Rhodium-catalyzed synthesis of isothiocyanate from isonitrile and sulfur

Article abstract of DOI:10.1016/j.tetlet.2005.01.069

Rhodium complexes RhH(PPh₃)₄ and Rh(acac)(CH ₂CH₂)₂ catalyze sulfuration of isonitrile with sulfur giving isothiocyanates in high yields. The metal-catalyzed reaction is rapid in refluxing acetone, and completes within 3 h in most cases. The reaction exhibits induction period, which disappeared by preheating sulfur in refluxing acetone for 1.5 h. Use of several organic polysulfides in this transformation was examined in order to compare the reactivity.

Full text of DOI:10.1016/j.tetlet.2005.01.069

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1727–1729
Rhodium-catalyzed synthesis of isothiocyanate
from isonitrile and sulfur
Mieko Arisawa, Masanori Ashikawa, Atsushi Suwa and Masahiko Yamaguchi*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Sendai 980-8578, Japan
Received 22 December 2004; revised 7 January 2005; accepted 7 January 2005
Available online 29 January 2005
Abstract—Rhodium complexes RhH(PPh3)4 and Rh(acac)(CH2@CH2)2 catalyze sulfuration of isonitrile with sulfur giving isothio-
cyanates in high yields. The metal-catalyzed reaction is rapid in refluxing acetone, and completes within 3 h in most cases. The
reaction exhibits induction period, which disappeared by preheating sulfur in refluxing acetone for 1.5 h. Use of several
organic polysulfides in this transformation was examined in order to compare the reactivity.
Ó 2005 Elsevier Ltd. All rights reserved.
Utilization of sulfur is a challenging synthetic methodol-
ogy for the preparation of organosulfur compounds.
Conventional methods, however, in general required
harsh conditions. It was considered that transition metal
catalyzed activation of elemental sulfur could be an
interesting approach to control such sulfuration reac-
tion. We investigated catalytic cleavage of organic disul-
fides with transition metal catalysts, which was utilized
in the transformations such as disulfide exchange1 or
addition to unsaturated compounds.2 As for the activa-
tion of elemental sulfur, we recently reported the cata-
lytic exchange reaction of sulfur atom between organic
polysulfides and elemental sulfur.3 As an extension of
the sulfur activation methodology, we describe here rho-
dium-catalyzed sulfuration reaction of isonitriles giving
isothiocyanates.
pletion in the presence of 1 mol % complex. Described in
the present study is a rhodium-catalyzed reaction of iso-
nitrile and sulfur giving isothiocyanate. The reaction is
much faster than the molybdenum method, and com-
pletes in most cases within 3 h at acetone reflux employ-
ing the same catalyst loading.
To a mixture of RhH(PPh3)4 (1 mol %) in acetone was
added cyclohexyl isonitrile 1, and the solution was
stirred for 5 min at room temperature. Then, sulfur
(1.2 atom equivalents) was added, and the mixture was
heated at reflux for 2 h giving cyclohexyl isothiocyanate
2 in 91% yield (Table 1).7 The rhodium complex is criti-
cal for the reaction, and 2 was not detected in its
absence after 2 days at 50 °C in a sealed NMR tube.
Triphenylphosphine sulfide was formed in 80% yield
during the sulfuration, and the phosphine ligand
appears not to be essential for the reaction. In accor-
dance, screening of the metal complexes8 revealed that
a non-phosphine complex Rh(acac)(CH2@CH2)2 was
also effective, and gave the product in 88% yield under
the same reaction conditions. In this case, the amount
of sulfur could be reduced to 1.1 atom equivalents, since
it was not consumed by phosphine. Several aliphatic and
aromatic isonitriles were reacted with sulfur in the pres-
ence of RhH(PPh3)4 or Rh(acac)(CH2@CH2)2, which
gave similar results. It may reasonably be assumed that
both reactions proceeded via the same active rhodium
species lacking the phosphine ligand.
Isothiocyanates are a group of compounds possessing
biological activities, and a variety of methods were
developed for their synthesis.4 Reaction of isonitrile
and a sulfur reagent is a convenient method, if sulfur
could be used in the presence of an appropriate catalyst.
Such transformation was reported by Sonoda employ-
ing selenium or tellurium catalysts.5 As for the transition
metal method, molybdenum catalyst was examined by
Bargon and co-workers.6 The reaction, however, was
sluggish, and required 72 h in refluxing acetone for com-
Keywords: Rhodium complex; Sulfur; Isothiocyanate; Isonitrile;
Induction period.
The reactions of RhH(PPh3)4 and Rh(acac)-
(CH2@CH2)2 catalysts exhibited induction periods.
For example, the reaction of 1 and sulfur in the presence
*
Corresponding author. Tel.: +81 22 217 6812; fax: +81 22 217
6811; e-mail: yama@mail.pharm.tohoku.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.069

1728
M. Arisawa et al. / Tetrahedron Letters 46 (2005) 1727–1729
Table 1. Rh-catalyzed synthesis of isothiocyanate
Table 2. Rh-catalyzed sulfuration of 1 with organic polysulfide
RhH(PPh3)4 or Rh(acac)(CH2=CH2)2
RhH(PPh3)4
NCS
RSnSR
+
NC
RNCS
RNC
+ S8
acetone, refl.
acetone, refl.
1
2
R
Time/h
Yield/%
Entry
RSnR
Time/h
Yield/%a
Cat Aa
Cat Ba
1
2
3
4
5
6
7
(n-Bu)2S3
(p-tol)2S3
1.5
1.5
5
7
1
cyclo-C6H11
n-C8H17
–
2
91
94
90
95
83
96
96
87
92
93
88
94
87
91
90
92
91
87
90
88
–
2
82
68a
11b
94
10
t-BuCH2CMe2–
PhCH2–
1.5
2.5
3
Et2S4
(p-tol)2S4
1.5
1.5
5
HOCH2CMe2CH2–
Me3SiOCH2CMe2CH2–
2,6-Me2C6H3–
p-ClC6H4–
1.5
2.5
8
(p-ClC6H4)2S4
1.5
a Recovered polysulfides: disulfide (12%), trisulfide (53%), tetrasulfide
(20%), pentasulfide (5%), and hexasulfide (1%).
b Recovered polysulfides: disulfide (32%), trisulfide (30%), tetrasulfide
(19%), and pentasulfide (19%).
p-MeC6H4–
p-MeOC6H4
3
6
a Cat A: RhH(PPh3)4. Cat B: Rh(acac)(CH2@CH2)2.
not significant. Higher reactivity of the alkyl tetrasulfide
compared to the alkyl trisulfide can be ascribed to the S–
S bond dissociation energy, which was reported to be
the following order: RSS–SSR < RSS–SR.12 Di(p-tolyl)
and di(p-chlorophenyl) tetrasulfides,10 however, were
less effective compared to diethyl tetrasulfide (entries 5
and 7). The recovered di(p-tolyl) polysulfides were a
mixture of comparable amounts of disulfide (32%), tri-
sulfide (30%), tetrasulfide (29%), and pentasulfide
(19%). The sulfur exchange reaction rapidly took place
in these aromatic cases, and the sulfuration of 1 was
slower. It is noticed that the polysulfide sulfuration
also exhibits induction period as indicated by the reac-
tions of aromatic trisulfide and tetrasulfide (entries 3
and 6). The results again suggested the formation of
reactive polysulfide species during the sulfur exchange
reaction.13
of RhH(PPh3)4 started after ca. 40 min, and completed
after 80 min (Fig. 1). It was ascribed to the slow forma-
tion of the true active species. Notably, the treatment of
sulfur in refluxing acetone for 1.5 h prior to the reaction
resulted in the disappearance of the induction period,
which suggested the formation of an active ÔsulfurÕ
species.
100
80
60
40
The mechanism likely involves the initial formation of a
low valent rhodium complex (RNC)mRhLn from isoni-
trile and a rhodium species (Scheme 1). An activated sul-
fur species generated from elemental sulfur undergoes
oxidative addition to the complex, and transfer of sulfur
atom to isonitrile takes place giving isothiocyanate.14,15
The mechanism is consistent with the observation that it
is essential to add isonitrile to the rhodium complex
prior to the addition of sulfur. Otherwise, no reaction
took place.
S8 refluxed in acetone
20
Control
0
0
20
40
60
80
100
Time (min)
Figure 1. Time course of RhH(PPh3)4 catalyzed conversion of 1 to 2.
In order to compare the reactivity of the sulfur reagents,
equimolar amounts of organic polysulfides were reacted
with 1 in refluxing acetone for 1.5 h in the presence of
RhH(PPh3)4 (1 mol %) (Table 2). Diphenyl disulfide
did not react with 1 under the conditions. The reactions
of several trisulfides and tetrasulfides gave 2, although
less efficient than elemental sulfur. Dibutyl trisulfide9
and di(p-tolyl) trisulfide10 gave 2 in less than 20% yield
after 1.5 h (entries 1 and 2). Diethyl tetrasulfide11 turned
out to be more reactive, and 2 was obtained in 68% yield
(entry 4). The recovered diethyl polysulfides in this reac-
tion contained mostly trisulfide (53%) with smaller
amounts of disulfide (12%), tetrasulfide (20%), and the
higher homologs. The sulfur transfer proceeded fairly
cleanly from the tetrasulfide to 1 with the formation of
trisulfide, and disproportionation of the polysulfides is
(RNC)mRhLn
"activatied S8"
S8
RNC
S
(RNC)m-1RhLn
(RNC)mRhLn
S
RNC=S
Scheme 1.

M. Arisawa et al. / Tetrahedron Letters 46 (2005) 1727–1729
1729
(1 mol %, 5.8 mg), cyclohexyl isonitrile
1
(0.5 mmol,
Acknowledgements
54.6 mg), and elemental sulfur (1.0 mmol atom, 32 mg)
in acetone (1 mL) under an argon atmosphere. The
mixture was stirred and heated in oil bath at reflux for
1.5 h. Then, the solvent was removed under reduced
pressure, and the residue was purified by flash chroma-
tography on silica gel giving cyclohexyl isothiocyanate 2
(62 mg, 89%). Purification of isonitrile by repeated
recrystallization or distillation is very important for the
high yield sulfuration, which may be due to the catalyst
deactivation by small amounts of impurity.
8. Metal complexes examined were as follows, all of which
exhibited modest activities: Pd(OAc)2, RhCl(PPh3)3,
[RhCl(cod)]2, Rh(cod)BF4, Rh(acac)(CO)2.
9. Banerji, A.; Kalena, G. P. Tetrahedron Lett. 1980, 21,
3003.
10. Zysman-Colman, E.; Harpp, D. N. J. Org. Chem. 2003,
68, 2487.
11. Andrzej, Z. R.; Harpp, D. N. Tetrahedron Lett. 2000, 41,
7169.
12. Allen, T. L. J. Chem. Phys. 1959, 31, 1039; Kende, I.;
Pickering, T. L.; Tobolsky, A. V. J. Am. Chem. Soc. 1965,
87, 5582.
13. For examples: Tebbe, F. N.; Wasserman, E.; Peet, W. G.;
Vatvars, A.; Hayman, A. C. J. Am. Chem. Soc. 1982, 104,
4971; Bosser, G.; Anouti, M.; Paris, J. J. Chem. Soc.,
Perkin Trans. 2 1996, 1993.
14. Insertion of isonitrile into Pd–S bond: Kuniyasu, H.;
Sugoh, K.; Su, M. S.; Kurosawa, H. J. Am. Chem. Soc.
1997, 119, 4669.
15. Pd-catalyzed reaction of disulfide and isonitrile: Kuniyasu,
H.; Maruyama, A.; Kurosawa, H. Organometallics 1998,
17, 908.
This work was supported by grants from the Japan
Society of Promotion of Science (Nos. 14207094 and
16109001). M.A. thanks support from NEDO of Japan
(No. 02A44003d).
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