CuO-promoted construction of N -2-aryl-substituted-1,2,3-triazoles via azide-chalcone oxidative cycloaddition and post-triazole arylation

Article abstract of DOI:10.1021/ol202718d

An efficient one-pot three-component stepwise approach for the synthesis of N-2-aryl-substituted-1,2,3-triazoles has been developed. By using this azide-chalcone oxidative cycloaddition and post-triazole arylation, a series of N-2-aryl-substituted-1,2,3-triazoles are readily prepared under mild conditions in excellent yields and high regioselectivity. Both the catalyst and substrates are readily available.

Full text of DOI:10.1021/ol202718d

ORGANIC
LETTERS
2012
Vol. 14, No. 1
26–29
CuO-Promoted Construction of N-2-Aryl-
Substituted-1,2,3-Triazoles via
Azide-Chalcone Oxidative Cycloaddition
and Post-Triazole Arylation
Yuanqing Zhang, Xiaolong Li, Jihui Li, Jinying Chen, Xu Meng, Mingming Zhao, and
Baohua Chen*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu
Lanzhou 730000, P. R. China, and Key Laboratory of Nonferrous Metal Chemistry and
Resources Utilization of Gansu Province, Lanzhou, 730000, P. R. China
chbh@lzu.edu.cn
Received October 11, 2011
ABSTRACT
An efficient one-pot three-component stepwise approach for the synthesis of N-2-aryl-substituted-1,2,3-triazoles has been developed. By using
this azide-chalcone oxidative cycloaddition and post-triazole arylation, a series of N-2-aryl-substituted-1,2,3-triazoles are readily prepared under
mild conditions in excellent yields and high regioselectivity. Both the catalyst and substrates are readily available.
Since the remarkable discovery of Cu-catalyzed-
azide-alkyne-cycloaddition (CuAAC, also referred as
“click-chemistry”), 1,2,3-triazoles have attracted signifi-
cant attention as one of the most important heterocycles.1
Within the past few years, applications of this building
block have been extended widely into various research
fields,2 such as chemical biology, material science, and
medicinal chemistry. Recently described methods for the
catalytic direct functionalization of triazole and its deriva-
tives have also been proven attractive but are mainly
limited to the N-1 position,3 although few methodolo-
gies have been reported for the direct functionalization
of triazoles at the N-2 position.4 Traditional routes to
prepare 1,2,3-triazoles often suffered from poor regios-
electivity, a rather tedious reaction procedure, and a
significant amount of expensive and difficult-to-pre-
pare catalysts. 1-Substituted triazoles and the parent
unsubstituted compounds can be synthesized by the
reaction of organic azides, metal azides, or hydrazoic acid
with alkynes respectively. The reaction with alkenes can
(1) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596. (c) Wu, P.;
Fokin, V. V. Aldrichimica Acta 2007, 40, 7. (d) Cohrt, A. E.; Jensen, J. F.;
Nielsen, T. E. Org. Lett. 2011, 12, 5414.
(2) (a) Maliakal, A.; Lem, G.; Turro, N. J.; Ravichandran, R.;
Suhadolnik, J. C.; DeBellis, A. D.; Wood, M. G.; Lau, J. J. Phys. Chem.
A 2002, 106, 7680. (b) Kolb, H. C.; Sharpless, K. B. Drug Discovery
Today 2003, 8, 1128. (c) Wu, P.; Feldman, A. K.; Nugent, A. K.;
ꢀ
Hawker, C. J.; Scheel, A.; Voit, B.; Pyun, J.; Frechet, J. M. J.; Sharpless,
K. B.; Fokin, V. V. Angew. Chem., Int. Ed. 2004, 43, 3928. (d) Agard,
N. J.; Prescher, J. A.; Bertozzi, C. R. J. Am. Chem. Soc. 2004, 126, 15046.
(f) Wacharasindhu, S.; Bardhan, S.; Wan, Z.-K.; Tabei, K.; Mansour,
T. S. J. Am. Chem. Soc. 2009, 131, 4174.
(3) Selective methods of synthesizing N-1 substituted 1,2,3-triazoles:
(a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057. (b) Aucagne, V.; Leigh, D. A. Org. Lett. 2006, 8, 4505.
(c) Majireck, M. M.; Weinreb, S. J. Org. Chem. 2006, 71, 8680. (d) Yang,
D.; Fu, N.; Liu, Z.; Li, Y.; Chen, B. Synlett 2007, 278. (e) Sreedhar, B.;
Reddy, P. S.; Krishna, V. R. Tetrahedron Lett. 2007, 48, 5831. (f) Shi, F.;
Waldo, J. P.; Chen, Y.; Larock, R. C. Org. Lett. 2008, 10, 2409. (g) Qian,
W.; Winternheimer, D.; Allen, J. Org. Lett. 2011, 13, 1682.
(4) Methods of regioselectively synthesizing N-2 substituted 1,2,3-
triazoles: (a) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Am. Chem.
Soc. 2002, 125, 7786. (b) Chen, Y.; Liu, Y.; Petersena, J. L.; Shi, X.
Chem. Commun. 2008, 3254. (c) Kalisiak, J.; Sharpless, K. B.; Fokin,
V. V. Org. Lett. 2008, 10, 3171. (d) Liu, Y.; Yan, W.; Chen, Y.; Petersen,
J. L.; Shi, X. Org. Lett. 2008, 10, 5389. (e) Wang, X.; Zhang, L.; Lee, H.;
Haddad, N.; Krishnamurthy, D.; Senanayake, C. H. Org. Lett. 2009, 11,
5026.
r
10.1021/ol202718d
Published on Web 12/01/2011
2011 American Chemical Society

only take place when organic azides exist, mainly
because 1,4-conjugate addition and formation of linear
adducts are inclined to interact with azide ions and
hydrazoic acid.6
azide-chalcone oxidative cycloaddition and post-triazole
arylation in one pot.
Table 1. Optimization Studiesa
Scheme 1. N-2-Aryl-1,2,3-triazole Synthesis
T
yieldb
(%)
entry
Cu
(°C)
equiv
solvent
1
CuCl2
Cu(OAc)2
Cu(acac)2
CuI
80
80
80
80
80
80
80
rt
1
DMF
DMF
DMF
DMF
DMF
DMA
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
21
2
1
none
trace
none
93
3
1
4
1
5
CuO
CuO
1
6
1
79
7
CuO
1
67
8
CuO
1
none
71
9
CuO
120
80
80
80
80
1
10
11
12
13
none
none
0.2
0.5
2
none
80
CuO
CuO
61
CuO
76
To date, our group has been working on the inves-
tigation of 1,2,3-triazole derivatives in transition metal
catalysis.7 However, the highly regioselective intro-
duction of a substituent at N-2 was not possible via
these chemistry methods. The general approach for
N-2-aryl triazole is from the hydrazine/R-hydoxyke-
tone condensation8 as shown in Scheme 1A. We were
interested in further investigating the utility of the Cu-
based approach for synthesizing triazoles with differ-
ent substitution patterns, especially those allowing
access to the N-2 position. Currently, we had success-
fully developed a metal- and base-free three-compo-
nent reaction of ynones, sodium azide, and alkyl
halides for regioselectively synthesizing 2,4,5-trisub-
stituted 1,2,3-triazoles (Scheme 1B).7b At the outset of
the above-mentioned investigation, we initially envisioned
one novel and operationally simple way of regioselec-
tively synthesizing 2,4,5-trisubstituted 1,2,3-triazoles via
a All of the reactions were carried out with substrate 1a (0.2 mmol),
NaN3 (0.2 mmol), and 1 equiv of CuO in the solvent (2 mL) at 80 °C
under air for 24 h first, then 2-NO2-C6H4F (0.2 mmol) was added to the
mixture, and the reaction continued for 6 h. b Isolated yields.
With this goal, we initiated our studies by choosing
3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (1a) as a
model substrate with different Cu sources and solvents
at varied temperature (Table 1). The reaction was con-
ducted in DMF at 80 °C in the presence of 1 equiv of
CuCl2 under air for 24 h first, then 2-NO2-C6H4F was
added to the mixture, and the reaction continued for 6 h
providing the desired product 2aa (Figure 1) only in 21%
yield (Table 1, entry 1). This inspired us to examine the
optimal conditions for the reaction in order to obtain
more satisfactory results. The catalytic activity of the
(5) (a) Peng, W.; Zhu, S. Tetrahedron 2003, 59, 4395. (b) Peng, W.;
Zhu, S. J. Fluorine Chem. 2002, 116, 81. (c) Zanirato, P. J. Chem. Soc.,
Perkin Trans. 1 2002, 1420. (d) Freeze, S.; Norris, P. Heterocycles 1999,
51, 1807. (e) Louerat, F.; Bougrin, K.; Loupy, A.; Ochoa de Retana,
A. M.; Pagalday, J.; Palacios, F. Heterocycles 1998, 48, 161.
(6) For examples of 1,3-dipolar cycloadditions of N3À/HN3 to
€
alkenes, see: (a) Huisgen, R.; Knorr, R.; Mo bius, L.; Szeimies, G.
Chem. Ber. 1965, 98, 4014. (b) Tanaka, Y.; Miller, S. I. J. Org. Chem.
1972, 37, 3370. (c) Norbedo, I.; Benedetti, F.; Berti, F.; Nardin, G.;
Adamo, S. Tetrahedron Lett. 2003, 44, 9095. (d) Kamalraj, V. R.;
Senthil, S.; Kannan, P. J. Mol. Struct. 2008, 892, 210. (e) Donohoe,
T. J.; Bower, J. F.; Baker, D. B.; Basutto, J. A.; Chan, L. K.; Gallagher,
P. Chem. Commun. 2011, 10611.
(7) (a) Li, J.; Wang, D.; Zhang, Y.; Li, J.; Chen, B. Org. Lett. 2009, 11,
3024. (b) Li, J; Zhang, Y; Wang, D.; Wang, W.; Gao, T.; Wang, L.; Li, J.;
Huang, G.; Chen, B. Synlett 2010, 1617. (c) Meng, X.; Xu, X.; Gao, T.;
Chen, B. Eur. J. Org. Chem. 2010, 5409. (d) Li, N.; Wang, D.; Li, J.; Shi,
W.; Li, C.; Chen, B. Tetrahedron Lett. 2011, 52, 980.
Figure 1. X-ray crystal structures of 2aa and 2ea.
(8) Tang, W.; Hu, Y. Synth. Commun. 2006, 36, 2461.
Org. Lett., Vol. 14, No. 1, 2012
27

different copper sources such as Cu(OAc)2, Cu(acac)2,
CuI, and CuO were tested (Table 1, entries 1À5). Among
these tested copper sources, CuO was found to be super-
ior and resulted in a 93% yield. The effect of the solvent
was also investigated; changing the solvent from DMA to
DMSO failed to improve the yield of the product
(Table 1, entries 6À7). Although no anticipated product
was observed at room temperature, no improvement was
achieved when the reaction was conducted at 120 °C. In
addition, neither increasing nor decreasing the loading of
CuO gave any obvious improvement in the yields.
2,4,5-trisubstituted 1,2,3-triazoles with excellent yields
(Table 3, entries 1, 3À5). When 2-NO2-C6H4Cl and the
electron-rich aryl chlorides 2-CH3-C6H4Cl were explored,
the reactions did not yield any desired products (Table 3,
entries 2 and 6). The structure of compound 2ea was
unambiguously confirmed by X-ray analysis (Figure 1).
Table 3. Substrate Scope of Aryl Halidesa
After obtaining the optimized reaction conditions, a
variety of chalcones were used as substrates to investigate
the scope of the reaction as shown in Table 2.
Table 2. Substrate Scope of Chalconesa
yieldb
entry
Ar3X
(%)
product
1
2
3
4
5
6
2-NO2-C6H4F
93
2aa
2ba
2ca
2da
2ea
2fa
2-NO2-C6H4Cl
none
98
2, 4-diNO2-C6H3Cl
2, 5-diF-C6H3NO2
3, 4-diF-C6H3NO2
2-CH3-C6H4Cl
79
88
none
yieldb
a All of the reactions were carried out with 1a (0.2 mmol), NaN3
(0.2 mmol), and 1 equiv of CuO in the DMF (2 mL) at 80 °C for 24 h
under air first, then aryl halide Ar3X (0.2 mmol) was added to the
mixture, and the reaction continued for 6 h. b Isolated yields.
entry
Ar1
Ar2
C6H5
(%)
product
1
4-ClC6H4
4-NO2C6H4
4-FC6H4
4-CH3C6H4
3,4-(CH3)2C6H3
C6H5
93
85
75
71
65
72
76
28
90
92
90
97
83
0
2aa
2ab
2ac
2ad
2ae
2ah
2af
2
C6H5
3
C6H5
4
C6H5
To probe the mechanism of this transformation, reac-
tions of 1a in the presence of 0.2 equiv of CuO under air
and in the absence of CuO under air were investigated
respectively. We were surprised to find that the latter
reaction did not afford any expected product. We there-
fore postulated that CuO acted not only as the oxidant but
also as an initiator to trigger this catalytic process, and
then Cu was oxidized to CuO by air. On the basis of the
above results, a plausible reaction pathway for the oxida-
tive dehydrogenative coupling is illustrated in Scheme 2.
5
C6H5
6
4-CH3OC6H4
C6H5
7
C6H5
8
4-CH3C6H4
C6H5
4-CH3OC6H4
4-NO2C6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
4-CH3OC6H4
C6H5
2ag
2ai
9
10
11
12
13
14
C6H5
2aj
C6H5
2ak
2al
4-CH3OC6H4
4-ClC6H4
Fc
2am
2an
a All of the reactions were carried out with chalcones (0.2 mmol),
NaN3 (0.2 mmol), and 1 equiv of CuO in DMF (2 mL) at 80 °C for 24 h
under air first, then 2-NO2-C6H4F (0.2 mmol) was added to the mixture,
and the reaction continued for 6 h. b Isolated yields.
Scheme 2
Generally, chalcones with electron-withdrawing sub-
stituents on Ar1 and/or Ar2 led to higher yields (Table 2,
entries 1À3, 10À13). In contrast, chalcones with electron-
donating substituents gave lower but still acceptable
yields (Table 2, entries 4À7). Notably, when the chalcone
bearing two electron-donating groups was employed,
the yield dropped to 28% (Table 2, entry 8). In addi-
tion, replacing the aryl group of Ar1 of 1a with ethynyl
ferrocene (Fc) gave no desirable product.
To further explore the generality and scope of this
protocol, several aryl halides were also investigated. As
illustrated in Table 3, when the highly electron-deficient
aryl halides were used, the reactions were conducted slug-
gishly and regioselectively produced the corresponding
In conclusion, the combination of azide-chalcone
oxidative cycloaddition and post-triazole arylation pre-
sented herein is a powerful approach in diversity-
oriented, multiple component condensation sequences.
To the best of our knowledge, this is an efficient example of
the selective preparation of N-2 triazole compounds with
clear characterization of the different N-isomers. With the
continuously growing interest in 1,2,3-triazoles, we believe
this strategy will greatly benefit researchers in various
28
Org. Lett., Vol. 14, No. 1, 2012

fields. Application of this general concept to the con-
struction of other triazole-containing scaffolds with
potential biological activity is currently under investi-
gation in our group and will be reported in due course.
Education Ministry (No.107108) and the Project of Na-
tional Science Foundation of P. R. China (No. J0730425).
Supporting Information Available. Experimental de-
tails and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We are grateful for support of the
project by the Scientific Research Foundation for the State
Org. Lett., Vol. 14, No. 1, 2012
29