Solution-phase and solid-phase synthesis of 1-pyrazol-3-ylbenzimidazoles

Article abstract of DOI:10.1055/s-2008-1032030

The facile solution and solid-phase synthesis of 1-pyrazol-3- ylbenzimidazoles from 4-fluoro-3-nitrobenzoate derivatives and 5(3)-amino-3(5)-subtituted-1H-pyrazoles is reported. The key step is the unexpected nucleophilic aromatic displacement of the activated fluorine by the exocyclic amino group of the pyrazole ring leading to 4-pyrazolylamino-3- nitrobenzoate derivatives, which are easily converted into the corresponding 1-pyrazol-3-ylbenzimidazoles in very high isolated yield. These novel methodologies would be very useful for the generation of libraries of diverse 1-heteroaryl derivatives of benzimidazoles. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032030

PAPER
387
Solution-Phase and Solid-Phase Synthesis of 1-Pyrazol-3-ylbenzimidazoles
S
ynthesis
a
of 1-Pyrazo
i
l-3-ylb
m
e
nzimidazoles e Portilla,a Jairo Quiroga,*a Rodrigo Abonía,a Braulio Insuasty,a Manuel Nogueras,b Justo Cobo,b
Ernesto G. Mata*c
a
Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, A. A. 25360, Cali, Colombia
E-mail: jaiquir@gmail.com
Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, 23071 Jaén, Spain
Instituto de Química Orgánica de Síntesis (CONICET - UNR), Facultad de Ciencias Bioquímicas y Farmacéuticas,
Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina
Fax +54(341)4370477; E-mail: mata@iquios.gov.ar
b
c
Received 21 September 2007; revised 7 November 2007
tagonists of angiotensin 1,8 and inhibitors of proton
pumps.9All these features, together with its close structur-
al relationship to benzodiazepines, place the benzimida-
zole scaffold among the privileged structures.10
Abstract: The facile solution and solid-phase synthesis of 1-pyra-
zol-3-ylbenzimidazoles from 4-fluoro-3-nitrobenzoate derivatives
and 5(3)-amino-3(5)-subtituted-1H-pyrazoles is reported. The key
step is the unexpected nucleophilic aromatic displacement of the ac-
tivated fluorine by the exocyclic amino group of the pyrazole ring
leading to 4-pyrazolylamino-3-nitrobenzoate derivatives, which are
easily converted into the corresponding 1-pyrazol-3-ylbenzimida-
zoles in very high isolated yield. These novel methodologies would
be very useful for the generation of libraries of diverse 1-heteroaryl
derivatives of benzimidazoles.
As part of our interest in novel biologically active nitro-
gen-containing heterocyclic scaffolds11 and the applica-
tion of solid-phase techniques to their synthesis,12 we
describe herein an efficient synthesis of new 1-pyrazol-3-
ylbenzimidazoles (1, Figure 1) that could be adapted for
the solution or solid-phase parallel or combinatorial syn-
thesis of this significant core skeleton.13,14
Key words: solid-phase synthesis, combinatorial chemistry, het-
erocycles, benzimidazoles, pyrazoles
MeO2C
N
R"
N
Combinatorial synthesis of low-molecular-weight struc-
tures by either solid- and liquid-phase approaches has
emerged in the last few years as an important tool for the
discovery and development of novel lead compounds and
for the optimization of therapeutic efficacy.1 Synthesis on
a solid support shows a number of advantages over solu-
tion chemistry:2 (i) filtration can be used for rapid purifi-
cation; (ii) excess of reagents can be used to drive the
reaction to completion; (iii) automation is easily accom-
plished;and (iv) relative site isolation is achieved with the
‘pseudo-dilution effect’.3 However, solid-phase synthesis
has some limitations, mainly related to difficult character-
ization of supported products and the lack of precedent of
several organic transformations on solid support. For this
reason, synthetic approaches to develop combinatorial li-
braries are sometime a compromise between solution-
phase and solid-phase strategies.
N
NH
R'
1
Figure 1 1-Pyrazol-3-ylbenzimidazoles 1
Before starting with the development of a solid-phase ap-
proach, we decided to test analogous strategies in solution
phase in order to obtain models for a subsequent transla-
tion to the solid-supported chemistry. In the search of
new, biologically promising heterocycle derivatives, we
decided to test the reaction between methyl 4-fluoro-3-ni-
trobenzoate (2) and 5(3)-amino-3(5)-phenyl-1H-pyrazole
(3a, R¢ = Ph) (Scheme 1). Interestingly, when this reac-
tion was performed in DMSO at room temperature for two
hours, the unexpected methyl 4-pyrazolylamino-3-ni-
trobenzoate (6a) was obtained as the sole product in very
high yield (90%). Nucleophilic aromatic displacement
(SNAr) of the activated fluorine in 215 was achieved by the
amino group of 3a instead of the expected attack by the
more nucleophilic nitrogen of the aromatic ring. The ex-
pected methyl 4-(5-amino-3-phenyl-1H-pyrazol-1-yl)-3-
nitrobenzoate (4a) was only obtained when the reaction
was heated in an oil bath at 120 °C for 10 minutes, how-
ever, the product was mixed with 6a in a 1:1 propor-
tion.16,17 Similar results were found for other pyrazoles
3b,c (Table 1). With the 4-pyrazolylamino-3-nitroben-
zoates 6a–c in hand, we investigated the synthesis of the
corresponding benzimidazole derivatives. Thus, catalytic
reduction of the nitro group in 6a–c was efficiently
From the realm of organic chemistry, heterocycles are of
particular interest in combinatorial synthesis, due to the
possible similarities with many natural and synthetic mol-
ecules with known biological activity.4 Benzimidazole is
an important heterocycle whose effectiveness has been
clearly demonstrated in a number of clinically important
therapeutic areas. Apart from the antihistamine
Astemizole5 and the antiulcerative Omeprazol,6 benzimi-
dazole-based compounds have shown biological activity
as, for example, inhibitors of phosphodiesterase IV,7 an-
SYNTHESIS 2008, No. 3, pp 0387–0394
x
x
.
x
x
.2
0
0
8
Advanced online publication: 10.01.2008
DOI: 10.1055/s-2008-1032030; Art ID: M06807SS
© Georg Thieme Verlag Stuttgart · New York

388
J. Portilla et al.
PAPER
R'
N
H2N
O2N
DMSO
N
120 °C, 10 min
6
+
F
O2N
4
CO2Me
R'
CO2Me
+
R'
R'
2
HN
N
HN
N
HN
N
HN
N
R"
R"C(OMe)3
DMSO
r.t., 2 h
NH
N
NH
H2N
R'
Ra-Ni
(8a–c)
O2N
N
H2N
3a–c
DMF, reflux
NH2NH2⋅H2O
MeOH
CO2Me
CO2Me
CO2Me
6a–c
7a–c
1aa–cc
Scheme 1
Having established the feasibility of the synthetic strategy
in solution, we next carried out the synthesis of a solid-
phase library of 1-pyrazol-3-ylbenzimidazoles. Commer-
cially available Wang resin 9 was chosen as a proper link-
er and 4-fluoro-3-nitrobenzoic acid (10) was immobilized
to that resin using the DIC/DMAP coupling procedure
(Scheme 2). Again, as in homogeneous synthesis, treat-
ment of 11 with a series of 5(3)-amino-3(5)-substituted
1H-pyrazoles 3a–f in DMSO at room temperature, afford-
ed the resin-bound 4-pyrazolylamino-3-nitrobenzoates
12a–f by the attack of the amino group over the activated
fluorine. Formation of 12a–c was corroborated by treat-
ment with TFA and esterification with diazomethane, to
yield the already characterized benzoates 6a–c. Reduction
of the nitro group of 12a–f with Raney-Ni and hydrazine
hydrate was inefficient on solid phase and the removal of
Raney-Ni residues was problematic. Therefore, this re-
duction was carried out in the presence of tin(II) chloride
dihydrate in DMF (reflux, 5 min) to give the desired o-
phenylenediamine derivatives 13a–f tethered to Wang
resin. Subsequently, cyclization was achieved by treating
13a–f with excess of trimethyl orthocarboxylates 8a–c in
DMF at reflux, to afford the resin-bound benzimidazoles
14aa–fb. Cleavage of 14aa–fb from the resin was accom-
plished with 50% TFA–CH2Cl2. Finally, esterification
with MeOH in the presence of H2SO4 gave the 1-pyrazol-
3-ylbenzimidazoles 1aa–fb in very high overall yield af-
ter isolation by column chromatography (Table 2).
Table 1 Solution-Phase Synthesis of 1-Pyrazol-3-ylbenzimidazoles
1aa–cc from Methyl 4-Fluoro-3-nitrobenzoate (2)
Entry R¢
Yield
Yield
R¢¢
Product Yield
(%)b of 1
(%) of 6 (%)a of 7
1
2
3
4
5
6
7
8
Ph
–
–
H
1aa
1ab
1ac
1ba
1bb
1ca
1cb
1cc
65
Ph
90
–
90
–
Me
Ph
H
66
45
77
79
83
84
68
Ph
Me
Me
Me
t-Bu
t-Bu
93
–
92
–
Me
H
–
–
95
–
95
–
Me
Ph
a From compound 6.
b Overall isolated yield.
achieved using Raney-Ni and hydrazine hydrate to give
the desired amines 7a–c in yields ranging from 90 to 95%.
Further treatment of 7a–c with the trimethyl orthocarbox-
ylates 8a–c, afforded the corresponding 1-pyrazol-3-yl-
benzimidazoles 1aa–cc18 in high isolated yields
(Scheme 1 and Table 1).
These results have opened the door to a new solution and
solid-phase synthesis of a scarcely reported series of het-
erocyclic compounds. While the synthesis of 2-pyrazol-3-
ylbenzimidazoles is well documented,19 synthesis of 1-
pyrazol-3-ylbenzimidazoles have been only reported
through the ring contraction of a benzodiazepine moiety.13
Our methodology allows the introduction of the pyrazole
ring before cyclization to the benzimidazole derivative
and, consequently, it could allow the introduction of di-
verse heterocycles to give libraries of 1-heteroaryl deriv-
atives of benzimidazoles.
In summary, we have reported an efficient and high-yield-
ing methodology for solution and solid-phase synthesis of
1-pyrazol-3-ylbenzimidazoles. A fourteen-member li-
brary of these scarcely reported heterocyclic compounds
has been developed by the solid-phase strategy and the
products were obtained in very high overall yield for the
five reaction steps. We anticipate that this approach
should allow the generation of libraries of biologically
promising 1-heteroaryl derivatives of benzimidazoles.
Synthesis 2008, No. 3, 387–394 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-Pyrazol-3-ylbenzimidazoles
389
R'
HN
HN
N
N
F
F
HO
H2N
R'
3a–f
W
O2N
O2N
9
NH
O2N
CO2H
O
10
11
O
W
12a–f
O
O
W
R'
R'
R'
HN
N
HN
N
HN
N
R"
R"C(OMe)3
(8a–c)
R"
N
i) 50% TFA–CH2Cl2
NH
SnCl2⋅2H2O
N
N
H2N
N
DMF, reflux
DMF, reflux
ii) MeOH–H2SO4
(10:1)
13a–f
14aa–fb
O
CO2Me
1aa–fb
O
O
W
O
W
Scheme 2
Table 2 Solid-Phase Synthesis of 1-Pyrazol-3-ylbenzimidazoles
1aa–fb
were recorded on a Hewlett-Packard HP Engine-5989 spectrometer
(equipped with a direct inlet probe) operating at 70 eV. The elemen-
tal analyses were obtained using a LECO CHNS-900 elemental an-
alyzer. Analytical TLC was carried out with silica gel 60 F254 pre-
coated aluminum sheets (Merck). Flash column chromatography
was performed using Merck silica gel 60 (230–400 mesh).
Entry
1
Product
1aa
1ab
1ac
R¢
R¢¢
H
Yield of 1 (%)a
Ph
68
70
65
75
77
80
81
70
74
78
76
79
78
80
2
Ph
Me
Ph
H
Methyl 4-[(5-Alkyl/aryl-1H-pyrazol-3-yl)amino]-3-nitroben-
zoates 6a–c; General Procedure
A solution of 3a–c (2 mmol) and methyl 4-fluoro-3-nitrobenzoate
(2; 398 mg, 2 mmol) in DMSO (2 mL) was stirred at 25 °C for 2 h.
The precipitate was filtered and washed with MeOH (10 mL) to
give 6a–c as orange solids (Table 1).
3
Ph
4
1ba
1bb
1ca
Me
5
Me
Me
H
6
t-Bu
Methyl 3-Nitro-4-[(5-phenyl-1H-pyrazol-3-yl)amino]benzoate
(6a)
Orange crystals; mp 257–258 °C.
IR (KBr): 3261 (NH), 1696 (C=O), 1623 cm–1 (C=N).
1H NMR (300 MHz, DMSO-d6): d = 3.85 (s, 3 H, OCH3), 6.73 (s, 1
H, 4-H), 7.38 (t, J = 7.93 Hz, 1 H, Hp-C6H5), 7.48 (t, J = 7.18, 7.93
Hz, 2 H, Hm-C6H5), 7.76 (d, J = 7.18 Hz, 2 H, Ho-C6H5), 8.03 (d,
J = 9.06 Hz, 1 H, 6-H, Ar), 8.06 (d, J = 9.06 Hz, 1 H, 5-H, Ar), 8.66
(s, 1 H, 2-H, Ar), 9.98 (s, 1 H, 5-NHAr), 13.19 (s, 1 H, NH).
13C NMR (75.6 MHz, DMSO-d6): d = 52.6 (OCH3), 96.5 (C-4),
117.9 (C-5, Ar), 119.0 (C-1, Ar), 125.6 (Co-C6H5), 128.3 (C-2, Ar),
129.0 (Cp-C6H5), 129.3 (Ci-C6H5), 129.5 (Cm-C6H5), 132.4 (C-4,
Ar), 136.1 (C-6, Ar), 143.7 (C-3), 143.4 (C-3, Ar), 148.5 (C-5),
165.2 (C=O).
7
1cb
1cc
t-Bu
Me
Ph
H
8
t-Bu
9
1da
1db
1ea
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
10
11
12
13
14
Me
H
1eb
1fa
Me
H
1fb
Me
a Overall isolated yield after flash column chromatography (based on
the initial loading level of Wang resin, five reaction steps).
MS (70 eV): m/z (%) = 338 (M+, 100), 307 (12), 292 (40).
HRMS: m/z calcd for C17H14N4O4 (M+): 338.1015; found:
338.1021.
Chemical reagents were purchased from commercial sources and
were used without further purification, unless otherwise noted. Sol-
vents were of analytical grade or purified by standard procedures
prior to use. Resins were purchased from Novabiochem (San Diego,
CA, USA). IR spectra were recorded on a Shimadzu Prestige 21
spectrophotometer and only partial spectral data are listed. NMR
spectra were run on Bruker Avance 300 and Bruker Avance 400
spectrometers using TMS as internal reference. The mass spectra
Methyl 4-[(5-Methyl-1H-pyrazol-3-yl)amino]-3-nitrobenzoate
(6b)
Orange crystals; mp 225–226 °C.
IR (KBr): 3284 (NH), 1698 (C=O), 1621 cm–1 (C=N).
1H NMR (300 MHz, DMSO-d6): d = 2.24 (s, 3 H, 3-CH3), 3.82 (s,
3 H, OCH3), 6.03 (s, 1 H, 4-H), 7.96 (d, J = 9.21 Hz 1 H, 6-H, Ar),
Synthesis 2008, No. 3, 387–394 © Thieme Stuttgart · New York

390
J. Portilla et al.
PAPER
7.99 (d, J = 9.21 Hz 1 H, 5-H, Ar), 8.62 (s, 1 H, 2-H, Ar), 9.89 (s, 1
H, 5-NHAr), 12.43 (s, 1 H, NH).
13C NMR (75.6 MHz, DMSO-d6): d = 11.1 (3-CH3), 52.6 (OCH3),
97.8 (C-4), 117.2 (C-5, Ar), 118.6 (C-1, Ar), 128.3 (C-2, Ar), 131.9
(C-4, Ar), 136.0 (C-6, Ar), 140.3 (C-3), 144.4 (C-3, Ar), 147.5 (C-
5), 165.2 (C=O).
13C NMR (75.6 MHz, DMSO-d6): d = 11.2 (3-CH3), 51.8 (OCH3),
94.8 (C-4), 113.5 (C-5, Ar), 115.6 (C-2, Ar), 119.7 (C-1, Ar), 120.1
(C-6, Ar), 135.4 (C-3, Ar), 135.9 (C-4, Ar), 139.6 (C-3), 151.3 (C-
5), 167.2 (C=O).
MS (70 eV): m/z (%) = 246 (M+, 33), 215 (100).
HRMS: m/z calcd for C12H14N4O2 (M+): 246.1117; found:
MS (70 eV): m/z (%) = 276 (M+, 100), 245 (12).
246.1119.
Anal. Calcd for C12H12N4O4: C, 52.17; H, 4.38; N, 20.28. Found: C,
52.08; H, 4.67; N, 20.13.
Methyl 3-Amino-4-[(5-tert-butyl-1H-pyrazol-3-yl)amino]ben-
zoate (7c)
White solid; mp 190–191 °C.
IR (KBr): 3303, 3150 (NH2), 1698 (C=O), 1597 cm–1 (C=N).
Methyl 4-[(5-tert-Butyl-1H-pyrazol-3-yl)amino]-3-nitroben-
zoate (6c)
Orange crystals; mp 239–240 °C.
IR (KBr): 3370, 3315 (NH), 1705 (C=O), 1625 cm–1 (C=N).
1H NMR (300 MHz, DMSO-d6): d = 1.26 (s, 9 H, t-C4H9), 3.74 (s,
3 H, OCH3), 5.01 (s, 2 H, ArNH2), 5.71 (s, 1 H, 4-H), 7.20 (d, J =
8.50 Hz, 1 H, 6-H, Ar), 7.25 (s, 1 H, 2-H, Ar), 7.44 (s, 1 H, 5-NH),
7.63 (d, J = 8.50 Hz, 1 H, 5-H, Ar), 11.84 (s, 1 H, NH).
13C NMR (75.6 MHz, DMSO-d6): d = 30.4 [C(CH3)3], 31.1
[C(CH3)3], 51.7 (OCH3), 91.7 (C-4), 113.7 (C-5, Ar), 115.7 (C-2,
Ar), 120.0 (C-1, Ar), 120.2 (C-6, Ar), 135.4 (C-3, Ar), 136.1 (C-4,
Ar), 150.2 (C-5), 153.6 (C-3), 167.2 (C=O).
1H NMR (300 MHz, DMSO-d6): d = 1.28 (s, 9 H, t-C4H9), 3.83 (s,
3 H, OCH3), 6.04 (s, 1 H, 4-H), 8.01 (m, 1 H, 6-H, Ar), 8.00 (m, 1
H, 5-H, Ar), 8.63 (s, 1 H, 2-H, Ar), 9.89 (s, 1 H, 5-NHAr), 12.41 (s,
1 H, NH).
13C NMR (75.6 MHz, DMSO-d6): d = 30.3 [C(CH3)3], 31.2
[C(CH3)3], 52.6 (OCH3), 94.8 (C-4), 117.9 (C-5, Ar), 118.7 (C-1,
Ar), 128.3 (C-2, Ar), 132.0 (C-4, Ar), 136.0 (C-6, Ar), 144.3 (C-3,
Ar), 147.0 (C-5), 154.3 (C-3), 165.2 (C=O).
MS (70 eV): m/z (%) = 288 (M+, 100), 262 (12), 247 (23).
Anal. Calcd for C15H20N4O2·0.5H2O: C, 60.59; H, 7.12; N, 18.84.
Found: C, 60.79; H, 7.10; N, 18.91.
MS (70 eV): m/z (%) = 318 (M+, 100), 287 (15).
HRMS: m/z calcd for C15H18N4O4 (M+): 318.1328; found:
318.1334.
1-Pyrazol-3-ylbenzimidazoles 1aa–cc; General Procedure
The o-phenylenediamine derivatives 7a–c (1 mmol) and an excess
of the corresponding trimethyl orthocarboxylate 8a–c (1 mL) were
mixed in DMF (1 mL). The resulting mixture was refluxed under
magnetic stirring for 5 h and then cooled to r.t. The precipitate ob-
tained was isolated by filtration, washed with MeOH (5 mL) and the
residue was crystallized from DMSO to give 1aa–cc as white crys-
tals.
Methyl 3-Amino-4-[(5-Alkyl/aryl-1H-pyrazol-3-yl)amino]ben-
zoates 7a–c; General Procedure
A mixture of 6a–c (1.5 mmol), hydrazine hydrate (225 mg, 4.5
mmol), and Raney-Ni (70 mg) in MeOH (15 mL) was refluxed un-
der magnetic stirring for 15 min. After that, the mixture was filtered
to remove the Raney-Ni. The filtrate was cooled and the deposited
solid was collected by filtration and crystallized from MeOH to give
7a–c as white solids.
Methyl 1-(5-Phenyl-1H-pyrazol-3-yl)-1H-benzimidazole-5-car-
boxylate (1aa)
White solid; mp 257–258 °C.
IR (KBr): 3199 (NH), 1722 (C=O), 1622 cm–1 (C=N).
Methyl3-Amino-4-[(5-phenyl-1H-pyrazol-3-yl)amino]benzoate
(7a)
White solid; mp 235–236 °C.
IR (KBr): 3372, 3186 (NH2), 1683 (C=O), 1597 cm–1 (C=N).
1H NMR (300 MHz, DMSO-d6): d = 3.98 (s, 3 H, OCH3), 7.35 (s, 1
H, H-4¢), 7.52 (t, J = 7.35 Hz, 1 H, Hp-C6H5), 7.62 (t, J = 6.87, 7.35
Hz, 2 H, Hm-C6H5), 7.94 (d, J = 6.87 Hz, 2 H, Ho-C6H5), 8.12 (d,
J = 8.93 Hz, 1 H, H-6), 8.28 (d, J = 8.93 Hz, 1 H, H-7), 8.45 (s, 1 H,
H-4), 8.98 (s, 1 H, H-2), 13.73 (s, 1 H, NH).
13C NMR (75.6 MHz, DMSO-d6): d = 52.6 (OCH3), 94.4 (C-4¢),
113.3 (C-7), 121.8 (C-4), 124.8 (C-5), 125.3 (C-6), 125.8 (Co-
C6H5), 129.0 (Ci-C6H5), 129.4 (Cp-C6H5), 129.6 (Cm-C6H5), 135.7
(C-7a), 144.5 (C-5¢), 143.6 (C-3a), 144.6 (C-2), 146.4 (C-3¢), 167.0
(C=O).
1H NMR (300 MHz, DMSO-d6): d = 3.75 (s, 3 H, OCH3), 5.03 (s, 2
H, ArNH2), 6.39 (s, 1 H, 4-H), 7.23 (d, J = 9.21 Hz, 1 H, 6-H, Ar),
7.32 (s, 1 H, 2-H, Ar), 7.33 (t, J = 7.84 Hz, 1 H, Hp-C6H5), 7.44 (t,
J = 7.29, 7.84 Hz, 2 H, Hm-C6H5), 7.61 (d, J = 9.21 Hz, 1 H, 5-H,
Ar), 7.67 (s, 1 H, 5-NH), 7.72 (d, J = 7.29 Hz, 2 H, Ho-C6H5), 11.94
(s, 1 H, NH).
13C NMR (75.6 MHz, DMSO-d6): d = 51.8 (OCH3), 93.0 (C-4),
113.8 (C-5, Ar), 115.7 (C-2, Ar), 120.1 (C-6, Ar), 120.2 (C-1, Ar),
125.5 (Co-C6H5), 128.6 (Cp-C6H5), 129.4 (Cm-C6H5), 130.1 (Ci-
C6H5), 135.6 (C-3, Ar), 135.9 (C-4, Ar), 142.7 (C-3), 151.6 (C-5),
167.1 (C=O).
MS (70 eV): m/z (%) = 318 (M+, 88), 287 (100), 197 (24).
Anal. Calcd for C18H14N4O2·0.5H2O: C, 66.05; H, 4.62; N, 17.12.
Found: C, 66.30; H, 4.57; N, 16.96.
MS (70 eV): m/z (%) = 308 (M+, 100), 297 (10), 277 (20).
Methyl 2-Methyl-1-(5-phenyl-1H-pyrazol-3-yl)-1H-benzimida-
zole-5-carboxylate (1ab)
White solid; mp 231–233 °C.
Anal. Calcd for C17H16N4O2·0.5H2O: C, 64.34; H, 5.40; N, 17.66.
Found: C, 63.91; H, 5.39; N, 17.82.
Methyl3-Amino-4-[(5-methyl-1H-pyrazol-3-yl)amino]benzoate
IR (KBr): 3197 (NH), 1709 (C=O), 1615 cm–1 (C=N).
(7b)
1H NMR (400 MHz, DMSO-d6): d = 2.65 (s, 3 H, CH3), 3.89 (s, 3
H, OCH3), 6.53 (s, 1 H, H-4¢), 7.53 (m, 1 H, Hp-C6H5), 7.58 (m, 2
H, Hm-C6H5), 7.90 (d, J = 6.82 Hz, 2 H, Ho-C6H5), 7.46 (d, J = 8.48
Hz, 1 H, H-7), 7.76 (d, J = 8.48 Hz, 1 H, H-6), 8.24 (s, 1 H, H-4),
12.83 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 14.5 (CH3), 51.9 (OCH3), 98.1
(C-4¢), 111.0 (C-7), 120.0 (C-4), 123.7 (C-5), 123.8 (C-6), 125.3
White solid; mp 210–211 °C.
IR (KBr): 3172, 3376 (NH2), 1716 (C=O), 1649 cm–1 (C=N).
1H NMR (300 MHz, DMSO-d6): d = 2.19 (s, 3 H, 3-CH3), 3.74 (s,
3 H, OCH3), 4.98 (s, 2 H, ArNH2), 5.72 (s, 1 H, 4-H), 7.18 (d, J =
8.70 Hz, 1 H, 6-H, Ar), 7.26 (s, 1 H, 2-H, Ar), 7.46 (s, 1 H, 5-NH),
7.59 (d, J = 8.70 Hz, 1 H, 5-H, Ar), 11.84 (s, 1 H, NH).
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Synthesis of 1-Pyrazol-3-ylbenzimidazoles
391
(Co-C6H5), 134.4 (Ci-C6H5), 128.0 (Cp-C6H5), 129.0 (Cm-C6H5),
138.6 (C-7a), 144.1 (C-5¢), 141.9 (C-3a), 153.7 (C-2), 144.3 (C-3¢),
166.7 (C=O).
Methyl 1-(5-tert-Butyl-1H-pyrazol-3-yl)-1H-benzimidazole-5-
carboxylate (1ca)
White solid; mp 200–201 °C.
MS (70 eV): m/z (%) = 332 (M+, 95), 301 (100), 273 (15).
IR (KBr): 3327 (NH), 1704 (C=O), 1615 cm–1 (C=N).
Anal. Calcd for C19H16N4O2·H2O: C, 65.13; H, 5.18; N, 15.99.
Found: C, 65.18; H, 5.17; N, 16.31.
1H NMR (300 MHz, CDCl3): d = 1.42 (s, 9 H, t-C4H9), 3.97 (s, 3 H,
OCH3), 6.27 (s, 1 H, H-4¢), 8.01 (d, J = 7.65 Hz, 1 H, H-7), 8.18 (d,
J = 7.65 Hz, 1 H, H-6), 8.59 (s, 1 H, H-4), 8.50 (s, 1 H, H-2), 13.71
(s, 1 H, NH).
13C NMR (75.6 MHz, CDCl3): d = 30.1 [C(CH3)3], 31.4 [C(CH3)3],
52.2 (OCH3), 93.2 (C-4¢), 112.4 (C-7), 122.3 (C-4), 125.3 (C-5),
125.7 (C-6), 135.8 (C-7a), 155.5 (C-5¢), 142.5 (C-3a), 143.0 (C-2),
145.4 (C-3¢), 167.6 (C=O).
Methyl 2-Phenyl-1-(5-phenyl-1H-pyrazol-3-yl)-1H-benzimida-
zole-5-carboxylate (1ac)
White solid; mp 296–298 °C.
IR (KBr): 3263 (NH), 1680 (C=O), 1612 cm–1 (C=N).
1H NMR (400 MHz, DMSO-d6): d = 3.74 (s, 3 H, OCH3), 6.40 (s, 1
H, H-4¢), 7.41 (m, 1 H, Hp-C6H5), 7.46 (m, 2 H, Hm-C6H5), 7.51 (d,
J = 8.62 Hz, 1 H, H-7), 7.54 (m, 1 H, Hp¢-C6H5), 7.72 (m, 2 H, Hm¢-
C6H5), 7.78 (d, J = 7.36 Hz, 2 H, Ho-C6H5), 7.84 (d, J = 8.59 Hz, 1
H, H-6), 7.98 (d, J = 7.43 Hz, 2 H, Ho¢-C6H5), 8.26 (s, 1 H, H-4),
12.68 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 52.2 (OCH3), 97.9 (C-4¢),
111.2 (C-7), 120.8 (C-4), 124.3 (C-5), 124.4 (C-6), 128.1 (Cp-
C6H5), 128.2 (Cm-C6H5), 128.8 (Co-C6H5), 129.3 (Ci-C6H5), 127.1
(Co¢-C6H5), 128.8 (Cm¢-C6H5), 129.0 (Cp¢-C6H5), 132.3 (Ci¢-C6H5),
140.1 (C-7a), 141.9 (C-3a), 143.3 (C-3¢), 153.9 (C-2), 154.8 (C-5¢),
166.5 (C=O).
MS (70 eV): m/z (%) = 298 (M+, 80), 283 (15), 267 (100), 197 (24).
HRMS: m/z calcd for C16H18N4O2 (M+): 298.1430; found:
298.1426.
Methyl (5-tert-Butyl-1H-pyrazol-3-yl)-2-methyl-1H-benzimida-
zole-5-carboxylate (1cb)
White solid; mp 190–192 °C.
IR (KBr): 3203 (NH), 1705 (C=O), 1621 cm–1 (C=N).
1H NMR (400 MHz, DMSO-d6): d = 1.37 (s, 9 H, t-C4H9), 2.59 (s,
3 H, CH3), 3.88 (s, 3 H, OCH3), 6.41 (s, 1 H, H-4¢), 7.52 (d, J = 6.82
Hz, 1 H, H-7), 7.87 (d, J = 6.82 Hz, 1 H, H-6), 8.21 (s, 1 H, H-4),
13.03 (s, 1 H, NH).
MS (70 eV): m/z (%) = 394 (M+, 93), 363 (100), 220 (35).
Anal. Calcd for C24H18N4O2·0.33H2O: C, 71.99; H, 4.70; N, 13.99.
Found: C, 72.11; H, 4.68; N, 14.03.
13C NMR (100 MHz, DMSO-d6): d = 14.5 (CH3), 29.8 [C(CH3)3],
31.0 [C(CH3)3], 52.2 (OCH3), 96.4 (C-4¢), 110.9 (C-7), 119.9 (C-4),
123.6 (C-5), 123.7 (C-6), 138.5 (C-7a), 143.1 (C-3¢), 141.8 (C-3a),
153.7 (C-2), 154.5 (C-5¢), 166.7 (C=O).
MS (70 eV): m/z (%) = 312 (M+, 71), 281 (100), 253 (12).
HRMS: m/z calcd for C17H20N4O2 (M+): 312.1586; found:
Methyl 1-(5-Methyl-1H-pyrazol-3-yl)-1H-benzimidazole-5-car-
boxylate (1ba)
White solid; mp 245–246 °C.
IR (KBr): 3276 (NH), 1705 (C=O), 1609 cm–1 (C=N).
1H NMR (300 MHz, DMSO-d6): d = 2.42 (s, 3 H, CH3), 3.97 (s, 3
H, OCH3), 6.61 (s, 1 H, H-4¢), 8.06 (d, J = 8.47 Hz, 1 H, H-6), 8.17
(d, J = 8.47 Hz, 1 H, H-7), 8.41 (s, 1 H, H-4), 8.87 (s, 1 H, H-2),
13.70 (s, 1 H, NH).
13C NMR (75.6 MHz, DMSO-d6): d = 11.1 (CH3), 52.6 (OCH3),
95.8 (C-4¢), 113.3 (C-7), 121.7 (C-4), 124.7 (C-5), 125.2 (C-6),
135.7 (C-7a), 141.3 (C-5¢), 143.4 (C-3a), 144.6 (C-2), 145.6 (C-3¢),
167.0 (C=O).
312.1601.
Methyl 1-(5-tert-Butyl-1H-pyrazol-3-yl)-2-phenyl-1H-benzimi-
dazole-5-carboxylate (1cc)
White solid; mp 202–204 °C.
IR (KBr): 3188 (NH), 1714 (C=O), 1616 cm–1 (C=N).
1H NMR (400 MHz, DMSO-d6): d = 1.32 (s, 9 H, t-C4H9), 3.90 (s,
3 H, OCH3), 6.15 (s, 1 H, H-4¢), 7.42 (m, 1 H, Hp-C6H5), 7.44 (m, 2
H, Hm-C6H5), 7.52 (d, J = 8.06 Hz, 1 H, H-7), 7.65 (d, J = 7.24 Hz,
2 H, Ho-C6H5), 7.92 (d, J = 8.06 Hz, 1 H, H-6), 8.37 (s, 1 H, H-4),
13.09 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 29.7 [C(CH3)3], 30.9
[C(CH3)3], 52.2 (OCH3), 97.9 (C-4¢), 111.2 (C-7), 120.8 (C-4),
124.3 (C-5), 124.4 (C-6), 128.1 (Cp-C6H5), 128.2 (Cm-C6H5), 128.8
(Co-C6H5), 129.3 (Ci-C6H5), 140.1 (C-7a), 141.9 (C-3a), 143.3 (C-
3¢), 153.9 (C-2), 154.8 (C-5¢), 166.5 (C=O).
MS (70 eV): m/z (%) = 256 (M+, 93), 225 (100), 197 (24).
Anal. Calcd for C13H12N4O2·0.25H2O: C, 59.88; H, 4.83; N, 21.43.
Found: C, 59.78; H, 4.87; N, 21.77.
Methyl 2-Methyl-1-(5-methyl-1H-pyrazol-3-yl)-1H-benzimida-
zole-5-carboxylate (1bb)
White solid; mp 228–229 °C.
IR (KBr): 3194 (NH), 1710 (C=O), 1612 cm–1 (C=N).
1H NMR (400 MHz, DMSO-d6): d = 2.37 (s, 3 H, 5¢-CH3), 2.57 (s,
3 H, 2-CH3), 3.88 (s, 3 H, OCH3), 6.38 (s, 1 H, H-4¢), 7.48 (d, J =
8.48 Hz, 1 H, H-7), 7.87 (d, J = 8.48 Hz, 1 H, H-6), 8.20 (s, 1 H, H-
4), 13.00 (s, 1 H, NH).
MS (70 eV): m/z (%) = 374 (M+, 100), 359 (37), 343 (31), 77 (26),
41 (20).
Anal. Calcd for C22H22N4O2·0.67H2O: C, 68.38; H, 6.09; N, 14.50.
Found: C, 68.41; H, 5.99; N, 14.62.
13C NMR (100 MHz, DMSO-d6): d = 10.7 (5¢-CH3), 14.4 (2-CH3),
51.9 (OCH3), 94.4 (C-4¢), 110.8 (C-7), 119.9 (C-4), 123.7 (C-5),
123.6 (C-6), 138.6 (C-7a), 140.6 (C-5¢), 141.8 (C-3a), 143.6 (C-3¢),
153.7 (C-2), 166.7 (C=O).
Solid-Phase Synthesis of 1-Pyrazol-3-ylbenzimidazoles 1aa–fb;
General Procedure
To a suspension of Wang resin 9 (1 g, 1.1 mmol, 1.1 mmol/g load-
ing) in DMF (8 mL) was added successively 4-fluoro-3-nitrobenzo-
ic acid (10; 815 mg, 4.4 mmol), DIC (0.75 mL, 2.2 mmol), and
DMAP (14 mg, 0.11 mmol). The suspension was stirred for 15 h at
r.t., and the yellow solid-supported 4-fluoro-3-nitrobenzoate 11 res-
in formed was then filtered and washed with DMF (2 × 6 mL),
MeOH (2 × 6 mL), and CH2Cl2 (2 × 6 mL), and dried under high
MS (70 eV): m/z (%) = 270 (M+, 77), 239 (100), 211 (26), 42 (26).
Anal. Calcd for C14H14N4O2·2H2O: C, 54.89; H, 5.92; N, 18.29.
Found: C, 55.01; H, 5.87; N, 18.34.
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392
J. Portilla et al.
PAPER
vacuum. An aliquot of resin 11 (250 mg, 0.23 mmol) was then treat-
ed with 3a–f (1.15 mmol) in DMSO (3 mL) at r.t. for 20 h to afford
the resin-bound aminoarylpyrazoles 12a–f. The orange resin was
washed with DMF (3 × 3 mL), MeOH (3 × 3 mL) and CH2Cl2
(3 × 3 mL), and dried under high vacuum. Each immobilized 3-ni-
trobenzoate 12a–f (0.21 mmol) was treated with a suspension of 2.0
M solution of SnCl2·2H2O in DMF (1 mL, 2.0 mmol) in DMF (3
mL) at reflux for 5 min. The resulting white resin was washed with
DMF (3 × 3 mL), 20% H2O–THF (at 60 °C, 3 × 3 mL), MeOH
(3 × 3 mL) and CH2Cl2 (3 × 3 mL), and dried under high vacuum.
The resin-bound o-phenylenediamine derivatives 13a–f (0.19
mmol) were then treated with the corresponding orthoesters 8a–c
(0.5 mL) in DMF (2 mL) at reflux for 5 h. The resin-bound 1-pyra-
zol-3-ylbenzimidazoles 14aa–fb obtained were then washed with
DMF (3 × 3 mL), MeOH (3 × 3 mL) and CH2Cl2 (3 × 3 mL), and
dried under high vacuum. For releasing the product from the solid
phase, each benzimidazole resin (0.17 mmol) was treated with 50%
TFA (2 mL) in CH2Cl2 (2 mL) for 2 h at r.t. The mixture was filtered
and the filtrate was evaporated under reduced pressure. Esterifica-
tion with MeOH in the presence of H2SO4 (in a ratio of 10:1, respec-
tively) by heating at reflux for 2 h, afforded the crude product,
which was then purified by column chromatography (MeOH–
CH2Cl2, 1:30) to give the desired 1-pyrazol-3-ylbenzimidazoles
1aa–fb in high overall yields (65–81%), based on the initial loading
level of the Wang resin.
Anal. Calcd for C20H18N4O2: C, 69.35; H, 5.24; N, 16.17. Found: C,
69.34; H, 5.40; N, 15.97.
Methyl 1-[5-(4-Chlorophenyl)-1H-pyrazol-3-yl]-1H-benzimida-
zole-5-carboxylate (1ea)
White solid; mp 296–297 °C.
IR (KBr): 3289 (NH), 1704 (C=O), 1612 cm–1 (C=N).
1H NMR (400 MHz, DMSO-d6): d = 3.87 (s, 3 H, OCH3), 7.22 (s, 1
H, H-4¢), 7.56 (t, J = 7.78 Hz, 2 H, Hm-C6H5), 7.84 (d, J = 7.78 Hz,
2 H, Ho-C6H5), 8.00 (d, J = 8.78 Hz, 1 H, H-6), 8.12 (d, J = 8.78 Hz,
1 H, H-7), 8.34 (s, 1 H, H-4), 8.82 (s, 1 H, H-2), 13.38 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 52.5 (OCH3), 94.9 (C-4¢),
112.9 (C-7), 121.8 (C-4), 124.9 (C-5), 125.2 (C-6), 127.6 (Co-
C6H5), 128.9 (Ci-C6H5), 129.6 (Cm-C6H5), 131.3 (Cp-C6H5), 135.9
(C-7a), 144.8 (C-5¢), 143.7 (C-3a), 145.1 (C-2), 147.0 (C-3¢), 167.4
(C=O).
MS (70 eV): m/z (%) = 354/352 (M+, 29/85), 323/321 (36/100).
Anal. Calcd for C18H13ClN4O2: C, 61.28; H, 3.71; N, 15.88. Found:
C, 61.33; H, 3.68; N, 15.96.
Methyl 1-[5-(4-Chlorophenyl)-1H-pyrazol-3-yl]-2-methyl-1H-
benzimidazole-5-carboxylate (1eb)
White solid; mp 276–277 °C.
IR (KBr): 3289 (NH), 1704 (C=O), 1612 cm–1 (C=N).
For the analytical and spectral properties of 1aa–1cc, see above.
1H NMR (400 MHz, DMSO-d6): d = 2.60 (s, 3 H, CH3), 3.85 (s, 3
H, OCH3), 7.10 (s, 1 H, H-4¢), 7.54 (t, J = 8.03 Hz, 2 H, Hm-C6H5),
7.84 (d, J = 8.03 Hz, 2 H, Ho-C6H5), 7.56 (d, J = 8.29 Hz, 1 H, H-7),
7.87 (d, J = 8.29 Hz, 1 H, H-6), 8.20 (s, 1 H, H-4), 13.85 (s, 1 H,
NH).
Methyl 1-[5-(4-Methylphenyl)-1H-pyrazol-3-yl]-1H-benzimi-
dazole-5-carboxylate (1da)
Yellow solid; mp 219–220 °C.
IR (KBr): 3271 (NH), 1713 (C=O), 1613 cm–1 (C=N).
13C NMR (100 MHz, DMSO-d6): d = 15.0 (CH3), 52.6 (OCH3), 98.9
(C-4¢), 111.4 (C-7), 120.5 (C-4), 124.4 (C-5), 125.0 (C-6), 127.5
(Cm-C6H5), 129.6 (Co-C6H5), 131.0 (Cp-C6H5), 134.4 (Ci-C6H5),
138.9 (C-7a), 143.2 (C-5¢), 141.6 (C-3a), 144.9 (C-3¢), 152.1 (C-2),
167.3 (C=O).
1H NMR (400 MHz, DMSO-d6): d = 2.37 (s, 3 H, ArCH3), 3.91 (s,
3 H, OCH3), 7.23 (s, 1 H, H-4¢), 7.60 (t, J = 7.85 Hz, 2 H, Hm-C6H5),
7.75 (d, J = 7.85 Hz, 2 H, Ho-C6H5), 8.05 (d, J = 8.66 Hz, 1 H, H-6),
8.19 (d, J = 8.66 Hz, 1 H, H-7), 8.37 (s, 1 H, H-4), 8.90 (s, 1 H, H-
2), 13.54 (s, 1 H, NH).
MS (70 eV): m/z (%) = 368/366 (M+, 36/100), 337/335 (35/99).
13C NMR (100 MHz, DMSO-d6): d = 20.7 (ArCH3), 52.1 (OCH3),
93.5 (C-4¢), 112.9 (C-7), 121.4 (C-4), 124.8 (C-5), 125.8 (C-6),
125.3 (Co-C6H5), 126.9 (Ci-C6H5), 130.7 (Cm-C6H5), 138.4 (Cp-
C6H5), 135.3 (C-7a), 144.0 (C-5¢), 143.2 (C-3a), 144.1 (C-2), 146.0
(C-3¢), 166.6 (C=O).
Anal. Calcd for C19H15ClN4O2: C, 62.22; H, 4.12; N, 15.27. Found:
C, 62.27; H, 4.11; N, 15.39.
Methyl 1-[5-(4-Bromophenyl)-1H-pyrazol-3-yl]-1H-benzimida-
zole-3-carboxylate (1fa)
MS (70 eV): m/z (%) = 332 (M+, 100), 301 (86).
White solid; mp 294–295 °C.
IR (KBr): 3275 (NH), 1716 (C=O), 1614 cm–1 (C=N).
Anal. Calcd for C19H16N4O2·2H2O: C, 61.95; H, 5.47; N, 15.21.
Found: C, 62.01; H, 5.41; N, 15.39.
1H NMR (400 MHz, DMSO-d6): d = 3.85 (s, 3 H, OCH3), 7.21 (s, 1
H, H-4¢), 7.68 (t, J = 7.89 Hz, 2 H, Hm-C6H5), 7.73 (d, J = 7.89 Hz,
2 H, Ho-C6H5), 7.97 (d, J = 8.29 Hz, 1 H, H-6), 8.11 (d, J = 8.29 Hz,
1 H, H-7), 8.30 (s, 1 H, H-4), 8.81 (s, 1 H, H-2), 13.63 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 52.5 (OCH3), 94.6 (C-4¢),
113.2 (C-7), 121.8 (C-4), 124.7 (C-5), 125.2 (C-6), 127.7 (Co-
C6H5), 122.4 (Ci-C6H5), 132.5 (Cm-C6H5), 128.1 (Cp-C6H5), 135.6
(C-7a), 143.3 (C-5¢), 143.3 (C-3a), 144.4 (C-2), 146.5 (C-3¢), 166.9
(C=O).
Methyl 2-Methyl-1-[5-(4-methylphenyl)-1H-pyrazol-3-yl]-1H-
benzimidazole-3-carboxylate (1db)
Yellow solid; mp 225–226 °C.
IR (KBr): 3287 (NH), 1723 (C=O), 1619 cm–1 (C=N).
1H NMR (400 MHz, DMSO-d6): d = 2.37 (s, 3 H, ArCH3), 2.65 (s,
3 H, 2-CH3), 3.89 (s, 3 H, OCH3), 7.07 (s, 1 H, H-4¢), 7.33 (t, J =
8.06 Hz, 2 H, Hm-C6H5), 7.77 (d, J = 8.06 Hz, 2 H, Ho-C6H5), 7.60
(d, J = 8.48 Hz, 1 H, H-7), 7.90 (d, J = 8.48 Hz, 1 H, H-6), 8.24 (s,
1 H, H-4), 13.72 (s, 1 H, NH).
MS (70 eV): m/z (%) = 398/396 (M+, 98/100), 367/365 (99/98).
13C NMR (100 MHz, DMSO-d6): d = 15.0 (CH3), 52.6 (OCH3), 98.9
(C-4¢), 111.4 (C-7), 120.5 (C-4), 124.4 (C-5), 125.0 (C-6), 127.5
(Cm-C6H5), 129.6 (Co-C6H5), 138.3 (Cp-C6H5), 126.5 (Ci-C6H5),
138.5 (C-7a), 144.5 (C-5¢), 141.9 (C-3a), 144.1 (C-3¢), 153.7 (C-2),
166.6 (C=O).
Anal. Calcd for C18H13BrN4O2·H2O: C, 52.07; H, 3.64; N, 13.49.
Found: C, 52.12; H, 3.75; N, 14.01.
Methyl 1-[5-(4-Bromophenyl)-1H-pyrazol-3-yl]-2-methyl-1H-
benzimidazole-3-carboxylate (1fb)
White solid; mp 280–281 °C.
MS (70 eV): m/z (%) = 346 (M+, 100), 315 (90).
IR (KBr): 3285 (NH), 1721 (C=O), 1614 cm–1 (C=N).
Synthesis 2008, No. 3, 387–394 © Thieme Stuttgart · New York

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Synthesis of 1-Pyrazol-3-ylbenzimidazoles
393
1H NMR (400 MHz, DMSO-d6): d = 2.60 (s, 3 H, CH3), 3.85 (s, 3
H, OCH3), 7.12 (s, 1 H, H-4¢), 7.58 (d, J = 8.03 Hz, 1 H, H-7), 7.69
(t, J = 7.78 Hz, 2 H, Hm-C6H5), 7.79 (d, J = 7.78 Hz, 2 H, Ho-C6H5),
7.86 (d, J = 8.03 Hz, 1 H, H-6), 8.19 (s, 1 H, H-4), 13.86 (s, 1 H,
NH).
13C NMR (100 MHz, DMSO-d6): d = 15.0 (CH3), 52.5 (OCH3), 99.0
(C-4¢), 111.4 (C-7), 120.4 (C-4), 121.6 (Ci-C6H5), 122.4 (C-5),
124.4 (C-6), 127.8 (Cm-C6H5), 132.1 (Cp-C6H5), 132.5 (Co-C6H5),
138.9 (C-7a), 142.4 (C-5¢), 142.0 (C-3a), 143.4 (C-3¢), 154.3 (C-2),
167.1 (C=O).
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Cisneros, C.; Insuasty, B.; Abonía, R.; Nogueras, M.;
Sortino, M.; Zacchino, S. J. Heterocycl. Chem. 2006, 43,
463. (e) Quiroga, J.; Cruz, S.; Insuasty, B.; Abonía, R.;
Nogueras, M.; Cobo, J. Tetrahedron Lett. 2006, 47, 27.
(f) Quiroga, J.; Portilla, J.; Insuasty, B.; Abonía, R.;
Nogueras, M.; Sortino, M.; Zacchino, S. J. Heterocycl.
Chem. 2005, 42, 61.
MS (70 eV): m/z (%) = 412/410 (M+, 100/98), 379/381 (90/91).
Anal. Calcd for C19H15BrN4O2: C, 55.49; H, 3.68; N, 13.62. Found:
C, 55.51; H, 3.67; N, 13.79.
Acknowledgment
Financial support from Consejo Nacional de Investigaciones
Científicas y Técnicas (CONICET), Agencia Nacional de Promo-
ción Científica y Tecnológica and Universidad Nacional de Rosario
from Argentina is gratefully acknowledged. Authors are also grate-
ful to COLCIENCIAS (Colombia), Universidad del Valle (Colom-
bia), the Spanish ‘Consejería de Innovación, Ciencia y Empresa,
Junta de Andalucía’, and Servicios Técnicos de Investigación de la
Universidad de Jaén. J.P. thanks COLCIENCIAS for a fellowship.
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