Simple synthesis of alkyl 5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-7-carboxylates from 5-acetyl-4-aminopyrimidines

Article abstract of DOI:10.1023/A:1021304619076

A method for the synthesis of methyl and ethyl 2-R¹-4-R ²-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-7-carboxylates was proposed. The method is based on condensation of 2-R¹-6-R ²-5-acetyl-4-aminopyrimidines with ethyl oxalate in the presence of MeONa or EtONa. Products of the Friedlaender self-condensation of the starting pyrimidines were also obtained.

Full text of DOI:10.1023/A:1021304619076

Russian Chemical Bulletin, International Edition, Vol. 51, No. 10, pp. 1875—1878, October, 2002
1875
Simple synthesis of alkyl 5ꢀoxoꢀ5,8ꢀdihydropyrido[2,3ꢀd]pyrimidineꢀ
7ꢀcarboxylates from 5ꢀacetylꢀ4ꢀaminopyrimidines
A. V. Komkov and V. A. Dorokhovꢀ
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: vador@ioc.ac.ru
A method for the synthesis of methyl and ethyl 2ꢀR1ꢀ4ꢀR2ꢀ5ꢀoxoꢀ5,8ꢀdihydropyriꢀ
do[2,3ꢀd]pyrimidineꢀ7ꢀcarboxylates was proposed. The method is based on condensation of
2ꢀR1ꢀ6ꢀR2ꢀ5ꢀacetylꢀ4ꢀaminopyrimidines with ethyl oxalate in the presence of MeONa or
EtONa. Products of the Friedländer selfꢀcondensation of the starting pyrimidines were also
obtained.
Key words: 5ꢀacetylꢀ4ꢀaminopyrimidines, ethyl oxalate, condensation, the Friedländer
selfꢀcondensation, alkyl 5ꢀoxopyrido[2,3ꢀd]pyrimidineꢀ7ꢀcarboxylates, 7ꢀpyrimidinylpyriꢀ
do[2,3ꢀd]pyrimidines.
Pyrido[2,3ꢀd]pyrimidines exhibit a variety of biologiꢀ
cal activity, which makes them subjects of intensive inꢀ
vestigation. The methods for the synthesis of these comꢀ
pounds are widely covered in the literature (see the reꢀ
views1,2 and some of the recent communications3—7).
Derivatives of pyrido[2,3ꢀd]pyrimidineꢀ6ꢀcarboxylic acid
are still attracting particular attention;8—10 earlier,2
such well known antibacterial preparations as piromidic
and pipemidic acids were discovered among them.
for the synthesis of alkyl esters of 2,4ꢀdisubstituted 5ꢀoxoꢀ
5,8ꢀdihydropyrido[2,3ꢀd]pyrimidineꢀ7ꢀcarboxylic acids
(2a,b; 3a—g) (Scheme 1). Recently,16 ethyl 7ꢀarylꢀ
(1H,5H)ꢀ4,5ꢀdioxopyrano[4,3ꢀb]pyridineꢀ2ꢀcarboxylates
were obtained by heating 3ꢀacetylꢀ4ꢀaminoꢀ6ꢀarylpyranꢀ
2ꢀones (like pyrimidines 1, they contain vicinal Ac and
NH2 groups) with ethyl oxalate in EtOH in the presence
of EtONa. It turned out that a similar approach makes it
possible to obtain ethyl esters 2a,b from pyrimidines 1a,b
even at room temperature. The reactions of compounds
1a—g with ethyl oxalate in MeOH in the presence of
MeONa afforded the corresponding methyl esters 3a—g*.
However, refluxing was required for pyrimidines 1e—g
because of their poor solubility in MeOH.
Esters 2a,b and 3a—g are white crystalline substances.
They are well soluble in CHCl3 and DMSO, moderately
soluble in acetone, and insoluble in water. The exceptions
are compounds 3e—g, which are poorly soluble in all
solvents, including DMSO. The structures of compounds
2 and 3 were confirmed by spectroscopic data. Their mass
spectra contain intense molecular ion peaks (except for
ester 3c with the most intense [M – H]+ ion peak).
The IR spectra of esters 2 and 3 show a narrow ν(NH)
band at 3376—3384 (in CHCl3) or 3296—3344 cm–1 (KBr)
and ν(CO) bands at 1720—1736 and 1640—1656 cm–1
(Tables 1, 2). The 1H NMR spectra exhibit singlets at
δ 6.70—7.07 for the H(6) atom and at δ 2.95—3.13 for the
methyl group that is peri to the CO group, as well as
signals for the COOMe or COOEt protons.
At the same time, derivatives of isomeric pyriꢀ
do[2,3ꢀd]pyrimidineꢀ7ꢀcarboxylic acid remain almost
uninvestigated. Thus, methyl esters of substituted
2,4,5ꢀtrioxopyrido[2,3ꢀd]pyrimidineꢀ7ꢀcarboxylic acids
have been isolated only as byꢀproducts in the reaction of
6ꢀRꢀaminoꢀ1,3ꢀdimethyluracils with dimethyl acetyleneꢀ
dicarboxylate.11 Ethyl 2ꢀaminoꢀ4ꢀoxoꢀ and 4ꢀoxoꢀ5ꢀpheꢀ
nylꢀ3,4ꢀdihydropyrido[2,3ꢀd]pyrimidineꢀ7ꢀcarboxylates
have been synthesized very recently12 by the reactions of
2,6ꢀdiaminoꢀ6ꢀhydroxypyrimidine with the correspondꢀ
ing ethyl 4ꢀRꢀ2ꢀoxobutꢀ3ꢀynoates (R = Me3Si and Ph).
Earlier,13—15 we demonstrated that substituted 5ꢀaceꢀ
tylꢀ4ꢀaminopyrimidines, which are conveniently syntheꢀ
sized from acetylacetone or benzoylacetone, can be used
as efficient block reagents for construction of a pyriꢀ
do[2,3ꢀd]pyrimidine system. For instance, their condenꢀ
sation with amide acetals easily affords the corresponding
pyrimidinylamidines, which then undergo cyclization unꢀ
der the action of MeONa into substituted 8Hꢀpyriꢀ
do[2,3ꢀd]pyrimidinꢀ5ꢀones.14,15 Under analogous condiꢀ
tions, the latter can be obtained by intramolecular cyꢀ
clization of 4ꢀbenzoylaminoꢀ5ꢀacetylpyrimidines.14
In continuation of these studies, 2ꢀR1ꢀ6ꢀR2ꢀ5ꢀacetylꢀ
4ꢀaminopyrimidines (1a—g) were used as starting reagents
* No traces of ethyl esters were detected (1H NMR data). Both
ethyl oxalate and ethyl esters 2 were experimentally found
to undergo transesterification under the action of MeONa
in MeOH.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1726—1729, October, 2002.
1066ꢀ5285/02/5110ꢀ1875 $27.00 © 2002 Plenum Publishing Corporation

1876
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
Komkov and Dorokhov
Scheme 1
Scheme 2
R1
Me
Ph
R2
Me
Me
Ph
R1
Ph
R2
SMe
Me
a
b
c
d
e
f
g
4ꢀClC6H4
4ꢀNO2C6H4
Me
Me
CCl
Me
3
R
3 = Et (2), Me (3)
Reagents and conditions: 1) (EtOOC)2, R3ONa, R3OH,
20—65 °C; 2) AcOH, 20 °C.
R1 = R2 = Me (a); R1 = Ph, R2 = Me (b)
It is essential that a competitive Friedländer selfꢀconꢀ
densation of pyrimidines 1 is prevented under the choꢀ
sen temperature conditions. Thus the corresponding
7ꢀ(4ꢀaminopyrimidinꢀ5ꢀyl)pyrido[2,3ꢀd]pyrimidines 4a,b
were obtained in 76 and 85% yields, respectively, by reꢀ
fluxing compounds 1a,b with EtONa in EtOH in the abꢀ
sence of ethyl oxalate (Scheme 2). In a MeONa—MeOH
system, the starting reagents were recovered unchanged.
Compounds 4a,b are insoluble in organic solvents,
though pyridopyrimidine 4b is rather well soluble
in DMSO. Their mass spectra show intense [M]+•
,
[M – H]+, and [M – Me]+ ion peaks. The 1H NMR
spectra of these compounds in DMSOꢀd6 contain singlets
at δ 7.5—7.6 for the H(6) atoms and at δ 6.8—7.0 for the
NH2 group. Biheterocycles 4a,b are of interest by themꢀ
selves as potential chelating ligands. In addition, the NH2
group allows them to be easily modified.
The methods for the synthesis of pyrido[2,3ꢀd]pyrꢀ
imidines 2—4 are simple and involve accessible starting
Table 1. Yields, melting points, elemental analysis data, and mass spectra of compounds 2a,b and 3a—g
Comꢀ Yield M.p.
pound (%) /°C
Found
Calculated
Molecular
formula
MS,
m/z (Irel (%))
(%)
N
С
Н
2a
57 184—185 58.36 5.39 17.08 C12H13N3O3 247 [M]+ (100), 219 [M – CO]+ (40), 175 [M – C2H4 – CO2]+ (30),
58.29 5.30 17.00
173 [M – EtOH – CO]+ (75), 147 [M – C2H4 – CO2 – CO] (28),
132 [M – EtOH – CO – MeCN]+ (55), 68 (55)
2b
3a
3b
3c
3d
3e
3f
56 186—187 65.84 4.83 13.64 C17H15N3O3 309 [M]+ (100), 281 [M – CO]+ (13), 237 [M – C2H4 – CO2]+ (9),
66.01 4.89 13.59
209 [M – C2H4 – CO2 – CO]+ (8), 104 [PhC=NH]+ (26)
63 244—245 56.44 4.63 18.12 C11H11N3O3 233 [M]+ (100), 175 [M – CH2 – CO2]+ (15), 173 [M – MeOH – CO]+
56.65 4.75 18.02
(48), 132 [M – MeOH – CO – MeCN]+ (43), 42 (61)
74 249—250 65.11 4.55 14.05 C16H13N3O3 295 [M]+ (100), 237 [M – CH2 – CO2]+ (20),
65.08 4.44 14.23
235 [M – MeOH – CO]+ (26), 104 [PhC=NH]+ (100)
50 254—255 64.84 4.51 14.16 C16H13N3O3 295 [M]+ (17), 294 [M – H]+ (59), 235 [M – MeOH – CO]+ (14),
65.08 4.44 14.23
234 [M – H – MeOH – CO]+ (27), 43 (100)
74 203—204 39.51 2.52 12.66 C11H8Cl3N3O3 335 [M]+ (100), 300 [M – Cl]+ (37), 275 [M – MeOH – CO]+ (8),
39.25 2.40 12.49
240 [M – Cl – MeOH – CO]+ (34), 68 (79)
77 304—305 59.26 4.41 12.79 C16H13N3O3S 327 [M]+ (96), 294 [M – SH]+ (100), 267 [M – MeOH – CO]+ (39),
58.70 4.00 12.84
234 [M – SH – MeOH – CO]+ (49), 104 [PhC=NH]+ (59)
85 279—280 58.10 3.93 13.16 C16H12ClN3O3 329 [M]+ (100), 269 [M – MeOH – CO]+ (20),
58.28 3.67 12.47
138 [ClC6H4=NH]+ (75)
79 267—268 55.79 3.47 16.45 C16H12N4O5 340 [M]+ (100), 310 [M – NO]+ (9), 280 [M – MeOH – CO]+ (21),
56.47 3.55 16.47
234 [M – C6H4NO]+ (12), 149 [NO2C6H4=NH]+ (35)
3g

5ꢀOxopyrido[2,3ꢀd]pyrimidineꢀ7ꢀcarboxylates
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
1877
Table 2. IR and 1H NMR spectra of compounds 2a,b and 3a—g
Comꢀ
pound
IR
1H NMR
Conꢀ
ditions
ν/cm–1
Solvent
CDCl3
δ, J/Hz
2a
2b
CHCl3 3384 (NH), 1728 (COOEt),
1644 (CO), 1584, 1552, 1520
1.43 (t, 3 H, CH3CH2, J = 6.8); 2.70, 3.02 (both s, 3 H each, Me);
4.48 (q, 2 H, CH2, J = 6.8); 6.97 (s, 1 H, H(6));
9.25 (br.s, 1 H, NH)
CHCl3 3384 (NH), 1728 (COOEt),
1644 (CO), 1584, 1528
CDCl3
1.45 (t, 3 H, CH3CH2, J = 6.8); 3.12 (s, 3 H, Me);
4.50 (q, 2 H, CH2, J = 6.8); 6.99 (s, 1 H, H(6)); 7.45—7.60
(m, 3 H, Ph); 8.50—8.60 (m, 2 H, Ph); 9.23 (br.s, 1 H, NH)
3a
3b
CHCl3 3384 (NH), 1736 (COOMe),
1644 (CO), 1584, 1552, 1520
CDCl3
CDCl3
2.69, 3.02 (both s, 3 H each, Me); 4.02 (s, 3 H, COOMe);
6.95 (s, 1 H, H(6)); 9.19 (br.s, 1 H, NH)
CHCl3 3384 (NH), 1736 (COOMe),
1644 (CO), 1576, 1536, 1520
3.13 (s, 3 H, Me); 4.05 (s, 3 H, COOMe); 6.98 (s, 1 H, H(6));
7.45—7.60 (m, 3 H, Ph); 8.48—8.60 (m, 2 H, Ph);
9.21 (br.s, 1 H, NH)
3c
CHCl3 3384 (NH), 1736 (COOMe),
1644 (CO), 1576, 1540, 1512
CDCl3
CDCl3
2.80 (s, 3 H, Me); 4.05 (s, 3 H, COOMe); 6.93 (s, 1 H, H(6));
7.40—7.58 (m, 3 H, Ph); 7.58—7.68 (m, 2 H, Ph);
9.30 (br.s, 1 H, NH)
3d
3e
CHCl3 3376 (NH), 1736 (COOMe),
1648 (CO), 1580, 1548, 1520
3.13 (s, 3 H, Me); 4.09 (s, 3 H, COOMe);
7.07 (s, 1 H, H(6)); 9.42 (br.s, 1 H, NH)
KBr
3296 (NH), 1728 (COOMe), DMSOꢀd6 2.61 (s, 3 H, SMe); 3.92 (s, 3 H, COOMe); 6.71 (s, 1 H, H(6));
1640 (CO), 1596, 1572, 1520
7.48—7.68 (m, 3 H, Ph); 8.45—8.60 (m, 2 H, Ph);
12.32 (br.s, 1 H, NH)
3f
KBr
KBr
3296 (NH), 1720 (COOMe), DMSOꢀd6 2.95 (s, 3 H, Me); 3.94 (s, 3 H, COOMe); 6.70 (s, 1 H, H(6));
1648 (CO), 1576, 1536, 1512 7.61 and 8.46 (both d, 2 H each, Ph, J = 7.5); 12.30 (br.s, 1 H, NH)
3344 (NH), 1728 (COOMe), DMSOꢀd6 2.98 (s, 3 H, Me); 3.96 (s, 3 H, COOMe);
3g
1656 (CO), 1608, 1576,
1544, 1512
6.71 (s, 1 H, H(6)); 8.38 and 8.68
(both d, 2 H each, Ph, J = 8.0)
3495 and 3360 (NH2), 1660 (CO), 1598, 1535. 1H NMR (CDCl3),
δ: 2.63, 2.73 (both s, 3 H each, Me), 6.91 (br.s, 2 H, NH2).
5ꢀAcetylꢀ4ꢀaminoꢀ2ꢀ(4ꢀchlorophenyl)ꢀ6ꢀmethylpyrimidine
(1f). Yield 51%, m.p. 180—181 °C (from benzene). Found (%):
C, 59.64; H, 4.73; N, 16.17. C13H12ClN3O. Calculated (%):
C, 59.66; H, 4.62; N, 16.06. IR (CHCl3), ν/cm–1: 3504 and
reagents. The obtained results confirmed that 5ꢀacetylꢀ4ꢀ
aminopyrimidines are effective for use in construction of
fused heterocyclic systems.
Experimental
1
3360 (NH2), 1648 (CO), 1584, 1544. H NMR (DMSOꢀd6), δ:
2.52, 2.58 (both s, 3 H each, Me); 7.54 (br.s, 2 H, NH2); 7.61
1
H NMR spectra were recorded on a Brucker WMꢀ250 inꢀ
strument. IR spectra were recorded on a Specord Mꢀ80 instruꢀ
ment. Mass spectra were obtained with a Kratos MSꢀ30 instruꢀ
ment (EI, 70 eV, ionization chamber temperature 250 °C, direct
inlet of samples).
Substituted 5ꢀacetylꢀ4ꢀaminopyrimidines 1a—c,e were preꢀ
pared according to the known procedures.13—15
Synthesis of 5ꢀacetylꢀ4ꢀaminoꢀ6ꢀmethylpyrimidines (1d,f,g)
(general procedure). A mixture of a corresponding Nꢀcyanoꢀ
amidine (5.0 mmol) and Ni(OAc)2 (5.0 mmol) in 12 mL of
acetylacetone was stirred at 130—140 °C for 5 h. The solvent
was evaporated in vacuo, and the residue was chromatographed
on SiO2 in C6H6 (for 1d) or CHCl3 (for 1f,g). The solvent was
removed in vacuo, and the residue was recrystallized from an
appropriate solvent.
and 8.42 (both d, 2 H each, Ph, J = 7.5 Hz).
5ꢀAcetylꢀ4ꢀaminoꢀ6ꢀmethylꢀ2ꢀ(4ꢀnitrophenyl)pyrimidine
(1g). Yield 66%, m.p. 175—176 °C (from benzene). Found (%):
C, 57.50; H, 4.61; N, 21.12. C13H12N4O3. Calculated (%):
C, 57.35; H, 4.44; N, 20.58. IR (CHCl3), ν/cm–1: 3504 and
3352 (NH2), 1652 (CO), 1588, 1540. 1H NMR (CDCl3), δ:
2.64, 2.78 (both s, 3 H each, Me); 6.85 (br.s, 2 H, NH2); 8.30
and 8.60 (both d, 2 H each, Ph, J = 8.0 Hz).
Ethyl 5ꢀoxoꢀ5,8ꢀdihydropyrido[2,3ꢀd]pyrimidineꢀ7ꢀcarboxyꢀ
lates (2a,b). Ethyl oxalate (6.0 mmol) and EtONa (7.2 mmol) in
5 mL of EtOH were added to pyrimidine 1a or 1b (2.0 mmol) in
6 mL of anhydrous EtOH. The homogeneous reaction mixture
was stirred at 20 °C for 2 h (in the case of compound 2b, a
precipitate of its sodium salt was formed), acidified with AcOH
to pH ∼6.0, and stirred at ∼20 °C for an additional 15 min. The
precipitate that formed was filtered off, washed with water, and
dried to give compounds 2a,b (their yields, melting points, and
5ꢀAcetylꢀ4ꢀaminoꢀ6ꢀmethylꢀ2ꢀtrichloromethylpyrimidine (1d).
Yield 78%, m.p. 133—134 °C (from hexane). Found (%): C, 36.29;
H, 3.10; Cl, 39.88; N, 15.87. C8H8Cl3N3O. Calculated (%):
C, 35.75; H, 2.98; Cl, 39.66; N, 15.64. IR (CHCl3), ν/cm–1
:
spectroscopic data are given in Tables 1 and 2).

1878
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 10, October, 2002
Komkov and Dorokhov
Methyl 5ꢀoxoꢀ5,8ꢀdihydropyrido[2,3ꢀd]pyrimidineꢀ7ꢀcarbꢀ
oxylates (3a—d). Esters 3a—d were obtained analogously from
pyrimidines 1a—d, ethyl oxalate, and MeONa in MeOH. In the
case of pyrimidines 1c,d, the filtrate was concentrated in vacuo,
and water (10 mL) was added. The product was extracted with
chloroform (2×20 mL), and the organic layer was concentrated.
The residue was recrystallized from MeCN to give additional
amounts of esters 3c,d. Their yields, melting points, and specꢀ
troscopic data are given in Tables 1 and 2.
Methyl 5ꢀoxoꢀ5,8ꢀdihydropyrido[2,3ꢀd]pyrimidineꢀ7ꢀcarꢀ
boxylates (3e—g). Ethyl oxalate (12.0 mmol) and MeONa
(14.4 mmol) in 10 mL of MeOH were added to a pyrimidine
(1e—g) (2.0 mmol) in 8 mL of anhydrous MeOH. The reaction
mixture was refluxed for 30 min and then stirred at ∼20 °C for
12 h. The resulting heterogeneous mixture was acidified with
AcOH and stirred at ∼20 °C for 30 min. The precipitate that
formed was filtered off, washed with water, dried, and refluxed
with MeCN (10 mL) to eliminate the unreacted pyrimidines
1e—g. After the mixture was cooled to ∼20 °C, the precipitate
was filtered off to give esters 3e—g (their yields, melting points,
and spectroscopic data are given in Tables 1 and 2).
3.17 (all s, 3 H each, Me); 6.99 (br.s, 2 H, NH2); 7.45—7.55,
7.55—7.65 (both m, 3 H each, Ph); 7.61 (s, 1 H, H(6));
8.32—8.42, 8.52—8.65 (both m, 2 H each, Ph).
References
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Conversion of ethyl ester 2b into methyl ester 3b. A mixture
of ethyl ester 2b (0.155 g, 0.5 mmol) and MeONa (1.5 mmol) in
6 mL of MeOH was stirred at ∼20 °C for 2 h and acidified with
AcOH. The precipitate that formed was filtered off and washed
with MeOH (3 mL) to give ester 3b (0.11 g, 77%). The product
has the same melting point and 1H NMR spectrum as comꢀ
pound 3b synthesized from pyrimidine 1b and ethyl oxalate.
7ꢀ(4ꢀAminoꢀ2,6ꢀdimethylpyrimidinꢀ5ꢀyl)ꢀ2,4,5ꢀtrimethylꢀ
pyrido[2,3ꢀd]pyrimidine (4a). A mixture of pyrimidine 1a
(0.413 g, 2.5 mmol) and EtONa (2.5 mmol) in 8 mL of EtOH
was refluxed 6 h and then cooled to ∼20 °C. The precipitate that
formed was filtered off and washed with EtOH (5 mL) to give
compound 4a (0.279 g, 76%), m.p. 327—328 °C (decomp.).
Found (%): C, 64.92; H, 6.47; N, 29.08. C16H18N6. Calculated
(%): C, 65.28; H, 6.16; N, 28.55. MS, m/z (Irel (%)): 294 [M]+
(63), 293 [M – H]+ (100), 279 [M – Me]+ (98). IR (KBr),
ν/cm–1
:
3352 and 3304 (NH2), 1592, 1556. 1H NMR
(DMSOꢀd6), δ: 2.15, 2.37, 2.70, 2.91, 3.04 (all s, 3 H each, Me);
6.76 (br.s, 2 H, NH2); 7.52 (s, 1 H, H(6)).
7ꢀ(4ꢀAminoꢀ6ꢀmethylꢀ2ꢀphenylpyrimidinꢀ5ꢀyl)ꢀ4,5ꢀdimethylꢀ
2ꢀphenylpyrido[2,3ꢀd]pyrimidine (4b) was synthesized analoꢀ
gously from pyrimidine 1b. The yield of compound 4b was 85%,
m.p. 247—248 °C. Found (%): C, 74.38; H, 5.22; N, 20.12.
C26H22N6. Calculated (%): C, 74.62; H, 5.30; N, 20.08. MS,
m/z (Irel (%)): 418 [M]+ (68), 417 [M – H]+ (83), 403 [M – Me]+
(98), 104 [PhC=NH]+ (100). IR (KBr), ν/cm–1: 3384 and 3300
1
(NH2), 1624, 1592, 1540. H NMR (DMSOꢀd6), δ: 2.32, 2.92,
Received April 24, 2002