The synthesis of imidazo[4,5-d]pyridines from a substituted imidazole and acyl or sulfonyl acetonitrile

Article abstract of DOI:10.1016/j.tet.2007.02.078

1-Aryl-5-amino-4-cyanoformimidoyl imidazoles were reacted with acyl and sulfonyl acetonitriles, under mild experimental conditions, leading to imidazo[4,5-b]pyridines and imidazo[4,5-b]pyridine-5-ones. A reaction intermediate could be isolated in the reac

Full text of DOI:10.1016/j.tet.2007.02.078

Tetrahedron 63 (2007) 3745–3753
The synthesis of imidazo[4,5-d]pyridines from a substituted
imidazole and acyl or sulfonyl acetonitrile
*
Magdi E. A. Zaki and M. Fernanda Proenc¸a
Departamento de Quꢀımica, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
Received 24 November 2006; revised 13 February 2007; accepted 20 February 2007
Available online 23 February 2007
Abstract—1-Aryl-5-amino-4-cyanoformimidoyl imidazoles were reacted with acyl and sulfonyl acetonitriles, under mild experimental con-
ditions, leading to imidazo[4,5-b]pyridines and imidazo[4,5-b]pyridine-5-ones. A reaction intermediate could be isolated in the reaction with
methyl cyanoacetate, under carefully controlled experimental conditions. This intermediate cyclized to imidazo[4,5-b]pyridine-5-one, in the
presence of DBU. Reaction between 5-amino-4-cyanoformimidoyl-1-(4-fluorophenyl)imidazole and acetylacetone, occurred by a different
pathway to give a 6-carbamoylpurine.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
dihydro-3H-imidazo[4,5-b]pyridine-7-carboxylate in 36%
yield.10 Oxidation of 3-(2-(4-benzylphenoxy)ethyl)-3H-
imidazo[4,5-b]pyridine with m-CPBA provided the N-oxide
formation in the pyridine ring. Treatment of this compound
with trifluoroacetic anhydride yielded the corresponding
3-substituted 3H-imidazo[4,5-b]pyridine-5(4H)-one. The
parent imidazo[4,5-b]pyridine proved to be a potent inhibitor
of leukotriene A4 hydrolase, and the functionalization to
the imidazo[4,5-b]pyridine-5(4H)one considerably improved
the enzyme inhibitory potency, as well as a good oral activity
in a mouse in vivo assay.11
Imidazo[4,5-b]pyridines are an important class of biologi-
cally active compounds showing high affinity to cortico-
tropin-releasing factor1 and also anticancer,2 antiviral,3
antimitotic,4 and tuberculostatic5 action depending on the
nature and position of substituents on the heterocycle. In
addition, certain members of this class display high affinity
for the AT1 receptor, and are thus potent nonpeptide angio-
tensin IIantagonists.6 Imidazo[4,5-b]pyridines weretypically
prepared by condensation of an appropriate 2,3-diamino-
pyridine and an electrophilic carbon unit. The reaction of
2-methoxyethylamino-3-aminopyridine with aromatic alde-
hydes led to 1-methoxyethyl-2-aryl-1H-imidazo[4,5-b]pyri-
dines.7 A similar reaction occurred from N-substituted
nitropyridines, when these compounds were reduced in the
presence of aldehydes.8 2-Amino-3-nitropyridines have
also been used in the regioselective synthesis of either N-1
or N-3 substituted imidazo[4,5-b]pyridines by reaction with
aldehydes under carefully selected experimental conditions
and in the presence of an appropriate reducing agent.9 Imi-
dazo[4,5-b]pyridine-5-ones are difficult to prepare by this
method and only a few synthetic approaches have been re-
ported in the literature. Reaction of 5-amino-1,2-disubsti-
tuted imidazole with dialkyl acetylenedicarboxylate, at
room temperature, led to a dialkyl 1-(5-amino-1,2-disubsti-
tuted imidazol-4-yl)ethylene-1,2-dicarboxylate in yields
ranging from 35 to 44%. One of these compounds, dimethyl
1-(5-amino-1,2-dimethylimidazol-4-yl)ethylene-1,2-dicar-
boxylate, underwent thermal cyclization when heated at
190 ꢀC (1 min) giving methyl 2,3-dimethyl-5-oxo-4,5-
2. Results and discussion
In our research group, we have been studying the reactivity
of 5-amino-4-cyanoformimidoyl imidazoles 1, as versatile
precursors to 6-substituted purines12 and other fused nitro-
gen heterocycles.13 The cyanoformimidoyl unit plays a fun-
damental role in the reactivity of these compounds.
In this work, functionalized imidazo[4,5-b]pyridines 5
were isolated in good yield from the reaction between
N-aryl-5-amino-4-(cyanoformimidoyl)-imidazoles
1 and
3-phenyl-3-oxopropanenitrile 2a or 3-(7-methyl-1H-indol-
3-yl)-3-oxopropanenitrile 2b, in ethanol/acetonitrile or
ethanol/DMF. Product 5 gradually precipitated from the
homogeneous solution as a white solid and was isolated by
filtration (Scheme 1). The reaction must proceed through
the formation of intermediate 4, generated from adduct 3
by elimination of ammonia. Nucleophilic attack of the
amino group in the 5-position to the acyl substituent was
the only observed pathway, leading to the imidazo[4,5-
b]pyridine 5. Attempts to isolate this intermediate from
* Corresponding author. Tel.: +351 253604379; fax: +351 253678983;
e-mail: fproenca@quimica.uminho.pt
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.078

3746
M. E. A. Zaki, M. F. Proenc¸a / Tetrahedron 63 (2007) 3745–3753
R
N
R
N
R
N
R
N
NH2
NH
CN
NH2
NH2
COR'
NH2
N
R'
+
COR'
CN
NC COR'
- NH3
- H2O
N
N
N
N
CN
NC
NC
CN
H
CN
1a, R=4-CH3C6H4 2a, R'=C6H5
3
4
5
b, R=4-CNC6H4
c, R=4-CH3OC6H4
d, R=4-FC6H4
b, R'=
N
H
CH3
Compound
R
R´
Yield (%)
Reaction
Conditionsa)
4-MeC6H4
4-CNC6H4
C6H5
C6H5
5a
5b
ethanol:acetonitrile (5:1), 4h
ethanol:DMF(10:3), 8 days
C6H5
C6H5
ethanol:DMF (2:1), 20 h
4-MeOC6H4
4-FC6H4
5c
5d
ethanol:acetonitrile (5:1), 4 h
acetonitrile:diethyl ether (3:20), 4 h (0 ºC); 1 day
ethanol:DMF (10:3), 7 days
Indolyl
Indolyl
4-CNC6H4
5e
5f
4-MeOC6H4
Ethanol:DMF (2:1), 72 h
4-FC
6H4
Indolyl
ethanol:acetonitrile (10:3), 30 min
5g
a) All the experiments were carried out at room temperature
Scheme 1.
imidazole 1d and 3-phenyl-3-oxopropanenitrile in aceto-
nitrile and diethyl ether (3:20) failed, as the only product
isolated was again the imidazo[4,5-b]pyridine 5d (61%).
precipitated as a white solid. The compound was identified
as having structure 8 on the basis of spectroscopic analysis.
The reaction of imidazole 1a with phenylsulfonyl aceto-
nitrile in the presence of 1 equiv of DBU led to a complex
mixture after 7 days at room temperature and no attempts
were made to identify their components.
When imidazoles 1a and 1d were reacted with 3-phenyl-3-
oxopropanenitrile in the presence of one molar equivalent
of DBU, elimination of HCN from adduct 3a was the major
pathway, leading to the 7-amino-imidazo[4,5-b]pyridines 7
in very good yield (Scheme 2). Imidazole 6 must be the pre-
cursor of 7, which was formed by intramolecular cyclization
between the amino and carbonyl groups. Structures analo-
gous to 5 and 7 were previously isolated when imidazole 1
was reacted with malononitrile in the absence and in the
presence of DBU, respectively.13b
The reaction of imidazoles 1a–d with methyl cyanoacetate
2d using acetonitrile or acetonitrile/DMF as solvent
(Scheme 4) led to the formation of imidazo[4,5-b]pyri-
dine-5-ones 11, as was previously communicated.14 The
product precipitated as the ammonium salt 10 and was iso-
lated by filtration.
Imidazoles 1a, 1c, and 1d were also reacted with phenylsul-
fonyl acetonitrile 2c in ethanol/acetonitrile or ethanol/aceto-
nitrile/DMF (Scheme 3). When the homogeneous solution
was stirred at room temperature, the product gradually
Addition of acetic acid to a solution of compounds 10a–c in
water/ethanol enabled the isolation of the corresponding
imidazo[4,5-b]pyridine-5-ones 11 in excellent yield. Com-
pound 10d could not be fully neutralized by acetic acid
R
N
R
N
R
N
R
N
NH2
N
Ph
NH2
NH2
COPh
NH2
NH
CN
DBU
NC COPh
COPh
CN
+
- HCN
- H2O
N
N
N
N
CN
H2N
NH2
NC
H
CN
2a
1a, R=4-CH3C6H4
d, R=4-FC6H4
6
7
3
Compound
Reaction
Conditionsa)
R
Yield (%)
DBU (1.2 eq.); 2a (1.2 eq.)
61
96
4-MeC6H4
7a
ethanol:acetonitrile (5:8); 4h (0 ºC); 5 days
DBU (1.2 eq.); 2a (1.2 eq.)
ethanol:acetonitrile (1:1); 4h (0 ºC); 10 days
71
DBU (1.2 eq.);
2a (1.2 eq.)
4-FC6H4
7d
ethanol:acetonitrile (5:8); 4h (0 ºC); 5 days
a) All the experiments were carried out at room temperature
Scheme 2.

M. E. A. Zaki, M. F. Proenc¸a / Tetrahedron 63 (2007) 3745–3753
3747
R
R
N
N
NH2
NH2
NH
N
O
+
NC
S
O
Ph
- NH3
O
Ph
N
N
S
CN
O
CN
2c
1a, R=4-CH3C6H4
c, R=4-CH3OC6H4
d, R=4-FC6H4
8
Compound
R
Reaction
Yield (%)
Conditionsa)
8a
8c
8d
4-MeC6H4
4-MeOC6H4
4-FC6H4
ethanol:acetonitrile (5:1), 3 days
88
72
82
ethanol:DMF:acetonitrile(10:5:2), 5 days
ethanol:acetonitrile (2:1), 5 days
a) All the experiments were carried out at room temperature
Scheme 3.
(pKa¼4.76),15 as the product consistently incorporated half
an equivalent of ammonia, according to elemental analysis
and 1H NMR data. Neutralization of 10d was achieved
when trifluoroacetic acid (pKa¼0.23)15 was added to a solu-
tion of the compound in a mixture of aqueous ethanol and
DMF.
1650 cmꢁ1, confirming the presence of a six-membered
lactam ring. In the 13C NMR spectrum it was possible to
identify the signals for the cyano groups at d 112–113 and
116–117 ppm (for compounds 5), at d 117.4 ppm (for com-
pounds 7), and in the d 111–114 ppm region for compounds
8 and 11 The C–H signal in the d 141.5–151 ppm region
confirms the presence of the imidazo-pyridine system in
these compounds. The signal for the lactam carbonyl in
compounds 11a–d is also consistently present at around
d 162.5 ppm. In the 1H NMR spectrum of these compounds
a very acidic N–H was identified as a broad singlet in the
d 13–14 ppm. For compounds 5, 7, 8, and 11, the C–H signal
between d 8.6 and 9.5 ppm confirms that a fused aromatic
system is present.
The reaction pathway must occur by initial formation of
intermediate 9, which could be isolated from reaction of
1d with methyl cyanoacetate in acetonitrile/diethyl ether
(1:10), at ꢁ10 ꢀC. The orange solid 9d cyclized to com-
pound 10d after refluxing for 1 h in ethanol solution, in the
presence of DBU. Compound 9d showed a very intense car-
bonyl absorption in the IR spectrum (1707 cmꢁ1) and the
stretching vibration of the two cyano groups corresponded
to two intense bands at 2219 and 2202 cmꢁ1. In the 13C
NMR spectrum, these signals were identified at d 116.5
and 115.3 ppm. The ester carbonyl group is at d 163.0 ppm
and the C–H signal, at d 137.0 ppm, is typical of an imid-
DBU (2 equiv) was added to a solution of imidazole 1d and
methyl cyanoacetate in acetonitrile/diethyl ether, conditions
that would favor elimination of HCN from 3d to give an
intermediate analogous to 6, ultimately leading to the
7-amino-6-cyanoimidazo[4,5-b]pyridine-5-one structure.
The major product was 5-amino-1-aryl-4-cyanoimidazole,
together with traces of imidazole 1d indicating that, in the
presence of base, elimination of HCN from imidazole 1d
is much faster than reaction with methyl cyanoacetate.
1
azole structure. This was confirmed by H NMR spectrum,
where the signal for this proton is at d 7.77 ppm.
For the ammonium salts 10, the IR spectrum confirmed the
presence of two cyano groups showing a strong band at
around 2210 cmꢁ1 and a medium/weak signal in the 2230–
2239 cmꢁ1 region. In the 13C NMR spectrum, these groups
were present at around d 118.5 and 114.5 ppm. The lactam
carbonyl was in the d 166.9–168.1 ppm region and the C–
H signal was at d 141.6–143.7 ppm region. In the 1H NMR
spectrum this proton appears in the d 8.39–8.65 ppm region,
and a singlet at around d 7.2 ppm integrating for four protons
was assigned to the ammonium ion.
In the reaction of imidazole 1 with phenylsulfonyl aceto-
nitrile and methyl cyanoacetate, elimination of ammonia
from intermediate 3 was the only observed pathway. The be-
havior of 3-phenyl-3-oxoacetonitrile compared with that of
malononitrile,13b leading to imidazo[4,5-b]pyridine 5 or 7
depends on the presence or absence of DBU in the reaction
mixture. The pathway leading to 7 (by elimination of HCN
from adduct 3) seems to occur only if the carbon acid has
a pKa lower than ca. 12 (values obtained in DMSO solution).
This is the case of 3-oxo-3-phenylacetonitrile (pKa¼10.2)15
and malononitrile (pKa¼11.1).16 Phenylsulfonyl acetonitrile
(pKa¼12.0)15 or methylcyanoacetate (pKa¼13.1)17 are
weaker carbon acids and the formation of the carbanion
from the active methylene compound does not occur in an
appreciable extent by the addition of DBU (pKa ca. 12)18
to the active methylene compound (Scheme 5).
For compounds 5, 7, and 11, the IR spectra showed a single
intense band in the 2206–2243 cmꢁ1 region, assigned to the
stretching vibration of the cyano group. A minor shoulder
was also present in the spectrum of compounds 5a, 5c, and
5d, for the second cyano substituent. For compounds 8,
a weak absorption band was present in the 2230–
2236 cmꢁ1 region. The carbonyl stretching vibration is ab-
sent in the spectrum of compounds 11a–c, which shows an
intense band in the 1590–1600 cmꢁ1 region. This may be
an indication that 11B is the predominant tautomer in the
solid state. Compound 11d showed an intense band at
The formation of the anion from the carbon acid would gen-
erate the intermediate 3A that easily eliminates the cyanide

3748
M. E. A. Zaki, M. F. Proenc¸a / Tetrahedron 63 (2007) 3745–3753
R
N
R
N
R
N
NC COOMe
NH2
NH2
COOMe
NH2
NH2
NH
CN
2d
COOMe
CN
- NH3
0 to -10 ºC
N
N
N
NC
NC
H
CN
9
1a, R=4-CH3C6H4
b, R=4-CNC6H4
c, R=4-CH3OC6H4
d, R=4-FC6H4
3
XH
R
N
R
N
R
N
H
N
N
OH
CN
O
N
O
Acid
N
N
N
CN
CN
CN
11B
CN
11A
CN
10
Reaction
Conditions
Yield (%)
R
Compound
36a)
88a)
acetonitrile:diethyl ether (1:10)
4 h (0 ºC); 1 day (-10 ºC)
4-FC6H4
4-MeC6H4
4-CNC6H4
9d
acetonitrile:DMF (3:2)
6 h (0 ºC); 1 day (-10 ºC)
10a
X=NH3
86a)
86a)
acetonitrile:DMF (5:2)
6 h (0 ºC); 8 days (-10 ºC)
10b
X=NH3
acetonitrile:DMF (1:1)
6 h (0 ºC); 3 days (-10 ºC)
4-MeOC6H4
4-FC6H4
10c
X=NH3
acetonitrile:DMF (1:1)
8 h (0 ºC); 15 h (-10 ºC)
86a)
10d
X=NH3
82b)
84c)
79c)
Ethanol; DBU
1 h (reflux)
4-FC6H4
10d
X=DBU
H2O:Ethanol:HOAc (5:2:1.5)
30 min (rt)
4-MeC6H4
4-CNC6H4
4-MeOC6H4
4-FC6H4
11a
11b
11c
11d
H2O:Ethanol:HOAc (5:2:1.5)
30 min (rt)
82c)
50c)
H2O:Ethanol:HOAc (5:3:1)
30 min (rt)
H2O:Ethanol:DMF:CF3CO2H
(5:3:2:0.04), 30 min (rt)
a) Yield and reaction conditions from imidazole 1 and methyl cyanoacetate.
b) Yield and reaction conditions from imidazole 9d.
c) Yield and reaction conditions from the ammonium salt of imidazo[4,5-b]pyridine-5-one 10.
Scheme 4.
ion, leading to imidazole 6 in either the Z or the E configu-
ration. The carbon acid can also react with the cyanoform-
imidoyl substituent of imidazole 12, but in this case the
proton would be intramolecularly transferred to the imine ni-
trogen, to generate the amine. The acidic proton can further
protonate this amine unit, leading to the formation of imid-
azoles 4, also in either the Z or the E configuration, upon
elimination of ammonia.
The presence of only one carbonyl/sulfoxide group in the ac-
tive methylene compound also determines this reaction path-
way. The reaction between 1d and acetylacetone, which has
a pKa value of 13.319 (similar to that of methylcyanoacetate),
under similar conditions to those used above, gave the 6-car-
bamoyl purine 14, formed by the pathway shown in Scheme
6. The formation of 6-carbamoyl purines is known to occur
when 5-amino-4-cyanoformimidoyl imidazoles 1 react with
aldehydes or ketones12a–c,13 and was also reported in the
presence of ethyl acetoacetate.13b
The formation of imidazo[4,5-b]pyridines 5 and 13 or 7 and
12 was expected by intramolecular cyclization of intermedi-
ate 4 or 6, respectively. In the present work, compounds 5
and 7 were the only products isolated, possibly because these
reactions occur with elimination of 1 equiv of water, and are
thus energetically favored.
In conclusion, a mild and efficient synthesis of biologically
interesting functionalized imidazo[4,5-b]pyridines and imi-
dazo[4,5-b]pyridine-5-ones has been developed. A limited
number of methods were previously reported for the

M. E. A. Zaki, M. F. Proenc¸a / Tetrahedron 63 (2007) 3745–3753
3749
R
N
R
N
R
N
R
N
DBUH
NC EW
NH2
NH
EW
NH2
NH
CN
NH2
NH
CN
NH2
NH2
EW
DBU
+
NC
EW
+
N
N
N
N
NC
NC
H
1
H
1
CN
CN
3A
3B
- NH3
EW = COPh
- HCN
EW = COPh
R
N
R
N
R
N
R
N
NH2
NH2
NH2
NH2
EW
CN
EW
CN
CN
CN
EW
N
N
N
N
NC
E-4
H2N
H2N
EW
NC
Z-6
E-6
Z-4
R
N
R
N
R
N
R
N
N
Ph
N
NH2
COPh
N
Ph
N
NH2
COPh
N
F
N
N
N
CN
CN
NH2
NH2
CN
CN
13
5
7
12
Scheme 5.
F
F
H
O
O
O
O
Me
Me
Me
Me
NH2
NH2
NH2
N
N
N
N
N
N
N
CH3
NH
CN
N
CH2
CH3
Me
Me
OH
C
C
N
O
HN
O
H2
O
1d
F
F
F
Me
Me
N
NH
N
N
N
N
N
N
CH2COMe
- acetone
CH3
N
N
O
Me
O
NH
O
N
H2C
H2N
O
H2N
H2N
14
Scheme 6.
preparation of these structures, which may be biologically
important. The compounds prepared have been submitted
to TAACF20 for screening their tuberculostatic activity and
studies on their antioxidant properties are also in progress.
the samples, and confirmed using the HMBC and HMQC
techniques (to identify the signals for the aromatic Ci and
Cp). The IR spectra were obtained with an FTIR Bomem-
MB104 spectrophotometer using Nujol mulls and NaCl
plates. Elemental analysis was performed on an LECO
CHNS-932 instrument. Melting points were determined
using a Gallenkamp melting point apparatus and are
uncorrected.
3. Experimental
3.1. General techniques
3.2. General procedure for the synthesis of 3-aryl-5-
phenyl-3H-imidazo[4,5-b]pyridine-6,7-dicarbonitriles
(5a–d) and 3-aryl-5-(7-methyl-1H-indol-3-yl)-3H-imid-
azo[4,5-b]pyridine-6,7-dicarbonitriles (5e–g)
The 5-amino-1-aryl-4-(cyanoformimidoyl)imidazoles 1a–d
used in this work were prepared according to previously
described procedures.21 Compound 2b was prepared accord-
ing to the procedure described by Bergman et al.22 NMR
spectra were recorded on a Varian Unity Plus 300 spectro-
meter with TMS as an internal standard. The fluorine cou-
pling constants in the 13C NMR spectra were verified in all
A solution of 5-amino-1-aryl-4-cyanoformimidoyl imid-
azole (0.65–1.33 mmol) in ethanol/DMF (for 5b, 5c, 5e,
and 5f), ethanol/acetonitrile (for 5a, 5d, and 5g) (3–5 mL),

3750
M. E. A. Zaki, M. F. Proenc¸a / Tetrahedron 63 (2007) 3745–3753
or acetonitrile/diethyl ether (3:20) (for 5d) was combined
with 3-oxo-3-phenylpropanenitrile or (7-methyl-1H-indol-
3-yl)-3-oxopropanenitrile (1.5 molar equiv) and the solution
was stirred at room temperature or in an ice bath. The prod-
uct 5 gradually precipitates from solution as a white solid
and is filtered after 30 min to 8 days.
1H NMR (300 MHz, DMSO-d6): d¼2.48 (s, 3H, CH3),
7.03 (m, 2H), 7.97 (t, 1H), 8.31 (s, 1H), 8.15 (d, J¼8.4 Hz,
2H), 8.24 (d, J¼8.4 Hz, 2H), 9.34 (s, 1H), 11.8 (br, NH);
13C NMR (75 MHz, DMSO-d6): d¼16.7, 100.5, 110.8,
112.2, 115.0, 117.1, 118.2, 121.3, 121.4, 123.3, 123.9,
125.0, 128.5, 132.4, 133.8, 135.7, 137.7, 148.4, 148.9,
152.7. Anal. Calcd for C24H13N7$0.2H2O (403.02): C,
71.53; H, 3.35; N, 24.33. Found: C, 71.29; H, 3.63; N, 24.09.
3.2.1. 3-(40-Tolyl)-5-phenyl-3H-imidazo[4,5-b]pyridine-
6,7-dicarbonitrile (5a). Yield 0.28 g, 0.83 mmol (94%);
mp 278–279 ꢀC. IR (Nujol mull) 2224 (m), 2237 (w),
3.2.6. 3-(40-Methoxyphenyl)-5-(7-methyl-1H-indol-3-yl)-
3H-imidazo[4,5-b]pyridine-6,7-dicarbonitrile (5f). Yield
0.27 g, 0.65 mmol (78%); mp above 350 ꢀC. IR (Nujol
mull) 2221 (m), 1656 (m), 1616 (w), 1600 (m), 1561 (w),
1
1593 (s), 1560 (w), 1526 (w), 1517 (s) cmꢁ1; H NMR
(300 MHz, DMSO-d6): d¼2.39 (s, 3H, CH3), 7.44 (d,
J¼8.4 Hz, 2H), 7.58–7.60 (m, 3H), 7.78 (d, J¼8.4 Hz,
2H), 7.85–7.89 (m, 2H), 9.36 (s, 1H); 13C NMR (75 MHz,
DMSO-d6): d¼20.7, 103.5, 113.0, 114.5, 116.2, 123.9,
128.7, 129.3, 130.2, 130.4, 131.2, 136.6, 137.4, 138.5,
148.7, 151.0, 156.5. Anal. Calcd for C21H13N5 (335.37):
C, 75.21; H, 3.91; N, 20.88. Found: C, 75.14; H, 3.98; N,
20.90.
1
1532 (s), 1517 (s) cmꢁ1; H NMR (300 MHz, DMSO-d6):
d¼2.48 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 6.97 (d,
J¼4.8 Hz, 2H), 7.18 (d, J¼8.7 Hz, 2H), 7.81 (d, J¼8.7 Hz,
2H), 8.01 (m, 1H), 8.30 (s, 1H), 9.13 (s, 1H), 11.85 (br s,
NH); 13C NMR (75 MHz, DMSO-d6): d¼16.7, 55.6,
100.0, 112.4, 113.1, 114.6, 117.4, 119.0, 121.1, 121.2,
123.2, 125.2, 125.6, 126.7, 128.2, 132.1, 135.7, 148.8,
149.7, 152.6, 159.2. Anal. Calcd for C24H16N6O$0.75H2O
(417.94): C, 68.97; H, 4.22; N, 20.11. Found: C, 69.18; H,
4.613; N, 20.49.
3.2.2. 3-(40-Cyanophenyl)-5-phenyl-3H-imidazo[4,5-
b]pyridine-6,7-dicarbonitrile
0.44 mmol (70%); mp 301–302 ꢀC. IR (Nujol mull) 2229
(s), 1597 (s), 1578 (w), 1510 (s) cmꢁ1 1H NMR
(5b).
Yield
0.16 g,
;
(300 MHz, DMSO-d6): d¼7.60–7.62 (m, 3H), 7.89–7.92
(m, 2H), 8.16 (d, J¼8.7 Hz, 2H), 8.25 (d, J¼8.7 Hz, 2H),
9.51 (s, 1H); 13C NMR (75 MHz, DMSO-d6): d¼104.0,
111.0, 112.8, 114.8, 115.9, 118.1, 128.7, 129.1, 129.3,
130.5, 133.5, 134.8, 136.4, 137.5, 148.4, 150.5, 156.7.
Anal. Calcd for C21H10N6$0.2DMF (360.97): C, 71.87; H,
3.18; N, 24.06. Found: C, 71.74; H, 3.40; N, 23.72.
3.2.7. 3-(40-Fluorophenyl)-5-(7-methyl-1H-indol-3-yl)-
3H-imidazo[4,5-b]pyridine-6,7-dicarbonitrile (5g). Yield
0.29 g, 0.71 mmol (81%); mp 334–336 ꢀC. IR (Nujol
1
mull) 2228 (m), 1599 (m), 1536 (m), 1518 (s) cmꢁ1; H
NMR (300 MHz, DMSO-d6): d¼2.48 (s, 3H, CH3), 6.98–
7.03 (m, 2H), 7.54 (t, J¼8.7 Hz, 2H), 7.96–8.01 (m, 3H),
8.33 (s, 1H), 9.22 (s, 1H), 11.90 (s, NH); 13C NMR
(75 MHz, DMSO-d6): d¼16.7, 100.4, 112.4, 113.1, 114.9,
116.5 (J¼22.9 Hz), 117.3, 118.9, 121.2, 121.4, 123.2,
125.3, 126.6 (J¼8.9 Hz), 128.4, 130.2 (J¼2.9 Hz), 132.2,
135.8, 149.0, 149.7, 152.8, 161.7 (J¼244.6 Hz). Anal. Calcd
for C23H13N6F$1.75H2O (423.93): C, 65.17; H, 3.92; N,
19.82. Found: C, 65.08; H, 4.27; N, 19.47.
3.2.3. 3-(40-Methoxyphenyl)-5-phenyl-3H-imidazo[4,5-
b]pyridine-6,7-dicarbonitrile
0.83 mmol (79%); mp 238–239 ꢀC. IR (Nujol mull) 2243
(w), 2255 (m), 1612 (w), 1598 (s), 1520 (s) cmꢁ1 1H
(5c).
Yield
0.29 g,
;
NMR (300 MHz, DMSO-d6): d¼3.83 (s, 3H, OCH3),
7.16–7.19 (d, 2H, J¼9.0 Hz), 7.57–7.60 (d, 2H, J¼
9.0 Hz), 7.56–7.60 (m, 3H), 7.84–7.90 (m, 2H), 9.31 (s,
1H); 13C NMR (75 MHz, DMSO-d6): d¼55.6, 103.4,
113.0, 114.4, 114.8, 116.1, 125.6, 126.4, 128.7, 129.3,
130.3, 134.3, 136.6, 148.8, 151.1, 156.4, 159.3. Anal. Calcd
for C21H13N5O (351.37): C, 71.80; H, 3.73; N, 19.93. Found:
C, 71.74; H, 3.81; N, 19.91.
3.3. General procedure for the reaction of 5-amino-
1-aryl-4-cyanoformimidoylimidazole with 3-oxo-3-
phenylpropanenitrile in the presence of DBU
3-Oxo-3-phenylpropanenitrile (0.8 mmol) was added to a so-
lution of DBU (0.8 mmol) in ethanol (5 mL) and the mixture
was stirred in an ice bath for 1 h. A solution of imidazole 1
(0.67 mmol) in acetonitrile (8 mL) was added to the reaction
mixture, which was stirred in an ice bath for 4 h, and then at
room temperature for 5–10 days. The suspension was filtered
and washed with diethyl ether, leading to a white solid iden-
tified as compound 7.
3.2.4. 3-(40-Fluorophenyl)-5-phenyl-3H-imidazo[4,5-
b]pyridine-6,7-dicarbonitrile
(5d).
Yield
0.13 g,
0.38 mmol (87%); mp 276–278 ꢀC. IR (Nujol mull) 2226
(m), 2237 (w), 1606 (w), 1593 (s), 1565 (s), 1517
(s) cmꢁ1
;
1H NMR (300 MHz, DMSO-d6): d¼7.50 (t,
J¼8.7 Hz, 2H), 7.57–7.59 (m, 3H), 7.82–7.89 (m, 2H),
7.97 (dd, J¼8.7, 4.7 Hz, 2H), 9.36 (s, 1H); 13C NMR
(75 MHz, DMSO-d6): d¼103.6, 112.9, 114.5, 116.1, 116.7
(J¼23.2 Hz), 126.4 (J¼8.9 Hz), 128.7, 129.3, 130.0
(J¼3.2 Hz), 130.4, 134.4, 136.5, 148.7, 151.0, 156.6,
161.7 (J¼244.9 Hz). Anal. Calcd for C20H10N5F (339.33):
C, 70.79; H, 2.97; N, 20.64. Found: C, 70.42; H, 3.12; N,
20.65.
3.3.1. 7-Amino-3-(4-tolylphenyl)-5-phenyl-3H-imid-
azo[4,5-b]pyridine-6-carbonitrile (7a). Yield 0.19 g,
0.53 mmol (61%); mp 226–227 ꢀC. IR (Nujol mull) 2207
(s), 1650 (s), 1604 (s), 1562 (m) cmꢁ1
;
1H NMR
(300 MHz, DMSO-d6): d¼2.36 (s, 3H, CH3), 7.37 (d,
J¼8.4 Hz, 2H), 7.49 (s, 2H, NH2), 7.45–7.50 (m, 3H), 7.74
(d, J¼8.4 Hz, 2H), 7.75–7.72 (m, 2H), 8.62 (s, 1H); 13C
NMR (75 MHz, DMSO-d6): d¼20.6, 84.6, 121.0, 123.4,
128.1, 128.9, 129.2, 129.9, 132.5, 137.2, 138.9, 141.5,
146.7, 150.5, 158.1. Anal. Calcd for C20H15N5$1.7H2O
(356.01): C, 67.48; H, 5.19; N, 19.67. Found: C, 67.49; H,
5.08; N, 19.64.
3.2.5. 3-(40-Cyanophenyl)-5-(7-methyl-1H-indol-3-yl)-
3H-imidazo[4,5-b]pyridine-6,7-dicarbonitrile (5e). Yield
0.16 g, 0.40 mmol (63%); mp above 350 ꢀC. IR (Nujol
mull) 2233 (m), 1594 (s), 1530 (s), 1514 (s) cmꢁ1
;

M. E. A. Zaki, M. F. Proenc¸a / Tetrahedron 63 (2007) 3745–3753
3751
3.3.2. 7-Amino-3-(4-fluorophenyl)-5-phenyl-3H-imid-
azo[4,5-b]pyridine-6-carbonitrile 7d. Yield 0.17 g,
0.48 mmol (71%); mp 209–210 ꢀC. IR (Nujol mull) 2206
Calcd for C19H12N5O2FS (393.38): C, 58.01; H, 3.07;
N, 17.80; S, 8.15. Found: C, 58.19; H, 3.39; N, 17.75; S,
8.18.
(s), 1662 (s), 1604 (m), 1565 (m) cmꢁ1
;
1H NMR
(300 MHz, DMSO-d6): d¼7.43 (t, J¼9.0 Hz, 2H), 7.46–
7.51 (m, 3H), 7.71–7.75 (m, 2H), 7.94 (dd, J¼9.0, 5.0 Hz,
2H), 8.65 (s, 1H); 13C NMR (75 MHz, DMSO-d6):
d¼84.8, 116.3 (d, J¼23.0 Hz), 120.9, 125.8 (d, J¼8.6 Hz),
128.2, 128.9, 129.2, 131.3 (d, J¼2.9 Hz), 138.8, 141.5,
146.7, 150.5, 158.3, 161.0 (d, J¼243.0 Hz). Anal. Calcd
for C19H12N5F$1.5H2O (356.36): C, 64.04; H, 4.24; N,
19.65. Found: C, 63.83; H, 4.195; N, 19.40.
3.5. Reaction of 5-amino-4-cyanoformimidoyl-1-(40-
tolylphenyl)imidazole with phenylsulfonyl acetonitrile
in the presence of DBU
A solution of 5-amino-4-cyanoformimidoyl-1-(40-tolylphe-
nyl)imidazole 1a (0.20 g, 0.89 mmol) in acetonitrile
(3 mL) was added to a solution of phenylsulfonyl aceto-
nitrile (0.30 g, 1.80 mmol) and DBU (0.28 g, 1.80 mmol)
in ethanol (10 mL) that had been stirred in an ice bath for
2 h. The solution was stirred in the ice bath for another 3 h
and the mixture was kept standing at ꢁ10 ꢀC for 3 days.
The reaction was followed by TLC, which showed that
a complex mixture had been formed, together with extensive
degradation.
3.4. General procedure for the synthesis of 5-amino-3-
aryl-6-(phenylsulfonyl)-3H-imidazo[4,5-b]pyridine-7-
carbonitriles (8a–d)
A solution of 5-amino-1-aryl-4-cyanoformimidoyl imid-
azole 1 (0.62–0.87 mmol) in ethanol/acetonitrile (3–5 mL)
(for 8a and 8d) or ethanol/acetonitrile/DMF (for 9c) was
combined with phenylsulfonyl acetonitrile (1.5–1.6 molar
equivalent) and the homogeneous solution was stirred at
room temperature. The product gradually precipitates from
solution as a white solid and is filtered after 3–5 days.
3.6. General procedure for the synthesis of the ammo-
nium salt of 3-aryl-6,7-dicyano-5-oxo-4,5-dihydro-3H-
imidazo[4,5-b]pyridine (10a–d)
A solution of 5-amino-1-aryl-4-cyanoformimidoyl imid-
azole 1 (0.4–1.2 mmol) in acetonitrile (3–5 mL) and di-
methylformamide (1–3 mL) was combined with methyl
cyanoacetate (1.4–2.4 molar equivalent) and the mixture
was stirred in an ice bath for 6–8 h. After standing at
ꢁ10 ꢀC for 1–8 days, the solid suspension was filtered and
washed with diethyl ether. A second crop of the same prod-
uct could be recovered from the mother liquor after concen-
tration on the rotary evaporator.
3.4.1. 5-Amino-3-(40-tolyl)-6-(phenylsulfonyl)-3H-imid-
azo[4,5-b]pyridine-7-carbonitrile (8a). Yield 0.23 g,
0.59 mmol (88%); mp 268–269 ꢀC. IR (Nujol mull) 2231
(w), 1802 (w), 1607 (s), 1583 (s), 1573 (w) cmꢁ1 1H
;
NMR (300 MHz, DMSO-d6): d¼2.35 (s, 3H, CH3), 7.33
(d, J¼8.4 Hz, 2H), 7.34 (s, 2H, NH2), 7.62 (t, J¼8.4 Hz,
2H), 7.67–7.75 (m, 3H), 8.07–8.10 (d, 2H, J¼8.7 Hz),
8.76 (s, 1H); 13C NMR (75 MHz, DMSO-d6): d¼20.6,
111.2, 111.6, 112.7, 123.9, 126.6, 129.8, 129.8, 131.3,
131.5, 134.5, 137.9, 140.4, 147.0, 149.9, 154.5. Anal. Calcd
for C20H15N5O2S (389.42): C, 61.69; H, 3.88; N, 17.98.
Found: C, 61.47; H, 3.90; N, 17.97.
3.6.1. Ammonium salt of 6,7-dicyano-3-(40-tolyl)-5-oxo-
4,5-dihydro-3H-imidazo[4,5-b]pyridine (10a). Yield
0.025 g, 0.78 mmol (88%); mp 317–318 ꢀC. IR (Nujol
1
mull) 2239 (w), 2211 (m), 1598 (m), 1585 (w) cmꢁ1; H
NMR (300 MHz, DMSO-d6): d¼2.35 (s, 3H), 7.20 (s, 4H),
7.32 (d, J¼8.4 Hz, 2H), 7.69 (d, J¼8.4 Hz, 2H), 8.42 (s,
1H); 13C NMR (75 MHz, DMSO-d6): d¼20.6, 92.7, 113.5,
114.1, 118.9, 122.6, 123.5, 129.6, 132.7, 136.3, 142.3,
151.2, 168.1. Anal. Calcd for C15H9N5O$NH3$1.5H2O
(319.32): C, 56.42; H, 4.74; N, 26.32. Found: C, 56.56; H,
4.61; N, 26.08.
3.4.2. 5-Amino-3-(40-methoxyphenyl)-6-(phenylsul-
fonyl)-3H-imidazo[4,5-b]pyridine-7-carbonitrile (8c).
Yield 0.18 g, 0.44 mmol (72%); mp 248–249 ꢀC. IR (Nujol
mull) 2229 (w), 1802 (w), 1603 (s), 1582 (s), 1572 (s) cmꢁ1
;
1H NMR (300 MHz, DMSO-d6): d¼3.09 (s, 3H, OCH3),
7.09 (d, J¼9.0 Hz, 2H), 7.33 (s, 2H, NH2), 7.63 (d,
J¼9.0 Hz, 2H), 7.67 (t, J¼7.8 Hz, 2H), 7.76 (t, J¼7.8 Hz,
1H), 8.08 (d, J¼7.8 Hz, 2H), 8.70 (s, 1H); 13C NMR
(75 MHz, DMSO-d6): d¼55.6, 111.1, 111.6, 112.7, 114.6,
125.9, 126.6, 126.8, 129.8, 131.1, 134.5, 140.4, 147.3,
150.1, 154.5, 159.1. Anal. Calcd for C20H15N5O3S
(405.42): C, 59.25; H, 3.73; N, 17.27; S, 7.90. Found: C,
59.15; H, 4.03; N, 17.20; S, 7.97.
3.6.2. Ammonium salt of 6,7-dicyano-3-(40-cyanophenyl)-
5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridine (10b).
Yield 0.13 g, 0.42 mmol (86%); mp 345–346 ꢀC. IR
(Nujol mull) 2235 (w), 2211 (s), 1652 (s), 1598 (s), 1587
(s), 1553 (s) cmꢁ1
;
1H NMR (300 MHz, DMSO-d6):
d¼7.20 (s, 4H), 8.00 (d, J¼9.0 Hz, 2H), 8.21 (d, J¼
9.0 Hz, 2H), 8.65 (s, 1H); 13C NMR (75 MHz, DMSO-d6):
d¼93.20, 108.8, 113.9, 114.0, 118.6, 118.5, 122.2, 123.7,
133.5, 139.0, 141.6, 150.9, 168.0. Anal. Calcd for
C15H6N6O$NH3$0.2H2O (306.89): C, 58.71; H, 3.08; N,
31.95. Found: C, 58.85; H, 3.15; N, 31.78.
3.4.3. 5-Amino-3-(40-fluorophenyl)-6-(methylsulfonyl)-
3H-imidazo[4,5-b]pyridine-7-carbonitriles (8d). Yield
0.28 g, 0.71 mmol (82%); mp 279–280 ꢀC. IR (Nujol
mull) 2236 (w), 1743 (w), 1616 (s), 1598 (s), 1573
1
(s) cmꢁ1; H NMR (300 MHz, DMSO-d6): d¼7.38 (s, 2H,
NH2), 7.42 (t, J¼9.0 Hz, 2H), 7.67 (t, J¼7.5 Hz, 2H), 7.76
(t, J¼7.5 Hz, 1H), 7.81 (dd, J¼4.8, 9.0 Hz), 8.09 (d, 2H,
J¼7.5 Hz), 8.77 (s, 1H); 13C NMR (75 MHz, DMSO-d6):
d¼111.3, 111.7, 112.6, 116.3 (J¼22.9 Hz), 126.5 (J¼
8.9 Hz), 126.6, 129.8, 130.4 (J¼2.9 Hz), 131.1, 134.5,
140.4, 147.0, 150.0, 154.6, 161.4 (J¼244.3 Hz). Anal.
3.6.3. Ammonium salt of 6,7-dicyano-3-(40-methoxy-
phenyl)-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridine
(10c). Yield 0.11 g, 0.35 mmol (86%); mp 306–307 ꢀC. IR
(Nujol mull) 2235 (w), 2211 (s), 1652 (s), 1598 (s), 1587
(s), 1553 (s) cmꢁ1
;
1H NMR (300 MHz, DMSO-d6):
d¼3.80 (s, 3H), 7.07 (d, J¼9.0 Hz, 2H), 7.21 (br s, 4H),

3752
M. E. A. Zaki, M. F. Proenc¸a / Tetrahedron 63 (2007) 3745–3753
7.67 (d, J¼9.0 Hz, 2H), 8.39 (s, 1H); 13C NMR (75 MHz,
DMSO-d6): d¼55.5, 92.6, 113.5, 114.2, 114.4, 118.9,
124.6, 128.0, 142.8, 158.2, 168.0. Anal. Calcd for
C15H9N5O2$NH3$0.2H2O (311.90): C, 57.76; H, 4.01; N,
26.95. Found: C, 57.69; H, 4.22; N, 26.61.
148.5, 159.4, 162.5. Anal. Calcd for C15H9N5O2 (291.27):
C, 61.85; H, 3.11; N, 24.04. Found: C, 61.88; H, 3.22; N,
23.84.
3.7.4. 6,7-Dicyano-3-(40-fluorophenyl)-5-oxo-4,5-di-
hydro-3H-imidazo[4,5-b]pyridine (11d). Yield 0.06 g,
0.17 mmol (50%); mp 315.5–316.5 ꢀC. IR (Nujol mull)
3.6.4. Ammonium salt of 6,7-dicyano-3-(40-fluoro-
phenyl)-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridine
(10d). Yield 0.31 g, 1.03 mmol (86%); mp 302–304 ꢀC. IR
(Nujol mull) 2239 (w), 2210 (s), 1596 (s), 1552 (s), 1519
(s) cmꢁ1; 1H NMR (300 MHz, DMSO-d6): d¼7.19 (s, 4H),
7.38 (t, J¼9.0 Hz, 2H), 7.83 (dd, J¼9.0, 4.8 Hz, 2H), 8.58
(s, 1H); 13C NMR (75 MHz, DMSO-d6) d¼92.5, 113.8,
114.1, 116.1 (d, J¼22.9 Hz), 117.7, 125.1, 125.4 (d, J¼
8.6 Hz), 131.1, 143.7, 150.4, 160.9 (d, J¼243.2 Hz),
166.9. Anal. Calcd for C14H6N5OF$NH3$H2O$0.5C3H7NO
(350.83): C, 53.07; H, 4.17; N, 25.96. Found: C, 53.39; H,
4.30; N, 25.84.
1
2227 (s), 1650 (s), 1593 (s), 1521 (s), 1500 (m) cmꢁ1; H
NMR (300 MHz, DMSO-d6): d¼7.49 (t, J¼8.7 Hz, 2H),
7.84 (dd, J¼8.7, 4.8 Hz, 2H), 8.96 (s, 1H), 13.2–14.0 (br s,
1H); 13C NMR (75 MHz, DMSO-d6): d¼91.3, 112.8,
114.4, 115.2, 116.6 (d, J¼22.9 Hz), 127.0 (d, J¼8.8 Hz),
130.0, 130.1 (d, J¼2.8 Hz), 147.7, 148.4, 161.8 (d,
J¼244.9 Hz), 162.6. Anal. Calcd for C14H6N5OF$C3H7NO
(352.33): C, 57.95; H, 3.72; N, 23.85. Found: C, 58.08; H,
3.84; N, 23.67.
3.8. Synthesis of methyl 2-[5-amino-(40-fluorophenyl)-
imidazol-4-yl]-1,2-dicyanocarboxylate (9d)
3.7. General procedure for the synthesis of 3-aryl-6,7-
dicyano-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridines
(11a–d)
A solution of 5-amino-4-cyanoformimidoyl-(40-fluorophe-
nyl)imidazole 1d (0.10 g, 0.44 mmol) in acetonitrile
(2 mL) and diethyl ether (20 mL) was combined with methyl
cyanoacetate (0.06 g, 0.60 mmol) while the reaction mixture
was kept stirring in an ice bath. The solution was allowed to
stand at ꢁ10 ꢀC for 24 h, when the solvent was partially re-
moved in the rotary evaporator. Addition of ethanol (10 mL)
led to an orange solid that was filtered and washed with di-
ethyl ether to give the title compound (0.05 g, 36%) as a red
solid; mp 253–255 ꢀC. IR (Nujol mull) 2219 (m), 2202 (m),
A solution of the ammonium salt of 3-aryl-6,7-dicyano-
5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridine (ca. 0.35
mmol) in ethanol (3 mL), water (5 mL), and acetic acid (1–
1.5 mL) (for 11a–c) or ethanol (3 mL), water (5 mL), DMF
(2 mL), and trifluoroacetic acid (40 mL) (for 11d) was stirred
at room temperature. Turbidity gradually developed and after
10–30 min the solid was filtered and washed with ethanol and
diethyl ether.
1
1707 (s), 1629 (s), 1541 (s) cmꢁ1; H NMR (300 MHz,
DMSO-d6): d¼3.77 (s, 3H), 7.18 (s, 2H), 7.46 (t,
J¼9.0 Hz, 2H), 7.60 (dd, J¼9.0, 4.8 Hz, 2H), 7.77 (s, 1H);
13C NMR (75 MHz, DMSO-d6): d¼52.6, 115.3, 116.5,
117.0 (d, J¼23.2 Hz), 122.8, 129.1 (d, J¼9.5 Hz), 137.0,
148.4, 162.5 (d, J¼245.0 Hz), 163.0. Anal. Calcd for
C15H10N5O2F (313.28): C, 57.88; H, 3.24; N, 22.50. Found:
C, 57.61; H, 3.55; N, 22.46.
3.7.1. 6,7-Dicyano-3-(40-tolyl)-5-oxo-4,5-dihydro-3H-imid-
azo[4,5-b]pyridine (11a). Yield 0.09 g, 0.23 mmol (84%);
mp 323–324 ꢀC. IR (Nujol mull) 2231 (s), 1603 (s), 1576
(m), 1519 (s), 1493 (s) cmꢁ1
;
1H NMR (300 MHz,
DMSO-d6): d¼2.40 (s, 3H), 7.42 (d, J¼8.4 Hz, 2H), 7.65
(d, J¼8.4 Hz, 2H), 8.95 (s, 1H), 13.2–13.8 (br s, 1H);
13C NMR (75 MHz, DMSO-d6): d¼20.6, 91.2, 112.8,
114.34, 115.1, 124.2, 130.0, 130.3, 131.2, 138.5, 147.5,
148.3, 162.4. Anal. Calcd for C15H9N5O$0.2H2O (278.87):
C, 64.61; H, 3.40; N, 25.11. Found: C, 64.77; H, 3.62; N,
24.76.
3.9. Cyclization of methyl 2-[5-amino-(40-fluorophenyl)-
imidazol-4-yl]-1,2-dicyanocarboxylate (9d)
DBU (0.05 g, 0.34 mmol) was added to a suspension of
imidazole 9d (0.03 g, 0.10 mmol) in ethanol (5 mL)
and the mixture was refluxed for 1 h. A precipitate
was formed on cooling and was filtered and washed
with ethanol to give the DBU salt of 6,7-dicyano-3-(40-
fluorophenyl)-5-oxo-4,5-dihydro-3H-imidazo[4,5-b]pyridine
(0.03 g, 0.82 mmol, 82%) as a yellow solid; mp 227–
229 ꢀC. IR (Nujol mull) 2219 (m), 2202 (m), 1707 (s),
3.7.2. 6,7-Dicyano-3-(40-cyanophenyl)-5-oxo-4,5-di-
hydro-3H-imidazo[4,5-b]pyridine (11b). Yield 0.08 g,
0.26 mmol (79%); mp 348–349 ꢀC. IR (Nujol mull)
1
2235 (s), 1597 (s), 1519 (m), 1500 (m) cmꢁ1; H NMR
(300 MHz, DMSO-d6): d¼8.14 (s, 4H), 9.14 (s, 1H),
12.60–14.40 (br s, 1H); 13C NMR (75 MHz, DMSO-d6):
d¼91.8, 110.9, 112.7, 114.3, 115.5, 118.3, 124.1, 130.3,
133.9, 137.7, 146.9, 147.9, 162.7. Anal. Calcd for
C15H6N6O$1.5H2O (313.28): C, 57.51; H, 2.88. Found: C,
57.32; H, 2.93.
1
1629 (s), 1541 (s) cmꢁ1; H NMR (300 MHz, DMSO-d6):
d¼1.50–1.70 (m, ½ 6H), 1.90 (m, ½ 2H), 2.61 (m, ½
2H), 3.23 (m, ½ 2H), 3.46 (t, J¼5.7 Hz, ½ 2H), 3.53 (m,
½ 2H), 7.44 (t, J¼9.0 Hz, 2H), 7.80 (dd, J¼9.0, 4.5 Hz,
2H), 8.76 (s, 1H), 9.60 (s, ½ 1H); 13C NMR (75 MHz,
DMSO-d6): d¼18.9 (DBU), 23.4 (DBU), 25.9 (DBU),
28.3 (DBU), 31.8 (DBU), 37.7 (DBU), 47.9 (DBU),
53.4 (DBU), 91.9, 113.3, 114.6, 116.4 (d, J¼23.0 Hz),
126.2 (d, J¼9.0 Hz), 127.4, 130.6 (d, J¼2.6 Hz), 145.6,
149.5, 161.3 (d, J¼243.9 Hz), 164.6 (DBU), 165.4. Anal.
Calcd for C14H6N5OF$0.5(C9H16N2)$0.5H2O (364.36):
C, 60.98; H, 4.12; N, 23.08. Found: C, 61.17; H, 3.80;
N, 23.39.
3.7.3. 6,7-Dicyano-3-(40-methoxyphenyl)-5-oxo-4,5-di-
hydro-3H-imidazo[4,5-b]pyridine (11c). Yield 0.08 g,
0.27 mmol (82%); mp 311–312 ꢀC. IR (Nujol mull) 2233
1
(s), 1590 (s), 1576 (s), 1521 (s), 1500 (s) cmꢁ1; H NMR
(300 MHz, DMSO-d6) d¼3.80 (s, 3H), 7.16 (d, J¼9.0 Hz,
2H), 7.67 (d, J¼9.0 Hz, 2H), 8.89 (s, 1H), 13.00–13.20
(br s, 1H); 13C NMR (75 MHz, DMSO-d6): d¼55.6, 91.1,
112.8, 114.4, 114.7, 115.0, 126.2, 126.4, 129.9, 147.8,

M. E. A. Zaki, M. F. Proenc¸a / Tetrahedron 63 (2007) 3745–3753
3753
3.10. Reaction of 5-amino-4-cyanoformimidoyl-1-(40-
fluorophenyl)imidazole with acetylacetone
E. M.; Langer, T.; Valoti, M.; Giorgi, G.; Vomero, S. J. Med.
Chem. 2006, 49, 6451.
7. Krasavin, M.; Kobak, V. V.; Bondarenko, T. Y.; Kravchenko,
D. V. Heterocycles 2005, 65, 2189.
8. Yang, D. L.; Fokas, L. J. Z.; Yu, L. B.; Baldino, C. M. Synthesis
2005, 1, 47.
9. Khanna, I. K.; Weier, R. M.; Lentz, K. T.; Swenton, L.; Lankin,
D. C. J. Org. Chem. 1995, 60, 960.
10. Al-Shaar, A. H. M.; Gilmour, D. W.; Lythgoe, D. J.;
McClenaghan, I.; Ramsden, C. A. J. Chem. Soc., Perkin
Trans. 1 1992, 2779.
Acetylacetone (5 mL) was added to a solution of 5-amino-4-
cyanoformimidoyl-1-(40-fluorophenyl)imidazole 1d (0.12 g,
0.52 mmol) in acetonitrile (10 mL) and the mixture was
stirred at room temperature for 2 days. The solid suspension
was filtered and washed with diethyl ether. The white solid
was identified as 6-carbamoyl-2-methyl-9-(40-fluorophe-
nyl)purine 14 (0.10 g, 69%); mp 298–299 ꢀC. IR (Nujol
mull) 1712 (s), 1575 (s), 1520 (s) cmꢁ1
;
1H NMR
11. Penning, T. D.; Chandrakumar, N. S.; Desai, B. N.; Djuric,
S. W.; Gasiecki, A. F.; Malecha, J. W.; Miyashiro, J. M.;
Russel, M. A.; Askonas, L. J.; Gierse, J. K.; Harding, E. I.;
Highkin, M. K.; Kachur, J. F.; Kim, S. H.; Villani-Price, D.;
Pyla, E. Y.; Ghoreishi-Haack, N. S.; Smith, W. G. Bioorg.
Med. Chem. Lett. 2003, 13, 1137.
(300 MHz, DMSO-d6): d¼2.74 (s, 3H), 7.50 (t, J¼8.7 Hz,
2H), 7.92 (dd, J¼8.7, 4.8 Hz, 2H), 8.06 (s, 1H), 8.35 (s,
1H), 9.00 (s, 1H); 13C NMR (75 MHz, DMSO-d6):
d¼25.6, 116.5 (d, J¼22.8 Hz), 126.2 (d, J¼8.7 Hz), 129.1,
130.5, 146.4, 148.1, 153.5, 161.4 (d, J¼244.2 Hz), 161.5,
164.3. Anal. Calcd for C13H10N5OF$0.2H2O (274.86): C,
56.82; H, 3.78; N, 25.49. Found: C, 57.24; H, 3.91; N, 25.26.
12. (a) Alves, M. J.; Booth, B. L.; Freitas, A. P.; Proenc¸a, M. F.
J. Chem. Soc., Perkin Trans. 1 1992, 913; (b) Booth, B. L.;
Dias, A. M.; Proenc¸a, M. F. J. Chem. Soc., Perkin Trans. 1
1992, 2119; (c) Alves, M. J.; Booth, B. L.; Proenc¸a, M. F.
J. Heterocycl. Chem. 1994, 31, 345; (d) Booth, B. L.; Coster,
R. D.; Proenc¸a, M. F. Synthesis 1988, 389; (e) Alves, M. J.;
Booth, B. L.; Carvalho, M. A.; Pritchard, R. G.; Proenc¸a,
M. F. J. Heterocycl. Chem. 1997, 739; (f) Al-Azmi, A.;
Booth, B. L.; Carpenter, R. A.; Carvalho, M. A.; Marrelec,
E.; Pritchard, R. G.; Proenc¸a, M. F. J. Chem. Soc., Perkin
Trans. 1 2001, 2532; (g) Booth, B. L.; Cabral, I. M.; Dias,
A. M.; Freitas, A. P.; Matos-Beja, A. M.; Proenc¸a, M. F.;
Ramos-Silva, M. J. Chem. Soc., Perkin Trans. 1 2001, 1241;
(h) Carvalho, M. A.; Esteves, T. M.; Proenc¸a, M. F.; Booth,
B. L. Org. Biomol. Chem. 2004, 2, 1019; (i) Carvalho, M. A.;
Acknowledgements
The authors gratefully acknowledge the financial support by
~
^
the University of Minho and Fundac¸ao para a Ciencia e Tec-
nologia (project PRAXIS/C/QUI/45391/2002) and a post-
docgrantawardedtoDr. M.E.A.Z. (SFRH/BPD/12044/2003).
References and notes
1. Arvanitis, A. G.; Rescinito, J. T.; Arnold, C. R.; Wilde, R. G.;
Cain, G. A.; Sun, J. H.; Yan, J. S.; Teleha, C. A.; Fitzgerald,
L. W.; McElroy, J.; Zaczek, R.; Hartig, P. R.; Grossman, S.;
Arneric, S. P.; Gilligan, P. J.; Olson, R. E.; Robertson, D. W.
Bioorg. Med. Chem. Lett. 2003, 13, 125.
2. (a) Temple, C.; Rose, J. D.; Comber, R. N.; Rener, G. A. J. Med.
Chem. 1987, 30, 1746; (b) Cristalli, G.; Vittori, S.; Eleuteri, A.;
Grifantini, M.; Volpini, R.; Lupidi, G.; Capolongo, L.; Pesenti,
E. J. Med. Chem. 1991, 34, 2226.
ꢀ
Alvares, Y.; Zaki, M. E.; Proenc¸a, M. F.; Booth, B. L. Org.
Biomol. Chem. 2004, 2, 2340.
13. (a) Dias, A. M.; Cabral, I. M.; Proenc¸a, M. F.; Booth, B. L.
J. Org. Chem. 2002, 67, 5546; (b) Zaki, M. E.; Proenc¸a,
M. F.; Booth, B. L. J. Org. Chem. 2003, 68, 276.
14. Zaki, M. E. A.; Proenc¸a, M. F.; Booth, B. L. Synlett 2005,
2429.
15. Handbook of Chemistry and Physics, 76th ed.; Lide, D. R.,
Editor-in-chief, Ed.; CRC: New York, NY, 1995.
16. Bordwell, F. G.; Van Der Puy, M.; Vanier, N. R. J. Org. Chem.
1976, 41, 1883.
17. Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.;
Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.;
McCollum, G. J.; Vanier, N. R. J. Am. Chem. Soc. 1975, 97,
7006.
3. (a) Cristalli, G.; Vittori, S.; Eleuteri, A.; Volpini, R.; Camaioni,
E.; Lupidi, G.; Mohmoud, N.; Bevilacqua, F.; Palu, G. J. Med.
Chem. 1995, 38, 4019; (b) Cundy, D. J.; Holan, G.; Otaegui, M.;
Simpson, G. W. Bioorg. Med. Chem. Lett. 1997, 7, 669.
4. Temple, C. J. Med. Chem. 1990, 33, 656.
5. Bukowski, L.; Janowiec, M. Pharmazie 1989, 44, 267.
6. (a) Mantlo, N. B.; Chakravarty, P. K.; Ondeyka, D. L.; Siegel,
P. K. S.; Chang, R. S.; Lotti, V. J.; Faust, K. A.; Chen, T. B.;
Schorn, T. W.; Sweet, C. S.; Emmert, S. E.; Patchett, A. A.;
Greenlee, W. J. J. Med. Chem. 1991, 34, 2919; (b) Kim, D.;
Mantlo, N. B.; Chang, R. S.; Kivlighn, S. D.; Greenlee, W. J.
Bioorg. Med. Chem. Lett. 1994, 4, 41; (c) Cappelli, A.; Mohr,
G. P.; Gallelli, A.; Rizzo, M.; Anzini, M.; Vomero, S.;
Mennuni, L.; Ferrari, F.; Makovec, F.; Menziani, M. C.; De
Benedetti, P. G.; Giorgi, G. J. Med. Chem. 2004, 47, 2574;
(d) Cappelli, A.; Mohr, G. P.; Giuliani, G.; Galeazi, S.;
Anzini, M.; Mennuni, L.; Ferrari, F.; Makovec, F.; Kleinrath,
18. Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1981, 46, 4327.
19. Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
20. Tuberculosis Antimicrobial Acquisition
& Coordinating
Facility, Southern Research Institute, Birmingham, Alabama,
USA.
21. Alves, M. J.; Booth, B. L.; Al-Duaij, O. K.; Eastwood, P.;
Nezhat, L.; Proenc¸a, M. F.; Ramos, A. S. J. Chem. Res.,
Synop. 1993, 402; J. Chem. Res., Miniprint 1993, 2701.
€
22. Slatt, J.; Romero, I.; Bergman, J. Synthesis 2004, 2760.