Copper-catalyzed domino intra- And intermodular C-S cross-coupling reactions: Synthesis of 2-(Arylthio)arylcyanamides

Article abstract of DOI:10.1021/ol9024088

Chemical Equation Presented One-pot synthesis of 2-(arylthio)arylcyanamides is accomplished using cheap and air-stable CuSO ₄·5H₂O as a catalyst by domino intra- and intermolecular C-S cross-coupling reactions of 2-(iodoaryl)thioureas with aryl iodides under ligand-free conditions

Full text of DOI:10.1021/ol9024088

ORGANIC
LETTERS
2010
Vol. 12, No. 1
84-87
Copper-Catalyzed Domino Intra- and
Intermolecular C-S Cross-Coupling
Reactions: Synthesis of
2-(Arylthio)arylcyanamides
Tamminana Ramana, Prasenjit Saha, Manas Das, and
Tharmalingam Punniyamurthy*
Department of Chemistry, Indian Institute of Technology Guwahati,
Guwahati-781039, India
tpunni@iitg.ernet.in
Received October 20, 2009
ABSTRACT
One-pot synthesis of 2-(arylthio)arylcyanamides is accomplished using cheap and air-stable CuSO4·5H2O as a catalyst by domino intra- and
intermolecular C-S cross-coupling reactions of 2-(iodoaryl)thioureas with aryl iodides under ligand-free conditions.
The recent development in cross-coupling reactions using
transition-metal catalysis affords powerful tools for the
formation of carbon-heteroatom bonds.1 Among these,
carbon-sulfur bond formation has received much attention
due to the presence of this moiety in many molecules that
are of biological, pharmaceutical, and material interest.2
Similarly, compounds containing a cyanamide functional
group have received considerable attention in synthetic
chemistry due to their unique structure and reactivity.3,4 For
example, cyanamides are important intermediates for the
synthesis of biologically active compounds such as mon-
oxidil5 and herbicides.6 Cyanamides are also used as tumor
inhibitors7 and precursors for the synthesis of pharmaceuti-
cally important heterocyclic compounds.8 Herein, we report
the one-pot synthesis of these two aforementioned moieties
containing 2-(arylthio)arylcyanamides by copper-catalyzed
domino intra- and intermolecular C-S cross-coupling reac-
tions of aryl thioureas with aryl iodides under air. The
catalyst is commercially available, cheap, and air stable and
functions under ligand-free conditions. Furthermore, both the
substrates containing the electron-donating and -withdrawing
(2) For some studies on C-S coupling reactions, see: (a) Zheng, N.;
McWilliams, J. C.; Fleitz, F. J.; Armstrong, J. D.; Volante, R. P. J. Org.
Chem. 1998, 63, 9606–9607. (b) Fernandez-Rodriguez, M. A.; Shen, Q.;
Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 2180–2181. (c) Li, G. Y. Angew.
Chem., Int. Ed. 2001, 40, 1513–1516. (d) Li, G. Y.; Zheng, G.; Noonan,
A. F. J. Org. Chem. 2001, 66, 8677–8681. (e) Lv, X.; Bao, W. J. Org.
Chem. 2007, 72, 3863–386. (f) Sperotto, E.; van Klink, G. P. M.; de Vries,
J. G.; van Koten, G. J. Org. Chem. 2008, 73, 5625–5628. (g) Rout, L.;
Saha, P.; Jammi, S.; Punniyamurthy, T. Eur. J. Org. Chem. 2008, 4, 640–
643. (h) Rout, L.; Sen, T. K.; Punniyamurthy, T. Angew. Chem., Int. Ed.
2007, 46, 5583–558. (i) Correa, A.; Carril, M.; Bolm, C. Angew. Chem.,
Int. Ed. 2008, 47, 2880–2883. (j) Buchwald, S. L.; Bolm, C. Angew. Chem.,
Int. Ed. 2009, 48, 5586–5587.
(1) For some recent reviews, see: (a) Beletskaya, I. P.; Cheprakov, A. V.
Coord. Chem. ReV. 2004, 248, 2337–2364. (b) Hartwig, J. F. Synlett 2006,
1283–1294. (c) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003,
42, 5400–5449. (d) Corbet, J.-P.; Mignani, G. Chem. ReV. 2006, 106, 2651–
2710. (e) Evano, G.; Blanchard, N.; Toymi, M. Chem. ReV. 2008, 108,
3054–3131. (f) Kondo, T.; mitsudo, T.-A. Chem. ReV. 2000, 100, 3205–
3220. (g) Choi, T. A.; Czerwonka, R.; Forke, R.; Jaeger, A.; Knoell, J.;
Krahl, M. P.; Krause, T.; Reddy, K. R.; Franzblau, S. G.; Knoelker, H.-J.
Med. Chem. Res. 2008, 17, 374–385. (h) Correa, A.; Garc´ıa Manchen˜o,
O.; Bolm, C. Chem. Soc. ReV. 2008, 37, 1108–1117. (i) Monnier, F.;
Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954–6971. (j) Wu¨rtz, S.;
Glorius, F. Acc. Chem. Res. 2008, 41, 1523–1533.
10.1021/ol9024088  2010 American Chemical Society
Published on Web 11/25/2009

Table 1. Synthesis of 2-(Arylthio)arylcyanamides: Optimization
Table 2. Reactions of Aryl Halidesa
of the Reaction Conditionsa
product(s) (%)b
product(s) (%)b
entry
X
Y
A
B
entry
catalyst
base
solvent time (h)
A
B
1
I
I
I
I
Br
Cl
100
20
<5
10
n.d.
n.d.
n.d.
n.d.
90
1
2
3
4
6
7
8
9
CuSO4·5H2O Cs2CO3 DMSO
CuSO4·5H2O K2CO3 DMSO
CuSO4·5H2O K3PO4 DMSO
CuSO4·5H2O Cs2CO3 DMF
CuSO4·5H2O Cs2CO3 Toluene
CuSO4·5H2O Cs2CO3 1,4-dioxane
CuSO4·5H2O Cs2CO3 CH3CN
CuSO4·5H2O Cs2CO3 2-propanol
3
6
6
5
6
6
6
6
5
5
3
3
3
3
3
3
100
100
45
n.d.
n.d.
55
n.d
100
100
60
100
35
41
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
2c
3d
4
Br
Cl
I
100
n.d.
n.d.
40
5
I
100
a Thiourea (0.5 mmol), aryl halide (0.5 mmol), CuSO4·5H2O (2.5 mol
%), and Cs2CO3 (0.75 mmol) were stirred at 90 °C for 3 h in DMSO (1
mL). b Determined by 1H NMR. c N-(2-Bromophenyl)cyanamide obtained
in 70% yield as a byproduct. d N-(2-Chlorophenyl)cyanamide obtained in
82% yield as a byproduct.
n.d.
10 CuSO4·5H2O Cs2CO3 DMSO
11 CuSO4·5H2O Cs2CO3 DMSO
65c
59d
100
100
100
100
100
100
12 CuI
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
13 CuBr
14 Cu2O
15 CuBr2
16 CuCl2·2H2O
when the reaction was pursued at 90 °C using 2.5 mol % of
the copper salts such as CuSO4·5H2O, CuI, CuBr, Cu2O,
CuBr2, CuCl2·2H2O, and Cu(OAc)2·H2O in the presence of
Cs2CO3 in DMSO affording the desired 2-(phenylthio)phe-
nylcyanamide A in 100% conversion. The reactions with
solvent, DMF, and base, K2CO3, required longer reaction
time to afford A in quantitative yield. In contrast, solvents
such as toluene, 1,4-dioxane, CH3CN, and 2-propanol, and
base, K3PO4, were less effective providing either aminoben-
zothiazole9 B or a mixture of A and B as the product(s).
Similarly, lowering of the reaction temperature (80 °C) or
base (1 equiv) led to the formation of a mixture of A and B.
The control experiment confirmed that in the absence of the
copper salts no reaction occurred.
17 Cu(OAc)2·H2O Cs2CO3 DMSO
a N-(2-Iodophenyl)thiourea (0.5 mmol), iodobenzene (0.5 mmol), copper
catalyst (2.5 mol %), and base (0.75 mmol) were stirred at 90 °C for an
appropriate time in solvent (1 mL). Determined by H NMR. c Cs2CO3
b
1
(0.5 mmol) used. d Reaction temperature 80 °C. n.d. ) not detected.
substituents are compatible with this protocol to provide the
rearranged cross-coupled 2-thioarylcyanamides in high yield.
The optimization of the reaction conditions was carried
out with N-(2-iodophenyl)thiourea and iodobenzene as model
substrates using different bases, solvents, and copper sources
at varied temperatures (Table 1). The best result was obtained
(3) For some studies on cyanamide synthesis, see: (a) Kaupp, G.;
Schmeyers, J.; Boy, J. Chem.sEur. J. 1998, 4, 2467–2474. (b) Sato, R.;
Itoh, K.; Itoh, K.; Nishina, H.; Goto, T.; Saito, M. Chem. Lett. 1984, 1913–
1916. (c) Bakunov, S. A.; Rukavishnikov, A. V.; Tkachev, A. V. Synthesis
2000, 1148–1159. (d) Chen, C.-Y.; Wong, F. F.; Huang, J. J.; Lin, S.-K.;
Yeh, M.-Y. Tetrahedron Lett. 2008, 49, 6505–6507. (e) Chaudhuri, K. H.;
Mahajan, U. S.; Bhalerao, D. S.; Akamanchi, K. G. Synlett 2007, 2815–
2818.
The reactions of the aryl halides were next screened using
CuSO4·5H2O as a catalyst. Iodobenzene proceeded cross-
coupling with N-(2-iodophenyl)thiourea to give 2-(phenyl-
thio)phenylcyanamide A in 100% conversion. In contrast,
bromobenzene and chlorobenzene exhibited moderate reac-
tivity yielding either a mixture of A and B or B as the
product(s) (Table 2). In contrast, N-(2-bromo-) and N-(2-
chlorophenyl)thioureas proceeded reactions with iodobenzene
to afford A in <20% yield along with 2-halophenylcyana-
mide.
Encouraged by these results, we further pursued the scope
of the process with respect to the other substrates. Aryl
iodides having 2-Cl, 2-OMe, 3-NO2, 4-NH2, 4-Cl, 4-OMe,
4-NO2, 2,4-di-Me, 2,5-di-Me, 2,6-di-Me, 3,4-di-Me, and 3,5-
di-Me substituents and 1-naphthyl iodide proceeded reactions
with N-(2-iodo-4-methylphenyl)thiourea to give the corre-
sponding 2-(arylthio)arylcyanamide in 83-98% yield (Table
(4) For structure and reactivity of cyanamides, see: (a) Sandler, S. R.;
Karo, W. Organic Functional Group Preparations; Academic: New York,
1972; Vol. 3, pp 286-287. (b) Miyasaka, H.; Clerac, R.; Campos-Fernandez,
C. S.; Dunbar, K. R. Inorg. Chem. 2001, 40, 1663–1671. (c) Hollebone,
B. R.; Nyholm, R. S. J. Chem. Soc. A 1971, 332–337. (d) Pombeiro, A. J. L.
Inorg. Chim. Acta 1992, 198, 179–186. (e) Kamijo, S.; Jin, T.; Yamamoto,
Y. Angew. Chem., Int. Ed. 2002, 41, 1780–1782. (f) Brand, H.; Mayer, P.;
Schulz, A.; Soller, T.; Villinger, A. Chem. Asian J. 2008, 3, 1050–1058.
(g) Renodon-Corniere, A.; Dijols, S.; Perollier, C.; Lefevre-Groboillot, D.;
Boucher, J.-L.; Attias, R.; Sari, M.-A.; Stuehr, D.; Mansuy, D. J. Med.
Chem. 2002, 45, 944–954. (h) Hughes, T. V.; Hammond, S. D.; Cava, M. P.
J. Org. Chem. 1998, 63, 401–402.
(5) McCall, J. M.; TenBrink, R. E.; Ursprung, J. J. J. Org. Chem. 1975,
40, 3304–3306.
(6) (a) Hu, L. Y.; Guyo, J.; Magar, S. S.; Fischer, J. B.; Burke-Howie,
K. J.; Durant, G. J. J. Med. Chem. 1997, 40, 4281–4289. (b) Robinson,
J. R.; Brown, W. H. Can. J. Chem. 1951, 29, 1069–1074.
(7) (a) Gilman, G.; Goodman, L. S.; Rall, T. W.; Murad, F. Goodman
and Gilman’s The Pharmacological Basis of Therapeutics, 7th ed.;
Pergamon Press: New York, 1990; p 89. (b) Saneyoshi, M.; Tokuzen, R.;
Maeda, M.; Fukuoka, F. Chem. Pharm. Bull. 1968, 16, 505–508. (c) Nickon,
A.; Fieser, L. F. J. Am. Chem. Soc. 1952, 74, 5566–5570. (d) Jia, Q.; Cai,
T.; Huang, M.; Li, H.; Xian, M.; Poulos, T. L.; Wang, P. G. J. Med. Chem.
2003, 46, 2271–2274. (e) Kumar, L.; Kaushik, M. P.; Mazumdar, A. Eur.
J. Org. Chem. 2008, 1910–1916.
(8) (a) Donetti, A.; Omodei-Sale, A.; Mantegani, A. Tetrahedron Lett.
1969, 39, 3327–3328. (b) Pala, G.; Mantegani, A.; Zugna, E. Tetrahedron
1970, 26, 1275–1279. (c) Currie, A. C.; Newbold, G. T.; Spring, F. S.
J. Chem. Soc. 1961, 4693–4700.
(9) (a) Ding, Q.; He, X.; Wu, J. J. Comb. Chem. 2009, 11, 587–591.
(b) Wang, J.; Peng, F.; Jiang, J.; Lu, Z.; Wang, L.; Bai, J.; Pan, Y.
Tetrahedron Lett. 2008, 49, 467–470.
Org. Lett., Vol. 12, No. 1, 2010
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Table 3. Reactions of N-(2-Iodo-4-methylphenyl)thiourea with
Table 4. Reactions of Different Substituted Thioureas with
Different Substituted Aryl Iodidesa
1-Iodo-4-methylbenzenea
a N-(2-Iodoaryl)thiourea (0.5 mmol), 1-iodo-4-methylbenzene (0.5
mmol), CuSO4·5H2O (2.5 mol %), and Cs2CO3 (0.75 mmol) were stirred at
90 °C for 3 h in DMSO (1 mL).
4-methylbenzene in 90-95% yield (Table 4). These studies
clearly reveal that the substrates having electron-donating
and -withdrawing groups are compatible with this process
to afford the substituted 2-(arylthio)arylcyanamides in high
yield. Recrystallization of 2-(2,5-dimethylphenyl-thio)-4-
methylphenylcyanamide in MeOH provided single crystals
whose X-ray structure is given in Figure 1 (Table 3, entry
10).10
These reactions involve a homogeneous process, and the
proposed catalytic cycle is shown in Scheme 1. Reduction
of the copper(II) salt with thiourea11 can give copper(I)
species which can undergo oxidative addition with N-(2-
iodoaryl)thiourea to yield copper(III) intermediate a. The
a N-(2-Iodo-4-methylphenyl)thiourea (0.5 mmol), aryl iodide (0.5 mmol),
CuSO4·5H2O (2.5 mol %), and Cs2CO3 (0.75 mmol) were stirred at 90 °C
in DMSO (1 mL).
Figure 1. ORTEP diagram of 2-(2,5-dimethylphenylthio)-4-meth-
ylphenylcyanamide (Table 3, entry 10) with 50% ellipsoid. H-atoms
are omitted for clarity.10
3). Similarly, N-(2-iodophenyl)thiourea having 4-Cl, 4-Me,
and 4,5-di-Me substituents underwent reactions with 1-iodo-
86
Org. Lett., Vol. 12, No. 1, 2010

Scheme 1. Proposed Catalytic Cycle
latter can react with base to undergo intramolecular cycliza-
tion via b to give thiazole B. Oxidative addition of aryl iodide
with copper(I) species can lead to the formation of c which
can undergo intermolecular C-S cross-coupling reaction
with thiazole B to give the intermediate d that can complete
the catalytic cycle by reductive eliminaton of 2-(arylthio)-
arylcyanamide A. For example, when N-(2-iodoaryl)thiourea
was reacted with CuSO4·5H2O in the absence of iodobenzene,
thiazole B was obtained in 0.5 h with 100% conversion.
Moreover, thiazole B readily underwent reaction with
iodobenzene in the presence of 2.5 mol % of CuSO4·5H2O
and 2.5 mol % of N-(2-iodoaryl)thiourea to afford the
cyanamide A quantitatively. These studies clearly suggest
that N-(2-iodoaryl)thiourea first may undergo intramolecular
C-S cross-coupling reaction to give thiazole B which could
be transformed to cyanamide A by intermolecular C-S
cross-coupling reaction.
In summary, we have developed a method for the synthesis
of 2-(arylthio)arylcyanamides from substituted N-(2-ha-
loaryl)thioureas with aryl iodides by domino intra- and
intermolecular C-S cross-coupling reactions. The catalyst
is cheap and air stable and functions under ligand-free
conditions.
Acknowledgment. We thank the Department of Science
and Technology, New Delhi, and Council of Scientific and
Industrial Research, New Delhi, for financial support.
(10) Recrystallization of 2-(2,5-dimethyl-phenylthio)-4-methyl-phenyl-
cyanamide in MeOH afforded single crystals whose X-ray data were
collected on a Bruker SMART APEX equipped with a CCD area detector
using Mo KR radiation in the scan range 1.20°-28.31°. C16H16N2S, Mw )
268.38, orthorhombic; space group Pna2(1), a ) 22.1067(10), b )
8.7972(4), c ) 7.6712(3) Å; R ) 90°, ꢀ ) 90°, γ ) 90°, V ) 1491.87(11)
Å3, Z ) 4, Dcalcd ) 1.195 mg/m3, T ) 296(2) K, crystal dimension 0.40 ×
Supporting Information Available: Materials and meth-
ods, experimental procedure, characterization data, and NMR
spectra (1H and 13C) of the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
0.35 × 0.20 mm3; 19 186 reflections; (I > 2σ(I)); R1 ) 0.0396, wR2
0.0654, GOF (on F2) ) 1.005.
)
(11) For the reduction of copper(II) salts to copper(I) species using
thiourea, see: Bowmaker, G. A.; Hanna, J. V.; Pakawatchai, C.; Skelton,
B. W.; Thanyasirikul, Y.; White, A. H. Inorg. Chem. 2009, 48, 350–368.
OL9024088
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