Straightforward and regiospecific synthesis of pyrazole-5-carboxylates from unsymmetrical enaminodiketones

Article abstract of DOI:10.1055/s-2008-1078482

A series of 4-substituted 1H-pyrazole-5-carboxylates was prepared from the cyclocondensation reaction of unsymmetrical enaminodiketones [RC(O)C(=CNMe ₂)C(O)CO₂Et, where R = Ph, 4-MeOC₆H ₄, 4-ClC₆H₄, 4-FC₆H₄, 4-O₂NC₆H₄, thien-2-yl, benzofur-2-yl, CCl ₃ and CF₃] with tert-butylhydrazine hydrochloride or carboxymethylhydrazine. The compounds were obtained regiospecifically and in good to excellent yields (73-94%). In addition, 5-carboxyethyl-1-(1,1- dimethylethyl)-1H-pyrazole-4-carboxylic acid was synthesized from regiospecific conversion of ethyl 4-(2,2,2-trichloroacetyl)-1-(1,1-dimethylethyl)- 1H-pyrazole-5-carboxylate. The carbonyl substitution reaction was regiospecific for the trichloroacetyl group and did not affect the ester group. Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1078482

LETTER
1673
Straightforward and Regiospecific Synthesis of Pyrazole-5-carboxylates from
Unsymmetrical Enaminodiketones
S
traightforwar
e
dand
R
egi
r
ospecific
n
Synthesis
o
a
f
Pyrazole
-
n
5-carboxylat
d
es a A. Rosa, Pablo Machado, Pâmela S. Vargas, Helio G. Bonacorso, Nilo Zanatta, Marcos A. P. Martins*
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria,
97.105-900 Santa Maria, RS, Brazil
Fax +55(55)32208031; E-mail: mmartins@base.ufsm.br
Received 26 January 2008
or crystallization in the isolation procedure, is highly de-
Abstract: A series of 4-substituted 1H-pyrazole-5-carboxylates
was prepared from the cyclocondensation reaction of unsymmetri-
cal enaminodiketones [RC(O)C(=CNMe2)C(O)CO2Et, where
R = Ph, 4-MeOC6H4, 4-ClC6H4, 4-FC6H4, 4-O2NC6H4, thien-2-yl,
sirable from both an environmental and an economic per-
spective. Data from the literature have demonstrated the
application of enaminodiketones, compounds analogous
benzofur-2-yl, CCl3 and CF3] with tert-butylhydrazine hydrochlo- to the 1,3-dicarbonyl, as interesting building blocks for
the synthesis of heterocycles such as pyrazoles7–10 and py-
ride or carboxymethylhydrazine. The compounds were obtained re-
rimidines.11–13 However, only few examples have been re-
giospecifically and in good to excellent yields (73–94%). In
addition, 5-carboxyethyl-1-(1,1-dimethylethyl)-1H-pyrazole-4-car-
ported in the literature dealing with the use of such
boxylic acid was synthesized from regiospecific conversion of ethyl
building blocks for the regiospecific construction of pyra-
4-(2,2,2-trichloroacetyl)-1-(1,1-dimethylethyl)-1H-pyrazole-5-car-
zoles. Hojo and co-workers reported the reaction of di-
alkylamino methylenehexafluoroacetylacetone with
methylhydrazine, tert-butylhydrazine and phenylhydra-
zine. The reaction with methylhydrazine and tert-butylhy-
drazine resulted in the formation of a sole regioisomer
while the reaction with phenylhydrazine led to a mixture
of regioisomers.7 On the other hand, Kascheres and co-
workers9 showed the reactivity of a-acylenamino ketones
in reactions with hydrazines under different conditions. In
most of the cases, regardless of the solvent and hydrazine
used, the products were obtained as a mixture of isomers
and the presence of side products was observed. In addi-
tion, Mirand and co-workers10 reported the reaction of tri-
fluoromethylated enaminodiketones with methyl-
hydrazine and phenylhydrazine carried out in MeCN. The
result was a mixture of two regioisomers or a mixture of
three regioisomers.
boxylate. The carbonyl substitution reaction was regiospecific for
the trichloroacetyl group and did not affect the ester group.
Key words: enones, cyclizations, regioselectivity, pyrazoles,
heterocycles
The synthesis of pyrazole has been the subject of consis-
tent interest because of the wide applications for such het-
erocycles in the pharmaceutical and agrochemical
industries.1 Among the range of properties, compounds
containing a pyrazole scaffold have been shown to exhibit
HIV-1 reverse transcriptase and IL-1 synthesis inhibition,
as well as antihyperglycemic, antibacterial, sedative-hyp-
notic, anti-inflammatory, antipyretic and analgesic activi-
ties.2 More specifically, pyrazole-5-carboxylic acid
derivatives are compounds of considerable pharmacolog-
ical relevance3 and also represent useful synthetic build-
ing blocks in organic chemistry.4 The synthesis of
pyrazole derivatives has been well explored using the so-
called [3+2]-atom fragments, where b-diketones or a,b-
unsaturated ketones are used as 3-atom building blocks
and hydrazines as the 2-atom fragment. In the last few de-
cades, our research group has reported the general synthe-
sis of 1,1,1-trihalo-4-alkoxy-3-alken-2-ones, a 3-atom
building block, and demonstrated their usefulness in het-
erocyclic preparations.5 However, with unsymmetrical
1,3-dicarbonyl substrates this method often suffers from
the formation of a regioisomeric mixture of pyrazoles
with generally poor selectivity.6 Moreover, pyrazole re-
gioisomers can often be difficult to separate by chroma-
tography and repeated crystallization may be necessary to
remove the undesired regioisomer. Thus, development of
effective and efficient methods for synthesis of such com-
pounds, which avoid the use of column chromatography
We have reported recently the synthesis of a variety of
enaminodiketones 1 from C-acylation of enaminones with
ethyl oxalyl chloride.14,15 These precursors are highly
attractive for the construction of new heterocycle deriva-
tives. Therefore, we are interested in the reaction of such
compounds with hydrazines in a preliminary study on the
different electrophilic centers present in the enaminodike-
tone system (1, Scheme 1) in the attempt to find a straight-
forward and regiospecific method for the synthesis of
pyrazole derivatives.
We began our studies with the reaction of enaminodike-
tone 1 with tert-butylhydrazine hydrochloride carried out
in ethanol with the aim of determining the relative reactiv-
ity of the four electrophilic centers during a nucleophilic
attack. Surprisingly, from the preliminary results it was
observed that 1-tert-butylpyrazole 2 was obtained as the
sole regioisomer (A, Scheme 1).
The product identified can be explained by an addition–
elimination reaction, in which the more reactive amino
group of the hydrazine attacks the b-carbon atom of com-
SYNLETT 2008, No. 11, pp 1673–1678
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1078482; Art ID: S01108ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
8

1674
F. A. Rosa et al.
LETTER
R
N
EtO2C
N
R1
A
O
O
δ+
OEt
O
δ+
R
δ+
EtO
O
O
H2NNHR1
δ+
Me2N
N
1
R
N
R1
B
R = CX3, aryl and heteroaryl
R(CO
Me2N
HO
Figure 1 ORTEP diagram of 1-tert-butylpyrazole 2h
N
N
(R)EtO2C
Table 1 Regiospecific Synthesis of 4-Substituted 1-tert-Butylpyra-
zole-5-carboxylates 2a–i from the Reaction of Enaminodiketones
1a–i with tert-Butylhydrazine Hydrochloride
R1
C
O
O
O
R
Scheme 1 Enaminodiketone 1 and representation of possible com-
pounds (A, B, C) from reaction with hydrazines
OEt
EtOH
R
H2NNHCMe3⋅HCl
+
N
EtO2C
reflux, 1 h
O
N
Me2N
1
pound 1 to form adduct I, which undergoes an elimination
of dimethylamine to form the b-hydrazino unsaturated ke-
tone II (Scheme 2). Then, the subsequent heterocycliza-
tion was attained from the attack of the second amino
group of hydrazine to the carbonylic carbon neighbor to
the ester group. This attack suggests that the intermediate
b-hydrazino unsaturated ketone II presents the RCO
group trans to the hydrazino group9 that seems to be ster-
ically less hindered in relation to the tert-butyl group. The
structure of 1-tert-butylpyrazole-5-carboxylates 2 was de-
2
Entry Enaminodiketone R
Pyrazole Yield (%)a
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
Ph
2a
2b
2c
2d
2e
2f
77
90
73
83
91
79
86
78
76
4-MeOC6H4
4-ClC6H4
4-FC6H4
4-O2NC6H4
thien-2-yl
benzofur-2-yl
CCl3
1
termined by H NMR and 13C NMR spectroscopy, GC–
MS and elemental analysis and confirmed by crystallo-
graphic data (compound 2h, Figure 1).16,17
1g
1h
1i
2g
2h
2i
OE
OEt
R
R
H NNHCMe ⋅HCl
2 3
+
O
O
(Me)2N
NHNHCM
Me2N
CF3
1
I
a Yield of isolated product.
– HNM
it is important to mention that an acyl group at the 4-posi-
tion and a carboxylic acid ethyl ester at the 5-position
were present in the structure of the obtained multifunc-
tionalized products 2.
O
O
R
O
R
cyclization
– H2O
OEt
N
EtO2C
N
O
NHNHCM
In the second part of this work, we performed the reaction
of enaminodiketones 1a–i with carboxymethylhydrazine.
This reaction was carried out in ethanol at room tempera-
ture for one hour. The reaction was regiospecific and fur-
nished only the regioisomer A (Scheme 1). The synthesis
of these products also can be explained by an addition–
elimination reaction as shown in Scheme 2. However, the
product was not obtained as carboxymethylpyrazole, but
in the form of 1H-pyrazoles 3 even under mild conditions
(Table 2). Even so, this result was interesting considering
that the reaction of compound 1 with monohydrate hydra-
zine led to a mixture of 1H-pyrazole regioisomers. The re-
action of enaminodiketones 1a–i with carboxy-
2
II (Z)-isomer
Scheme 2 Formation of pyrazoles 2 by an addition–elimination
reaction
The reaction of enaminodiketones 1a–i with tert-butylhy-
drazine hydrochloride was regiospecific and afforded a
series of pyrazoles in good to excellent yields (73–91%),
independently of the structure of the substituent R present
in the enaminodiketone (Table 1, entries 1–9). In addition,
Synlett 2008, No. 11, 1673–1678 © Thieme Stuttgart · New York

LETTER
Straightforward and Regiospecific Synthesis of Pyrazole-5-carboxylates
1675
methylhydrazine was regiospecific and gave good to ex- We also examined the conversion of pyrazole 2h to pyra-
cellent yields (74–94%), for all substituents present in the zole carboxylic acid7 and the product obtained was pyra-
enaminodiketone (Table 2, entries 1–7). The exceptions zole-4-carboxylic acid 420 in 76% yield, where the
were the reaction of 1h and 1i, where the respective prod- carbonyl substitution reaction was regiospecific for the
ucts were not identified (Table 2, entries 8 and 9). The trichloroacetyl group and did not affect the ester group
pyrazoles 3a–g (Table 2, entries 1–7) were obtained with (Scheme 3).
a high degree of purity and without an additional step of
purification.
O
O
Cl3C
HO
Table 2 Regiospecific Synthesis of 4-Substituted 1H-Pyrazole-5-
carboxylates 3a–g from the Reaction of Enaminodiketones 1a–i with
Carboxymethylhydrazine
KOH/H2O
N
EtO2C
N
EtOH, r.t., 4 h
EtO2C
N
N
O
O
O
2h
4
R
OEt
EtOH, r.t., 1 h
R
H NNHCO Me
2 2
+
Scheme 3 Synthesis of pyrazole-4,5-dicarboxylic acid derivative 4
from the regiospecific conversion of the COCCl3 group into carboxy-
lic group.
N
EtO2C
O
N
H
3
(Me)2N
1
In summary, we have developed a straightforward and re-
giospecific method for the synthesis of new pyrazole car-
Entry Enaminodiketone R
Pyrazole Yield (%)a
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
Ph
3a
3b
3c
3d
3e
3f
75
85
86
88
94
74
89
–
boxylic
acid
derivatives
from
unsymmetrical
enaminodiketones containing different reactivity centers.
In addition, we demonstrated that the COCCl3 group can
be transformed into the carboxylic acid moiety regiospe-
cifically. Moreover, this new class of pyrazoles comprises
versatile precursors for the synthesis of other heterocyclic
compounds such as pyrazolopyridazinone derivatives and
the carboxylic acid ethyl ester moiety at the 5-position can
be easily transformed into other useful functionalities of
interest.
4-MeOC6H4
4-ClC6H4
4-FC6H4
4-O2NC6H4
thien-2-yl
benzofur-2-yl
CCl3
1g
1h
1i
3g
b
–
Acknowledgment
b
CF3
–
–
The authors thank the Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq/PADCT) and the Fundação de
Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS)
for financial support. The fellowships from CNPq, CAPES and
FAPERGS are also acknowledged.
a Yield of isolated product.
b Product was not identified.
On the other hand, preliminary results have shown that the
reaction of compound 1 with phenylhydrazine and with
monohydrate hydrazine led to a mixture of compounds A
and B (ratio 3:1 and 2:1, respectively; Scheme 1), which
were difficult to separate. The structures of compounds 3
were also determined by 1H NMR and 13C NMR spectros-
copy, GC–MS and elemental analysis.18 Moreover, X-ray
crystallography data confirmed the structure of compound
3d (Figure 2).19
References and Notes
(1) (a) Elguero, J. In Comprehensive Heterocyclic Chemistry II,
Vol. 3; Katritzky, A. R.; Rees, C. W.; Scriven, E. F., Eds.;
Pergamon: Oxford, 1996. (b) Katritzky, A. R.; Wang, M.;
Zhang, S.; Voronkov, M. V. J. Org. Chem. 2001, 66, 6787.
(2) (a) Kees, K. L.; Fitzgerald, J. J. Jr.; Steiner, K. E.; Mattes, J.
F.; Mihan, B.; Tosi, T.; Mondoro, D.; McCaleb, M. L. J.
Med. Chem. 1996, 39, 3920. (b) Genin, M. J.; Biles, C.;
Keiser, B. J.; Poppe, S. M.; Swaney, S. M.; Tarpley, W. G.;
Yagi, Y.; Romero, D. L. J. Med. Chem. 2000, 43, 1034.
(c) Manfredini, S.; Bazzanini, R.; Baralgi, P. G.; Guarneri,
M.; Simoni, D.; Marongiu, M. E.; Pani, A.; Tramontano, E.;
Colla, P. L. J. Med. Chem. 1992, 35, 917. (d) Jungheim, L.
N. Tetrahedron Lett. 1989, 30, 1889. (e) Dannhardt, G.;
Laufer, S. Curr. Med. Chem. 2000, 7, 1101. (f) Penning, T.
D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P.
W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.;
Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.;
Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S.
A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen,
Figure 2 ORTEP diagram of 1H-pyrazole 3d
Synlett 2008, No. 11, 1673–1678 © Thieme Stuttgart · New York

1676
F. A. Rosa et al.
LETTER
A. W.; Zangh, Y. Y.; Isakson, P. C. J. Med. Chem. 1997, 40,
1347. (g) Sauzem, P. D.; Machado, P.; Rubin, M. A.;
Sant’Anna, G. S.; Faber, H. B.; Souza, A. H.; Mello, C. F.;
Beck, P.; Burrow, R. A.; Bonacorso, H. G.; Zanatta, N.;
Martins, M. A. P. Eur. J. Med. Chem. 2008, in press.
carboxylate (2a): yield: 1.15 g (77%); oil. 1H NMR (200
MHz, CDCl3): d = 1.34 (t, 3 H, OCMe), 1.69 (s, 9 H, t-Bu),
4.37 (q, 2 H, OCH2), 7.51–7.84 (m, 5 H, Ph), 7.71 (s, 1 H,
H3). 13C NMR (50 MHz, CDCl3): d = 13.5 (Me), 29.6 (3 ×
Me), 62.6 (OCH2), 62.9 [NC(CH)3], 122.4 (C4), 128.4,
128.9, 132.4, 138.8 (Ph), 136.9 (C5), 138.3 (C3), 163.0
(CO2), 188.5 (CO). MS (EI, 70 eV): m/z (%) = 300(16) [M+],
245 (49), 199 (100), 167 (72), 139 (49), 121 (14), 105 (37),
77 (38). Anal. Calcd for C17H20N2O3: C, 67.98; H, 6.71; N,
9.33. Found: C, 67.93; H, 6.62; N, 9.15.
Ethyl 4-(4-Methoxybenzoyl)-1-(1,1-dimethylethyl)-1H-
pyrazole-5-carboxylate (2b): yield: 1.48 g (90%); oil. 1H
NMR (200 MHz, CDCl3): d = 1.33 (t, 3 H, OCMe), 1.69 (s,
9 H, t-Bu), 3.87 (s, 3 H, OMe), 4.37 (q, 2 H, OCH2), 6.96–
7.86 (m, 4 H, C6H4), 7.70 (s, 1 H, H3). 13C NMR (50 MHz,
CDCl3): d = 13.5 (Me), 29.6 (3 × Me), 55.4 (OMe), 62.6
(OCH2), 62.8 [NC(CH)3], 113.6, 131.0, 131.3, 163.1 (C6H4),
122.9 (C4), 136.7 (C5), 138.4 (C3), 163.1 (CO2), 187.2
(CO). MS (EI, 70 eV): m/z (%) = 330 (45) [M+], 274 (32),
230 (100), 201 (26), 167 (20), 139 (29), 135 (54), 107 (8), 77
(14). Anal. Calcd for C18H22N2O4: C, 65.44; H, 6.71; N, 8.48.
Found: C, 65.52; H, 6.65; N, 8.31.
(3) van Herck, T.; Brussee, J.; van den Nieuwendijk, A. M. C.
H.; van der Klein, P. A. M.; Ijzerman, A. P.; Stanneck, C.;
Burmeister, A.; Lorenzen, A. J. Med. Chem. 2003, 46, 3945.
(4) Varano, F.; Catarzi, D.; Colotta, V.; Filacchioni, G.; Galli,
A.; Costagli, C.; Carlà, V. J. Med. Chem. 2002, 45, 1035.
(5) (a) Martins, M. A. P.; Cunico, W.; Pereira, C. M. P.;
Sinhorin, A. P.; Flores, A. F. C.; Bonacorso, H. G.; Zanatta,
N. C. Org. Synth. 2004, 1, 391; and references therein.
(b) Martins, M. A. P.; Pereira, C. M. P.; Moura, S.; Fiss, G.
F.; Frizzo, C. P.; Emmerich, D. J.; Zanatta, N.; Bonacorso,
H. G. ARKIVOC 2006, (xiii), 187.
(6) Gilchrist, T. L. Heterocyclic Chemistry, 2nd ed.; Wiley:
New York, 1992, Chap. 8, 294.
(7) Okada, E.; Masuda, R.; Hojo, M. Heterocycl. Chem. 1992,
34, 791.
(8) Soufyane, M.; Mirand, C.; Lévy, J. Tetrahedron Lett. 1993,
34, 7737.
(9) Negri, G.; Kascheres, C. J. Heterocycl. Chem. 2001, 38, 109.
(10) Touzot, A.; Soufyane, M.; Berber, H.; Toupet, L.; Mirand,
C. J. Fluorine Chem. 2004, 125, 1299.
(11) Soufyane, M.; van den Brock, S.; Khamliche, L.; Mirand, C.
Heterocycl. Chem. 1999, 51, 2445.
Ethyl 4-(4-Chlorobenzoyl)-1-(1,1-dimethylethyl)-1H-
pyrazole-5-carboxylate (2c): yield: 1.22 g (73%); mp 54–
56 °C. 1H NMR (200 MHz, CDCl3): d = 1.35 (t, 3 H, OCMe),
1.69 (s, 9 H, t-Bu), 4.39 (q, 2 H, OCH2), 7.46–7.79 (m, 4 H,
C6H4), 7.67 (s, 1 H, H3). 13C NMR (50 MHz, CDCl3):
d = 13.6 (Me), 29.6 (3 × Me), 62.8 (OCH2), 63.1 [NC(CH)3],
122.1 (C4), 128.7, 130.3, 138.3, 138.6 (C6H4), 131.7 (C5),
136.6 (C3), 162.9 (CO2), 187.2 (CO). MS (EI, 70 eV): m/z
(%) = 334 (15) [M+], 279 (46), 233 (89), 199 (70), 167 (76),
139 (100), 111 (28). Anal. Calcd for C17H19ClN2O3: C,
60.99; H, 5.72; N, 8.37. Found: C, 60.83; H, 5.57; N, 8.13.
Ethyl 4-(4-Fluorobenzoyl)-1-(1,1-dimethylethyl)-1H-
pyrazole-5-carboxylate (2d): yield: 1.32 g (83%); mp 53–
55 °C. 1H NMR (200 MHz, CDCl3): d = 1.35 (t, 3 H, OCMe),
1.69 (s, 9 H, t-Bu), 4.40 (q, 2 H, OCH2), 7.16–7.88 (m, 4 H,
C6H4), 7.68 (s, 1 H, H3). 13C NMR (50 MHz, CDCl3): d =
13.6 (Me), 29.6 (3 × Me), 62.7 (OCH2), 63.0 [NC(CH)3],
115.5 (d, 2J = 21 Hz, C6H4), 122.3 (C4), 131.5 (d, 3J = 9 Hz,
C6H4), 134.6 (d, 4J = 3 Hz, C6H4), 136.9 (C5), 138.6 (C3),
162.9 (CO2), 165.3 (d, 1J = 254 Hz, C6H4), 187.0 (CO). MS
(EI, 70 eV): m/z (%) = 318 (12) [M+], 263 (42), 217 (100),
189 (21), 167 (50), 139 (41), 123 (60), 95 (43). Anal. Calcd
for C17H19FN2O3: C, 64.14; H, 6.02; N, 8.80. Found: C,
63.94; H, 5.99; N, 8.53.
Ethyl 1-(1,1-Dimethylethyl)-4-(4-nitrobenzoyl)-1H-
pyrazole-5-carboxylate (2e): yield: 1.57 g (91%); mp 84–
85 °C. 1H NMR (200 MHz, CDCl3): d = 1.39 (t, 3 H, OCMe),
1.70 (s, 9 H, t-Bu), 4.43 (q, 2 H, OCH2), 7.67 (s, 1 H, H3),
8.00–8.34 (m, 4 H, C6H4). 13C NMR (50 MHz, CDCl3): d =
13.6 (Me), 29.6 (3 × Me), 62.9 (OCH2), 63.4 [NC(CH)3],
121.4 (C4), 123.7, 129.7, 143.3, 149.8 (C6H4), 137.3 (C5),
138.8 (C3), 162.7 (CO2), 186.5 (CO). MS (EI, 70 eV): m/z
(%) = 345 (15) [M+], 290 (96), 244 (100), 198 (22), 167 (57),
150 (20), 139 (54), 104 (19). Anal. Calcd for C17H19FN3O5:
C, 59.12; H, 5.55; N, 12.17. Found: C, 58.75; H, 5.18; N,
11.94.
(12) Berber, H.; Soufyane, M.; Mirand, C.; Schmidt, S.;
Aubertin, A.-M. Tetrahedron 2001, 57, 7369.
(13) Berber, H.; Soufyane, M.; Santillana-Hayat, M.; Mirand, C.
Tetrahedron Lett. 2002, 43, 9233.
(14) Rosa, F. A.; Machado, P.; Rossatto, M.; Vargas, P. S.;
Bonacorso, H. G.; Zanatta, N.; Martins, M. A. P. Synlett
2007, 3165.
(15) 4-Dimethylamino-3-(4-methoxybenzoyl)-2-oxobut-3-
enoic Acid Ethyl Ester (1b): yield: 86%; oil. 1H NMR (200
MHz, CDCl3): d = 1.11 (t, 3 H, OCMe), 2.78 (s, 3 H, NMe2),
3.33 (s, 3 H, NMe2), 3.85 (s, 3 H, OMe), 3.93 (q, 2 H, OCH2),
6.91–7.75 (m, 4 H, C6H4), 7.85 (s, 1 H, H4). 13C NMR (100
MHz, CDCl3): d = 13.5 (OCMe), 42.2 (NMe2), 47.7 (NMe2),
55.3 (OMe), 61.3 (OCH2), 107.8 (C3), 113.5, 131.3, 132.8,
162.9 (C6H4), 158.4 (C4), 164.6 (C1), 183.1 (C2), 192.3
(C3¢). MS (EI, 70 eV): m/z (%) = 305 (3) [M+], 232 (29), 135
(100), 107 (4), 77 (10). Anal. Calcd for C16H19NO5: C,
62.94; H, 6.27; N, 4.59. Found: C, 63.15; H, 6.43; N, 4.81.
3-(Benzofuran-2-carbonyl)-4-dimethylamino-2-oxobut-
3-enoic Acid Ethyl Ester (1g): yield: 89%; oil. 1H NMR
(200 MHz, CDCl3): d = 1.03 (t, 3 H, OCMe), 2.91 (s, 3 H,
NMe2), 3.40 (s, 3 H, NMe2), 3.94 (q, 2 H, OCH2), 7.28–7.66
(m, 5 H, benzofur-2-yl), 7.90 (s, 1 H, H4). 13C NMR (100
MHz, CDCl3): d = 13.5 (OCMe), 42.8 (NMe2), 48.2 (NMe2),
61.7 (OCH2), 107.6 (C3), 112.1, 113.3, 122.9, 123.7, 126.9,
127.7, 154.2, 155.4 (benzofur-2-yl), 159.5 (C4), 164.0 (C1),
180.8 (C2), 182.5 (C3¢). MS (EI, 70 eV): m/z (%) = 315 (10)
[M+], 242 (77), 169 (39), 145 (100), 89 (33). Anal. Calcd for
C17H17NO5: C, 64.75; H, 5.43; N, 4.44. Found: C, 64.92; H,
5.56; N, 4.67.
(16) General Procedure for the Synthesis of Pyrazoles 2: A
mixture of enaminodiketone 1 (5 mmol) and tert-butyl-
hydrazine hydrochloride (0.748 g, 6 mmol) was stirred under
reflux in anhyd EtOH (20 mL) for 1 h. Then the mixture was
cooled to r.t. and the solvent was evaporated under vacuum.
The residue was washed with H2O (20 mL) and extracted
with CH2Cl2 (3 × 30 mL) and the organic layers were dried
over Na2SO4, and evaporated under vacuum. Recrystalli-
zation from hexane afforded the pure pyrazoles 2a–i.
Ethyl 4-Benzoyl-1-(1,1-dimethylethyl)-1H-pyrazole-5-
Ethyl 1-(1,1-Dimethylethyl)-4-(thiophene-2-carbonyl)-
1H-pyrazole-5-carboxylate (2f): yield: 1.21 g (79%); oil.
1H NMR (200 MHz, CDCl3): d = 1.36 (t, 3 H, OCMe), 1.69
(s, 9 H, t-Bu), 4.42 (q, 2 H, OCH2), 7.17–7.77 (m, 3 H, thien-
2-yl), 7.91 (s, 1 H, H3). 13C NMR (50 MHz, CDCl3): d = 13.6
(Me), 29.6 (3 × Me), 62.7 (OCH2), 63.0 [NC(CH)3], 122.4
(C4), 127.9, 132.7, 133.3, 143.9 (thien-2-yl), 136.8 (C5),
137.6 (C3), 162.9 (CO2), 179.4 (CO). MS (EI, 70 eV): m/z
(%) = 306 (28) [M+], 251 (32), 206 (100), 178 (47), 139 (36),
Synlett 2008, No. 11, 1673–1678 © Thieme Stuttgart · New York

LETTER
Straightforward and Regiospecific Synthesis of Pyrazole-5-carboxylates
1677
111 (61), 83 (6). Anal. Calcd for C15H18N2O3S: C, 58.80; H,
5.92; N, 9.14. Found: C, 58.61; H, 6.21; N, 9.26.
[M+], 247 (20), 230 (58), 201 (21), 167 (16), 139 (52), 135
(100), 121 (40), 107 (24), 91 (47), 77 (62). Anal. Calcd for
C14H14N2O4: C, 61.31; H, 5.14; N, 10.21. Found: C, 61.10;
H, 4.93; N, 9.99.
Ethyl 4-(4-Chlorobenzoyl)-1H-pyrazole-5-carboxylate
(3c): yield: 1.20 g (86%); mp 190–192 °C. 1H NMR (200
MHz, CDCl3): d = 0.98 (t, 3 H, OCMe), 4.14 (q, 2 H, OCH2),
7.45–7.81 (m, 4 H, C6H4), 8.22 (s, 1 H, H3), 14.45 (br, 1 H,
NH). 13C NMR (100 MHz, DMSO-d6): d = 13.6 (Me), 60.7
(OCH2), 121.1 (C4), 128.8, 130.8, 136.8, 138.0 (C6H4),
133.0 (C3), 142.7 (C5), 161.9 (CO2), 188.2 (CO). MS (NICI,
CH4): m/z (%) = 278 (100) [M+]. Anal. Calcd for
Ethyl 4-(Benzofuran-2-carbonyl)-1-(1,1-dimethylethyl)-
1H-pyrazole-5-carboxylate (2g): yield: 1.46 g (86%); mp
84–85 °C. 1H NMR (200 MHz, CDCl3): d = 1.40 (t, 3 H,
OCMe), 1.70 (s, 9 H, t-Bu), 4.46 (q, 2 H, OCH2), 7.31–8.32
(m, 5 H, benzofur-2-yl), 7.61 (s, 1 H, H3). 13C NMR (50
MHz, CDCl3): d = 13.6 (Me), 29.6 (3 × Me), 62.8 (OCH2),
63.0 [NC(CH)3], 112.2, 113.6, 123.1, 123.9, 126.9, 128.0,
153.0, 155.5 (benzofur-2-yl), 121.2 (C4), 137.5 (C5), 138.6
(C3), 163.2 (CO2), 175.8 (CO). MS (EI, 70 eV): m/z (%) =
340 (100) [M+], 284 (74), 240 (78), 211 (73), 195 (49), 167
(17), 145 (44), 139 (39), 121 (17), 89 (36). Anal. Calcd for
C19H20N2O4: C, 67.05; H, 5.92; N, 8.23. Found: C, 67.44; H,
6.15; N, 8.01.
Ethyl 4-(2,2,2-Trichloroacetyl)-1-(1,1-dimethylethyl)-
1H-pyrazole-5-carboxylate (2h): yield: 1.33 g (78%); mp
96–98 °C. 1H NMR (200 MHz, CDCl3): d = 1.43 (t, 3 H,
OCMe), 1.66 (s, 9 H, t-Bu), 4.50 (q, 2 H, OCH2), 8.10 (s, 1
H, H3). 13C NMR (50 MHz, CDCl3): d = 13.6 (Me), 29.5
(3 × Me), 63.2 (OCH2), 63.5 [NC(CH)3], 95.3 (CCl3), 113.1
(C4), 139.3 (C3), 140.2 (C5), 162.6 (CO2), 175.2 (CO). MS
(EI, 70 eV): m/z (%) = 297 (2) [M + 2 – OEt], 239 (5), 223
(20), 167 (100), 139 (50), 121 (11). Anal. Calcd for
C12H15Cl3N2O3: C, 42.19; H, 4.43; N, 8.20. Found: C, 42.39;
H, 4.58; N, 8.32.
C13H11ClN2O3: C, 56.03; H, 3.98; N, 10.05. Found: C, 55.77;
H, 3.62; N, 9.95.
Ethyl 4-(4-Fluorobenzoyl)-1H-pyrazole-5-carboxylate
(3d): yield: 1.15 g (88%); mp 189–191 °C. 1H NMR (200
MHz, CDCl3): d = 0.98 (t, 3 H, OCMe), 4.15 (q, 2 H, OCH2),
7.15–7.90 (m, 4 H, C6H4), 8.21 (s, 1 H, H3). 13C NMR (100
MHz, DMSO-d6): d = 13.6 (Me), 60.7 (OCH2), 115.7 (d,
2J = 22 Hz, C6H4), 121.3 (C4), 131.9 (d, 3J = 9 Hz, C6H4),
132.7 (C3), 134.8 (d, 4J = 3 Hz, C6H4), 142.7 (C5), 161.8
(CO2), 165.0 (d, 1J = 251 Hz, C6H4), 187.9 (CO). MS (EI, 70
eV): m/z (%) = 262 (100) [M+], 218 (76), 189 (13), 167 (67),
139 (71), 123 (64), 107 (7), 95 (82). Anal. Calcd for
C13H11FN2O3: C, 59.54; H, 4.23; N, 10.68. Found: C, 59.17;
H, 3.86; N, 10.67.
Ethyl 4-(2,2,2-Tri-fluoroacetyl)-1-(1,1-dimethylethyl)-
1H-pyrazole-5-carboxylate (2i): yield: 1.11 g (76%); oil.
1H NMR (200 MHz, CDCl3): d = 1.42 (t, 3 H, OCMe), 1.66
Ethyl 4-(4-Nitrobenzoyl)-1H-pyrazole-5-carboxylate
(3e): yield: 1.36 g (94%); mp 177–179 °C. 1H NMR (200
MHz, CDCl3): d = 1.02 (t, 3 H, OCMe), 4.15 (q, 2 H, OCH2),
8.00–8.31 (m, 4 H, C6H4), 8.18 (s, 1 H, H3), 13.72 (br, 1 H,
NH). 13C NMR (50 MHz, CDCl3): d = 13.6 (Me), 61.8
(OCH2), 121.7 (C4), 123.7, 130.2, 143.3, 150.4 (C6H4),
135.1 (C3), 141.0 (C5), 161.1 (CO2), 188.3 (CO). MS (EI, 70
eV): m/z (%) = 289 (11) [M+], 262 (13), 245 (21), 199 (21),
167 (66), 139 (100), 122 (72), 104 (30), 76 (18). Anal. Calcd
for C13H11N3O5: C, 53.98; H, 3.83; N, 14.53. Found: C,
53.99; H, 3.59; N, 14.58.
Ethyl 4-(Thiophene-2-carbonyl)-1H-pyrazole-5-
carboxylate (3f): yield: 0.92 g (74%); mp 140–142 °C. 1H
NMR (200 MHz, CDCl3): d = 1.11 (t, 3 H, OCMe), 4.25 (q,
2 H, OCH2), 7.14–7.72 (m, 3 H, thien-2-yl), 8.24 (s, 1 H,
H3), 14.31 (br, 1 H, NH). 13C NMR (100 MHz, CDCl3): d =
13.5 (Me), 61.5 (OCH2), 122.0 (C4), 128.0, 134.3, 134.4,
145.2 (thien-2-yl), 133.0 (C3), 141.3 (C5), 161.7 (CO2),
181.7 (CO). MS (NICI, CH4): m/z (%) = 250 (100) [M+].
Anal. Calcd for C11H10N2O3S: C, 52.79; H, 4.03; N, 11.19.
Found: C, 52.59; H, 3.77; N, 11.28. Ethyl 4-(Benzofuran-
2-carbonyl)-1H-pyrazole-5-carboxylate(3g):yield: 1.26 g
(89%); mp 158–160 °C. 1H NMR (200 MHz, CDCl3): d =
1.08 (t, 3 H, OCMe), 4.23 (q, 2 H, OCH2), 7.32–7.71 (m, 5
H, benzofur-2-yl), 8.35 (s, 1 H, H3), 13.55 (br, 1 H, NH). 13C
NMR (100 MHz, DMSO-d6): d = 13.6 (Me), 60.7 (OCH2),
112.1, 114.6, 120.2 (C4), 123.6, 124.0, 126.8, 128.4, 133.1
(C3), 143.3 (C5), 152.5, 155.0 (benzofur-2-yl), 162.1 (CO2),
177.0 (CO). MS (EI, 70 eV): m/z (%) = 284 (100) [M+], 257
(4), 240 (27), 211 (33), 184 (16), 167 (12), 145 (38), 139
(53), 89 (68). Anal. Calcd for C15H12N2O4: C, 63.38; H, 4.25;
N, 9.85. Found: C, 63.30; H, 4.21; N, 9.97.
(s, 9 H, t-Bu), 4.49 (q, 2 H, OCH2), 7.90 (s, 1 H, H3). 13
C
NMR (50 MHz, CDCl3): d = 13.6 (Me), 29.5 (3 × Me), 63.4
(OCH2), 63.9 [NC(CH)3], 115.3 (C4), 116.2 (q, 1J = 290 Hz,
CF3), 138.7 (C5), 138.8 (C3), 162.2 (CO2), 174.2 (q, 2J = 37
Hz, CO). MS (EI, 70 eV): m/z (%) = 292 (4) [M+], 277 (4),
237 (65), 231 (35), 223 (23), 209 (12), 191 (100), 167 (55),
139 (40), 121 (13), 69 (4). Anal. Calcd for C12H15F3N2O3: C,
49.32; H, 5.17; N, 9.59. Found: C, 49.09; H, 5.37; N, 9.86.
(17) Crystallographic data for compound 2h, reported in this
paper, have been deposited with the Cambridge
Crystallographic Data Centre (CCDC 669661). Copies of
the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax:
+44(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk.
(18) General Procedure for the Synthesis of Pyrazoles 3:
A mixture of enaminodiketone 1 (5 mmol) and carboxy-
methylhydrazine (0.540 g, 6 mmol) was stirred at r.t. in
anhyd EtOH (20 mL) for 1 h. Then the product was filtered,
washed with EtOH and dried under vacuum affording the
pure pyrazoles 3a–g.
Ethyl 4-Benzoyl-1H-pyrazole-5-carboxylate (3a): yield:
0.91 g (75%); mp 196–198 °C. 1H NMR (200 MHz, CDCl3):
d = 0.93 (t, 3 H, OCMe), 4.10 (q, 2 H, OCH2), 7.47–7.87 (m,
5 H, Ph), 8.24 (s, 1 H, H3), 14.56 (br, 1 H, NH). 13C NMR
(100 MHz, CDCl3): d = 13.3 (Me), 61.4 (OCH2), 122.1 (C4),
128.3, 129.4, 133.0, 138.6 (Ph), 133.7 (C3), 141.6 (C5),
161.8 (CO2), 190.2 (CO). MS (EI, 70 eV): m/z (%) = 244
(18) [M+], 217 (6), 200(45), 171 (11), 167 (41), 139 (52),
121 (29), 105 (43), 77 (100). Anal. Calcd for C13H12N2O3: C,
63.93; H, 4.95; N, 11.47. Found: C, 64.11; H, 5.33; N, 11.76.
Ethyl 4-(4-Methoxybenzoyl)-1H-pyrazole-5-carboxylate
(3b): yield: 1.16 g (85%); mp 156–158 °C. 1H NMR (200
MHz, CDCl3): d = 1.00 (t, 3 H, OCMe), 3.88 (s, 3 H, OMe),
4.15 (q, 2 H, OCH2), 6.94–7.85 (m, 4 H, C6H4), 8.16 (s, 1 H,
H3), 14.34 (br, 1 H, NH). 13C NMR (100 MHz, CDCl3): d =
13.5 (Me), 55.4 (OMe), 61.3 (OCH2), 113.6, 131.4, 131.8,
163.6 (C6H4), 122.4 (C4), 133.2 (C3), 141.3 (C5), 161.8
(CO2), 188.9 (CO). MS (EI, 70 eV): m/z (%) = 274 (100)
(19) Crystallographic data for compound 3d, reported in this
paper, have been deposited with the Cambridge
Crystallographic Data Centre (CCDC 669660). Copies of
the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax:
+44(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk.
(20) Procedure for the Synthesis of Pyrazole 4: To a stirred
solution of 2h (0.341 g, 1 mmol) in EtOH (4 mL) was added
sat. aq solution of KOH (2 mL) and stirring was continued at
Synlett 2008, No. 11, 1673–1678 © Thieme Stuttgart · New York

1678
F. A. Rosa et al.
LETTER
r.t. for 4 h. The basic solution was acidified with 2 N HCl (20
mL) in an ice-bath. Most of the solvent was removed under
reduced pressure and the resulting mixture was diluted with
CH2Cl2 (20 mL), and dried over Na2SO4. Evaporation of the
solvent gave pyrazole 4 with a high degree of purity.
5-Carboxyethyl-1-(1,1-dimethylethyl)-1H-pyrazole-4-
carboxylic Acid (4): yield: 0.18 g (76%); mp 99–101 °C.
1H NMR (200 MHz, CDCl3): d = 1.36 (t, 3 H, OCMe), 1.64
(s, 9 H, t-Bu), 4.44 (q, 2 H, OCH2), 7.89 (s, 1 H, H3). 13
C
NMR (100 MHz, CDCl3): d = 13.6 (Me), 29.5 (3 × Me), 62.8
(OCH2), 62.9 [NC(CH)3], 113.3 (C4), 137.3 (C5), 139.3
(C3), 162.9 (CO2), 167.5 (COOH). MS (EI, 70 eV):
mz (%) = 240 (4) [M+], 225 (4), 207 (19), 195 (6), 185 (30),
167 (90), 139 (100), 121 (9), 68 (12). Anal. Calcd for
C11H16N2O4: C, 54.99; H, 6.71; N, 11.66. Found: C, 55.01;
H, 6.88; N, 11.72.
Synlett 2008, No. 11, 1673–1678 © Thieme Stuttgart · New York