Efficient copper-catalyzed C-S cross-coupling of heterocyclic thiols with aryl iodides

Article abstract of DOI:10.1016/j.tet.2011.02.064

A copper-catalyzed cross-coupling of heterocyclic thiols with aryl iodides is reported. The reaction was carried out in the presence of CuI (5 mol %), 1,10-phenanthroline (10 mol %) and K₂CO₃ (1.3 equiv) in DMF at 120 °C. A variety o

Full text of DOI:10.1016/j.tet.2011.02.064

Tetrahedron 67 (2011) 2878e2881
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Efficient copper-catalyzed CeS cross-coupling of heterocyclic thiols with
aryl iodides
*
Liang-Feng Niu, Yan Cai, Chao Liang, Xin-Ping Hui , Peng-Fei Xu
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A copper-catalyzed cross-coupling of heterocyclic thiols with aryl iodides is reported. The reaction was
carried out in the presence of CuI (5 mol %), 1,10-phenanthroline (10 mol %) and K2CO3 (1.3 equiv) in DMF
at 120 ꢀC. A variety of heterocyclic sulfides were prepared in high selectivities and yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 2 November 2010
Received in revised form 16 January 2011
Accepted 22 February 2011
Available online 2 March 2011
Keywords:
Sulfide
Copper(I) iodide
Aryl iodide
1,10-Phenanthroline
1. Introduction
2. Results and discussion
The formation of C(aryl)eS bonds represents a key step in the
synthesis of many molecules that are of biological, pharmaceutical,
and material interest.1 In the past decade, many catalytic systems of
transition-metal (palladium,2 nickel,3 copper,4 cobalt,5 iron,6 and
indium7) with appropriate ligands have been developed to catalyze
the cross-coupling reactions of aryl halides with thiols and enable
the synthesis of aryl sulfides in high yields.
Heterocyclic sulfides are an important class of organic com-
pounds, which exhibit numerous pharmaceutical activities. In con-
trast to aryl sulfides, methods for the synthesis of heterocyclic
sulfides including azole moiety are very limited. Alemagna et al.8
reported that 2-phenylthio-5-phenyl-1,3,4-thiadiazole could be
prepared by nucleophilic substituted reaction of benzenethiol with
2-aryl-5-chloro-1,3,4-thiadiazole. In 1997, Alam and Koldobskii9
found that 2-alkyl(aryl)thio-5-aryl-1,3,4-oxadiazoles were suc-
cessfully achieved by treatment of 5-alkyl(aryl)thiotetrazoles with
of benzoic anhydride. Recently, Wunderlich and Knochel10 discov-
ered that 2-phenyl-5-(phenylthio)-1,3,4-oxadiazole was obtained in
75% yield by quenching di(5-phenyl-1,3,4-oxadiazol-2-yl)zinc with
PhSSO2Ph in the presence of catalytic amount of CuCN$2LiCl. Ac-
cordingly, development of alterative inexpensive, non-air sensitive
catalytic systems for heterocyclic sulfides is highly desirable. Herein,
we present our preliminary results of a copper-catalyzed coupling
reaction between heterocyclic thiols and aryl iodides.
A preliminary survey of reaction conditions was conducted with
5-phenyl-1,3,4-oxadiazl-2-thione (1a) and iodobenzene as a model
reaction. In the first instance, the impact of catalyst was tested. As
shown in Table 1, in the absence of copper(I) sources, no C(aryl)eS
Table 1
Screening of the reaction conditionsa
N
NH
N N
5 mol % Cu(I), 10 mol% Ligand
Base, Solvent
+
PhI
Ph
S
Ph
S
Ph
O
O
1a
2a
Entry Catalyst Solvent Base
Ligand
Yield
(%)b
1,10-phenanthroline n.r.
d 59
1
d
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
Xylene
K2CO3 (1.3 equiv)
K2CO3 (1.3 equiv)
K2CO3 (1.3 equiv)
K2CO3 (1.3 equiv)
K2CO3 (1.3 equiv)
K2CO3 (1.3 equiv)
K2CO3 (1.3 equiv)
K2CO3 (1.3 equiv)
2
3
4
5
6
7
8
9
10
11
12
13
14
CuI
CuCl
Cu2O
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
1,10-phenanthroline 81
1,10-phenanthroline 93
1,10-phenanthroline 98
ethane-1,2-diol
-proline
4-OH- -proline
50
70
76
L
L
Cs2CO3 (1.3 equiv) 1,10-phenanthroline 83
K3PO4 (1.3 equiv)
K2CO3 (1.1 equiv)
K2CO3 (1.5 equiv)
K2CO3 (1.3 equiv)
K2CO3 (1.3 equiv)
1,10-phenanthroline 86
1,10-phenanthroline 94
1,10-phenanthroline 94
1,10-phenanthroline 59
1,10-phenanthroline 31
a
Reaction conditions: 1a/PhI¼1:1.2 (molar ratio); reaction temperature: 120 ꢀC;
* Corresponding author. Fax: þ86 931 8915557; e-mail address: huixp@lzu.
reaction time: 10 h.
b
edu.cn (X.-P. Hui).
Isolated yield.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.064

L.-F. Niu et al. / Tetrahedron 67 (2011) 2878e2881
2879
Table 2
system of CuI and 1,10-phenanthroline was the most effective and
gave heterocyclic sulfide 2a in 98% yield when heating a mixture of
iodobenzene, 5-phenyl-1,3,4-oxadiazole-2-thione, K2CO3, CuI, and
1,10-phenanthroline in DMF at 120 ꢀC for 10 h (entry 5). After
screening the kind and amount of bases, we found that K2CO3 gave
excellent yield, whereas Cs2CO3 and K3PO4 were effective to some
extent (entries 5, 9e12). In addition, we investigated the coupling
reaction in different solvents, DMF was found to be the best (entries
5, 13 and 14). Thus, the optimized reaction conditions turned out to
be using CuI (5 mol %), K2CO3 (1.3 equiv), and 1,10-phenanthroline
(10 mol %) in reagent-grade DMF at 120 ꢀC for 10 h.
With the optimized conditions defined, we started to in-
vestigate the scope of the coupling reaction. The results are sum-
marized in Table 2. As could be seen, in general, the process was
highly tolerant for a variety of common functional groups and the
heterocyclic sulfides 2aen were formed in 61e98% yields. For 1,3,4-
oxadiazol-2-thiones, electron-withdrawing groups in the para and
meta position led to moderate yields (entries 6e10). When 5-(4-
pyridyl)-1,3,4-oxadiazol-2-thione was used as substrate, product 2l
was obtained in 61% yield (entry 12). For 1,3,4-thiadiazol-2-thiones,
electron-rich and electron-poor thiones were tolerated and the
yields of coupling products 4aen (entries 15e28) are higher than
1,3,4-oxadizol-2-thiones counterparts did.
Coupling of iodobenzene with 1,3,4-oxadiazol-2-thiones or 1,3,4-thiadiazol-2-
thionesa
N
N
N
NH
CuI, 1,10-Phenanthroline, K2CO3
DMF, 120 °C, 10 h
+
I
R1
S
R1
S
Z
Z
Z = O (2a-2n)
Z = S (4a-4n)
Z = O (1a-1n)
Z = S (3a-3n)
Entry R1
Z
Products Yield Entry R1
(%)b
Z
Products Yield
(%)b
1
2
3
4
5
6
7
8
C6H5
O
O
O
O
O
O
O
O
O
O
O
O
O
O
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
98
91
90
90
95
88
86
75
77
73
76
61
97
97
15
16
17
18
19
20
21
22
23
24
25
26
27
28
C6H5
S
S
S
S
S
S
S
S
S
S
S
S
S
S
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
95
95
98
97
95
90
94
97
95
80
91
83
98
98
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
4-MeOC6H4
3-FC6H4
4-FC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
1-C10H7
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
3-FC6H4
4-FC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
1-C10H7
4-Py
9
10
11
12
13
14
4-Py
CH3
CH3(CH2)4
CH3
CH3(CH2)4
a
Reaction condition: CuI/1,10-phenanthroline/K2CO3/PhI/1 or 3¼0.05:0.1:1.3:
1.2:1 (molar ratio).
b
To continue exploring the scope of the reaction, various aryl
iodides were also reacted with 5-phenyl-1,3,4-oxadiazol-2-thione
(Table 3). Aryl iodides bearing electron-donating substituents gave
lower yields (Table 1, entry 5; Table 3, entries 1e2). Under the same
conditions, benzo[d]thiazole-2-thiol, 1-methyl-1H-tetrazole-5-
thiol and 4,6-dimethylpyrimidine-2-thiol reacted similarly and the
products 5eef were obtained in excellent yields (entries 5 and 6).
The reaction of 4,5-diphenyl-4H-1,2,4-triazole-3-thione with
iodobenzene exhibited a moderate yield (entry 7).
Isolated yield.
bond coupling product 2-phenyl-5-(phenylthio)-1,3,4-oxadiazole
(2a) was obtained (entry 1). The heterocyclic sulfide 2a was
obtained in low yield in the absence of ligand (entry 2). Though
CuCl, CuI, and Cu2O were efficient catalysts (entries 3e5), we chose
to focus on the use of CuI due to its stability to air. Among the li-
gands tested, amino acids and diol showed a poor ability to pro-
mote this reaction and low yields were observed (entries 6e8). The
Table 3
CuI-catalyzed carbon-sulfur bond formation of heterocyclic thiols with aryl iodidesa
CuI, 1,10-Phenanthroline, K2CO3
DMF, 120 °C, 10 h
R2
Y
Z
N
Y
Z
N
+
R2
SH
X
I
S
X
(Ar-I)
X = O, S, N; Y = C, N; Z = C, N
(R-SH)
Entry
1
ReSH
AreI
Product
Yield (%)b
95
N
N
N N
I
CH3
Ph
Ph
SH
S
5a
CH3
OCH3
Cl
O
O
2
3
4
86
91
85
N
N
N
N
N
N
N N
I
OCH3
Ph
S
5b
Ph
Ph
Ph
SH
SH
SH
O
O
O
O
N
N
I
Cl
Ph
S
5c
O
I
N
N
Ph
S
O
5d
5
6
98
98
N
Ph
N
I
SH
S
S
S
5e
N
N
Ph
N
N
N
N
N
I
SH
S
N
5f
(continued on next page)

2880
L.-F. Niu et al. / Tetrahedron 67 (2011) 2878e2881
Table 3 (continued )
Entry
7
ReSH
AreI
Product
Yield (%)b
77
N
N
N N
I
Ph
S
Ph
SH
Ph
N
N
5g
Ph
Ph
8
85
I
Ph
N
N
SH
S
N
N
5h
a
Reaction condition: CuI/1,10-phenanthroline/K2CO3/AreI/ReSH¼0.05:0.1:1.3:1.2:1 (molar ratio).
b
Isolated yield.
Because compounds 1aen and 3aen existed preferably in thio-
(0.5 mmol) in DMF (1.5 mL). The reaction mixturewas then stirred at
120 ꢀC for 10 h. The mixture was allowed to cool to room tempera-
ture. Ethyl acetate (10 mL) and H2O (10 mL) were added, and the
organic phase was separated. The aqueous phase was extracted with
ethyl acetate (10 mLꢂ3). The combined organic phases were washed
with saturated brine, dried over anhydrous Na2SO4. The organic
solvent was removed in vacuo, and the residue was purified by
chromatography on silica gel to afford the desired products.13
nes rather than in thiols forms, and both sulfur and nitrogen atoms
could proceed arylation reaction. By analyzing the mass spectrum of
compound 2d, base peak at m/z 159 corresponding to [MꢁSC6H5]þ
confirming that S-arylation product was formed under this reaction.
In addition, the structure of the coupling product 4a was proven to
be an S-arylation product by single-crystal X-ray diffraction analysis
(Fig. 1).11 Other products were assigned by analogy.
4.2.1. 2-Phenyl-5-(phenylthio)-1,3,4-oxadiazole (2a). 126 mg (yield:
98%). White solid. Mp 59.5e60 ꢀC (lit.2 62.4e63.1 ꢀC). 1H NMR
(300 MHz, CDCl3):
d
¼7.98e7.94 (m, 2H, ArH), 7.69e7.66 (m, 2H,
ArH), 7.51e7.42 (m, 2H, ArH). 13C NMR (75 MHz, CDCl3):
d
¼166.24,
162.79, 133.51, 131.74, 129.72, 128.92, 126.96, 126.65, 123.38. IR
(KBr): 3064, 1550, 1468, 1440, 1166, 1068, 751, 691 cmꢁ1. EIeMS (m/
z): 254 (Mþ, 48), 145 (100), 109 (16), 77 (79).
Acknowledgements
Fig. 1. X-ray crystallography structure of compound 4a.
This work was supported by National Natural Science Founda-
tion of China (NSFC 20702022) and International Cooperation
Project of Gansu Province (1011WCGA170).
3. Conclusions
In summary, we have developed an efficient copper(I)-catalyzed
cross-coupling reaction of heterocyclic thiols with aryl iodides.
Noteworthy, the coupling products heterocyclic sulfides could be
obtained in high selectivities and yields. Thus, our protocol is
a convenient, and efficient alternative.
Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.02.064. These data include MOL files and
InChiKeys of the most important compounds described in this article.
4. Experimental
4.1. General
References and notes
1. (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046; (b) Wolfe, J. P.; Wagaw, S.;
Marcoux, J. F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805; (c) Hassan, J.;
Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359; (d)
Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337; (e) Corbet,
J. P.; Mignani, G. Chem. Rev. 2006, 106, 2651.
2. (a) Dickens, M. J.; Gilday, J. P.; Mowlem, T. J.; Widdowson, D. A. Tetrahedron 1991,
47, 8621; (b) Ishiyama, T.; Mori, M.; Suzuki, A.; Miyaura, N. J. Organomet. Chem.
1996, 525, 225; (c) Zheng, N.; McWilliams, J. C.; Fleitz, F. J.; Armstrong, J. D.; Vo-
lante, R. P. J. Org. Chem. 1998, 63, 9606; (d) Mann, G.; Baranano, D.; Hartwig, J. F.;
Rheingold, A. L.; Guzei, I. A. J. Am. Chem. Soc. 1998, 120, 9205; (e) Schopfer, U.;
Schlapbach, A. Tetrahedron 2001, 57, 3069; (f) Li, G. Y. Angew. Chem., Int. Ed. 2001,
40, 1513; (g) Li, G. Y.; Zheng, G.; Noonan, A. F. J. Org. Chem. 2001, 66, 8677; (h)
Murata, M.; Buchwald, S. L. Tetrahedron 2004, 60, 7397; (i) Itoh, T.; Mase, T. Org.
Lett. 2004, 6, 4587; (j) Mispelaere-Canivet, C.; Spindler, J. F.; Perrio, S.; Beslin, P.
Melting points were determined using an XT-4 melting point
apparatus and were uncorrected. 1H NMR and 13C NMR spectra
were recorded on Varian Mercury-400 MHz or Bruker AM-400
spectrometer with TMS as an internal standard. IR spectra were
obtained on Nicolet NEXUS 670 FT-IR instrument. Elemental anal-
yses were performed on Elementar vario EL. HRMS data were
performed on Bruker Apex II mass instrument (ESI). Mass spectra
were performed on Thermo DSQ mass instrument (EI at 70 eV).
Copper(I) iodide, 1,10-phenanthroline and N,N-dimethylformamide
were commercially available and used without further purification.
4,5-Diphenyl-1,2,4-triazol-3-thione was prepared according to
literature method.12
ꢀ
Tetrahedron 2005, 61, 5253; (k) Fernandez-Rodríguez, M. A.; Shen, Q.; Hartwig, J.
F. Chem.dEur. J. 2006,12, 7782; (l) Fernandez-Rodríguez, M. A.; Shen, Q.; Hartwig,
J. F. J. Am. Chem. Soc. 2006,128, 2180; (m) Barbieri, R. S.; Bellato, C. R.; Dias, A. K. C.;
Massabni, A. C. Catal. Lett. 2006, 109, 171.
ꢀ
ꢀ
3. (a) Zhang, Y.; Ngeow, K. N.; Ying, J. Y. Org. Lett. 2007, 9, 3495; (b) Saxena, A.;
Kumar, A.; Mozumdar, S. Appl. Catal., A 2007, 317, 210; (c) Jammi, S.; Barua, P.;
Rout, L.; Saha, P.; Punniyamurthy, T. Tetrahedron Lett. 2008, 49, 1484.
4. (a) Palomo, C.; Oiarbide, M.; Lopez, R.; Gomez-Bengoa, E. Tetrahedron Lett. 2000,
41, 1283; (b) Herradura, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett. 2000, 2, 2019; (c)
Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517; (d) Bates, C. G.;
Gujadhur, R. K.; Venkataraman, D. Org. Lett. 2002, 4, 2803; (e) Savarin, C.; Srogl,
J.; Liebeskind, L. S. Org. Lett. 2002, 4, 4309; (f) Ley, S. V.; Thomas, A. W. Angew.
Chem., Int. Ed. 2003, 42, 5400; (g) Deng, W.; Zou, Y.; Wang, Y. F.; Liu, L.; Guo, Q. X.
4.2. General procedure for copper-catalyzed cross-coupling of
heterocyclic thiols with aryl iodides
To a solution of CuI (0.025 mmol, 4.8 mg), 1,10-phenanthroline
(0.05 mmol, 9 mg), and K2CO3 (0.65 mmol, 90 mg) in DMF (1.5 mL)
was added aryl iodides (0.6 mmol) followed by heterocyclic thiols

L.-F. Niu et al. / Tetrahedron 67 (2011) 2878e2881
5. Wong, Y. C.; Jayanth, T. T.; Cheng, C. H. Org. Lett. 2006, 8, 5613.
2881
Synlett 2004, 1254; (h) Bates, C. G.; Saejueng, P.; Doherty, M. Q.;
Venkataraman, D. Org. Lett. 2004, 6, 5005; (i) Zeni, G. Tetrahedron Lett. 2005, 46,
2647; (j) Chen, Y. J.; Chen, H. H. Org. Lett. 2006, 8, 5609; (k) Zhu, D.; Xu, L.; Wu, F.;
Wan, B. Tetrahedron Lett. 2006, 47, 5781; (l) Verma, A. K.; Singh, J.; Chaudhary, R.
Tetrahedron Lett. 2007, 48, 7199; (m) Rout, L.; Sen, T. K.; Punniyamurty, T. Angew.
Chem., Int. Ed. 2007, 46, 5583; (n) Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863; (o)
Sperotto, E.; van Klink, G. P. M.; de Vries, J. G.; van Koten, G. J. Org. Chem. 2008, 73,
5625; (p) Xu, H. J.; Zhao, X. Y.; Deng, J.; Fu, Y.; Feng, Y. S. Tetrahedron Lett. 2009,
50, 434; (q) Murru, S.; Ghosh, H.; Sahoo, S. K.; Patel, B. K. Org. Lett. 2009, 11, 4254;
(r) Feng, Y.; Zhao, X.; Wang, J.; Zheng, F.; Xu, H. Chin. J. Chem. 2009, 27, 2423;
(s) Jogdand, N. R.; Shingate, B. B.; Shingare, M. S. Tetrahedron Lett. 2009, 50, 6092;
(t) Feng, Y.; Wang, H.; Sun, F.; Li, Y.; Fu, X. ,; Jin, K. Tetrahedron 2009, 65, 9737; (u)
Prasad, D. J. C.; Naidu, A. B.; Sekar, G. Tetrahedron Lett. 2009, 50, 1411; (v) Larsson,
P.-F.; Correa, A.; Carril, M.; Norrby, P.-O.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48,
5691; (w) Chen, C.-K.; Chen, Y.-W.; Lin, C.-H.; Lin, H.-P.; Lee, C.-F. Chem. Commun.
2010, 282; (x) Ramana, T.; Saha, P.; Das, M.; Punniyamurthy, T. Org. Lett. 2010, 12,
84; (y) Kabir, M. S.; Lorenz, M.; Van Linn, M. L.; Namjoshi, O. A.; Ara, S.; Cook, J. M.
J. Org. Chem. 2010, 75, 3626; (z) Feng, Y.-S.; Li, Y.-Y.; Tang, L.; Wu, W.; Xu, H.-J.
Tetrahedron Lett. 2010, 51, 2489.
6. (a) Correa, A.; Carril, M.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47, 2880;
(b) Correa, A.; Mancheno, O. G.; Bolm, C. Chem. Soc. Rev. 2008, 37, 1108.
7. (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.
8. Alemagna, A.; Bacchetti, T.; Beltrame, P. Tetrahedron 1968, 24, 3209.
9. Alam, L. M.; Koldobskii, G. I. Russ. J. Org. Chem. 1997, 33, 1149.
~
10. Wunderlich, S. H.; Knochel, P. Angew. Chem., Int. Ed. 2007, 46, 7685.
11. The CCDC number is 796990. The data were collected on a Kappa CCD diffrac-
ꢁ
tometer equipped with a graphite mono- chromated Mo K
a
(l
¼0.71073 A) radi-
ation by using Envaf Nonius 591 Kappa CCD single crystal diffraction (1.49<q<27.
71ꢀ) at 296 K. Orthorhombic crystals; C14H10N2S2; unit cell parameters: a¼5.8604
(11), b¼8.1663(15), c¼27.369(5) A,
a
¼90.00ꢀ,ꢁb3¼90.00ꢀ,
g
¼90.00ꢀ, Z¼4, V¼1309.8
ꢁ
3
ꢁ
(4) A , space group P212121, Dx¼1.371 Mg m
, m (Mo Ka
)¼0.388 mmꢁ1, F(000)¼
560. The structure was refined to the final R¼0.0437 and wR¼0.1059 for 8008
independent reflections (Rint¼0.0286) and 3021 observed reflections (I>2
s(I)).
12. Nigam, S. C.; Saharia, G. S.; Sharma, H. R. J. Indian Chem. Soc. 1983, 60, 583.
13. All new compounds give satisfied analytical and spectral data, which is available
via the Internet at http://www.sciencedirect.com/.