A convenient synthesis of pyrrolo[2,3-b]pyridines and pyrido[2′, 3′:5,4]pyrrolo[2,3-d]pyrimidines

Article abstract of DOI:10.1007/s00706-007-0839-3

2-Chloro-6-ethoxy-4-phenylpyridine-3,5-dicarbonitrile was taken as versatile building block that allows the synthesis of 1H-pyrrolo[2,3-b]pyridine, thieno[2,3-b]pyridine and pyrido[2′,3′:5,4]pyrrolo[2,3-b]pyrimidine systems. Some of the synthesized compou

Full text of DOI:10.1007/s00706-007-0839-3

Monatsh Chem 139, 1233–1240 (2008)
DOI 10.1007/s00706-007-0839-3
Printed in The Netherlands
A convenient synthesis of pyrrolo[2,3-b]pyridines and pyrido-
[20,30:5,4]pyrrolo[2,3-d]pyrimidines
Shawkat A. Abdel-Mohsen, Ahmed A. Geies
Chemistry Department, Faculty of Science, Assiut University, Assiut, Egypt
Received 1 September 2007; Accepted 25 October 2007; Published online 24 July 2008
# Springer-Verlag 2008
Abstract 2-Chloro-6-ethoxy-4-phenylpyridine-3,5-
dicarbonitrile was taken as versatile building block
that allows the synthesis of 1H-pyrrolo[2,3-b]pyri-
dine, thieno[2,3-b]pyridine and pyrido[20,30:5,4]-
pyrrolo[2,3-b]pyrimidine systems. Some of the
synthesized compounds were screened as antibacteri-
al agents.
Results and discussion
To reach this target, we started with 3,5-dicyano-6-
ethoxypyridine-2(1H)-one 4 which was synthesized
by Otto et al. [13] through the reaction of ethyl
benzylidenecyanoacetate and malononitrile in etha-
nolic sodium ethoxide solution, they suggested that
the reaction should be proceeded via the intermedi-
ate 3. Fortunately, we succeeded in separation of
the aminopyrane 3, which underwent Dimroth rear-
rangement to give finally the pyridinone derivative
4. Compound 4 was used as a key intermediate to
synthesize some new pyrrolo-, thieno-, pyrazolopyr-
idines, and other fused tri- and=or tetracyclic deriva-
tives. Thus, refluxing of 4 with a mixture of POCl3=
PCl5 yielded the corresponding 2-chloropyridine de-
rivative 5. The ring system pyrrolo[2,3-b]pyridine
was obtained via the following steps: Treatment of
5 with an equimolar ratio of ethyl glycinate hydro-
chloride in DMF in the presence of K2CO3 resulted
in the formation of ethyl (3,5-dicyano-6-ethoxy-4-
phenylpyridine-2-yl)glycinate (6). The latter was
easily methylated by its reaction with methyl iodide
to give N-methyl derivative 7. Upon treatment with
ethanolic sodium ethoxide, 7 underwent cyclization
to afford ethyl 3-amino-5-cyano-6-ethoxy-1-methyl-
4-phenylpyrrolo[2,3-b]pyridine-2-carboxylate (8).
The structure of 8 was established using microanal-
yses and spectral data. Thus, the IR spectrum re-
vealed the strong absorption bands for CO (ester)
at 1695 cmꢀ1 and for NH2 at 3480 and 3380 cmꢀ1.
Keywords Heterocycles; Antibacterial agents.
Introduction
Pyrrolopyridines have attracted considerable at-
tention as an analog of indole nucleus because
of their interesting biological activities [1–6].
There are only a few pyrrolopyridine derivatives
in nature, so many pyrrolopyridine derivatives are
synthetically prepared for the development of phar-
maceutical agents. Also, pyridopyrrolopyrimidines
e.g., Variolins, isolated by Munro et al. [7] from the
antartic red sponge Kirckpatrickia varialosa, are alka-
loids that exhibit antitumor and antiviral properties,
Variolin B, the most active molecule of the group,
has attracted considerable interest. In our research pro-
gram devoted to the synthesis of different heterocyclic
systems incorporated pyrrole moiety [8–12], we
planned to prepare new pyrrolo[2,3-b]pyridine deriva-
tives based on the 7-azaindole framework.
Correspondence: Shawkat A. Abdel-Mohsen, Chemistry De-
partment, Faculty of Science, Assiut University, Assiut 71516,
Egypt. E-mail: shawk662001@yahoo.com
l
The H NMR spectrum revealed the presence of

1234
Sh. A. Abdel-Mohsen, A. A. Geies
two triplets at ꢀ ¼ 1.30, 1.45 ppm for 2 CH3, a singlet
at ꢀ ¼ 3.9 ppm for N–CH3, two quartets at ꢀ ¼ 4.30,
4.40ppm for 2 CH2, a singlet at ꢀ ¼ 4.85 ppm for
NH2 (exchangeable with D2O) in addition to the sig-
nals for aromatic protons. The mass spectrum showed
Mþ peak at 363.99 which was in agreement with
molecular formula C20H20N4O3 (m=z ¼ 364). Anoth-
er pyrrolopyridine derivative 9 was achieved via the
reaction of 6 with phenacyl bromide in acetone=
K2CO3 to give 3-amino-2-benzoyl-5-cyano-6-eth-
oxy-1-ethoxycarbonylmethyl-4-phenylpyrrolo[2,3-
b]pyridine (10). The formation of 10 rather than its
Scheme 1

Pyrrolo [2,3-b]pyridines and pyrido[20,30:5,4]pyrrolo[2,3-d]pyrimidines
1235
isomer N-benzoylmethyl was assumed to proceed
via intermediate 9 followed by its subsequent intra-
cyclization of the CH2(COPh) to the neighboring
pyridine C-3 CN function. Structure of 10 was estab-
lished by spectral analysis. Thus, its IR spectrum
showed band for the C¼O (ester) that was shifted
to longer wavelength (ꢁꢀ¼ 1735 cmꢀ1) rather than
the C¼O (ester) attached directly to the pyrrole ring.
On the other hand, thieno[2,3-b]pyridine derivatives
12a–12e were obtained via the reaction of thione
derivative 11 with ꢂ-halo compounds. By a similar
way, 12a–12e underwent cyclization using ethanolic
sodium ethoxide solution to furnish 2-substituted 3-
amino-5-cyano-6-ethoxy-4-phenylthieno[2,3-b]pyri-
dines 13a–13e (Scheme 1).
The o-aminoester 8 was condensed with formam-
ide to yield 8-cyano-7-ethoxy-5-methyl-9-phenyl-
pyrido[20,30:5,4]pyrrolo[2,3-b]pyrimidine-4(3H)-one
(14). Chlorination at the C-4 position was performed
on 14 to afford the chloropyridopyrrolopyrimidine
derivative 15 in 66% yield. Compound 15 in turn
could be transformed to the 4-hydrazino or the
Scheme 2

1236
Sh. A. Abdel-Mohsen, A. A. Geies
Scheme 3
4-mercapto compounds 16, 17 by its reaction with
hydrazine hydrate or thiourea in ethanol (Scheme 2).
The hydrazine 16 was used to build a new triazolo-
pyridopyrrolopyrimidine 18 via the condensation
with triethyl orthoformate in ethanol in the presence
of catalytic amounts of acetic acid. The formation of
18 from 16 was supported by elemental analyses and
by the absence of absorption bands at ꢁꢀ¼ 3450,
3350, and 3150 cmꢀ1 for the respective stretching
vibration of NHNH2 in its IR spectrum. The thione
derivative 17 was allowed to react with ꢂ-chloroa-
cetone in ethanol containing anhydrous sodium ace-
tate to give the corresponding 4-acetylmethylthio
derivative 19 in a good yield.
Other derivatives of o-aminoester 8 were synthe-
sized via its reaction with DMTHF or hydrazine hy-
drate to furnish 3-pyrrolyl and the corresponding
carbohydrazide 20 and 21. The latter was further
reacted with carbon disulfide in pyridine to give 2-
(oxadiazolyl)pyrrolopyridine 22, which was easily
S-alkylated with ethyl chloroacetate in ethanol con-
taining anhydrous sodium acetate to give the thioe-
ster derivative 23 (Scheme 2).
Antibacterial activity
Twelve compounds were selected and screened in
vitro for their antibacterial activity against five
strains of bacteria (Bacillus cereus, Escherichia coli,
Pseudomonas aeruginosa, Serratia marcescens, and
Staphylococcus aureus) using the filter paper disc
method [14]. The biological activity, as expressed
by the growth of the inhibition zones of the tested
microorganism are summarized in Table 1. From
Table 1, it was observed that all of the tested com-
pounds have a moderate activity against E. coli and
S. marcescens. Among the derivatives of pyridopyr-
Table 1 Antibacterial activities for most of synthesized com-
pounds (diameter of inhibition zones, mm)
Compd. B.
no.
E.
cereus coli aureus aeruginosa marcescens
S.
P.
S.
7
8
ꢀve
ꢀve
ꢀve
ꢀve
ꢀve
ꢀve
ꢀve
ꢀve
ꢀve
ꢀve
ꢀve
ꢀve
42
12
15
13
18
12
11
10
12
11
14
12
10
25
ꢀve
ꢀve
ꢀve
ꢀve
ꢀve
27
ꢀve
ꢀve
ꢀve
ꢀve
ꢀve
ꢀve
ꢀve
ꢀve
ꢀve
ꢀve
ꢀve
ꢀve
20
15
19
15
14
15
22
14
13
11
13
15
14
30
13c
13d
14
15
17
18
19
20
24
The pyridinone 4 was also used to synthesize
3-amino-5-cyano-4-phenyl-1H-pyrazolo[3,4-b]pyri-
dine-7(6H)-one 24 by its reaction with hydrazine
hydrate. Finally, the pyrazolopyridinone derivative
24 was converted into the corresponding thione 25
by refluxing with P2S5 in dry pyridine, which when
treated with methyl iodide afforded the 6-methylthio
derivative 26 in a good yield (Scheme 3).
ꢀve
21
13
ꢀve
ꢀve
10
25
Sutrim
20
ꢀve No inhibition zone

Pyrrolo [2,3-b]pyridines and pyrido[20,30:5,4]pyrrolo[2,3-d]pyrimidines
1237
Ethyl (3,5-dicyano-6-ethoxy-4-phenylpyridine-2-yl)-N-methyl
glycinate (7, C20H20N4O3)
rolopyrimidines compounds 14, 17, 15, 18, and 19,
only 4-chloropyrimidine derivative 15 and the tria-
zolopyridopyrrolopyrimidine 18 exhibited a remark-
able antimicrobial activity against S. aureus. None of
the investigated compounds possessed any antibac-
terial activity towards the rest of the bacteria species
B. cereus and P. aeruginosa.
A mixture of 1.75g 6 (0.005mol), 0.24g methyl iodide
(0.005mol), and 0.5 g anhydrous potassium carbonate in
30cm3 acetone was refluxed for 3 h, then allowed to cool,
and poured into cold water. The solid product was collected,
washed thoroughly with water, dried, and recrystallized from
ethanol to give 1.43 g (79%) white crystals of 7; mp 165–
167ꢁC; IR (KBr): ꢁꢀ¼ 2220 (CN), 1710 (C¼O) cmꢀ1
;
1H
NMR (CDCl3): ꢀ ¼ 1.30 (t, J ¼ 7.4 Hz, CH3 ethoxy), 1.40 (t,
J ¼ 7.4 Hz, CH3 ester), 3.85 (s, N–CH3), 4.25 (q, J ¼
6.8 Hz, CH2 ethoxy), 4.40 (q, J ¼ 6.5 Hz, CH2 ester), 4.7 (s,
N–CH2), 7.55–7.80 (m, 5Ar–H) ppm.
Experimental
All melting points were determined on a Gallenkamp
apparatus. IR spectra were recorded on a Pye-Unicam spectro-
1
photometer using the KBr wafer technique. H NMR spectra
were obtained on a Bruker 250 MHz NMR spectrometer. MS
on a Jeol JMS-600 mass spectrometer. Elemental analyses were
determined using Perkin-Elmer 240C Microanalyzer and all
results were within the acceptable range.
Ethyl 3-amino-5-cyano-6-ethoxy-1-methyl-4-phenylpyrrolo-
[2,3-b]pyridine-2-carboxylate (8, C20H20N4O3)
To a solution of 0.364 g 7 (0.001 mol) in 30 cm3 absolute
ethanol was added a few drops of ethanolic sodium ethox-
ide solution, and the mixture was refluxed for 30 min. The
solid product was collected and recrystallized from ethanol
to give 0.29 g (82%) yellow crystals of 8; mp 225–225ꢁC;
IR (KBr): ꢁꢀ¼ 3450, 3350 (NH2), 2220 (CN), 1660 (C¼O)
2-Amino-3,5-dicyano-4-phenyl-6-ethoxypyrane (3,C15H13N3O2)
To a mixture of 2.01 g ethyl benzylidenecyanoacetate (1)
(0.01 mol) and 0.66g malononitrile 2 (0.01 mol) in 30cm3
absolute ethanol, 0.1 g sodium ethoxide in 10 cm3 ethanol
were added. The mixture was heated for 30 min. The solid
product that precipitated during the reflux was filtered off,
dried, and recrystallized from ethanol to give 1.89 g (71%)
pale yellow crystals of 3; mp 160–162ꢁC; IR (KBr): ꢁꢀ¼
1
cmꢀ1; H NMR (CDCl3): ꢀ ¼ 1.30 (t, J ¼ 7.4 Hz, CH3 eth-
oxy), 1.45 (t, J ¼ 7.3 Hz, CH3 ester), 3.90 (s, N–CH3), 4.30
(q, J ¼ 6.7 Hz, CH2 ethoxy), 4.40 (q, J ¼ 6.7 Hz, CH2 ester),
4.85 (s, NH2), 7.40–7.80 (m, 5Ar–H) ppm; MS: m=z ¼
363.99 [Mþ].
1
3450, 3350 (NH2), 2220 (CN) cmꢀ1; H NMR (DMSO-d6):
ꢀ ¼ 1.4 (t, J ¼ 7.1 Hz, CH3), 4.50 (q, J ¼ 6.8 Hz, CH2), 4.75 (s,
3-Amino-2-benzoyl-5-cyano-6-ethoxy-1-ethoxycarbonyl-
methyl-4-phenylpyrrolo[2,3-b]pyridine (10, C27H24N4O4)
A mixture of 1.75 g 6 (0.005 mol), 0.99 g phenacyl bromide
(0.005mol), and 0.5 g anhydrous potassium carbonate in
30cm3 acetone was refluxed for 6 h, and then allowed to cool.
The solid product was collected, washed thoroughly with
water, dried and recrystallized from ethanol to give 1.66g
(71%) orange plates of 10; mp 215–216ꢁC; IR (KBr): ꢁꢀ¼
3450, 3390 (NH2), 2220 (CN), 1735 (C¼O), 1665 (C¼O)
cmꢀ1; 1H NMR (CDCl3): ꢀ ¼ 1.20 (t, J ¼ 7.2 Hz, CH3 ethoxy),
1.40 (t, J ¼ 7.2 Hz, CH3 ester), 4.20 (q, J ¼ 6.6 Hz, CH2 eth-
oxy), 4.40 (q, J ¼ 6.4 Hz, CH2 ester), 4.65 (s, N–CH2), 6.15
(s, NH2), 6.95–7.90 (m, 10Ar–H) ppm.
CH pyran), 5.80 (s, NH2), 7.20–7.70 (m, 5Ar–H) ppm.
3,5-Dicyano-6-ethoxy 4-phenylpyridine-2-(1H)-one (4)
This compound was synthesized according to Ref. [13].
2-Chloro-3,5-dicyano-4-phenyl-6-ethoxypyridine
(5, C15H10N3OCl)
A mixture of 2.65g 4 (0.01 mol), 10cm3 phosphorus
oxychloride and 10 g phosphorus pentachloride was heated
on a water bath for 5 h, allowed to cool, and poured into ice
cold water. The solid product was collected and recrystallized
from ethanol to yield 1.83g (65%) white crystals of 5;
1
mp 140–142ꢁC; IR (KBr): ꢁꢀ¼ 2220 (CN) cmꢀ1; H NMR
(DMSO-d6): ꢀ ¼ 1.35 (t, J ¼ 7.3 Hz, CH3), 4.45 (q, J ¼ 6.5 Hz,
CH2), 7.20–7.60 (m, 5Ar–H) ppm.
3,5-Dicyano-6-ethoxy-4-phenylpyridine-2-(1H)-thione (11)
This compound was synthesized according to Ref. [15].
Ethyl (3,5-dicyano-4-phenyl-6-ethoxypyridine-2-yl)
glycinate (6, C19H18N4O3)
5-Substituted 3,5-dicyano-6-ethoxy-4-phenyl-2-pyridinethiols
12a–12e. General procedure
A mixture of 1.15g 11 (0.005mol), (0.005mol) halo com-
pounds and 2 g sodium acetate in 30cm3 ethanol was refluxed
for 1 h, and then allowed to cool. The solid product was
collected, washed with water several times, dried, and recrys-
tallized from ethanol.
A mixture of 2.8 g 5 (0.01 mol), 1.4g ethyl glycinate hydro-
chloride (0.01 mol), and 0.2 g anhydrous potassium carbonate
in 20cm3 DMF was heated at 70ꢁC with stirring for 9 h,
allowed to cool, and poured into cold water. The solid product
was collected and recrystallized from ethanol to give 2.6 g
(75%) white crystals of 6; mp 137–138ꢁC; IR (KBr):
ꢁꢀ¼ 3390 (NH), 2220 (CN), 1720 (C¼O) cmꢀ1
;
1H NMR
2-(Acetylthio)-3,5-dicyano-6-ethoxy-4-phenylpyridine
(12a, C18H15N3O2S)
(CDCl3): ꢀ ¼ 1.35 (t, J ¼ 7.4 Hz, CH3 ethoxy), 1.45 (t, J ¼
7.4 Hz, CH3 ester), 4.25 (q, J ¼ 6.6 Hz, CH2 ethoxy), 4.4 (d,
N–CH2), 4.45 (q, J ¼ 6.7 Hz, CH2 ester), 6.25 (s, NH), 7.50–
7.80 (m, 5Ar–H) ppm.
Yield 1.44 g (86%); mp 210–211ꢁC; IR (KBr): ꢁꢀ¼ 2220
1
(CN), 1700 (CO) cmꢀ1; H NMR (CDCl3): ꢀ ¼ 1.40 (t, 3H,

1238
Sh. A. Abdel-Mohsen, A. A. Geies
3-Amino-5-cyano-6-ethoxy-2-(ethoxycarbonyl)-4-
J ¼ 6.8 Hz, CH3), 2.45 (s, 3H, CH3), 4.30 (q, 2H, J ¼ 6.05 Hz,
CH2), 4.55 (s, 2H, CH2), 7.20–7.70 (m, 5H, Ar–H) ppm.
phenylthieno[2,3-b]pyridine (13c, C19H17N3O3S)
Yield 1.49g (83%); mp 287–288ꢁC; IR (KBr): ꢁꢀ¼ 3500, 3380
1
3,5-Dicyano-6-ethoxy-4-phenyl-2-(phenylcarbonylthio)-
pyridine (12b, C23H17N3O2S)
(NH2), 2200 (CN), 1670 (CO) cmꢀ1; H NMR (DMSO-d6):
ꢀ ¼ 1.30 (t, 3H, J ¼ 7.4 Hz, CH3 ethoxy), 1.40 (t, 3H, J ¼
7.4 Hz, CH3 ester), 4.20 (q, 2H, J ¼ 6.8 Hz, CH2 ethoxy), 4.5
(q, 2H, J ¼ 6.5 Hz, CH2 ester), 5.5 (s, 2H, NH2), 7.30–7.70
(m, 5H, Ar–H) ppm; MS: m=z ¼ 366.93 [Mþ].
Yield 1.53 g (77%); mp 199–200ꢁC; IR (KBr): ꢁꢀ¼ 2220
1
(CN), 1690 (CO) cmꢀ1; H NMR (DMSO-d6): ꢀ ¼ 1.45 (t,
3H, J ¼ 7.3 Hz, CH3), 4.15 (q, 2H, J ¼ 6.1 Hz, CH2), 4.60 (s,
2H, CH2), 6.90–7.70 (m, 10H, Ar–H) ppm.
3-Amino-2-[(4-chlorophenyl)aminocarbonyl]-5-cyano-6-
ethoxy-4-phenylthieno[2,3-b]pyridine (13d, C23H17N4O2ClS)
Yield 1.81g (86%); mp 260–262ꢁC; IR (KBr): ꢁꢀ¼ 3480,
3,5-Dicyano-6-ethoxy-2-(ethoxycarbonylthio)-4-phenylpyridine
(12c, C19H17N3O3S)
3380, 3300 (NH2, NH), 2200 (CN), 1640 (CO) cmꢀ1 1H
;
Yield 1.46 g (80%); mp 145–146ꢁC; IR (KBr): ꢁꢀ¼ 2220
1
(CN), 1720 (CO) cmꢀ1; H NMR (DMSO-d6): ꢀ ¼ 1.30 (t,
NMR (DMSO-d6): ꢀ ¼ 1.40 (t, 3H, J ¼ 7.3 Hz, CH3), 4.40
(q, 2H, J ¼ 6.6 Hz, CH2), 5.6 (s, 2H, NH2), 7.3–7.70 (m,
9H, Ar–H), 9.6 (s, 1H, NH) ppm.
3H, J ¼ 7.4 Hz, CH3 ethoxy), 1.40 (t, 3H, J ¼ 7.4 Hz, CH3
ester), 4.20 (q, 2H, J ¼ 6.8 Hz, CH2 ethoxy), 4.40 (q, 2H,
J ¼ 6.5 Hz, CH2 ester), 4.70 (s, 2H, CH2), 7.20–7.80 (m,
5H, Ar–H) ppm.
3-Amino-5-cyano-6-ethoxy-2-[(4-methoxyphenyl)amino-
carbonyl]-4-phenylthieno[2,3-b]pyridine (13e, C24H20N4O3S)
Yield 1.39g (69%); mp 270–272ꢁC; IR (KBr): ꢁꢀ¼ 3500,
2-[(4-Chlorophenyl)aminocarbonylthio]-3,5-dicyano-6-
ethoxy-4-phenylpyridine (12d, C23H17ClN4O2S)
3380, 3320 (NH2, NH), 2220 (CN), 1650 (CO) cmꢀ1 1H
;
Yield 1.79 g (80%); mp 242–243ꢁC; IR (KBr): ꢁꢀ¼ 3380
NMR (DMSO-d6): ꢀ ¼ 1.30 (t, 3H, J ¼ 7.3 Hz, CH3), 3.50 (s,
3H, CH3), 4.30 (q, 2H, J ¼ 6.6 Hz, CH2), 5.60 (s, 2H, NH2),
6.5–7.6 (m, 9H, Ar–H), 8.7 (s, 1H, NH) ppm.
1
(NH), 2220 (CN), 1640 (CO) cmꢀ1; H NMR (DMSO-d6):
ꢀ ¼ 1.35 (t, 3H, J ¼ 7.2 Hz, CH3), 4.20 (q, 2H, J ¼ 6.6 Hz,
CH2), 4.4 (s, 2H, CH2), 6.80–7.90 (m, 9H, Ar–H), 8.9 (s,
1H, NH) ppm.
8-Cyano-7-ethoxy-5-methyl-9-phenylpyrido[20,30:5,4]-
pyrrolo[2,3-d]pyrimidine-4(3H)-one (14, C19H15N5O2)
A sample of 1.82g 8 (0.005 mol) in 10cm3 formamide was
refluxed for 3 h. The solid product which separated from the
hot mixture was filtered off and recrystallized from dioxane to
give 1.35g (78%) pale yellow crystals of 14; mp 275–277ꢁC;
3,5-Dicyano-6-ethoxy-2-[(4-methoxyphenyl)amino-
carbonylthio]-4-phenylpyridine (12e, C24H20N4O3S)
Yield 1.72 g (77%); mp 178–180ꢁC; IR (KBr): ꢁꢀ¼ 3370
1
(NH), 2220 (CN), 1650 (CO) cmꢀ1; H NMR (DMSO-d6):
IR (KBr): ꢁꢀ¼ 3300 (NH), 2220 (CN), 1660 (CO) cmꢀ1
;
ꢀ ¼ 1.40 (t, 3H, J ¼ 6.8 Hz, CH3), 3.65 (s, 3H, CH3), 4.30 (q,
2H, J ¼ 6.6 Hz, CH2), 4.60 (s, 2H, CH2), 6.90–8.20 (m, 9H,
Ar–H), 9.20 (s, 1H, NH) ppm.
1H NMR (DMSO-d6): ꢀ ¼ 1.30 (t, 3H, J ¼ 7.30Hz, CH3),
3.90 (s, 3H, N–CH3), 4.40 (q, 2H, J ¼ 6.5 Hz, CH2), 7.45–
7.85 (m, 5H, Ar–H), 8.6 (s, 1H, CH pyrimidine), 9.2 (s, 1H,
NH) ppm; MS: m=z ¼ 345.02 [Mþ].
2-Substituted 3-amino-5-cyano-6-ethoxy-4-phenylthieno-
[2,3-b]pyridines 13a–13e
Compounds 13a–13g were prepared according to the method
reported for the synthesis of compound 8, starting from
0.005 mol 12a–12e. The precipitate was filtered off and
recrystallized from ethanol.
4-Chloro-8-cyano-7-ethoxy-5-methyl-9-phenylpyrido-
[20,30:5,4]pyrrolo[2,3-d]pyrimidine (15, C19H14N5OCl)
A mixture of 1.73 g 14 (0.01 mol) and 30 cm3 phosphorus
oxychloride was heated under reflux for 5 h, then allowed
to cool and poured into ice cold water. The solid product
was collected and recrystallized from ethanol to give 1.19g
(66%) white crystals of 15; mp 184–186ꢁC; IR (KBr):
2-Acetyl-3-amino-5-cyano-6-ethoxy-4-phenylthieno[2,3-b]-
pyridine (13a, C18H15N3O2S)
1
ꢁꢀ¼ 2200 (CN) cmꢀ1; H NMR (DMSO-d6): ꢀ ¼ 1.30 (t, 3H,
Yield 1.41 g (82%); mp 280–282ꢁC; IR (KBr): ꢁꢀ¼ 3450,
3350 (NH2), 2220 (CN), 1640 (CO) cmꢀ1
;
1H NMR
J ¼ 6.8 Hz, CH3), 3.85 (s, 3H, N–CH3), 4.40 (q, 2H, J ¼
6.4 Hz, CH2), 7.40–7.8 (m, 5H, Ar–H), 8.80 (s, 1H, CH py-
rimidine) ppm.
(DMSO-d6): ꢀ ¼ 1.30 (t, 3H, J ¼ 7.2 Hz, CH3), 2.50 (s, 3H,
CH3), 4.20 (q, 2H, J ¼ 6.8 Hz, CH2), 5.8 (s, 2H, NH2), 7.40–
7.90, (m, 5H, Ar–H) ppm.
8-Cyano-7-ethoxy-4-hydrazino-5-methyl-9-phenylpyrido-
[20,30:5,4]pyrrolo[2,3-d]pyrimidine (16, C19H17N7O)
3-Amino-5-cyano-6-ethoxy-4-phenyl-2-(phenylcarbonyl)-
thieno[2,3-b]pyridine (13b, C23H17N3O2S)
A mixture of 1.82 g 15 (0.005 mol) and 0.25 g hydra-
zine hydrate (0.005 mol) in 30 cm3 ethanol was refluxed
for 3 h and then left to cool. The precipitate solid was
collected and recrystallized from dioxane to give 1.12 g
(66%) yellow crystals of 16; mp 225–227ꢁC; IR (KBr):
Yield 1.50 g (75%); mp 215–217ꢁC; IR (KBr): ꢁꢀ¼ 3480,
3330 (NH2), 2220 (CN), 1630 (CO) cmꢀ1
;
1H NMR
(DMSO-d6): ꢀ ¼ 1.30 (t, 3H, J ¼ 7.2 Hz, CH3), 4.20 (q, 2H,
J ¼ 6.2 Hz, CH2), 6.25 (s, 2H, NH2), 6.80–7.90 (m, 10H, Ar–
H) ppm.
ꢁꢀ¼ 3450, 3350, 3150 (NH2, NH), 2220 (CN) cmꢀ1
;

Pyrrolo [2,3-b]pyridines and pyrido[20,30:5,4]pyrrolo[2,3-d]pyrimidines
1H NMR (DMSO-d6): ꢀ ¼ 1.40 (t, 3H, J ¼ 7.05 Hz, CH3),
1239
3-Amino-5-cyano-6-ethoxy-1-methyl-4-phenylpyrrolo[2,3-b]-
pyridine-2-carbohydrazide (21, C18H18N6O2)
3.90 (s, 3H, N–CH3), 4.55 (q, 2H, J ¼ 6.8 Hz, CH2), 4.8 (br,
s, 2H, NH2), 7.50–7.80 (m, 5H, Ar–H), 8.70 (s, 1H, CH
pyrimidine), 10.7 (s, 1H, NH) ppm.
A mixture of 1.82 g 8 (0.005mol) and 2 cm3 hydrazine hydrate
was refluxed in 20cm3 ethanol for 4 h. The solid separated
from the hot mixture was filtered off and recrystallized from
dioxane to give 1.20g (70%) yellow crystals of 21; mp 287ꢁC;
IR (KBr): ꢁꢀ¼ 3400, 3350, 3200 (NH2, NHNH2), 2220 (CN),
8-Cyano-7-ethoxy-5-methyl-9-phenylpyrido[20,30:5,4]-
pyrrolo[2,3-d]pyrimidin-4(3H)-thione (17, C19H15N5OS)
A mixture of 1.82 g 15 (0.005 mol) and 0.76 g thiourea
(0.01 mol) in 30 cm3 ethanol was refluxed for 8 h and then
left to cool. The precipitate solid was collected and recrys-
tallized from acetic acid to give 1.20 g (65%) orange crys-
1
1660 (CO) cmꢀ1; H NMR (DMSO-d6): ꢀ ¼ 1.30 (t, 3H, J ¼
7.15Hz, CH3), 3.70 (s, 3H, N–CH3), 4.30 (s, 2H, NH2), 4.40
(q, 2H, J ¼ 6.8 Hz, CH2), 5.7 (s, 2H, NH2), 7.50–7.8 (m, 5H,
Ar–H), 9.20 (s, 1H, NH) ppm.
1
tals of 17; mp >300ꢁC; IR (KBr): ꢁꢀ¼ 2220 (CN) cmꢀ1; H
NMR (DMSO-d6): ꢀ ¼ 1.40 (t, 3H, J ¼ 7.25 Hz, CH3), 3.90
(s, 3H, N–CH3), 4.20 (q, 2H, J ¼ 6.6 Hz, CH2), 7.40–7.90
(m, 5H, Ar–H), 8.60 (s, 1H, CH pyrimidine), 10.8 (s, 1H,
NH) ppm.
3-Amino-5-cyano-6-ethoxy-2-(5-mercapto-1,3,4-oxadiazol-
2-yl)-1-methyl-4-phenylpyrrolo[2,3-b]pyridine
(22, C19H16N6O2S)
A mixture of 1.75 g 21 (0.005mol) and5 cm3 carbon disulfide in
20cm3 pyridine was heated on a water bath for 24 h, and then
cooled. The precipitated product was filtered off and washed
several times with ethanol and recrystallized from dioxane to
give 1.37 g (70%) orange crystals of 22; mp 285–287ꢁC; IR
3-Cyano-2-ethoxy-11-methyl-4-phenylpyrido[20,30:5,4]-
pyrrolo[2,3-d]triazolo[3,4-f]pyrimidine (18, C20H15N7O)
To a mixture of 1.79g 16 (0.005 mol) and 2 cm3 triethyl ortho-
formate, in 20 cm3 ethanol a few drops of acetic acid were
added as a catalyst. The mixture was heated under reflux for
2 h. The solid product separated from the hot mixture was
filtered off and recrystallized from dioxane to give 1.20g
(65%) yellow crystals of 18; mp >300ꢁC; IR (KBr): ꢁꢀ¼ 222
(CN) cmꢀ1; 1H NMR (DMSO-d6): ꢀ ¼ 1.20 (t, 3H, J ¼ 6.4 Hz,
CH3), 3.80 (s, 3H, N–CH3), 4.20 (q, 2H, J ¼ 6.6 Hz, CH2),
7.32–7.90 (m, 5H, Ar–H), 8.80, 9.20 (2s, 2H, 2CH); MS:
m=z ¼ 369.52 [Mþ] ppm.
(KBr): ꢁꢀ¼ 3400, 3350, (NH2), 2600 (SH), 2220 (CN) cmꢀ1
;
1H NMR (DMSO-d6): ꢀ ¼ 1.30 (t, 3H, J ¼ 7.30Hz, CH3), 3.70
(s, 3H, N–CH3), 3.90 (br. s, 1H, SH), 4.50 (q, 2H, J ¼ 6.7 Hz,
CH2), 5.8 (s, 2H, NH2), 7.40–7.90 (m, 5H, Ar–H) ppm.
3-Amino-5-cyano-6-ethoxy-2-(5-ethoxycarbonylmethylthio-
1,3,4-oxadiazol-2-yl)-1-methyl-4-phenylpyrrolo[2,3-b]-
pyridine (23, C23H22N6O4S)
A mixture of 0.78g 22 (0.002 mol) and 0.245g ethyl chlor-
oacetate (0.002mol) in 20 cm3 ethanol containing 2 g anhy-
drous sodium acetate was refluxed for 2 h. After cooling, the
crude product was filtered off, washed with water, and air
dried. Recrystallisation from ethanol yielded 0.70g (75%)
yellow crystals of 23; mp 190–192ꢁC; IR (KBr): ꢁꢀ¼ 3450,
3350, (NH2), 2220 (CN), 1730 (CO) cmꢀ1; 1H NMR (CDCl3):
ꢀ ¼ 1.30 (t, 3H, J ¼ 7.11 Hz, CH3 ethoxy),1.50 (t, 3H, J ¼
7.2 Hz, CH3 ester), 3.90 (s, 3H, N–CH3), 4.20 (s, 2H, CH2),
4.30 (q, 2H, J ¼ 6.8 Hz, CH2 ethoxy), 4.50 (q, 2H, J ¼
6.8 Hz, CH2 ester), 6.20 (s, 2H, NH2), 7.50–7.90 (m, 5H,
Ar–H) ppm.
4-Acetylmethylthio-8-cyano-7-ethoxy-5-methyl-9-phenyl-
pyrido[20,30:5,4]pyrrolo[2,3-b]pyrimidine (19, C22H19N5O2S)
Compound 19 was prepared in a similar procedure to that
described for compounds 12a–12e, starting from the mix-
ture of 361 mg 17 (0.001 mol) and 93 mg ꢂ-chloroacetone
(0.001 mol). The solid product was collected and recrystal-
lized from ethanol to give 0.29 g (70%) yellow crystals of
19; mp 195–196ꢁC; IR (KBr): ꢁꢀ¼ 2220 (CN), 1690 (CO)
cmꢀ1
;
1H NMR (DMSO-d6): ꢀ ¼ 1.30 (t, 3H, J ¼ 6.4 Hz,
CH3), 2.45 (s, 3H, CH3), 3.80 (s, 3H, N–CH3), 4.40 (q, 2H,
J ¼ 6.7 Hz, CH2), 4.8 (s, 2H, CH2), 7.50–7.80 (m, 5H, Ar–H),
8.90 (s, 1H, CH pyrimidine) ppm.
5-Amino-3-cyano-4-phenyl-7(H)-pyrazolo[3,4-b]pyridine-
2(1H)-one (24, C13H9N5O)
A mixture of 0.53g 4 (0.002mol) and 5 cm3 hydrazine hydrate
was fused together for 30min, and then 20cm3 ethanol were
added. The mixture was refluxed for 3 h and then left to cool.
The precipitated solid was collected and recrystallized from
dioxane to give 0.4 g (80%) yellow crystals of 24; mp
>300ꢁC; IR (KBr): ꢁꢀ¼ 3450, 3350, 3200 (NH, NH2), 2220
Ethyl 5-cyano-6-ethoxy-1-methyl-3-(1-pyrrolyl)-4-phenyl-
pyrrolo[2,3-b]pyridine-2-carboxylate (20, C24H22N4O3)
A mixture of 1.82g 8 (0.005 mol) and 1.32 mg 2,5-di-
methoxytetrahydrofurane (0.01 mol) in 20cm3 glacial acetic
acid was refluxed for 3 h, the solvent was reduced to one
third of its volume under reduced pressure, and then cooled,
the solid separated was collected and recrystallized from
ethanol to give 1.45 g (70%) white crystals of 20; mp
135–137ꢁC; IR (KBr): ꢁꢀ¼ 2220 (CN), cmꢀ1, 1700 (CO);
1H NMR (CDCl3): ꢀ ¼ 1.20 (t, 3H, J ¼ 7.3 Hz, CH3 ethoxy),
1.40 (t, 3H, J ¼ 7.2 Hz, CH3 ester), 3.80 (s, 3H, N–CH3),
4.20 (q, 2H, J ¼ 6.6 Hz, CH2 ethoxy), 4.40 (q, 2H, J ¼
6.8 Hz, CH2 ester), 5.80 (t, 2H, J ¼ 2.0 Hz, 2CH pyrrolyl),
6.30 (t, 2H, J ¼ 2.4 Hz, 2CH pyrrolyl), 7.5–7.70 (m, 5H,
Ar–H) ppm.
1
(CN),1630 (C¼O) cmꢀ1; H NMR (DMSO-d6): ꢀ ¼ 5.60 (s,
2H, NH2), 6.5 (s, 1H, NH pyrazole), 7.50–8.0 (m, 5H, Ar–H),
10.9 (S, 1H, NH) ppm.
5-Amino-3-cyano-4-phenyl-7(H)-pyrazolo[3,4-b]pyridine-
2(1H)-thione (25, C13H9N5S)
A mixture of 0.5 g 24 (0.002 mol) and 385 mg phosphorus
pentasulfide (0.002mol) in 30cm3 pyridine was refluxed for
6 h, allowed to cool, and poured into an acetic acid=water

1240
Sh. A. Abdel-Mohsen, A. A. Geies
mixture. The precipitated solid was collected and recrystal-
lized from acetic acid to give 0.43 g (82%) orange crystals of
25; mp 292–293ꢁC; IR (KBr): ꢁꢀ¼ 3450, 3300, 3250 (NH,
3. Allen JR, Amegadzie AK, Gardinier KM, Gregory GS,
Hitchcock SA, Hoogestraat PJ, Jones WD, Smith DL
(2005) Appl Int WO 066126 CA 143:133274
4. Bennabi S, Heckroth H, Schirok H, Mittendorf J, Kast R,
Stasch JP, Gnoth MJ, Muenter K, Lang D, Perez SF,
Bauser M, Feurer A, Ehmke H (2005) Appl Int WO
058891 CA 143:97339
1
NH2), 2220 (CN) cmꢀ1; H NMR (DMSO-d6): ꢀ ¼ 5.60 (s,
2H, NH2), 6.40 (s, 1H, NH pyrazole), 7.40–7.9 (m, 5H, Ar–
H), 11.5 (s, 1H, NH) ppm.
5. Dillon MP, Lin CJJ, Moore AG, O’Yang C, Zhai YUS
(2004) Patent Appl 224,973, 2004 CA 141:410926
6. Graczyk P, Khan A, Bhatia G, Iimura Y (2004) Appl Int
WO 078756 CA 141:277498
7. a) Perry NB, Ettouati L, Litaudon M, Blunt JW, Munro
MHG, Parkin S, Hope H (1994) Tetrahedron 50:3987; b)
Trimurtulu G, Faulkner DJ, Perry NB, Ettouati L,
Litaudon M, Blunt JW, Munro MHG, Jameson GB
(1994) Tetrahedron 50:3993
8. Abdel-Mohsen SA, Abdel-Hafez SH, Geies AA (2006) J
Chin Chem Soc 53(4):909
9. Kamal El-Dean AM, Geies AA, El-Kashef HS, Rault S,
D’Allemagne P, Lancelot JC (2000) J Heterocyclic Chem
37(6):1520
10. Kamal El-Dean AM, Geies AA, Radwan SM (1999) Bull
Polish Acad Sci Chem 47(2):135
11. Geies AA, Bakhite EA, El-Kashef HS (1998) Pharmazie
53:686
12. Geies AA, Kamal El-Dean AM, Moustafa OS (1996)
Monatsh Chem 127:1263
5-Amino-3-cyano-2-methythio-4-phenyl-7(H)-pyrazolo[3,4-b]-
pyridine (26, C14H11N5S)
Compound 25 was prepared in a similar procedure to that
described for compounds 12a–12e. The solid product was
collected and recrystallized from dioxane to give 0.45g
(82%) yellow crystals of 26; mp 221–222ꢁC; IR (KBr): ꢁꢀ¼
1
3450, 3300, 3250 (NH, NH2), 2220 (CN) cmꢀ1; H NMR
(DMSO-d6): ꢀ ¼ 3.20 (s, 3H, CH3), 5.40 (s, 2H, NH2), 6.30
(s, 1H, NH pyrazole), 7.50–7.9 (m, 5H, Ar–H) ppm.
Biological screening
The screened compounds were dissolved in DMSO to get a
solution of 1% concentration. Filter paper discs (Whatman No.
1, 5 mm diameter) were saturated with this solution. The discs
were placed on the surface of solidified nutrient agar dishes
seeded by the tested bacteria. The inhibition zones were mea-
sured at the end of an incubation period of 48h (at 37ꢁC for
bacteria). Sutrim was used as the reference substance.
13. Otto HH, Rinus O, Schmetz H (1978) Synthesis:681
14. Kalyoncuoglu N, Rollas S, Sur-Altiner D, Yegenoglu Z,
Ang O (1992) Pharmazie 47:769
15. Peinador C, Ojea V, Quintela JM (1992) J Heterocycl
Chem 29(7):1693
References
1. Merour JY, Joseph B (2001) Curr Org Chem 5:471
2. Florence Popowycz A, Sylvain Routier B, Joseph B,
Merour JY (2007) Tetrahedron 63:1031