Some nucleophilic substitutions in 2-cyano-3-nitroimidazo[1,2-a]pyridine

Article abstract of DOI:10.1002/jhet.5570430307

In some nucleophilic substitution reactions of 2-cyano-3-nitroimidazo[1,2- a]pyridine, nitrogen (alkylamines, guanidine) and oxygen nucleophiles (alkoxides) underwent substitution of the 2-cyano group, while sulfur nucleophiles (alkylthiols) underwent sub

Full text of DOI:10.1002/jhet.5570430307

May-Jun 2006
565
Some Nucleophilic Substitutions In
2
-Cyano-3-Nitroimidazo[1,2-a]Pyridine
1
1
2
1
Lucina Arias, Héctor Salgado-Zamora, * Humberto Cervantes, Elena Campos,
1
3
Alicia Reyes and Edward C. Taylor
1
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, IPN. Prol. Carpio y Plan de
2
Ayala s/n México 11340 D.F. Área de Química, Universidad Autónoma Metropolitana (Unidad Azcapotzalco).
3
México 02200 D.F. Department of Chemistry, Princeton University, Princeton N.J. 08544 U.S.A
Received July 5, 2005
N
Nucl
N
Nucl.
N
N
CN
RNH
2
–RONa
N
NO2
NO2
N
RSH
CN
SR
In some nucleophilic substitution reactions of 2-cyano-3-nitroimidazo[1,2-a]pyridine, nitrogen
alkylamines, guanidine) and oxygen nucleophiles (alkoxides) underwent substitution of the 2-cyano
group, while sulfur nucleophiles (alkylthiols) underwent substitution of the 3-nitro group.
(
J. Heterocyclic Chem., 43, 565 (2006).
Introduction.
It is well known that the nitro group is a far better
leaving group than the cyano group, particularly in
aromatic nucleophilic substitutions [7,8]. Thus, the
reaction of methyl 3-nitropyridine-4-carboxylate or 3-nitro-
pyridine-4-carbonitrile undergoes substitution of the 3-
nitro group [9]. It is also known that the nitrile group
undergoes two types of reaction toward the nucleophile,
the nucleophilic substitution as well as the nucleophilic
addition. The former example is shown in the conversion
of some aldehydes to corresponding esters, where the ꢀ-
oxonitriles, prepared by hydrocyanation of the aldehydes
with hydrogen cyanide followed by oxidation with
manganese dioxide, readily gave the corresponding esters
by treatment with alcohols [10]. The latter mode, the
nucleophilic adition, is shown in the condensation of 2-
amino-5-nitrobenzonitrile with 4-nitrobenzonitrile giving 2-
(4-nitrophenyl)-4-amino-6-nitroquinazoline [11]. The cine-
The imidazo[1,2-a]pyridine ring is a versatile system
which has shown an outstanding array of biological activities
[1]. The incorporation of the imidazo[1,2-a]pyridine moiety
in structures investigated in relation to potential pharma-
cological activities has continued [2]. Electrophiles
predominantly attack on the position 3 of the heterocycle
[
(
3]. Furthermore ipso electrophilic attack on 3-substituted
Br, NO2, CHO)-5-methylimidazo[1,2-a]pyridines by
chlorine (NCS) rendered 3-chloro substituted derivatives
albeit in low yields [4]. Nucleophiles attack both positions, 2
and 3, thus the reaction of 2-chloro-3-nitroimidazo[1,2-a]-
pyridine with diethylamine undergoes substitution of the 2-
chloro group [5]. While the nitro functional group has been
displaced from the 3-position by thiol nucleophiles if an
electron–attracting substituent is present at the 2-position [6].
Scheme I
N
aq. NH
4
OH
N
CO
2
ET
N
CONH
2
POCl
3
CN
N
r t/12 h
N
N
1
10 °C/1 h
NO
2
NO
2
NO
2
1
2
3
N
N
H
CN
NH
N
N
N
NH
2
NH
NH
5
NO
2
H
2
N
4
a

5
66
L. Arias, H. Salgado-Zamora, H. Cervantes, E. Campos, A. Reyes and E. C. Taylor
Vol 43
substitution in the 2-cyano-5-nitrofuran with carbanions
and thiols also shows that the nitro group is a better
leaving group than the cyano [12].
In the ir spectra of products 4a-g and 6a-b, the
nitrile band disappeared and the nitro absorption
–
1
bands appeared at ꢀ 1300-1360 and 1500-1528 cm .
1
In the H nmr spectra of 4a-g and 6a,b, the H-5 signal
Results and Discussion.
showed at low field in the interval ꢀ 9.0 - 9.2 as has
been established for 3-nitro substituted imidazo-
pyridines [5,6] and as a clear indication of the
permanence of the 3-nitro group. In the ir spectra of
As shown in Scheme 1, 3-nitroimidazo[1,2-a]pyridine-2-
carbonitrile (3) was prepared from ethyl 3-nitroimidazo[1,2-a]-
pyridine-2-carboxylate (1) [13] by ammonolysis with aqueous
ammonia to give carboxamide 2 [14], followed by dehydration of
the latter with phosphoryl oxychloride. The 3-nitro-2-carbonitrile
-
1
7
a,b, the cyano bands appeared at 2238-2250 cm and
the nitro bands disappeared. In the pmr spectra of
a,b, the H-5 signals shifted upfield, thus showing the
3
was then subjected to nucleophilic substitution reactions with
7
guanidine in n-butanol. Unexpectedly this process yielded 2-
guanidinyl-3-nitroimidazo[1,2-a]pyridine (4a), not 3-guan-
idinylimidazo[1,2-a]pyridine-2-carbonitrile (5), i.e. cyanide had
been displaced in preference to the better leaving nitro group.
Treatment of 3 with excess amounts of some alkyl amines,
as shown in Scheme II, in the absence of solvent gave the
corresponding 2-alkylamino-3-nitroimidazo[1,2-a]pyridines
displacement of the 3-nitro by thiol.
As shown in Scheme 3, treatment of 3 with other
nitrogen nucleophiles, such as ammonia, hydroxylamine
and phenylhydrazine showed no substitution on the 2-
cyano or on the 3-nitro. Thus, treatment of 3 with
aqueous ammonia at room temperature simply caused
the hydrolysis of the nitrile to give 3-nitroimidazo[1,2-a]
pyridine-2-carboxamide (2). Treatment of 3 with
hydroxyl amine caused the nucleophilic addition on the
nitrile to give 3-nitroimidazo[1,2-a]pyridine-2-carbox-
amide-oxime (8). Treatment of 3 with an excess of
phenylhydrazine at 70-75 °C caused the reduction [15]
of the 3-nitro to give 3-aminoimidazo[1,2-a]pyridine-2-
carbonitrile (9) in 73% yield.
(4b-g) in moderate to high yields. Use of microwave in
treatment of 3 with cyclohexylamine reduced the reaction
time from 2 h to 14 min and the molar ratio from 8.6
equivalents to 3, and improved the reaction yield from 62% to
97%. Treatment of 3 with aromatic amines caused no
substitution. Treatment of 3 with excess amounts of two
alkoxides, ethoxide and isopropoxide, in ethyl and isopropyl
alcohol respectively, gave corresponding 2-alkoxy-3-nitro-
imidazo[1,2-a] pyridines (6a,b) in moderate yields.
Scheme III
Treatment of 3 with equal anount of two thiols, propane-
thiol and ethyl thioglycolate in DMF, gave corresponding 3-
alkylthioimidazo[1,2-a]pyridine-2-carbonitriles (7a,b) in
moderate yields. Results for these substitution reactions are
summarized in Table 1. It is very interesting that the nitrogen
and oxygen nucleophiles showed the substitutions taking
place on the 2-cyano (the less favored leaving group), and
that sulfur nucleophiles showed the substitution on the 3-
nitro (the more favored leaving group).
N
CONH
2
N
aqueous NH
4
OH
NO
2
2
N
NH
2
CN
2
NH OH/2-propanol
N
N
N
NOH
NO
2
NO
2
3
PhNHNH
2
8
Scheme II
N
N
NHR
CN
N
N
NH
2
excess RNH
2
NO
2
9
4
a-g
N
Although displacement of either group may be
mechanistically understandable in terms of an initial
Michael type addition to either carbon supporting the
leaving group, followed by an elimination process, it is
also possible that the site in which the group itself is
attached to the imidazopyridine system might be playing a
decisive role on the preference for substitution. Therefore
further efforts are on the way to determine whether this is
the case. It is noteworthy to mention that the nitrile carbon
CN
N
RONa/ROH
N
OR
N
NO
2
NO
2
3
RSH/NaHCO
3
6
a.b
N
CN
N
SR
1
3
7
a,b
in 3 shows a C nmr shift at ꢁ 90, unusually high.

May-Jun 2006
567
Some Nucleophilic Substitutions In 2-Cyano-3-Nitroimidazo[1,2-a]Pyridine
Table 1
Nucleophilic cyanide displacement in 2-cyano-3-nitroimidazoimidazo[1,2-a]pyridine 3.
Compound
R
Reaction conditions
Melting point
Yield
%
°C
4
4
4
4
4
4
a
b
c
d
d
e
NH
PhCH
(CH CH
Cyclohexyl
Cyclohexyl
n-Butyl
2
C(NH)
BuONa/BuOH, 80 ºC
222-223
157-158
153-155
157-159
157-159
73.5-74.5
186-187
102-103.5
147-149
142-143
65
77
93
62
97
72
88
48
75
70
2
60-70°C
60-70°C
60-70°C
Microwave
60-70°C
3
)
2
4
f
Cyclopropyl
60-70°C
60-70°C
4
6
6
g
a
b
(S)-(-)-Ph(CH
CH CH
(CH CH
3
)CH
3
2
EtONa, 1.5 mol/EtOH, 10 mL, 60 ºC
IPrONa, 1.5 mol /iPrOH, 10 mL, 60 ºC
3 2
)
1
Conclusion.
(NO
2
); H nmr (DMSO-d
6
): ꢀ 9.37 (td, J = 7.0, 1.0 Hz, 1H, H-5);
7
.63 (td, J = 7.9, 1.0 Hz, 1H, H-7); 7.43 (td, J = 8.8, 1.2 Hz, 1H,
In conclusion, several nitrogen and oxygen nucleophiles
have shown a preference for cyanide displacement over
the better leaving nitro group in 2-cyano-3-nitroimidazo-
H-8); 7.14 (bs, 4H, NH ) 7.12 (td, J = 7.0, 1.2 Hz, 1H, H-6);
cmr: ꢀ 160.84, 157.2, 144.5 133.2, 129.1, 122.03, 115.1, 114.7;
ms; m/z (%) 220 M (6.3), 120 (100).
2
+
[
1,2-a]pyridine. However alkylthiol nucleophiles did
Anal. Calcd. for C H N O : C, 43.63; H, 3.66. Found: C,
8 8 6 2
4
3.70; H, 3.45.
displace the nitro group.
General Procedure for Preparation of 2-Alkylamino-3-nitroimi-
dazo[1,2-a]pyridine 4b-4g.
EXPERIMENTAL
A mixture of 2-cyano-3-nitroimidazo[1,2-a]pyridine 3 (1.0 g,
5.32 mmol) and alkylamine (16.3 mmol) was stirred at 60-70 °C
for 2 hours. After cooling, the solid formed was collected by
filtration and washed with cold ethanol, and recrystallized from
ethanol to afford the corresponding 2-alkylamino-3-nitroimi-
dazo[1,2-a] pyridine 4b-g.
Melting points were measured on an Electrothermal melting
point apparatus and are uncorrected. The ir spectra were taken
1
on a Perkin Elmer 1600 series FTIR spectrophotometer. H and
13
C nmr spectral data were recorded at 300 and 75 MHz
respectively using a Bruker DPX 300 MHz NMR spectrometer.
Chemical shifts (ꢀ) are given in parts per million downfield from
TMS (ꢀ = 0). Mass spectra were obtained with a Jeol
JMSAX505HA instrument.
2
-(N-Benzyl)amino-3-nitroimidazo[1,2-a]pyridine 4b.
-
1
Obtained in 77% yield, mp 157-158 °C; Ir (KBr, cm ) ꢀ 3339
1
(
NH); 1605 (C=C); 1469, 1317 (NO ); H nmr (DMSO-d ): ꢀ
2
6
2
-Cyano-3-nitroimidazoimidazo[1,2-a]pyridine (3).
9
.25 (d, J = 6.8 Hz, 1H, H-5); 8.52 (t, J = 4.5 Hz, 1H, NH); 7.69
A suspension of 3-nitroimidazo[1,2-a]pyridine-2-carboxamide
(ddd, J = 8.5, 7.2, 1.4 Hz, 1H, H-7); 7.47 (d, J = 8.8 Hz, 1H, H-
8); 7.39-7.18 (m, 5H, -C H ); 7.16 (ddd, J = 7.2, 7.0, 1.0 Hz, 1H,
2
(8.5 g, 41.6 mmol) in POCl (85 mL) was stirred at 115 °C for 1
3
6
5
hour. After cooling, the mixture was concentrated under vacuum,
and treated with ice (100 g). The yellow solid formed was
collected by filtration and washed with cold water (50 mL x 2),
and recrystallized from DMSO to afford 3, 96% yield, mp 166-
H-6); 4.73 (d, J = 6.5 Hz, 2H, CH ); cmr: ꢀ 153.8 (C-2); 146.6
(C-8a); 139.3 (Ar, ipso); 134.3 (C-7); 128.7 (C-5); 128.3 (Ar,
2
m); 127.3 (Ar, o); 126.9 (Ar, p); 117.6 (C-3?); 114.7 (C-8);114.1
+
(C-6); 45.1 (CH
); ms; m/z (%) 268 M (15.8), 91 (100).
2
-1
1
67 °C (lit. 162 °C [16,17]); Ir (KBr, cm ) ꢀ 2250 (CN); 1629
Anal. Calcd. for C14H N O : C, 62.67; H, 4.50. Found: C,
12 4 2
62.43; H, 4.67.
1
(C=C); 1480, 1360 (NO ); H nmr (deuteriochloroform): ꢁ 9.42
2
(
td, J = 7.0, 1.1 Hz, 1H, H-5); 7.95 (td, J = 9.1, 1.1 Hz, 1H, H-8);
2
-(N-Isopropyl)amino-3-nitroimidazo[1,2-a]pyridine (4c).
7
1
1
.81 (ddd, J = 9.1, 7.0, 1.1 Hz, 1H, H-7); 7.5 (td, J = 7.0, 1.1 Hz,
H, H-6); cmr: 145.3, 131.9, 127.2, 125.8, 120.7, 119.6, 118.9,
-1
Obtained in 93% yield, mp 153-155°C; Ir (KBr cm ) ꢀ 3369
+
1
11.7; ms: m/z (%) 188 (M , 38), 78 (100).
(NH); l606 (C=C); 1454, 1332 (NO ); H nmr (DMSO-d ): ꢀ 9.24
2 6
(
7
td, J = 6.7, 1.1 Hz, 1H, H-5); 7.73 (td, J = 8.0, 1.4 Hz, 1H, H-7);
.58(d, J = 8.4 Hz, 1H, NH); 7.50 (td, J = 8.8, 1.1 Hz, 1H, H-8);
7.16 (td, J =7.0, 1.2 Hz, 1H, H-6); 4.27 (m, 1H, CH); 1.28 (d, J =
6.6 Hz, 6H, CH ); cmr: ꢀ 153.2, 146.8, 134.4, 128.7, 117.5, 114.7,
114.1, 44.2, 22.3; ms; m/z (%) 220 M (76), 78 (100).
Anal. Calcd. For C10 : C, 54.53; H, 5.49; N, 25.44.
Found: C, 54.65; H, 5.74
2
-Guanidinyl-3-nitroimidazo[1,2-a]pyridine (4a).
To a sodium n-butoxide/butanol solution, prepared from
sodium metal (147 mg, 6.38 mmol) and n-butanol (20 mL) was
added guanidine hydrochloride (508 mg, 5.32 mmol), and 2-
cyano-3-nitroimidazo[1,2-a]pyridine 3 (1.0 g, 5.32 mmol) was
added to the guanidine n-butanol solution. The mixture was
stirred at 80 °C for 1 hour. After cooling, the solid formed was
collected by filtration, washed with cold ethanol, and
recrystallized from ethanol to afford 4a, 65% yield, mp 222-223
3
+
H N O
12 4 2
2
-(N-Cyclohexyl)amino-3-nitroimidazo[1,2-a]pyridine (4d).
-1
Obtained in 62% yield, mp 157-159°C. Ir (KBr cm ) ꢀ 3333
-
1
1
°
C; Ir (KBr, cm ) ꢀ 3425, 3335, 3232 (NH); 1627 (C=C); 1482
(NH); l606 (C=C); 1461, 1332 (NO ); H nmr (DMSO-d ): ꢀ
2 6

5
68
L. Arias, H. Salgado-Zamora, H. Cervantes, E. Campos, A. Reyes and E. C. Taylor
Vol 43
9
7
.23 (d, J = 7.0 Hz, 1H, H-5); 7.73 (td, J =8.0, 1.2 Hz, 1H, H-7);
.57(d, J = 8.5 Hz, 1H, NH); 7.51 (d, J = 8.8 Hz, 1H, H-8); 7.16
Hz, 2H, OCH ); 1.56 (t, J = 7.2 Hz, 3H, CH ); cmr: ꢀ 158.7,
2
3
142.1, 131.7, 128.1, 116.3, 115.5, 66.5, 14.6; ms; m/z (%) 207
+
(t, J =7.0 Hz, 1H, H-6); 3.93 (m, 1H, CHcyclohexyl); 1.18-1.94 (m,
M (41), 78.1 (100).
1
1
2
0H, CH2 (cyclohexyl)); cmr: ꢀ 153.1, 146.9, 134.5, 128.7, 117.5,
14.7, 114.1, 51.1, 32.3, 25.1, 24.7; ms; m/z (%) 260 M (97.5),
43 (100).
Anal. Calcd. For C H N O : C, 52.17; H, 4.37; N, 20.28.
9
9
3
3
+
Found: 52.39, H, 5.74
-Isopropoxy-3-nitroimidazo[1,2-a]pyridine (6b).
Obtained in 70 % yield, mp 142-143°C. Ir (KBr cm ) ꢀl
2
Anal. Calcd. For C H N O : C, 59.98; H, 6.19; N, 21.52.
13
16
4
2
-
1
Found: C, 59.68; H, 6.34
-(N-1-Butyl)amino-3-nitroimidazo[1,2-a]pyridine (4e).
1
(
6
C=C); (NO ); (C-O-C); H nmr (DMSO-d ): ꢀ 9.39 (dd, J =
2
6
2
.6, 1.2 Hz, 1H, H-5); 7.78 (td, J =8.0, 1.4 Hz, 1H, H-7); 7.70
-1
Obtained in 72% yield, mp 73.5-74.5°C. Ir (KBr cm ) ꢀ 3375
(dd, J = 7.7, 1.2 Hz, 1H, H-8); 7.36 (td, J =6.9, 1.6 Hz, 1H, H-
6); 5.44 (m, 1H, CH) ; 1.48 (d, J = 6.3 Hz, 6H, CH ) ; cmr: ꢀ
156.1, 140.2, 131.6, 130.6, 126.3, 114.6, 114.3, 71.8, 20.1; ms;
1
(NH); l606 (C=C); 1461, 1332 (NO ); H nmr (deuterio-
3
2
chloroform): ꢀ 9.37 (ddd, J = 6.8, 1.4, 1.0 Hz, 1H, H-5); 7.60
td, J =8.0, 1.5 Hz, 1H, H-7); 7.46(bs, 1H, NH); 7.42 (td, J =8.8,
+
+
(
1
2
m/z (%) 221 M (51), 222 MH (100).
Anal. Calcd. For C10 : C, 54.29; H, 5.01; N,
18.99.Found: C, 53.91, H, 4.65.
.1 Hz, 1H, H-8); 7.03 (td, J = 7.0, 1.2 Hz, 1H, H-6); 3.65 (m,
H, CH2 (n-butyl)); 1.72 (m, 2H, CH2 (n-butyl)); 1.47 (m, 2H, CH2 (n-
H N O
11 3 3
butyl)); 0.98 (t, J = 7.3 Hz, 3H, CH3 (n-butyl)); cmr: ꢀ 154.4, 147.2,
33.5, 128.6, 118.0, 114.9, 113.5, 42.1, 31.6, 19.9, 13.6; ms;
m/z (%) 234 M (95), 146.2 (100).
General procedure for the synthesis of compounds 7a,b.
1
+
To a well-stirred, cold solution (ice bath) containing 0.2 g
(1.06 mmol) of 2-cyano-3-nitroimidazo[1,2-a]pyridine (3) and
0.1 mL (1.06 mmol) of methyl thioglycolate in DMF (2.1 mL),
Anal. Calcd. For C H N O : C, 56.39; H, 6.02; N, 23.91.
11
14
4
2
Found: 56.23; H, 5.81
-(N-Cyclopropyl)amino-3-nitroimidazo[1,2-a]pyridine (4f).
0
.09 g of sodium bicarbonate (1.06 mmol) was slowly added.
2
The mixture was stirred for 1 h at low temperature and then at
room temperature during 2 h. The solution was poured into ice-
water and the precipitated cyanothioester was collected by
filtration, washed with water (2x5 mL) and cold ethanol (5 mL)
The solid was further purified by re-crystallization from ethanol.
-1
Obtained in 88% yield, mp 186-187°C. Ir (KBr cm ) ꢀ 3329
1
(
NH); l611 (C=C); 1468, 1334 (NO ); H nmr (deuterio-
2
chloroform): ꢀ 9.38 (td, J =6.8, 1.1 Hz, 1H, H-5); 7.62 (td, J
7.9, 1.5 Hz, 1H, H-7); 7.53 (td, J = 8.8, 1.1 Hz, 1H, H-8)
=
7
1
.51(bs, 1H, NH); 7.07 (td, J =6.9, 1.3 Hz, 1H, H-6); 3.03 (m,
H, CH cyclopropyl); 0.98 (m, 2H, CH2 (cyclopropyl)); 0.76 (m, 2H, CH2
Methyl 2-Cyanoimidazo[1,2-a]pyridine-3-thioglycolate (7a).
(cyclopropyl)); cmr: ꢀ 155.1, 146.9, 133.4, 128.5, 118.1, 115.3,
This compound was obtained in 88% yield, mp 96-98°C. Ir
(KBr cm ) ꢀ 2250 (CN); 1742 (C=O); 1436 (C=C); H nmr
(DMSO-d6): ꢀ 8.67 (td, J =8.1, 1.1 Hz, 1H, H-5); 7.76 (td, J
+
-1
1
1
13.8, 24.5, 7.3; ms; m/z (%) 218 M (8), 201 (100).
Anal. Calcd. For C H N O : C, 55.04; H, 4.61; N, 25.67.
10
10
4
2
Found: C, 55.41; H, 4.85
=9.2, 1.1 Hz, 1H, H-8); 7.60 (s, 2H, SCH
2
); 3.57 (m, 2H, OCH );
3
cmr: ꢀ 168.89, 146.55, 129.04, 125.82, 124.28, 120.23, 117.87,
2
-(N-(S)-(-)-ꢁ-Methylbenzyl)amino-3-nitroimidazo[1,2-a]pyri-
+
1
15.20, 114.22, 52.28, 36.10; ms; m/z (%) 247 M (31), 174
100).
Anal. Calcd. For C11
16.99.Found: C, 53.38; H, 3.45.
dine (4g).
(
-1
Obtained in 48% yield, mp 102-103°C. Ir (KBr cm ) ꢀ3346
H N O S: C, 53.43; H, 3.66; N,
9 3 2
1
(NH); 1601 (C=C); 1457, 1334 (NO ); H nmr (deuterio-
2
chloroform): ꢀ 9.35 (td, J = 6.8, 1.2 Hz, 1H, H-5); 7.74 (d, J =
.0 Hz, 1H, NH) 7.56 (td, J =8.0, 1.4 Hz, 1H, H-7); 7.45-7.24
m, 6H, H-8 and Ph) 7.01 (td, J =6.8, 1.2 Hz, 1H, H-6); 5.40 (m,
2
-Cyano-3-propanethiolimidazo[1,2-a]pyridine (7b).
8
(
This compound was obtained in 74% yield, mp 77-78 °C. Ir
-1
1
1
1
5
H, CH); 1.69 (d, J = 9.2 Hz, 3H, CH ); cmr: ꢀ 153.4, 147.0,
(KBr cm ) ꢀ (CN); (C=C); H nmr (deuteriochloroform): ꢀ 8.42
(td, J = 7.0, 1.1 Hz, 1H, H-5); 7.68 (td, J = 9.2, 1.1 Hz, 1H, H-
8); 7.43 (ddd, J = 9.2, 6.9, 1.2 Hz, 1H, H-7); 7.09 (td, J =6.9, 1.1
Hz, 1H, H-6); 2.78 (t, J = 7.4 Hz, 3H, SCH ); 1.6 (m, 2H, CH );
3
42.8, 133.3, 128.66, 128.60, 127.43, 125.96, 115.1, 113.6,
+
1.8, 22.8; ms; m/z (%) 282 M (27), 265.1 (100).
Anal. Calcd. For C H N O : C, 63.81; H, 4.99; N, 19.84.
15
14
4
2
2
2
Found: C, 63.64; H, 4.67
1.03 (t, J = 7.4 Hz, 3H, CH ); cmr: ꢀ 146.76, 133.85, 127.84,
3
1
1
25.08, 124.55, 122.74, 118.76, 114.78, 114.31, 38.03, 23.25,
2.96; ms; m/z (%) 217 M (21), 175 (100).
General procedure for the synthesis of 2-alkoxy-3 nitroimidazo-
+
[1,2-a]pyridine (6a,b).
Anal. Calcd. For C H N S: C, 60.80; H, 5.10; N, 19.33.
1
1
11
3
A mixture of 2-cyano-3-nitroimidazo[1,2-a]pyridine 3 (1.0 g,
Found: C, 60.52; H, 4.86.
5
.32 mmol), sodium alkoxide (8 mmol) and the corresponding
2
-Amidoxime-3-nitroimidazo[1,2-a]pyridine (8).
alcohol (10 mL) was stirred at ca. 60 °C for 2 hours. After
cooling, the solid formed was collected by filtration and washed
with cold ethanol, and recrystallized from ethanol to afford the
corresponding 2-alkoxy-3-nitroimidazo[1,2-a]pyridine 6a,b.
2-Cyano-3-nitroimidazo[1,2-a]pyridine (0.2g, 1.06 mmol),
hydroxylamine hydrochloride (0.36 g, 5.32 mmol) and sodium
acetate (0.43 g, 5.32 mmol) were suspended in 2-propanol and
heated to a reflux temperature for 2 h. The reaction mixture was
allowed to cool to room temperature and the formed solid was
collected by filtration and washed with cold water. The title
compound was isolated as a yellow solid (0.2 g, 85 % yield), mp
2
-Ethoxy-3-nitroimidazo[1,2-a]pyridine (6a).
Obtained in 75 % yield, mp 147-149°C, Ir (KBr cm ) ꢀ l540
-1
1
(C=C); 1486, 1327 (NO ); 1210, 1022 (C-O-C); H nmr
2
-
1
(CDCl ): ꢀ 9.47 (td, J =6.8, 1.0 Hz, 1H, H-5); 7.69-7.57 (m, 2H,
178-180 °C. IR (KBr cm ) ꢀ 3453, 3353 (NH ); l643 (C=N);
1485, 1338 (NO ); H nmr (DMSO-d ): ꢀ 9.86 (s, 1H, OH); 9.35
3
2
1
H-8 and H-7); 7.23 (td, J =6.8, 1.6 Hz, 1H, H-6); 4.71 (c, J = 7.2
2
6

May-Jun 2006
569
Some Nucleophilic Substitutions In 2-Cyano-3-Nitroimidazo[1,2-a]Pyridine
(
d, J = 6.4 Hz, 1H, H-5); 7.94 (d, J = 8.4 Hz, 1H, H-8); 7.82 (td,
[2]
Wilson and D. W. Boykin, J. Med. Chem., 47, 3658 (2004).
M. I. Ismail, R. Brun, T. Wenzler, F. A. Tanious, W. D.
J = 7.8, 1.3 Hz, 1H, H-7); 7.49 (td, J = 7.0, 1.2 Hz, 1H, H-6);
5
1
[
3]
W. W. Paudler and H. L. Blewitt, Tetrahedron, 21, 353
.92 (s, 2H, NH ): cmr ꢀ 145.9, 143.9, 141.9, 131.3, 127.6,
2
+
(1965).
18.0, 117.3; ms; m/z (%) 221 M (49), 78.1 (100).
[
[
4]
5]
T. Ikemoto and M. Wakimasu, Heterocycles, 55, 99 (2000).
J. P. Paolini and R. K. Robins, J. Org. Chem., 30, 4085
Anal. Calcd. For C H N O : C, 43.44; H, 3.18; N, 31.66.
8
7
5
3
Found: C, 43.08; H, 2.87
(1965).
[
6]
J. C. Teulade, G. Grassy, R. Escale and J. P. Chapat, J. Org.
3
-Aminoimidazo[1,2-a]pyridine-2-carbonitrile (9).
Chem., 46, 1026 (1981).
[
7]
F. Effenberger, M. Kochand W. Streicher, Chem. Ber., 124,
A mixture of 2-cyano-3-nitroimidazo[1,2-a]pyridine 3 (0.5 g,
.65 mmol) and phenylhydrazine (25.4 mmol) was stirred at 60-
0 °C for 12 hours. After cooling, the solid formed was
collected by filtration, washed with ethyl ether (10 mL), and
recrystallized from ethanol to afford the corresponding 3-amino-
imidazo[1,2-a]pyridine-2-carbonitrile (9) (0.3 g, 73 % yield),
mp 238-239 °C (dec.), lit. mp 209-211 °C [18].
1
63 (1991).
2
7
[
[
8]
9]
J. R. Beck, Tetrahedron, 34, 2057 (1978).
J. Holt, F. Tjosas, J. M. Bakke and A. Fiksdahl, J.
Heterocyclic Chem., 41, 987 (2004).
10] E. J. Corey, N. W. Gilman, B. E. Ganem, J. Am. Chem. Soc.,
0, 5616 (1968).
[
9
[11] E. C. Taylor and A. L. Borror, J. Org. Chem., 26, 4967
(
1961).
Acknowledgment.
[
12] M. Makosza, Polish J. Chem., 66, 3 (1992).
13] J.-C. Teulade, G. Grassy, J.-P. Girard, and J.-P. Chapat. Eur.
[
Financial support from the Instituto Politécnico Nacional
México) through grants 20030766 and 20040295 is gratefully
acknowledged.
J. Med. Chem., 13, 271 (1978).
14] H. Salgado-Zamora, B. Rizo, E. Campos, R. Jiménez and A.
Reyes. J. Heterocyclic Chem., 41, 91 (2004).
(
[
[15] R. Walther, J. Prakt Chem. 52, 141 (1895); 53, 433 (1896).
[
16] V.E Winkelmann, W. Raether, H. Hartung, and W.H.
REFERENCES AND NOTES
A. Gueiffier, M. Lhassani, A. Elhakmaoui, R. Snoeck, G.
Wagner. Arznelm. –Forsch./Drug Res., 27, 82 (1977)
17] J.-C. Teulade, G. Grassy, J.-P. Girard and J.-P- Chapat. Eur.
[
[
1]
J. Med. Chem., 13, 271 (1978).
Andrei, O. Chavignon, J-C. Teulade, A. Kerbal, E. M. Essassi, J-C.
Debouzy, M. Witvrouw, Y. Balzarini, E. D. Clercq and J-P Chapat, J
Med. Chem., 39, 2856 (1996).
[18] A. Gueiffier, O. Chavignon, S. Mavel, J.-M. Chezal, J.-C.
Teulade, I. Blache, and J.-P. Chapat, Heterocyclic Commun., 2, 241
(1996).