Synthesis of pyrazoles from 2-azidoacrylates and hydrazonyl chlorides

Article abstract of DOI:10.1016/j.tetlet.2011.05.147

A regioselective synthesis of 1,3,4,5-tetrasubstituted pyrazoles is established between 2-azidoacrylates and hydrazonyl chlorides in the presence of triethylamine. The yields are moderate (43-73%) and a possible mechanism for this transformation is postul

Full text of DOI:10.1016/j.tetlet.2011.05.147

Tetrahedron Letters 52 (2011) 4161–4163
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Tetrahedron Letters
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Synthesis of pyrazoles from 2-azidoacrylates and hydrazonyl chlorides
⇑
⇑
Yao Li, Deng Hong, Ping Lu , Yanguang Wang
Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A regioselective synthesis of 1,3,4,5-tetrasubstituted pyrazoles is established between 2-azidoacrylates
and hydrazonyl chlorides in the presence of triethylamine. The yields are moderate (43–73%) and a pos-
sible mechanism for this transformation is postulated.
Received 24 April 2011
Revised 24 May 2011
Accepted 31 May 2011
Available online 12 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
2-Azidoacrylates
Hydrazonyl chlorides
Pyrazoles
Cycloaddition
1. Introduction
adding triethylamine to a solution of ethyl 2-azido-3-phenylacry-
late (1a) and N0-phenylbenzohydrazonoyl chloride (2a) in tetrahy-
As an important type of nitrogen-containing heterocycle, pyra-
zole has been employed as a key structural motif, which widely ex-
ists in nature and behaves with excellent biological activity in
pharmaceuticals, such as celebrex,1 viagra2 and rimonabant.3 In
addition, 1,3,4,5-tetrasubstituted pyrazoles exhibited intense
luminescence in solid states which might be used for optoelec-
tronic devices,4 such as organic light emitting diodes, organic light-
ening, and so on. Thus, lots of synthetic routes5 leading to
pyrazoles have been established. As a typical example among
established methods, 1,3-dipolar cycloaddition between hydrazo-
nyl chlorides and alkynes6 or alkyne alternatives7 presented its un-
ique convenience and effectiveness. In these cases, alkyne
alternatives are normally alkenes bearing a good leaving group.8
With respect to the interesting chemistry of 2-azidoacrylates,9
we have efficiently constructed indoles,10a isoquinolines,10b and
triazolines,10c respectively. Meanwhile, we realized that hydrazo-
nyl chlorides11 could generate active nitrilimine in situ and partic-
ipate in 1,3-dipolar cycloaddition with an alkyne alternative.
Combining these two key features, we tested the reaction between
2-azidoacrylates and hydrazonyl chlorides in the presence of base.
Fortunately, a series of 1,3,4,5-tetrasubstituted pyrazoles are ob-
tained with high regioselectivity. Crystal analysis of 3c further con-
firmed pyrazole structure with multi-substituents (Fig. 1).
drofuran (Table 1, entry 1). No main product was detected
although both starting materials disappeared based on TLC track-
ing. Similar observation was seen when toluene was used as the
solvent (Table 1, entry 2). By changing the solvent to N,N-dimethyl-
foramide (Table 1, entry 3), 1,3,4,5-tetrasubstituted pyrazole (3a)
was isolated in 20% yield. To our delight, the yields could be signif-
icantly improved by applying methylene chloride or acetonitrile as
the solvent (Table 1, entries 4 and 5). Alternating triethylamine to
Cs2CO3 or K2CO3, yields were decreased apparently (Table 1, entries
6 and 7). Pyridine did not work for this transformation (Table 1,
2. Results and discussion
zAs we mentioned above, hydrazonyl chlorides could be trans-
ferred into nitrilimines in the presence of base.12 Our initial test is
⇑
Corresponding authors. Tel./fax: +86 571 87951512.
E-mail addresses: pinglu@zju.edu.cn (P. Lu), orgwyg@zju.edu.cn (Y. Wang).
Figure 1. X-ray crystal structure of 3c.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.147

4162
Y. Li et al. / Tetrahedron Letters 52 (2011) 4161–4163
Table 1
Et3N
H
Screening for the reaction conditionsa
Ph
Cl
N
Ph
Ph
Ph
Ph
N
Ph
Ph
COOEt
-Et3N HCl
COOEt
COOEt
N
N H
N
N2
N
N
Cl
COOEt
H
N
N
Ph
Ph
Ph
Et3N
Ph
A
+
N
N
Et3N
N
Ph
N
Ph
N3
1a
2a
Ph
1a
CH3CN
rt,12 h
N
3a
B
2a
Entry
Solvent
Reaction temperature (°C)
Base
Yieldb (%)
-Et3N HN3
1
2
3
THF
PhMe
DMF
25
25
25
25
25
25
25
25
50
80
25
25
25
Et3N
Et3N
Et3N
Et3N
0
Trace
20
69
71
64
58
0
52
47
52
72
67
Ph
Ph
4
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
5
Et3N
6c
Cs2CO3
K2CO3
Pyridine
Et3N
Et3N
Et3N
N
COOEt
N
7d
8
Ph
9c
3a
10e
11f
12g
13h
Scheme 1. Possible mechanism for this reaction.
Et3N
Et3N
a
Reaction conditions: 1a (0.5 mmol), 2a (1.25 mmol), base (1.75 mmol), solvent
(8 mL), 12 h.
larly, either electron donating or electron withdrawing on aryl part
of 2-azido-3-aryllacrylate (1a–g) (Table 2, entries 1, 9–14) did not
affect reactions and afforded the desired products (3a, 3i–n)
smoothly. When R2 in substrate 2 was the alkyl group (Table 2, en-
try 15), the desired product 3o was obtained in lower yield.
Based on the investigations of reaction condition and substrate
diversity, a possible mechanism for this reaction is described in
Scheme 1. At the beginning, nitrilimines A, generated in situ from
2a by treatment with triethylamine, reacted with 1a to form inter-
mediate B via [3+2] cycloaddition reaction with high regioselectiv-
ity. Aromatization of the resulting heterocycle B by kicking off
hydrogen azide assisted by triethylamine constructed the final
product 3a.
b
Isolated yields referred to 1a.
Reaction was performed for 8 h.
Reaction was performed for 10 h.
Reaction was performed for 6 h.
Compound 1a (0.5 mmol), 2a (1 mmol), base (1.5 mmol).
Compound 1a (0.5 mmol), 2a (1.5 mmol), base (2.0 mmol).
Compound 1a (0.5 mmol), 2a (1.25 mmol), base (2.0 mmol).
c
d
e
f
g
h
entry 8). By raising the reaction temperature to 50 or 80 °C, short-
ening the reaction time accordingly as indicated in the notes of Ta-
ble 1, yields were influenced (Table 1, entries 9 and 10). Besides
these variations, the suitable ratio of starting materials to base
(1a:2a:Et3N) was found to be 1:2.5:3.5 (Table 1, entries 11–13) con-
sidering both yields and benign to environment.
With the optimized reaction conditions in hand, we subse-
quently examined the scope of this transformation. A number of
substituted hydrazonyl chlorides (2a–h) (Table 2, entries 1–8)
were tested and found to tolerate the reaction. No significant sub-
stituent effect was observed for component 2. Compounds 3a–h
were prepared in yields between 56% and 73% accordingly. Simi-
In conclusion, we have developed an efficient method to con-
struct tetrasubstituted pyrazoles from 2-azidoacrylates and hyd-
razonyl chlorides in moderate to good yields.13 Reactions are
carried under mild condition and with high regioselectivity. A rea-
sonable mechanism, including [3+2] cycloaddition was postulated.
Acknowledgment
Ping Lu and Yanguang Wang thank the National Nature Science
Foundation of China (Nos. 21032005 and 20972137) for financial
support.
Table 2
Scope of the reactiona
Cl
R1
COOEt
H
N
Et3N, C H3CN
25oC, 12h
Supplementary data
COOEt
R1
R2
N
R3
+
R2
N
R3
N3
N
3
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.147.
1
2
Entry
1 (R1)
2 (R2/R3)
3
Yieldb (%)
References and notes
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a (C6H5)
2a (C6H5/C6H5)
2b (4-MeC6H4/C6H5)
2c (4-MeOC6H4/C6H5)
2d (4-BrC6H4/C6H5)
2e (2-ClC6H4/C6H5)
2f (C6H5/4-MeC6H4)
2g (C6H5/2-ClC6H4)
2h (C6H5/4-ClC6H4)
2a
2a
2a
2a
2a
2a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
71
63
56
73
69
62
66
61
66
62
70
67
72
62
43
1a
1a
1a
1a
1a
1a
1a
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