Utility of nitriles in synthesis of pyrido[2,3-d]pyrimidines, thiazolo[3,2-a]pyridines, pyrano[2,3-b]benzopyrrole, and pyrido[2,3-d] benzopyrroles

Article abstract of DOI:10.1080/10426500701506465

3-Aryl-2-cyanoacrylonitriles (1a,b) reacted with 6-aminothiouracil, 2-ethoxy carbonylmethyl-4-oxo-Δ2-thiazoline, 2-cyanomethyl-4-oxo-Δ2- thiazoline and indan-2-one to give pyrido[2,3-d]pyrimidines, thiazolo[3,2-a]pyridines, pyrano [2,3-b]benzopyrrole and pyrido[2,3-b] benzopyrrole, respectively. The IR, MS and 1H-NMR of the synthesized compounds were discussed. The antimicrobial activity of some of the synthesized compounds was tested. Copyright Taylor & Francis Group, LLC.

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Phosphorus, Sulfur, and Silicon
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Utility of Nitriles in
Synthesis of Pyrido[2,3-
d]pyrimidines, Thiazolo[3,2-
a]pyridines, Pyrano[2,3-
b]benzopyrrole, and
Pyrido[2,3-d]benzopyrroles
M. R. Mahmoud a , E. A. A. El-Bordany a , N. F.
Hassan a & F. S. M. Abu El-Azm a
a Chemistry Department, Faculty of Science, Ain
Shams University, Cairo, Egypt
Version of record first published: 25 Sep 2007.
To cite this article: M. R. Mahmoud , E. A. A. El-Bordany , N. F. Hassan & F. S.
M. Abu El-Azm (2007): Utility of Nitriles in Synthesis of Pyrido[2,3-d]pyrimidines,
Thiazolo[3,2-a]pyridines, Pyrano[2,3-b]benzopyrrole, and Pyrido[2,3-d]benzopyrroles,
Phosphorus, Sulfur, and Silicon and the Related Elements, 182:11, 2507-2521
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Phosphorus, Sulfur, and Silicon, 182:2507–2521, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701506465
Utility of Nitriles in Synthesis of Pyrido[2,3-d]pyrimidines,
Thiazolo[3,2-a]pyridines, Pyrano[2,3-b]benzopyrrole, and
Pyrido[2,3-d]benzopyrroles
M. R. Mahmoud
E. A. A. El-Bordany
N. F. Hassan
F. S. M. Abu El-Azm
Chemistry Department, Faculty of Science, Ain Shams University,
Cairo, Egypt
3-Aryl-2-cyanoacrylonitriles (1a,b) reacted with 6-aminothiouracil, 2-ethoxy
carbonylmethyl-4-oxo-ꢀ2-thiazoline,
2-cyanomethyl-4-oxo-ꢀ2-thiazoline
and
indan-2-one to give pyrido[2,3-d]pyrimidines, thiazolo[3,2-a]pyridines, pyrano
[2,3-b]benzopyrrole and pyrido[2,3-b]benzopyrrole, respectively. The IR, MS and
1H-NMR of the synthesized compounds were discussed. The antimicrobial activity
of some of the synthesized compounds was tested.
Keywords Pyrido[2,3-d]pyrimidines; thiazolopyridines; pyrano-; pyridobenzopyrroles;
antimicrobial activity
INTRODUCTION
Pyrido[2,3-d]pyrimidines standout for their antitumer,1 anticonvul-
sive,2 antiasthmatic, antiallergic,3 anthihypertensive,4 and useful as
diuretic compound.5–9 Previously, we have reported several new syn-
thesis of fused heterocyclic compounds utilizing laboratory available
activated nitrile derivatives as starting materials.10–20 In the present
article, we report on the utility of the substituted acrylonitriles for syn-
thesis of several pyrido[2,3-d]pyrimidine, thiazolo[3,2-a]pyridines with
the aim of finding new chemotherapeutic agents.
RESULTS AND DISCUSSION
The reaction of 3-aryl-2-cyanoacrylonitrile 1a,b with 6-aminothiouracil
2 in ethanol in the presence of catalytic amount of piperidine
Received February 10, 2007; accepted March 4, 2007.
Address correspondence to F.S.M. Abu El-Azm, Chemistry Department, Faculty of Sci-
ence, Ain Shams University, Abbassia 11566, Cairo, Egypt. E-mail: ftmsaber@Yahoo.com
2507

2508
M. R. Mahmoud et al.
afforded the 1:1 adduct, the structure of the adduct was estab-
lished as pyrido[2,3-d]pyrimidine derivative 3 rather than pyrano[2,3-
d]pyrimidine or thiazino[3,2-a]pyrimidine on the basis of spectroscopic
data which revealed a pattern completely in accord with structure 3.
Thus, the IR spectrum shows the stretching absorption bands char-
acteristic for NH2, C=N, C=O and C=S groups at 3378, 3220, 3113,
2206, 1687, 1640, and 1128 cm−1, respectively, which in accord with the
1
proposed structure 3. Furthermore, H-NMR spectrum of 3b revealed
two signals at δ 12.7 (s, 1H, NH, exchangeable with D2O) and 12.2 (s,
1H, NH, exchangeable with D2O) characteristic for -NH-CS-NH- group
(c.f. Exp.). Alkylation of 3b using ethylbromoacetate or ethyl iodide
in ethanol containing anhydrous sodium acetate gave the S-alkylated
products 4 and 5, respectively. The reaction of 3b with hydrazine hy-
drate in boiling ethanol yielded the Sulfur-free compound 6 which also
obtained upon treatment of the S-alkylated product 5 with hydrazine
hydrate. The hydrazino derivative 6 was used as the key intermedi-
ate for the synthesis of polyheterocyclic compounds. Treatment of com-
pound 6 with freshly distilled acetic anhydride afforded the pyridotria-
zolopyrimidine derivative 7. When a solution of 6 in dilute hydrochloric
acid was refluxed with 2,4-pentadione and/or 1-phenylbut-1,3-dione in
pyridine afforded pyrazol-1-ylpyridopyrimidine derivatives 8a and 8b,
respectively (Scheme 1).
The reaction of 1a with 2-ethoxy carbonylmethyl-4-oxo-ꢀ2-thiazoline
9a in absolute ethanol in the presence of piperidine afforded the
adduct thiazolo[3,2-a]pyridine 10a. Treatment of 10a with triethy-
lorthoformate yielded thiazolo[3,2-a]pyridine derivative 11. The reac-
tion of 11 with benzylamine results in the formation of the thiazolopyri-
dine derivative 12. The reaction of 2-cyanomethyl-4-oxo-ꢀ2-thiazoline
9b with 1a in ethanol in the presence of catalytic amount of piperi-
dine resulted in the formation of thiazolo[3,2-a]pyridine derivative 10b
(Scheme 2).
The carbanion derived from indan-2-one in absolute ethanol upon
treatment with piperidine reacts with 1a to afford 3-arylidene indan-
2-one 13a (ethanol insoluble fraction) and pyrano[2,3-b]benzopyrrole
14 (ethanol soluble fraction). It is worthy to mention that 13a could
be obtained from the reaction of indan-2-one with 1-naphthaldehyde in
boiling ethanol and pyrano benzopyrrole 14 prepared upon treatment
of 13a with malononitrile in refluxing ethanol in the presence of piperi-
dine. Similarly, the reaction of 2-bromobenzaldehyde with indanone un-
der the same conditions yielded the 3-(2-bromobenzylidene)indan-2-one
13b. Compound 13b when fused with malononitrile in the presence
of ammonium acetate at 190–200◦C afforded pyrido[2,3-b]benzopyrrole
15. Hydrazinolysis of 13a in refluxing ethanol afforded the azine 16 not

Synthesis of Pyrimidines, Pyridines, and Benzopyrroles
2509
SCHEME 1
pyrazolobenzopyrrole derivative 17. Treatment of compound 13a,b with
freshly distilled acetic anhydride yielded the N-acyl derivative 18a,b.
The reaction of the N-acyl derivative 18b with β-cyanoethylhydrazine
in ethanol yielded pyrazolo[3,4-b]indole 19 (Scheme 3).
Biological Investigation
Antimicrobial Activity
The antimicrobial screening of some of the synthesized compounds
was done using the agar diffusion assay. This screening was performed
against the Gram-negative bacteria, Escherichia coli ATCC 10536 and
Gram-positive bacteria, Staphylococcus aurous ATCC 06538 in addition
to the pathogenic fungi Candida albicans ATCC 1023 and Aspergilus
flavus. A moderate activity was observed with compounds 7, 10a, 14,

2510
M. R. Mahmoud et al.
SCHEME 2
SCHEME 3

Synthesis of Pyrimidines, Pyridines, and Benzopyrroles
2511
TABLE I Antimicrobial Screening Results of the Tested Compounds
at 1000 µg/ml
Compd. no.
E. coli
S. aurous
C. albicans
3b
4
5
7
8a
8b
10a
10b
11
12
13a
14
15
18a
18b
19
00
00
00
13
00
00
12
00
00
00
00
17
16
10
12
11
00
20
00
00
00
00
12
00
00
12
00
00
00
00
15
15
11
13
11
22
21
00
00
00
00
12
00
00
11
00
00
00
00
15
15
11
12
9
Ampicillin
Streptomycin
Nystatin
00
00
22
00, no activity (inhibition zone < 7 mm); weak activity (7–10 mm); moderate activity
(11–15 mm); strong activity (>15 mm). Solvent: DMSO (6 mm).
15, 18a, 18b, and 19, which proved to possess marked activity against
E. coli, S. aurous, and C. albicans. The inhibitory concentration was
determined for each of the active compounds along with Ampicillin,
Streptomycin, and Nystatin as positive controlled. No activity was de-
tected for all the synthesized compounds towards Aspergilus flavus.
Results are shown in Table I.
CONCLUSION
The results of this article indicates that activated nitriles are
used as the key starting materials for synthesis of biologically ac-
tive fused heterocyclic compounds such as Pyrido[2,3-d]pyrimidines,
Thiazolo[3,2-a]pyridines, Pyrano[2,3-b]benzopyrrole, and Pyrido[2,3-
d]benzopyrroles.
EXPERIMENTAL
All melting points are uncorrected. The infrared spectra were recorded
on FTIR Maltson (infinity series) spectrometers as KBr discs. The

2512
M. R. Mahmoud et al.
1H-NMR spectra were measured on Varian Gemini 200 MHz instru-
ment with chemical shift (δ) expressed in ppm downfield from TMS.
Mass spectra were recorded on Shimaduzu GC-MS, QP 1000 EX instru-
ment operating at 70 eV. The monitoring of the progress of all reactions
and homogeneity of the synthesized compounds was carried out by TLC.
TLC was runned using TLC aluminum sheets silica gel F254 (Merck).
7-Amino-6-cyano-5-aryl-4-oxo-1H,3H-pyrido[2,3-d]pyrimidin-
2-thione 3a,b
A mixture of 3-aryl-2-cyanoacrylonitrile 1a,b (10 mmol) and 6-amino-
thiouracil (1.43 g, 10 mmol) in ethanol (50 ml) containing 1 ml piperidine
was heated under reflux for 2 h (TLC). The pale yellow product that
deposited during reflux, was collected by suction, washed with ethanol,
dried, and then recrystallized from the proper solvent to give 3a and/or
3b.
7-Amino-6-cyano-5-[1ꢀ-naphthyl]-4-oxo-1H,3H-pyrido-
[2,3-d]pyrimidin-2(H)-thione 3a
Recrystallized from ethanol as pale yellow crystals, m.p.: 326–328◦C,
yield 46%. IR (KBr): 3378, 3220, 3113 cm−1 (NH2), 2206 cm−1 (C≡N),
1687 cm−1 (C=O), 1640 cm−1 (C=N) and 1128 cm−1 (C=S).1H-NMR
(DMSO-d6)δ (ppm): 12.08 (s, 1H, NH, exchangeable with D2O), 11.7
(s, 1H, NH, exchangeable with D2O), 7.1 (br.s, 2H, NH2, exchangeable
with D2O) and 8.0–7.5 (m, 7Harom.). 13C-NMR (DMSO-d6)δ (ppm): 173.8
(CS), 160.2 (CO), 114 (CN), 102 (C4a), 153.8 (C5), 80.1 (C6), 156 (C7),
160.7 (N=C-N), 124.8-138.2 (naphthyl carbons). MS m/z (%): 345 (M+.,
98.2), 344 (M-1, 100), 343 (40.3), 285 (11.6), 215 (17.9). Anal. calcd. for
C18H11N5OS (345): C, 62.6%; H, 3.19%; N, 20.28%; S, 9.27%. Found: C,
62.48%; H, 3.32%; N, 19.77%; S, 9.30%.
7-Amino-6-cyano-5-(3ꢀ,4ꢀ-dimethoxyphenyl)-4-oxo-1H,3H-
pyrido[2,3-d] pyrimidin-2(H)-thione 3b
Recrystallized from ethanol as yellow crystals, m.p.: 344–346◦C, yield
48%. IR (KBr): 3377, 3299, 3216 cm−1 (NH2), 2206 cm−1 (C≡N), 1696
cm−1 (C=O), 1640 cm−1 (C=N), and 1128 cm−1 (C=S). 1H-NMR (DMSO-
d6)δ (ppm): 12.7 (s, 1H, NH, exchangeable with D2O), 12.2 (s, 1H, NH,
exchangeable with D2O), 7.7 (br.s, 2H, NH2, exchangeable with D2O),
7.04-6.8 (m, 3Harom.), 3.84 (s, 3H, OMe) and 3.74 (s, 3H, OMe).
13C-NMR (DMSO-d6)δ (ppm): 174.7 (CS), 161.3 (CO), 158.4 (C5), 82.4
(C6), 112.6 (CN), 160.1 (C7), 102 (C4a), 155.3 (N=C-N), 132 (C8a), 158.9

Synthesis of Pyrimidines, Pyridines, and Benzopyrroles
2513
(C-OMe), 160.2 (C-OMe), 56.1 (OMe), 55.7 (OMe), 121.8, 122.9, 126.3
(Carom.). MS m/z (%): 355 (M+., 100). Anal. calcd. for C16H13N5O3S (355):
C, 54.08%; H, 3.6%; N, 19.7%; S, 9.0%. Found: C, 52.86%; H, 4.0%; N,
20.09%; S, 8.66%.
7-Amino-6-cyano-5-(3ꢀ,4ꢀ-dimethoxyphenyl)-2-
ethoxycarbonylmethylthiopyrido[2,3-d]pyrimidin-4(3H)-one 4
A mixture of 3b (3.5 g, 10 mmol), ethylbromoacetate (1.67 ml, 10 mmol),
and anhydrous sodium acetate (5 g, 160 mmol) in absolute ethanol
(50 ml) was refluxed for 6 h (TLC). Most of the solvent was distilled and
the reaction mixture was poured onto water to afford a white substance
which was filtered off, washed several times with hot water, dried and
recrystallized from dioxane to give 4. m.p.: 321–323◦C, yield 85%. IR
(KBr): 3478, 3389, 3214, 3144 cm−1 (NH2, NH), 2212, 2182 cm−1 (C≡N),
1737 cm−1 (C=O ester), 1669 cm−1 (C=O pyrimidone), and 1630 cm−1
(C=N).1H-NMR (DMSO-d6)δ (ppm): 12.5 (s, 1H, NH, exchangeable with
D2O), 7.6 (br.s, 2H, NH2, exchangeable with D2O), 7.03–6.8 (m, 3Harom.),
4.2 (q, 2H, COOCH2CH3), 3.8 (s, 2H, SCH2COOEt), 3.7 (s, 6H, 2OMe)
and 1.2 (t, 3H, COOCH2CH3).13C-NMR (DMSO-d6)δ (ppm): 158.7 (C2),
162.1 (C4), 99.3 (C4a), 155.2 (C5), 89.7 (C6), 161.7 (C7), 158.1 (C8a), 114.9
(CN), 132.4 (Cꢀ1), 126.3 (C2ꢀ ), 156 (C3ꢀ ), 150.9 (Cꢀ4), 120.3 (C5ꢀ ), 124.3 (Cꢀ6),
55.8 (OMe), 55.7 (OMe), 32.4 (SCH2), 171.3 (COester), 57.7 (OCH2), 14.8
(Me). MS m/z (%): 441 (M+., 73.8), 396 (33.6), 368 (87.9), 355 (100), 323
(17.4). Anal. calcd. for C20H19N5O5S (441): C, 54.4%; H, 4.3%; N, 15.8%;
S, 7.2%. Found: C, 54.43%; H, 4.52%; N, 16.31%; S, 6.99%.
7-Amino-6-cyano-5-(3ꢀ,4ꢀ-dimethoxyphenyl)-2-
ethylthiopyrido[2,3-d]pyrimidin-4(3H)-one 5
A mixture of 3b (3.5 g, 10 mmol), ethyl iodide (1.5 ml, 10 mmol) and
anhydrous sodium acetate (5 g, 160 mmol) in absolute ethanol (50 ml)

2514
M. R. Mahmoud et al.
was heated under reflux for 3 h (TLC). Most of the solvent was distilled
and the reaction mixture was stirred with hot water to give a white
substance which was filtered off, dried and recrystallized from dioxane
to give 5. m.p.: 361–363◦C, yield 90%. IR (KBr): 3449, 3301, 3217 cm−1
(NH2,NH), 2215 cm−1 (C≡N), 1697 cm−1 (C=O), 1622 cm−1 (C=N). 1H-
NMR (DMSO-d6)δ (ppm): 12.2 (s, 1H, NH, exchangeable with D2O),
7.7 (br.s, 2H, NH2, exchangeable with D2O), 7.0-6.8 (m, 3Harom.), 3.84
(s, 3H, OMe), 3.74 (s, 3H, OMe), 3.2 (q, 2H, SCH2CH3) and 1.3 (t, 3H,
SCH2CH3). MS m/z (%): 383 (M+., 48), 355 (100), 340 (28.1). Anal. calcd.
for C18H17N5O3S (383): C, 56.3%; H, 4.4%; N, 18.2%; S, 8.3%. Found: C,
56.1%; H, 4.8%; N, 17.68%; S, 8.0%.
7-Amino-6-cyano-2-hydrazino-5-(3ꢀ,4ꢀ-dimethoxphenyl)-
pyrido[2,3-d]pyri-midin-4(3H)-one 6
Method 1
A mixture of 3b (3.5 g, 10 mmol) and hydrazine hydrate 80% (0.5 ml,
10 mmol) in absolute ethanol (50 ml) was heated under reflux for 3 h.
The yellowish white product that deposited during reflux, was collected
by suction and washed with ethanol to give 6. m.p.: >360◦C, yield 20%.
IR (KBr): 3451, 3303, 3208 cm−1 (NH2), 2215 cm−1 (C≡N), 1691 cm−1
(C=O).1H-NMR (DMSO-d6)δ (ppm): 10.9 (s, 1H, NH, exchangeable with
D2O), 8.4 (br.s, 2H, NH2, exchangeable with D2O), 8.1 (br.s, 2H, NH2,
exchangeable with D2O), 7.3 (s, 2H, NH2, exchangeable with D2O), 7.2–
6.9 (m, 3Harom.), 3.83 (s, 3H, OMe), and 3.79 (s, 3H, OMe). MS m/z
(%): 353 (M+., 100), 323 (40), 308 (31.2), 280 (23.1). Anal. calcd. for
C16H15N7O3 (353): C, 54.3%; H, 4.2%; N, 27.7%. Found: C, 54.71%; H,
3.93%; N, 28.21%.
Method 2
A mixture of 5 (3.83 g, 10 mmol) and hydrazine hydrate 80% (0.5
ml, 10 mmol) in absolute ethanol (50 ml) was heated under reflux for 3
h. The excess solvent was removed by suction. The deposited solid was
filtered off and washed by ethanol to give 6 (yield 80%).
8-Diacetylamino-7-cyano-6-(3ꢀ,4ꢀ-dimethoxyphenyl)-3-methyl-
5-oxo-1H,1, 2,4-triazolo[4,5-a]pyrido[2,3-d]pyrimidine 7
A solution of 6 (1 g, 2.8 mmol) in freshly distilled acetic anhydride
(10 ml) was heated under reflux for 6 h, left to cool, and diluted with
cold water. The crude pale green solid that separated out was collected,
washed with cold water, dried and then recrystallized from ethanol to
give 7. m.p.: 195–196◦C, yield 82%. IR (KBr): 2229 cm−1 (C≡N), 1740,

Synthesis of Pyrimidines, Pyridines, and Benzopyrroles
2515
1704, 1691 cm−1 (C=O).1H-NMR (CDCl3)δ (ppm): 8.9 (s, 1H, NH, ex-
changeable with D2O), 6.9–6.8 (m, 3Harom.), 3.95 (s, 3H, OMe), 3.88 (s,
3H, OMe), 2.5 (s, 3H, COCH3), 2.4 (s, 3H, COCH3) and 2.2 (s, 3H, N=C–
CH3). MS m/z (%): 461 (M+., 21.3), 419 (100), 404 (41.5), 377 (78.1), 362
(33.6). Anal. calcd. for C22H19N7O5 (461): C, 57.2%; H, 4.1%; N, 21.2%.
Found: C, 56.76%; H, 3.81%; N, 21.7%.
7-Amino-6-cyano-5-(3ꢀ,4ꢀ-dimethoxyphenyl)-2-(3ꢀꢀ,5ꢀꢀ-
dimethylpyrazolo-1-yl)-3H-pyrido[2,3-d]pyrimidin-4(3H)-one
8a and 7-Amino-6-cyano-5-(3ꢀ, 4ꢀ-dimethoxyphenyl)-2-(3ꢀꢀ-
methyl-1-phenylpyrazolo-2ꢀꢀ-yl)-3H-pyrido-
[2,3-d]pyrimidin-4(3H)-one 8b
A solution of 6 (1 g, 2.8 mmol) in dilute hydrochloric acid (10 ml, 50%)
was heated under reflux with 2,4-pentadione (0.28 ml, 2.8 mmol) or 1-
phenylbut-1,3-dione (0.45 g, 2.8 mmol) in pyridine (10 ml) for 0.5 h. The
pale yellow product deposited on hot, was collected by suction, dried and
then recrystallized from dioxane to give 8a and 8b, respectively.
8a. m.p.: 342–344◦C, yield 76%. IR (KBr): 3459, 3301, 3211 cm−1
(NH2), 2213 cm−1 (C≡N), 1682 cm−1 (C=O).1H-NMR (DMSO-d6)δ
(ppm): 11.45 (s, 1H, NH, exchangeable with D2O), 7.68 (br.s, 2H, NH2,
exchangeable with D2O), 7.0–6.8 (m, 3Harom.), 6.3 (s, 1H, =CH), 3.86
(s, 3H, OMe), 3.76 (s, 3H, OMe), 2.6 (s, 3H, Cꢀ5-CH3), and 2.25 (s, 3H,
Cꢀ3-CH3). MS m/z (%): 417 (M+., 100), 402 (50.7), 95 (18.2). Anal. calcd.
for C21H19N7O3 (417): C, 60.4%; H, 4.5%; N, 23.5%. Found: C, 59.33%;
H, 4.5%; N, 23.9%.
8b. m.p.: 311–313◦C, yield 80%. IR (KBr): 3484, 3336, 3289 cm−1
(NH2), 2208 cm−1 (C≡N), 1698 cm−1 (C=O).1H-NMR (DMSO-d6)δ
(ppm): 12.03 (s, 1H, NH, exchangeable with D2O), 7.74(br.s, 2H, NH2,
exchangeable with D2O), 7.5–7.0 (m, 8Harom.), 6.7 (s, 1H), 3.87 (s, 3H,
OMe), 3.77 (s, 3H, OMe), and 2.52 (s, 3H, Cꢀ3-Me). MS m/z (%): 479 (M+.,
100), 464 (28.2), 157 (6.9). Anal. calcd. for C26H21N7O3 (479): C, 65.1%;
H, 4.38%; N, 20.4%. Found: C, 64.77%; H, 4.41%; N, 20.91%.
5-Amino-7-aryl-2-arylidene-6-cyano-8-substituted-3-oxo-
2H,3H,7H-thiazolo-[3,2-a]-pyridine 10a,b
A mixture of 1a (4.08 g, 20 mmol) and 2-ethoxycarbonylmethyl-4-
oxo-ꢀ2-thiazoline 9a and/or 2-cyanomethyl-4-oxo-ꢀ2-thiazoline 9b (10
mmol) in absolute ethanol (50 ml) containing 1 ml piperidine was heated
under reflux for 1 h. The yellow product that deposited during reflux,

2516
M. R. Mahmoud et al.
was collected by suction, washed by ethanol, dried and recrystallized
from the proper solvent to give 10a and 10b, respectively.
5-Amino-6-cyano-8-ethoxycarbonyl-3-oxo-2-[1-
naphthylidene]-7-[1-naphth-yl]-2H,3H,
7H-thiazolo[3,2-a]pyridine 10a
Recrystallized from dioxane to give a yellow crystals, m.p.: 265–266◦C,
yield 63%. IR (KBr): 3457, 3347 cm−1 (NH2), 2196 cm−1 (C≡N), 1691
cm−1 (C=O unsaturated ester), 1643 cm−1 (C=O unsaturated cyclic
imide).1H-NMR (CDCl3)δ (ppm): 8.6–7.6 (m, 14Harom.), 7.3 (br.s, 2H,
NH2 exchangeable with D2O), 6.6 (s, 1H, olefinic proton), 4.8 (s, 1H,
C7-H), 3.89 (q, 2H, COOCH2CH3), and 0.98 (t, 3H, COOCH2CH3). MS
m/z (%): 529 (M+., 10.3), 402 (24), 403 (100), 152 (12.8). Anal. calcd.
for C32H23N3O3S (529): C, 72.5%; H, 4.3%; N, 7.9%; S, 6.0%. Found: C,
73.06%; H, 4.09%; N, 8.32%; S, 5.49%.
5-Amino-6,8-dicyano-3-oxo-2-(1-naphthylidene)-7-
(1-naphthyl)-2H,3H,7H-thiazolo[3,2-d]pyridine 10b
Recrystallized from dioxane as yellow crystals, m.p.: 290–291◦C, yield
70%. IR (KBr): 3387, 3331, 3287 cm−1 (NH2), 2196 cm−1 (C≡N), 1717
cm−1 (C=O), 1653 cm−1 (C=N).1H-NMR (DMSO-d6)δ (ppm): 8.81–7.4
(m, 14Harom.), 7.1 (s, 1H, olefinic proton), 6.5 (br.s, 2H, NH2 exchange-
able with D2O) and 4.6 (s, 1H, C7-H). MS m/z (%): 355 (M+.-C10H. , 19.4),
301 (100), 184 (62.2). Anal. calcd. for C30H18N4OS (482): C, 747.6%; H,
3.7%; N, 11.6%; S, 6.6%. Found: C, 74.26%; H, 3.63%; N, 11.24%; S,
6.72%.
6-Cyano-5-ethoxymethyleneamino-8-ethoxycarbonyl-
3-oxo-2-(1-naphthyl-idene)-7-(1-naphthyl)-2H,3H,7H-thiazolo-
[3,2-a]pyridine 11
A mixture of 10a (1 g, 1.9 mmol) and triethylorthoformate (10 ml, 67
mmol) in freshly distilled acetic anhydride (10 ml) was heated under
reflux for 8 h. The pale green solid deposited during reflux, was col-
lected by filtration, washed with light-petroleum ether (b.p. 80–100)
and, then, recrystallized from benzene to give 11. m.p.: 236–238C, yield
57%. IR (KBr): devoid νNH2, 2205 cm−1 (C≡N), 1723 cm−1 (C=O ester),
1690 cm−1 (C=O αβ-unsaturated ketone), 1626 cm−1 (C=N).1H-NMR
(CDCl3)δ (ppm): 8.5–7.3 (m, 15Harom.+ N=CH), 7.2 (s, 1H, =CH), 5.7 (s,
1H, C7-H), 4.4 (q, 2H, CH3CH2–OCO), 3.9 (q, 2H, CH3CH2–O), 1.5 (t,
3H, CH3CH2-O-CO) and 0.7 (t, 3H, CH3CH2O). MS m/z (%): 585 (M+.,

Synthesis of Pyrimidines, Pyridines, and Benzopyrroles
2517
12.1), 458 (100), 312 (10.1), 184 (16). Anal. calcd. for C35H27N3O4S (585):
C, 71.79%; H, 4.6%; N, 7.17%; S, 5.47%. Found: C, 71.56%; H, 4.23%; N,
7.62%; S, 5.81%.
Formation of the Thiazolo Pyridine Derivative 12
A mixture of 12 (5.85 g, 10 mmol) and benzylamine (1 ml, 10 mmol) in
dry pyridine (30 ml) was heated under reflux for 6 h. The reaction mix-
ture was cooled and acidified with cold dilute acetic acid. The solid de-
posited was filtered off, washed several times with water and dried, then
recrystallized from dioxane to give 12. m.p.: 257–259◦C, yield 80%. IR
(KBr): 3450, 3341 cm−1 (NH), 2194 cm−1 (C≡N), 1694 cm−1 (C=O), 1643
cm-1 (C=O).1H-NMR (CDCl3)δ (ppm): 9.1 (br.s, 2H, NH2, exchangeable
with D2O), 8.5–7.4 (m, 24Harom.), 7.0 (s, 1H, olefinic proton), 6.93 (s,
1H, N=CH), 4.9 (s, 1H, C7-H), and 4.34 (d,d, 4H, benzylic protons).
MS m/z (%): 590 [M+.-(PhCH2, CN), 2.6], 402 (15.5), 184 (15.5), 152
(20.38), 127 (100). Anal. calcd. for C45H33N5O2S (707): C, 76.37%; H,
4.6%; N, 9.9%; S, 4. %5. Found: C, 76.71%; H, 4.3%6; N, 10.21%; S,
4.32%.
Reaction of 1a with 2-indanone: Formation of 13a and 14
A mixture of 1a (2.04 g, 10 mmol) and indan-2-one (1.33 g, 10 mmol) in
absolute ethanol (50 ml) containing 1 ml piperidine was heated un-
der reflux for 2 h (TLC). The reaction mixture was cooled and the
solid deposited was collected by suction, washed by ethanol and re-
crystallized from benzene to give 13a. Most of the solvent of the mother
liquor was distilled off and then acidified with cold dilute hydrochlo-
ric acid. The green solid that separated out was collected by filtration,
washed by cold water, dried and recrystallized from ethanol to give
14.
13a. m.p.: 190–192◦C, yield 50%. IR (KBr): 3179, 3151 cm−1 (NH),
1710 cm−1 (C=O), 1616 cm−1 (C=C).1H-NMR (CDCl3)δ (ppm): 8.3 (s,
1H, NH), 8.0–7.2 (m, 11Harom.), and 6.7 (s, 1H, CH=). MS m/z (%): 271
(M+., 79.3), 270 (100), 144 (11.2), 120 (9). Anal. calcd. for C19H13NO
(271): C, 84.1%; H, 4.79%; N, 5.1%. Found: C, 83.75%; H, 5.0%; N, 4.77%.
Authentic Sample
A solution of indan-2-one (1.33 g, 10 mmol) in absolute ethanol (30
ml) was stirred with 1-naphthaldehyde (1.56 ml, 10 mmol) for 1/ h and
2
then refluxed for 1 h. The excess solvent was removed and left a crude

2518
M. R. Mahmoud et al.
product which recrystallized from benzene to give 13a (identity by m.p.,
mixed m.p. and TLC).
14. m.p.: 327–329◦C, yield 20%. IR (KBr): 3429, 3317, 3211 cm−1
(NH2), 2210 cm−1 (C≡N), 1645 cm−1 (C=N). 1H-NMR (CDCl3)δ (ppm):
10.4 (s, 1H, NH, exchangeable with D2O), 8.18-7.0 (m, 11Harom.), 6.7
(br.s, 2H, NH2, exchangeable with D2O), and 4.86 (s, 1H). MS m/z (%):
337 (M+., 37.6), 334 (100), 307 (17.8). Anal. calcd. for C22H15N3O (337):
C, 78.3%; H, 4.45%; N, 12.46%. Found: C, 78.0%; H, 4.61%; N, 12.09%.
Reaction of 13a with Malononitrile
A mixture of 13a (2.71 g, 10 mmol) and malononitrile (0.99 g, 15 mmol)
in absolute ethanol (50 ml) and 1 ml piperidine was refluxed for 3 h. The
excess solvent was collected by distillation and the residual acidified
with cold dilute acetic acid to give 14 (yield 28.7%) (identity by m.p.,
mixed m.p., IR, and TLC).
Formation of 13b
A mixture of indan-2-one (1.33 g, 10 mmol) and 2-bromobenz-aldehyde
(1.85 ml, 10 mmol) in absolute ethanol (50 ml) was refluxed for 4 h. The
resulting yellow product (one spot in TLC) was collected by filtration
and then recrystallized from benzene to give 13b. m.p.: 166–167◦C,
yield 80%. IR (KBr): 3143 cm−1 (NH), 1713 cm−1 (C=O). MS m/z (%):
300 (M+., 100), 301 (9.6), 302 (30). Anal. calcd. For C15H10NOBr (300):
C, 60.0%; H, 3.3%; N, 4.6%; Br, 26.6%. Found: C, 59.4%; H, 3.4%; N,
4.4%; Br, 27.0%.
2-Amino-3-cyano-4-(2-bromophenyl)-pyrido-
[2,3-b]benzopyrrole 15
A mixture of 13b (1 g, 3.3 mmol), malononitrile (0.22 g, 3.3 mmol) and
ammonium acetate (3 g, 40 mmol) was firstly fused for 2 min, then
heated under reflux in absolute ethanol (25 ml) for 6 h. Most of the
solvent was distilled off and the reaction mixture was poured onto wa-
ter. The pale green solid that separated out was collected by filtration,
dried and then, recrystallized from benzene to give 15. m.p.: 165–167◦C,
yield 30%. IR (KBr): 3475, 3331, 3217 cm−1 (NH2), 2196 cm−1 (C≡N),
and no band for C=O group.1H-NMR (CDCl3)δ (ppm): 10.3 (s, 1H, NH,
exchangeable with D2O), 8.1-7.3 (m, 8Harom.), and 6.88 (br.s, 2H, NH2,
exchangeable with D2O).13C-NMR (CDCl3)δ (ppm):

Synthesis of Pyrimidines, Pyridines, and Benzopyrroles
2519
MS m/z (%): 363 (M+., 22.5), 364 (9.2), M+2 (9.2), 283 (100). Anal.
calcd. for C18H11N4Br (363): C, 59.5%; H, 3.0%; N, 15.4%; Br, 22.0%.
Found: C, 59.28%; H, 3.01%; N, 15.63%; Br, 22.46%.
Reaction of 13a with Hydrazine Hydrate; Formation of the
Azine 16
A mixture of 13a (10 mmol) and hydrazine hydrate (1.5 mmol) in
ethanol (25 ml) was heated under reflux for 2 h . The solid deposited af-
ter evaporation of the solvent, was filtered off, dried, and recrystallized
from light petroleum ether (b.p. 80–100◦C) to give 16. m.p.: 63–65◦C,
yield 43%. MS m/z (%): 308 (M+., 32.9), 280 (100), 181 (59), 154 (71.1),
127 (87.3). Identity (m.p, mixed m.p, TLC) with authentic sample re-
sulted from the reaction of 1-naphthaldehyde with hydrazine hydrate
in ethanol.
Acetylation of 13a,b; Formation of 18a,b
A solution of 13a or 13b (1 g) in freshly distilled acetic anhydride (10 ml)
was heated under reflux on water bath for 2 h. The solid deposited on
hot was collected by suction, washed several times with light petroleum
ether and recrystallized from the proper solvent to give 18a and/or 18b.
18a. Recrystallized from light petroleum ether (b.p. 80–100◦C), m.p.:
112–114◦C, yield 65%. IR (KBr): 1733, 1704 cm−1 (C=O). 1H-NMR
(CDCl3)δ (ppm) : 8.4–7.2 (m, 11Harom.), 6.9 (d, 1H, C=CH), and 2.8 (s, 3H,
COMe). MS m/z (%): 313 (M+., 32.2), 271 (95.3), 270 (95.3), 270 (100),
242 (19.5), 144 (12.6). Anal. calcd. for C21H15NO2 (313): C, 80.5%; H,
4.79%; N, 4.47%. Found : C, 80.23%; H, 4.72%; N, 4.39%.
18b. Recrystallized from benzene, m.p.: 138–139◦C, yield 90%. IR
(KBr): 1734, 1708 cm−1 (C=O).1H-NMR (CDCl3)δ (ppm) : 8.8–7.6 (m,
8Harom.), 7.2 (s, 1H, C=CH) and 2.45 (s, 3H, COMe). MS m/z (%): 342
(M+., 3.1), 262 (17.4), 220 (100). Anal. calcd. for C17H12NO2Br (342): C,

2520
M. R. Mahmoud et al.
59.6%; H, 3.5%; N, 4.1%; Br, 23.39%. Found : C, 59.1%; H, 3.84%; N,
4.44%; Br, 23.69%.
8-Acetyl-1-(2ꢀ-cyanoethyl)-3-(2ꢀ-bromophenyl)-2,3-
dihydropyrazolo [3,4-b]indole 19
A solution of compound 18b (3.42 g, 10 mmol) in pyridine (50 ml) was
stirred with β-cyanoethylhydrazine (0.7 ml, 10 mmol) for 1 h and then
refluxed for 3 h on water bath. The reaction mixture was concentrated
and acidified with cold dilute acetic acid. The deposited solid was filtered
off, dried and then recrystallized from ethanol to give 19 as yellow crys-
tals. m.p.: 177–178◦C, yield 40%. IR (KBr): 3242, 3183 cm−1 (NH), 2253
1
cm−1 (C≡N), 1695 cm−1 (C=O), 1647 cm−1 (C=N). H-NMR (CDCl3)δ
(ppm) : 8.3–7.3 (m, 8Harom.), 5.3 (d, 1H), 4.2 (d, 1H, NH, exchangeable
with D2O), 3.4 (t, 2H, N-CH2-CH2-), 3.1 (t, 2H, CH2CN) and 2.45 (s,
3H, COMe). MS m/z (%): 383 (M–CN., 11.1), 220 (100). Anal. calcd. for
C20H17N4OBr (409): C, 58.6%; H, 4.1%; N, 13.69%; Br, 19.5%. Found C,
58.32%; H, 3.81%; N, 14.02%; Br, 20.0%.
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