One-pot synthesis of pyrazole-5-carboxylates by cyclization of hydrazone 1,4-dianions with diethyl oxalate

Article abstract of DOI:10.1016/j.tetlet.2007.03.093

The cyclization of hydrazone dianions with diethyl oxalate afforded pyrazole-5-carboxylates.

Full text of DOI:10.1016/j.tetlet.2007.03.093

Tetrahedron Letters 48 (2007) 3591–3593
One-pot synthesis of pyrazole-5-carboxylates by cyclization
of hydrazone 1,4-dianions with diethyl oxalate
Tuan Thanh Dang,a Tung Thanh Danga and Peter Langera,b,
*
aInstitut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
bLeibniz-Institut fu¨r Katalyse, e. V. an der Universita¨t Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 21 December 2006; revised 13 March 2007; accepted 16 March 2007
Available online 21 March 2007
Abstract—The cyclization of hydrazone dianions with diethyl oxalate afforded pyrazole-5-carboxylates.
Ó 2007 Elsevier Ltd. All rights reserved.
Pyrazole-5-carboxylic acid derivatives are of consider-
able pharmacological relevance and also represent use-
ful synthetic building blocks in organic and medicinal
chemistry. For example, it has been recently demon-
strated that pyrazole-5-carboxylic acids represent partial
agonists for the nicotinic acid receptor.1 Pyrazolo[1,5-c]-
quinazoline-2-carboxylates, which can be regarded as
tricyclic pyrazole-5-carboxylate derivatives, act as excit-
atory amino acid antagonists (Fig. 1).2 Bis(benzo[g]ind-
azole-3-carboxamides) exhibit antiproliferative activity
against various cancer cell lines.3 General and classical
syntheses of pyrazoles rely on the 1,3-dipolar cycloaddi-
tion of diazoalkanes with alkynes and related [3+2] cyc-
loadditions.4 The cyclization of 1,3-diketones with
hydrazine also constitutes an important approach to
pyrazoles.5 In addition, the Michael reaction of hydra-
zines with a,b-unsaturated ketones is widely used.6 Pyr-
azoles have been prepared by cyclization7 of hydrazone
dianions with esters,8 acid chlorides9 and nitriles.10 Pyr-
azolines are available by cyclization of hydrazone dia-
nions with a-haloketones.11 Recently, an efficient
approach to pyrazole carboxylates from Weinreb
amides, hydrazines and propiolates has been reported.12
We reported the synthesis of 1,2-oxazines and oxaz-
olo[3,4-b]pyridazin-7-ones by cyclization of oxime and
hydrazone dianions with epibromohydrin, respec-
tively.13 We also reported the synthesis of isoxazole-5-
carboxylates by cyclization of oxime dianions with
diethyl oxalate.14 Herein, we report a new and conve-
CO2R
N
N
N
O
H
Figure 1.
nient approach to pyrazole-5-carboxylates by what
are, to the best of our knowledge, the first one-pot cycli-
zations of hydrazone dianions with diethyl oxalate.
The reaction of diethyl oxalate (2) with the dianion of
acetophenone hydrazone 1a, generated by n-butyl-
lithium (2.5 equiv), and subsequent aqueous work-up
resulted in the formation of ethyl N-ethoxycarbonyl-
4,5-dihydropyrazol-5-ol-5-carboxylate. Stirring of
a
toluene solution of the latter in the presence of p-tolu-
enesulfonic acid (PTSA) under reflux resulted in dehy-
dration and cleavage of the ester protective group to
give the pyrazole-5-carboxylate 3a (Scheme 1).15 Based
on these findings, we successfully developed a one-pot
procedure for the synthesis of 3a. Best results were ob-
tained when the reaction mixture was allowed to slowly
warm from ꢀ78 to 20 °C. The solvent was removed in
vacuo without aqueous work-up and a toluene solution
of the residue was simply refluxed in the presence of
PTSA for 10 h. Notably, the use of diethyl oxalate
proved to be important; oxalyl chloride or ethyl 2-
chloro-2-oxoacetate gave unsatisfactory results, due to
polymerization. The use of the hydrazone containing a
tosyl protective group was not successful (formation of
complex mixtures). The formation of 3a can be
Keywords: Cyclizations; Dianions; Hydrazones; Oxalic acid deriva-
tives; One-pot reactions.
*
Corresponding author. Tel.: +49 381 4986410; fax: +49 381
4986412; e-mail: peter.langer@uni-rostock.de
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.093

3592
T. T. Dang et al. / Tetrahedron Letters 48 (2007) 3591–3593
CO2Et
NH
O
CO2Et
NH
O
N
N
HN
i, ii
HN
R1
O
OEt
N
N
OEt
+
EtO
2
R2
R1
R2
O
OEt
i, ii
1a-m
2
3a-m
3n (49%)
1n
i
ii
Scheme 2. Synthesis of 3n. Reagents and conditions: (i) (1) n-BuLi
(2.5 equiv), 1 h, ꢀ78 °C; (2) 10 min, 20 °C; (3) 2, ꢀ78 ! 20 °C, 16 h;
(ii) p-TsOH (4.0 equiv), toluene, reflux, 6 h.
CO2Et
O
EtO2C
Li
N
N
N
N
Li
R2
OEt
OLi
R1
R1
R2
CO2Et
A
N
C
NH
HN
()n
O
N
2
CO2Et
OEt
NLi
O
i, ii
N
()n
OEt
R1
3o-r
1o-r
R2
O
Scheme 3. Synthesis of 3o–r. Reagents and conditions: (i) (1) n-BuLi
(2.5 equiv), 1 h, ꢀ78 °C; (2) 10 min, 20 °C; (3) 2, ꢀ78 ! 20 °C, 16 h;
(ii) concd H2SO4, toluene, reflux, 8 h.
B
Scheme 1. Synthesis of pyrazole-5-carboxylates 3a–m. Reagents and
conditions: (i) (1) n-BuLi (2.5 equiv), THF, 45 min, ꢀ78 °C; (2) 15 min,
20 °C; (3) 2, ꢀ78 ! 20 °C, 16 h; (ii) p-TsOH (4.0 equiv), toluene,
reflux, 10 h.
Table 2. Products and yields
3
n
% (3)a
explained by attack of the carbon atom of the dianion
(intermediate A) onto the ester group to give intermedi-
ate B, subsequent cyclization by attack of the nitrogen
atom onto the keto group to give intermediate C and
subsequent aromatization (Scheme 1).
o
p
q
r
1
2
3
7
43
40
38
31
a Yields of isolated products.
The one-pot procedure was successfully applied to the
synthesis of the aryl-substituted pyrazole-5-carboxylates
3a–j which were isolated in moderate to good yields
(Table 1). The cyclization of 2 with the dilithiated hydra-
zone of p-nitroacetophenone was unsuccessful. The
cyclization of diethyl oxalate with the dianions of
hydrazones 1k and 1l, prepared from 3-methylbutane-
2-one and pentane-2-one, afforded alkyl-substituted
pyrazole-5-carboxylates 3k and 3l in good yields, respec-
tively. Pyrazole-5-carboxylate 3m, containing a phenyl
and a methyl substituent, was prepared by cyclization
of 2 with hydrazone 1m (available from propiophe-
none). The structure of 3b was independently confirmed
by crystal structure analysis.16
The cyclization of the dianion of tetralone hydrazone 1n
with diethyl oxalate afforded the tricyclic pyrazole 3n
(Scheme 2).
The cyclization of diethyl oxalate with the dianion of
cyclohexanone hydrazone gave 4,5,6,7-tetrahydro-1H-
indazole 3o (Scheme 3, Table 2). Likewise, 5,7-, 5,8-
and 5,12-bicyclic pyrazoles 3p–r were prepared from
the corresponding hydrazones 1p–r. The reaction of
diethyl oxalate with the hydrazones of cyclopentanone
and N-Boc-4-piperidone resulted in the formation of
complex mixtures.
Table 1. Yields of 3a–m
3
R1
R2
% (3)a
a
b
c
d
e
f
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
Me
53
57
61
41
45
41
45
38
42
45
69
72
62
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-(MeO)C6H4
2-(MeO)C6H4
1-Naphthyl
2-Naphthyl
4-ClC6H4
4-FC6H4
i-Pr
In conclusion, we have reported a convenient and regio-
selective synthesis of pyrazole-5-carboxylates by cycliza-
tion of hydrazone dianions with diethyl oxalate.
g
h
i
j
Acknowledgement
k
l
n-Pr
C6H5
Financial support from the Ministry of Education and
Training of Vietnam (scholarships for T.T.D. and
T.T.D.) is gratefully acknowledged.
m
a Yields of isolated products.

T. T. Dang et al. / Tetrahedron Letters 48 (2007) 3591–3593
3593
13. Dang, T. T.; Albrecht, U.; Gerwien, K.; Siebert, M.;
Langer, P. J. Org. Chem. 2006, 71, 2293.
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15. Typical procedure for the synthesis of pyrazole-5-carboxy-
lates 3: To a THF solution of hydrazone 1b (2.0 mmol,
0.46 g) was added n-butyllithium (2 mL, 2.5 M solution in
hexane) at ꢀ78 °C. After stirring for 45 min at ꢀ78 °C, the
mixture was stirred for 15 min at 20 °C and, subsequently,
diethyloxalate (2.2 mmol) was added at ꢀ78 °C. After
warming of the reaction mixture to 20 °C within 16 h, the
solvent (THF) was removed in vacuo. To the residue were
added p-TsOH (8.0 mmol, 1.52 g) and 30 mL of toluene.
The mixture was stirred under reflux for 8 h. After cooling
to 20 °C, a saturated solution (20 mL) of NaHCO3 was
added and the mixture was stirred for 15 min at 20 °C. The
combined organic layers were dried (Na2SO4), filtered and
the solvent of the filtrate was removed in vacuo. The
residue was purified by chromatography (silica gel, n-
hexane/EtOAc = 3:1) to give 3b (57%, 262 mg) as a
colourless solid, mp 145–147 °C. 1H NMR (300 MHz,
CDCl3): d = 1.21 (t, 3J = 7.2 Hz, 3H, OCH2CH3), 2.37 (s,
`
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3
3H, CH3), 4.25 (q, J = 7.2 Hz, 2H, OCH2CH3), 6.95 (s,
1H, CH), 7.18 (d, 2H, ArH), 7.59 (d, 1H, ArH), 13C NMR
(75 MHz, CDCl3): d = 12.08 (CH2CH3), 19.34 (CH3),
58.84 (OCH2CH3), 102.7 (CH), 123.52, 123.52, 127.48,
127.48 (CH, ArH), 125.06, 136.47 (2C, Ar), 139.18, 145.12
(C, pyrazole), 159.30 (CO). IR (KBr, cmꢀ1): m ¼ 3215 (w),
~
2922 (w), 1728 (s), 1412 (w), 1242 (s), 1131 (s), 986 (m), 816
(m), 782 (w), 506 (w). MS (EI, 70 eV): m/z (%) = 230 (M+,
100), 185 (13), 158 (9), 128 (86), 131 (8), 69 (21), 57 (8).
HRMS (EI, 70 eV): calcd for C13H14O2N2 (M+): 230.1139;
found, 230.1134.
16. Dang, T. T.; Dang, T. T.; Go¨rls, H.; Langer, P.,
unpublished results.