One-pot three-component reaction for synthesis of highly substituted pyrazolo[1,2-a][1,2,4]triazole derivatives

Article abstract of DOI:10.2174/157017811799304188

A straightforward, simple and efficient method is described for the synthesis of pyrazolo[1,2-a][1,2,4]triazole derivates via one-pot three-component reaction between isocyanides, dialkyl acetylenedicarboxylate and 4-phenyl urazole (as a NH-acid) in acetone without using any catalyst at ambient temperature. This method offers several advantages such as high yield of products, easy work-up procedure and mild reaction conditions.

Full text of DOI:10.2174/157017811799304188

Letters in Organic Chemistry, 2011, 8, 743-748
743
One-Pot Three-Component Reaction for Synthesis of Highly Substituted
Pyrazolo[1,2-a][1,2,4]triazole Derivatives
Seyed S. Sajadikhah, Malek T. Maghsoodlou*, Nourallah Hazeri and Sayyed M. Habibi-Khorassani
Department of Chemistry, University of Sistan and Baluchestan, P. O. Box 98135-674, Zahedan, Iran
Received May 04, 2011: Revised September 06, 2011: Accepted September 16, 2011
Abstract: A straightforward, simple and efficient method is described for the synthesis of pyrazolo[1,2-a][1,2,4]triazole
derivates via one-pot three-component reaction between isocyanides, dialkyl acetylenedicarboxylate and 4-phenyl urazole
(as a NH-acid) in acetone without using any catalyst at ambient temperature. This method offers several advantages such
as high yield of products, easy work-up procedure and mild reaction conditions.
Keywords: Dialkyl acetylenedicarboxylate, isocyanide, multi-component reaction, pyrazolo[1,2-a][1,2,4]triazole, urazole.
INTRODUCTION
As a result, it is necessary to further develop more efficient
procedures, which allow the ready synthesis of urazole
polycyclic systems. In continuing our interest in isocyanide-
based multi-component reactions [24-28], here we report a
simple and efficient synthesis of dialkyl 7-(alkyl or
arylamino)-1,2,3,5-tetrahydro-1,3-dioxo-2-phenylpyrazolo
[1,2-a][1,2,4]triazole-5,6-dicarboxylate 4 from one-pot three-
component reaction between isocyanide 1, dialkyl
acetylenedicarboxylate 2 and 4-phenyl urazole 3 without
using any catalyst at ambient temperature in acetone
(Scheme 2).
The design of novel multi-component reactions (MCRs)
has attracted great attention from research groups in
medicinal chemistry, drug discovery and materials science
due to their significant advantages over conventional liner-
type syntheses, simple procedures, environmental
friendliness, atom economy, and their ability to generate
architecturally complex molecules in one synthetic step [1].
In the last decades, pyrazole derivatives have played an
essential role in biologically active compounds and therefore
represent an interesting template for medicinal chemistry.
They have been reported to possess wide variety of
biological activities including anticancer [2], PGE2
inhibitory [3], anti-inflammatory [3, 4], anti-microbial [5],
antibacterial [6], analgesic, anti-hypoxic and anti-pyretic
activities [7].
RESULTS AND DISCUSSION
First of all, to optimize the reaction conditions, the
reaction of 2,6-dimethylphenyl isocyanide (1 mmol),
dimethyl acetylenedicarboxylate (1mmol) and 4-phenyl
urazole (1 mmol) was selected as a model reaction, and its
behavior was studied in the different solvents at ambient
temperature. The results are summarized in Table 1. As it is
shown in Table 1, the best result was obtained in acetone.
When the reaction was carried out under solvent-free
conditions, the product was obtained in a moderate yield (41
%) that may be due to the lack of effective interaction
between reactants.
On the other hand, during the last decades, heterocycles
containing an urazole moiety have received considerable
attention in pharmaceutical researches due to their activities
such as anticonvulsant [8], fungicidal [9], inhibitor of HSP
induction [10], thrombolin inhibitor and protease inhibitor
(Scheme 1) [11].
R3
O
O
R2
Using the optimized reaction conditions, several reac-
tions between isocyanide 1, dialkyl acetylenedicarboxylate 2
N
N
N
N
Ph
N
R4
N
O
and urazole
3 were examined, and the results are
H
summarized in Table 2. All reactions proceeded smoothly at
ambient temperature in acetone, to produce the pyrazolo[1,2-
a][1,2,4]triazole 4 within 24 h in 54-89 % yields. TLC and
1H NMR spectra of the crude products clearly indicated
formation of pyrazolo[1,2-a][1,2,4]triazole 4.
O
O
R1
N
HO
O
O
H
Inhibitore of HSP induction10
Scheme 1.
Protease inhibitor11b
The essential structures of the products 4a-h were
1
characterized from their elemental analysis, IR, H and 13C
In the recent years, many procedures have been described
in the literature for preparation of heterocyclic compounds
by the isocyanide-based multi-component reactions [12-23].
NMR, and mass spectra. The mass spectra of these
compounds showed molecular ion peaks at appropriate m/z
values, and initial fragmentation involving the loss of the
side chains.
*Address correspondence to this author at the Department of Chemistry,
University of Sistan and Baluchestan, P. O. Box 98135-674, Zahedan, Iran;
Tel/Fax: +98-541-2450995; E-mail: mt_maghsoodlou@yahoo.com
1
The H NMR spectrum of compound 4a exhibited two
singlets at ꢀ 2.33 and 2.40 ppm for methyl protons on
1875-6255/11 $58.00+.00
© 2011 Bentham Science Publishers

744 Letters in Organic Chemistry, 2011, Vol. 8, No. 10
Sajadikhah et al.
CO2R2
O
O
CO2R2
C
N
N
NH
NH
Acetone
r.t., 24 h
CO2R2
R1
N
C
Ph
N
Ph
N
+
+
C
CO2R2
HN
R1
O
O
1
2
3
4
Scheme 2. Synthesis of pyrazolo[1,2-a][1,2,4]triazole 4
Table 1. Optimization of the Reaction Conditions for the Reaction of 2,6-dimethylphenyl Isocyanide, Dimethyl
Acetylenedicarboxylate and 4-phenyl Urazole at Ambient Temperature
Entry
Solvent
Time (h)
Yield (%)a
1
2
3
4
5
CH3CN
EtOH
24
24
24
24
48
73
35
40
89
41
MeOH
Acetone
Solvent-free
aIsolated Yield.
Table 2. Synthesis of Pyrazolo[1,2-a][1,2,4]triazole 4
CO2Et
CO2Me
O
CO2CMe3
CO2Me
CO2Me
O
O
O
N
N
N
N
N
N
CO2Et
Me
N
N
CO2Me
Me
CO2CMe3
Me
Ph
N
Ph
N
Ph N
Ph
N
HN
Me
HN
Me
HN
Me
HN
O
O
O
O
4a
4c
4d
4b
CO2CMe3
CO2CMe3
CO2CMe3
CO2Me
CO2Me
CO2CMe3
CO2CMe3
O
O
O
O
N
N
N
N
N
N
CO2CMe3
Me
Ph
N
Ph
N
Ph
N
Ph N
N
N
HN
O
O
O
HN
N
HN
O
O
O
H
Me
Me
O
O
4e
4h
4f
4g
Entry
R1
R2
Product
Yield (%)a
1
2
3
4
5
6
7
8
2,6-diMe-C6H3
2,6-diMe-C6H3
2,6-diMe-C6H3
PhCH2
Me
Et
4a
4b
4c
4d
4e
4f
89
85
88
70
54
81
59
84
CMe3
Me
cyclohexyl
EtOOCCH2
EtOOCCH2
CMe3
CMe3
Me
CMe3
CMe3
4g
4h
aIsolated yields.

One-Pot Three-Component Reaction for Synthesis
Letters in Organic Chemistry, 2011, Vol. 8, No. 10
745
CO2R2
C
R1
N
C
+
R1
N
C
C
C
CO2R2
C
CO2R2
CO2R2
1
2
5
O
NH
NH
Ph
N
O
O
O
N
R1
N
C
C
C
CO2R2
Ph
N
+
3
H
NH
CO2R2
6
7
1,4-addition
1,2-addition
NR1
CO2R2
CO2R2
O
O
CO2R2
CO2R2
N
N
Ph
N
Ph
N
NH
NH
C
NR1
O
O
8
9
CO2R2
CO2R2
O
N
N
Ph
N
HN
R1
O
4
Scheme 3. The proposed mechanism for synthesis of pyrazolo[1,2-a][1,2,4]triazole.
benzene ring. The methyl protons of carbmethoxy groups
were observed as two singlets at ꢀ 3.80 and 3.87 ppm and the
methine proton appeared as singlet at ꢀ 5.47 ppm. The
aromatic protons were shown as two multiplets at ꢀ 7.12-
7.17 ppm and ꢀ 7.34-7.45 ppm. A broad signal for the NH
proton at ꢀ 8.61 ppm, indicated intramolecular hydrogen
bond formation with vicinal carbonyl group. The 13C NMR
spectrum of compound 4a showed 20 distinct resonances
consistent with the pyrazolotriazole structure. The structural
assignments of compounds 4a-h made on the basis of NMR
spectra were supported by their IR spectra. The IR spectrum
of these compounds, in general, exhibited the strong
carbonyl absorption band around 1769-1650 cm-1 and fairly
broad NH absorption at nearly 3320-3255 cm-1.
Although the mechanism of this reaction has not been
established experimentally, on the basis of the proposed
mechanism in the literature [12-14], it is reasonable to
assume that compound 4 resulted from initial addition of the
isocyanide 1 to dialkyl acetylenedicarboxylate
2 and
subsequent protonation of the 1:1 adduct 5 by 4-phenyl
urazole 3 (NH-acid) affording the vinylisonitrilium cation 6.
Then, vinylisonitrilium cation 6 is probably attacked by the
anion of the NH-acid 7 on the two possible electrophilic sites
(1,2-addition and 1,4-conjugate addition) to generate two
possible intermediate 8 and 9 in equilibrium with each other.
Finally, these intermediates apparently isomerize under the
reaction conditions, to produce the fused heterocyclic system
4 (Scheme 3).

746 Letters in Organic Chemistry, 2011, Vol. 8, No. 10
Sajadikhah et al.
EXPERIMENTAL
Di-tert-butyl 7-(2,6-dimethylphenylamino)-1,2,3,5-tetra-
hydro-1,3-dioxo-2-phenylpyrazolo[1,2-a][1,2,4]triazole-5,6-
dicarboxylate (4c): White powder, mp 164-166 °C. IR (KBr)
Melting points and IR spectra of all compounds were
measured on an Electrothermal 9100 apparatus and a
1
(ꢁmax/cm-1): 3270, (NH), 2978, 1765, 1729, 1657, 1622; H
Shimadzu IR-460 spectrometer, respectively. The 1H and 13
C
NMR (250 MHz, CDCl3) ꢀ = 1.51 (9H, s, C(CH3)3), 1.54
(9H, s, C(CH3)3), 2.30 (3H, s, CH3), 2.38 (3H, s, CH3), 5.23
(1H, s, CHN), 7.05-7.08 (3H, m, ArH), 7.30-7.37 (5H, m,
ArH), 8.62 (1H, br s, NH); 13C NMR (62.9 MHz, CDCl3) ꢀ =
18.54 (CH3), 19.14 (CH3), 27.98 (C(CH3)3), 28.52
(C(CH3)3), 63.37 (CHN), 80.98 (C(CH3)3), 83.13 (C(CH3)3),
83.74 (C=C–N), 125.98, 127.41, 128.21, 128.60, 129.15,
130.82, 135.21, 136.53, 147.80 (C=C–N), 150.20 (NC=O),
153.25 (NC=O), 165.25 (C=O), 167.89 (C=O); MS m/z (%):
534 (M+, 2), 433 (26), 405 (11), 377 (51), 240 (24), 212 (11),
149 (78), 119 (16), 91 (35), 73 (31), 57 (100); Anal. Calcd
for C29H34N4O6: C 65.15, H 6.41, N 10.48; Found: C 65.27,
H 6.50, N 10.56.
NMR spectra were obtained on BRUKER DRX-250 and 400
AVANCE instruments with CDCl3 as a solvent. Elemental
analyses were performed using a Heraeus CHN-O-Rapid
analyzer. Mass spectra were recorded on Agilent Technology
(HP) spectrometer operating at an ionization potential of 70
eV. All reagents and solvents were obtained from Merck
(Darmastadt, Germany), Acros (Geel, Belgium) and Fluka
(Buchs, Switzerland), and were used without further
purification.
General Procedure for the Synthesis of Compounds 4
To a magnetically stirred solution of isocyanide 1
(1mmol) and 4-phenyl urazole 3 (1mmol) in acetone (20
Dimethyl 7-(benzylamino)-1,2,3,5-tetrahydro-1,3-dioxo-
2-phenylpyrazolo[1,2-a][1,2,4]triazole-5,6-dicarboxylate
(4d): Yellow powder, mp 95-97 °C. IR (KBr) (ꢁmax/cm-1):
mL) was added dropwise
a
mixture of dialkyl
acetylenedicarboxylate 2 (1 mmol) in acetone (2 mL) at
ambient temperature over 15 min. The reaction mixture was
stirred at ambient temperature for 24 h. After completion of
the reaction, as indicated by TLC, the solvent removed under
reduced pressure and the solid residue was washed with
diethyl ether (3 ꢀ 2 mL) to give the pure product 4.
1
3255 (NH), 2982, 1758, 1728, 1650, 1620; H NMR (250
MHz, CDCl3) ꢀ = 3.73 (3H, s, OCH3), 3.80 (3H, s, OCH3),
4.92 (2H, d, J = 5.5 Hz, CH2), 5.35 (1H, s, CHN), 7.30-7.42
(5H, m, ArH), 7.46-7.50 (5H, m, ArH), 7.61 (1H, br s, NH);
13C NMR (62.9 MHz, CDCl3) ꢀ = 50.70 (CH2), 51.21
(OCH3), 53.08 (OCH3), 62.14 (CHN), 81.50 (C=C–N),
126.09, 127.37, 127.94, 128.89, 129.08, 129.38, 130.69,
137.30, 149.08 (C=C–N), 150.94 (NC=O), 153.12 (NC=O),
165.51 (C=O), 169.16 (C=O); MS m/z (%): 437 (M+1, 5),
405 (3), 377 (100), 226 (7), 140 (3), 119 (15), 91 (72); Anal.
Calcd for C22H20N4O6: C 60.55, H 4.62, N 12.84; Found: C
60.82, H 4.59, N 12.90.
Dimethyl 7-(2,6-dimethylphenylamino)-1,2,3,5-tetrahy-
dro-1,3-dioxo-2-phenylpyrazolo[1,2-a][1,2,4]triazole-5,6-
dicarboxylate (4a): White powder, mp 153-155 °C. IR (KBr)
1
(ꢁmax/cm-1): 3291 (NH), 2984, 1758, 1721, 1660, 1620; H
NMR (400 MHz, CDCl3) ꢀ = 2.33 (3H, s, CH3), 2.40 (3H, s,
CH3), 3.80 (3H, s, OCH3), 3.87 (3H, s, OCH3), 5.47 (1H, s,
CHN), 7.12-7.17 (3H, m, ArH), 7.34-7.45 (5H, m, ArH),
8.61 (1H, br s, NH); 13C NMR (100 MHz, CDCl3) ꢀ = 18.63
(CH3), 18.97 (CH3), 51.39 (OCH3), 53.18 (OCH3), 62.02
(NCH), 82.50 (C=C–N), 126.14, 127.76, 128.31, 128.41,
128.90, 129.28, 135.34, 136.25, 136.26, 147.85 (C=C–N),
150.65 (NC=O), 153.31 (NC=O), 165.55 (C=O), 169. 41
(C=O); MS m/z (%): 450 (M+, 9), 391 (100), 330 (14), 240
(48), 183 (18), 149 (33), 119 (40), 91 (8), 77 (15); Anal.
Calcd for C23H22N4O6: C 61.33, H 4.92, N 12.44; Found: C
61.49, H 4.99, N 12.49.
Di-tert-butyl 7-(cyclohexylamino)-1,2,3,5-tetrahydro-1,3-
dioxo-2-phenylpyrazolo[1,2-a][1,2,4]triazole-5,6-dicarboxy-
late (4e): White powder, mp 178-180 °C. IR (KBr) (ꢁmax/cm-
1): 3320, (NH), 2995, 1769, 1724, 1668, 1635; 1H NMR (250
MHz, CDCl3) ꢀ = 1.28-2.20 (10H, m. CH2 cyclohexyl), 1.50
(9H, s, C(CH3)3), 1.53 (9H, s, C(CH3)3), 4.07 (1H, m, NCH
cyclohexyl), 5.15 (1H, s, CHN), 7.17 (1H, br, NH), 7.44-
7.53 (5h, m, ArH); 13C NMR (100 MHz, CDCl3) ꢀ = 24.60,
25.38, 25.47 (CH2 cyclohexyl), 27.95 (C(CH3)3), 28.50
(C(CH3)3), 33.28 (CH2 cyclohexyl), 54.15 (NCH2
cyclohexyl), 62.98 (CHN), 81.05 (C(CH3)3), 83.30
(C(CH3)3), 87.96 (C=C–N), 125.94, 129.22, 129.37, 130.61,
149.14 (C=C–N), 149.77 (NC=O), 153.50 (NC=O), 165.70
(C=O), 169.38 (C=O); MS m/z (%): 512 (M+, 1), 510 (12),
368 (53), 313 (34), 236 (60), 211 (19), 177 (35), 119 (39), 97
(65), 57 (100); Anal. Calcd for C27H36N4O6: C 63.26, H 7.08,
N 10.93; Found: C 63.49, H 7.17, N 11.02.
Diethyl 7-(2,6-dimethylphenylamino)-1,2,3,5-tetrahydro-
1,3-dioxo-2-phenylpyrazolo[1,2-a][1,2,4]triazole-5,6-dicar-
boxylate (4b): white powder, mp 125-127 °C. IR (KBr)
1
(ꢁmax/cm-1): 3259 (NH), 2980, 1750, 1728, 1663, 1617; H
NMR (250 MHz, CDCl3) ꢀ = 1.31 (3H, t, J = 7.0 Hz,
OCH2CH3), 1.32 (3H, t, J = 7.0 Hz, OCH2CH3), 2.31 (3H, s,
CH3), 2.37 (3H, s, CH3), 4.13-4.33 (4H, m, 2OCH2CH3),
5.43 (1H, s, CHN), 7.07-7.15 (3H, m, ArH), 7.34-7.39 (5H,
m, ArH), 8.61 (1H, br s, NH); 13C NMR (62.9 MHz, CDCl3)
ꢀ = 14.12 (OCH2CH3), 14.42 (OCH2CH3), 18.59 (CH3),
18.96 (CH3), 60.04 (OCH2CH3), 62.17 (NCH), 62.26
(OCH2CH3), 82.12 (C=C–N), 126.05, 127.65, 128.25,
128.33, 128.77, 129.19, 135.31, 136.21, 136.30, 147.80
(C=C–N), 15057 (NC=O), 153.26 (NC=O), 165.33 (C=O),
168.90 (C=O); MS m/z (%): 478 (M+, 5), 405 (100), 377 (3),
359 (2), 302 (15), 240 (39), 212 (16), 149 (84), 119 (31), 91
(31), 77 (27), 57 (53); Anal. Calcd for C25H26N4O6: C 62.75,
H 5.48, N 11.71; Found: C 62.68, H 5.43, N 11.77.
Dimethyl 7-((ethoxycarbonyl)methylamino)-1,2,3,5-tet-
rahydro-1,3-dioxo-2-phenylpyrazolo[1,2-a][1,2,4]triazole-
5,6-dicarboxylate (4f): Yellow powder, mp 110-112 °C. IR
(KBr) (ꢁmax/cm-1): 3320 (NH), 2990, 1762, 1726, 1660,
1
1624; H NMR (400 MHz, CDCl3) ꢀ = 1.30 (t, 3H, J = 7.2
Hz, OCH2CH3), 3.78 (s, 3H, OCH3), 3.82 (s, 3H, OCH3),
4.24-4.29 (m, 2H, NCH2), 4.44-4.60 (m, 2H, OCH2CH3),
5.38 (s, 1H, CHN), 7.42-7.54 (m, 5H, ArH), 7.78 (br, 1H,
NH); 13C NMR (100 MHz, CDCl3) ꢀ = 14.11 (OCH2CH3),
47.75 (NCH2), 51.37 (OCH3), 53.15 (OCH3), 61.85
(OCH2CH3), 62.17 (CHN), 82.25 (C=C–N), 126.07, 129.20,

One-Pot Three-Component Reaction for Synthesis
Letters in Organic Chemistry, 2011, Vol. 8, No. 10
747
5786; (b) Sui, Z.; Guan, J.; Ferro, M.P.; MeCoy, K.; Wachter,
M.P.; Murray, W.V.; Singer, M.; Steber, M.; Ritchie, D.M.;
Argentieri, D.C. 1,3-Diarylcycloalkanopyrazoles and diphenyl
hydrazides as selective inhibitors of cyclooxygenase-2. Bioorg.
Med. Chem. Lett. 2000, 10, 601-604; (c) Bekhit, A.A.; Hymete, A.;
Bekhit, A.; El-Din A.; Damtew, A.; Aboul-Enein, H.Y. Pyrazoles
as promising scaffold for the synthesis of anti-inflammatory and/or
antimicrobial agent: a review. Mini-Rev. in Med. Chem. 2010, 10,
1014-1033; (d) Selvam, C.; Jachak, S.M.; Thilagavathi, R.;
Chakraborti, A.K. Design, synthesis, biological evaluation and
molecular docking of curcumin analogues as antioxidant,
cyclooxygenase inhibitory and anti-inflammatory agents. Bioorg.
Med. Chem. Lett. 2005, 15, 1793-1797.
(a) Sridhar, R.; Perumal, P.T.; Etti, S.; Shanmugam, G.;
Ponnuswamy, M.N.; Prabavathy, V.R.; Mathivanan, N. Design,
synthesis and anti-microbial activity of 1H-pyrazole carboxylates.
Bioorg. Med. Chem. Lett. 2004, 14, 6035-6040; (b) Akbas, E.;
Berber, I.; Sener, A.; Hasanov, B. Synthesis and antibacterial
activity of 4-benzoyl-1-methyl-5-phenyl-1H-pyrazole-3-carboxylic
acid and derivatives. IL FARMACO. 2005, 60, 23-26; (c) Abunada,
N.M.; Hassaneen, H.M.; Kandile, N.G.; Miqdad, O.A. Synthesis
and antimicrobial activity of some new pyrazole, fused
129.37, 130.56, 149.21 (C=C–N), 150.35 (NC=O), 152.90
(NC=O), 165.10 (C=O), 169.04 (C=O), 169.44 (C=O); MS
m/z (%): 432 (M+, 7), 373 (100), 355 (15), 248 (39), 227
(24), 171 (30), 157 (8), 119 (26), 77 (19); Anal. Calcd for
C19H20N4O8: C 52.78, H 4.66, N 12.96; Found: C 52.95, H
4.74, N 13.05.
Di-tert-butyl 7-((ethoxycarbonyl)methylamino)-1,2,3,5-
tetrahydro-1,3-dioxo-2-phenylpyrazolo[1,2-a][1,2,4]triazole-
5,6-dicarboxylate (4g): White powder, mp 182-185 °C. IR
(KBr) (ꢀmax/cm-1): 3328 (NH), 2990, 1758, 1720, 1667,
1
[5]
1633; H NMR (400 MHz, CDCl3) ꢀ = 1.31 (3H, t, J = 6.9
Hz, OCH2CH3), 1.51 (9H, s, C(CH3)3), 1.53 (9H, s,
C(CH3)3), 4.24-4.56 (4H, m, NCH2, OCH2CH3), 5.19 (1H, s,
CHN), 7.39-7.51 (5H, m, ArH), 7.74 (1H, br, NH); 13C NMR
(100 MHz, CDCl3) ꢀ = 14.98 (OCH2CH3), 27.10 (C(CH3)3),
28.68 (C(CH3)3), 47.96 (NCH2), 60.97 (OCH2CH3), 63.40
(CHN), 80.56 (C(CH3)3), 82.99 (C(CH3)3), 84.11 (C=C–N),
126.00, 129.18, 129.52, 130.71, 149.45 (C=C–N), 149.72
(NC=O), 153.18 (NC=O), 165.21 (C=O), 168.92 (C=O),
169.51 (C=O); MS m/z (%): 515 (M+-1, 1), 415 (5), 359
(13), 256 (15), 213 (10), 177 (100), 149 (45), 119 (88), 69
(80), 43 (750; Anal. Calcd for C25H32N4O8: C 58.13, H 6.24,
N 10.85; Found: C 58.34, H 6.32, N 10.96.
pyrazolo[3,4-d]-pyrimidine
and
pyrazolo[4,3-e][1,2,4]-
triazolo[1,5-c]pyrimidine Derivatives. Molecules 2008, 13, 1501-
1517.
[6]
[7]
Tanitame, A.; Oyamad, Y.; Ofuji, K.; Fujimoto, M.; Suzuki, K.;
Ueda, T.; Terauchi, H.; Kawasaki, M.; Nagai, K.; Wachi, M.;
Yamagishi, J.–I. Synthesis and antibacterial activity of novel and
potent DNA gyrase inhibitors with azole ring. Bioorg. Med. Chem.
2004, 12, 5515-5524.
Al-Assar, F.; Zelenin, K.N.; Lesiovskaya, E.E.; Bezhan, I.P.;
Chakchir, B.A. Synthesis and pharmacological activity of 1-
hydroxy-, 1-amino-, and 1-hydrazino-substituted 2,3-dihydro-1H-
Di-tert-butyl 7-(tert-butylamino)-1,2,3,5-tetrahydro-1,3-
dioxo-2-phenylpyrazolo[1,2-a][1,2,4]triazole-5,6-dicarboxy-
late (4h): White powder, mp 174-176 °C. IR (KBr) (ꢀmax/cm-
1): 3302 (NH), 2975, 1747, 1730, 1664, 1615; 1H NMR (250
MHz, CDCl3) ꢀ = 1.47 (9H, s, C(CH3)3), 1.48 (9H, s,
C(CH3)3), 1.50 (9H, s, C(CH3)3), 5.13 (1H, s, CHN), 7.41
(1H, br s, NH) 7.44-7.49 (5H, m, ArH); 13C NMR (62.9
MHz, CDCl3) ꢀ = 27.93 (OC(CH3)3), 28.41 (OC(CH3)3),
30.35 (NC(CH3)3), 57.52 (NC(CH3)3), 63.56 (CHN), 80.84
(OC(CH3)3), 83.13 (OC(CH3)3), 88.31 (C=C–N), 125.97,
128.71, 129.26, 131.03, 149.35 (C=C–N), 149.70 (NC=O),
154.00 (NC=O), 164.65 (C=O), 167.92 (C=O); MS m/z (%):
486 (M+, 5), 429 (11), 405 (65), 385 (43), 284 (7), 227 (15),
212 (10), 147 (8), 119 (21), 91 (41), 57 (100); Anal. Calcd
for C25H34N4O6: C 61.71, H 7.04, N 11.51; Found: C 61.90,
H 7.13, N 11.44.
pyrazolo[1,2-a]pyridazine-5,8-diones
and
2,3-dihydro-1H-
pyrazolo[1,2-b]phthalazine-5,10-diones. Pharm. Chem. J. 2002, 36,
598-603.
Jacobson, C.R.; D’Adamo, A.; Cosgrove, C. E. U. S. Patent 1972,
3, 663, 564; Chem. Abstr. 76, p 34259a.
Shgematsu, T.; Tomita, M.; Shibahara, T.; Nakazawa, M.;
Munakata, S.; Jpn. Patent 1977, 52, 083, 562; Chem. Abstr. 87, p
168017f.
Kiriazis, A.; Ruffer, T.; Jantti, S.; Lang, H.; Yli-Kauhaluama, J.
Stereoselective aza Diels-Alder reaction on solid-phase: a facile
synthesis of hexahydrocinnoline derivatives. J. Comb. Chem. 2007,
9, 263-266.
(a) Boatman, P.D.; Urban, J.; Nguyen, M.; Qabar, M.; Khan, M.
High-throughput synthesis and optimization of thrombin inhibitors
via urazole ꢃ-addition and Michael addition. Bioorg. Med. Chem.
Lett. 2003, 13, 1445-1449; (b) Ogbu, C.O.; Qabar, M.N.; Boatman,
P.D.; Urban, J.; Meara, J.P.; Ferguson, M.D.; Tulinsky, J.; Lum, C.;
Babu, S.; Balskovich, M.A.; Nakanishi, H.; Ruan, F.; Cao, B.;
Minarik, R.; Little, T.; Nelson, S.; Nguyen, M.; Gall, A.; Khan, M.
Highly efficient and versatile synthesis of libraries of constrained
ꢄ-strand mimetics. Bioorg. Med. Chem. Lett. 1998, 8, 2321-2326.
Adib, M.; Sayahi, M.H.; Rahbari, S. Reactions between
isocyanides and dialkyl acetylenedicarboxylates in the presence of
1,2-diacylhydrazines. One-pot synthesis of highly functionalized
pyrazoles. Tetrahedron Lett. 2005, 46, 6545-6547.
Teimouri, M.B. One-pot three-component reaction of isocyanides,
dialkyl acetylenedicarboxylates and phthalhydrazide: synthesis of
highly functionalized 1H-pyrazolo[1,2-b]phthalazine-5,10-diones.
Tetrahedron 2006, 62, 10849-10853.
Teimouri, M.B.; Mansouri, F.; Bazhrang, R. Facile synthesis of
1H-pyrazolo[1,2-a]pyridazine-5,8-dione derivatives by a one-pot,
three-component reactions Tetrahedron 2010, 66, 259-264.
Hasaninejad, A.; Zare, A.; Shekouhy, M. Highly efficient synthesis
of triazolo[1,2-a]indazole-triones and novel spiro triazolo[1,2-
a]indazole-tetraones under solvent-free conditions. Tetrahedron
2011, 67, 390-400.
[8]
[9]
[10]
[11]
ACKNOWLEDGEMENT
We gratefully acknowledge financial support from the
Research Council of University of Sistan and Baluchestan.
[12]
[13]
REFERENCES
[1]
(a) Zhu, J.; Bienayme, H.; Multicomponent reactions: Wiley-VCH:
Weinheim 2005; (b) Dömling, A.; Ugi, I. Multicomponent with
isocyanides. Angew. Chem. Int. Ed. 2000, 39, 3168-3210; (c)
Ganem, B. Strategies for innovation in multicomponent reaction
design. Acc. Chem. Res. 2009, 42, 463-472.
[14]
[15]
[2]
[3]
Nitulescu, G.M.; Draghici, C.; Missir, A.V. Synthesis of new
pyrazole derivatives and their anticancer evaluation. Eur. J. Med.
Chem. 2010, 45, 4914-4919.
Barsoum, F.F.; Girgis, A.S. Facile synthesis of bis(4,5-dihydro-1H-
pyrazole-1-carboxamides) and their thio-analogues of potential
PGE2 inhibitory properties. Eur. J. Med. Chem. 2009, 44, 2172-
2177.
[16]
[17]
Yavari, I.; Bayat, M.J.; Sirouspour, M.; Souri, S. One-pot synthesis
of highly functionalized 1,2-dihydropyridines from primary
alkylamines, alkyl isocyanides, and acetylenic esters. Tetrahedron
2010, 66, 7995-7999.
Alizadeh, A.; Rostamnia, S.; Long-Guan, Z. A novel pseudo-seven-
component diastereoselective synthesis of ꢅ5-phosphanylidene
bis(2,5-dioxotetrahydro-1H-pyrrole-3-carboxylates) via binucleo-
philic systems. Tetrahedron Lett. 2010, 51, 4750-4754.
[4]
(a) Gökhan-Kelekçi, N.; Yabanoꢁlu, S.; Kꢂpeli, E.; Salgin, U.;
Özgen, Ö.; Uçar, G.; Ye ilada, E.; Kendi, E.; Ye ilada, A.; Bilgin,
A.A. A new therapeutic approach in Alzheimer disease: Some
novel pyrazole derivatives as dual MAO-B inhibitors and
antiinflammatory analgesics. Bioorg. Med. Chem. 2007, 15, 5775-

748 Letters in Organic Chemistry, 2011, Vol. 8, No. 10
Sajadikhah et al.
[18]
[19]
[20]
Yavari, I.; Khalili, G.; Mirzaei, A. Tandem synthesis of 1-
(alkylamino)-2,4-diarylpyrimido[6,1-a]isoquinolin-5-ium chlorides
from isoquinoline, N-alkyl-benzimidoyl chlorides, and isocyanides.
Tetrahedron Lett. 2010, 51, 1190-1192.
Adib, M.; Mahdavi, M.; Ansari, S.; Malihi, F.; Long-Guan, Z.;
Bijanzadeh, H. R. Reaction between isocyanides and nitrostyrenes
in water: a novel and efficient synthesis of 5-(alkylamino)-4-aryl-3-
isoxazolecarboxamides. Tetrahedron Lett. 2009, 50, 7246-7248.
Shaabani, A.; Rezayan, A. H.; Ghasemi, S.; Sarvary, A. A mild and
efficient method for the synthesis of 2,5-dihydro-5-imino-2-
Makha, M. Synthesis of cyano-2,3-dihydropyrrolo[1,2-f]phenan-
thridine derivatives via a domino-Knoevenagel-cyclization. Mol.
Divers. 2011, 15, 197-201.
Maghsoodlou, M.T.; Marandi, G.; Hazeri, N.;·Habibi-Khorassani,
S.M.; Mirzaei, A.A. Synthesis of 5-aryl-1,3-dimethyl-6-(alkyl- or
aryl-amino) furo [2,3-d]pyrimidine derivatives by reaction between
isocyanides and pyridinecarbaldehydes in the presence of 1,3-
dimethylbarbituric acid. Mol. Divers. 2011, 15, 227-231.
Maghsoodlou, M.T.; Marandi, G.; Hazeri, N.; Aminkhani, A.;
[25]
[26]
[27]
Kabiri, R.
A facile synthesis of oxazolo[3,2-a][1,10]phenan-
methylfuran-3,4-dicarboxylates
via
an
isocyanide-based
throlines via a new multicomponent reaction. Tetrahedron Lett.
2007, 48, 3197-3199.
multicomponent reaction. Tetrahedron Lett. 2009, 50, 1456-1458.
Heravi, M.M.; Baghernejad, B.; Oskooie, H.A. A novel three-
component reaction for the synthesis of N-cyclohexyl-3-aryl-
quinoxaline-2-amines. Tetrahedron Lett. 2009, 50, 767-769.
Shaabani, A.; Sarvari, A.; Rezayan, A.H.; Keshipour, S. Synthesis
[21]
[22]
Marandi, G.; Maghsoodlou, M.T.; Hazeri, N.; Heydari, R.; Habibi-
Khorassani, S.M.; Ebrahimi, A.; Mollaeepoor, S.; Hosseini-
Mahdiabad, H.; Nassiri, M.; Kabiri, R. Study of reaction between
activated acetylenes and N, N'-diethyl-2-thiobarbituric acid in the
presence of isocyanides or triphenyphosphine. Heteroatom Chem.
2010, 21, 228-235.
Maghsoodlou, M.T.; Hazeri, N.; Habibi-Khorassani, S.M.;
Ziyaadini, M.; Khandan-Barni, K.; Ebrahimi, A.; Rostami-Charati,
F.; Sobolev, A.; Makha, M. Diastereoselective synthesis of ꢀ-
dispiroiminolactone bearing naphthalene or bipyridine pendant
groups. J. Heterocycl. Chem. 2009, 46, 843-848.
of fully substituted pyrano[2,3-c]pyrazole derivatives via
a
multicomponent reaction of isocyanides. Tetrahedron 2009, 65,
3492-3495.
Shaabani, A.; Maleki, A.; Mofakham, H.; Moghimi-Rad, J. A novel
one-pot pseudo-five-component synthesis of 4,5,6,7-tetrahydro-1H-
1,4-diazepine-5-carboxamide derivatives. J. Org. Chem. 2008, 73,
3925-3927.
[28]
[23]
[24]
Marandi, G.; Maghsoodlou, M.T.; Hazeri, N.; Habibi-Khorassani,
S.M.; Akbarzadeh-Torbati, N.; Rostami-Charati, F.; Skelton, B.W.;