A novel one-pot, three-component synthesis of dialkyl 5-(alkylamino)-1- aryl-1H-pyrazole-3,4-dicarboxylates

Article abstract of DOI:10.1055/s-0028-1087365

A novel, one-pot, and three-component synthesis of dialkyl 5-(alkylamino)-1-aryl-1H-pyrazole-3,4-dicarboxylates is described. The reactive 1:1 zwitterionic intermediate, formed by the addition of isocyanides to dialkyl acetylenedicarboxylates, was trapped by hydrazinecarboxamides to afford the title compounds in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087365

3180
LETTER
A Novel One-Pot, Three-Component Synthesis of Dialkyl 5-(Alkylamino)-1-
aryl-1H-pyrazole-3,4-dicarboxylates
Synthesis of
D
ialkyl 5-
e
(Alkylamin
h
o)-1-aryl-1
H
d
-pyrazole-3,
i
4-dicarboxyla
A
te
s
dib,*a Bagher Mohammadi,a Hamid Reza Bijanzadehb
a
School of Chemistry, University College of Science, University of Tehran, P.O. Box 14155-6455, Tehran, Iran
Fax +98(21)66495291; E-mail: madib@khayam.ut.ac.ir
b
Department of Chemistry, Tarbiat Modarres University, P.O. Box 14115-175, Tehran, Iran
Received 2 July 2008
O
Abstract: A novel, one-pot, and three-component synthesis of di-
alkyl 5-(alkylamino)-1-aryl-1H-pyrazole-3,4-dicarboxylates is de-
scribed. The reactive 1:1 zwitterionic intermediate, formed by the
addition of isocyanides to dialkyl acetylenedicarboxylates, was
trapped by hydrazinecarboxamides to afford the title compounds in
good yields.
S
CN
F3C
N
H2N
Cl
Br
N
NH2O2S
Cl
N
Key words: 5-amino-1-aryl-1H-pyrazole-3,4-dicarboxylates, three-
component reactions, isocyanides, cyclizations, heterocycles
N
N
H
H
CF3
fipronil
CDK2 inhibitor 1
Figure 1 Examples of biologically active 5-aminopyrazoles
Multicomponent reactions (MCR) are important for the
achievement of high levels of diversity, as they allow
more than two building blocks to be combined in practi-
cal, time-saving one-pot operations, giving rise to com-
plex structures by simultaneous formation of two or more
bonds.1 Multicomponent reactions, leading to interesting
heterocyclic scaffolds, are particularly useful for the con-
struction of diverse chemical libraries of ‘drug-like’ mol-
ecules. The isocyanide-based MCR are especially
important in this area.1g,h
subsequent cyclization of the amide intermediate by
POCl3,10 nucleophilic substitution reaction of 5-chloropy-
razoles with an amine,11 and condensation of 3,3-dimer-
captopropenones with aniline derivatives and subsequent
treatment of intermediate with hydrazine.4a
We report herein a facile synthesis of highly functional-
ized 5-aminopyrazoles from [1+2+2] atom fragments [C +
CC + NN]. Thus a mixture of an isocyanide 2, a dialkyl
acetylenedicarboxylate 3, and a hydrazinecarboxamide 4
underwent a smooth addition reaction in dry acetone at
ambient temperature to produce dialkyl 5-(alkylamino)-1-
aryl-1H-pyrazole-3,4-dicarboxylates 5 in 60–72% yields
(Scheme 1, Table 1).
Pyrazole, a five-membered heterocycle with two adjacent
nitrogen atoms, is a motif found in many natural products,
pharmaceuticals, and synthetic intermediates.2,3 Some
pyrazoles are used in supramolecular and polymer chem-
istry, food, cosmetic colorings, and UV stabilizers, whilst
some have liquid crystal properties.3
CO2R2
Pyrazoles containing 5-alkyl/arylamino substituents have
been exploited in the design of pharmaceutical and agro-
chemical agents. Recently, some 5-aminopyrazoles have
been reported as cyclin dependent kinase (e.g., 1;
Figure 1) and glycogen synthase kinase inhibitors.4
Fipronil (Figure 1) is a new 5-aminopyrazole with high
insecticide activity.5
R2O2C
R1NH
CO2R2
O
C
+
N
acetone
r.t., 36 h
–
C
R1
+
+
ArNHNH
NHPh
C
N
CO2R2
N
Ar
2
3
4
5
Scheme 1
A number of synthetic routes have been reported for the
preparation of 5-aminopyrazoles; these include one-pot
reaction of b-ketoamides, hydrazines, and Lawesson’s re-
agent,6 reaction of a-haloketone hydrazones with isocya-
nides,7 Mannich reaction of hydrazones, aldehydes, and
benzylpiperazine and subsequent [4+1] cycloaddition of
hydrazonopiperazine intermediates with isocyanides,8 re-
action of hydrazines with acetoacetamides,9 addition of
lithiated b-hydrazonophosphine oxides to isocyanates and
The reactions were carried out by first mixing the acety-
lenic ester 3 and the hydrazinecarboxamide 4 in dry ace-
tone. Then, a solution of the isocyanide 2 in dry acetone
was added to the reaction mixture. The reaction proceeded
spontaneously at ambient temperature and was complete
within 36 hours. TLC and 1H NMR analysis of the reac-
tion mixtures clearly indicated formation of the highly fluo-
rescent 5-alkylamino-1H-pyrazoles 5 in good yields.12
The isolated products were characterized on the basis of
IR, 1H NMR and 13C NMR spectroscopy, mass spectrom-
etry, and elemental analysis.12
SYNLETT 2008, No. 20, pp 3180–3182
Advanced online publication: 28.11.2008
DOI: 10.1055/s-0028-1087365; Art ID: D25008ST
1
6
.1
2
.2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Dialkyl 5-(Alkylamino)-1-aryl-1H-pyrazole-3,4-dicarboxylates
3181
the synthesis of 5-alkylamino-1H-pyrazoles of potential
synthetic and pharmacological interest. The present meth-
od carries the advantage of being performed under neutral
conditions and requires no activation or modification of
the educts. The simplicity of this method makes it an in-
teresting alternative to the multistep approaches.
Table 1 Synthesis of 5-Amino-1H-pyrazoles 5a–h
5
R1
R2
Me
Et
Ar
Ph
Ph
Ph
Ph
Tol
Tol
Ph
Ph
Yield (%)
5a
5b
5c
5d
5e
5f
t-Bu
72
66
72
70
69
65
62
60
t-Bu
Cy
Me
Et
Acknowledgment
Cy
This research was supported by the Research Council of University
of Tehran as a research project (6102036/1/03).
Cy
Me
Et
Cy
References and Notes
5g
5h
1,1,3,3-tetramethylbutyl
1,1,3,3-tetramethylbutyl
Me
Et
(1) (a) Bagley, M. C.; Dale, J. W.; Bower, J. Chem. Commun.
2002, 1682. (b) Mont, N.; Teixidó, J.; Borrell, J. I.; Kappe,
C. O. Tetrahedron Lett. 2003, 44, 5385. (c) Simon, C.;
Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004,
4957. (d) Cui, S. L.; Lin, X. F.; Wang, Y. G. J. Org. Chem.
2005, 70, 2866. (e) Huang, Y. J.; Yang, F. Y.; Zhu, C. J.
J. Am. Chem. Soc. 2005, 127, 16386. (f) Ramón, D. J.; Yus,
M. Angew. Chem. Int. Ed. 2005, 44, 1602. (g) Dömling, A.
Chem. Rev. 2006, 106, 17. (h) Dömling, A.; Ugi, I. Angew.
Chem. Int. Ed. 2000, 39, 3168.
(2) Greenhill, J. V. In Comprehensive Heterocyclic Chemistry
I, Vol. 5; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon:
London, 1984, 302.
(3) Elguero, J. In Comprehensive Heterocyclic Chemistry II,
Vol. 3; Katritzky, A. R.; Rees, C. W.; Scriven, E. V. F., Eds.;
Pergamon: London, 1996, 1–75; and references cited
therein.
A mechanistic rationalization for this reaction is provided
in Scheme 2. On the basis of the well-established chemis-
try of isocyanides,1g,h,13–15 it is reasonable to assume that
the functionalized pyrazoles 5 may result from initial ad-
dition of the isocyanide to the acetylenic ester and subse-
quent protonation of 1:1 zwitterionic adduct 6 by the
hydrazinecarboxamide 4, followed by addition of conju-
gate base of the NH acid 8 to positively charged ion 7 to
form ketenimine intermediate 9. The ketenimine 9 may
undergo intramolecular cyclization to 2,3-dihydropyra-
zole intermediate 10, from which a carbon monoxide and
an aniline molecule may be removed to afford the highly
functionalized pyrazole 5.
(4) (a) Tang, J.; Shewchuk, L. M.; Sato, H.; Hasegawa, M.;
Washio, Y.; Nishigaki, N. Bioorg. Med. Chem. Lett. 2003,
13, 2985. (b) Cooper, C. B.; Helal, C. J.; Sanner, M. A.;
Wagner, T. T. WO 02/18346A1, 2002; Chem. Abstr. 2002,
136, 232297g.
Isolation and identification of 2,3-dihydropyrazole inter-
mediate 10 (R1 = Cy, R2 = Me, Ar = Ph) from the reaction
mixture would support the proposed mechanism.16
The GC-MS analysis of the reaction mixture of 5c re-
vealed the presence of aniline and N,N¢-diphenylurea,
which suggested another route for pyrazole formation and
corroborated the structure of the intermediate.
(5) Mohamed, F.; Senarathna, L.; Percy, A.; Abeyewardene,
M.; Eaglesham, G.; Cheng, R.; Azher, S.; Hittarage, A.;
Dissanayake, W.; Sheriff, M. H. R.; Davies, W.; Buckley,
N. A.; Eddleston, M. J. Toxicol. Clin. Toxicol. 2004, 42, 955.
(6) Dodda, D. S.; Martinez, R. L. Tetrahedron Lett. 2004, 45,
4265.
In summary, the one-pot and three-component reaction
between isocyanides, dialkyl acetylenedicarboxylates,
and hydrazinecarboxamides provides a simple entry into
(7) Atlan, V.; Buron, C.; El Kaïm, L. Synlett 2000, 489.
O
CO2R2
C
–
N+
C
O
ArNHNH
Ar
NHPh
+
N
–
C
CO2R2
R1
R1
C
C
+
C
4
CO2R2
CO2R2
6
2
3
O
HN
N
R1N
NHPh
+
N
–
CH CO2R2
•
R1
C
ArNHN
C
NHPh
CO2R2
CO2R2
R2O2C
8
9
7
CO2R2
H
R2O2C
CO2R2
R2O2C
O
+
CO
+
PhNH2
N
N
R1NH
R1NH
N
N
NHPh
10
Ar
Ar
5
Scheme 2
Synlett 2008, No. 20, 3180–3182 © Thieme Stuttgart · New York

3182
M. Adib et al.
LETTER
(8) (a) Atlan, V.; El Kaïm, L.; Grimaud, L.; Jana, N. K.; Majee,
A. Synlett 2002, 352. (b) Ancel, J. E.; El Kaïm, L.; Gadras,
A.; Grimaud, L.; Jana, N. K. Tetrahedron Lett. 2002, 43,
8319.
(9) Moreno-Manãs, M.; Sebastián, R. M.; Vallribera, A.; Carini,
F. Synthesis 1999, 157.
(10) Palacios, F.; Aparicio, D.; de los Santos, J. M. Tetrahedron
1996, 52, 4123.
(11) Sakya, S. M.; Rast, B. Tetrahedron Lett. 2003, 44, 7629.
(12) Synthesis of Dimethyl 5-(tert-Butylamino)-1-phenyl-1H-
pyrazole-3,4-dicarboxylate (5a)
CH). 13C NMR (125.8 MHz, CDCl3): d = 24.74, 25.87 and
33.22 (3 × CH2), 51.23 (NCH), 51.37 and 53.08 (2 × OCH3),
99.32 (N2C=C), 123.23, 127.97 and 129.15 (3 × CH),
135.96, 139.24 and 156.34 (3 × C), 161.89 and 163.98 (2 ×
C=O). MS: m/z (%) = 357 (94) [M+], 342 (28), 324 (15), 314
(53), 282 (100), 275 (50), 256 (12), 243 (10), 167 (11), 149
(26), 77 (42), 69 (15), 55 (17). Anal. Calcd (%) for
C19H23N3O4 (357.41): C, 63.85; H, 6.49; N, 11.76. Found: C,
63.8; H, 6.5; N, 11.7.
(13) Ugi, I. Isonitrile Chemistry; Academic Press: London, 1971.
(14) Ugi, I. Angew. Chem., Int. Ed. Engl. 1982, 21, 810.
(15) Walborsky, H. M.; Periasamy, M. P. In The Chemistry of
Functional Groups, Suppl. C; Patai, S.; Rappaport, Z., Eds.;
Wiley: New York, 1983, Chap. 20, 835–837.
(16) After 2 h from the beginning of the reaction, TLC analysis of
the reaction mixture clearly indicated formation of an
intermediate in good yield. The reaction was quenched by
rapid evaporation of the solvent and the intermediate was
purified by a rapid column chromatography using n-hexane–
EtOAc (1:1) as eluent. The solvent was removed and the
intermediate precipitated from H2O–EtOH (1:1).
The procedure for the preparation of dimethyl 5-(tert-
butylamino)-1-phenyl-1H-pyrazole-3,4-dicarboxylate (5a)
is described as an example. To a magnetically stirred
solution of N¢,2-diphenyl-1-hydrazinecarboxamide (0.455 g,
2 mmol) and dimethyl acetylenedicarboxylate (0.284 g,
2 mmol) in dry acetone (10 mL) was added dropwise a
solution of tert-butyl isocyanide (0.166 g, 2 mmol) in dry
acetone (2 mL) at ambient temperature over 10 min. Then
the reaction mixture was stirred for 36 h. The solvent was
removed, and the residue was purified by column
chromatography using n-hexane–EtOAc (5:1) as eluent. The
solvent was removed and the product was obtained as
colorless oil; yield 0.48 g (72%). IR (KBr): 3423 (NH),
1745, 1697 (C=O), 1597, 1557, 1543, 1510, 1483, 1443,
1420, 1391, 1364, 1271, 1221, 1132, 1094, 1072, 1047, 941,
791, 758, 692 cm–1. 1H NMR (500.1 MHz, CDCl3): d = 1.46
[s, 9 H, C(CH3)3], 3.81 and 3.86 (2 s, 6 H, 2 × OCH3), 5.63
(br s, 1 H, NH), 7.33 (t, J = 7.5 Hz, 1 H, CH), 7.42 (dd,
J = 8.2, 7.5 Hz, 2 H, 2 × CH), 7.49 (d, J = 8.2 Hz, 2 H, 2 ×
CH). 13C NMR (125.8 MHz, CDCl3): d = 29.06 [C(CH3)3],
51.37 [NC(CH3)3], 51.42 and 53.17 (2 × OCH3), 100.25
(N2C=C), 122.76, 127.71 and 129.14 (3 × CH), 135.25,
139.41 and 155.73 (3 × C), 162.34 and 164.18 (2 × C=O).
MS: m/z (%) = 331 (18) [M+], 316 (56), 300(6), 284 (100),
275 (7), 252 (8), 243 (17), 214 (4), 185 (4), 143 (6), 77 (28),
57 (8), 41 (8). Anal. Calcd (%) for C17H21N3O4 (331.37): C,
61.62; H, 6.39; N, 12.68. Found: C, 61.6; H, 6.5; N, 12.6.
Dimethyl 5-(Cyclohexylamino)-1-phenyl-1H-pyrazole-
3,4-dicarboxylate (5c)
Dimethyl 2-(Anilinocarbonyl)-5-(cyclohexylamino)-1-
phenyl-2,3-dihydro-1H-pyrazole-3,4-dicarboxylate (10c)
White powder, mp 79–81 °C. IR (KBr): 3381 and 3300
(NH), 1745, 1710 and 1685 (C=O), 1624, 1599, 1537, 1495,
1443, 1365, 1313, 1259, 1198, 1088, 1053, 1030, 1005, 781,
754, 692 cm–1. 1H NMR (500.1 MHz, CDCl3): d = 1.17–1.91
[m, 10 H, CH(CH2)5], 3.17–3.25 (m, 1 H, NHCH), 3.58 and
3.73 (2 s, 6 H, 2 × OCH3), 5.63 (s, 1 H, NCH), 7.11 (t, J = 7.5
Hz, 1 H, CH), 7.21 (d, J = 8.5 Hz, 1 H, NH), 7.25 (t, J = 7.4
Hz, 1 H, CH), 7.34 (dd, J = 7.8, 7.5 Hz, 2 H, 2 × CH), 7.38
(dd, J = 8.4, 7.4 Hz, 2 H, 2 × CH), 7.44 (d, J = 7.7 Hz, 2 H,
2 × CH), 7.47 (d, J = 8.4 Hz, 2 H, 2 × CH), 8.20 (s, 1 H,
NHCO). 13C NMR (125.8 MHz, CDCl3): d = 24.04, 24.13,
25.06, 32.28 and 34.68 (5 × CH2), 50.62 (NHCH), 52.20 and
53.10 (2 × OCH3), 62.79 (NCH), 83.40 (N2C=C), 119.17,
122.28, 123.85, 126.90, 129.01 and 129.27 (6 × CH), 137.51
and 145.79 (2 × C), 157.16 and 159.71 (N2C=C and C=O,
urea), 166.28 and 171.07 (2 × C=O, ester). MS: m/z
(%) = 479 (20) [M+ + 1], 463 (10) [M – CH3], 446 (12) [M –
OCH3], 419 (46) [M – CO2CH3], 386 (11) [M – PhNH], 343
(8) [M – (CO2CH3 + Ph)], 326 (10) [M – (CO2CH3 +
PhNH)], 300(100) [M – (CO2CH3 + PhNHCO)], 252 (69),
225 (15) [PhN=NCOPh+], 218 (30), 186 (25), 170 (58), 119
(34) [PhNCO+], 91 (34), 77 (62), 55 (88). Anal. Calcd (%)
for C26H30N4O5 (478.55): C, 65.26; H, 6.32; N, 11.71.
Found: C, 65.0; H, 6.6; N, 11.4.
Yield 0.51 g (72%); colorless crystals, mp 76 °C. IR (KBr):
3440 (NH), 1742 and 1688 (C=O), 1565, 1549, 1508, 1481,
1450, 1421, 1367, 1288, 1260, 1236, 1190, 1161, 1136,
1105, 1095, 1070, 792, 765, 696 cm–1. 1H NMR (500.1 MHz,
CDCl3): d = 1.21–2.13 [m, 10 H, CH(CH2)5], 3.62–3.66 (m,
1 H, NHCH), 3.81 and 3.83 (2 s, 6 H, 2 × OCH3), 5.44 (d,
J = 7.6 Hz, 1 H, NH), 7.33 (t, J = 7.4 Hz, 1 H, CH), 7.41 (dd,
J = 7.4, 7.7 Hz, 2 H, 2 × CH), 7.47 (d, J = 7.7 Hz, 2 H, 2 ×
Synlett 2008, No. 20, 3180–3182 © Thieme Stuttgart · New York

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