A facile one-pot synthesis of pyrido[2,3-d]pyrimidines and pyrido[2,3- d:6,5-d']dipyrimidines

Article abstract of DOI:10.1039/a806513f

The reactions of enaminones (6-aminouracils) 1a-c and 4 with cyano olefins 2a-b and 5a-f led to the formation of pyrido[2,3-d]pyrimidines. 3a-f and 6a-f in good yield, while the treatment of 4-amino-2-thiouracil 4 with aromatic aldehydes afforded pyridodipyrimidines 7a-c.

Full text of DOI:10.1039/a806513f

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112 J. CHEM. RESEARCH (S), 1999
J. Chem. Research (S),
1999, 112±113$
A Facile One-pot Synthesis of Pyrido[2,3-d]-
pyrimidines and Pyrido[2,3-d:6,5-d']dipyrimidines$
Shaker Youssif,* Said El-Bahaie and Esam Nabih
Department of Chemistry, Faculty of Science, University of Zagazig, Egypt
The reactions of enaminones (6-aminouracils) 1a±c and 4 with cyano olefins 2a±b and 5a±f led to the formation of
pyrido[2,3-d]pyrimidines 3a±f and 6a±f in good yield, while the treatment of 4-amino-2-thiouracil 4 with aromatic
aldehydes afforded pyridodipyrimidines 7a±c.
The preparation of pyrido[2,3-d]pyrimidines has been
reported by a number of investigators and may involve
suitably substituted 6-aminouracils1±4 followed by annela-
tion of the pyridine ring or cyclocondensation of 2-amino-3-
cyanopyridines5±8 with suitable reagents. The importance
of pyrido[2,3-d]pyrimidines as biologically active com-
pounds includes their use as antitumor,9 antibacterial10±13
and anticonvulsive14 agents. This prompted us to continue
our research program on the cyclization of 6-anilinouracil
derivatives.15 We allowed 1-methyl-6-anilinouracils15
1
to react with reactive cyano compounds like benzyl-
idenemalononitrile16 2a and benzylidenecyanoacetate 2b
producing
6-cyano-5,8-dihydropyrido[2,3-d]pyrimidine-
2,4(1H,3H)-diones 3a±c and the corresponding ethoxycar-
bonyl compounds 3a±f respectively, as shown in Scheme 1.
The products were fully characterized through spectral and
elemental analysis. The structure of 3a was indicated by
1
broad IR bands at 3460±3360 cm corresponding to the
1
chelated amino group and at 2210 cm corresponding to
CN group; the 13C NMR spectrum shows 17 lines.
Scheme 2
the treatment of 4-amino-2-thiouracil 4 by heating with
aryl aldehydes in acetic acid under re¯ux a€orded pyrido-
dipyrimidines 7a±c as shown in Scheme 2; 5-deaza¯avins
were not obtained.
The structures of compounds 7a±c were established on
the basis of satisfactory analytical and spectral data and
particularly the 13C NMR spectra which showed only 9
lines for 7a and 10 lines for 7b; the mass spectrum of 7b
gave a molecular ion peak at m/z 385.
Scheme 1
Experimental
Melting points were determined with an electrothermal
Gallenkamp apparatus and are uncorrected. The 1H and 13C NMR
On the other hand, the reaction of 4-amino-2-thiouracil17
4 with arylidenemalononitriles 5a±c and arylidenecyano-
acetates 5d±f a€orded the thiones 6a±c and 6d±f respect-
ively, as shown in Scheme 2, fully con®rmed by spectral and
elemental analysis. The IR spectra of 6a exhibited sharp
bands at 3439 and 3321 cm (NH3), and 2215 cm (CN);
1
Its NMR H spectrum showed a singlet at d 7.72 (NH2) and
a doublet at d 7.50±7.29 (aromatic protons). The yields of
compounds 6a±f were lower than of 3a±f; this may be
due to the higher nucleophilicity at C-5 of N-alkyluracils
than that of uracil itself. It has been found that the
spectra were recorded on
a Bruker AC 250 spectrometer in
with (CD3)2SO as solvent and with Me4Si as internal standard.
Electron impact mass spectra were recorded on a Mat 1125 70 eV
spectrometer. IR spectra were recorded on a Perkin-Elmer 1430
spectrometer. The microanalyses were performed in the micro-
analytical laboratory, University of Cairo, Giza, Egypt.
General Procedure for the Synthesis of 6-Substituted 2-Amino-
5-phenyl-8-aryl-5,8-dihydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione
3a±f.ÐA mixture of equimolar amounts of uracils 1 and the appro-
priate 3-phenyl-2-substituted cyano ole®ns 2 (2 mmol) in absolute
ethanol (10 ml) in the presence of trimethylamine (5 drops) was
heated at re¯ux for 3±6 h. The reaction mixture was concentrated
and then cooled. The solid obtained was ®ltered o€, washed with
ethanol and recrystallized from DMF±EtOH (2:1). The products
3a±f were obtained in 70±90% yield and their physical constants
are as follows:
1
1
intramolecular cyclization of 6-(N-alkylanilino)uracils with
18
dimethylformamide (DMF)±POCl3
or with o-haloaryl-
aldehydes19 in DMF or with arylaldehydes20 in acetic acid
a€orded 5-deaza¯avins. In the present work, we found that
3a: Yield (83%); mp 302±303 8C; 1H NMR d 11.10 (s, 1H), 7.35±
7.15 (m, Jo 7, Jm 3 Hz, 10H), 6.04 (brs, 2H), 4.66 (s, 1H), 2.78
(s, 3H); 13C NMR d 31.94 (N±C-1), 36.68 (C-5), 66.94, 102.94,
119.97, 126.68, 127.03, 127.16, 127.87, 128.24, 129.47, 141.38,
143.76, 148.81, 151.20, 155.20, 161.47; m/z (%) 371 (9), 307 (14),
305 (23), 304 (44), 295 (18), 294 (100), 261 (10), 251 (19), 228 (21),
*To receive any correspondence.
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1999, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).

102 (13), 91 (18), 77 (30), 66 (48) (Calc. for C21H17N5O2: C, 67.91;
H, 4.61; N, 18.85. Found: C, 67.88; H, 4.60; N, 18.79%).
6e : Yield (75%); mp 272±274 8
C; 1H NMR d 11.42 (s, 1H), 11.27
J. CHEM. RESEARCH (S), 1999 113
View Online
(s, 1H), 8.08±8.04 (d, Jo 8.8 Hz, 2H), 7.15±7.11 (d, Jo 8.8 Hz, 2H),
6.30 (s, 2H), 4.35±4.27 (q, 2H), 3.88 (s, 3H), 1.34±1.28 (t, 3H); 13C
NMR d 13.95 (C±CH3), 55.73 (O±CH3), 62.01 (O±CH2), 78.27,
98.84, 114.94, 116.05, 124.00, 131.21, 133.40, 154.30, 161.56, 162.32,
163.56, 174.71; m/z (%) 372 (20), 300 (12), 299 (31), 296 (19), 219
(100), 173 (52), 77 (71), 43 (12) (Calc. for C17H16N4O4S: C, 54.83;
H, 4.33; N, 15.04. Found: C, 54.68; H, 4.31; N, 14.90%).
3b: Yield (89%); mp 319±320 8C; 1H NMR d 10.95 (s, 1H), 7.38±
7.16 (m, Jm 3, Jo 8 Hz, 7H), 6.92±6.87 (d, Jm 2, Jo 6.8 Hz, 2H), 5.92
(s, 2H), 4.64 (s, 1H), 3.76 (s, 3H), 2.92 (s, 3H); 13C NMR d 32.17
(N±C-1), 36.59 (C-5), 55.67, 66.39, 102.17, 114.94, 120.09, 126.69,
127.04, 128.28, 128.89, 133.85, 144.02, 148.95, 151.29, 155.42,
158.97, 161.49; m/z (%) 401 (11), 337 (20), 335 (63), 334 (61), 325
(16), 324 (84), 258 (71), 121 (14), 102 (12), 77 (10), 66 (100) (Calc.
for C22H19N5O3: C, 65.82; H, 4.77; N, 17.44. Found: C, 65.76;
H, 4.74 N, 17.38%).
6f: Yield (79%); mp 345±346 8C; 1H NMR d 11.35 (s, 1H), 10.99
(brs, 1H), 7.45±7.41 (d, Jo 8.3 Hz, 2H), 7.27±7.24 (d, Jo 8.3 Hz, 2H),
5.09 (s, 2H), 4.15±4.06 (q, 2H), 1.20±1.14 (t, 3H); 13C NMR d 13.55
(C±CH3), 62.12 (O±CH2), 72.20, 93.66, 116.62, 127.45, 129.48,
132.65, 136.54, 155.16, 159.61, 162.71, 163.51, 174.78; m/z (%) 378
(30), 377 (22), 376 (100), 304 (39), 294 (15), 261 (10), 288 (18), 77
(59) (Calc. for C16H13ClN4O3S: C, 51.00; H, 3.47; N, 14.87. Found:
C, 50.94; H, 3.44; N, 14.80%).
3c: Yield (78%); mp 308±309 8C; 1H NMR d 11.40 (s, 1H),
7.59±7.56 (d, Jo 8.8 Hz, 2H), 7.34±7.19 (m, Jm 2.3, Jo 8.1 Hz, 7H),
6.46 (s, 2H), 4.62 (s, 1H), 2.75 (s, 3H); 13C NMR d 31.81 (N±C-1),
36.40 (C-5), 66.48, 103.22, 120.09, 120.61, 126.76, 126.88, 128.31,
128.94, 132.25, 140.58, 143.35, 148.29, 151.05, 155.10, 161.44; m/z
(%) 451 (8), 449 (8), 384 (9), 383 (7), 382 (8), 375 (14), 374 (97), 372
(100), 331 (19), 329 (20), 294 (27), 155 (11), 140 (7), 127 (7), 102
(17), 77 (16); (Calc. for C21H16BrN5O2: C, 56.00; H, 3.58; N, 15.54.
Found: C, 55.89; H, 3.56; N, 15.37%).
General Procedure for the Synthesis of 5-Substituted 1,3,8,9-Tetra-
hydro-2,8-dithioxopyrido[2,3-d:6,5-d']pyrimidine-4,6(1H,7H)-diones
7a±c.ÐA solution of 6-amino-2-thiouracil 4 (2.32 mmol) in glacial
acetic acid (15 ml) and 0.5 equiv. of the appropriate aromatic
aldehyde was heated under re¯ux for 4 h. The reaction mixture was
diluted with water, then allowed to cool to room temperature. The
crude product was collected and recrystallized from a suitable
solvent. The physical constants are as follows:
3d: Yield (85%); mp 290±293 8C; 1H NMR d 10.93 (s, 1H), 7.42±
7.15 (m, 10H), 7.12±7.09 (d, 2H), 5.14 (s, 1H), 4.10±4.01 (q, 2H),
2.80 (s, 3H), 1.11±1.06 (t, 3H); 13C NMR d 14.19 (C±CH3), 31.58
(N±C-1), 34.16 (O±C), 58.97, 86.00, 105.14, 124.78, 126.57, 127.22,
127.42, 127.78, 129.26, 141.55, 145.60, 148.52, 151.26, 156.21,
161.61, 168.25; m/z (%) 418 (18), 346 (12), 345 (41), 342 (14), 341
(100), 295 (18), 77 (48) (Calc. for C23H22N4O4: C, 66.01; H, 5.29;
N, 13.38. Found: C, 65.92; H, 5.27; N, 13.21%).
1
7a: Yield (71%); mp 278±280 8C (from ethanol); H NMR d 12.02
(s, 2H), 11.81 (brs, 2H), 7.25±7.06 (m, 5H); 13C NMR d 72.19,
90.18, 125.22, 126.38, 127.75, 137.85, 153.38, 162.93, 172.72; m/z
(%) 355 (18), 295 (15), 270 (43), 109 (100), 77 (19), 68 (71) (Calc.
for C15H9N5O2S2: C, 50.71; H, 2.55; N, 19.71. Found: C, 50.68;
H, 2.53; N, 19.55%).
3e: Yield (80%); mp 268±260 8C; 1H NMR d 10.64 (brs, 1H),
7.28±7.25 (d, J 7.3 Hz, 2H), 7.20±7.12 (m, Jm 3, Jo 6.5 Hz, 5H),
7.10±7.07 (d, Jo 7, Jm 2.7 Hz, 2H), 6.88±6.84 (d, Jm 2, Jo 6.9 Hz,
2H), 5.13 (s, 1H), 4.10±4.01 (q, 2H), 3.75 (s, 3H), 2.82 (s, 3H),
1.26±1.06 (t, 3H); 13C NMR d 14.19 (C±CH3), 31.86 (N±C-1),
34.00, 55.64, 58.89, 85.24, 104.14, 114.82, 125.96, 127.21, 127.81,
128.64, 133.98, 145.93, 148.56, 151.33, 156.37, 158.75, 161.90,
168.27; m/z (%) 448 (10), 376 (10), 375 (38), 372 (20), 371 (100),
325 (13), 77 (61), 43 (12) (Calc. for C24H24N4O5: C, 64.27; H, 5.39;
N, 12.49. Found: C, 64.23; H, 5.36; N, 12.35%).
7b: Yield (73%); mp 292±294 8C (from ethanol±DMF 2;1); 1H
NMR d 11.94 (s 2H), 11.75 (brs, 2H), 6.97±6.76 (dd, 4H), 3.70 (s,
3H); 13C NMR d 54.85 (O±CH3), 72.19, 90.45, 113.18, 127.43,
129.47, 153.32, 157.03, 162.89, 172.67; m/z (%) 385 (14), 263 (41),
260 (87), 143 (100), 121 (74), 115 (44), 68 (86), 43 (78) (Calc. for
C
16H11N5O3S2: C, 49.87; H, 2.87; N, 18.17. Found: C, 49.80;
H, 2.83; N, 18.01%).
7c: Yield (81%); mp 334±336 8C (from DMF±ethanol 5:1); 1H
NMR: d 11.89 (s, 2H), 11.70 (s, 2H), 7.26±7.08 (dd, 4H); 13C
NMR: d 72.23, 89.99, 127.59, 128.46, 129.86, 137.17, 153.37, 162.91,
172.91; m/z (%): 391 (26), 389 (48), 329 (16), 304 (45), 264 (66), 205
(23), 143 (100) (Calc. for C15H8ClN5O2S2: C, 46.22; H, 2.06;
N, 17.97. Found: C, 46.18; H, 2.00; N, 17.86%).
3f: Yield (74%); mp 257±259 8C; 1H NMR d 10.95 (s, 1H), 7.48±
7.44 (d, J 8.8 Hz, 2H), 7.24±7.08 (m, Jm 3, Jo 6.6 Hz, 9H), 5.11 (s,
1H), 4.10±4.02 (q, 2H), 2.83 (s, 3H), 1.12±1.06 (t, 3H);
13
C NMR
d 14.19 (C±CH3), 31.40 (N±C-1), 34.23 (O±C), 59.06, 87.00, 105.96,
119.95, 126.02, 127.15, 127.85, 127.88, 132.20, 140.99, 145.24,
148.25, 151.16, 156.06, 161.88, 168.13; m/z (%) 498 (6), 497 (10),
425 (19), 424 (51), 421 (16), 420 (100), 77 (58), 43 (11) (Calc. for
C23H21BrN4O4: C, 55.53; H, 4.25; N, 11.26. Found: C, 55.49;
H, 4.23; N, 11.18%).
Received, 18th August 1998; Accepted, 28th October 1998
Paper E/8/06513F
Synthesis of 6-Substituted 7-Amino-5-aryl-2-thioxo-2,3-dihydro-
pyrido[2,3-d]pyrimidin-4(1H)-one 6a±f.ÐThe compounds 6a±f were
prepared in 70±90% yield by the method described for the synthesis
of 3a±f.
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6a: Yield (79%); mp >380 8C; 1H NMR d 12.65 (s, 1H), 12.07
(s, 1H), 7.61 (s, 2H), 7.42±7.40 (m, Jm 3, Jo 6.2 Hz, 3H), 7.28±7.25
(d, Jm 2.3, Jo 9 Hz, 2 h); 13C NMR d 90.13, 100.35, 115.05, 126.83,
127.54, 128.80, 136.29, 154.30, 157.22, 158.80, 160.85, 175.96; m/z
(%) 295 (100), 294 (49), 262 (12), 237 (9), 146 (28), 77 (51) (Calc.
for C14H9N5OS: C, 56.95; H, 3.07; N, 23.71. Found: C, 56.88;
H, 2.98; N, 23.54%).
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6b: Yield (72%); mp >380 8C; 1H NMR d 12.70 (brs, 1H), 12.07
(s, 1H), 7.68 (s, 2H), 7.24±7.21 (d, Jo 8.7 Hz, 2H), 6.98±6.95 (d, Jo
8.6 Hz, 2H), 3.81 (s, 3H); 13C NMR d 55.02 (O±C), 78.11, 90.18,
100.31, 112.94, 115.13, 128.06, 129.32, 133.28, 154.22, 157.33,
159.44, 175.73; m/z (%) 325 (100), 324 (32), 292 (15), 267 (13), 77
(18), 66 (72) (Calc. for C15H11N5O2S: C, 55.38; H, 3.40; N, 21.53.
Found: C, 55.29; H, 3.34; N, 21.37%).
9 E. M. Grivsky, S. Lee, C. W. Sigel, D. S. Duch and C. A.
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6c: Yield (78%); mp >360 8C; 1H NMR d 12.70 (brs, 1H), 12.08
(s, 1H), 7.72 (s, 2H), 7.50±7.46 (d, Jm 2, Jo 8.4 Hz, 2H), 7.33±7.29
(d, 2H); 13C NMR d 89.93, 100.28, 114.96, 127.69, 129.52, 133.22,
135.13, 154.15, 157.31, 157.47, 160.75, 175.88; m/z (%) 331 (36), 330
(32), 329 (100), 328 (45), 296 (14), 271 (11), 180 (23), 164 (9) (Calc.
for C14H8ClN5OS: C, 51.00; H, 2.44; N, 21.24. Found: C, 50.89;
H, 2.41; N, 21.00%).
6d: Yield (86%); mp 288±289 8C; 1H NMR d 11.59 (s, 1H), 11.51
(s, 1H), 8.06 (dd, 2H), 7.5 (m, 3H), 6.37 (s, 2H), 4.37±4.29 (q, 2H),
1.34±1.29 (t, 3H); 13C NMR d 13.89 (C±CH3), 62.31 (O±CH2),
78.11, 102.28, 125.38, 129.22, 130.68, 131.28, 133.29, 138.01, 154.28,
155.01, 161.61, 174.79; m/z (%) 342 (10), 270 (11), 269 (38), 266
(20), 220 (12), 77 (15), 43 (10) (Calc. for C16H14N4O3S: C, 56.13;
H, 4.12; N, 16.36. Found: C, 56.05; H, 4.09; N, 16.11%).
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