Copper(II)-mediated homocoupling of thioamides for the synthesis of 1,2,4-thiadiazoles

Article abstract of DOI:10.1002/ejoc.201402194

A copper(II)-mediated highly selective oxidative cyclization reaction of thioamides to provide 3,5-disubstituted 1,2,4-thiadiazoles was developed. The copper species plays a key role in this transformation and different functional groups are tolerated under the optimal reaction conditions. Copyright

Full text of DOI:10.1002/ejoc.201402194

Job/Unit: O42194
/KAP1
Date: 04-06-14 18:29:43
Pages: 6
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402194
Copper(II)-Mediated Homocoupling of Thioamides for the Synthesis of
1,2,4-Thiadiazoles
Yadong Sun,[a,b] Wanqing Wu,[a] and Huanfeng Jiang*[a]
Keywords: Synthetic methods / Sulfur heterocycles / Nitrogen heterocycles / Copper / Cyclization
A copper(II)-mediated highly selective oxidative cyclization
in this transformation and different functional groups are tol-
reaction of thioamides to provide 3,5-disubstituted 1,2,4-thia- erated under the optimal reaction conditions.
diazoles was developed. The copper species plays a key role
on.[5] However, these methods have limited application ow-
Introduction
ing to low functional group tolerance, the high cost of the
oxidant, and the formation of abundant toxic chemical
waste byproducts. Herein, we provide an complementary
strategy to generate thiadiazoles by utilizing easily available
and less expensive oxidant and regents, and the challenge
of this transformation lies in the dehydrosulfurization of
thioamides to generate nitriles under oxidative reaction
conditions (Scheme 1, path a).[6]
Thiadiazoles are regarded as an important class of five-
membered heterocycles for many bioactive molecules con-
taining this scaffold exhibit broad-spectrum biological ac-
tivity.[1] For example, compounds I and II have much higher
inhibitory activity against aromatase than resveratrol;[2]
compound III showed potent anticancer activity[3] (Fig-
ure 1).
Scheme 1. Transformations of thioamides under oxidative reaction
conditions.
Figure 1. Examples of bioactive substituted thiadiazoles.
The common method for the preparation of 1,2,4-thiadi-
azoles is 1,3-dipolar cycloaddition of nitrile sulfides with
nitriles.[4] An alternative method for the preparation of
1,2,4-thiadiazoles containing the same groups in the 3- and
5-positions is the oxidative dimerization of the correspond-
ing thioamide (Scheme 1, path b). The latter can be
achieved by using different oxidizing agents, such as nitrous
acid, 2-iodoxybenzoic acid (IBX), 2-chloro-1,3-dimethyl-
imidazolinium chloride (DMC), phenyliodine diacetate,
tert-butyl hypochlorite, methyl bromocyanoacetate, and so
The transition-metal-mediated oxidative transformation
to construct heterocycles has attracted great interest over
the past decade. In particular, copper salts have been suc-
cessfully used in the formation of C–heteroatom or hetero-
atom–heteroatom bonds, which exhibit great potential for
the construction of various heterocycles.[7] To date, a range
of copper-mediated methods aiming to afford heterocyclic
compounds have been developed.[8] Glorius and co-workers
reported a copper(II)-mediated [3+2] cycloaddition of en-
amines with nitriles to prepare pyrazoles derivatives.[9] Re-
cently, Punniyamurthy et al. reported the copper(II)-medi-
ated oxidative cyclization of N-benzyl-substituted bisarylhy-
drazones and bisaryloxime ethers to prepare benzimidazole
and benzoxazole derivatives, respectively.[10] On the basis of
our recently developed Cu-catalyzed method for the synthe-
sis of heterocycles[11] and our increasing interest in oxidative
cross-coupling reactions of two nucleophiles,[12] herein we
disclose a novel method for the synthesis of 3,5-disubsti-
[a] School of Chemistry and Chemical Engineering, South China
University of Technology,
Guangzhou 510640, China
E-mail: jianghf@scut.edu.cn
http://www2.scut.edu.cn/ce/lshxyjzx/english/index.html
[b] College of Chemistry and Chemical Engineering, Xinjiang
University,
Urumqi 830046, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402194.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O42194
/KAP1
Date: 04-06-14 18:29:43
Pages: 6
Y. Sun, W. Wu, H. Jiang
SHORT COMMUNICATION
tuted 1,2,4-thiadiazoles through the copper(II)-mediated screening of the solvent and reaction time revealed that
homocoupling of thioamides involving C–N and N–S bond CH3CN was the best solvent and that full conversion was
formation (Scheme 1, path c).
obtained after only 0.25 h (Table 1, entries 12–16). Next, a
series of copper salts, such as CuCl, CuBr, Cu(OAc)2, and
CuBr2, was screened, and it was found that they were all
less effective than Cu(OTf)2 (Table 1, entries 17–20). No-
tably, target 2a could not been detected in the absence of
copper salts or bases (Table 1, entries 21 and 22). Thus, the
optimal reaction conditions consist of Cu(OTf)2 (100 mol-
%) and K2CO3 (2.0 equiv.) in CH3CN at 70 °C in air for
15 min. Under the optimized reaction conditions, the yield
of isolated target 2a was as high as 90% and the GC yield
Results and Discussion
We initially investigated the reaction of thiobenzamide
(0.5 mmol) with K2CO3 (1.0 mmol) and CuCl (20 mol-%)
in 1,4-dioxane at 70 °C in air (Table 1, entry 1). Unfortu-
nately, the desired product was only afforded in trace
amount despite many attempts, whereas benzonitrile was
obtained as the major product (Table 1, entries 1–3). To our
delight, desired thiadiazole 2a was obtained in 18% yield,
as determined by GC analysis, in the presence of copper(II)
trifluoromethanesulfonate [Cu(OTf)2, 20 mol-%; Table 1,
entry 5]. However, this process is not an aerobic oxidative
reaction (Table 1, entry 6). Further investigation revealed
that if the reaction was performed with 1 equiv. of Cu-
(OTf)2, up to 91% yield of the target product could be
achieved. The result was similar under a nitrogen atmo-
sphere (Table 1, entries 7 and 8). Next, we studied the ef-
fects of various bases. It was clear that strong bases such as
NaOH and NaOtBu were ineffective, and NaOAc gave only
moderate yields (Table 1, entries 9–11). Subsequently, a
Table 2. Reaction of substituted thiobenzamides.[a,b]
Table 1. Optimization of the reaction conditions.[a]
Entry
[Cu] (mol-%)
Base
Solvent
Yield[b] [%]
1
2
3
4
CuCl (20)
CuBr (20)
Cu(OAc)2 (20) K2CO3
CuBr2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (100) K2CO3
Cu(OTf)2 (100) K2CO3
Cu(OTf)2 (100) NaOH
K2CO3
K2CO3
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
trace
trace
trace
6
18
12
91
90
n.d.
n.d.
68
95
95 (90)
20
26
17
trace
26
trace
41
n.d.
n.d.
K2CO3
K2CO3
K2CO3
5
6[c]
7
8[d]
9
10
11
12
Cu(OTf)2 (100) NaOtBu 1,4-dioxane
Cu(OTf)2 (100) NaOAc
Cu(OTf)2 (100) K2CO3
Cu(OTf)2 (100) K2CO3
Cu(OTf)2 (100) K2CO3
Cu(OTf)2 (100) K2CO3
Cu(OTf)2 (100) K2CO3
CuCl (100)
CuBr (100)
Cu(OAc)2 (100) K2CO3
1,4-dioxane
CH3CN
CH3CN
ethanol
toluene
DMF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
13[e]
14[e]
15[e]
16[e]
17[e]
18[e]
19[e]
20[e]
21
K2CO3
K2CO3
CuBr2 (100)
–
Cu(OTf)2 (100)
K2CO3
K2CO3
–
22
[a] Reaction conditions: 1a (0.5 mmol), copper salt, base (2 equiv.),
solvent (2 mL), 1 h; n.d.: not detected. [b] Determined by GC. The
value in parentheses is the yield of the isolated product. [c] Under
an O2 atmosphere (balloon). [d] Under a N2 atmosphere. [e] Reac-
tion time: 15 min.
[a] Reaction conditions: 1 (0.5 mmol), Cu(OTf)2 (1 equiv.), K2CO3
(2 equiv.), CH3CN (2 mL), 70 °C, 15 min. [b] Yield of isolated
product.
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42194
/KAP1
Date: 04-06-14 18:29:43
Pages: 6
Copper(II)-Mediated Homocoupling of Thioamides
of the benzonitrile byproduct was only 5%, and thus the were also good partners for this reaction; thioacetamide-
higher efficiency of this transformation relative to that with containing substituted phenyls reacted smoothly to afford
the use of hypervalent iodine(III) reagents was demon- the corresponding thiadiazole products in good yields.
strated.[5b]
Table 3. Reaction of other substituted thioamides.[a,b]
Under the optimized reaction conditions, we conducted
a survey of various substituted thiobenzamides to explore
the scope for this transformation. As shown in Table 2, the
reactions with substituted thiobenzamides bearing electron-
donating or electron-withdrawing groups at the phenyl ring
proceeded smoothly to provide desired thiadiazoles 2b–p in
moderate to good yields. Halogen groups substituted at the
phenyl ring of the thiobenzamides, such as fluoro, chloro,
and bromo, were well tolerated under the optimized reac-
tion conditions, which gave the opportunity for further
transformation to synthesize more complex thiadiazole
derivatives. Substitutions at the ortho position of the thio-
benzamides affected the reaction yield slightly; for example,
2-methylthiobenzamide and 2-chlorothiobenzamide were
investigated, and they gave the corresponding products in
69 and 78% yield, respectively. Notably, in the case of ether-
or ester-substituted thiobenzamides, the formation of the
thiadiazoles was not accompanied by hydrolysis of the cor-
responding functional groups. In addition, if polysubsti-
tuted thiobenzamides including 4-bromo-2-methylthioben-
zamide and 2,4-dichlorothiobenzamide were used, both
produced desired thiadiazoles 2o and 2p in moderate yields.
However, 4-aminothiobenzamide was not suitable for this
transformation. To prove the practicality of the present
method in the synthesis of 3,5-disubstituted 1,2,4-thiadi-
azoles, a gram-scale synthesis of 2a was performed, and if
1.37 g of 1a was utilized, 0.98 g of product 2a (82% yield)
was obtained.
[a] Reaction conditions: 1 (0.5 mmol), Cu(OTf)2 (1 equiv.), K2CO3
This oxidative cyclization reaction was further expanded
to other aromatic thioamides, heterocyclic thioamides, and
aliphatic thioamides (Table 3). Aromatic and heterocyclic
(2 equiv.), CH3CN (2 mL), 70 °C, 15 min. [b] Yield of isolated
product.
thioamides containing naphthyl, pyridine, thiophene,
To explore the reaction mechanism, the following experi-
morpholine, 2,3-dihydrobenzo[1,4]dioxine, and piperazine ments were conducted (Scheme 2). We first used 1a and 4-
were transformed into the desired products in good yields bromobenzonitrile as the reaction partners, as a small
ranging from 78 to 92%. Moreover, aliphatic thioamides amount of nitrile was observed during the course of the
Scheme 2. Control experiments.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O42194
/KAP1
Date: 04-06-14 18:29:43
Pages: 6
Y. Sun, W. Wu, H. Jiang
SHORT COMMUNICATION
reaction [Scheme 2, Equation (1)]. However, the [3+2] cy- CuII–metallacycle D, which is followed by ligand oxidation
cloaddition reaction of 1a with 4-bromobenzonitrile did not by CuII to give desired thiadiazole 2 as well as a reduced
occur. Moreover, a mixture of 2ak and 2ka was obtained by copper species; the reduced copper species is oxidized to
cross-coupling of 1a with 1k under the standard conditions CuII.
[Scheme 2, Equation (2)]. These results revealed that nitrile
was not the intermediate of this reaction and that this is an
intermolecular reaction of thioamides. In a third experi-
ment, if the radical trapping reagent (2,2,6,6-tetramethylpi-
peridin-1-yl)oxidanyl (TEMPO) was added, the existence of
TEMPO did not prohibit this reaction absolutely
[Scheme 2, Equation (3)]. This result suggested that this
transformation did not involve a free-radical process.
The black powder obtained from one of the reactions
mainly containing CuS and a small quantity of CuO was
tested by scanning electron microscopy (SEM, see Figure 2)
Scheme 3. Possible reaction mechanism.
and energy-dispersive X-ray spectroscopy (EDS, see the
Supporting Information). As can be seen from Figure 2,
there is clear indication for the existence of the black pow-
der in the form of granulates. EDS analyses revealed that
Conclusions
In conclusion, we developed an efficient and practical
method for the synthesis of 3,5-disubstituted 1,2,4-thiadi-
azoles through copper(II)-mediated highly selective oxidat-
ive cyclization reaction of thioamides. The low cost of the
reagents, compatibility with a wide range of substrates, and
an operationally simple procedure make this method a
powerful component to existing methods for the synthesis
of thiadiazole derivatives. Further expansion of the scope
of the reaction is currently underway in our laboratory.
the black powder was composed of the elements copper,
sulfur, and oxygen in an atomic ratio of 51:36:10. So the
black powder was a mixture of CuS and CuO.
Experimental Section
Typical Procedure for the Synthesis of 3,5-Disubstituted 1,2,4-Thia-
diazoles: Thioamide (0.5 mmol), Cu(OTf)2 (1 equiv.), K2CO3
(2 equiv.) and acetonitrile (2.0 mL) were added to a tube equipped
with magnetic stirrer bar. The mixture was stirred at 70 °C (oil bath
temperature) for 15 min. After the reaction was finished (moni-
tored by TLC), the mixture was cooled to room temperature and
quenched with brine, and the crude product was extracted with
ethyl acetate. The organic extract was dried with Na2SO4 and con-
centrated in vacuo, and the resulting residue was purified by col-
umn chromatography (silica gel, petroleum ether/ethyl acetate) to
afford the desired product.
Figure 2. SEM of copper salt.
Cu(OTf)2 and the acetonitrile solvent were very impor-
tant for this transformation. Cu(OTf)2 was used as a Lewis
acid activator and the oxidizing agent in this reaction. In
the course of C–N bond formation, Cu(OTf)2 activates the
C=N bond of the isomerized thioamides. In the course of
N–S bond formation, CuII serves as the oxidizing agent that
oxidizes two nucleophilic centers. In comparison with other
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental procedures, characterization data, 1H NMR
and 13C NMR spectra, MS data, and IR spectra.
Acknowledgments
–
counterions, OTf can be easily exchanged. Acetonitrile is
The authors are grateful to the National Natural Science Founda-
tion of China (NSFC) (grant number 20932002), the National Ba-
sic Research Program of China (973 Program, grant number
2011CB808600), the Guangdong Natural Science Foundation
(grant number 10351064101000000), the China Postdoctoral Sci-
ence Foundation (grant number 2011M501318), and the Funda-
mental Research Funds for the Central Universities (grant number
a
good solvent for both thioamides and Cu-
(OTf)2.
On the basis of the above observations and previous re-
ports,[8i,9,13] a proposed mechanism is outlined in Scheme 3.
Under basic conditions, an equilibrium between thioamide
1 and isomer A occurs. Then, reaction of A with Cu(OTf)2
probably leads to the formation of CuII species B with the 2012ZB0011) for financial support.
aid of base, which should induce intermolecular nucleo-
philic addition to generate intermediate C. Subsequently,
[1] a) Y. Li, J. Geng, Y. Liu, S. Yu, G. Zhao, ChemMedChem 2013,
8, 27; b) D. Kumar, N. M. Kumar, K. H. Chang, K. Shah, Eur.
further deprotonation and the departure of CuS[6d] provides
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42194
/KAP1
Date: 04-06-14 18:29:43
Pages: 6
Copper(II)-Mediated Homocoupling of Thioamides
J. Med. Chem. 2010, 45, 4664; c) A. I. Rosenbaum, C. C. Co-
sner, C. J. Mariani, F. R. Maxfield, O. Wiest, P. Helquist, J.
Med. Chem. 2010, 53, 5281; d) S. K. De, J. L. Stebbins, L. H.
Chen, M. Riel-Mehan, T. Machleidt, R. Dahl, H. Yuan, A.
Emdadi, E. Barile, V. Chen, R. Murphy, M. Pellecchia, J. Med.
Chem. 2009, 52, 1943.
S. S. Stahl, Angew. Chem. Int. Ed. 2011, 50, 11062; Angew.
Chem. 2011, 123, 11256.
[8] For selected copper-mediated methods for the synthesis of het-
erocycles, see: a) R. Martín, M. Rodríguez Rivero, S. L. Buch-
wald, Angew. Chem. Int. Ed. 2006, 45, 7079; Angew. Chem.
2006, 118, 7237; b) B. Zou, Q. Yuan, D. Ma, Angew. Chem.
Int. Ed. 2007, 46, 2598; Angew. Chem. 2007, 119, 2652; c) A. K.
Verma, T. Kesharwani, J. Singh, V. Tandon, R. C. Larock, An-
gew. Chem. Int. Ed. 2009, 48, 1138; Angew. Chem. 2009, 121,
1158; d) K. K. Toh, Y. F. Wang, E. P. J. Ng, S. Chiba, J. Am.
Chem. Soc. 2011, 133, 13942; e) Y. Wei, N. Yoshikai, J. Am.
Chem. Soc. 2013, 135, 3756; f) G. Zhang, J. Miao, Y. Zhao, H.
Ge, Angew. Chem. Int. Ed. 2012, 51, 8318; Angew. Chem. 2012,
124, 8443; g) C. Wan, J. Zhang, S. Wang, J. Fan, Z. Wang, Org.
Lett. 2010, 12, 2338; h) S. Murru, H. Ghosh, S. K. Sahoo,
B. K. Patel, Org. Lett. 2009, 11, 4254; i) S. Guin, T. Ghosh,
S. K. Rout, A. Banerjee, B. K. Patel, Org. Lett. 2011, 13, 5976.
[9] J. J. Neumann, M. Suri, F. Glorius, Angew. Chem. Int. Ed.
2010, 49, 7790; Angew. Chem. 2010, 122, 7957.
[2]
[3]
[4]
A. S. Mayhoub, L. Marler, T. P. Kondratyuk, E. J. Park, J. M.
Pezzuto, M. Cushman, Bioorg. Med. Chem. 2012, 20, 510.
D. Kumar, N. M. Kumar, K. Chang, R. Gupta, K. Shah, Bi-
oorg. Med. Chem. Lett. 2011, 21, 5897.
a) R. K. Howe, T. A. Gruner, J. E. Franz, J. Org. Chem. 1977,
42, 1813; b) R. M. Paton, F. M. Robertson, J. F. Ross, J. Chem.
Soc. Perkin Trans. 1 1985, 1515.
[5] a) M. W. Cronyn, T. W. Nakagawa, J. Am. Chem. Soc. 1952,
74, 3693; b) A. A. Shah, Z. A. Khan, N. Choudhary, C.
Lohölter, S. Schäfer, G. P. L. Marie, U. Farooq, B. Witulski, T.
Wirth, Org. Lett. 2009, 11, 3578; c) T. Isobe, T. Ishikawa, J.
Org. Chem. 1999, 64, 6989; d) E. A. Mamaeva, A. A. Bakibaev,
Tetrahedron 2003, 59, 7521; e) M. T. M. El-Wassimy, K. A.
Jørgensen, S. O. Lawesson, Tetrahedron 1983, 39, 1729; f) A. S.
Mayhoub, E. Kiselev, M. Cushman, Tetrahedron Lett. 2011,
52, 4941; g) P. C. Patil, D. S. Bhalerao, P. S. Dangate, K. G.
Akamanchi, Tetrahedron Lett. 2009, 50, 5820.
[6] a) K. Yamaguchi, K. Yajima, N. Mizuno, Chem. Commun.
2012, 48, 11247; b) M. I. Lim, W. Y. Ren, R. S. Klein, J. Org.
Chem. 1982, 47, 4594; c) J. R. Cashman, R. P. Hanzlik, J. Org.
Chem. 1982, 47, 4645; d) S. Guin, S. K. Rout, A. Gogoi, S.
Nandi, K. K. Ghara, B. K. Patel, Adv. Synth. Catal. 2012, 354,
2757; e) R. Yella, B. K. Patel, J. Comb. Chem. 2010, 12, 754.
[7] For selected reviews on transition-metal-mediated and copper-
catalyzed reactions, see: a) A. V. Gulevich, A. S. Dudnik, N. C.
Chernyak, V. Gevorgyan, Chem. Rev. 2013, 113, 3084; b) S. E.
Allen, R. R. Walvoord, R. Padilla-Salinas, M. C. Kozlowski,
Chem. Rev. 2013, 113, 6234; c) A. E. Wendlandt, A. M. Suess,
[10] M. M. Guru, M. A. Ali, T. Punniyamurthy, J. Org. Chem. 2011,
76, 5295.
[11] a) L. Huang, H. Jiang, C. Qi, X. Liu, J. Am. Chem. Soc. 2010,
132, 17652; b) X. Li, L. Huang, H. Chen, W. Wu, H. Huang,
H. Jiang, Chem. Sci. 2012, 3, 3463; c) X. Li, L. He, H. Chen,
W. Wu, H. Jiang, J. Org. Chem. 2013, 78, 3636; d) Y. Gao, M.
Yin, W. Wu, H. Huang, H. Jiang, Adv. Synth. Catal. 2013, 355,
2263; e) W. Zeng, W. Wu, H. Jiang, L. Huang, Y. Sun, Z. Chen,
X. Li, Chem. Commun. 2013, 49, 6611; f) Y. Sun, H. Jiang, W.
Wu, W. Zeng, X. Wu, Org. Lett. 2013, 15, 1598.
[12] C. Liu, H. Zhang, W. Shi, A. Lei, Chem. Rev. 2011, 111, 1780.
[13] a) Z. Wang, Y. Kuninobu, M. Kanai, J. Org. Chem. 2013, 78,
7337; b) Y. F. Wang, X. Zhu, S. Chiba, J. Am. Chem. Soc. 2012,
134, 3679.
Received: May 8, 2014
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O42194
/KAP1
Date: 04-06-14 18:29:43
Pages: 6
Y. Sun, W. Wu, H. Jiang
SHORT COMMUNICATION
Copper(II)-Mediated Homocoupling
Y. Sun, W. Wu, H. Jiang* ................ 1–6
A copper(II)-mediated highly selective oxi-
dative cyclization reaction of thioamides to
provide 3,5-disubstituted 1,2,4-thiadiazoles
is reported. The copper species plays a key
role in this transformation and different
functional groups are tolerated under the
optimal reaction conditions.
Copper(II)-Mediated Homocoupling of
Thioamides for the Synthesis of 1,2,4-Thia-
diazoles
Keywords: Synthetic methods / Sulfur het-
erocycles / Nitrogen heterocycles / Copper /
Cyclization
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0