New one-pot synthesis of pyrazole-5-carboxylates by 1,3-dipole cycloadditions of ethyl diazoacetate with α-methylene carbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2009.07.152

A facile one-pot procedure for the synthesis of pyrazole-5-carboxylates by 1,3-dipolar cycloaddition of ethyl diazoacetate is described. Cycloadditions with α-methylene carbonyl compounds utilizing 1,8-diazabicyclo[5.4.0]undec-7-ene as base and acetonitri

Full text of DOI:10.1016/j.tetlet.2009.07.152

Tetrahedron Letters 50 (2009) 5978–5980
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Tetrahedron Letters
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New one-pot synthesis of pyrazole-5-carboxylates by 1,3-dipole
cycloadditions of ethyl diazoacetate with a-methylene carbonyl compounds
Antimo Gioiello a, Asiya Khamidullina a, Maria Carmela Fulco a, Francesco Venturoni a, Simon Zlotsky b,
Roberto Pellicciari a,
*
a Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Perugia 06123, Italy
b Department of Chemistry, Ufa State Technical University, Ufa, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile one-pot procedure for the synthesis of pyrazole-5-carboxylates by 1,3-dipolar cycloaddition of
Received 18 June 2009
Revised 17 July 2009
Accepted 27 July 2009
Available online 6 August 2009
ethyl diazoacetate is described. Cycloadditions with
a-methylene carbonyl compounds utilizing 1,8-
diazabicyclo[5.4.0]undec-7-ene as base and acetonitrile as solvent provide pyrazoles with excellent reg-
ioselectivity and good yields. The reaction was found to proceed by a domino 1,3-dipolar cycloaddition-
water elimination.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazole
Ethyl diazoacetate
1,3-Dipolar cycloaddition
The discovery of new methods for the synthesis of pyrazoles1
continues to attract a great deal of attention due to their extensive
utilization in the pharmaceutical and agrochemical fields.2 The
pyrazole nucleus, in particular, is a ‘privileged’ structure represent-
ing the common structural framework of a great number of com-
pounds endowed with hypoglycemic,2a sedative-hypnotic,2b
antiinflammatory,2c analgesic,2d antimicrobial,2e as well as insecti-
cides properties.2f
zole-5-carboxylates. This can be explained by considering the en-
ergy gap and similarity of the interacting HOMO and LUMO
orbitals of both dipolarophile and dipole.14 Indeed, in agreement
with the known influence of substituents on the orbital energy lev-
els,15 the introduction of electron-withdrawing groups in position
alpha to the diazo moiety lowers the HOMO energy thus decreas-
ing the cycloaddition rate. Possible solutions to this problem rely in
the use of high temperature, microwave heating, or the presence of
Lewis acids,12 although the upfront decomposition of the diazo
moiety under these conditions, with the consequent formation of
a complex array of insertion, cyclopropanation or dimerizzation
side products, has greatly limited the synthetic usefulness of this
approach.
The most widely used synthetic route to pyrazoles involves the
reaction between 1,3-dicarbonyl compounds and hydrazines,3
a
methodology somehow limited by the harsh reaction conditions
and by the often laborious procedures required for the synthesis
of the precursors. Pyrazole derivatives have also been prepared
by cyclization4 of hydrazone dianions with esters,5 acid chlorides,6
Given the potential synthetic utility of the ‘diazocarbonyl route’
to 5-carboxyethyl-pyrazoles, we have investigated ways to im-
prove it. It has been the purpose of the current study, in particular,
to explore the hitherto unreported reaction of EDA (1) with
nitriles,7 and by cyclization of hydrazone dianions with
a-haloke-
tones.8 Recently, a novel and efficient method for the synthesis
of pyrazole carboxylates starting from Weinreb amides, hydrazines
and propiolates has also been described.9
a-methylene carbonyl precursors (Scheme 1).
An alternative largely explored method to pyrazole derivatives
involves the inter- and intramolecular cycloadditions of diazo com-
pounds to alkenes.10–13 It is well known, in this regard, that while
the corresponding pyrazole derivatives are obtained in good yield
with electron-rich diazo compounds, such as diazomethane,10,11
analogous reactions with electron-deficient diazocompounds, such
as ethyl diazoacetate (EDA, 1), fail to give the corresponding pyra-
While initial attempts to carry out the [3+2] cycloaddition reac-
tion between EDA (1) and 2-phenylacetophenone (2a), chosen as
dipolarophile, in a neutral medium or in the presence of Lewis
R1
N
R2
N
R2
CO2Et
R1
CO2Et
O
N2
R1
EtO2C
+
+
R2
N
N
H
4a-f
EDA (1)
H
2a-f
3a-f
* Corresponding author. Tel.: +39 075 5855120; fax: +39 075 5855124.
E-mail address: rp@unipg.it (R. Pellicciari).
Scheme 1. Synthesis of pyrazole-5-carboxylates from EDA (1).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.152

A. Gioiello et al. / Tetrahedron Letters 50 (2009) 5978–5980
5979
Table 2
acids led to unsatisfactory results, we were pleasantly surprised by
1,3-Dipolar cycloaddition of EDA (1) with a-methylene carbonyl compounds 2
the results obtained when the reaction was carried out in basic
conditions (Table 1).
Educt
R1
R2
Isolated products (%yield)a
In particular, when EDA (1) was reacted with 2a in the presence
of 1,7 equiv of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in aceto-
nitrile under argon atmosphere at room temperature for 90’, ethyl
3,4-diphenyl-1H-pyrazole-5-carboxylate (3a) was obtained in 65%
yield after flash chromatography (Table 1, entry 4). Interestingly, a
significant shortening of the reaction time was achieved when the
reaction mixture was submitted to ultrasound and microwave
heating (Table 1, entries 8 and 9), while lowering DBU equivalents
decreased the reaction yields (Table 1, entries 5–7).
2a
2b
2c
2d
2e
2f
Ph
Ph
oMeO-Ph
oF-Ph
CH3
Ph
3a (65%)
CH3
CH3
CH3
Ph
3b18 (54%) 5 (8%)
3c (88%)
3d (60%)
—
3f (9%) 6 (52%)
Ph
H
a
Calculated after purification by flash chromatography on silica gel.
Encouraged by these results, we have then extended this newly
developed methodology to a variety of substituted
a-methylene
O
O
O
OH
MeI
MeI
carbonyl derivatives.16 As shown in Table 2, the reaction could be
applied to a reasonable range of aryl-propanones and provides
the corresponding pyrazole derivatives in fairly good yield with
excellent regioselectivities. In all cases, pyrazoles 3a–d were
formed as exclusive products of cycloaddition, with the exception
of phenylacetone (2b) which afforded 5 (Fig. 1) as by-products in
8% yield (Table 2, educt 2b). Only 1-phenyl-propan-1-one (2e)
failed to give the desired product of cycloaddition. This difference
of reactivity can be explained with the diverse pKa values of the
proton in position alpha to the carbonyl moiety. Indeed, the cyclo-
addition reaction proceeds with the initial abstraction of such pro-
ton and, as a consequence, low pKa values (acid proton) should
favor the reactivity of the carbonyl compounds. As a confirmation
of this hypothesis, preliminary ab initio studies performed using
the Jaguar module of Maestro have indicated significant lower
pKa values for the propan-2-ones 2a–b (pKa2a = 18.7, pKa2b = 19.6)
with respect to the propan-1-one 2e (pKa = 25.6).17
We were quite intrigued by the results obtained when EDA (1)
is reacted with phenyl-acetaldehyde (2f) (Table 2, educt 2f). In this
case, ethyl 3-phenyl-4-hydroxy-1H-pyrazole-5-carboxylate (6,
Fig. 1) was formed as major product of reaction (52% yield), while
ethyl 3-phenyl-1H-pyrazole-5-carboxylate (3f) was isolated in 9%
yield.
The regiochemistry of the products was assigned based on the
literature19 as well as on NMR analysis. Pyrazoles 5 and 6 were
characterized by additional NMR NOE analysis of the correspond-
ing methylated products 7 and 8, obtained by reaction with iodo-
methane in THF at room temperature (Fig. 1).
N
HN
N
N
CO2Et
CO2Et
CO2Et
N
CO2Et
N
N
N
H
6
5
7
8
A'
A'
C
H3C
CH
C
CH3
O
C
O
HA'
CH3
O
N
H2A
C
B
N
N
N
H2
C
A
O
CH3
B
O
7
8
Figure 1. Synthesis and diagnostic 1H NMR NOE for 6 and 7.
The formation of pyrazoles 3a–d, f can be explained based on the
plausible mechanism20 illustrated in Scheme 2. The reaction pro-
ceeds by the initial 1,3-dipolar cycloaddition between the diazo di-
pole 1 and the enolate ions followed by a spontaneous dehydration
of the pyrazolinic intermediate 9. In addition, when phenyl-acetal-
dehyde (2f) is used as dipolarophile, hydrogen elimination may oc-
cur to afford the corresponding 4-hydroxy-pyrazole derivative 6.
In conclusion, we have described a simple and efficient DBU-
catalyzed [3+2] cycloaddition of EDA (1) and established a new
one-pot route to obtain pyrazoles in good yields using mild reac-
tion conditions. Preliminary mechanistic studies support the pro-
posed mechanism, and the results of additional investigations
that are ongoing in our laboratory will be reported in due course.
Table 1
Optimization of reaction conditions for cycloaddition between EDA (1) and 2-phenylacetophenone (2a)
Entry
Base (equiv)
Temp
Time
GC yielda
Isolated yieldb
1
2
3
Et3N (1.7)
Pyridine (1.7)
NaOH (1.7)
rt
rt
rt
900
900
900
—
—
45%
—
—
22%
O
1a, base
CH3CN
- H2O
HN
N
CO2Et
CO2Et
N
N
H
2a
3a
4
5
6
7
8
9
DBU (1.7)
DBU (1.5)
DBU (1.1)
DBU (0.5)
DBU (1.7)
DBU (1.7)
rt
rt
rt
rt
900
100%
63%
43%
27%
100%
100%
65%
ndc
ndc
ndc
ndc
ndc
1200
1200
1200
600
40 °C (US)
MW
400
a
b
c
Determined by GC analysis of the crude reaction mixture.
Calculated after purification by silica gel flash chromatography.
nd: not determined.

5980
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DBU
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O
-H2O
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-H2
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Scheme 2. Proposed mechanism for 5-carboxyethyl-pyrazoles formation.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.152.
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(11.5 mmol) were added to a magnetically stirred solution of the
a-methylene
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*
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deprotonated species were computed using gas phase geometry
approximations. The ultrafine accuracy level for the SCF convergence was
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