Highly regioselective ruthenium-catalyzed direct arylation of thiazolo[3,2-b]-1,2,4-triazoles with aryl iodides and aryl bromides via C-H bond activation

Article abstract of DOI:10.1016/j.jorganchem.2013.12.055

We have developed a convenient ruthenium-catalyzed direct arylation for highly regioselective synthesis of thiazolo[3,2-b]-1,2,4-triazole derivatives via C-H bond activation. This transformation has provided a new synthetic route to a variety of thiazolo[3,2-b]-1,2,4-triazoles and afforded desired products in good yields.

Full text of DOI:10.1016/j.jorganchem.2013.12.055

Journal of Organometallic Chemistry 756 (2014) 47e51
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Communication
Highly regioselective ruthenium-catalyzed direct arylation of thiazolo
[3,2-b]-1,2,4-triazoles with aryl iodides and aryl bromides via CeH
bond activation
*
Huiping Zhang
Department of Chemistry and Chemical Engineering, Jining University, Qufu, Shandong 273155, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a convenient ruthenium-catalyzed direct arylation for highly regioselective synthesis
of thiazolo[3,2-b]-1,2,4-triazole derivatives via CeH bond activation. This transformation has provided a
new synthetic route to a variety of thiazolo[3,2-b]-1,2,4-triazoles and afforded desired products in good
yields.
Received 13 December 2013
Received in revised form
28 December 2013
Accepted 31 December 2013
Ó 2014 Elsevier B.V. All rights reserved.
Keywords:
Ruthenium-catalyzed
Thiazolo[3,2-b]-1,2,4-triazole
Coupling reaction
Aryl halides
CeH bond activation
1. Introduction
The thiazolo[3,2-b]-1,2,4-triazole nucleus is arguably one of the
most significant heterocycles since they are found in numerous
Heteroaromatic compounds are an important class of building
blocks found in a variety of areas, such as many natural products,
medicines, and functional materials [1e3]. Therefore, the devel-
opment of new transformation for direct and selective arylation to
prepare heteroaromatic compounds is a persistent challenge for
organic synthetic chemists. In the past few years, many successful
and elegant transition-metal-catalyzed arylation of heterocycles
via CeH bonds activation have been developed [4e13]. Among the
metal catalysts, the palladium- [14e19], copper- [20e25],
rhodium- [26e28], ruthenium- [29e41], nickel- [42e45] catalyzed
arylation of heterocycles are the most important and convenient
methods to construct complex heteroaromatic molecules.
Although many synthetic routes for their construction have been
developed, this field is still highly favorable. Exploration for effi-
cient transition-metal-catalyzed direct arylation synthesis of het-
eroaromatic compounds continues to attract the interest of
synthetic chemists.
natural products and bioactive molecules [46e48]. In particular,
thiazolo[3,2-b]-1,2,4-triazole derivatives with a biaryl motif have
been widely investigated as anti-inflammatory, antibacterials,
anticancer, antimicrobial, and analgesic molecules [49e53] (Fig. 1).
Generally, there are mainly four routes to prepare thiazolo[3,2-b]-
1,2,4-triazole derivatives: (i) cyclization of 3-mercapto-1,2,4-
triazoles with a-haloketones; (ii) cyclization of 2-imino-3-amino
thiazoles with acids or anhydrides; (iii) cyclization of bis(1H-
1,2,4-triazolyl)sulfoxide with chalcones; (iv) arylation of thiazolo
[3,2-b]-1,2,4-triazoles [54e58]. Despite of several methodologies
have been developed during the last decades, there have only been
rare examples for metal-catalyzed arylation of thiazolo[3,2-b]-
1,2,4-triazoles.
Herein, we reported our new finding which was a facile highly
regioselective Ruthenium-catalyzed direct arylation of thiazolo
[3,2-b]-1,2,4-triazoles with aryl halide in Scheme 1. To the best of
our knowledge, this is the first example of the Ruthenium-
catalyzed direct arylation of thiazolo[3,2-b]-1,2,4-triazoles.
2. Results and discussion
Initially, our efforts were focused on identifying the catalytic
system and reaction conditions for direct arylation of 6-
* Fax: þ86 5373196089.
E-mail address: hpzhangjn@126.com.
0022-328X/$ e see front matter Ó 2014 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jorganchem.2013.12.055

48
H. Zhang / Journal of Organometallic Chemistry 756 (2014) 47e51
Table 1
R
Optimization of reaction conditions for the arylation of 6-phenylthiazolo[3,2-b]-
1,2,4-triazole with iodobenzene.a
F
Ph
Ph
N
N
N
N
N
N
N
N
N
cat. base
solvent
SO2Me
N
N
+
Cl
N
I
Ph
S
S
S
S
N
Cl
3a
1a
2a
R
NO2
Entry
Catalyst (mol%)
Base
Solvent
T (ꢀC)
Yield (%)b
N
N
N
N
N
1
2
3
4
5
6
7
8
[RuCl2(p-cymene)]2
RuCl3(H2O)n
RuCl2(PPh3)3
Ru3(CO)12
Ru(acac)2
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
Ru3(CO)12
e
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
DMSO
NMP
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
140
160
100
140
42
13
38
64
20
67
76
53
37
42
68
65
84
45
41
87
86
55
ec
PhSO2
S
S
Fig. 1. Thiazolo[3,2-b]-1,2,4-triazole derivatives with biological activities.
Cs2CO3
KH2PO4
t-BuONa
KOAc
9
10
11
12
13
14
15
16
17
18
19
phenylthiazolo[3,2-b]-1,2,4-triazole 1a with iodobenzene 2a. A
variety of Ruthenium-catalysts in conjunction with different ba-
ses, solvents and temperatures were tested and the results were
described in Table 1. To our delight, the desired product 5,6-
diphenylthiazolo[3,2-b]-1,2,4-triazole 3a was formed in the
presence of [RuCl2(p-cymene)]2 and Na2CO3 in DMA at 120 ꢀC for
12 h. After this, other Ruthenium catalysts, such as RuCl3(H2O)n,
RuCl2(PPh3)3, Ru3(CO)12 and Ru(acac)2, were also employed in
reaction and the corresponding arylation product 3a was ob-
tained in 13%, 38%, 64% and 20% yields respectively (Table 1, en-
tries 2e5). The results indicated that Ru3(CO)12 was the most
efficient catalyst in this reaction. Next, the effects of bases were
also tested in this arylation (Table 1, entries 6e10). Among a va-
riety of inorganic bases, Cs2CO3 was proved to be the most suit-
able in present of Ru3(CO)12 in DMA at 120 ꢀC. However, relative
lower yields were obtained when the other bases were used, such
as K2CO3, KH2PO4, t-BuONa and KOAc. We next attempted to
improve the yields by using various solvents. As entries 11e15 of
Table 1 indicated, NMP was the most effective media for this
arylation process. The effects of temperature was also detected
(Table 1, entries 16e18) and it was evident that 140 ꢀC was the
most optimal one for this Ru3(CO)12-catalyzed arylation. Finally,
the control experiment results showed that product 3a was not
formed in the absence of Ru3(CO)12 by using Cs2CO3 as bases in
NMP at 140 ꢀC.
With the optimized conditions in hand, that is, thiazolo[3,2-
b]-1,2,4-triazoles (0.5 mmol), aryl iodides (0.7 mmol), Ru3(CO)12
as the catalyst, Cs2CO3 as the bases and NMP as the solvent, we
next turned our attention to the scope of the Ruthenium-
catalyzed direct arylation of thiazolo[3,2-b]-1,2,4-triazoles with
aryl iodides. As shown in Table 2, 6-substituted thiazolo[3,2-b]-
1,2,4-triazoles were examined and the results showed that a
variety of aryl iodides with either electron-donating or electron-
withdrawing groups attached to the benzene rings, were able to
undergo arylation smoothly and generated the corresponding
products in good yields (3ae3o). As expected, the group (CF3) on
the phenyl ring of aryl iodides was compatible under this
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
1,4-dioxane
Toluene
NMP
NMP
NMP
NMP
a
Reaction conditions: 1a (0.5 mmol), 2a (0.7 mmol), catalyst (3 mol%), base
(1.0 mmol), solvent (2 mL), 100e160 ꢀC, 12 h.
b
GC yields.
No product.
c
process, and the corresponding product was isolated in 80e81%
yields. In addition, bromobenzene as a substrate was tested
and the desired product was formed in 80% yields. All these
cases showed high functional group tolerance (CH3, F, Cl, Br, CF3)
for the arylation. Pleasingly, all reactions were very clean,
and the sole arylation products were obtained with highly
regioselective at C-5 position under our standard experimental
conditions.
Subsequently, we were interested in evaluating the scope of
this Ru3(CO)12-catalyzed arylation by using 2,6-disubstituted
thiazolo[3,2-b]-1,2,4-triazoles as substrates and the results
showed in Table 3. The reaction conditions had proven to be useful
for a range of 2,6-disubstituted thiazolo[3,2-b]-1,2,4-triazoles. The
reaction of 2,6-disubstituted thiazolo[3,2-b]-1,2,4-triazoles with
differently substituted on the phenyl ring of aryl iodides, such as 4-
CH3, 2-CH3, 2-F, 3-Cl and 4-CF3, had a beneficial effect on the re-
action outcomes, and in most cases the corresponding arylation
products were obtained in good yields under the previously
optimized conditions. These results indicated that all of the aryl
iodides, regardless of their electronic or steric properties, pro-
ceeded smoothly in good yields to afford the expected arylation
products.
A
proposed mechanism of the direct arylation could be
described in Scheme 2. A mechanism similar to those of previous
arylation of heterocycles may be involved for the present reaction.
First, Ru3(CO)12 reacted with aryl iodides to form Ru-complexes A
which directed electrophilic attack on 1a to generate the inter-
mediate B. Subsequently, the deprotonation of intermediate B with
the help of Cs2CO3 would give intermediate C, which would then
undergo reductive elimination to form the 3 and release the Ru
catalyst.
R
R
R1
N
N
R1
N
N
Ru. Base
Solvent
N
N
+
I
R2
R2
S
S
Scheme 1. Ru-catalyzed arylation of thiazolo[3,2-b]-1,2,4-triazole with aryl halide.

H. Zhang / Journal of Organometallic Chemistry 756 (2014) 47e51
49
Table 2
Regioselective synthesis of thiazolo[3,2-b]-1,2,4-triazoles.a
R
R
N
N
R1
N
N
Ru3(CO)12, NMP
140 oC, Cs2CO3
X= I, Br
N
Ar
+
X
S
N
S
1
2
3
Ph
Ph
Ph
N
N
N
N
N
N
N
N
S
S
S
N
CH3
H3C
3a 85%b (80%)c
3b 82%
3c 86%
Ph
Ph
Ph
N
N
N
N
N
N
S
N
N
N
CH3
F
Cl
S
N
S
3d 87%
3f 88%
3e 86%
Ph
Ph
CH3
N
N
N
N
N
N
S
N
Br
CF3
S
S
N
3g 82%
3h 80%
CH3
3i 87%
CH3
N
CH3
N
N
N
N
N
N
CH3
S
N
S
N
N
S
H3C
CH3
3j 84%
3k 85%
3l 89%
CH3
CH3
CH3
N
N
N
N
N
N
Br
F
S
S
N
N
S
Cl
3m 83%
3n 87%
3o 83%
3. Conclusion
In summary, an efficient highly region selective Ru3(CO)12
Heraeus elemental analyzer. All the other chemicals were pur-
chased from Aldrich Chemicals.
-
catalyzed direct arylation of thiazolo[3,2-b]-1,2,4-triazoles with
aryl iodides via CeH activation has been developed. This trans-
formation provided a convergent approach for the formation of
hetero-aryl bonds to prepare thiazolo[3,2-b]-1,2,4-triazole de-
rivatives in good yields.
4.1. General procedure for the synthesis of 3a
6-Phenylthiazolo[3,2-b]-1,2,4-triazole 1a (0.5 mmol, 100.5 mg),
iodobenzene 2a (0.7 mmol, 142.8 mg), Ru3(CO)12 (3 mol%), and
Cs2CO3 (1.0 mmol) were stirred in 2 mL of NMP at 140 ꢀC for 12 h.
After completion of the reaction (monitored by TLC), the water
(15 mL) was added. The aqueous solution was extracted with ethyl
acetate (3 ꢁ 10 mL) and the combined extract was dried with
anhydrous Na2SO4. The solvent was removed and the crude
product was separated by column chromatography (eluted with
petroleum ether/ethyl acetate ¼ 8:1) to give a pure product of 3a
(117.7 mg).
4. Experimental section
NMR spectra were recorded using a Bruker Avance 400 MHz
NMR spectrometer (100 MHz for carbon) and respectively refer-
enced to 7.26 and 77.0 ppm for chloroform-d solvent with TMS as
internal standard. ESI-MS spectra were measured on Finnigan Mat
TSQ 7000 instruments. Elemental analyses were performed on a

50
H. Zhang / Journal of Organometallic Chemistry 756 (2014) 47e51
Table 3
Synthesis of thiazolo[3,2-b]-1,2,4-triazoles.a
CH3
CH3
N
N
R1
N
N
Ru3(CO)12, NMP
140 oC, Cs2CO3
N
N
R2
R2
+
I
Ar
S
S
2
4
1
CH3
CH3
CH3
N
N
N
N
N
N
N
N
H3C
CH3
H3C
H3C
N
S
S
S
F
82%
b
4a
85%
4c
4b
87%
CH3
CH3
CH3
N
N
N
N
N
N
N
H3C
CF3
H3C
Ph
S
N
N
S
N
S
Cl
4f
87%
4d
4e
84%
80%
CH3
CH3
CH3
N
N
N
N
N
N
N
Ph
F
CF3
Ph
Ph
S
N
S
S
H3C
4i
78%
4g
4h
83%
85%
[13] D.R. Stuart, K. Fagnou, Science 316 (2007) 1172e1175.
[14] C.-Y. He, S. Fan, X. Zhang, J. Am. Chem. Soc. 132 (2010) 12850e12852.
[15] X. Gong, G. Song, H. Zhang, X. Li, Org. Lett. 13 (2011) 1766e1769.
[16] M.V. Leskinen, K.T. Yip, A. Valkonen, P.M. Pihko, J. Am. Chem. Soc. 134 (2012)
5750e5753.
[17] Z. Li, L. Ma, J. Xu, L. Kong, X. Wu, H. Yao, Chem. Commun. 48 (2012)
3763e3765.
[18] S. Potavathri, A.S. Dumas, T.A. Dwight, G.R. Naumiec, J.M. Hammann,
B. Deboef, Tetrahedron Lett. 49 (2008) 4050e4053.
[19] K. Hattori, K. Yamaguchi, J. Yamaguchi, K. Itami, Tetrahedron 68 (2012)
7605e7612.
[20] M. Kitahara, N. Umeda, K. Hirano, T. Satoh, M. Miura, J. Am. Chem. Soc. 133
(2011) 2160e2162.
[21] M. Nishino, K. Hirano, T. Satoh, M. Miura, Angew. Chem. Int. Ed. 51 (2012)
6993e6997.
[22] J.C. Wu, R.J. Song, Z.Q. Wang, X.C. Huang, Y.X. Xie, J.H. Li, Angew. Chem. Int. Ed.
Engl. 51 (2012) 3453e3457.
Ph
N
N
RuLn
N
Ar
S
3
Ph
Ar
Ar
RuLn
N
A
N
LnRu
C
I
S
N
Ph
HI
Cs2CO3
N
N
Ph
N
Ar
N
N
N
S
RuLn
I
[23] Z. Mao, Z. Wang, Z. Xu, F. Huang, Z. Yu, R. Wang, Org. Lett. 14 (2012)
3854e3857.
[24] Y. Li, L.X. Gao, F.S. Han, Chem. Commun. 48 (2012) 2719e2721.
[25] H. Cao, H.Y. Zhan, Y.G. Lin, X.L. Lin, Z.D. Du, H.F. Jiang, Org. Lett. 14 (2012)
1688e1691.
S
B
1a
Scheme 2. Plausible reaction mechanism.
[26] X. Qin, H. Liu, D. Qin, Q. Wu, J. You, D. Zhao, Q. Guo, X. Huang, J. Lan, Chem. Sci.
4 (2013) 1964e1969.
[27] J. Wencel-Delord, C. Nimphius, F.W. Patureau, F. Glorius, Angew. Chem. Int.
Ed. 51 (2012) 2247e2251.
References
[1] L.F. Tietze, A. Modi, Med. Res. Rev. 20 (2000) 304e322.
[28] X. Wang, B.S. Lane, D. Sames, J. Am. Chem. Soc. 127 (2005) 4996e4997.
[29] M.K. Lakshman, A.C. Deb, R.R. Chamala, P. Pradhan, R. Pratap, Angew. Chem.
Int. Ed. Engl. 50 (2011) 11400e11404.
[30] H. Li, W. Wei, Y. Xu, C. Zhang, X. Wan, Chem. Commun. 47 (2011) 1497e1499.
[31] A. Prades, M. Poyatos, E. Peris, Adv. Synth. Catal. 352 (2010) 1155e1162.
[32] F. Kakiuchi, Y. Matsuura, S. Kan, N. Chatani, J. Am. Chem. Soc. 127 (2005)
5936e5945.
[33] I. Özdemir, S. Demir, B. Cetinkaya, C. Gourlaouen, F. Maseras, C. Bruneau,
P.H. Dixneuf, J. Am. Chem. Soc. 130 (2008) 1156e1157.
[34] L. Ackermann, A. Althammer, R. Born, Angew. Chem. Int. Ed. 45 (2006)
2619e2622.
[35] L. Ackermann, A. Althammer, R. Born, Tetrahedron 64 (2008) 6115e6124.
[36] L. Ackermann, R. Vicente, Top. Curr. Chem. 292 (2010) 211e229.
[37] L. Ackermann, R. Vicente, A. Althammer, Org. Lett. 10 (2008) 2299e2302.
[38] S.G. Ouellet, A. Roy, C. Molinaro, R. Angelaud, J. Marcoux, P.D. O’Shea,
I.W. Davies, J. Org. Chem. 76 (2011) 1436e1439.
[2] B.B. Toure, D.G. Hall, Chem. Rev. 109 (2009) 4439e4486.
[3] S. Yu, S. Ma, Angew. Chem. Int. Ed. 51 (2012) 3074e3112.
[4] J.-P. Corbet, G. Mignani, Chem. Rev. 106 (2006) 2651e2710.
[5] J. Hassan, M. Sévignon, C. Gozzi, E. Schulz, M. Lemaire, Chem. Rev. 102 (2002)
1359e1470.
[6] X. Chen, K.M. Engle, D.H. Wang, J.Q. Yu, Angew. Chem. Int. Ed. Engl. 48 (2009)
5094e5115.
[7] M.C. Kozlowski, B.J. Morgan, E.C. Linton, Chem. Soc. Rev. 38 (2009) 3193e
3207.
[8] N. Kuhl, M.N. Hopkinson, J. Wencel-Delord, F. Glorius, Angew. Chem. Int. Ed.
Engl. 51 (2012) 10236e10254.
[9] C. Liu, H. Zhang, W. Shi, A. Lei, Chem. Rev. 111 (2011) 1780e1824.
[10] R. Martin, S.L. Buchwald, Acc. Chem. Res. 41 (2008) 1461e1473.
[11] C.S. Yeung, V.M. Dong, Chem. Rev. 111 (2011) 1215e1292.
[12] D.-G. Yu, B.J. Li, Z.-J. Shi, Tetrahedron 68 (2012) 5130e5136.

H. Zhang / Journal of Organometallic Chemistry 756 (2014) 47e51
51
[39] T. Ueyama, S. Mochida, T. Fukutani, K. Hirano, T. Satoh, M. Miura, Org. Lett. 13
(2011) 706e708.
[40] F. Yang, L. Ackermann, Org. Lett. 15 (2013) 718e720.
[41] V.S. Thirunavukkarasu, S.I. Kozhushkov, L. Ackermann, Chem. Commun.
(2014), http://dx.doi.org/10.1039/C1033CC47852A.
[42] H. Hachiya, K. Hirano, T. Satoh, M. Miura, ChemCatChem 2 (2010) 1403e1406.
[43] J. Canivet, J. Yamaguchi, I. Ban, K. Itami, Org. Lett. 11 (2009) 1733e1736.
[44] H. Hachiya, K. Hirano, T. Satoh, M. Miura, Org. Lett. 11 (2009) 1737e1740.
[45] H. Hachiya, K. Hirano, T. Satoh, M. Miura, Angew. Chem. Int. Ed. 49 (2010)
2202e2205.
[50] R. Pignatello, S. Mazzone, A.M. Panico, G. Mazzone, G. Pennisi, R. Castana,
M. Matera, G. Blandino, Eur. J. Med. Chem. 26 (1991) 929e938.
[51] P. Roy, Y. Leblanc, R.G. Ball, C. Brideau, C.C. Chan, N. Chauret, W. Cromlish,
D. Ethier, J.Y. Gauthier, R. Gordon, G. Greig, J. Guan, S. Kargman, C.K. Lau,
G. O’Neil, J. Silva, M. Thérien, C. Vvanstaden, E. Wong, L. Xu, P. Prasit, Bioorg.
Med. Chem. Lett. 7 (1997) 57e62.
[52] I. Simiti, A. Marie, Rev. Roum. Chim. 27 (1982) 273e279.
[53] P. Kumar, A. Kumar, J.K. Makrandi, J. Heterocyclic Chem. 50 (2013) 1223e1229.
[54] Z. Xie, X. Zhu, Y. Guan, D. Zhu, H. Hu, C. Lin, Y. Pan, J. Jiang, L. Wang, Org.
Biomol. Chem. 11 (2013) 1390e1398.
[46] S.-F. Barbuceanu, G.L. Almajan, I. Saramet, C. Draghici, A.I. Tarcomnicu,
G. Bancescu, Eur. J. Med. Chem. 44 (2009) 4752e4757.
[47] B. Berk, G. Aktay, E. Yesilada, M. Ertan, Pharmazie 56 (2001) 613e616.
[48] M.S. Karthikeyan, Eur. J. Med. Chem. 44 (2009) 827e833.
[49] R. Lesyk, O. Vladzimirska, S. Holota, L. Zaprutko, A. Gzella, Eur. J. Med. Chem.
42 (2007) 641e648.
[55] A. Davoodnia, S. Ameli, H.N. Tavakoli, Asian J. Chem. 23 (2011) 3707e3712.
[56] A.R. Katritzky, A. Pastor, M. Voronkov, Org. Lett. 2 (2000) 429e431.
[57] H.A.H. El-Sherief, Z.A. Hozien, A.F.M. El-Mahdy, A.A.O. Sarhan, ARKIVOC
(2011) 71e84.
[58] H.A.H. El-Sherif, A.M. Mahmoud, A.A.O. Sarhan, Z.A. Hozien, O.M.A. Habib,
J. Sulfur Chem. 27 (2006) 65e85.