An unequivocal synthesis of 4-amino-1,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-2,7-diones and 2-amino-3,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-4,7-diones

Article abstract of DOI:10.1135/cccc19960901

An unequivocal set of procedures for the synthesis of 4-amino-1,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-2,7-diones (7) and 2-amino-3,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-4,7-diones (8), in a maximum of four steps from an α,β-unsaturated ester 1, is reported. Thus, the acid hydrolysis of the 2,4-diaminopyrido[2.3-d]pyrimidines 3 yields the 4-amino-2-oxopyrido[2,3-d]pyrimidines 7 while the cyclization of the Michael adducts 9 (formed by reaction of 1 and methyl cyanoacetate) with guanidine affords the corresponding 2-amino-4-oxopyrido[2,3-d]pyrimidines 8. Both isomers were also obtained by hydrolysis of the 4-amino-2-bromo- and 2-amino-4-bromo-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones 5 and 6, respectively.

Full text of DOI:10.1135/cccc19960901

Synthesis of Aminopyrido[2,3-d]pyrimidinediones
901
AN UNEQUIVOCAL SYNTHESIS OF 4-AMINO-1,5,6,8-TETRAHYDRO-
PYRIDO[2,3-d]PYRIMIDINE-2,7-DIONES AND 2-AMINO-3,5,6,8-TETRA-
HYDROPYRIDO[2,3-d]PYRIMIDINE-4,7-DIONES
1
2
3
3
Jose I. BORRELL , Jordi TEIXIDO , Blanca MARTINEZ-TEIPEL , Blanca SERRA ,
3
3
4
Josep Lluis MATALLANA , Marta COSTA and Xavier BATLLORI
Departament de Quimica Organica, CETS Institut Químic de Sarria, Universitat Ramon Llull,
Via Augusta 390, E-08017 Barcelona, Spain; e-mail: 1 jibor@iqs.url.es, 2 jteix@iqs.url.es,
3 synth@iqs.url.es, 4 xbatl@iqs.url.es
Received February 27, 1996
Accepted March 24, 1996
An unequivocal set of procedures for the synthesis of 4-amino-1,5,6,8-tetrahydropyrido[2,3-d]pyri-
midine-2,7-diones (7) and 2-amino-3,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-4,7-diones (8), in a
maximum of four steps from an α,β-unsaturated ester 1, is reported. Thus, the acid hydrolysis of the
2,4-diaminopyrido[2,3-d]pyrimidines 3 yields the 4-amino-2-oxopyrido[2,3-d]pyrimidines 7 while the
cyclization of the Michael adducts 9 (formed by reaction of 1 and methyl cyanoacetate) with gua-
nidine affords the corresponding 2-amino-4-oxopyrido[2,3-d]pyrimidines 8. Both isomers were also
obtained by hydrolysis of the 4-amino-2-bromo- and 2-amino-4-bromo-5,6-dihydropyrido[2,3-d]pyri-
midin-7(8H)-ones 5 and 6, respectively.
Key words: 4-Oxopyrido[2,3-d]pyrimidines; 2-Oxopyrido[2,3-d]pyrimidines; Dinitrile cyclization;
Michael reaction.
During the past years our group has developed a general procedure for the synthesis of
5,6,7,8-tetrahydropyrido[2,3-d]pyrimidines starting from α,β-unsaturated esters1
(Scheme 1). The procedure starts by the condensation of an α,β-unsaturated ester 1
with malononitrile and sodium methanolate in methanol at reflux to afford the corres-
ponding 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles 2 in moderate to
good yields depending on the nature of R1 and R2. This reaction has been tested with a
wide range of alkyl, aryl or heteroaryl substituted esters.
The subsequent treatment of the pyridones 2 with quanidine in methanol at reflux
afforded in all cases the 2,4-diamino-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones 3
in good yields2 (75–97%). On the other hand, the substitution of the methoxy group of
pyridones 2 by cyanamide, carried out in dioxane at reflux in the presence of a stoi-
chiometric amount of sodium, gave the sodium salts 4 in quantitative yields. Treatment
of salts 4 with an equimolar amount of hydrogen chloride in ethanol afforded the corres-
ponding cyanoamino substituted pyridones2. Cyclization of the later compounds with
HBr in dioxane yielded both the positional isomers 5 and 6 depending on the thermal
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

902
Borrell et al.:
level employed. Thus, when the reaction was carried out at low temperature (10–15 °C) the
2-amino-4-bromo-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones 6 were preferently
formed, but when it was done at high temperature (95–100 °C) the 4-amino-2-bromo
substituted compounds 5 were selectively obtained3,5. Finally, these halogen derivatives
were found to be excellent substrates for aromatic nucleophilic substitution by a wide
range of nitrogen nucleophiles6.
Very recently, in connection with a project concerning the synthesis of a series of
folic acid analogs, we needed an unequivocal method to obtain 4-amino-1,5,6,8-tetra-
hydropyrido[2,3-d]pyrimidine-2,7-diones 7 and 2-amino-3,5,6,8-tetrahydropyrido-4,7-
diones 8. The present paper deals with the results obtained in such study.
H
N
H
N
O
1
N
NH
2
O
1
OMe
O
1
OMe
CN
CH (CN)
HN C(NH )
2
2
2 2
N
NaOMe, MeOH
MeOH, refl.
R
R
R
2
2
2
R
R
R
NH
2
1a-1d
2a-2d
H NCN
3a-3d
NCCH COOMe
2
6 M HCl
2
8a-8d
NaOMe, THF
Na, dioxane
O
1
OMe
CN
H
N
H
N
H
O
1
N
O
1
N
O
CN
R
COOMe
2
R
N
R
R
CN
Na
2
2
R
R
NH
9a-9d
HN C(NH )
2
4a-4d
7a-7d
2 2
MeOH, refl.
HBr, H O, refl.
2
H
N
H
N
O
1
N
4
NH
H
2
2
O
1
N
Br
7
HBr, dioxane, refl.
N
5
6
R
or HBr, H O, r.t.
2
N
R
2
R
O
2
o
R
NH
HBr, dioxane, 15
C
2
8a-8d
5a-5d
H
N
1
2
R
R
1-9
NH
O
1
N
2
HBr, H O, refl.
a
b
c
d
Me
H
H
2
N
Me
H
R
2
Ph
H
R
Br
Ph
6a-6d
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Synthesis of Aminopyrido[2,3-d]pyrimidinediones
903
EXPERIMENTAL
Melting points were determined on a Büchi–Tottoli apparatus and are uncorrected. IR spectra were
recorded on a BOMEM Michelson 100 (FTIR) or a Perkin–Elmer 683 spectrophotometers. 1H and
13C NMR spectra (δ, ppm; J, Hz) were measured in (CD3)2SO (compounds 5, 6; CDCl3 (compounds 9) or
CF3COOD (7, 8) on a Perkin–Elmer R-24 (1H NMR, 60 MHz) or a Varian Gemini 300 spectrometer
using TMS or sodium 2,2,3,3-tetradeuteriotrimethylsilylpropionate as an internal standard. Mass spectra
(m/z (%), EI, 70 eV) were performed on a HP 5995 A spectrometer. Elemental analyses were obtained
on a Carlo–Erba CHNS-O/EA 1108 analyzer. Column chromatography was carried out on silica gel
(70–230 mesh). Compounds 2–4, 6a and 6b were prepared according to reported procedures3–6
.
4-Amino-2-bromo-6-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (5a)
An amount of 2.08 g (10.6 mmol) of the sodium salt 4a were treated with 30 ml of 45% aqueous
HBr at room temperature for 16 h. The solution was neutralized with aqueous ammonia while cool-
ing on an ice bath. The solid was filtered off and washed with water, methanol and diethyl ether and
dried over phosphorus pentoxide to give 2.05 g (76%) of 5a, m.p. 264–265 °C. IR spectrum: 3 360
1
and 3 320 (NH2), 3 180 (NHCO); 1 695 (C=O), 1 645, 1 595, 1 560. H NMR spectrum: 1.2 d, 3 H,
3J = 5.8 Hz (Me); 2.2–3.0 m, 3 H (H-6 and 2 × H-5); 7.1 brs, 2 H (NH2); 10.5 brs, 1 H (NH). 13C NMR
spectrum: 148.5 (C-2), 162.1 (C-4), 92.6 (C-4a), 25.0 (C-5), 33.8 (C-6), 172.9 (C-7), 156.9 (C-8a),
15.3 (Me). Mass spectrum: 258 (M+ + 2, 88), 256 (M+, 100), 241 (17), 201 (10), 177 (24). For
C8H9BrN4O (257.1) calculated: 37.37% C, 3.53% H, 31.08% Br, 21.79% N; found: 37.25% C,
3.45% H, 31.07% Br, 21.58% N.
4-Amino-2-bromo-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (5b)
Prepared as given above starting from 2.00 g (10.5 mmol) of 4b, reaction time 20 h, yield: 1.92 g
(71%) of 5b, m.p. 273–274 °C (ref.3 gives 273–275 °C).
4-Amino-2-bromo-6-phenyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (5c)
Prepared as given for the compound 5a starting from 1.62 g (6.2 mmol) of 4c, reaction time 1 h,
yield: 1.42 g (72%) of 5c, m.p. 284–285 °C. IR spectrum: 3 500 and 3 310 (NH2), 3 240 and 3 120
(NHCO), 1 715 (C=O), 1 645, 1 605, 1 570. 1H NMR spectrum: 2.9 and 3.0 m, 2 H, 2J = 16.4,
3
3
3
3J (5,6-trans) = 10.1, J (5,6-cis) = 7.2 (2 × H-5); 3.9 dd, 1 H, J = 10.1 and J = 7.2 (H-6); 7.1 brs,
2 H (NH2); 7.3 m, 5 H (Ph), 10.9 brs, 1 H (NH). 13C NMR spectrum: 161.4 (C-2), 151.0 (C-4),
103.1 (C-4a), 30.0 (C-5), 45.7 (C-6), 171.9 (C-7), 158.3 (C-8a), 127.1, 128.1, 128.4 and 138.5 (Ph).
Mass spectrum: 320 (M+ + 2, 35), 318 (M+, 36), 241 (27), 201 (31), 118 (100). For C13H11BrN4O
(319.2) calculated: 48.92% C, 3.47% H, 25.04% Br, 17.55% N; found: 48.81% C, 3.11% H, 24.94% Br,
17.27% N.
4-Amino-2-bromo-5-phenyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (5d)
Prepared as given above starting from 1.00 g (3.8 mmol) of 4d, reaction time 6 h, yield: 1.00 g
(80%) of 5d, m.p. > 300 °C. IR spectrum: 3 350 and 3 325 (NH2), 3 190 (NHCO), 1 705 (C=O), 1 650,
1
2
3
3
1 590, 1 555. H NMR spectrum: 2.6 and 3.1 m, 2 H, J = 16.2, J (6,5-trans) = 7.5, J (6,5-cis) = 1.2
(2 × H-6); 4.3 dd, 1 H, 3J = 7.5 and 1.2 (H-5); 7.2 m, 5 H (Ph). 13C NMR spectrum: 149.5 (C-2),
162.1 (C-4), 95.3 (C-4a), 33.1 (C-5), 38.4 (C-6), 168.8 (C-7), 157.4 (C-8a), 126.7, 127.1, 128.7 and
140.8 (Ph). Mass spectrum: 320 (M+ + 2, 100), 318 (M+, 96), 241 (55), 239 (5). For C13H11BrN4O
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

904
Borrell et al.:
(319.2) calculated: 48.92% C, 3.47% H, 25.04% Br, 17.55% N; found: 49.02% C, 3.26% H, 24.88%
Br, 17.63% N.
2-Amino-4-bromo-6-phenyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (6c)
A stream of dry hydrogen bromide was bubbled through a suspension of 1.52 g (5.8 mmol) of the
sodium salt 4c in anhydrous dioxane (140 ml) at 10–15°C until saturation (15 min) and the resulting
suspension was stirred at room temperature for 2 h. The mixture was concentrated in vacuo, the
residue was suspended in methanol (50 ml) and neutralized with 2 M methanolic ammonia. The sol-
vent was eliminated in vacuo, the solid obtained was suspended in water (100 ml), filtered, washed
with water and dried over phosphorus pentoxide to give 1.57 g of a 75 : 25 isomeric mixture of 6c
and 5c. The solid was extracted with ethanol in a Soxhlet apparatus for 5 h to afford 0.63 g (34%)
of 6c, m.p. > 300 °C. IR spectrum: 3 355 (NH2), 3 210 (NHCO), 1 690 (C=O), 1 655, 1 620, 1 545.
1H NMR spectrum: 3.0 m, 2 H (H-5); 4.0 m, 1 H (H-6); 6.9 brs, 2 H (NH2); 7.3 m, 5 H (Ph); 10.9 brs,
1 H (NH). 13C NMR spectrum: 148.7 (C-2), 162.0 (C-4), 92.7 (C-4a), 25.3 (C-5), 45.3 (C-6), 171.4
(C-7), 156.8 (C-8a), 127.0, 128.2, 128.4 and 139.0 (Ph). Mass spectrum: 320 (M+ + 2, 40), 318 (M+, 41),
241 (47), 201 (51), 118 (100). For C13H11BrN4O (319.2) calculated: 48.92% C, 3.47% H, 25.04% Br,
17.55% N; found: 48.64% C, 3.48% H, 24.95% Br, 17.51% N.
2-Amino-4-bromo-5-phenyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (6d)
Prepared as given above for the compound 6c starting from 1.52 g (5.8 mmol) of 4d, yield: 1.30 g
(70%) of 6d, m.p. > 300 °C. IR spectrum: 3 320 (NH2), 3 180 (NHCO), 1 690 (C=O), 1 655, 1 610,
1
3
1 535. H NMR spectrum: 2.6 and 3.2 m, 2 H, 2J = 16.0, J (6,5-trans) = 7.2, 3J (6,5-cis) = 1.2, (2 × H-6);
4.3 dd, 1 H, 3J = 7.2 and J = 1.5 (H-5); 7.0 brs, 2 H (NH2); 7.2 m, 5 H (Ph); 10.9 brs, 1 H (NH).
3
13C NMR spectrum: 161.6 (C-2), 152.4 (C-4), 105.4 (C-4a), 38.4 (C-5), 39.1 (C-6), 170.3 (C-7),
158.9 (C-8a), 126.5, 126.9, 128.8 and 141.7 (Ph). Mass spectrum: 320 (M+ + 2, 52), 318 (M+, 51),
241 (100), 239 (23), 162 (13). For C13H11BrN4O (319.2) calculated: 48.92% C, 3.47% H, 25.04% Br,
17.55% N; found: 48.95% C, 3.23% H, 24.74% Br, 17.84% N.
Dimethyl 2-Cyano-4-methylglutarate (9a)
Methyl cyanoacetate (38.60 g, 0.39 mol) was added dropwise to a solution of sodium (8.97 g, 0.39 mol)
in methanol (80 ml). The mixture was heated at reflux for 10 min and then 39.00 g (0.39 mol)
methyl methacrylate (1a) were added dropwise. The mixture was refluxed for 1.5 h, cooled and neu-
tralized with acetic acid. The solution was concentrated in vacuo, the residue was poured into water
and extracted with diethyl ether. The organic extracts were dried (MgSO4), evaporated at reduced
pressure and the residue was distilled to afford 39.80 g (51%) of 9a, b.p. 110–115 °C/0.27 kPa. IR spec-
1
trum (neat): 2 950, 2 250 (CN), 1 750 (C=O), 1 440. H NMR spectrum (60 MHz): 1.3 d, 3 H, J = 5.3
(Me); 1.8–2.8 m, 3 H (H-3 and H-4); 3.7 m, 1 H (H-2); 3.7 s, 3 H (COOMe); 3.8 s, 3 H (COOMe).
Dimethyl 2-Cyano-3-methylglutarate (9b)
Prepared as given above using 19.30 g (0.20 mol) methyl cyanoacetate, 4.50 g (0.20 mol) sodium
in 40 ml methanol and 19.50 g (0.20 mol) methyl crotonate (1b) to give 25.40 g (66%) of 9b,
b.p. 144–147 °C/0.40 kPa. IR spectrum (neat): 2 960, 2 250 (CN), 1 750 (C=O), 1 440. 1H NMR spectrum
(60 MHz): 1.3 d, 1.5 H, J = 3.8 (Me); 1.4 d, 1.5 H, J = 3.0 Hz (Me); 2.6 m, 3 H (H-3 and H-4); 3.7 s,
3 H (COOMe); 3.8 s, 3 H (COOMe); 4.0 m, 1 H (H-2).
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Synthesis of Aminopyrido[2,3-d]pyrimidinediones
Dimethyl 2-Cyano-4-phenylglutarate (9c)
905
Prepared as given above using 0.62 g (6.2 mmol) methyl cyanoacetate, 0.14 g (6.2 mmol) sodium in 5 ml
methanol and 1.00 g (6.2 mmol) methyl atropate (1c) to give 0.91 g (56%) of 9c, b.p. 142–145 °C/0.27 kPa.
IR spectrum (neat): 3 020, 2 250 (CN), 1 750 (C=O), 1 610 and 1 500 (C=C), 765, 700. 1H NMR spectrum
(60 MHz): 2.3–3.5 m, 3 H (H-3 and H-4); 3.9 s, 3 H (COOMe); 4.1 s, 3 H (COOMe); 4.3 m, 1 H (H-2);
7.4 s, 5 H (Ph).
Dimethyl 2-Cyano-3-phenylglutarate (9d)
Prepared as given above using 4.95 g (0.05 mol) methyl cyanoacetate, 1.15 g (0.05 mol) sodium in 15 ml
methanol and 8.10 g (0.05 mol) methyl cinnamate (1d) to give 7.67 g (57%) of 9d, b.p. 166–170 °C/0.27 kPa.
IR spectrum (neat): 3 010, 2 240 (CN), 1 745 (C=O), 1 600 and 1 500 (C=C), 755, 700. 1H NMR
spectrum (60 MHz): 3.0 m, 2 H (H-4); 3.6–4.0 m, 7 H (2 × COOMe and H-3); 4.3 d, 1 H, J = 4.5
(H-2); 7.3 s, 5 H (Ph).
4-Amino-6-methyl-1,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-2,7-dione (7a)
A. A suspension of 3a (0.50 g, 2.6 mmol) in 6 M hydrochloric acid (20 ml) was heated at reflux
for 48 h. The resulting solution was allowed to cool and neutralized with 30% NaOH. The solid thus
obtained was filtered off, washed with water and methanol and dried over phosporus pentoxide to
afford 0.49 g (98%) of 7a as a white solid, m.p. > 300 °C. IR spectrum: 3 500 (NH2), 3 320 and 3 040
1
(NHCO), 2 930, 2 840, 1 715 and 1 695 (C=O), 1 630, 1 605, 1 520. H NMR spectrum: 1.4 d, 3 H,
J = 6.6 (Me); 2.5 m, 1 H (H-6); 3.0 m, 2 H (H-5). 13C NMR spectrum: 15.8 (Me), 25.6 (C-5), 36.7
(C-6), 85.3 (C-4a), 150.7 (C-2), 151.6 (C-8a), 159.3 (C-4), 178.3 (C-7). Mass spectrum: 194 (M+, 100),
179 (46). For C8H10N4O2 (194.2) calculated: 49.48% C, 5.19% H, 28.85% N; found: 49.45% C,
5.25% H, 28.73% N.
B. A suspension of 5a (0.15 g, 0.6 mmol) in 45% aqueous HBr (5 ml) was heated at reflux for 4 h.
The resulting solution was cooled and neutralized with NaOH pellets. The solid was filtered, washed
with water, methanol, diethyl ether and dried over phosphorus pentoxide to give 0.10 g (96%) of 7a.
4-Amino-5-methyl-1,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-2,7-dione (7b)
A. The same procedure as described for 7a (A) was used starting from 0.47 g (2.44 mmol) of 3b
and 20 ml 6 M hydrochloric acid to give, after 96 h at reflux, 0.42 g (89%) of 7b, m.p. > 300 °C. IR
spectrum: 3 500 (NH2); 3 300 and 3 020 (NHCO), 2 910, 2 830, 1 715 and 1 695 (C=O), 1 650, 1 615,
1 515. 1H NMR spectrum: 1.3 d, 3 H, J = 4.8 (Me); 2.8–3.0 m, 2 H (H-6); 3.3 m, 1 H (H-5).
13C NMR spectrum: 18.7 (Me), 25.3 (C-5), 38.6 (C-6), 90.7 (C-4a), 150.5 (C-2), 150.7 (C-8a), 158.8
(C-4), 175.3 (C-7). Mass spectrum: 194 (M+, 25), 179 (100). For C8H10N4O2 (194.2) calculated:
49.48% C, 5.19% H, 28.85% N; found: 49.52% C, 5.28% H, 29.13% N.
B. As given in procedure B but using 0.42 g (1.6 mmol) of 5b to afford 0.19 g (60%) of 7b.
4-Amino-6-phenyl-1,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-2,7-dione (7c)
A. From 3c: As given above starting from 0.47 g (1.84 mmol) of 3c and 20 ml 6 M hydrochloric
acid to give 0.38 g (81%) of 7c, m.p. > 300 °C. IR spectrum: 3 500 (NH2); 3 300 and 3 040
1
(NHCO), 2 930, 2 830, 1 735 and 1 700 (C=O), 1 650, 1 625, 1 515. H NMR spectrum: 3.1 m, 2 H
(H-5); 4.1 m, 1 H (H-6); 7.2–7.4 m, 5 H (Ph). 13C NMR spectrum: 25.7 (C-5), 47.6 (C-6), 85.3
(C-4a), 129.5 (C-2′), 130.9 (C-4′), 131.2 (C-3′), 135.8 (C-1′), 150.4 (C-2), 151.0 (C-8a), 159.0 (C-4),
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

906
Borrell et al.:
176.6 (C-7). Mass spectrum: 256 (M+, 100), 179 (24). For C13H12N4O2 (256.3) calculated: 60.93% C,
4.72% H, 21.86% N; found: 60.79% C, 4.79% H, 21.88% N.
B. From 5c: As given above but using 0.50 g (1.6 mmol) of 5c to afford 0.30 g (76%) of 7c.
4-Amino-5-phenyl-1,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-2,7-dione (7d)
A. From 3d: As given above starting from 0.75 g (2.94 mmol) of 3d and 20 ml of 6 M hydro-
chloric acid to give 0.40 g (53%) of 7d, m.p. > 300 °C. IR spectrum: 3 500 (NH2), 3 305 and 3 045
1
(NHCO), 2 930, 2 840, 1 700 (C=O), 1 650, 1 625, 1 510. H NMR spectrum: 3.1–3.3 m, 2 H (H-6);
4.4 m, 1 H (H-5); 7.2–7.3 m, 5 H (Ph). 13C NMR spectrum: 36.0 (C-5), 40.3 (C-6), 87.9 (C-4a),
127.9 (C-2′), 131.2 (C-4′), 131.9 (C-3′), 138.2 (C-1′), 150.4 (C-2), 152.0 (C-8a), 159.1 (C-4), 174.2
(C-7). Mass spectrum: 256 (M+, 100), 179 (92). For C13H12N4O2 (256.3) calculated: 60.93% C,
4.72% H, 21.86% N; found: 60.77% C, 4.81% H, 21.95% N.
B. From 5d: As given above but using 0.50 g (1.6 mmol) of 5d to afford 0.34 g (85%) of 7d.
2-Amino-6-methyl-3,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-4,7-dione (8a)
A. A suspension of 6a (0.30 g, 1.17 mmol) in 45% aqueous HBr (5 ml) was heated at reflux for
4 h. The resulting solution was cooled and neutralized with NaOH pellets. The solid was filtered,
washed with water, methanol, diethyl ether and dried over phosphorus pentoxide to give 0.15 g
(68%) of 8a, m.p. > 300 °C. IR spectrum: 3 500–3 000 (N–H), 1 695 and 1 650 (C=O), 1 595 and
1
1 535 (C=C). H NMR spectrum: 1.3 d, 3 H, J = 6.0 (Me); 2.5 m, 1 H (H-5); 2.9 m, 1 H (H-6); 3.0 m,
1 H (H-5). 13C NMR spectrum: 15.4 (Me), 24.8 (C-5), 36.4 (C-6), 94.3 (C-4a), 147.5 (C-8a), 153.0
(C-2), 162.9 (C-4), 179.4 (C-7). Mass spectrum: 194 (M+, 100), 179 (98). For C8H10N4O2 (194.2)
calculated: 49.48% C, 5.19% H, 28.85% N; found: 49.32% C, 5.38% H, 28.83% N.
B. Guanidine carbonate (2.20 g, 13.0 mmol) was added to a solution of sodium (0.60 g, 26.0
mmol) in methanol (50 ml). The mixture was heated at reflux for 15 min. The sodium carbonate
formed was filtered and washed with methanol. 2.50 g (13.0 mmol) of compound 9a were added to
the filtrate and the resulting mixture was heated at reflux for 24 h. The precipitate formed was fil-
tered, washed with methanol and dried over phosphorus pentoxide to give 2.08 g (82%) of 8a.
2-Amino-5-methyl-3,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-4,7-dione (8b)
A. From 6b: As given above but using 0.30 g (1.2 mmol) of 6b to afford 0.10 g (43%) of 8b, m.p. > 300 °C.
IR spectrum: 3 500–3 000 (N–H), 1 670 and 1 635 (C=O), 1 595 (C=C). 1H NMR spectrum: 1.2 d,
2
3
3 H, J = 7.0 (Me); 2.7 and 3.0 m, 2 H, J = 17.0, J (6,5-trans) = 7.0 (2 × H-6); 3.36 m, 1 H (H-5).
13C NMR spectrum: 18.9 (Me), 25.2 (C-5), 38.5 (C-6), 99.9 (C-4a), 146.8 (C-8a), 153.1 (C-2), 163.2
(C-4), 176.8 (C-7). Mass spectrum: 194 (M+, 15), 179 (100). For C8H10N4O2 (194.2) calculated:
49.48% C, 5.19% H, 28.85% N; found: 49,60% C, 5.17% H, 28.58% N.
B. From 9b: As given above but using 2.50 g (13.0 mmol) of 9b, 0.60 g (26.0 mmol) sodium in
methanol (50 ml) and guanidine carbonate (2.20 g, 13.0 mmol) to yield 2.06 g (82%) of 8b.
2-Amino-6-phenyl-3,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-4,7-dione (8c)
A. From 6c: As given above but using 0.35 g (1.1 mmol) of 6c to afford 0.06 g (19%) of 8c,
m.p. > 300 °C. IR spectrum: 3 500–3 000 (N–H), 1 690 and 1 625 (C=O), 1 600 and 1 540 (C=C),
1
2
3
3
770, 700. H NMR spectrum: 3.0 and 3.2 m, 2 H, J = 17.0, J (5,6-trans) = 11.0, J (5,6-cis) = 7.0
(2 × H-5); 4.0 dd, 1 H J (5,6-trans) = 11.0, J = (5,6-cis) = 7.0 (H-6); 7.2–7.3 m, 5 H (Ph). 13C NMR
3
3
spectrum: 25.4 (C-5), 48.1 (C-6), 94.9 (C-4a), 129.8, 130.8, 131.3 and 136.6 (Ph), 147.7 (C-8a),
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Synthesis of Aminopyrido[2,3-d]pyrimidinediones
907
153.1 (C-2), 159.9 (C-4), 178.0 (C-7). Mass spectrum: 256 (M+, 100), 179 (48). For C13H12N4O2
(256.3) calculated: 60.91% C, 4.72% H, 21.87% N; found: 60.78% C, 4.84% H, 22.06% N.
B. From 9c: As given above but using 2.50 g (9.6 mmol) of 9c, 0.44 g (19.1 mmol) sodium in
methanol (50 ml) and guanidine carbonate (1.72 g, 9.6 mmol) to give 2.00 g (82%) of 8c.
2-Amino-5-phenyl-3,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-4,7-dione (8d)
A. From 6d: As given above but using 0.12 g (0.4 mmol) of 6d to afford 0.06 g (62%) of 8d,
m.p. > 300 °C. IR spectrum: 3 500–3 000 (N–H), 1 685 and 1 650 (C=O), 1 600 and 1 535 (C=C),
740, 690. 1H NMR spectrum: 3.0–3.3 m, 2 H (2 × H-6); 4.5 m, 1 H (H-5); 7.1–7.3 m, 5 H (Ph). 13C NMR
spectrum: 35.3 (C-5), 39.1 (C-6), 98.0 (C-4a), 127.8, 130.3, 131.2 and 140.6 (Ph), 147.9 (C-8a),
153.2 (C-2), 159.8 (C-4), 176.0 (C-7). Mass spectrum: 256 (M+, 63), 179 (100). For C13H12N4O2
(256.3) calculated: 60.91% C, 4.72% H, 21.87% N; found: 61.12% C, 4.85% H, 21.92% N.
B. Starting from 9d. As given above using 2.50 g (9.6 mmol) of 9d, 0.44 g (19.1 mmol) sodium
in methanol (50 ml) and guanidine carbonate (1.72 g, 9.6 mmol) to give 1.91 g (78%) of 8d.
RESULTS AND DISCUSSION
The starting point for our research was the work of Trattner et al. on the selective
hydrolysis o 2,4-diaminopyrimidine systems7. According to this author, the treatment
of 2,4-diaminopyrimidines with 6 M hydrochloric acid always causes the hydrolysis of
the 4-amino group. The reaction was particularly fast (< 0.5 h) in the case of 2,4-
diamino-7-butyl-6-propylpyrido[2,3-d]pyrimidine which afforded the corresponding
4-oxo derivative in 80% yield (90% when 3.5 M sulfuric acid was used). The hydrolysis
of the 2-amino group only was observed after the transformation of the 4-amino group.
Taking these results into account, we carried out the treatment of the 2,4-diamino-
pyrido[2,3-d]pyrimidine 3a with 6 M hydrochloric acid. The reaction afforded a carbo-
nyl compound in almost quantitative yield, to which the 4-oxo substituted structure 8a
was initially assigned in accordance with the work of Trattner. In order to confirm such
assignment, we decided to obtain unequivocally the two possible positional isomers 7a
and 8a. Consequently, we synthesized the sodium salt 4a and we converted it to the
2-amino-4-bromopyrido[2,3-d]pyrimidine 6a by using hydrogen bromide in dioxane at
15 °C. On the other hand, we found that the treatment of 4a with concentrated hydro-
bromic acid at room temperature is a much more favorable method for the synthesis of
the corresponding 4-amino-2-bromo isomer 5a.
Once the two bromo substituted positional isomers 5a and 6a were obtained, we
treated them with boiling concentrated hydrobromic acid to respectively afford the 4-
amino-2-oxo- and 2-amino-4-oxopyrido[2,3-d]pyrimidines 7a and 8a in fairly good
yields. Surprisingly, when the compound obtained by the acid hydrolysis of the 2,4-
diaminopyrido[2,3-d]pyrimidine 3a was compared with the unequivocally assigned oxo
derivatives, we found that it was in fact the 4-amino-2-oxopyrido[2,3-d]pyrimidine 7a.
That is to say, contrary to the prediction of Trattner, the hydrolysis proceeds on the
theoretically less reactive amino group.
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908
Borrell et al.:
We have proved the general applicability of this method by carrying out the acid
hydrolysis of the 2,4-diaminopyrido[2,3-d]pyrimidines 3b–3d which afforded the
corresponding 4-amino-2-oxopyrido[2,3-d]pyrimidines 7b–7d. Similarly, the hydro-
lysis of the bromo substituted isomers 5b–5d and 6b–6d, obtained by cyclization of the
sodium salts 4b–4d with HBr in water at the room temperature and HBr in dioxane at
15 °C, respectively, yielded the corresponding oxo derivatives 7b–7d and 8b–8d.
The procedure described so far is a good method for the synthesis of 4-amino-
1,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-2,7-diones 7 in three steps from an α,β-un-
saturated ester through the sequence 1 → 2 → 3 → 7, however, it is far from being an
efficient method for the synthesis of 2-amino-3,5,6,8-tetrahydropyrido[2,3-d]pyri-
midine-4,7-diones 8. These compounds are obtained through a four steps sequence
1 → 2 → 4 → 6 → 8 that includes a treatment with gaseous hydrogen bromide in
dioxane at 15 °C in which the 4-bromo substituted intermediates 6 are only selectively
formed.
This fact and the great interest of the 4-oxo substituted isomers in connection with
folic acid analogues let us to search a more convenient way to obtain 2-amino-3,5,6,8-
tetrahydropyrido[2,3-d]pyrimidine-4,7-diones 8. A bibliographic search revealed that
Schoffstall described in 1971 a synthesis for 8a by cyclization of the Michael adduct 9a
(formed by reaction of 1a and ethyl cyanoacetate) and guanidine (1 : 1) in ethanol at
room temperature (14% overall yield)8. In order to extend this reaction for the synthesis
of the 2-amino-4-oxopyrido[2,3-d]pyrimidines 8a–8d, we decided to carry out a careful
revision of the work of Schoffstall. Then, we obtain the corresponding Michael adducts
9a–9d (50–66% yield) and we treated them with guanidine (1 : 1) in ethanol at reflux
in order to increase the yield of the pyridopyrimidine formed. However, although the
yields were increased, in no case they were greater than 50%. The substitution of ethanol
by solvents of a higher boiling point (tert-BuOH or DMF) did not increase the yields.
The analysis of the products left in solution after the filtration of the 4-oxo deriva-
tives seemed to indicate the presence of open chain products, formed by reaction of two
molecules of the corresponding Michael adduct 9a–9d and one molecule of guanidine,
which do not evolve to the cyclized compounds. In order to avoid the formation of
these products, we decided to use a twofold molar excess of guanidine respect to the
Michael adducts 9a–9d. Such treatment resulted in the formation of the 2-amino-4-oxo-
pyrido[2,3-d]pyrimidines 8a–8d in high yield (78–82%).
This result completes an unequivocal set of procedures for the synthesis of 4-amino-
1,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-2,7-diones 7 and 2-amino-3,5,6,8-tetra-
hydropyrido[2,3-d]pyrimidine-4,7-diones 8 in a maximum of four steps from an α,β-un-
saturated ester.
Support of this work by a grant from the Comissió Interdepartamental de Recerca i Innovació
Tecnològica (CIRIT) within the Programa de Química Fina (QFN93-4420) is gratefully acknowledged.
One of us (J. L. M.) would like to thank the CIRIT for a grant within the Formació de Personal
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Synthesis of Aminopyrido[2,3-d]pyrimidinediones
909
Investigador en Arees Prioritaries del Pla de Recerca. Two of us (B. S. and B. M.) are grateful to the
Fundacio Juan Salaner for a grant.
REFERENCES
1. Victory P., Borrell J. I.: Trends Heterocycl. Chem. 3, 235 (1993); and references therein.
2. Victory P., Nomen R., Colomina O., Garriga M., Crespo A.: Heterocycles 23, 1135 (1985).
3. Victory P., Garriga M.: Heterocycles 23, 1947 (1985).
4. Victory P., Garriga M.: Heterocycles 23, 2853 (1985).
5. Victory P., Garriga M.: Heterocycles 24, 3053 (1986).
6. Victory P., Crespo A., Garriga M., Nomen R.: J. Heterocycl. Chem. 25, 245 (1988).
7. Trattner R. B., Elion G. B., Hitchings G. H., Sharefkin D. M.: J. Org. Chem. 29, 2674 (1964).
8. Schoffstall A. M.: J. Org. Chem. 36, 2385 (1971).
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