An efficient regioselective copper-catalyzed approach to the synthesis of 1,2,3-triazoles from N-tosylhydrazones and azides

Article abstract of DOI:10.1016/j.tetlet.2016.10.033

An efficient regioselective copper-catalyzed strategy for the synthesis of 1,2,3-triazoles from N-tosylhydrazones and azides has been reported. This transformation opened a new route to synthesize 1,2,3-triazoles which is a common structural motif in natural products and pharmaceuticals. The reactions were smoothly under the optimized conditions and provided the desired product in good yields.

Full text of DOI:10.1016/j.tetlet.2016.10.033

Accepted Manuscript
An efficient regioselective copper-catalyzed approach to the synthesis of 1,2,3-
triazoles from N-tosylhydrazones and azides
Zhishuo Zheng, Lei Shi
PII:
S0040-4039(16)31336-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.033
TETL 48203
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 August 2016
6 October 2016
9 October 2016
Please cite this article as: Zheng, Z., Shi, L., An efficient regioselective copper-catalyzed approach to the synthesis
of 1,2,3-triazoles from N-tosylhydrazones and azides, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.10.033
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An efficient regioselective copper-catalyzed approach Leave this area blank for abstract info.
to the synthesis of 1,2,3-triazoles from
N-tosylhydrazones and azides
Zhishuo Zheng, Lei Shi*
N
NNHTs
N
N
CuCl2, DABCO/K2CO3
DMSO, O2, 100 oC 12 h
+
Ar
R N3
Ar
R

1
Tetrahedron Letters
journal homepage: www.els evier.com
An efficient regioselective copper-catalyzed approach to the synthesis of 1,2,3-
triazoles from N-tosylhydrazones and azides
Zhishuo Zheng a, Lei Shib, ∗
aDepartment of Physics and Information Engineering, Guangdong University of Education, Guangzhou 510303, P.R. of China
bDepartment of Chemistry, Guangdong University of Education, Guangzhou 510303, P.R. of China
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient regioselective copper-catalyzed strategy for the synthesis of 1,2,3-triazoles from N-
tosylhydrazones and azides has been reported. This transformation opened a new routes to
synthesize 1,2,3-triazoles which is a common structural motif in natural products and
pharmaceuticals. The reactions were smoothly under the optimized conditions and provided the
desired product in good yields.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Copper-catalyzed
1,2,3-triazoles
N-tosylhydrazones
Azides
N
N
1. Introduction
N
N
N
R1
N
+
R1
a)
+
N N N
R1
R
R
1,2,3-triazoles is an important motif and widely exist in natural
products, advanced functional materials, and bioactive
compounds.1 The development of synthetic strategy to prepare
those compounds2 still attracts attentions of organic chemists.
Click chemistry has recently emerged to become one of the most
powerful tools for the formation of carbon−heteroatom−carbon
bonds to construct 1,2,3-triazoles in drug discovery, chemical
biology, and proteomic applications.3
R
1,5-triazole
1,4-triazole
Cu
N
N
N
R1
+
N N N
R1
b)
c)
R
R
R
1,4-triazole
R1
N
N
Ru
N N N R1
Since the publications4 has been developed on the click
reaction by Huisgen, many papers5 have appeared to construct
those compounds. The classic6 click reaction is the copper-
catalyzed reaction of an azide with an alkyne to form a 5-
membered heteroatom ring. The copper-catalyzed Huisgen 1,3-
dipolar cycloaddition of alkynes to azides leads exclusively to
1,4-regioisomer of triazole product (Scheme 1b),7 in contrast to a
long-time known thermal noncatalytic version, which often
produces mixtures of both 1,4- and 1,5-regioisomers (Scheme 1a)
when using asymmetric alkynes. Fokin and Jia also reported8 that
1,5-regioisomeric triazoles (Scheme 1c) were obtained as the
major products when ruthenium catalysts are used instead of
copper in the reaction. Although thousands of papers are reported
in general aspects, including mechanism,9 drug discovery,10
modification of sugars,11 polymer, and material sciences,12 the
development of new strategy to prepare those compounds still
constitutes an exciting challenge for organic chemists. Herein, we
described a novel transformation for the preparation of 1,2,3-
N
+
R
1,5-triazole
Scheme 1. Synthesis of 1,2,3-triazoles
2. Results and discussion
In
phenylethylidene)benzenesulfonohydrazide
our
initial
studies,
4-methyl-N'-(1-
(1a)
and
(azidomethyl)benzene (2a) were chosen as the substrates to
investigate the formation of 1-benzyl-4-phenyl-1H-1,2,3-triazole
(3a). The results of the optimization study for the synthesis of 3a
are outlined in Table 1. The corresponding product 3a was
obtained in 16% yield when the reaction was carried out in a
sealed tube (25 mL) using Cu(OTf)2 as a catalyst in DMF at
100℃ for 12 h (Table 1, entry 1). Other copper salts (Table 1,
entries 2-6), such as Cu(OAc)2, CuBr2, CuCl2, CuI, and CuBr,
was tested to study their catalytic efficiency for the synthesis of
3a. Among them, CuCl2 is a more efficient catalyst than the other
tested. Further screening of this reaction was performed to
triazoles
from
N-tosylhydrazones13
and
azides.
———
∗ Lei Shi. Tel.: +86-(020)34113456; fax: +86-(020)34113456; e-mail: shil@gdei.edu.cn

2
Tetrahedron Letters
explore the effect of additives. However, the yield did not
This new transformation was further found to be successfully
applied to catalyze the reaction of N-tosylhydrazones with
aromatic or aliphatic azides.
improve significantly when DBU or K2CO3 or NaH2PO4 or
NaOAc, was added to the reaction. To our delight, the yield of 3a
could be increased to 76% (Table 1, entry 11) using DABCO and
K2CO3 as the additives. Having gained some crucial insight into
the effect of different catalysts and additives, further study of this
reaction was carried out using different oxidants (Table 1, entries
12-14). It was noted that 76% yield was obtained using TBHP as
oxidant. Lower yields was formed when DDQ or K2S2O8 was
added in the reaction. Furthermore, the effects of solvents were
next tested (Table 1, entries 15-17). We were delighted to find
that the product 3a was readily formed in 87% yields in DMSO.
Table 2 Cu-catalyzed synthesis of 1,2,3-triazolesa
N
NNHTs
N
N
CuCl2, DABCO/K2CO3
DMSO, O2, 100 oC12 h
+
Ar
Ar
N3
Ar
Ar
1
2
3
Ph
Ph
Ph
N
N
N
N
Ph
N
N
Cl
Ph
N
N
N
N
N
84%
N
3b 73%
3a
3c
89%
I
3d 83%
Br
Ph
Ph
Ph
N
Table 1 Optimization of the reaction conditionsa
N
N
N
N
OEt
N
N
N
N
3e 77%
3f
75%
3f 84%
N
NNHTs
N
N
catalyst, additives
+
Ph
Ph
N
N
N
N
N
Ph
N3
OEt
Ph
Ph
solvent, oxidant, 12 h
N
N
N
N
1a
2a
3a
Oxidant Solvent Yield(%)b
3j
3h
86%
76%
N
3i
81%
Br
Entry
Catalyst
Additive
N
N
N
N
N
Br
N
N
N
1
Cu(OTf)2
DABCO
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
toluene
DMSO
16
21
24
37
<10
trace
11
42
15
23
76
73
18
11
65
87
3k
3l
81%
83%
3m
80%
Br
2
Cu(OAc)2 DABCO
N
N
N
N
N
OEt
OEt
N
N
N
3p
80%
3
Cu Br2
CuCl2
CuI
DABCO
DABCO
DABCO
DABCO
DBU
N
3o
75%
3n
82%
4
F
N
N
N
N
Br
5
N
N
Cl
N
N
N
3q
81%
6
CuBr
3r
3s
69%
76%
N
N
7
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
N
N
N
Br
Cl
Cl
N
Cl
N
N
N
8
K2CO3
3t
78%
3v
3u
80%
83%
9
NaH2PO4
NaOAc
a
Isolated yields
10
11
12
13
14
15
16
17
Table 3 Cu-catalyzed synthesis of 1,2,3-triazoles using
different azidesa
DABCO/K2CO3 O2
DABCO/K2CO3 TBHP
DABCO/K2CO3 DDQ
DABCO/K2CO3 K2S2O8
DABCO/K2CO3 O2
DABCO/K2CO3 O2
DABCO/K2CO3 O2
N
NNHTs
N
N
CuCl2, DABCO/K2CO3
DMSO, O2, 100 oC 12 h
Ph
R
N3
+
R
Ph
1
2
4
N
N
N
N
N
N
N
N
4a 83%
N
dioxane 80
4b 85%
4c 82%
aReaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), additives (10 mol %),
catalyst (10 mol %); oxidant (1.0 mmol), solvents 3 mL, carried out in a
sealed tube (25 mL); 100 °C; stirred for 12 h; with oxygen ballon (500 mL)
except for entry 12-14.
O
Cl
N
N
N
N
N
N
N
4e 80%
N
N
bGC yield.
4d 84%
4f 87%
a Isolated yields
With the optimized reaction conditions established, the scope
of this Cu-catalyzed reaction was investigated for the synthesis of
1,2,3-triazoles. The results are summarized in Table 2. This
process proved to be a general strategy for the construction of
1,2,3-triazoles. First, various substituted N-tosylhydrazones were
tested as substrates for this transformation. A number of
functional groups on phenyl ring of N-tosylhydrazones were
tolerated under the optimized reaction condition, including a
CH3, Cl, Br, I, F, 4-OEt, and 2,4-dimetyl, were transformed to the
desired 1,2,3-triazoles in good yields. Subsequently, substituted
(azidomethyl)benzenes were employed. All those results clearly
indicated that this transformation could react smoothly and the
corresponding products (3i-3v) were obtained.
On the basis of the experimental results and previous reports,14
a possible mechanism is proposed in Scheme 2. Initially, the
copper carbene intermediate A is generated from the N-
tosylhydrazone in the presence of Cu and DABCO. The
intermediate B is formed via oxidation and dehydrogenation of
intermediate A with the assistance of O2 and base,14a followed
coordination of 2a to give the intermediate C. Subsequently, an
unusual six-membered copper metallacycle D is generated. Ring
contraction to a triazolyl-copper derivative E is followed by
protonolysis that delivers the triazole product 3a and released the
copper catalyst.
HL or H2O
CuLn-1
Ph
PhCH2N3
CuLn-2
N
DABCO
Cu
NNHTs
CuLn
The scope of this Cu-catalyzed synthesis of 1,2,3-triazoles has
been further explored by reacting 1a with different azides. The
results are outlined in Table 3. As expected, various aliphatic
azides have reacted with 1a to generate the corresponding
products 4a-4c in good to excellent yields under the standard
reaction conditions. Subsequently, aromatic azides were also
employed for this transformation (4d-4f). The results indicated
that the presence of electron-donating groups (OCH3) or electron-
withdrawing groups (Cl) on the benzene ring, were tolerated in
the reaction and afforded the desired products in good yields.
Ph
CH2Ph
Ph
N
Ph
A
B
N
1a
C
O2, base
CuII
CuLn-2
CH2Ph
CuLn-2
CH2Ph
Ph
N
Ph
Ph
N
N
N
CH2Ph
N
N
N
N
N
D
H+
E
3a

3
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In conclusion, we have developed a convenient copper-
catalyzed transformation for the synthesis of 1,2,3-triazoles from
N-tosylhydrazones and azides. This Cu-catalyzed strategy
tolerated a broad range of substrates and provided a new route to
prepare 1,2,3-triazoles, which should be significant for the
construction of 1,2,3-triazoles libraries. Further investigation into
the scope and synthetic applications of this system is being
carried out in the future.
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Acknowledgments
We thank the Guangdong Natural Science Foundation
(S2012040006270) and the National Training Programs of
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Innovation
(201614278073).
and
Entrepreneurship
for
Undergraduates
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Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/
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4
Tetrahedron
Cu-catalyzed route using N-tosylhydrazones and
azides as the substrates.
An efficient method for synthesis of 1,2,3-triazoles.
A new transformation for the formation of C-N
bond.