Efficient method for the synthesis of functionalized pyrazoles by catalyst-free one-pot tandem reaction of nitroalkenes with ethyl diazoacetate

Article abstract of DOI:10.1039/b915231h

The one-pot synthesis of multisubstituted pyrazole derivatives was achieved via catalyst-free 1,3-dipolar cycloaddition of ethyl diazoacetate and nitroalkenes as the key step and elimination of the leaving group (NO ₂ or Br) followed by intramo

Full text of DOI:10.1039/b915231h

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Efficient method for the synthesis of functionalized pyrazoles by catalyst-free
one-pot tandem reaction of nitroalkenes with ethyl diazoacetate†
Jian-Wu Xie,*a,b Zheng Wang,a Wei-Jun Yang,a Li-Chun Konga and Dong-Cheng Xua
Received 27th July 2009, Accepted 12th August 2009
First published as an Advance Article on the web 28th August 2009
DOI: 10.1039/b915231h
The one-pot synthesis of multisubstituted pyrazole deriva-
tives was achieved via catalyst-free 1,3-dipolar cycloaddition
of ethyl diazoacetate and nitroalkenes as the key step and
elimination of the leaving group (NO2 or Br) followed by
intramolecular proton transfer with satisfactory yields.
Pyrazoles and their derivatives which are present in a plethora
of natural and synthetic compounds are of considerable interest
as they possess a wide range of biological properties.1 Pyrazoles
are also efficient coordinating ligands in synthesis.2 Thus, a
variety of methods are known in the literature for the synthesis
of pyrazoles,3 which include reaction between hydrazines and
1,3-difunctional substrates (e.g. 1,3-dicarbonyl compounds,4 or
ynones5) and 1,3-dipolar cycloaddition of diazo compounds to
alkenes and alkynes using Lewis acid as catalyst.6,7 Although
the 1,3-dipolar cycloaddition of electron-rich diazo compounds
to alkenes is known, to the best our knowledge, catalyst-free
intermolecular 1,3-dipolar cycloaddition of electron-deficient di-
azo compounds with electron-deficient alkenes has rarely been
reported. Thus, a straightforward and “greener” approach to
pyrazoles is interesting. Herein, we report an efficient method for
the synthesis of functionalized pyrazoles by catalyst-free one-pot
tandem reaction of nitroalkenes with ethyl diazoacetate for the
first time.
The 1,3-dipolar cycloaddition reactions have been employed as
one of the most powerful synthetic tools to provide a variety of
five membered carbocycles as well as heterocycles.8 To accelerate
these types of reactions, one possible solution to the problem
is to lower the LUMO of the dipolarophiles, e.g. by a Lewis
acid.9 However, this often resulted in the decomposition of
the diazocarbonyl compounds, leading to various well known
competing side reactions.10 The use of readily available electron-
rich ethyl diazoacetate as dipole is well-known. On the other hand,
the electron-poor nitroalkene is a good dipolarophile with a good
leave group NO2. We envisioned that the new one-pot reactions
would be possible between nitroalkenes and ethyl diazoacetate, as
outlined in Scheme 1, giving pyrazoles with multiple substitutions.
The initial investigation started with the reaction of ethyl dia-
zoacetate and a-carbethoxy-1- nitrostyrene 1a (Scheme 2). First,
we tested several bases (for example NaOC2H5, NaOH) for their
Scheme 1 Proposed one-pot tandem reaction of nitroalkenes with ethyl
diazoacetate.
Scheme 2 1,3-Dipolar cycloaddition of a-carbethoxy-1- nitrostyrene 1a
to ethyl diazoacetate.
application in these highly sensitive 1,3-dipolar cycloadditions.
But all the 1,3-dipolar cycloadditions yielded varying mixtures, no
main product was observed. To our delight, further optimization
experiments revealed a clean 1, 3-dipolar cycloaddition in the
absence of any catalyst after 72h at room temperature in THF
and the cycloaddition product 2a was isolated in moderate yield
(61% yield). As could have been expected, the pyrazole is formed
in a one-pot tandem reaction via 1, 3-dipolar cycloaddition and
spontaneous elimination of the nitro group.
Under the above optimized conditions, these findings could
be extended to the application of various other a-carbethoxy-
1-nitrostyrenes 1a-1g. And the 1,3-dipolar cycloaddition of a-
carbethoxy-1-nitrostyrenes 1 to ethyl diazoacetate proceeded
smoothly to afford the pyrazoles 2a-2g as single regioisomers.
The reaction’s scope proved to be quite broad with respect to the
a-carbethoxy-1-nitrostyrenes. Good yields were obtained in the
reactions of electron-withdrawing substituents on the aryl ring of
a-carbethoxy-1-nitrostyrenes 1 with ethyl diazoacetate (Table 1).
In addition, an electron-donating substituent on the aryl ring
of a-carbethoxy-1-nitrostyrenes 1 substrates tended to decrease
their reactivity (Table 1, entry 5). Good yields were also obtained
for heteroaryl-substituted substrates 1f (entry 6). The high re-
gioselectivity observed in these 1,3-dipolar cycloadditions is in
keeping with previous literature reports involving cycloadditions
onto electron poor olefins.11 This can be explained by both the
steric interaction of the substituents of the reactants and the
atomic orbital coefficients of the HOMO (ethyl diazoacetate)-
LUMO (nitroalkene) favored interaction expected for this type
of cycloaddition.7a,12
aDepartment of Chemistry and Life Science, Zhejiang Normal University,
Jinhua, 321004, China
bZhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces, Zhe-
jiang Normal University, Jinhua, 321004, China. E-mail: xiejw@zjnu.cn;
Fax: +86 579 82282610
† Electronic supplementary information (ESI) available: Experimental
procedures, structural proofs, and NMR spectra of the products. See DOI:
10.1039/b915231h
Coumarins are important heterocycles widely present in natural
products exhibiting a broad range of biological and therapeutic
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Table 1 1,3-Dipolar cycloaddition of a-carbethoxy-1-nitrostyrenes (1) to
Table 3 1,3-Dipolar cycloaddition of acyclic a-bromo-a-nitroalkenes to
ethyl diazoacetatea
ethyl diazoacetatea
Entry
5
R
Yieldb (%)
Entry
1
R
Yieldb (%)
1
2
3
5a
5b
5c
C6H5
p-ClC6H4
p-BrC6H4
35 (6a)
49 (6b)
42 (6c)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
C6H5
61 (2a)
75 (2b)
65 (2c)
69 (2d)
59 (2e)
51 (2f)
48 (2g)
m-ClC6H4
p-BrC6H4
m-CH3OC6H4
p-CH3C6H4
2-furanyl
p-biphenyl
a All the reactions were performed with a-bromo-a- nitroalkenes 5
(0.5 mmol, 1 equiv.) and ethyl diazoacetate (2.5 mmol, 5 equiv.) and were
stirred at room temperature in THF (2 ml) for 96h. b Isolated yields.
1g
a All the reactions were performed with a-carbethoxy-1-nitrostyrene 1
(0.5 mmol, 1 equiv.) and ethyl diazoacetate (2.5 mmol, 5 equiv.) and were
stirred at room temperature in THF (2 ml) for 72h. b Isolated yields.
Table 4 1,3-Dipolar cycloaddition of acyclic nitroalkenes to ethyl
diazoacetatea
Table 2 1,3-Dipolar cycloaddition of 3-nitrocoumarins to ethyl
diazoacetatea
Entry
7
R
Yieldb (%)
1
2
3
4
7a
7b
7c
7d
C6H5
31 (91)c (8a)
43 (95)c (8b)
29 (90)c (8c)
26 (88)c (8d)
p-ClC6H4
p-MeOC6H4
2-furanyl
Entry
3
R
Yieldb (%)
a All the reactions were performed with nitrostyrene 7 (0.5 mmol, 1 equiv.)
and ethyl diazoacetate (2.5 mmol, 5 equiv.) and were stirred at room
temperature in THF (2 ml) for 96h. b Isolated yields. c Yields in bracket
based on recovered 7.
1
2
3
4
5
3a
3b
3c
3d
3e
H
5-F
5-Cl
5-Br
4-MeO
86 (4a)
89 (4b)
91 (4c)
82 (4d)
71 (4e)
a All the reactions were performed with 3-nitrocoumarins 3 (0.5 mmol,
1 equiv.) and ethyl diazoacetate (2.5 mmol, 5 equiv.) and were stirred at
room temperature in THF (2 ml) for 48h. b Isolated yields.
possesses an a-substituent which is a better leaving group than
the nitro group. This was realized by taking a-bromonitroalkenes
5 as cycloaddition partners with ethyl diazoacetate (Table 3).
Nitropyrazole 6 was the only product isolated when 5 was reacted
with ethyl diazoacetate (entries 1-3).
activities and have been the subject intensive research.13,14 Having
succeeded in synthesizing pyrazoles 2, we considered that the
incorporation of a pyrazole heterocyclic unit into coumarins
might provide new compounds that have important biological
and pharmaceutical activities. Thus, we turned our attention
to the possible synthesis of pyrazoles using 3-nitrocoumarins
3 as dipolarophiles. To our delight, the 1,3-dipolar cycload-
dition of 3-nitrocoumarins 3 to ethyl diazoacetate proceeded
smoothly in THF at room temperature. The corresponding 1,3-
dipolar cycloaddition products were isolated with high yields
as single regioisomers. Table 2 shows that 3-nitrocoumarins
with electron-withdrawing substituents provided the cycloadducts
benzopyrano[3,4-c]pyrazoles 4b-4d in excellent yields (82-91%,
entries 2-4). On the contrary, 3-nitrocoumarins with electron-
donating substituents resulted in a slight decrease in yield (71%,
entry 5).
During our ongoing studies of the one-pot tandem reaction,
the simple nitroolefins 7a exhibited low reactivity. The 1,3-dipolar
cycloaddition of nitroalkene 7a to ethyl diazoacetate proceeded
with a clean product 8a while the yield was low (Table 4, entry 1)
under the same conditions as above. A few nitroolefins derivatives
7a-7c with different substitutions were investigated. The electronic
effect was very marginal and low yield was achieved (entries 1-4).
In conclusion, an efficient method for the synthesis of func-
tionalized pyrazoles by catalyst-free one-pot tandem reaction of
nitroalkenes with ethyl diazoacetate has been investigated. The
one-pot reaction can proceed smoothly under mild conditions
and provides pure pyrazole derivatives in moderate to excellent
yield. The reaction’s scope proved to be quite broad. Notably,
we incorporated a pyrazole heterocyclic unit into coumarins and
provided substituted benzopyrano[3,4-c]pyrazole that might have
important biological and pharmaceutical activities in the future.
This novel methodology should be of great interest for natural
product synthesis because of the mild reaction conditions.
Nitroalkenes 1 and 3 were the cycloaddition partners with ethyl
diazoacetate in the above cases. However, the pyrazole formation
involved elimination of the nitro group, a synthetically and biolog-
ically useful functionality. Therefore, it was felt that the nitro group
could be retained in the pyrazole moiety, provided the nitroalkene
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Acknowledgements
This work was made possible by the grant from Zhejiang Normal
University.
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