Efficient synthesis of 3H-imidazo[4,5-b]pyridines from malononitrile and 5-amino-4-(cyanoformimidoyl)imidazoles

Article abstract of DOI:10.1021/jo020347f

1-Aryl-5-amino-4-(cyanoformimidoyl)imidazoles 2 were reacted with malononitrile under mild experimental conditions and led to 3-aryl-5,7-diamino-6-cyano-3H-imidazo[4,5-b]pyridines 5, when the reaction was carried out in the presence of DBU, or to 3-aryl-5-amino-6,7-dicyano-3H-imidazo[4,5-b]pyridines 3, in its absence. Both reactions evolved from the adduct formed by nucleophilic attack of the malononitrile anion to the carbon of the cyanoformimidoyl substituent. A 5-amino-1-aryl-4-(1-amino-2,2-dicyanovinyl)imidazole 4 was isolated when this reaction was carried out in the presence of DBU. The structure of compound 4 was confirmed by spectroscopic methods and by reaction with triethyl orthoformate and with acetic anhydride, leading respectively to 9-aryl-6-(cyanomethylidene)purines 11 and 12. Imidazole 2b was also reacted with ethyl acetoacetate, a carbon acid with a pK_a comparable to that of malononitrile. Similar reaction conditions were used and the product isolated was a 6-carbamoyl-1,2-dihydropurine 10, showing that a different mechanism was operating in this case.

Full text of DOI:10.1021/jo020347f

Efficien t Syn th esis of 3H-Im id a zo[4,5-b]p yr id in es fr om
Ma lon on itr ile a n d 5-Am in o-4-(cya n ofor m im id oyl)im id a zoles
Magdi E. A. Zaki, M. Fernanda Proenc¸a,* and Brian L. Booth†
Departamento de Quı´mica, Universidade do Minho, Campus de Gualtar, 4710 Braga, Portugal
fproenca@quimica.uminho.pt
Received May 22, 2002
1-Aryl-5-amino-4-(cyanoformimidoyl)imidazoles 2 were reacted with malononitrile under mild
experimental conditions and led to 3-aryl-5,7-diamino-6-cyano-3H-imidazo[4,5-b]pyridines 5, when
the reaction was carried out in the presence of DBU, or to 3-aryl-5-amino-6,7-dicyano-3H-imidazo-
[4,5-b]pyridines 3, in its absence. Both reactions evolved from the adduct formed by nucleophilic
attack of the malononitrile anion to the carbon of the cyanoformimidoyl substituent. A 5-amino-
1-aryl-4-(1-amino-2,2-dicyanovinyl)imidazole 4 was isolated when this reaction was carried out in
the presence of DBU. The structure of compound 4 was confirmed by spectroscopic methods and
by reaction with triethyl orthoformate and with acetic anhydride, leading respectively to 9-aryl-
6-(cyanomethylidene)purines 11 and 12. Imidazole 2b was also reacted with ethyl acetoacetate, a
carbon acid with a pKa comparable to that of malononitrile. Similar reaction conditions were used
and the product isolated was a 6-carbamoyl-1,2-dihydropurine 10, showing that a different
mechanism was operating in this case.
In tr od u ction
Most of the synthetic methods that were used for the
preparation of imidazo[4,5-b]pyridines generate the imi-
dazole ring from a substituted pyridine, under suitable
reaction conditions.1a,3,8Examples where the pyridine ring
is built from a conveniently substituted imidazole7c,9are
not as common.
In our research group, we have been interested in
studying the reactivity of 5-amino-4-(cyanoformimidoyl)-
imidazoles 2, easily prepared by base-catalyzed cycliza-
tion of Z-(N)-2-amino-1,2-dicyanovinyl formamidines.10,11
These substituted imidazoles are versatile precursors
of fused nitrogen heterocycles, especially the purine
ring. The synthesis of 6-carbamoyl-,11 6-cyano-,11c,12
6-alkoxy-,12 and 6-amidinopurines13 has been previously
reported, and all the reactions are initiated at the
Compounds incorporating the imidazo[4,5-b]pyridine
ring system can be considered structural analogues of
purines and have shown a diverse biological activity,
depending on the substituents of the heterocyclic ring.
Their activity includes anticancer,1 antiviral,2 antimi-
totic,3 and tuberculostatic4 action. They have also been
evaluated as antagonists of various biological receptors
including angiotensin II,5 and thromboxane A2.6 Ap-
propriately substituted imidazo[4,5-b]pyridines have also
displayed high affinity for A1 adenosine receptors.7
* To whom the correspondence should be addressed.
† Present address: Chemistry Department, University of Manches-
ter Institute of Science and Technology, Manchester M60 1QD, UK.
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10.1021/jo020347f CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/24/2002
276
J . Org. Chem. 2003, 68, 276-282

Efficient Synthesis of 3H-Imidazo[4,5-b]pyridines
SCHEME 1
cyanoformimidoyl unit in the 4-position of the imidazole
ring. This work reports the efficient synthesis of func-
tionalized imidazo[4,5-b]pyridines, isolated when mal-
ononitrile is combined with N-aryl-5-amino-4-(cyano-
formimidoyl)imidazoles.
Resu lts a n d Discu ssion
Addition of malononitrile (approximately 1.5 molar
equiv) to a suspension of 5-amino-4-(cyanoformimidoyl)-
imidazoles 2a or 2b in acetonitrile and stirring the
reaction mixture in an ice bath for 5 h followed by 2 days
at -10 °C led to the formation of a yellow solid identified
as the 3H-imidazo[4,5-b]pyridine 3a and 3b (Scheme 1).
These products were isolated in 91 and 93% yield,
respectively. When the same reaction was carried out
from imidazoles 2c and 2d , the poor solubility of these
compounds in acetonitrile required the addition of DMF
(1:1 volume ratio). The reaction occurred under similar
experimental conditions, leading selectively to the forma-
tion of compounds 3c (90%) and 3d (98%). The best
experimental conditions were those where the ammonia
evolved during the reaction was kept in solution until
all the starting material was consumed. When the serum
cap was removed at regular intervals (to follow the
reaction by TLC), lower yields were obtained for the
imidazopyridine (75-78%), suggesting that the cycliza-
tion reaction is base-catalyzed.
The reaction of malononitrile and 5-amino-4-(cyano-
formimidoyl)imidazole was repeated in the presence of
DBU (approximately 1.2 molar equiv) using ethanol (2b),
ethanol/acetonitrile (2a ), or ethanol/DMF (2c) as solvent
mixtures, and the product isolated after 3-4 days at -10
°C was identified as imidazole 4. Compounds 4a -c were
isolated in 93-95% yield. Compound 4d could not be
isolated under similar experimental conditions, as it
readily cyclizes to give the corresponding 3H-imidazo-
[4,5-b]pyridine 5d , isolated as a white solid in 69% yield.
The analogous imidazo[4,5-b]pyridines 5a -c were pre-
pared by intramolecular cyclization of 5-amino-1-aryl-4-
(1′-amino-2′,2′-dicyanovinyl)imidazoles 4. This reaction
occurred when compounds 4a and 4b were refluxed in
ethanol for 2 h, in the presence of a catalytic amount of
triethylamine. These experimental conditions could not
be used for imidazole 4c, due to its low solubility in
ethanol. In this case, only the starting material was
quantitatively recovered after a 2-h reflux period. When
a suspension of 4c in a mixture of ethanol:DMF (3:2) and
DBU (1.4 molar equivalents) was refluxed for 40 h, a
white solid, identified as 5c, was isolated in 80% yield.
To understand the mechanism for both reactions,
imidazole 2a (0.045 mmol) was combined with 1 equiv
of malononitrile in deuterated acetonitrile (700 µL), and
a
Yield and reaction conditions from amidine 1a . All the other
yields and experimental conditions correspond to reactions where
imidazole 2 was used as starting material.
When malononitrile (0.045 mmol) was combined with
1 equiv of DBU (ca. 7 µL) in deuterated acetonitrile (700
µL) and the imidazole 2a (0.045 mmol) was added to the
pale yellow solution, a much slower reaction occurred.
After 40 min at 24 °C, only traces of products 4a , 5a ,
and 5-amino-4-cyano-1-(4′-tolyl)imidazole were detected
in solution, which was gradually becoming pale brown.
After 22 h at 24 °C, the major product was 5-amino-4-
cyano-1-(4′-tolyl)imidazole (71% of the reaction mixture).
Under these experimental conditions, the concentration
of malononitrile anion is higher, but the added base
(DBU) competes for the elimination of HCN from the
5-amino-4-cyanoformimidoylimidazole 2a . This situation
1
the reaction was followed by H NMR at 24 °C. A yellow
color rapidly developed in solution, which was considered
an indication that a low concentration of the malononi-
trile anion had been formed. A fast reaction occurred, as
after 40 min at 24 °C, a considerable amount of imida-
zopyridine 3a precipitated out of solution, preventing the
registration of further spectra. The only compounds
detected in the reaction mixture were 2a , 7a , and 3a .
(13) 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.
J . Org. Chem, Vol. 68, No. 2, 2003 277

Zaki et al.
has been previously reported to occur with other bases
(usually NaOH).10b,11a,b
to generate a high concentration of the malononitrile
anion responsible for the formation of 5.
1H NMR was also used to confirm the elimination of
HCN by addition of DBU to imidazole 2a . When these
compounds (2a :DBU, 1:3 molar ratio) were combined in
The structure of imidazopyridines 3 and 5 and imida-
zole 4 was confirmed by spectroscopic methods. For
imidazole 4, the two cyano groups are present in the IR
spectrum as two distinct and intense bands in the 2203-
2220 and 2182-2195 cm-1 region. In the 13C NMR
spectrum, the signals for both cyano groups are either
absent or very weak bands around δ 112 and 114 ppm.
Another typical feature is the chemical shift of both
carbon atoms of the alkene substituent in the 4-position
of the imidazole ring. The carbon atom directly bonded
to the amino group gives a signal around δ 163 ppm,
while the adjacent carbon (bonded to the two cyano
groups) leads to a small band around δ 44 ppm. In the
1H NMR spectrum, the two amino groups lead to two
singlets (δ 5.0-5.8 and 7.7-8.0 ppm), each one integrat-
ing for two protons. The signal at δ 7.5 ppm for the C-H
proton supports the presence of the imidazole ring. For
imidazopyridines 3, the IR spectrum shows the two cyano
groups as a weak band around 2240 cm-1 and as a
medium intensity band in the 2180-2230 cm-1 region.
The presence of these two functional groups is confirmed
in the 13C NMR spectrum, as two peaks are always
present around δ 115 and 113 ppm. The chemical shifts
for C-5 (δ ≈ 158 ppm), C-6 (δ ≈ 87 ppm), and C-7 (δ ≈
114 ppm) are also typical of these compounds and reflect
the effect of the substituent. A single amino group is now
1
deuterated acetonitrile and the H NMR spectrum was
run after 3 h at 24 °C, the only compounds detected in
solution were 5-amino-4-cyanoimidazole and the starting
material 2a (7:3 ratio).
This study led us to consider for these reactions a
mechanism where the malononitrile anion is the nucleo-
phile in both cases (Scheme 1). In the presence of an
excess of a strong base (DBU), a high concentration of
the malononitrile anion is formed and reaction with
imidazole 2 leads to a stabilized carbanion, which promptly
evolves to the alkene by elimination of the cyanide ion,
leading to 4. When no other base is added, imidazole 2
may act as a mild base, and the positive charge generated
in this molecule accelerates the nucleophilic attack by
the malononitrile anion, even if its concentration in
solution is low. In this case, elimination of ammonia is
responsible for the formation of intermediate 7. This
compound could not be isolated, as it remains in solution
and readily cyclizes to give 3.
The use of an excess of DBU as a base proved to be
essential in order to generate selectively the imidazole 4
and consequently the imidazo[4,5-b]pyridine 5. The reac-
tion mixture has to be kept at 0 to -10 °C, as these
experimental conditions considerably reduced the com-
petitive formation of 5-amino-4-cyanoimidazole. A num-
ber of reactions were carried out using triethylamine as
base and imidazoles 2a and 2b as the starting material.
Imidazole 2a and malononitrile were combined in a 1:1.4
molar ratio using acetonitrile as solvent, and triethyl-
amine (approximately 0.1 molar equivalents) was added
to the reaction mixture (prepared in a 0.7 mmolar scale).
The solid isolated after 5 days at -10 °C proved to be a
mixture of compounds 3a and 4a in a 2:1 molar ratio,
1
visible in the H NMR spectrum as a singlet at δ 7.3-
7.4 ppm, integrating for two protons. For imidazopy-
ridines 5, the IR spectrum shows a single intense band
in the 1995-2200 cm-1 region, indicating that a single
cyano group is present. This observation is confirmed by
13C NMR, where a signal around δ 116 ppm can be
assigned to this functional group. Another typical feature
seems to be the chemical shift for C-5 (δ ≈ 159 ppm),
C-6 (δ ≈ 70 ppm), and C-7 (δ ≈ 147 ppm), reproducing
the electronic effect of the amino and cyano substituents.
The signal corresponding to C-6 is a very small peak in
the spectra of both compounds 3 and 5. The two amino
groups are visible both in the IR and in the 1H NMR
spectra, which shows two singlets at δ 6.2-6.4 and 7.0-
7.1 ppm, each one integrating for two protons.
1
according to the H NMR integration (75% crude yield).
Similar experimental conditions were applied to the
reaction of imidazole 2b with malononitrile, and the solid
isolated after 5 h at 0 °C was also a mixture of compounds
1
3b and 4b in a 2:1 molar ratio, by H NMR (71% crude
Considering that the acidity of malononitrile (pKa ≈
11-12)14 could be an important factor to the usefulness
of this synthetic method for the preparation of highly
functionalized imidazo[4,5-b]pyridines, a comparably
acidic carbon acid was reacted with 5-amino-4-(cyano-
formimidoyl)imidazole 2b. Ethyl acetoacetate (pKa ≈ 11)14
and imidazole 2b were combined in a 1.3:1 molar ratio,
using acetonitrile as solvent, and the mixture was stirred
at 0 °C for 3 h followed by 2 days at room temperature
(Scheme 2). An orange suspension developed and the
solid was identified as the 6-carbamoyl-1,2-dihydropurine
10 (43% yield), considering the typical spectroscopic
features previously reported for this type of com-
pounds.10a,11,15 The use of a 3:1 mixture of acetonitrile and
yield). When this reaction was repeated using triethyl-
amine (approximately 1.5 molar equiv), the solid mixture
isolated after 1 day at -10 °C showed that compounds
3b and 4b were formed in a 1:3 molar ratio (98% crude
yield). Increasing the imidazole 2b:malononitrile ratio to
1:2.5 with the same amount of triethylamine led to a
reaction mixture where 3b and 4b were again present
in a 1:3 molar ratio, after 1 day at -10 °C. Extensive
darkening of the reaction mixture may be responsible for
the lower isolated yield of the crude product (66%). These
results indicate that the strength of the external base is
crucial in order to get selective elimination of HCN from
the adduct.
The amount of DBU that is used in this reaction
(aproximately 1.2 equiv) is also important. When amidine
1a was combined with a catalytic amount of DBU,
cyclization to imidazole 2a occurred promptly. A slight
excess of malononitrile was added to the cold reaction
mixture, and the imidazopyridine 3a was isolated in 90%
yield after 24 h. This indicates that the amount of DBU
required to induce cyclization in amidine 1a is not enough
(14) Gordon, A. J .; Ford, R. A. In The Chemist’s Companion:
A
Handbook of Practical Data, Techniques and References; J ohn Wiley
& Sons: New York, 1972; p 62.
(15) (a) Alves, M. J .; Booth, B. L.; Carvalho, M. A.; Eastwood, P. R.;
Nezhat, L.; Pritchard, R. G.; Proenc¸a, M. F. J . Chem. Soc., Perkin
Trans. 2 1994, 1949. (b) Beagley, B.; Booth, B. L.; Eastwood, P. R.;
Kieger, S.; Pritchard, R. G.; Alves, M. J .; Carvalho, M. A.; Proenc¸a, M.
F. Acta Crystallogr. 1995, C49, 1467.
278 J . Org. Chem., Vol. 68, No. 2, 2003

Efficient Synthesis of 3H-Imidazo[4,5-b]pyridines
SCHEME 2
SCHEME 3
solution indicated the presence of a large amount of
imidazole, a faint spot that could be assigned to the 1,2-
dihydropurine, and two other minor contaminants. All
attempts to isolate a pure product from the mother liquor
failed, possibly because the solubility properties of these
compounds were similar to those of DBU.
These results indicate that the acidity of the carbon
acid is not the major factor controlling the reaction
mechanism. It is possible that the highly stable enol
forms 8A and 8C for ethyl acetoacetate greatly hinder
the capacity of this compound to act as a carbon nucleo-
phile through the anion of 8B. Active methylene com-
pounds stabilized by two adjacent carbonyl groups may
behave in a similar way, but all the other active meth-
ylene compounds are expected to act as malononitrile in
the reaction with 5-amino-4-(cyanoformimidoyl)imida-
zoles, leading to imidazo[4,5-b]pyridine structures.
Compounds 4a and 4b were used as precursors of 1,6-
dihydropurines (Scheme 3) by reaction with triethyl
orthoformate (leading to 11a and 11b) and with acetic
anhydride (leading to 12a and 12b), under reflux condi-
tions. A fast reaction occurs between both amine func-
tions of imidazole 4 and the electrophilic reagent used
as solvent, generating 9-aryl-6-(cyanomethylidene)pu-
rines 11 and 12. The synthesis of 6-cyanomethylidene-
9-substituted purines was previously reported by reaction
of 6-chloropurine with malononitrile17 or with the car-
banion derived from malononitrile.18 A similar reaction
occurred when the anion of malononitrile was reacted
with 6-methylsulfonylpurine.19
A detailed spectroscopic analysis carried out on purines
11 and 12 identifies the typical features associated with
these structures. The two cyano groups are present in
the IR spectrum as an intense band around 2214 cm-1
and a medium intensity band around 2190 cm-1. These
groups were visible only in the 13C NMR spectrum of
compounds 12a and 12b, as two distinct bands in the δ
117 ppm region. The identification of the ring carbon
atoms was made on the basis of HMBC data for com-
pound 11a . The three-bond interaction of C2-H (δ 8.27
DMF as solvents and 4.5 molar equiv of ethyl acetoace-
tate improved the isolated yield of product 10 (76%). The
same orange solid was isolated when the reaction was
carried out in chloroform, in the presence of 7.5 molar
equiv of ethyl acetoacetate, leading to purine 10 in 82%
yield. In this case, a different reaction mechanism
operates. This involves nucleophilic attack of the imine
nitrogen to the more reactive carbonyl carbon atom of
ethyl acetoacetate. The reaction proceeds with intramo-
lecular hydrolysis of the adjacent cyano group, through
an intermediate 9 that rapidly ring opens and cyclizes
again by nucleophilic attack of the 5-amino group to the
imine carbon atom. The formation of 1,2-dihydropurines
of type 10 was previously reported10a,11,15 and occurs when
a 5-amino-4-(cyanoformimidoyl)imidazole 2 (R ) alkyl,
aryl, NHR′) reacts with an aldehyde or ketone. The
mechanism for this reaction was confirmed with the
isolation and characterization of an intermediate analo-
gous to compound 9.16
This reaction was also performed under the same
experimental conditions that led to elimination of HCN
from the adduct of 2 and malononitrile (ice bath and
addition of 1.2 equiv of DBU). No evolution was detected
by TLC after 4 h at 0 °C, and the reaction mixture was
stirred at room temperature for a further 4 days. The
small amount of solid suspension was filtered and identi-
fied as imidazole 2b (10%). TLC on the pale orange
(17) Hamamichi, N.; Miyasaka, T. Heterocycles 1990, 31, 321.
(18) Hamamichi, N.; Miyasaka, T. J . Heterocycl. Chem. 1990, 27,
835.
(19) Yamane, A.; Matsuda, A.; Ueda, T. Chem. Pharm. Bull. 1980,
28, 150.
(16) Alves, M. J .; Booth, B. L.; Carvalho, M. A.; Dias A. M.; Proenc¸a,
M. F. J . Chemical Research (S) 1996, 212, J . Chem. Res. (M) 1996,
1101.
J . Org. Chem, Vol. 68, No. 2, 2003 279

Zaki et al.
and DMF in a 1:1 ratio (6 mL) (for 3c and 3d ). The addition
took place in an ice bath, and the mixture was stirred in ice
for 5 h. The reaction mixture was allowed to stand at -10 °C
for 2-10 days, when the solid was filtered and washed with
diethyl ether.
ppm) identifies C6 (δ 151.9 ppm) and C4 (δ 146.6 ppm).
The signals for C4 and C5 (δ 124.1 ppm) are also three-
bonds away from C8-H (δ 8.70 ppm). The signal for the
exocyclic double bond was absent in the 13C NMR
spectrum of compounds 11 and 12. Another typical
feature of these 1,6-dihydropurines is the chemical shift
R ea ct ion of Z-(N)-2-a m in o-1,2-d icya n ovin yl-(N′)-p -
tolylfor m am idin e 1a with Malon on itr ile. DBU (0.06 mmol)
was added to a suspension of formamidine 1a (0.10 g, 0.44
mmol) in ethanol (3 mL). The reaction mixture was stirred at
room temperature for 5 min and then cooled in an ice bath
before malononitrile (0.04 g, 0.61 mmol) was added. Stirring
in the ice bath was continued for another 4 h and the mixture
was allowed to stand at -10 °C for 24 h. The precipitate was
filtered and washed with diethyl ether and the yellow solid
was identified as compound 3a (0.11 g, 0.40 mmol, 90%).
1
for the acidic N-H, in the H NMR spectrum, identified
as a very broad singlet in the δ 12.6-13.6 ppm region.
1
The H NMR spectra of compounds 12a and 12b show
that these solids incorporate a small quantity of acetic
acid (δ 2.1 or 1.9 ppm for the methyl group of the acid or
its salt).20 This observation is confirmed by elemental
analysis, where calculations indicate the presence of 25%
of acid.
5-Am in o-6,7-d icya n o-3-(4′-t olyl)-3H-im id a zo[4,5-b]p y-
r id in e (3a ): 91% yield (0.40 mmol); mp 325-326 °C; 1H NMR
(DMSO-d6, 300 MHz) δ 8.76 (s, 1H), 7.64 (d, J ) 5.7 Hz, 2H),
7.38 (d, J ) 5.7 Hz, 2H), 7.36 (s, 2H), 2.38 (s, 3H); 13C NMR
(DMSO-d6, 75 MHz) δ 158.0, 149.7, 146.5, 138.1, 131.6, 130.0,
128.2, 124.0, 115.2, 114.4, 113.2, 86.0, 20.7; IR (Nujol mull)
2237 (w), 2217 (m), 1635 (s), 1602 (m), 1572 (m), 1522 (m),
1503 (m). Anal. Calcd for C15H10N6: C, 65.68; H, 3.67; N, 30.64.
Found: C, 65.60; H, 3.94; N, 30.67.
Con clu sion
The reaction of 5-amino-4-(cyanoformimidoyl)imida-
zoles 2 with malononitrile occurs selectively on the carbon
of the cyanoformimidoyl substituent. Intramolecular
cyclization of the adduct leads to 3H-imidazo[4,5-b]-
pyridines 3 or 5, depending on whether the reaction is
carried out in the absence or in the presence of DBU,
respectively.
When imidazole 2 was reacted with ethyl acetoacetate,
the 6-carbamoyl-1,2-dihydropurine 10 was isolated, in-
dicating that a different mechanism operates in this case.
This reaction is much slower in the presence of an excess
of DBU, as the starting material was identified as the
major component of the reaction mixture after 4 h at 0
°C and 4 days at room temperature. Three minor
products were also present in the reaction mixture, and
one of them was identified as the 1,2-dihydropurine 10.
This result confirms that the preferred pathway in the
reaction of imidazole 2 with active methylene compounds
does not depend solely on the pKa of the carbon acid. The
possibility of generating stable enol forms may be re-
sponsible for the different chemical behavior of these 1,3-
dicarbonyl compounds.
5-Am in o-6,7-d icya n o-3-(4′-flu or op h en yl)-3H -im id a zo-
[4,5-b]p yr id in e (3b): 93% yield (0.41 mmol); mp 333-334 °C;
1H NMR (DMSO-d6, 300 MHz) δ 9.88 (s, 1H), 8.78 (s, 1H), 7.82
(dd, J ) 8.7 Hz, J ) 5.1 Hz, 2H), 7.45 (t, J ) 8.7 Hz, 2H), 7.40
(s, 2H); 13C NMR (DMSO-d6, 75 MHz) δ 161.4 (d, J ) 244 Hz),
158.0, 149.7, 146.5, 130.4 (d, J ) 3 Hz), 128.1, 126.5 (d, J ) 9
Hz), 116.4 (d, J ) 23 Hz), 115.1, 114.4, 113.1, 86.8; IR (Nujol
mull) 2242 (w), 2226 (m), 1632 (s), 1601 (m), 1573 (m), 1522
(s), 1504 (m). Anal. Calcd for C14H7N6F: C, 60.43; H, 2.54; N,
30.20. Found: C, 60.43; H, 2.65; N, 30.13.
5-Am in o-6,7-dicyan o-3-(4′-m eth oxyph en yl)-3H-im idazo-
[4,5-b]p yr id in e (3c): 90% yield (0.37 mmol); 335-336 °C; 1H
NMR (DMSO-d6, 300 MHz) δ 8.71 (s, 1H), 7.64 (d, J ) 6.1 Hz,
2H), 7.30 (s, 2H), 7.12 (d, J ) 6.1 Hz, 2H), 3.82 (s, 3H); 13C
NMR (DMSO-d6, 75 MHz) δ 159.1, 158.0, 149.9, 146.8, 128.1,
126.8, 125.9, 115.2, 114.6, 114.3, 113.2, 86.6, 55.6; IR (Nujol
mull) 2239 (w), 2226 (s), 1651 (s), 1607 (s), 1569 (s), 1524 (s).
Anal. Calcd for C15H10N6O: C, 62.07; H, 3.45; N, 28.97.
Found: C, 62.52; H, 3.52; N, 28.63.
Imidazole 4, generated from compound 2 and malono-
nitrile upon elimination of hydrogen cyanide, is a good
precursor of 6-(cyanomethylidene)purines 11 and 12 by
reaction with triethyl orthoformate and acetic anhydride,
respectively.
5-Am in o-6,7-d icya n o-3-(4′-cya n op h en yl)-3H -im id a zo-
[4,5-b]p yr id in e (3d ): 98% yield (0.41 mmol); mp >355 °C; 1H
NMR (DMSO-d6, 300 MHz) δ 8.96 (s, 1H) 8.14 (d, J ) 6.2 Hz,
2H), 8.09 (d, J ) 6.2 Hz, 2H), 7.51 (s, 2H); 13C NMR (DMSO-
d6, 75 MHz) δ 158.1, 149.3, 145.7, 138.0, 133.8, 128.4, 123.6,
118.3, 115.0, 114.8, 113.0, 110.3, 87.2; IR (Nujol mull) 2225
(s), 2186 (w), 1634 (s), 1598 (m), 1573 (m), 1518 (s). Anal. Calcd
for C15H7N7: C, 63.16; H, 2.47; N, 34.37. Found: C, 62.92; H,
2.69; N, 33.93.
Exp er im en ta l Section
The fluorine coupling constants in the 13C NMR spectra were
verified in all the samples using DEPT 45 (where the aromatic
C-H signals were identified as doublets) and in some cases
using the HMBC technique (to identify the signals for the
aromatic Ci and Cp).
Sa fety. The reaction mixtures containing cyanide ion can
be oxidized with calcium hypochlorite in basic solution, to the
much less toxic cyanate ion, following the destruction proce-
dure described in the literature.21
Gen er a l P r oced u r e for th e Syn th esis of 5-Am in o-3-
a r yl-6,7-d icya n o-3H-im id a zo[4,5-b]p yr id in es (3). Malono-
nitrile (0.04 g, 0.61 mmol) was added to a suspension of
5-amino-1-aryl-4-(cyanoformimidoyl)imidazoles 2 (0.41-0.44
mmol) in acetonitrile (5 mL) (for 3a and 3b) or acetonitrile
Gen er a l P r oced u r e for th e Syn th esis of 5-Am in o-4-(1′-
a m in o-2′,2′-d icya n ovin yl)-1-a r ylim id a zoles (4). DBU (0.53
mmol) was added to a solution of malononitrile (0.61-1.21
mmol) in ethanol (10 mL) (for 4b), in a mixture of ethanol (30
mL) and acetonitrile (5 mL) (for 4a ), or in a mixture of ethanol
(3 mL) and DMF (2 mL) (for 4c), kept in an ice bath. The
mixture was stirred in ice for 1 h. A suspension of 5-amino-
1-aryl-4-(cyanoformimidoyl)imidazoles 2 (0.44 mmol) in etha-
nol (2 mL) was added dropwise, and the mixture was stirred
in the ice bath for 4 h. The reaction mixture was allowed to
stand at -10 °C for 3-4 days, when the solid was filtered and
washed with ethanol and diethyl ether.
5-Am in o-4-(1′-a m in o-2′,2′-d icya n ovin yl)-1-(4′-tolyl)im i-
d a zole (4a ): 95% yield (0.42 mmol); mp 223-224 °C; 1H NMR
(DMSO-d6, 300 MHz) δ 7.74 (s, 2H), 7.52 (s, 1H), 7.38 (d, J )
8.7 Hz, 2H), 7.32 (d, J ) 8.7 Hz, 2H), 5.67 (s, 2H), 2.38 (s,
3H); 13C NMR (DMSO-d6, 75 MHz) δ 163.2, 141.8, 138.5, 133.0,
131.3, 130.4, 125.5, 118.1, 43.8, 20.7; IR (Nujol mull) 2207 (s),
2187 (s), 1674 (m), 1622 (s) 1568 (m), 1543 (s), 1519 (m), 1496
(20) Pouchert, C. J .; Behnke, J . In The Aldrich Library of 13C and
1H FT NMR Spectra; ed. 1; Aldrich Chemical Co. Inc.: Milwaukee,
WI; 1993; Vol 1, 751A and 849A.
(21) Lunn, G.; Sansone, E. B. In Destruction of Hazardous Chemicals
in the Laboratory; J ohn Wiley & Sons: New York, 1990; p 77-82.
280 J . Org. Chem., Vol. 68, No. 2, 2003

Efficient Synthesis of 3H-Imidazo[4,5-b]pyridines
(m). Anal. Calcd for C14H12N6‚0.5H2O: C, 61.53; H, 4.79; N,
30.75. Found: C, 61.58; H, 4.94; N, 30.35.
(DMSO-d6, 300 MHz) δ 8.41 (s, 1H), 8.20 (d, J ) 8.7 Hz, 2H),
8.02 (d, J ) 8.7 Hz, 2H), 7.12 (s, 2H), 6.35 (s, 2H); 13C NMR
(DMSO-d6, 75 MHz) δ 159.2, 150.7, 147.2, 139.4, 137.0, 133.6,
122.7, 118.5, 116.8, 116.3, 109.0, 70.0; IR (Nujol mull) 2233
(s), 2194 (s), 1666 (s), 1631 (s), 1603 (s), 1588 (s), 1566 (s), 1521
(s). Anal. Calcd for C14H9N7‚0.20H2O: C, 60.30; H, 3.37; N,
35.18. Found: C, 60.65; H, 3.51; N, 34.92.
5-Am in o-4-(1′-am in o-2′,2′-dicyan ovin yl)-1-(4′-flu or oph e-
n yl)im id a zole (4b): 93% yield (0.41 mmol); mp 198-199 °C;
1H NMR (DMSO-d6, 300 MHz) δ 7.80 (s, 2H), 7.54 (s, 1H),
7.48-7.53 (m, 2H), 7.42 (t, J ) 8.7 Hz, 2H), 5.80 (s, 2H); 13C
NMR (DMSO-d6, 75 MHz) δ 161.9 (d, J ) 244 Hz), 163.2, 142.1,
133.0, 130.3 (d, J ) 3 Hz), 128.4 (d, J ) 10 Hz), 118.1, 116.8
(d, J ) 23 Hz), 111.9; IR (Nujol mull) 2204 (s), 2182 (s), 1673
(s), 1629 (m), 1571 (m), 1532 (s), 1518 (s), 1495 (s). Anal. Calcd
for C13H9N6F‚0.5H2O: C, 56.32; H, 3.61; N, 30.32. Found: C,
56.32; H, 3.27; N, 30.31.
5-Am in o-4-(1′-a m in o-2′,2′-d icya n ovin yl)-1-(4′-m eth oxy-
p h en yl)im id a zole (4c): 95% yield (0.39 mmol); mp 243-244
°C; 1H NMR (DMSO-d6, 300 MHz) δ 7.71 (s, 2H), 7.49 (s, 1H),
7.36 (d, J ) 9.0 Hz, 2H), 7.11 (d, J ) 9.0 Hz, 2H), 5.64 (s, 2H),
3.81 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 163.1, 159.4,
142.1, 133.2, 127.4, 126.4, 118.1, 115.0 114.6, 111.8, 55.5, 43.7.
Anal. Calcd for C14H12N6O: C, 60.00; H, 4.29; N, 30.00.
Found: C, 59.93; H, 4.46; N, 29.63; IR (Nujol mull) 2220 (s),
2196 (s), 1648 (s), 1620 (s), 1571 (m), 1546 (s), 1517 (s), 1500
(s).
Gen er a l P r oced u r e for th e Syn th esis of 5,7-Dia m in o-
3-a r yl-6-cya n o-3H-im id a zo[4,5-b]p yr id in es (5). A suspen-
sion of 5-amino-4-(1′-amino-2′,2′-dicyanovinyl)-1-arylimidazole
4 (0.30-1.12 mmol) in ethanol (5-10 mL) (for 5a and 5b) or
DMF (5 mL) (for 5c) was combined with a catalytic amount of
triethylamine (for 5a and 5b) or DBU (for 5c) and the mixture
was refluxed for 2 h (for 5a and 5b) or 40 h (for 5c). The solvent
was partially removed under vacuum and the white solid was
filtered and washed with ethanol and diethyl ether.
5,7-Dia m in o-6-cya n o-3-(4′-tolyl)-3H-im id a zo[4,5-b]p y-
r id in e (5a ): 40% yield (0.12 mmol); mp 310-312 °C; 1H NMR
(DMSO-d6, 300 MHz) δ 8.15 (s, 1H), 7.61 (d, J ) 8.2 Hz, 2H),
7.32 (d, J ) 8.2 Hz, 2H), 7.03 (s, 2H), 6.18 (s, 2H), 2.35 (s,
3H); 13C NMR (DMSO-d6, 75 MHz) δ 159.2, 150.8, 147.6, 138.0,
137.0, 133.0, 129.9, 123.6, 117.3, 116.0, 69.9, 20.8; IR (Nujol
mull) 2198 (s), 1664 (s), 1593 (s), 1571 (s), 1519 (s), 1494 (s).
Anal. Calcd for C14H12N6: C, 63.62; H, 4.58; N, 31.80. Found:
C, 63.64; H, 4.74; N, 31.62.
5,7-Dia m in o-6-cya n o-3-(4′-flu or op h en yl)-3H -im id a zo-
[4,5-b]p yr id in e (5b): 80% yield (0.90 mmol); mp 340-341 °C;
1H NMR (DMSO-d6, 300 MHz) δ 8.18 (s, 1H), 7.81 (dd, J )
9.0 Hz, J ) 4.8 Hz, 2H), 7.38 (t, J ) 9.0 Hz, 2H), 7.07 (s, 2H),
6.23 (s, 2H); 13C NMR (DMSO-d6, 75 MHz) δ 160.8 (d, J ) 245
Hz), 159.1, 150.7, 147.5, 137.7, 131.8 (d, J ) 3 Hz), 125.6 (d,
J ) 9 Hz), 117.0, 116.1 (d, J ) 23 Hz), 115.9, 69.8; IR (Nujol
mull) 2199 (s), 1687 (s), 1611 (s), 1578 (s), 1524 (s), 1512 (s),
1499 (s). Anal. Calcd for C13H9N6F: C, 58.21; H, 3.38; N, 31.33.
Found: C, 58.51; H, 3.55; N, 31.16.
5,7-Diam in o-6-cyan o-3-(4′-m eth oxyph en yl)-3H-im idazo-
[4,5-b]p yr id in e (5c): 80% yield (0.29 mmol); mp 328-329 °C;
1H NMR (DMSO-d6, 300 MHz) δ 8.09 (s, 1H), 7.63 (d, J ) 9.0
Hz, 2H), 7.07 (d, J ) 9.0 Hz, 2H), 7.01 (s, 2H), 6.17 (s, 2H),
3.80 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 159.0, 158.3,
150.6, 147.6, 138.0, 128.3, 125.2, 117.1, 115.8, 114.4, 69.5, 55.5;
IR (Nujol mull) 2202 (s), 1686 (s), 1613 (s), 1575 (s) 1499 (m).
Anal. Calcd for C14H12N6O‚0.25H2O: C, 59.05; H, 4.39; N,
29.53. Found: C, 59.47; H, 4.60; N, 29.15.
5,7-Dia m in o-6-cya n o-3-(4′-cya n op h en yl)-3H -im id a zo-
[4,5-b]p yr id in e (5d ). DBU (0.53 mmol) was added to a
solution of malononitrile (0.08 g, 1.21 mmol) in ethanol (5 mL)
and the mixture was stirred in an ice bath for 1 h. A
suspension of 5-amino-4-(cyanoformimidoyl)-1-(4′-cyanophe-
nyl)imidazole 2d (0.10 g, 0.42 mmol) in ethanol (10 mL) was
added dropwise and the mixture was stirred in the ice bath
for 4 h. The reaction mixture was allowed to stand at -10 °C
for 20 days, when TLC indicated the absence of imidazole 2d .
The solvent was partially removed under reduced pressure,
and the white solid was filtered and washed with diethyl ether.
The product was identified as the title compound 5d (0.08 g,
0.29 mmol, 69%). Characterization: mp >350 °C; 1H NMR
Rea ction of 5-Am in o-4-(cya n ofor m im id oyl)-1-(4′-tolyl)-
im id a zole 2a w it h Ma lon on it r ile in t h e P r esen ce of
Tr ieth yla m in e. Triethylamine (0.06 mmol) was added to a
solution of 5-amino-4-(cyanoformimidoyl)-1-(4′-toluyl)imidazole
2a (0.11 g, 0.47 mmol) and malononitrile (0.04 g, 0.66 mmol)
in acetonitrile (5 mL) and the mixture was kept stirring in an
ice bath. The mixture was stirred in the ice bath for 6 h and
then allowed to stand at -10 °C for 5 days. The solid was
filtered and washed with ethanol and diethyl ether, leading
to 0.10 g (0.35 mmol, 75%) of the crude mixture (3a and 4a in
1
a 2:1 molar ratio, by H NMR).
Rea ction of 5-Am in o-4-(cya n ofor m im id oyl)-1-(4′-flu o-
r op h en yl)im id a zole 2b w ith Ma lon on itr ile in th e P r es-
en ce of Tr ieth yla m in e. Meth od A. Triethylamine (0.06
mmol) was added to a solution of 5-amino-4-(cyanoformi-
midoyl)-1-(4′-fluorophenyl)imidazole 2b (0.15 g, 0.66 mmol)
and malononitrile (0.06 g, 0.91 mmol) in acetonitrile (5 mL)
and the mixture was kept stirring in an ice bath. After 5 h,
the solid was filtered and washed with ethanol and diethyl
ether, leading to 0.13 g (0.47 mmol, 71%) of the crude mixture
1
(3b and 4b in a 2:1 molar ratio, by H NMR).
Meth od B. Triethylamine (0.65 mmol) was added to a
solution of malononitrile (0.04 g, 0.61 mmol) in acetonitrile (3
mL) and the mixture was kept stirring in an ice bath. After
10 min, a solution of 5-amino-4-(cyanoformimidoyl)-1-(4′-
fluorophenyl)imidazole 2b (0.10 g, 0.44 mmol) in acetonitrile
(3 mL) was added dropwise to the reaction mixture. The
mixture was stirred in the ice bath for 5 h and then allowed
to stand at -10 °C for 1 day. The yellowish-green precipitate
was filtered from a yellow solution and washed with ethanol
and diethyl ether, leading to 0.12 g (0.42 mmol, 98%) of the
1
crude mixture (3b and 4b in a 1:3 molar ratio, by H NMR).
Meth od C. Triethylamine (0.65 mmol) was added to a
solution of malononitrile (0.07 g, 1.11 mmol) in acetonitrile (3
mL) and the mixture was kept stirring in an ice bath. After
30 min, a solution of 5-amino-4-(cyanoformimidoyl)-1-(4′-
fluorophenyl)imidazole 2b (0.10 g, 0.44 mmol) in acetonitrile
(3 mL) was added dropwise to the reaction mixture. The
mixture was stirred in the ice bath for 6 h and then allowed
to stand at -10 °C for 1 day. The yellowish-green precipitate
was filtered from a dark violet solution and washed with
ethanol and diethyl ether, leading to 0.08 g (0.29 mmol, 66%)
of the crude mixture (3b and 4b in a 1:3 molar ratio, by 1H
NMR).
Rea ction of 5-Am in o-4-(cya n ofor m im id oyl)-1-(4′-flu o-
r op h en yl)im id a zole 2b w ith Eth yl Acetoa ceta te. Ethyl
acetoacetate (0.11 g, 0.85 mmol) was added to a suspension of
imidazole 2b (0.15 g, 0.65 mmol) in acetonitrile (5 mL) and
the mixture was kept stirring in an ice bath. The mixture was
stirred in the ice bath for 3 h and then at room temperature
for 2 days. The orange solid was filtered and washed with
diethyl ether to give 6-carbamoyl-2-ethoxyacyl-2-methyl-9-(4-
fluorophenyl)-1,2-dihydropurine 10 (0.10 g, 0.28 mmol, 43%).
The above experimental procedure was repeated using ethyl
acetoacetate (0.26 g, 2.00 mmol) and imidazole 2b (0.10 g, 0.44
mmol) in acetonitrile (3 mL) and DMF (1 mL). Stirring for 2
days at room temperature led to compound 10 (0.12 g, 0.33
mmol, 76%). When ethyl acetoacetate (0.43 g, 3.30 mmol) and
imidazole 2b (0.10 g, 0.44 mmol) were combined in chloroform
(5 mL), compound 10 was also isolated after 2 days at room
temperature (0.13 g, 0.36 mmol, 82%). Characterization: mp
212-213 °C; 1H NMR (DMSO-d6, 300 MHz) δ 8.20 (s, 1H), 8.13
(s, 2H - amide NH + CH), 9.05 (s, 1H), 7.82 (dd, J ) 9.0 Hz,
J ) 4.8 Hz, 2H), 7.30 (t, J ) 9.0 Hz, 2H), 6.70 (s, 1H), 3.97
(dq, J q ) 7.2 Hz, J d ) 1.8 Hz, 2H), 2.77 (d, J ) 12.9 Hz, 1H,
J . Org. Chem, Vol. 68, No. 2, 2003 281

Zaki et al.
C2-CHAHB), 2.60 (d, J ) 12.9 Hz, 1H, C2-CHAHB), 1.55 (s,
3H), 1.07 (t, J ) 7.2 Hz); 13C NMR (DMSO-d6, 75 MHz) δ 170.0,
162.0, 159.8 (d, J ) 241.4 Hz), 156.2, 145.0, 133.1, 132.3 (d, J
) 2.5 Hz), 122.9 (d, J ) 8.3 Hz), 118.1, 116.0 (d, J ) 22.4 Hz),
73.9, 60.1, 45.9, 29.0, 14.1; IR (Nujol mull) 3367 (s), 3330 (s),
3121 (s), 1717 (s), 1693 (s), 1652 (s), 1623 (m) 1582 (s), 1524
(s), 1508 (s). Anal. Calcd for C17H17N5O2F‚H2O: C, 56.67; H,
5.28; N, 19.44. Found: C, 56.63; H, 5.12; N, 19.32.
Rea ction of 5-Am in o-4-(cya n ofor m im id oyl)-1-(4′-flu o-
r op h en yl)im id a zole 2b w ith Eth yl Acetoa ceta te in th e
P r esen ce of DBU. A solution of ethyl acetoacetate (0.16 g,
1.23 mmol) and DBU (0.53 mmol) in ethanol (5 mL) was stirred
in an ice bath for 1 h. A suspension of 5-amino-4-(cyano-
formimidoyl)-1-(4′-fluorophenyl)imidazole 2b (0.10 g, 0.44
mmol) in ethanol (10 mL) was added to the previous solution
and the mixture was stirred at 0 °C for 4 h. No reaction
occurred (by TLC) and the reaction mixture was stirred at
room temperature for 4 days. The solid suspension was filtered,
washed with diethyl ether, and identified as imidazole 2b (0.01
g, 0.04 mmol, 10%). No other products could be isolated from
the mother liquor, where imidazole 2b was identified by TLC
as the major product and three other minor components were
present.
Gen er a l P r oced u r e for th e Syn th esis of 9-Ar yl-6-
(cya n om eth ylid en e)p u r in e (11). A suspension of imidazole
4 (0.30-0.57 mmol) in triethyl orthoformate (10 mL) was
refluxed for 1.5-6 h. The resulting precipitate was filtered and
washed with ethanol to give the title compound.
6-(Cyan om eth yliden e)-9-(4′-m eth ylph en yl)pu r in e (11a):
77% yield (0.44 mmol); mp >355 °C; 1H NMR (DMSO-d6, 300
MHz) δ 8.69 (s, 1H), 8.26 (s, 1H), 7.63 (d, J ) 8.4 Hz, 2H),
7.41 (d, J ) 8.4 Hz, 2H), 2.39 (s, 3H); 13C NMR (DMSO-d6, 75
MHz) δ 150.8, 145.7, 145.5, 142.0, 138.3, 131.3, 130.0, 123.9,
123.1, 116.6, 20.7; IR (Nujol mull) 3200 (m), 3062 (m), 2213
(s), 2191 (m), 1627 (s), 1565 (s) 1520 (m). Anal. Calcd for
7.79 (dd, J ) 9.0 Hz, J ) 4.7 Hz, 2H), 7.48 (t, J ) 9.0 Hz, 2H);
13C NMR (DMSO-d6, 75 MHz) δ 161.6 (d, J ) 244.5 Hz), 150.9,
145.9, 145.6, 142.0, 130.1, 126.5 (d, J ) 8.3 Hz), 123.0, 116.5
(d, J ) 22.5 Hz); IR (Nujol mull) 3118 (m), 3058 (m), 2204 (s),
2186 (s) 1598 (s), 1542 (m) 1518 (s). Anal. Calcd for C14H7-
N6F.0.25C2H6O: C, 60.10; H, 2.94; N, 29.02. Found: C, 59.99;
H, 2.87; N, 28.99.
Gen er a l P r oced u r e for th e Syn th esis of 9-Ar yl-6-
(cya n om eth ylid en e)-2-m eth ylp u r in e (12). A suspension of
imidazole 4 (0.34-0.37 mmol) in acetic anhydride (10 mL) was
refluxed for 1-4 h. The reaction mixture was concentrated in
a rotary evaporator and the resulting solid was filtered and
washed with ethanol to give the title compound as a cream
solid.
6-(Cyan om eth yliden e)-9-(4′-m eth ylph en yl)-2-m eth ylpu -
r in e (12a ): 50% yield (0.17 mmol); mp >350 °C; 1H NMR
(DMSO-d6, 300 MHz) δ 12.60-12.90 (brs, 1H), 8.58 (s, 1H),
7.60 (d, J ) 8.1 Hz, 2H), 7.40 (d, J ) 8.1 Hz, 2H), 2.54 (s, 3H),
2.38 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 155.8, 150.9,
145.9, 141.6, 138.3, 131.3, 130.0, 124.1, 121.4, 117.0, 116.9,
22.0, 20.7; IR (Nujol mull) 2213 (s), 2194 (s), 1635 (s), 1602
(m), 1518 (m). Anal. Calcd for C16H12N6.0.25C2H4O2: C, 65.35;
H, 4.29; N, 27.72. Found: C, 65.53; H, 4.50; N, 27.87.
6-(Cya n om eth ylid en e)-9-(4′-flu or op h en yl)-2-m eth ylp u -
r in e (12b): 57% yield (0.21 mmol); mp >350 °C; 1H NMR
(DMSO-d6, 300 MHz) δ 12.60-13.00 (brs, 1H), 8.60 (s, 1H),
7.78 (dd, J ) 8.7 Hz, J ) 4.8 Hz, 2H), 7.47 (t, J ) 8.7 Hz, 2H),
2.55 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 161.6 (d, J )
244.7 Hz), 156.0, 150.9, 145.8, 141.6, 130.1, 126.6 (d, J ) 8.8
Hz), 121.4, 117.0, 116.8, 116.5 (d, J ) 23.3 Hz), 22.0; IR (Nujol
mull) 2237 (m), 2202 (s), 1644 (s), 1600 (m), 1520 (m), 1503
(m). Anal. Calcd for C15H9N6F.0.25C2H4O2: C, 60.58; H, 3.26;
N, 27.36. Found: C, 60.87; H, 3.40; N, 27.16.
Ack n ow led gm en t. The authors gratefully acknowl-
edge the financial support by the University of Minho
and Fundac¸a˜o para a Cieˆncia e Tecnologia (project
PRAXIS/C/QUI/10101/1998).
C
15H10N6: C, 65.68; H, 3.67; N, 30.64. Found: C, 65.45; H,
4.00; N, 30.50.
6-(Cya n om eth ylid en e)-9-(4′-flu or op h en yl)p u r in e (11b):
1
78% yield (0.29 mmol); mp 281-282 °C; H NMR (DMSO-d6,
300 MHz) δ 13.00-13.60 (brs, 1H), 8.70 (s, 1H), 8.27 (s, 1H),
J O020347F
282 J . Org. Chem., Vol. 68, No. 2, 2003