N-heterocyclic carbene copper(I) complex-catalyzed direct C-H thiolation of benzothiazoles

Article abstract of DOI:10.1016/j.tetlet.2013.06.104

N-heterocyclic carbene (NHC) copper(I) complexes based on imidazol-2-ylidene and 1,2,3-triazol-5-ylidene catalyzed the direct C-H thiolation of benzothiazoles and benzoxazoles with aryl and alkyl thiols to give 2-aryl and 2-alkylthiobenzothiazoles in moderate-to-good yields. The NHC copper(I) complex [(IPr)CuI] was the most effective catalyst for the reaction among the NHC-Cu(I) complexes examined in this study.

Full text of DOI:10.1016/j.tetlet.2013.06.104

Tetrahedron Letters 54 (2013) 4729–4731
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
N-heterocyclic carbene copper(I) complex-catalyzed direct C–H
thiolation of benzothiazoles
⇑
Hiroshi Inomata, Ayumi Toh, Takashi Mitsui, Shin-ichi Fukuzawa
Department of Applied Chemistry, Institute of Science Engineering, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
N-heterocyclic carbene (NHC) copper(I) complexes based on imidazol-2-ylidene and 1,2,3-triazol-5-yli-
dene catalyzed the direct C–H thiolation of benzothiazoles and benzoxazoles with aryl and alkyl thiols
to give 2-aryl and 2-alkylthiobenzothiazoles in moderate-to-good yields. The NHC copper(I) complex
[(IPr)CuI] was the most effective catalyst for the reaction among the NHC–Cu(I) complexes examined
in this study.
Received 13 May 2013
Revised 19 June 2013
Accepted 21 June 2013
Available online 29 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
C–H bond functionalization
Thiolation
N-heterocyclic carbene
Benzothiazole
Copper
C–S bond formation represents a key step in the synthesis of
aryl and heteroaromatic sulfides, which are biologically and phar-
copper (NHC–Cu) complexes,9 which was followed by our work
demonstrating that 1,2,3-triazolylidene carbene copper complexes
(tzNHC–Cu; this type of NHC is abbreviated as tzNHC to distinguish
it from conventional NHCs) worked more effectively than the cor-
responding NHC–Cu complexes in carboxylation with benzothia-
zole.10 Because a stoichiometric amount of CuI/2,20-bipyridine
complex is required for the thiolation with benzothiazole and
imidazole, we are interested in NHC–Cu and tzNHC–Cu complexes
as alternative copper catalysts for the C–H thiolation of azoles with
aryl thiols.11 We report here the direct C–H thiolation of benzo-
thiazoles using a catalytic amount of NHC–Cu and tzNHC–Cu
complexes.
We first examined the time-dependent yield of the C–H thiola-
tion of benzothiazole using various NHC–CuI and tzNHC–CuI com-
plexes as well as CuI to evaluate their catalytic activities (Fig. 1). In
the procedure, copper complex (20 mol % relative to the amount of
benzothiazole) and K2CO3 (two equivalents relative to the amount
of benzothiazole) were added to a vial, followed by benzothiazole
(1a), thiophenol (2a) (2 equiv relative to the amount of benzothia-
zole), and dimethylformamide (DMF) (Scheme 1). The vial was
maceutically important compounds and functional materials.1
A
direct method for the formation of C–S bond is cross-coupling reac-
tion of organic halide or organometallic compounds with organic
thiol (or disulfide).2 An alternative method is direct C–H thiolation
of aromatic compounds, which does not require the presence of
reactive functional groups such as halogens or metal moieties. Di-
rect C–H thiolation was not known before Yu and co-workers suc-
ceeded in copper-catalyzed thiolation of 2-phenylpyridine under
oxygen, where thiolation occurred at the ortho position of the phe-
nyl ring.3 Some other thiolation reactions based on the ortho-
directing group-assisted C–H activation have been reported.4 As
an unassisted direct C–H thiolation method, we developed direct
C–H thiolation of benzoxazoles using a CuI/2,20-bipyridine com-
plex under oxygen. In this reaction, thiolation occurred at the 2-po-
sition of benzoxazoles to give 2-thioethers.5 Subsequently, other
research groups expanded the copper-mediated direct C–H thiola-
tion to arenes and heteroarenes.6 Very recently, copper-catalyzed
direct thiolation of pentafluorobenzene was reported, where thio-
lation proceeded through C–H and C–F bond activation.7 Other me-
tal complex catalysts in addition to copper complex have been
developed for the C–S coupling reaction via direct C–H functional-
ization of arenes.8
Hou and Nolan research groups independently reported the di-
rect C–H carboxylation of azoles using imidazolylidene carbene
⇑
Corresponding author.
E-mail address: orgsynth@kc.chuo-u.ac.jp (S. Fukuzawa).
Figure 1. NHC–CuI and tzNHC–CuI complexes.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.104

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H. Inomata et al. / Tetrahedron Letters 54 (2013) 4729–4731
The scope of substituted benzothiazoles (1b–i) was examined
by using the most effective catalyst (IPr)CuI (20 mol %) and thio-
phenol 2a as a reactant in DMF at 140 °C with 3 h of reaction
time.12 The results are summarized in Table 1. The reactions of
4- and 6-substituted benzothiazoles were examined. Electron-
donating substituents at 4- and 6-positions gave lower (moderate)
yields than the electron-neutral substituents, regardless of their
position; thus, the position of the substituent hardly affected the
reaction (entries 2–5). 4- and 6-Chlorobenzothiazoles (1f,g) toler-
ated the thiolation and the reaction involved only the 2-oxazole
carbon to give the corresponding thioethers (3fa–3ga) in good
yields (entries 6 and 7). On the other hand, the reaction with 6-bro-
mobenzothiazole produced a significant amount of 3aa which re-
sulted from reduction of the bromo group of thiolation product
3ha. The reaction with 6-nitrobenzothiazole 1i gave hardly any
product (entry 9).
Scheme 1. Direct C–H thiolation of benzothiazole with thiophenol.
heated at 140 °C in the presence of air for a predetermined time.
After the reaction was quenched with water, the product was ex-
tracted with ethyl acetate, and the yield was determined by GC
using biphenyl as an internal standard. The yields obtained by dif-
ferent catalysts are shown in Figure 2 as a function of reaction time.
(IPr)CuI and (IMes)CuI, and (TPr)CuI, and (TMes)CuI were exam-
ined as typical NHC–Cu and tzNHC–Cu complexes, respectively. As
seen in Figure 2, when (IPr)CuI (j)was used as a catalyst, the reac-
tion was fastest and its yield reached 95% after 3 h of reaction time,
while the reaction with (IMes)CuI (N) reached a plateau after 6 h,
giving a maximum yield of 85%. In the reaction with (TPr)CuI
(h), the yield increased almost linearly and reached 95% after
7 h. The reaction rate with (TMes)CuI (4) was moderate and sim-
ilar to (IMes)CuI, and the yield reached approximately 80% after
7 h. Interestingly, ligand-free CuI (s) also catalyzed the reaction,
although it was earlier reported that CuI did not catalyze the direct
thiolation of benzothiazole in the presence of K3PO4 in DMSO at
100 °C. The reaction was faster than those with (TMes)CuI, (IMes)-
CuI, and (TPr)CuI, but slower than that with (IPr)CuI. Thus, (IPr)CuI
was revealed to be the most active copper complex. NHC–CuI Med-
iated the reaction at a catalytic amount and completed it in 6–7 h,
while the earlier reaction with CuI/2,20-bipyridine was stoichiom-
etric and required 24 h for the completion in heated DMF.6d
The reaction without the copper(I) catalyst or with the ligand
only (IPrꢀHCl) gave 12% and 21% yields under the same reaction
conditions, respectively. These control experiments showed that
the base (K2CO3) and/or ligand may mediate the reaction, but they
are not essential for it. When the reaction was carried out using
10 mol % of (IPr)CuI, the yield dropped to 55%; hence, 20 mol % cat-
alyst loading was necessary to obtain a satisfactory yield. The
reaction in the absence of air in a sealed tube resulted in 10% yield
indicating that oxygen was necessary for the reaction.
Table 1
Direct thiolation of substituted benzothiazoles with thiophenola
Entry
R
Product, yieldb (%)
1
2
3
4
5
6
7
8
9
1a, H
3aa, 81
3ba, 59
3ca, 46
3da, 61
3ea, 62
3fa, 82
3ga, 70
3ha, 66c
3ia, 0
1b, 6-Me
1c, 4-Me
1d, 6-MeO
1e, 4-MeO
1f, 6-Cl
1g, 4-Cl
1h, 6-Br
1i, 6-NO2
a
Compounds 1b–h (0.25 mmol), PhSH 2a (0.50 mmol), K2CO3 (0.50 mmol),
(IPr)CuCl (0.05 mmol), DMF (1.5 mL); 140 °C, 3 h.
b
Isolated yield.
Other product is 3aa (ca. 10%).
c
Table 2
Direct thiolation of benzothiazole with various thiolsa
Entry
R
Product, yieldb (%)
1
2a, C6H5
3aa, 81
3ab, 80
3ac, 78
3ad, 66d
3ae, 24
3af, 38
3ag, 31
3ah, 22
3ai, 68
3aj, 36
3ak, 33
2c
3c
4
2b, 4-MeC6H4
2c, 2-MeC6H4
2d, 4-MeOC6H4
2e, 4-NH2C6H4
2f, 4-FC6H4
2g, 4-ClC6H4
2h, 4-BrC6H4
2i, 2-C10H7
2j, n-C10H13
2k, Cy
5
6
7
8
9c
10
11
a
Compounds 1a (0.25 mmol), 2a–l (0.50 mmol), K2CO3 (0.50 mmol), (IPr)CuCl
(0.05 mmol), DMF (1.5 mL); 140 °C, 3 h.
b
Isolated yield.
0.75 mmol of thiol was used.
Other product is 4-methoxythioanisole.
Figure 2. Reaction yield (%) as a function of time for copper-catalyzed direct
arylation of benzothiazole with benzenethiol in the presence of different catalysts:
j(IPr)CuI, N(IMes)CuI, h(TPr)CuI, 4(TMes)CuI, and sCuI.
c
d

H. Inomata et al. / Tetrahedron Letters 54 (2013) 4729–4731
4731
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
06.104.
Scheme 2. Direct C–H thiolation of benzoxazole 5 with thiophenol.
References and notes
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Table 2 summarizes the scope of alkyl and arylthiol substrates
(2a–i) using 1a as a reactant under the optimal reaction conditions.
Both alkyl and aryl thiols could be coupled with 1a to give the cor-
responding thioethers 3aa–3ak in low-to-good yields. The reaction
with thiophenols bearing electron-donating substituents such as
4-methyl (2b) and 2-methyl (2c) groups gave the corresponding
thioethers in good yields (entries 2 and 3) using excess of thiols
(three equivalent to 1a). In the reaction with 4-methoxythiophenol
(2d), the by-production of 4-methoxythioanisole was observed,
decreasing the yield of the thiolation product (entry 4).13 The reac-
tion with amino-substituted benzenethiol (2e) gave the desired
thiolation product as a sole product, but in low yield. No coupling
product with the amino group was observed by GC/MS analysis
(entry 5); the reaction proceeded chemoselectively with the thiol
group.14 4-Fluorothiophenol (2f) reacted with 1a to give the corre-
sponding 4-fluorophenyl thioether 3af in low yield (entry 6). Nota-
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reaction with 4-chlorothiophenol (2g) or 4-bromothiophenol (2h)
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12. Typical experimental procedure for the direct C–H thiolation of benzothiazole
with benzenethiol.
NHC–Cu complexes could be applied to the direct thiolation of
benzoxazole 4 when the reaction was carried out in DMF at 80 °C
for 2 h using (TPr)CuI as a catalyst and K2CO3 as a base, and the
reaction with thiophenol quantitatively gave the corresponding
thioether 5 (Scheme 2).
In conclusion, NHC–CuI is a useful catalyst in the direct C–H thi-
olation of benzothiazoles and benzoxazoles with aryl and alkylthi-
ols, and various substituted 2-arylthio-benzothiazoles and
benzoxazoles can be readily prepared in moderate-to-good yields
in air.
13. Treatment of 4-methoxythiophenol in DMF or DMSO at 140 °C produced 4-
methoxythioanisole in the absence of 1a and copper(I) catalyst.
Acknowledgment
14. For a review of C–N cross-coupling reaction Jiang, L.; Buchwald, S. L. Metal-
catalyzed Cross-Coupling Reactions In Meijere, A., Diederich, F., Eds.; Wiley-
VCH: Weinheim, 2004; pp 699–760. Vol. 2, Chapter 13.
This work was financially supported by a Chuo University Grant
for Special Research.