Annulation of a pyridine ring with vicinal ethoxycarbonyl(methyl) pyrimidines

Article abstract of DOI:10.1007/s11172-009-0273-2

Pyridoannulation of 5-ethoxycarbonyl-4-methylpyrimidine and 7-methyl-6-ethoxy-carbonyl[1,2,4]triazolo[1,5-a]pyrimidine derivatives has been studied.

Full text of DOI:10.1007/s11172-009-0273-2

Russian Chemical Bulletin, International Edition, Vol. 58, No. 9, pp. 1996—1999, September, 2009
1996
Brief Communications
Annulation of a pyridine ring with
vicinal ethoxycarbonyl(methyl)pyrimidines
Kh. S. Shikhaliev, A. Yu. Potapov, E. L. Polukhin, and A. I. Slivkin
Voronezh State University,
1 Universitetskaya pl., 394006 Voronezh, Russian Federation.
Eꢀmail: chocd261@chem.vsu.ru
Pyridoannulation of 5ꢀethoxycarbonylꢀ4ꢀmethylpyrimidine and 7ꢀmethylꢀ6ꢀethoxyꢀ
carbonyl[1,2,4]triazolo[1,5ꢀa]pyrimidine derivatives has been studied.
Key words: vicinal ethoxycarbonyl(methyl)pyrimidine, dimethylformamide dimethyl
acetal, 4ꢀ(2ꢀdimethylaminovinyl)ꢀ5ꢀethoxycarbonylpyrimidines, (E)ꢀ7ꢀ(2ꢀdimethylaminoꢀ
vinyl)ꢀ6ꢀethoxycarbonyl[1,2,4]triazolo[1,5ꢀa]pyrimidines, amines, enamines, annulation,
pyridopyrimidines.
2ꢀphenylpyrazolopyrimidine derivatives5 with the use of
It has been previously shown that vicinal alkoxyꢀ
carbonyl(methyl)pyrimidines are convenient precursors
for the design of pyridine rings. Thus condensation of
2ꢀsubstituted 5ꢀmethoxycarbonylꢀ4ꢀmethylꢀpyrimidines1
with primary amines and dimethylformamide furnished
dihydropyridopyrimidinones (via carboxamide intermeꢀ
diates). Cyclization of 2,4ꢀdimethoxyꢀ5ꢀmethoxycarbonylꢀ
6ꢀmethylpyrimidine with Schiff bases resulted in tetraꢀ
hydropyridopyrimidines, which were converted to dihydroꢀ
pyridopyrimidinones by treatment with Nꢀbromosucꢀ
cinimide.2 This approach toward pyrido[4,3ꢀd]pyrimidine
construction was used for the synthesis of 6ꢀRꢀ4ꢀaminoꢀ
7ꢀhydroxyꢀ2ꢀphenylpyrido[4,3ꢀd]pyrimidinꢀ5ꢀones.3
A convenient preparative method for the synthesis of
1,6ꢀnaphthyridines has been developed. The procedure
involved pyridoannulation of 3,5ꢀdiethoxycarbonylꢀ2,6ꢀ
dimethylpyridine4 and 6ꢀethoxycarbonylꢀ7ꢀmethylꢀ
dimethylformamide dimethyl acetal. In the present work,
this method was successfully extended to 2ꢀaminosubꢀ
stituted pyrimidines (Scheme 1), as well as to fused
triazolopyrimidines (Scheme 2).
The first step of pyridoannulation was the reaction
of vicinal ethoxycarbonyl(methyl)pyrimidines (1a—d,
6a—d) with dimethylformamide dimethyl acetal (2). It
was found that optimum reaction conditions are refluxing
of the reactants in the minimum amount of DMF. The
reaction resulted in 4ꢀ(2ꢀdimethylaminovinyl)ꢀ5ꢀethoxyꢀ
carbonyl pyrimidines (3a—d) and (E)ꢀ7ꢀ(2ꢀdimethylꢀ
aminovinyl)ꢀ6ꢀethoxycarbonyl[1,2,4]triazolo[1,5ꢀa]pyriꢀ
midines 7a—d. The reaction proceeded more readily in
the case of triazolopyrimidines 6a—d due to high CHꢀ
acidity of the methyl group (the triazole moiety effect),
and low solubility of the resulting enamines 7a—d.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1934—1937, September, 2009.
1066ꢀ5285/09/5809ꢀ1996 © 2009 Springer Science+Business Media, Inc.

Pyridoannulation
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009 1997
Scheme 1
1, 3, 5: R1+ R2 = CH2—CH2—O—CH2—CH2 (a), CH2—CH2—N(Me)—CH2—CH2 (b), (CH2)5 (c), R1 = Ph, R2 = H (d),
R3 = CH2—CH2—Ph (4b, 5a,c), CH2—CH2—O—Me (4d, 5b,d)
Scheme 2
R = H (6a, 7a, 8a, 8e, 8f), Me (6b, 7b, 8b), CF3 (6c, 7c, 8c), Ph (6d, 7d, 8d, 8g)
R3 = H (4a, 8a), CH2—CH2—Ph (4b, 8b), Ph (4c, 8c), CH2—CH2—O—Me (4d, 8d), Me (4e, 8e), OH (4f, 8f), MeCH2CHCOOH (4g, 8g)
The second step involved cyclization of enamines
3a—d, 7a—d with a series of primary amines. Isolation
and purification of 4ꢀ(2ꢀdimethylaminovinyl)ꢀ5ꢀethoxyꢀ
carbonylpyrimidines 3a—d was very difficult due to their
excellent solubility. Therefore, they were used in cyclizaꢀ
tion with amines without isolation and characterization.
It was found that optimum conditions for the cyclization
of (E)ꢀ7ꢀ(2ꢀdimethylaminovinyl)ꢀ6ꢀethoxycarbonyl[1,2,4]ꢀ
triazolo[1,5ꢀa]pyrimidines 7a—d is refluxing in glacial
acetic acid, which being an acceptor of dimethylamine
(eliminated in the course of the reaction) shifted the equiꢀ
librium toward the product formation. For the synthesis
of 7ꢀmethylꢀ6,7ꢀdihydropyrido[3,4ꢀe][1,2,4]triazolo[1,5ꢀa]ꢀ
pyrimidinꢀ6ꢀone (8e) and 7ꢀhydroxyꢀ6,7ꢀdihydropyridoꢀ
[3,4ꢀe]triazolo[1,2,4][1,5ꢀa]pyrimidinꢀ6ꢀone (8f), methyꢀ
lamine and hydroxylamine were used as hydrochlorides
without hydrogen chloride acceptors. Enamines 7a—d are
yellow crystalline compounds insoluble in hydrocarbons
and alcohols and well soluble in chloroform. Pyridoꢀ
pyrimidines 5a—d and 8a—g are white solids soluble in
and dimethylamino groups present in the spectra of
enamines 7a—d.
The structures of the compounds synthesized were
established based on the data from 1H NMR spectroscopy
and mass spectrometry and confirmed by elemental analyꢀ
sis data.
Experimental
The course of the reaction as well as the purity of the
compounds synthesized was monitored by TLC on precoated
silica gel Silufol UVꢀ254 plates. The 1H NMR spectra were
recorded on a Bruker ACꢀ300 instrument (300 MHz) relative to
Me4Si (internal standard), DMSOꢀd6 was used as a solvent. The
mass spectra were run on a LKB 9000 instrument (70 eV).
The starting ethoxycarbonyl(methyl)pyrimidines 1, 6a—d
were synthesized according to the known procedure.6
5,6ꢀDihydropyrido[4,3ꢀd]pyrimidinꢀ5ꢀones 5a—d (general
procedure). A mixture of 5ꢀethoxycarbonylꢀ4ꢀmethylpyrimidine
1a—d (4 mmol) and dimethylformamide dimethyl acetal 2
(4.3 mmol) in DMF (3 mL) was refluxed for 2—4 h until
complete conversion of 1a—d into enamine 3a—d (TLC). Then
amine 4b,d was added and refluxing was continued for 3 h. The
mixture was cooled, the resulting precipitate was filtered off,
washed with PriOH and recrystallized from DMF.
1
DMF and DMSO with heating. The H NMR spectra of
compounds 5a—d and 8a—g exhibited signals for two pyriꢀ
dine protons, which appeared as two doublets (δ 6.18—7.24
and δ 7.59—8.49). The 1H NMR spectra of 8a—g
were devoid of the characteristic signals for the ethoxy
2ꢀMorpholinoꢀ6ꢀphenethylꢀ5,6ꢀdihydropyrido[4,3ꢀd]pyriꢀ
midinꢀ5ꢀone (5a). Yield 65%, m.p. 145—146 °C. 1H NMR, δ:

1998
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009
Shikhaliev et al.
2.95 (t, 2 H, CH2Ph, J = 8 Hz); 3.67 (m, 4 H, CH2NCH2
morph., J = 12 Hz); 3.83 (m, 4 H, CH2OCH2 morph., J = 12 Hz);
4.10 (t, 2 H, CH2, J = 8 Hz); 6.18 (d, 1 H, H pyrid., J = 7 Hz);
7.20 (m, 3 H, aryl); 7.28 (m, 2 H, arom.); 7.59 (m, 1 H,
H pyrid.); 9.1 (s, 1 H, H pyrimid.). MS, m/z 336 [M]+. Found (%):
C, 67.54; H, 5.78; N, 16.80. C19H20N4O2. Calculated (%):
C, 67.84; H, 5.99; N, 16.65.
C, 47.49; H, 4.32; N, 21.23. C13H14F3N5O2. Calculated (%):
C, 47.42; H, 4.29; N, 21.27.
(E)ꢀ7ꢀ(2ꢀDimethylaminovinyl)ꢀ6ꢀethoxycarbonylꢀ2ꢀphenylꢀ
[1,2,4]triazolo[1,5ꢀa]pyrimidine (7d). Yield 95%, m.p. 247—
248 °C. 1H NMR, δ: 1.07 (t, 3 H, CH2CH3, J = 8 Hz);
3.06, 3.30 (both s, each 3 H, N(CH3)2); 3.85 (m, 2 H, CH2CH3,
J = 8 Hz); 6.82 (d, 1 H, CH, J = 13 Hz); 7.48 (m, 3 H, arom.);
8.29 (m, 2 H, arom.); 8.50 (s, 1 H, H pyrim.); 9.40 (d, 1 H, CH,
J = 13 Hz). MS, m/z 337 [M]+. Found (%): C, 64.11; H, 5.65;
N, 20.73. C18H19N5O2. Calculated (%): C, 64.08; H, 5.68;
N, 20.76.
6,7ꢀDihydropyrido[3,4ꢀe][1,2,4]triazolo[1,5ꢀa]pyrimidinꢀ
6ꢀones 8a—g (general procedure). A mixture of (E)ꢀ7ꢀ(2ꢀdiꢀ
methylaminovinyl)ꢀ6ꢀethoxycarbonyl[1,2,4]triazolo[1,5ꢀa]ꢀ
pyrimidine 7a—d (4 mmol) and amine 4a—g (4 mmol) in glacial
acetic acid (5 mL) was refluxed for 30 min. The reaction mixture
was cooled, the resulting precipitate was filtered off and washed
with water to give compounds 8a—g.
6ꢀ(2ꢀMethoxyethyl)ꢀ2ꢀ(4ꢀmethylpiperazino)ꢀ5,6ꢀdihydroꢀ
pyrido[4,3ꢀd]pyrimidinꢀ5ꢀone (5b). Yield 77%, m.p. 159—160 °C.
1H NMR, δ: 2.30 (s, 3 H, CH3); 3.35 (s, 3 H, CH3O); 3.68 (t,
2 H, CH2O, J = 8 Hz); 3.82 (m, 4 H, CH2N(Me)CH2 piperaz.);
3.95 (m, 4 H, CH2NCH2 piperaz.); 4.08 (t, 2 H, CH2, J = 8 Hz);
6.21 (d, 1 H, H pyrid., J = 7 Hz); 7.26 (m, 3 H, arom.); 7.29 (m,
2 H, arom.); 7.60 (m, 1 H, H pyrid.); 9.05 (s, 1 H, H pyrimid.).
MS, m/z 303 [M]+. Found (%): C, 59.46; H, 7.00; N, 23.02.
C15H21N5O2. Calculated (%): C, 59.39; H, 6.98; N, 23.09.
6ꢀPhenethylꢀ2ꢀpiperidinoꢀ5,6ꢀdihydropyrido[4,3ꢀd]pyriꢀ
midinꢀ5ꢀone (5c). Yield 65%, m.p. 137—138 °C. 1H NMR, δ:
1.42—1.69 (m, 6 H, CH2CH2CH2,.); 2.93 (t, 2 H, CH2Ph,
J = 8 Hz); 3.62 (m, 4 H, CH2NCH2 piperid.); 4.09 (t, 2 H, CH2,
J = 7 Hz); 6.14 (d, 1 H, H pyrid., J = 8 Hz); 7.18 (m, 3 H, aryl);
7.25 (m, 2 H, arom.); 7.57 (m, 1 H, H pyrid.); 9.03 (s, 1 H,
H pyrimid.). MS, m/z 334 [M]+. Found (%): C, 71.51; H, 6.43;
N, 16.88. C20H24N4O. Calculated (%): C, 71.83; H, 6.63; N, 16.75.
2ꢀAnilinoꢀ6ꢀ(2ꢀmethoxyethyl)ꢀ5,6ꢀdihydropyrido[4,3ꢀd]ꢀ
pyrimidinꢀ5ꢀone (5d). Yield 60%, m.p. 219—221 °C. 1H NMR,
δ: 3.34 (s, 3 H, CH3O); 3.70 (t, 2 H, CH2O, J = 8 Hz); 4.33 (t,
2 H, CH2, J = 8 Hz); 7.11 (d, 1 H, H pyrid., J = 7 Hz); 7.36 (m,
3 H, arom.); 7.41 (m, 2 H, arom.); 7.59 (m, 1 H, H pyrid.); 8.12
(s, 1 H, NH); 9.10 (s, 1 H, H pyrimid.). MS, m/z 296 [M]+.
Found (%):C, 64.83; H, 5.41; N, 18.94. C16H16N4O2. Calcuꢀ
lated (%): C, 64.85; H, 5.44; N, 18.91.
6,7ꢀDihydropyrido[3,4ꢀe][1,2,4]triazolo[1,5ꢀa]pyrimidinꢀ
1
6ꢀone (8a). Yield 75%, m.p. 251—253 °C. H NMR, δ: 7.05 (d,
1 H, H pyrid., J = 7 Hz); 8.02 (d, 1 H, H pyrid., J = 7 Hz); 8.75
(s, 1 H, H triaz.); 9.30 (s, 1 H, H pyrimid.); 12.40 (br.s, 1 H, NH).
MS, m/z 187 [M]+. Found (%): C, 51.40; H, 2.66; N, 37.43.
C8H5N5O. Calculated (%): C, 51.34; H, 2.69; N, 37.42.
2ꢀMethylꢀ7ꢀphenethylꢀ6,7ꢀdihydropyrido[3,4ꢀe][1,2,4]triꢀ
azolo[1,5ꢀa]pyrimidinꢀ6ꢀone (8b). Yield 85%, m.p. 241—242 °C.
1H NMR, δ: 2.05 (s, 3 H, CH3); 3.04 (t, 2 H, CH2Ph, J = 8 Hz);
4.28 (t, 2 H, CH2, J = 8 Hz); 7.03 (d, 1 H, H pyrid., J = 7 Hz);
7.21—7,32 (m, 5 H, arom.); 8.15 (d, 1 H, H pyrid., J = 7 Hz);
9.33 (s, 1 H, H pyrimid.). MS, m/z 305 [M]+. Found (%):
C, 66.45; H, 4.75; N, 23.02. C16H13N5O. Calculated (%):
C, 66.87; H, 4.95; N, 22.94.
(E)ꢀ7ꢀ(2ꢀDimethylaminovinyl)ꢀ6ꢀethoxycarbonyl[1,2,4]ꢀ
triazolo[1,5ꢀa]pyrimidines 7a—d (general procedure). A mixture
of 6ꢀethoxycarbonylꢀ7ꢀmethyl[1,2,4]triazolo[1,5ꢀa]pyrimidine
6a—d (5 mmol) and dimethylformamide dimethyl acetal 2
(5.5 mmol) in DMF (5 mL) was refluxed for 20 min. The
precipitate that formed was filtered off and recrystallized
from DMF.
7ꢀPhenylꢀ2ꢀtrifluoromethylꢀ6,7ꢀdihydropyrido[3,4ꢀe][1,2,4]ꢀ
triazolo[1,5ꢀa]pyrimidinꢀ6ꢀone (8c). Yield 88%, m.p. 257—
259 °C. 1H NMR, δ: 7.12 (d, 1 H, H pyrid., J = 7 Hz);
7.50—7.62 (m, 5 H, arom.); 8.30 (d, 1 H, H pyrid., J = 7 Hz);
9.35 (s, 1 H, H pyrimid.). MS, m/z 331 [M]+. Found (%):
C, 54.43; H, 2.41; N, 21.16. C15H8F3N5O. Calculated (%):
C, 54.39; H, 2.43; N, 21.14.
(E)ꢀ7ꢀ(2ꢀDimethylaminovinyl)ꢀ6ꢀethoxycarbonyl[1,2,4]ꢀ
triazolo[1,5ꢀa]pyrimidine (7a). Yield 95%, m.p. 238—239 °C.
1H NMR, δ: 1.05 (t, 3 H, CH2CH3, J = 8 Hz); 3.05, 3.30
(both s, each 3 H, N(CH3)2); 3.83 (m, 2 H, CH2CH3); 6.72 (d,
1 H, CH, J = 13 Hz); 8.50 (s, 1 H, pyrimid.); 8.88 (s, 1 H, triaz.);
9.41 (d, 1 H, CH, J =13 Hz). MS, m/z 261 [M]+. Found (%):
C, 55.27; H, 5.61; N, 27.25. C12H15N5O2. Calculated (%):
C, 55.16; H, 5.79; N, 26.80.
7ꢀ(2ꢀMethoxyethyl)ꢀ2ꢀphenylꢀ6,7ꢀdihydropyrido[3,4ꢀe]ꢀ
[1,2,4]triazolo[1,5ꢀa]pyrimidinꢀ6ꢀone (8d). Yield 91%,
m.p. 211—212 °C. 1H NMR, δ: 3.28 (s, 3 H, CH3O), 3.65 (t,
2 H, CH2O, J = 8 Hz); 4.25 (t, 2 H, CH2, J = 8 Hz); 7.15 (d,
1 H, H pyrid., J = 7 Hz); 7.50 (m, 3 H, arom.); 8.11 (d, 1 H,
H pyrid., J = 7 Hz); 8.30 (m, 2 H, arom.); 9.44 (s, 1 H, H pyrimid.).
MS, m/z 321 [M]+. Found (%): C, 63.59; H, 4.68; N, 21.73.
C17H15N5O2. Calculated (%): C, 63.54; H, 4.71; N, 21.79.
7ꢀMethylꢀ6,7ꢀdihydropyrido[3,4ꢀe]triazolo[1,2,4][1,5ꢀa]ꢀ
pyrimidinꢀ6ꢀone (8e). Yield 79%, m.p. 236—237 °C. 1H NMR,
δ: 3.60 (s, 3 H, CH3); 7.07 (d, 1 H, H pyrid., J = 7 Hz); 8.30 (d,
1 H, H pyrid., J = 7 Hz); 8.73 (s, 1 H, H triaz.); 9.43 (s, 1 H,
H pyrimid.). MS, m/z 201 [M]+. Found (%): C, 53.67; H, 3.52;
N, 34.78. C9H7N5O. Calculated (%): C, 53.73; H, 3.51;
N, 34.81.
7ꢀHydroxyꢀ6,7ꢀdihydropyrido[3,4ꢀe][1,2,4]triazolo[1,5ꢀa]ꢀ
pyrimidinꢀ6ꢀone (8f). Yield 63%, m.p. >260 °C (infl.). 1H NMR,
δ: 7.05 (d, 1 H, H pyrid., J = 7 Hz); 8.49 (d, 1 H, H pyrid.,
J = 7 Hz); 8.75 (s, 1 H, H triaz.); 9.48 (s, 1 H, H pyrimid.);
12.28 (br.s, 1 H, OH). MS, m/z 203 [M]+. Found (%): C, 47.25;
H, 2.46; N, 34.43. C8H5N5O2. Calculated (%): C, 47.30;
H, 2.48; N, 34.47.
(E)ꢀ7ꢀ(2ꢀDimethylaminovinyl)ꢀ6ꢀethoxycarbonylꢀ2ꢀmethylꢀ
[1,2,4]triazolo[1,5ꢀa]pyrimidine (7b). Yield 85%, m.p. 205—
1
206 °C. H NMR, δ: 1.03 (t, 3 H, CH2CH3, J = 8 Hz); 2.06 (s,
3 H, CH3); 3.02, 3.29 (both s, each 3 H, N(CH3)2); 3.80 (m,
2 H, CH2CH3); 6.75 (d, 1 H, CH, J = 13 Hz); 8.48 (s, 1 H,
pyrimid.); 9.40 (d, 1 H, CH, J =13 Hz). Ms, m/z 275 [M]+.
Found (%): C, 56.80; H, 6.17; N, 25.50. C13H17N5O2. Calcuꢀ
lated (%): C, 56.72; H, 6.22; N, 25.44.
(E)ꢀ7ꢀ(2ꢀDimethylaminovinyl)ꢀ6ꢀethoxycarbonylꢀ2ꢀtrifuoroꢀ
methyl[1,2,4]triazolo[1,5ꢀa]pyrimidine (7c). Yield 90%,
m.p. 217—218 °C. 1H NMR, δ: 1.08 (t, 3 H, CH2CH3,
J = 8 Hz); 3.05, 3.31 (both s, each 3 H, N(CH3)2); 3.86 (m, 2 H,
CH2CH3); 6.75 (d, 1 H, CH, J =13 Hz); 8.51 (s, 1 H, pyrim.);
9.41 (d, 1 H, CH, J = 13 Hz). MS, m/z 329 [M]+. Found (%):

Pyridoannulation
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009 1999
2ꢀ(6ꢀOxoꢀ2ꢀphenylꢀ6,7ꢀdihydropyrido[3,4ꢀe][1,2,4]triazoloꢀ
[1,5ꢀa]pyrimidinꢀ7ꢀyl)butyric acid (8g). Yield 86%, m.p. 265—
267 °C. 1H NMR, δ: 0.88 (m, 3 H, CH3); 2.05—2.30 (m, 2 H,
CH2); 5.30 (m, 1 H, CH); 7.24 (d, 1 H, H pyrid., J = 7 Hz); 7.55
(m, 3 H, arom.); 8.24 (m, 2 H, arom.); 8.30 (d, 1 H, H pyrid.,
J = 7 Hz); 9.32 (s, 1 H, H pyrimid.); 13.25 (br.s, 1 H, COOH).
MS, m/z 273 [M]+. Found (%): C, 52.82; H, 4.03; N, 25.67.
C12H11N5O3. Calculated (%): C, 52.75; H, 4.06; N, 25.63.
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Received March 26, 2008,
in revised form November 27, 2008