An unequivocal synthesis of 4-methyl-2-oxo-(2H)-pyrido[1,2-a]pyrimidines

Article abstract of DOI:10.1081/SCC-120002513

An unequivocal high yielding synthesis of 4-methyl-2-oxo-(2H)-pyrido[1,2-a]pyrimidines from N-(1,3-dioxobutyl)-2-amino pyridines/picolines/quinoline, is being reported.

Full text of DOI:10.1081/SCC-120002513

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AN UNEQUIVOCAL SYNTHESIS OF 4-METHYL-2-OXO-
(
2H)-PYRIDO- [1,2-a]PYRIMIDINES*
a a a a
O. P. Suri , K. A. Suri , B. D. Gupta & N. K. Satti
a
Natural Product Chemistry Division , Regional Research Laboratory , Jammu, 180 001,
India
Published online: 16 Aug 2006.
To cite this article: O. P. Suri , K. A. Suri , B. D. Gupta & N. K. Satti (2002) AN UNEQUIVOCAL SYNTHESIS OF 4-METHYL-2-
OXO-(2H)-PYRIDO- [1,2-a]PYRIMIDINES*, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 32:5, 741-746, DOI: 10.1081/SCC-120002513
To link to this article: http://dx.doi.org/10.1081/SCC-120002513
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SYNTHETIC COMMUNICATIONS, 32(5), 741–746 (2002)
AN UNEQUIVOCAL SYNTHESIS
OF 4-METHYL-2-OXO-(2H)-PYRIDO-
[
1,2-a]PYRIMIDINES*
y
O. P. Suri, K. A. Suri, B. D. Gupta, and N. K. Satti
Natural Product Chemistry Division,
Regional Research Laboratory, Jammu-180 001, India
ABSTRACT
An unequivocal high yielding synthesis of 4-methyl-2-oxo-
(2H)-pyrido[1,2-a]pyrimidines from N-(1,3-dioxobutyl)-2-
amino pyridines/picolines/quinoline, is being reported.
Recently, we have observed that aryl and hetaryl amines get aceto-
l
acetylated on microwave assisted interaction with ethyl acetoacetate. The
N-(1,3-dioxobutyl)-2-aminopyridines/quinoline have been subjected to PPA
catalysed cyclization to get 2-oxo-(2H)-pyrido[1,2-a]pyrimidines in appreci-
able yields. This constitutes first report about unequivocal synthesis of
4-methyl-2-oxo-(2H)-pyrido[1,2-a]pyrimidines by interaction of b-oxoester
and 2-amino pyridines/picolines/quinoline. Earlier reported syntheses of title
compounds are poor yielding and in some cases the synthesized compounds
2
were later reassessed to be 4-oxo-(4H)-isomers.
3
In one of the reports, it was claimed that 2-oxo-(2H)-pyrido[1,2-a]-
pyrimidines are produced by interaction of 2-amino-4-methyl pyridines
*
RRL Communication No. 2336
Corresponding author.
y
7
41
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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SURI ET AL.
and ethyl ethoxymethylenecyanoacetate; however, the products were later
determined to be 4-oxo-isomers. Another poor yielding synthesis of 2-oxo-
(
2H)-pyrido[1,2-a]pyrimidines involved interaction of 2-aminopyrimidines
4
and an acid chloride. The therapeutic potential of 2-oxo-(2H)-pyrido[1,2-a]-
pyrimidines has not been explored vis-a-vis 4-oxo-(4H)-isomers, some of
which viz., pemirolast, pirenperone, metrenperone, risperidone, are
already in clinical use, in all probability, due to lack of sound synthetic
procedures.
In the present communication 4-methyl-2-oxo-(2H)-pyrido[1,2-a]-
pyrimidines have been synthesised via N-acetoacetylated products obtained
by microwave assisted condensation of 2-aminopyridines/picolines/
1
13
quinoline. The synthetics have been characterised by H-NMR, C-NMR
CPD, HOMOCOR and HETCOR), MS, IR spectroscopy and elemental
analytical data.
An important observation recorded on examination of HOMOCOR &
(
HETCOR spectra of the compounds was the effect of C-4 methyl on
chemical shifts of C-6 and its a-proton. In all the endproducts, C6-H, as
expected, was the most deshielded one and the C-6 possessed lower chemical
shift in comparison to C-8 except in compound 2, where C-6 is of quater-
nary character. The abnormal shielding of C-6, in spite of being attached to
nitrogen, can be easily attributed to peri-effect of C-4 methyl group.
EXPERIMENTAL
Melting points were determined in open capillaries, and are uncor-
rected. Mass spectra were recorded on JEOL JMS D-300 mass spectrometer
at 70 eV and IR spectra on Hitachi 270-30 spectrophotometer. NMR spectra
were recorded on Bruker DPX-200 spectrometer. Elemental analytical data
have been determined on Carlo Erba, Model 1106, elemental analyzer.
General Procedure
Phosphorous pentoxide and orthophosphoric acid in the ratio of w/v
3.5 g : 1.3 ml) were taken in a round bottomed flask fitted with a reflux
(
condenser and a guard tube. The mixture was heated for 4 h on a steam
bath with frequent shaking. The resulting PPA was used for the cyclization
reactions.
A mixture of N-acetoacetylated product obtained by microwave
assisted condensation of 2-amino pyridines/picolines/quinoline and PPA
in the ratio of 1 : 10 w/w was taken in a round bottomed flask fitted with

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-METHYL-2-OXO-(2H)-PYRIDO[1,2-a]PYRIMIDINES
743
a reflux condenser and a guard tube. The reaction mixture was heated
on steam bath with frequent shaking. The progress of the reaction was
monitored on TLC. After completion of the reaction, the reaction mixture
was diluted with distilled H O (20 ml), basified with ammonia solution
2
and then extracted with CHCl (5 ꢀ 50 ml). CHCl extract was dried over
3
3
anhy. Na SO and concentrated under reduced pressure. The products
2
4
were purified by filtration through a small silica gel column, using chloro-
Table. PPA Catalysed Cyclization of N-(1,3-Dioxobutyl)-2 Amino
Pyridines/Picolines/Quinoline

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44
SURI ET AL.
form : methanol (99 : 1) as eluant. TLC homogeneous fractions were crystal-
ꢁ
lised from pet. ether (60–80 ) in 52–72% yield (Table).
Spectral Data of Cyclised Products
4-Methyl-2-oxo-(2H)-pyrido[1,2-a]pyrimidine
1
IR (KBr): 1700 (CO), 1630 (C¼N); H NMR (CDCl ): d 2.47 (s, 3H,
3
CH ), 6.35 (s, 1H, H-3), 7.13 (dt, 1H, J ¼ 7.12 and 1.28 Hz, H-7), 7.60
3
(
(
bd, 1H, J ¼ 7.12 Hz, H-9), 7.74 (dt, 1H, J ¼ 7.12 and 1.28 Hz, H-8), 9.03
þ
bd, 1H, J ¼ 7.12 Hz, H-6); MS (m/z) M : 160, calcd for C H N O; C, 67.50;
9
8
2
1
3
H, 5.00; N, 17.50; found: C, 67.45; H, 5.09; N, 17.42%; C NMR: d 25.00
(
CH ), 103.63 (C-3), 115.39 (C-7), 126.14 (C-9), 127.56 (C-6), 136.61 (C-8),
3
151.06 (C-4), 158.18 (C-10), 165.62 (C-2).
4,6-Dimethyl-2-oxo-(2H)-pyrido[1,2-a]pyrimidine
1
IR (KBr): 1692 (CO), 1636 (C¼N); H NMR (CDCl ): d 2.35 (s, 3H,
3
C4-CH ), 3.03 (s, 3H, C6-CH ), 6.14 (s, 1H, H-3), 6.62 (dd, 1H, J ¼ 6.58 and
3
3
1
.26 Hz, H-9), 7.32 (dd, 1H, J ¼ 6.58 and 1.26 Hz, H-7), 7.42 (dd, 1H,
þ
J ¼ 6.58 Hz, H-8); MS (m/z) M : 174, calcd for C H N O; C, 68.96;
1
0
10
2
1
3
H, 5.74; N, 16.09; found: C, 68.92; H, 5.77; N, 15.96%; C NMR: d 24.16
(
(
C4-CH ), 25.09 (C6-CH ), 105.99 (C-3), 118.26 (C-9), 125.08 (C-7), 135.54
C-8), 144.29 (C-6), 153.61 (C-4), 162.43 (C-10), 163.75 (C-2).
3 3
4,7-Dimethyl-2-oxo-(2H)-pyrido[1,2-a]pyrimidine
1
IR (KBr): 1686 (CO), 1638 (C¼N); H NMR (CDCl ): d 2.42 (s, 3H,
3
C4-CH ), 2.45 (s, 3H, C7-CH ), 6.32 (s, 1H, H-3), 7.52 (d, 1H, J ¼ 9.04 Hz,
3
3
H-9), 7.60 (dd, 1H, J ¼ 9.04 and 1.25 Hz, H-8), 8.85 (bs, 1H, H-6); MS (m/z)
þ
M : 174, calcd for C H N O; C, 68.96; H, 5.74; N, 16.09; found; C, 68.84;
10
1
0
2
1
3
H, 5.79; N, 16.01%; C NMR: d 18.66 (C7-CH ), 24.98 (C4-CH ), 103.45
3
3
(
C-3), 116.96 (C-7), 125.06 (C-6), 125.65 (C-9), 139.54 (C-8), 150.07 (C-4),
158.16 (C-10), 165.12 (C-2).

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-METHYL-2-OXO-(2H)-PYRIDO[1,2-a]PYRIMIDINES
745
4,8-Dimethyl-2-oxo-(2H)-pyrido[1,2-a]pyrimidine
1
IR (KBr): 1706 (CO), 1642 (C¼N); H NMR (CDCl ): d 2.45 (s, 3H,
3
C4-CH ), 2.48 (s, 3H, C8-CH ), 6.27 (s, 1H, H-3), 6.95 (dd, 1H, J ¼ 7.27 and
3
3
1
.29 Hz, H-7), 7.38 (bs, 1H, H-9), 8.92 (d, 1H, J ¼ 7.27 Hz, H-6); MS (m/z)
þ
M : 174, calcd for C H N O; C, 68.96; H, 5.74; N, 16.09; found: C, 68.86;
1
0
10
2
1
3
H, 5.80; N, 16.13%; C NMR: d 21.81 (C8-CH ), 25.05 (C4-CH ), 102.82
3
3
(
C-3), 118.13 (C-7), 124.23 (C-9), 126.93 (C-6), 148.81 (C-8), 151.15 (C-4),
158.34 (C-10), 165.91 (C-2).
4,9-Dimethyl-2-oxo-(2H)-pyrido[1,2-a]pyrimidine
1
IR (KBr): 1688 (CO), 1628 (C¼N); H NMR (CDCl ): d 2.47 (s, 3H,
3
C4-CH ), 2.57 (s, 3H, C9-CH ), 6.33 (s, 1H, H-3), 6.99 (dd, 1H, J ¼ 7.12 Hz,
3
3
H-7), 7.55 (bd, 1H, J ¼ 7.12 Hz, H-8), 8.92 (bd, 1H, J ¼ 7.12 Hz, H-6); MS
þ
(
6
1
m/z) M : 174, calcd for C H N O; C, 68.96; H, 5.74; N, 16.09; found: C,
1
0
1
10
2
3
8.83; H, 5.81; N, 16.01%; C NMR: d 18.65 (C9-CH ), 25.27 (C4-CH ),
03.49 (C-3), 114.78 (C-7), 125.71 (C-6), 134.84 (C-9), 135.15 (C-8), 150.68
3
3
(
C-4), 158.84 (C-10), 164.86 (C-2).
7-Chloro-4-methyl-2-oxo-(2H)-pyrido[1,2-a]pyrimidine
1
IR (KBr): 1680 (CO), 1624 (C¼N); H NMR (CDCl ): d 2.47 (s, 3H,
3
CH ), 6.36 (s, 1H, H-3), 7.55 (d, 1H, J ¼ 9.44 Hz, H-9), 7.66 (dd, 1H,
3
þ
J ¼ 9.44 and 2.17 Hz, H-8), 9.05 (d, 1H, J ¼ 2.17 Hz, H-6); MS (m/z) M :
1
3
1
1
94, calcd for C H N OCl; C, 55.67; H, 3.60; N, 14.43; found: C, 55.59; H,
9 7 2
1
3
.53; N, 14.49%; C NMR: d 23.62 (CH ), 102.78 (C-3), 122.59 (C-7),
23.99 (C-6), 125.84 (C-9), 136.35 (C-8), 148.03 (C-4), 155.75 (C-10),
64.17 (C-2).
3
4-Methyl-benzo[f ]-2-oxo-(2H)-pyrido[1,2-a]pyrimidine
1
IR (KBr): 1664 (CO), 1630 (C¼N); H NMR (CDCl ): d 2.39 (s, 3H,
3
CH ), 6.39 (s, 1H, H-3), 7.24 (d, 1H, J ¼ 8.64 Hz, H-11), 7.61 (m, 4H, H-6,
3
þ
H-7, H-8 and H-9), 8.64 (d, 1H, J ¼ 8.64 Hz, H-10); MS (m/z) M : 210,
calcd for C H N O; C, 74.28; H, 4.76; N, 13.33; found: C, 74.21; H, 4.71;
2
1
3
1
10
3
N, 13.38%; C NMR: d 23.85 (CH ), 109.61 (C-3), 122.70 (C-10), 124.68
3
(
C-11), 125.20 (C-9a), 127.19 (C-6), 128.45 (C-8), 130.05 (C-7), 135.84, (C-
4), 136.90 (C-9), 151.47 (C-5a), 162.19 (C-11a), 163.67 (C¼O).

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SURI ET AL.
REFERENCES
1
2
. Suri, O.P.; Satti, N.K.; Suri, K.A. Synth. Commun. 2000, 30, 3709.
. Jahine, H.; Zaher, H.A.; Sherif, O.; Fawzy, M.M. Indian J. Chem. 1978,
6(B), 889.
1
3
4
. Antaki, M. J. Am. Chem. Soc. 1958, 80, 3066.
. Tkachenko, P.V.; Simonov, A.M.; Popov, I.I. Khim. Geterotsikl.
Soedin. 1978, 1, 90 (CA 1978, 88, 190727).
Received in the UK January 4, 2001

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