Aqueous C-S cross-coupling: Synthesis of 2-iminobenzo-1,3-oxathioles via CuCl2·H2O-catalyzed tandem reaction of 2-iodophenols with isothiocyanates

Article abstract of DOI:10.1016/j.tetlet.2011.02.061

A CuCl₂·H₂O-catalyzed tandem reaction of 2-iodophenol with isothiocyanate in water is described, which provides an environmentally benign, efficient, and practical route for the generation of 2-iminobenzo-1,3-oxathiole. It was notewo

Full text of DOI:10.1016/j.tetlet.2011.02.061

Tetrahedron Letters 52 (2011) 1964–1967
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Tetrahedron Letters
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Aqueous C–S cross-coupling: synthesis of 2-iminobenzo-1,3-oxathioles
via CuCl2ÁH2O-catalyzed tandem reaction of 2-iodophenols with isothiocyanates
Qiuping Ding a,b, , Xianjin Liu a, Banpeng Cao a, Zhenzhen Zong a, Yiyuan Peng a,b,
⇑
⇑
a College of Chemistry and Chemical Engineering, Jiangxi Normal University, 99 Ziyang Road, Nanchang 330022, China
b Key Laboratory of Functional Small Organic Molecule, Ministry of Education and Key Laboratory of Green Chemistry of Jiangxi Province, 99 Ziyang Road, Nanchang 330022, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A CuCl2ÁH2O-catalyzed tandem reaction of 2-iodophenol with isothiocyanate in water is described, which
provides an environmentally benign, efficient, and practical route for the generation of 2-iminobenzo-
1,3-oxathiole. It was noteworthy that most of the products were easily separated from the reaction sys-
tem by simple filtration.
Received 14 December 2010
Revised 22 January 2011
Accepted 15 February 2011
Available online 18 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Isothiocyanate
2-Iodophenol
Cross-coupling
Aqueous
As a privileged fragment, the benzo-1,3-oxathiole core is a ubiq-
uitous subunit in a variety of important heterocyclic compounds
with remarkable pharmaceutical or biochemical activities.1 Among
these, 2-iminobenzo-1,3-oxathiole is an important class of benzo-
1,3-oxathiole derivatives.2 The importance of the 2-iminobenzo-
1,3-oxathioles has stimulated the development of efficient
methods for their synthesis. However, there are still only a few
approaches for the synthesis of 2-iminobenzo-1,3-oxathioles.2
Recently, Bao and co-workers reported a very efficient method
for the synthesis of 2-iminobenzo-1,3-oxathioles via a copper(I)-
catalyzed one-pot cascade process in toluene.2a Nair et al. found
that the heterocyclic scaffolds could also be constructed by [4+1]
the cycloaddition reaction of o-thioquinones with isocyanides.2b
The narrow substrate scopes, expensive or toxic metal catalysts,
or organic solvents used by these approaches limited their applica-
tions. Thus, it is highly desired to develop efficient and environ-
mentally benign synthetic methods for access to functionalized
2-iminobenzo-1,3-oxathioles.
It is well-known that the transition-metal-catalyzed intermo-
lecular C–S cross-coupling reactions of aryl halides with thiols have
emerged as a powerful method.3–5 However, the area of one-pot
tandem addition/intramolecular C–S cross-coupling reactions to
achieve sulfur-containing heterocyclic compounds is still at a
developmental stage.6 In this area, many efforts were given to
the development of new benzothiazole scaffolds and the new
approaches for their construction.6 Nevertheless, only a few
one-pot strategies have been reported for the synthesis of other
heterocyclic compounds, such as benzo-1,3-oxathiole.2
On the other hand, to avoid using organic solvent in organic
synthesis reaction is one of the important goals in green chemistry.
Water as a useful alternative solvent has attracted much interest in
chemical transformation, owing to its many potential advantages,
such as safety, economy, and environmental concerns.6h,7 Recently,
we described the FeCl3-catalyzed one-pot synthesis of 2-amino-
benzothiazole from 2-iodoanilines with isothiocyanates in water.6h
As a part of our continual efforts to utilize water as a reaction med-
ium in organic transformation6h and to construct heterocyclic
compounds by C–S cross-coupling reaction,6e,h,8 herein we would
like to report the synthesis of 2-iminobenzo-1,3-oxathioles via
CuCl2ÁH2O-catalyzed tandem reaction of 2-iodophenols with
isothiocyanates in water.
According to our previous experience6h and Bao’s reaction con-
ditions,2a we began to optimize the reaction (Table 1). At the outset
of our studies, we examined the FeCl3-catalyzed tandem addition/
intramolecular C–S cross-coupling reaction between 2-iodophenol
1a and phenyl isothiocycanate 2a in the presence of 1,10-phenan-
throline (L-1, 10 mol %) and base (Cs2CO3, 2.0 equiv) in water at
80 °C. The desired 2-iminobenzo-1,3-oxathiole 3a was generated
in 53% yield (Table 1, entry 1). Encouraged by the result, we subse-
quently probed the catalytic activities of various inexpensive Fe
and Cu catalysts (Table 1, entries 2–9). Other Fe catalysts also
showed the similar catalytic activity, such as Fe2(SO4)3ÁH2O,
FeSO4Á7H2O (Table 1, entries 2 and 3). The significantly increased
reactivity was achieved when using Cu salts as catalyst, such as
CuI, CuCl, CuCl2Á2H2O, Cu2O (Table 1, entries 4 and 6–8). Among
these, CuCl2Á2H2O was the best choice (Table 1, entry 7, 90% yield).
⇑
Corresponding authors.
E-mail address: dqpjxnu@gmail.com (Q. Ding).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.061

Q. Ding et al. / Tetrahedron Letters 52 (2011) 1964–1967
1965
Table 1
investigated and the results are summarized in Table 2. The
optimized reaction conditions were applied to a series of isothiocy-
anates giving rise to the corresponding 2-iminobenzo-1,3-oxathi-
oles 3 in good to excellent yields, regardless of the electronic
nature of the groups on the aryl isothiocyanate (Table 2, entries
1–6). For instance, 2-iodophenol 1a reacted with 4-methoxyphenyl
isothiocyanate 2b or 4-methylphenyl isothiocyanate 2c leading to
the desired products in excellent yields (Table 2, entries 2 and 3).
When 4-nitrophenyl isothiocyanate 2d was employed in the
reaction of 1a under the standard condition, the product 3d was
afforded in 91% yield (Table 2, entry 4). Reaction of 1a with 2e or
2f gave rise to the 2-iminobenzo-1,3-oxathioles 3e or 3f in 95%
or 97% yield, respectively (Table 2, entries 5 and 6). Further inves-
tigation showed that alkyl isothiocyanate 2g was also a suitable
substrate in this process in moderate yield (Table 2, entry 7).
With respect to the electronic nature of the substituents on the
2-iodophenol, we further investigated the scope and the generality
of the method by varying the 2-iodophenol 1b–g. As shown in
Table 3, generally the reactions proceeded successfully to afford
the corresponding product 3 in moderate toexcellent yields,
Condition screening for tandem reaction of 2-iodophenol 1a with phenyl isothiocy-
anate 2a in watera
OH
I
Ph
O
S
Cat./L, Base
PhNCS
N
H2O, 80 oC, 24h
1a
2a
3a
O
O
N
L-proline
L-2
H2N
COOH
L-4
OH
N
N
L-1
L-3
L-5
Entry
Catalyst 10 mol %
L
Base
Yieldb (%)
1
2
3
4
5
6
7
8
FeCl3
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-2
L-3
L-4
L-5
––
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-1
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
53
60
55
74
62
85
90
79
41
24
44
25
40
16
37
67
85
80
96
94
90
94
94
85
94
65
94
Fe2(SO4)3ÁH2O
FeSO4Á7H2O
CuI
CuBr
CuCl
CuCl2Á2H2O
Cu2O
9
CuCl2Á2H2O
CuCl2Á2H2O
CuCl2Á2H2O
CuCl2Á2H2O
CuCl2Á2H2O
CuCl2Á2H2O
CuCl2Á2H2O
CuCl2Á2H2O
CuCl2Á2H2O
CuCl2Á2H2O
CuCl2Á2H2O
CuCl2Á2H2O
CuCl2Á2H2O
CuCl2Á2H2O
CuCl2Á2H2O
CuCl2Á2H2O
CuCl2Á2H2O (5 mol %)
CuCl2Á2H2O (1 mol %)
CuCl2Á2H2O (5 mol %)
10
11
12
13
14
15
16
17
18
19
20c
21d
22
23
24
25
26
27e
Cs2CO3
Table 2
CuCl2Á2H2O-catalyzed tandem reaction of 2-iodophenol 1a with isothiocyanate 2a,9
––
NaHCO3
NaOH
K2CO3
R2
CuCl2 2H2O/L-1
OH
O
R2NCS
N
DABCO 6H2O
S
Et3N
H2O, 80 oC, 24h
I
DABCOÁ6H2O
DABCOÁ6H2O
DABCOÁ6H2O
DABCOÁ6H2O
DABCOÁ6H2O
DABCOÁ6H2O
DABCOÁ6H2O
DABCOÁ6H2O
DABCOÁ6H2O
1a
2
3
Entry
1
2/R2
Product 3
Yieldb (%)
94
L-1 (5 mol %)
L-1 (2 mol %)
L-1 (1 mol %)
L-1
Ph
O
N
2a/C6H5
S
3a
L-1
OCH3
L-1 (2 mol %)
a
Reaction conditions: 2-iodophenol 1a (0.3 mmol), phenyl isothiocyanate 2a
2
3
2b/4-MeOC6H4
2c/4-MeC6H4
98
92
O
S
(1.5 equiv), cat. (10 mol %), L (10 mol %), base (2.0 equiv), H2O (3 mL), 80 °C, 24 h.
b
N
Isolated yield based on 2-iodophenol 1a.
1a with 2a in a 1:1.2 ratio.
1a with 2a in a 1:1.05 ratio.
c
3b
CH3
d
e
1a (0.3 mmol), 2a (1.2 equiv), CuCl2Á2H2O (5 mol %), L-1 (2 mol %), DABCOÁ2H2O
(2.0 equiv), H2O (3 mL), 80 °C, 24 h.
O
S
N
N
N
3c
NO2
And then, we investigated the influence of various ligands (such as
L-proline, acac, 2-aminoacetic acid, quinolin-8-ol), but the results
were all inferior to 1,10-phenanthroline (Table 1, entries 9–12).
Blank reactions showed that ligand L-1 and base are essential to
obtain good result (Table 1, entries 13 and 14). Further base
screening of the CuCl2Á2H2O-catalyzed reaction revealed that the
yield could be increased to 96% when DABCOÁ6H2O was utilized
as a replacement (Table 1, entry 19). Decreasing the amount of
phenyl isothiocycanate, the yield of the product 3a was slightly de-
creased (Table 1, entries 20 and 21). Furthermore, decreasing the
amount of the ligand (L-1) from 10 mol % to 2 mol %, a similar re-
sult was observed (Table 1, entries 22 and 23, both 94% yield). Even
an 85% yield of compound 3a was obtained when 1 mol % of ligand
(L-1) was employed (Table 1, entry 24). Decreasing the catalyst
amount to 5 mol % gave a similar result (Table 1, entry 25, 94%
yield). However, only a 65% yield of the desired product 3a was ob-
tained when the amount of catalyst was reduced to 1 mol % (Table
1, entry 26). When it was performed at room temperature, the
reaction was retarded.
4
5
2d/4-NO2C6H4
91
95
O
S
3d
F
2e/4-FC6H4
O
S
3e
Cl
6
7
2f/4-ClC6H4
2g/Cy
97
58
O
N
N
S
3f
Cy
O
S
3g
With this promising result in hand, we started to examine the
scope of this reaction under optimized conditions [CuCl2Á2H2O
(5 mol %), 1,10-phenanthroline (L-1, 2 mol %), DABCOÁ6H2O
(2.0 equiv), H2O, 80 °C]. Initially, the scope of isothiocyanates was
a
Reaction conditions: 2-iodophenol 1a (0.3 mmol), isothiocyanate 2 (1.2 equiv),
CuCl2Á2H2O (5 mol %), 1,10-phenanthroline (2 mol %), DABCOÁ6H2O (2.0 equiv), H2O
(3 mL), 80 °C.
b
Yield based on 2-iodophenol 1a.

1966
Q. Ding et al. / Tetrahedron Letters 52 (2011) 1964–1967
Table 3
anate 2a was able to proceed smoothly on a 15 mmol scale. The
product 3a was obtained in excellent yield (93%) in almost pure
form just by simple filtration and washing with saturated brine.
The large scale reaction of 2-iodo-4-methylphenol 1b with alkyl
isothiocyanate 2g was also examined, and gave the product 3m
in moderate yield (50%). The larger scale experiments illuminated
the applicability of the protocols in synthetic practice.
In conclusion, we have described an environmentally benign,
simple, and highly efficient method for the CuCl2ÁH2O-catalyzed
tandem synthesis of 2-iminobenzo-1,3-oxathioles in water. A vari-
ety of 2-iminobenzo-1,3-oxathioles have been synthesized in mod-
erate to excellent yield. The proposed approach of the tandem
reaction appears to be a combination of generation of an interme-
diate via addition of 2-iodophenol 1 to isothiocyanate 2, and an
intramolecular copper-catalyzed C–S cross-coupling reaction. It
was noteworthy that most of the products were easily separated
from the reaction system by simple filtration.
Cu-catalyzed tandem reaction of 2-iodophenol 1 with isothiocyanate 2a,9
R2
CuCl2 2H2O/L-1
OH
X
O
S
R2NCS
R1
N
R1
DABCO 6H2O
H2O, 80 oC, 24h
1
2
3
Entry
1/R1/X
2/R2
Product 3
Yieldb (%)
1
2
3
4
5
6
7
8
1b/4-CH3/I
1b/4-CH3/I
1b/4-CH3/I
1b/4-CH3/I
1b/4-CH3/I
1b/4-CH3/I
1c/4-tBu/I
1c/4-tBu/I
1c/4-tBu/I
1c/4-tBu/I
1c/4-tBu/I
1c/4-tBu/I
1d/4-Cl/I
2a/C6H5
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
90
98
90
87
95
52
92
92
93
86
94
70
92
96
93
88
90
20
2b/4-MeOC6H4
2c/4-MeC6H4
2d/4-NO2C6H4
2f/4-ClC6H4
2g/Cy
2a/C6H5
2b/4-MeOC6H4
2c/4-MeC6H4
2d/4-NO2C6H4
2f/4-ClC6H4
2g/Cy
9
10
11
12
13
14
15
16
17
18
3s
3t
2a/C6H5
Acknowledgments
1d/4-Cl/I
1d/4-Cl/I
1d/4-Cl/I
1d/4-Cl/I
2b/4-MeOC6H4
2c/4-MeC6H4
2d/4-NO2C6H4
2f/4-ClC6H4
2a/C6H5
3u
3v
3w
3x
3h
Financial Support from the National Natural Science Foundation
of China (No. 21002042), Natural Science Foundation of Jiangxi
Province of China (2009GQH0054), Jiangxi Educational Committee
(GJJ10387), and Startup Foundation for Doctors of Jiangxi Normal
University (200900266) is gratefully acknowledged.
1e/4-CH3/Br
1f/
I
OH
19
20
2d/4-NO2C6H4
3y
3z
40
72
Supplementary data
1g/
I
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.02.061.
OH
2a/C6H5
Cl
I
References and notes
a
Reaction conditions: 2-iodophenol 1 (0.3 mmol), isothiocyanate 2 (1.2 equiv),
CuCl2Á2H2O (5 mol %), 1,10-phenanthroline (2 mol %), DABCOÁ6H2O (2.0 equiv), H2O
1. (a) Konieczny, M. T.; Konieczny, W.; Sabisz, M.; Skladanowski, A.; Wakiec, R.;
Augustynowicz–Kopec, E.; Zwolska, Z. Eur. J. Med. Chem. 2007, 42, 729; (b)
Konieczny, M. T.; Konieczny, W.; Sabisz, M.; Skladanowski, A.; Wakiec, R.;
Augustynowicz–Kopec, E.; Zwolska, Z. Chem. Pharm. Bull. 2007, 55, 817; (c)
Jaquith, J. B.; Villeneuve, G.; Bureau, P.; Boudreault, A. Worldwide Patent
2005,012,281, 2005.; (d) Konieczny, M. T.; Konieczny, W.; Wolniewicz, S.;
(3 mL), 80 °C, 24 h.
b
Yield based on 2-iodophenol 1.
regardless of their electronic nature. For instance, reaction of 1b or
1c with various aryl isohtiocyanates 2 led to the corresponding
products 3 in good to excellent yields (Table 3, entries 1–5 and
7–11). The desired products were also isolated in good to excellent
yields, when the substrate 1d was employed in the reaction (Table
3, entries 13–17). Unfortunately, only 20% yield of desired product
was obtained when less reactive substrate (2-bromo-4-methylphe-
nol 1e) reacted with phenyl isothiocyanate 2a (Table 3, entry 18).
To our delight, diiodide 1g was also a suitable substrate in this pro-
cess in good yield (Table 3, entry 20, 72% yield).
´
Wierzba, K.; Suda, Y.; Sowinski, P. Tetrahedron 2005, 61, 8648.
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Mathew, B.; Vinod, A. U.; Mathen, J. S.; Ros, S.; Menon, R. S.; Varma, R. L.;
Srinivas, R. Synthesis 2003, 662; (c) Fathalla, W.; Marek, J.; Pazdera, P. J.
Heterocycl. Chem. 2002, 39, 1139; (d) Ibata, T.; Nakano, H. Bull. Chem. Soc. Jpn.
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Tetrahedron Lett. 1989, 30, 2259; (f) Kulka, M. Can. J. Chem. 1981, 59, 1557; (g)
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3. Copper-catalyzed C–S cross-coupling: (a) Ranu, B. C.; Saha, A.; Jana, R. Adv. Synth.
Catal. 2007, 349, 2690; (b) Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org.
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Gomez-Bengoa, E. Tetrahedron Lett. 2000, 41, 1283; (g) Rout, L.; Sen, T. K.;
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G. P. M.; de Vries, J. G.; van Koten, G. J. Org. Chem. 2008, 73, 5625.
To further highlight the superiority of this method, the gram-
scale synthesis of 2-iminobenzo-1,3-oxathiole derivatives under
the same conditions was performed (Scheme 1). We were pleased
to find that the reaction of 2-iodophenol 1a with phenyl isothiocy-
4. In-catalyzed C–S cross-coupling reaction: (a) Reddy, V. P.; Swapna, K.; Kumar, A.
V.; Rao, K. R. J. Org. Chem. 2009, 74, 3189; (b) Reddy, V. P.; Kumar, A. V.; Swapna,
K.; Rao, K. R. Org. Lett. 2009, 11, 1697.
OH
Ph
CuCl2 2H2O/L-1
O
S
PhNCS
N
5. Pd-catalyzed C–S cross-coupling reaction: (a) Jiang, Z.; Lin, J.; She, X. Adv. Synth.
Catal. 2009, 351, 2558; (b) Fu, C. -F.; Liu, Y. H.; Peng, S. M.; Liu, S. T. Tetrahedron
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5411; (d) Murata, M.; Buchwald, S. L. Tetrahedron 2004, 60, 7397; (e) Fernández-
Rodríguez, M. A.; Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 2180.
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G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802; (c) Wang, J.; Peng, F.; Jiang, J.; Lu, Z.;
Wang, L.; Bai, J.; Pan, Y. Tetrahedron Lett. 2008, 49, 467; (d) Benedí, C.; Bravo, F.;
Uriz, P.; Fernandez, E.; Claver, C.; Castillon, S. Tetrahedron Lett. 2003, 44, 6073;
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DABCO 6H2O
H2O, 80 oC, 24h
I
1a
2a
3a
3.17 g, 93% yield
3.30 g
2.43 g
Cy
OH
I
O
S
CuCl2 2H2O/L-1
N
CyNCS
DABCO 6H2O
H2O, 80 oC, 24h
1b
2g
2.54 g
3m
1.85 g, 50% yield
3.51 g
Scheme 1. Gram-scale synthesis of 3a and 3m.

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2.0 equiv), CuCl2ÁH2O (0.015 mmol, 5 mol %), 1,10-phenanthroline (L-1,
0.006 mmol, 2 mol %), was stirred in water (3 mL) at 80 °C for 24 h
(indicated by TLC). The mixture was cooled in an ice-water bath. The crude
was filtered and washed with saturated brine (2 Â 10 mL), then washed with
water (10 mL), and dried under vacuum to obtain product 3 in almost pure
form (except for 3d, 3k, 3q, 3w, 3y and 3z needing to pass through a small
plug of silica). In the case of liquid products (3g, 3m and 3s), the crude
reaction mixture was diluted with water (10 mL), and extracted with EtOAc
(3 Â 10 mL). The combined organic layers were dried on anhydrous MgSO4,
followed by the evaporation of the solvent to obtain the crude product, which
was passed through a small plug of silica to obtain pure product. For details,
please see the Supplementary data.
9. Synthesis of 2-iminobenzo-1,3-oxathioles 3:
A mixture of 2-iodophenol 1
(0.3 mmol), isothiocyanate (0.36 mmol, 1.2 equiv), DABCO (0.6 mmol,
2