding thioethers in moderate to excellent yields. Copyright

Full text of DOI:10.1002/cjoc.201200723

FULL PAPER
DOI: 10.1002/cjoc.201200723
Iodine-Mediated Thioetherification of Alcohols with Disulfides
or NaSH under Microwave Irradiation
Hu, Boluna(胡伯伦)
Sun, Leileia(孙垒垒)
Hu, Huananb(胡华南)
Tang, Riyuan*,a(汤日元)
a College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang 325035, China
b School of Pharmaceutical and Chemistry Engineering, Taizhou University, Taizhou, Zhejiang 317000, China
An efficient and novel method for the thioetherification of an alcohol with disulfides or NaSH under microwave
irradiation is presented. In the presence of iodine, a variety of alcohols were smoothly S-alkylated with disulfides or
NaSH to give the corresponding thioethers in moderate to excellent yields.
Keywords microwave synthesis, iodine, thioether, disulfide, alcohol
Introduction
cohols with disulfides or NaSH under microwave
irradiation.[13]
C—S bonds are common structural motifs, found in
many naturally occurring and biologically active or-
ganic molecules.[1,2] Considerable efforts have been de-
voted to the formation of C—S bonds.[2] In recent years,
increasing attention has been focused on the develop-
ment of S-alkylation methodologies for the formation of
certain unique C—S bonds.[3-6] The direct substitution
of the hydroxyl of alcohols with sulfur nucleophiles
turns out to be a desirable method for the synthesis of
thioethers, with water being generated as the only by-
product. Bronsted or Lewis acids are typically required
to facilitate this process.[6-8] For example, Wu and co-
workers have developed a Ga(OTf)3-catalyzed direct
substitution of alcohols with thiols, enabling a wide
range of alcohols to undergo facile S-alkylation with
phosphorothioic acid, phenyltetrazole and other hetero-
aromatic thiols, in the presence of catalytic Ga(OTf)3.[8]
In addition, both iodine and 2,2,4,4,6,6-hexachloro-
2,2,4,4,6,6-hexahydro-1,3,5,2,4,6-triazatriphosphorine
have been reported as efficient agents for the S-alkyla-
tion of thiols with alcohols.[9,10] However, these meth-
ods required the use of effluvial and virulent thiols or
the use of stoichiometric metal catalysts. In early years,
the S-alkylation of disulfides with alcohol has been
studied.[11] However, highly unstable and toxic tributyl-
phosphine or P2I4 is essential for this transformation,
and it suffers from limited substrate scope. Thus, the
development of a metal-free S-alkylation process using
low-toxicity and stable reagents is urgently required. As
part of our ongoing research program in iodine-medi-
ated C—S bond formation,[12] herein we report a metal-
free iodine-mediated method for the S-alkylation of al-
Experimental
NMR spectroscopy was performed on a Bruker
AV-500 spectrometer; mass spectrometry was per-
formed on a GCMS-QP2010 Ultra (SHIMADZU);
HRMS spectrometry was performed on an ESI-Q-TOF
(Bruker Daltonics). Microwave experiments were con-
ducted in a CEM Discover single mode using the inter-
nal probe (CEM Discover, made in USA). All reported
melting points are uncorrected.
Typical procedure for thioetherification of alcohols
(1a) with disulfides (2a)
A mixture of alcohol (1a) (0.6 mmol), diphenyl di-
sulfide (2a) (0.2 mmol) and I2 (0.8 mmol) in NMP (2
mL) was sealed in a pressure vessel tube, and was
stirred at 130 ℃ under microwave irradiation for 40
min. After the reaction finished, the residual iodine was
quenched with saturated Na2S2O3 solution (2 mL), then
filtered through glass filter and extracted with ethyl
acetate (10 mL×3). The organic layers were dried with
anhydrous Na2SO4 and evaporated under vacuum. The
residue was purified by flash column chromatography
[V(hexane)/V(EtOAc)＝50∶1] to give the correspond-
ing product (3).
Benzyl(phenyl)sulfane (3)[7a]
Yield: 0.0696 g
1
(87%), yellow oil; H NMR (500 MHz, CDCl3) δ: 7.31
—7.28 (m, 5H), 7.26—7.22 (m, 4H), 7.19—7.16 (m,
1H), 4.11 (s, 2H); 13C NMR (125 MHz, CDCl3) δ: 137.5,
136.4, 129.9, 128.8, 128.7, 128.5, 127.1, 126.3, 39.1;
LRMS (EI, 70 eV) m/z (%): 200 (M＋, 23), 91 (100), 109
*
E-mail: try@wzu.edu.cn; Tel.: 0086-577-8668-9615; Fax: 0086-577-8668-9615
Received July 14, 2012; accepted August 26, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc. 201200723 or from the author.
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Chin. J. Chem. 2012, 30, 2556—2562

Iodine-Mediated Thioetherification of Alcohols with Disulfides or NaSH
1
(5), 65 (19).
yellow oil; H NMR (500 MHz, CDCl3) δ: 7.32—7.24
Benzyl(p-tolyl)sulfane (4)[7a]
Yield: 0.0719 g
(m, 10H), 3.60 (s, 4H); 13C NMR (125 MHz, CDCl3) δ:
138.2, 129.0, 128.5, 127.0, 35.6; LRMS (EI, 70 eV) m/z
(%): 214 (M＋, 28), 91 (100), 123 (25), 65 (18).
1
(84%); yellow oil; H NMR (500 MHz, CDCl3) δ: 7.28
—7.19 (m, 7H), 7.05 (d, J＝8.0 Hz, 2H), 4.05 (s, 2H),
2.29 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 137.8,
136.5, 132.5, 130.7, 129.6, 128.8, 128.4, 127.0, 39.8,
21.0; LRMS (EI, 70 eV) m/z (%): 214 (M＋, 27), 91
(100), 65 (12).
Benzyl(cyclohexyl)sulfane (12)[7a] Yield: 0.0552 g
1
(67%); yellow oil; H NMR (500 MHz, CDCl3) δ: 7.33
—7.28 (m, 4H), 7.24—7.21 (m, 1H), 3.74 (s, 2H), 2.59
—2.53 (m, 1H), 1.95—1.93 (m, 2H), 1.76—1.73 (m,
2H), 1.59—1.57 (m, 2H), 1.37—1.28 (m, 4H); 13C
NMR (125 MHz, CDCl3) δ: 139.0, 128.7, 128.4, 126.7,
42.9, 34.6, 33.4, 26.0, 25.9; LRMS (EI, 70 eV) m/z (%):
206 (M＋, 25), 91 (100), 124 (17), 115 (23), 55 (17).
Benzyl(ethyl)sulfane (13) Yield: 0.0201 g (33%);
Benzyl(4-chlorophenyl)sulfane (5)[7a]
Yield:
0.0843 g (90%); yellow solid, m.p. 44.1—45.3 ℃
(ref.[7a] m.p. 43—44 ℃); 1H NMR (500 MHz, CDCl3) δ:
7.29—7.26 (m, 5H), 7.24—7.20 (m, 4H), 4.08 (s, 2H);
13C NMR (125 MHz, CDCl3) δ: 137.1, 134.7, 132.5,
131.5, 128.9, 128.8, 128.5, 127.3, 39.4; LRMS (EI, 70
eV) m/z (%): 234 (M＋, 14), 236 (M＋, 5), 91 (100), 108
(5), 65 (14).
1
yellow oil; H NMR (500 MHz, CDCl3) δ: 7.32—7.28
(m, 4H), 7.24—7.22 (m, 1H), 3.71 (s, 2H), 2.43 (q, J＝
7.5 Hz, 2H), 1.22 (t, J＝7.5 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ: 138.6, 128.8, 128.4, 126.8, 35.9, 25.2,
14.3; LRMS (EI, 70 eV) m/z (%): 152 (M＋, 33), 91
(100), 65 (11).
Benzyl(4-fluorophenyl)sulfane (6)[7b]
Yield:
0.0724 g (83%); yellow oil; 1H NMR (500 MHz, CDCl3)
δ: 7.27—7.25 (m, 4H), 7.23—7.20 (m, 3H), 6.93 (t, J＝
8.5 Hz, 2H), 4.02 (s, 2H); 13C NMR (125 MHz, CDCl3)
Benzyl(methyl)sulfane (14)
Yield: 0.0188 g
1
δ: 162.1 (d, JC-F＝245.4 Hz, 1C), 137.5, 133.4 (d, JC-F
＝
(34%); yellow oil; H NMR (500 MHz, CDCl3) δ: 7.32
—7.28 (m, 4H), 7.26—7.22 (m, 1H), 3.66 (s, 2H), 1.98
(s, 3H); 13C NMR (125 MHz, CDCl3) δ: 138.2, 128.8,
128.4, 126.9, 38.3, 14.9; LRMS (EI, 70 eV) m/z (%):
138 (M＋, 39), 91 (100), 65 (14).
12.5 Hz, 1C), 130.7 (d, JC-F＝3.3 Hz, 1C), 128.8, 128.4,
127.2, 115.9 (d, JC-F＝21.8 Hz, 1C), 40.4; LRMS (EI,
70 eV) m/z (%): 218 (M＋, 20), 91 (100), 127 (5), 65
(15).
Benzyl(3-fluorophenyl)sulfane (7) Yield: 0.0767
g (88%); yellow oil; H NMR (500 MHz, CDCl3) δ:
(4-Chlorobenzyl)(phenyl)sulfane (15)[10] Yield:
1
1
0.0767 g (82%); white solid, m.p. 71.9—73.2 ℃; H
7.32—7.17 (m, 6H), 7.05 (d, J＝8.0 Hz, 1H), 7.01—
6.98 (m, 1H), 6.87—6.83 (m, 1H), 4.12 (s, 2H); 13C
NMR (125 MHz, CDCl3) δ: 162.7 (d, JC-F＝246.6 Hz,
NMR (500 MHz, CDCl3) δ: 7.29—7.17 (m, 9H), 4.05 (s,
2H); 13C NMR (125 MHz, CDCl3) δ: 136.1, 135.7,
132.9, 130.3, 130.1, 128.9, 128.6, 126.7, 38.6; LRMS
(EI, 70 eV) m/z (%): 234 (M＋, 19), 236 (M＋, 7), 125
(100), 127 (32), 89 (15).
(2,6-Dichlorobenzyl)(phenyl)sulfane (16) Yield:
0.0911 g (85%); yellow oil; 1H NMR (500 MHz, CDCl3)
δ: 7.44—7.42 (m, 2H), 7.30—7.25 (m, 5H), 7.12 (t, J＝
8.0 Hz, 1H), 4.40 (s, 2H); 13C NMR (125 MHz, CDCl3)
δ: 135.8, 135.3, 133.9, 132.2, 128.8, 128.7, 128.3, 127.3,
35.6; LRMS (EI, 70 eV) m/z (%): 268 (M＋, 30), 270
(M＋, 20), 159 (100), 161 (64), 123 (10), 89 (7).
1C), 138.9 (d, JC-F＝7.8 Hz, 1C), 136.8, 130.0 (d, JC-F
＝
8.5 Hz, 1C), 128.8, 128.6, 127.4, 124.7 (d, JC-F＝3.0 Hz,
1C), 115.9 (d, JC-F＝22.9 Hz, 1C), 113.0 (d, JC-F＝21.1
Hz, 1C), 38.5; LRMS (EI, 70 eV) m/z (%): 218 (M＋, 17),
91 (100), 127 (4), 65 (15).
Benzyl(4-nitrophenyl)sulfane (8) Yield: 0.0794 g
1
(81%); yellow solid, m.p. 115.1—116.8 ℃; H NMR
(500 MHz, CDCl3) δ: 8.10 (dt, J＝8.0, 2.0 Hz, 2H), 7.39
—7.26 (m, 7H), 4.25 (s, 2H); 13C NMR (125 MHz,
CDCl3) δ: 147.2, 145.3, 135.5, 128.8, 128.7, 127.8,
126.7, 123.9, 37.1; LRMS (EI, 70 eV) m/z (%): 245
(M＋, 8), 91 (100), 124 (7), 65 (13).
3-(Benzylthio)pyridine (9) Yield: 0.0691 g (86%);
yellow oil; 1H NMR (500 MHz, CDCl3) δ: 8.47 (s, 1H),
7.49—7.45 (m, 1H), 7.42—7.40 (m, 2H), 7.31—7.23
(m, 3H), 7.16 (d, J＝8.0 Hz, 1H), 7.00—6.98 (m, 1H),
4.44 (s, 2H); 13C NMR (125 MHz, CDCl3) δ: 158.8,
149.4, 138.0, 136.0, 128.9, 128.5, 127.1, 122.1, 119.6,
34.5; LRMS (EI, 70 eV) m/z (%): 201 (M＋, 55), 168
(100), 121 (11), 91 (76), 65 (19).
(2-Bromo-4-fluorobenzyl)(phenyl)sulfane
(17)
Yield: 0.0734 g (62%); yellow oil; 1H NMR (500 MHz,
CDCl3) δ: 7.32—7.16 (m, 7H), 6.90 (td, J＝8.0, 2.5 Hz,
1H), 4.17 (s, 2H); 13C NMR (125 MHz, CDCl3) δ:
161.4 (d, JC-F＝249.3 Hz, 1C), 135.3, 132.9 (d, J＝3.4
Hz), 131.5 (d, J＝8.4 Hz), 131.0, 128.9, 127.0, 124.4
(d, J＝9.5 Hz), 120.1 (d, JC-F＝24.4 Hz, 1C), 114.5 (d,
J
C-F＝20.9 Hz, 1C), 39.0; LRMS (EI, 70 eV) m/z (%):
296 (M＋, 34), 298 (M＋, 36), 187 (100), 189 (97), 108
－
1
(44), 65 (11); IR (neat) ν: 1530, 1461, 1387, 1210 cm ;
HRMS (ESI) for C13H10BrFS (M－C6H5S)＋ : calcd
186.9553 and 188.9533, found 186.9567 and
188.9552.
3-(Benzylthio)-2-methylfuran (10) Yield: 0.0326
1
g (40%); yellow oil; H NMR (500 MHz, CDCl3) δ:
7.25—7.22 (m, 4H), 7.10—7.08 (m, 2H), 6.21 (d, J＝
1.5 Hz, 1H), 3.74 (s, 2H), 1.96 (s, 3H); 13C NMR (125
MHz, CDCl3) δ: 156.2, 140.4, 138.5, 128.9, 128.2,
126.9, 115.2, 109.3, 40.7, 11.2; LRMS (EI, 70 eV) m/z
(%): 204 (M＋, 26), 91 (100), 65 (13).
(4-Methyl-3-nitrobenzyl)(phenyl)sulfane
(18)
Yield: 0.0808 g (78%); yellow oil; 1H NMR (500 MHz,
CDCl3) δ: 7.85 (d, J＝2.0 Hz, 1H), 7.40—7.38 (dd,
J＝8.0, 2.0 Hz, 1H), 7.30—7.21 (m, 6H), 4.10 (s, 2H),
2.55 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 149.0,
137.2, 134.9, 133.2, 132.8, 132.3, 130.7, 129.0, 127.1,
Dibenzylsulfane (11)[7a] Yield: 0.0496 g (58%);
Chin. J. Chem. 2012, 30, 2556—2562
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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2557

Hu et al.
FULL PAPER
1
124.7, 38.3, 20.1; IR (neat) ν: 2958, 1533, 1467, 1405,
1352; LRMS (EI, 70 eV) m/z (%): 259 (M＋, 43), 150
(100), 103 (21), 77 (24); HRMS (ESI) for C14H13NO2S
(M＋H＋): calcd 260.0740, found 260.0735.
g (51%); yellow oil; H NMR (500 MHz, CDCl3) δ:
7.23—7.20 (m, 2H), 6.88—6.85 (m, 4H), 6.79 (dd, J＝
8.5, 2.0 Hz, 2H), 3.80 (s, 6H), 3.58 (s, 4H); 13C NMR
(125 MHz, CDCl3) δ: 159.7, 139.7, 129.4, 121.4, 114.4,
112.6, 55.2, 35.6; LRMS (EI, 70 eV) m/z (%): 274 (M＋,
12), 122 (100), 138 (4), 91 (19), 77 (11).
Bis(4-chlorobenzyl)sulfane (24) Yield: 0.0665 g
(59%); red oil; H NMR (500 MHz, CDCl3) δ: 7.27 (d,
J＝8.5 Hz, 4H), 7.19 (d, J＝8.5 Hz, 4H), 3.53 (s, 4H);
13C NMR (125 MHz, CDCl3) δ: 136.3, 132.8, 130.2,
128.6, 34.9; LRMS (EI, 70 eV) m/z (%): 282 (M＋, 15),
284 (10), 125 (100), 127 (32), 89 (18).
(3-Methoxybenzyl)(phenyl)sulfane (19)
Yield:
0.0405 g (44%); yellow oil; 1H NMR (500 MHz, CDCl3)
ν: 7.32—7.30 (m, 2H), 7.27—7.25 (m, 2H), 7.21—7.16
(m, 2H), 6.88 (d, J＝7.5 Hz, 1H), 6.83 (s, 1H), 6.79—
6.77 (m, 1H), 4.09 (s, 2H), 3.76 (s, 3H); 13C NMR (125
MHz, CDCl3) δ: 159.7, 139.0, 136.4, 129.9, 129.4,
128.8, 126.4, 121.1, 114.2, 112.9, 55.2, 39.1; LRMS (EI,
70 eV) m/z (%): 230 (M＋, 26), 121 (100), 193 (13), 91
(25), 65 (12).
1
5-((Phenylthio)methyl)benzo[d][1,3]dioxole (20)
Yield: 0.0654 g (67%); yellow solid, m.p. 40.3—41.5
℃; 1H NMR (500 MHz, CDCl3) δ: 7.32—7.19 (m, 4H),
7.19—7.17 (m, 1H), 6.81 (s, 1H), 6.71—6.70 (m, 2H),
5.93 (s, 2H), 4.04 (s, 2H); 13C NMR (125 MHz, CDCl3)
δ: 147.7, 146.7, 136.3, 131.2, 129.9, 128.8, 126.4, 122.0,
109.2, 108.1, 101.0, 39.1; LRMS (EI, 70 eV) m/z (%):
244 (M＋, 9), 135 (100), 77 (20), 51 (12).
Results and Discussion
The reaction of benzyl alcohol (1a) with diphenyl
disulfide (2a) and I2 (2 equiv.) was chosen as a model
reaction for our study and a variety of different condi-
tions were screened (Table 1). Unfortunately, when the
reaction was conducted in methylsulfinylmethane
(DMSO) at 110 ℃ under microwave irradiation for 40
min, only a trace of the desired product (3) was ob-
served by GC-MS (Entry 1). Several solvents were then
screened (Entries 2—4) and 1-methylpyrrolidin-2-one
(NMP) was found to be the most efficient solvent for
the process, giving product (3) in 80% yield (Entry 2).
The irradiation temperature was revealed to have a sig-
nificant impact on the yield of the reaction, with an 87%
yield obtained at 130 ℃ and an 18% yield at 150 ℃
(Entries 5 and 6, respectively). A reduction in the load-
ing of I2 also led to a lower yield, with a single equiva-
lent of I2 giving a yield of only 56% (Entry 7). A reduc-
tion in the loading of benzyl alcohol (1a) to a single
equivalent also led to a reduction in the yield to 72%
(Entry 8). The results also showed that shortening the
(Naphthalen-2-ylmethyl)(phenyl)sulfane
(21)
Yield: 0.089 g (89%); yellow solid, m.p. 58.4—59.8 ℃;
1H NMR (500 MHz, CDCl3) δ: 8.13 (d, J＝8.5 Hz, 1H),
7.85 (d, J＝8.0 Hz, 1H), 7.76—7.74 (m, 1H), 7.54—
7.49 (m, 2H), 7.34—7.31 (m, 4H), 7.27—7.19 (m, 3H),
4.55 (s, 2H); 13C NMR (125 MHz, CDCl3) δ: 136.7,
133.9, 132.7, 131.5, 130.2, 128.8, 128.8, 128.2, 127.3,
126.5, 126.2, 125.8, 125.2, 123.9, 37.2; LRMS (EI, 70
eV) m/z (%): 250 (M＋, 14), 141 (100), 115 (21).
2-((Phenylthio)methyl)thiophene (22)
Yield:
0.0354 g (43%); yellow oil; 1H NMR (500 MHz, CDCl3)
δ: 7.35—7.34 (m, 2H), 7.28—7.26 (m, 2H), 7.22—7.19
(m, 1H), 7.18—7.16 (m, 1H), 6.88—6.87 (m, 2H), 4.31
(s, 2H); 13C NMR (125 MHz, CDCl3) δ: 140.9, 135.7,
130.4, 128.9, 126.7, 126.7, 126.2, 124.9, 33.8; LRMS
(EI, 70 eV) m/z (%): 206 (M＋, 12), 97 (100), 109 (6), 53
(7).
Table 1 Screening for the optimal conditionsa
Ph
+
PhSSPh
S
Ph
OH
Typical procedure for S-alkylation of alcohols (1a)
with NaSH
1a
2a
3
A mixture of alcohol (1a) (0.8 mmol), NaSH (1.5
mmol) and I2 (1.6 mmol) in CH3CN (2 mL) was sealed
in a pressure vessel tube, and was stirred at 120 ℃
under microwave irradiation for 20 min. After the reac-
tion finished, the residual iodine was quenched with
saturated Na2S2O3 solution (2 mL), then filtered through
glass filter and extracted with ethyl acetate (10 mL×3).
The organic layers were dried with anhydrous Na2SO4
and evaporated under vacuum. The residue was purified
by flash column chromatography (hexane) to give the
corresponding product (11).
Entry
I2 (mmol)
0.8
Solvent T/℃
Isolated yield/%
1
2
DMSO
NMP
DCE
110
110
110
110
130
150
130
130
130
130
trace
80
0.8
3
0.8
trace
trace
87
4
0.8
DMA
NMP
NMP
NMP
NMP
NMP
NMP
5
0.8
6
0.8
18
7
0.4
56
8b
9c
10d
0.8
72
Dibenzylsulfane (11)[7a] Yield: 0.0599 g (70%),
0.8
71
1
0.8
33
yellow oil; H NMR (500 MHz, CDCl3) δ: 7.32—7.24
(m, 10H), 3.60 (s, 4H); 13C NMR (125 MHz, CDCl3) δ:
138.2, 129.0, 128.5, 127.0, 35.6; LRMS (EI, 70 eV) m/z
(%): 214 (M＋, 28), 91 (100), 123 (25), 65 (18).
a
Reaction conditions: 1a (0.6 mmol), 2a (0.2 mmol), I2 (0.8
mmol) in solvent (2 mL) for 40 min under microwave irradiation.
1a (0.4 mmol). c For 20 min. d Under conventional heating con-
b
ditions for 16 h.
Bis(3-methoxybenzyl)sulfane (23) Yield: 0.0559
2558
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2556—2562

Iodine-Mediated Thioetherification of Alcohols with Disulfides or NaSH
reaction time led to a lower product yield (Entry 9). In
sharp contrast, conventional heating conditions gave a
yield of only 33%, even with an extended reaction time
of 16 h (Entry 10). Overall, our initial investigations
established that the use of NMP as a solvent with 2
equivalent I2 at 130 ℃ under microwave irradiation for
40 min represented the optimal conditions for the trans-
formation.
With the optimized conditions in hand, the scope of
the S-alkylation reaction was then examined (Table 2).
Initially, a variety of disulfides (2) were used to investi-
gate the reaction with benzyl alcohol (1a) (Entries 1—
11). Both electron-withdrawing and electron-donating
groups were well tolerated on the aromatic ring of the
diaryl disulfides (Entries 1—5). Halo-substituted diaryl
disulfides, for example, reacted smoothly with benzyl
alcohol (1a) and I2 to afford the corresponding products
in good to excellent yields (Entries 2—4). Pleasingly,
the strong electron-withdrawing nitro group did not
have an adverse effect on this reaction, providing the
corresponding product (8) in 81% yield (Entry 5). Fur-
thermore, 1,2-di(pyridin-2-yl)disulfane (2g) was well
tolerated under the reaction conditions, affording the
target product (9) in 86% yield (Entry 6). In contrast,
1,2-bis(2-methylfuran-3-yl)disulfane (2h) only gave a
low yield (40%, Entry 7), whereas dibenzyl disulfide
worked well under the standard conditions, giving the
corresponding product in 58% yield (Entry 8). It is
worthy of note that the stable 1,2-dicyclohexyldisulfane
(2j) also underwent successful thiolation with benzyl
alcohol and I2 to furnish the corresponding product (12)
in 67% yield (Entry 9). Interestingly, treatment of
1,2-diethyldisulfane (2k) with benzyl alcohol (1a) af-
forded benzyl(ethyl)sulfane (13) in 33% yield,
Table 2 Iodine-mediated thiolation of alcohols with disulfides a
R
R
S R1
+
R1SSR1
OH
1
2
Entry
1
Alcohol 1
R1SSR1 2
Product
Isolated yield/%
84
S
S
S
OH
1a
4
2b
Cl
S
S
2
3
90
83
1a
1a
S
Cl
5
Cl
2c
F
S
S
S
F
6
F
2d
F
F
S
S
4
5
88
81
1a
1a
S
7
F
2e
O2N
S
S
S
S
NO2
8
NO
2 2f
N
6
7
86
40
1a
1a
N
S
S
S
S
N
9
2g
2h
O
O
S
O
10
Chin. J. Chem. 2012, 30, 2556—2562
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Hu et al.
FULL PAPER
Continued
Entry
8
Alcohol 1
R1SSR1 2
Product
Isolated yield/%
S
S
58
67
1a
S
S
11
12
2i
S
S
9
1a
2j
S
S
10
11
12
33＋38
34＋32
82
1a
1a
S
2k
Ph
S
S
Ph
13 ＋
11
S
S
2l
Ph
Ph
S
14 ＋
11
Cl
S
Cl
S
S
OH
1b
15
2a
Cl
Cl
Cl
13
85
2a
OH
S
Cl
1c
16
F
F
14
15
16
17
18
62
78
44
67
89
2a
2a
2a
2a
2a
OH
S
S
Br
Br
1d
1e
1f
17
OH
O2N
O2N
O
18
O
S
S
OH
19
20
O
O
OH
O
O
1g
OH
S
1h
21
OH
19
20
21
43
2a
2a
2a
S
S
S
1i
22
S
trace
trace
OH
1j
23
S
OH
1k
24
a Reaction conditions: 1 (0.6 mmol), 2 (0.2 mmol) and I2 (0.8 mmol) in NMP (2 mL) at 130 ℃ under microwave irradiation for 40 min.
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Chin. J. Chem. 2012, 30, 2556—2562

Iodine-Mediated Thioetherification of Alcohols with Disulfides or NaSH
and dibenzylsulfane (11) was also produced as a by-
product in 38% yield (Entry 10). Similarly, 1,2-dimeth-
yldisulfane (2l) gave products (11) and (14) in 32% and
34% yields, respectively (Entry 11). The scope of alco-
hol substrate (1) in the S-alkylation with disulfide (2a)
was also investigated (Entries 12—19). Electron-with-
drawing groups on the aromatic ring of the alcohol, in-
cluding chloro, bromo, fluoro and nitro groups, were
well tolerated by this reaction, affording the corre-
sponding products in good to excellent yields (Entries
12—15). Alcohols with an electron-donating group,
however, reacted poorly. For example, substrate (1f),
which contained a methoxyl group, gave product (19) in
only 44% yield (Entry 16). Pleasingly, naphthalen-1-
ylmethanol (1h) performed well and gave product (21)
in 89% (Entry 18). It is worthy of note that thio-
phen-2-ylmethanol (1i) was also tolerated by the reac-
tion conditions, giving the target (22) in 43% yield (En-
try 19). Unfortunately, aliphatic alcohols (1j) and (1k)
did not work under the standard conditions (Entries 20
and 21).
Scheme 2 Controlled experiments
MW, irradiation
I2
+
(Eq. 1)
(Eq. 2)
NMP, 130 oC
OH
I
1a
Aa 75%
MW, irradiation
+ PhSSPh
NMP, 130 oC
I
S
2a
Aa
(a): 36%, (b): 0%, (c): 87%, (d): 47%
Conditions for Eq. 2: Aa (0.4 mmol), 2a (0.2 mmol). (a) Without I2; (b)
without I2, under conventional heating conditions for 40 min; (c) I2 (1
equiv.) was added; (d) I2 (15 mol%) was added.
40 min (Eq. 2, condition (b)). The addition of a single
equivalent of I2 significantly promoted the same thiola-
tion reaction, giving product (3) in 87% yield (Eq. 2,
condition (c)), whereas the addition of 15 mol% of I2
gave a yield of only 47% (Eq. 2, condition (d)), sug-
gesting that the presence of iodine may accelerate the
cleavage of S—S bond in this reaction. The GC-MS
analysis showed that only a small amount of benzalde-
hyde byproduct was found in the reaction of phenyl-
methanol with diphenyl disulfide under the standard
conditions. Based on the present results and a mecha-
nism reported in the literature,[12a-12c,15] a possible
mechanism was proposed for the thiolation reaction
(Eqs. 1—5, Scheme 3). It was envisaged that the alcohol
reacts with I2 to provide intermediate (A) (Eq. 1). The
results demonstrate that S—S bond may undergo a ho-
molytic cleavage process to produce the free radical (B)
(Eq. 2). The reaction of free radical (B) with intermedi-
ate (A) affords the target product and free radical (C)
(Eq. 3). Free radical (C) reacts with disulfide to afford
free radical (B) and intermediate (D) (Eq. 4). The
self-coupling of intermediate (D) leads to disulfide and
iodine (Eq. 5).[16]
Recent years, NaSH has been demonstrated as a de-
sirable sulfur source for the formation of C—S bond.[14]
Thus, the reaction of NaSH with alcohol was investi-
gated under the microwave irradiation. Three examples
of the reaction are presented in Scheme 1. The treatment
of alcohols with NaSH and I2 in CH3CN at 120 ℃ un-
der microwave irradiation gave dibenzyl sulfides exclu-
sively, in good to moderate yields.
Scheme 1 S-Alkylation of benzyl alcohols with NaSH
I2 (2 equiv.)
R
MW, irradiation
CH3CN, 120 oC
20 min
R
R
+
NaSH
S
OH
O
S
S
O
Scheme 3 A possible mechanism
R
R
11, 70%
I2
+
23, 51%
(Eq. 1)
OH
I
A
Cl
Cl
R1SSR1
2 R1S
B
(Eq. 2)
(Eq. 3)
S
R1S
+
R
R
+
I
24, 59%
S R1
I
C
A
B
R1SSR1
R1S
B
+
R1SI
D
A series of control experiments were conducted to
elucidate the mechanism of the current reaction
(Scheme 2). It was established that, under the standard
conditions, benzyl alcohol (1a) reacted with I2 to afford
(iodomethyl)benzene (Aa) in 75% yield (Eq. 1). Inter-
estingly, in the reaction of (iodomethyl)benzene (Aa)
with diphenyl disulfide (2a) under microwave irradia-
tion, the thiolation reaction still occurred in the absence
of I2, giving the corresponding product (3) in 36% yield
(Eq. 2, condition (a)). However, no product (3) was
found under the conventional heating conditions for
(Eq. 4)
(Eq. 5)
+
I
C
R1SSR1
1
I2
+
2
R SI
D
Conclusions
In summary, we have developed an efficient iodine-
mediated method for the synthesis of thioethers by the
reaction of alcohols with disulfides under microwave
irradiation. Furthermore, dibenzyl thioether derivatives
Chin. J. Chem. 2012, 30, 2556—2562
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www.cjc.wiley-vch.de
2561

Hu et al.
FULL PAPER
[6] Sanz, R.; Martínez, A.; Miguel, D.; Álvarez-Gutiérrez, J. M.;
Rodríguez, F. Adv. Synth. Catal. 2006, 348, 1841.
[7] (a) Firouzabadi, H.; Iranpoor, N.; Jafarpour, M. Tetrahedron Lett.
2006, 47, 93; (b) Ouertani, M.; Collin, J.; Kagan, H. B. Tetrahedron
1985, 41, 3689; (c) Inada, Y.; Nishibayashi, Y.; Hidai, M.; Uemura,
S. J. Am. Chem. Soc. 2002, 124, 15172.
can be readily synthesized via this iodine-mediated
thiolation strategy. The present S-alkylation strategy has
several advantages over similar transformations, in
which both iodine and NaSH are inexpensive, and have
a low toxicity, and stable disulfides can be used instead
of effluvial and virulent thiols.
[8] (a) Han, X.-P.; Wu, J. Org. Lett. 2010, 12, 5780; (b) Robertson, F.;
Wu, J. Org. Lett. 2010, 12, 2668.
[9] Zhang, X.; Rao, W.; Chan, P. W. H. Synlett 2008, 2204.
[10] Bahrami, K.; Khodaei, M. M.; Khodadoustan, N. Synlett 2011, 2206.
[11] (a) Kotsuki, H.; Matsumoto, K.; Nishizawa, H. Tetrahedron Lett.
1991, 32, 4155; (b) Cleary, D. G. Synth. Commun. 1989, 19, 737; (c)
Suzuki, H.; Sato, N. Chem. Lett. 1981, 267.
[12] (a) Du, H.-A.; Zhang, X.-G.; Tang, R.-Y.; Li, J.-H. J. Org. Chem.
2009, 74, 7844; (b) Du, H.-A.; Tang, R.-Y.; Deng, C.-L.; Liu, Y.; Li,
J.-H.; Zhang, X.-G. Adv. Synth. Catal. 2011, 353, 2739; (c) Fang,
X.-L.; Tang, R.-Y.; Zhang, X.-G.; Li, J.-H. Synthesis 2011, 1099; (d)
Zhao, D.-Y.; Guo, X.-K.; Li, J.-H.; Tang, R.-Y. Synthesis 2012, 927.
[13] Selective papers for the application of microwave synthesis, see: (a)
Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35, 717;
(b) Wu, Y.-J.; He, H. Synlett 2003, 1789; (c) Bagley, M. C.; Dix, M.
C.; Fusillo, V. Tetrahedron Lett. 2009, 50, 3661; (d) Tan, C.-M.;
Chen, G. S.; Chen, C.-S.; Chern, J.-W. J. Chin. Chem. Soc. 2011, 58,
94.
Acknowledgement
We thank the National Natural Science Foundation
of China (Nos. 21002070 and 21102104), Zhejiang Pro-
vincial Natural Science Foundation of China (No.
Y4100307) and the Opening Foundation of Zhejiang
Provincial Top Key Discipline (No. 100061200110) for
financial support.
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