Synthesis of halogenated 4H-pyrido[1,2-a]pyrimidin-4-ones

Article abstract of DOI:10.3987/COM-09-11746

Halogenated 4H-pyrido[l,2-a]pyrimidin-4-one were synthesized by thermal cyclization and decarboxylation of isopropylidene (2-pyridylamino)methylenemalonates, prepared from 2-aminopyridines and isopropylidene methoxymethylenemalonate formed in situ. Instead of 4H-pyrido[l,2-a]pyrimidin-4-ones, the 6-chloro and 6-bromo derivatives afforded mixtures of 7-halo-l,4-dihydro-l,8-naphthyridin-4-ones and 1-(6-halo-2-pyridyl)-3-[(6-halo-2-pyridylamino)methylene]-1,2,3,4-tetrahydropyridine-2,4-diones. The latters formed from N-(2-pyridyl)iminoketenes, the common intermediates of 4H-pyrido[l,2-a]pyrimidin-4-one and l,8-naphthyridin-4-ones, via a "head-to-tail" [4+2] cycloaddition. 3-Halo-4H-pyrido[l,2-a]pyrimidin-4-ones were obtained from 4H-pyrido[1,2-a]pyrimidin-4-one with N-halosuccinimides. The structures of the new compounds were characterized by means of ¹H NMR and ¹³C NMR examinations.

Full text of DOI:10.3987/COM-09-11746

HETEROCYCLES, Vol. 78, No. 10, 2009
2477
HETEROCYCLES, Vol. 78, No. 10, 2009, pp. 2477 - 2488. © The Japan Institute of Heterocyclic Chemistry
Received, 5th May, 2009, Accepted, 1st July, 2009, Published online, 2nd July, 2009
DOI: 10.3987/COM-09-11746
SYNTHESIS OF HALOGENATED 4H-PYRIDO[1,2-a]PYRIMIDIN-
4-ONES1
Annamária Molnár,a,b Ferenc Faigl,b,c Benjamin Podányi,a Zoltán Finta,a
László Balázs,a and István Hermecza,b*
b
aChinoin Ltd, Tó utca 1-5, H-1045 Budapest, Hungary; Department of Organic
Chemistry and Technology, Budapest University of Technology and Economics,
c
Budafoki út 8, H-1111 Budapest, Hungary; Research Group for Organic
Chemical Technology, Hungarian Academy of Sciences, Budafoki út 8, H-1111
Budapest, Hungary
Abstract – Halogenated 4H-pyrido[1,2-a]pyrimidin-4-one were synthesized by
thermal
cyclization
and
decarboxylation
of
isopropylidene
(2-pyridylamino)methylenemalonates, prepared from 2-aminopyridines and
isopropylidene methoxymethylenemalonate formed in situ. Instead of
4H-pyrido[1,2-a]pyrimidin-4-ones, the 6-chloro and 6-bromo derivatives afforded
mixtures of 7-halo-1,4-dihydro-1,8-naphthyridin-4-ones and 1-(6-halo-2-pyridyl)-
3-[(6-halo-2-pyridylamino)methylene]-1,2,3,4-tetrahydropyridine-2,4-diones. The
latters formed from N-(2-pyridyl)iminoketenes, the common intermediates of
4H-pyrido[1,2-a]pyrimidin-4-one
and
1,8-naphthyridin-4-ones,
via
a
“head-to-tail” [4+2] cycloaddition. 3-Halo-4H-pyrido[1,2-a]pyrimidin-4-ones
were obtained from 4H-pyrido[1,2-a]pyrimidin-4-one with N-halosuccinimides.
1
The structures of the new compounds were characterized by means of H NMR
and 13C NMR examinations.
INTODUCTION
The pyrido[1,2-a]pyrimidine skeleton is a privileged scaffold for facile access to “drug-like” small
molecules,2 rule-of-five.3
which fulfill the requirements of the In particular,
4H-pyrido[1,2-a]pyrimidin-4-ones have attracted the attention of pharmaceutical community, as they
display diverse biological activities (Figure 1). The best-known 4H-pyrido[1,2-a]pyrimidin-4-one is the
atypical neuroleptic risperidone 1, which was one of the drugs most widely prescribed worldwide in
2007.4 Its active metabolite, the antipsychotic paliperidone 2, was registered by the FDA in 2007 for the

2478
HETEROCYCLES, Vol. 78, No. 10, 2009
treatment of bipolar disorders.5 The other outstanding members include the anti-allergic pemirolast 3,6
the non-narcotic analgesic rimazolium 4,7 an anti-ulcer agent 5,8 the tranquillizer pirenperone 6,9 the
anti-allergic ramastine 7,10 the antihypertensive seganserin 811 and the antidepressant lusaperidone 9.12
R
Me
Me
O
+
-
Me
N
N
N
O
MeSO4
N
S
N
N
N
O
N
O
N
F
N
CO2Et
N
-
N
N
Me
O
O
N
+
CO2Et
K
1 R = H, risperidone,
atypical neuroleptic
2 R = OH, paliperidone
N
O
5
4
rimazolium,
3 pemirolast,
anti-allergic ophthalmic
non-narcotic analgesic
anti-ulcerative
F
pirenperone,
tranquillizer
6 R =
F
N
Me
N
O
Me
O
O
8
R =
N
N
N
N
N
seganserin,
O
O
N
R
antihypertensive
9 lusaperidone,
ramastine,
anti-allergic agent
7
R =
N
F
N
antidepressant
H
Figure 1. Some biologically active 4H-pyrido[1,2-a]pyrimidin-4-ones
Transition metal-catalyzed carbon-carbon bond formation is a fundamental reaction for the
functionalization of aromatic and heteroaromatic ring systems.13 To date, no systematic investigation has
been reported on 4H-pyrido[1,2-a]pyrimidin-4-ones. Only a few published examples of transition
metal-catalyzed carbon-carbon bond formation are to be found for 4H-pyrido[1,2-a]pyrimidin-4-ones.14
In the present paper, we report on the synthesis of different halogen derivatives of
4H-pyrido[1,2-a]pyrimidin-4-one, which are very convenient substrates for cross-couplings (e.g. the
Suzuki-Miyaura, Heck, Sonogashira, and Buchwald-Hartwig reactions).
RESULTS AND DISCUSSION
For the synthesis of 4H-pyrido[1,2-a]pyrimidin-4-ones 17, Meldrum’s acid15 10 was selected as starting
material instead of dimethyl malonate, because 10 is a stronger CH acid (pKa = 7.32 ± 0.01 in DMSO16)
and therefore more reactive than dimethyl malonate (pKa = 15.87 ± 0.03 in DMSO16). Another advantage
is that 17 can be obtained from aminomethylenemalonates (14) in three reaction steps: cyclization, ester
hydrolysis and then decarboxylation,17 whereas aminomethylenemalonates (13) give
4H-pyrido[1,2-a]pyrimidin-4-ones (17) directly in a one-pot reaction under thermal conditions18 where
o
decarboxylation and cyclization occur during heating, at around 240-260 C. The alternative reaction

HETEROCYCLES, Vol. 78, No. 10, 2009
2479
sequences are depicted in Scheme 1. Carboxylic acid derivatives of nitrogen bridgehead ring systems
(e.g. 15, R = H) could be obtained from isopropylidene (2-hetarylamino)methylenemalonates even under
acidic conditions (e.g. in a mixture of POCl3 and PPA at 135-140 oC,19a and in PPA19b).
O
O
O
O
O
O
O
CO2Et
CO2Et
CO2Et


MeOCH
EtOCH
HC(OMe)3
+
HC(OEt)3
+
CO2Et
O
12
11
10
X
X
EtOH, rt
X
EtOH, rt
N
NH2
N
NH2
cyclization under
acidic conditions,
X
O
N
O
3
thermal cyclization or
O
O
CO2Et
CO2Et
then ROH
X
N
6
cyclization under
acidic conditions,
- CH3COCH3,
N
N
H
CO2R
R = H or alkyl
N
N
H
O
13
15
R = Et
14
thermal cyclization,
hydrolysis
N
- CO2
- MeCOMe,
9
N
decarboxylation
- CO2
X
X
N
N
3
CO2R
6
O
O
17
16
Scheme 1. Alternative synthetic routes for 4H-pyrido[1,2-a]pyrimidin-4-ones 17
The reaction between Meldrum’s acid 10 and trimethyl orthoformate smoothly yielded isopropylidene
methoxymethylenemalonate (11). After the reaction mixture had been heated for 4 h on an oil bath and
then evaporated to dryness in vacuo, the residue was left to react with the appropriate 2-aminopyridine in
EtOH at ambient temperature over night. The precipitated aminomethylenemalonate (13) was filtered off
from the cooled reaction mixture and used directly in the cyclization step without further purification
(yields are shown in Table 1).
The addition of (6-unsubstituted-2-pyridyl)aminomethylenemalonates (13a-k) to preheated Ph2O at 260
oC afforded 4H-pyrido[1,2-a]pyrimidin-4-ones (17) in good yields after dilution of the cold reaction
mixture with hexane and extraction with aqueous 2 N HCl, followed by adjustment of the pH of the
aqueous extract to
8
with 40% NaOH solution (see Table 1). The precipitated
4H-pyrido[1,2-a]pyrimidin-4-ones were filtered off and recrystallized from EtOH. Our work-up protocol
provided 15-30% better yields for 17f, 17i and 17k than in the earlier methods20,21 (50%, 62% and 44%,
respectively), where Ph2O was diluted with pentane or hexane and precipitated
4H-pyrido[1,2-a]pyrimidin-4-ones were filtered off. In the case of 17k, no mp was reported previously.21

2480
HETEROCYCLES, Vol. 78, No. 10, 2009
Table 1. Syntheses of aminomethylenemalonates 13a-k and 4H-pyrido[1,2-a]pyrimidin-4-ones 17
Yield
%
Mp
oC
Lit. Mp
oC
Yield
%
Mp
oC
Lit. Mp
oC
Compd
X
H
Compd
X
H
174-
175
175.2-
131-13222
1
13a
70
17a
80
130-131
176.418
2
3
4
5
13b
13c
13d
13e
3-F
5-F
87
81
85
79
193
200
17b
17c
17d
17e
9-F
7-F
65
75
75
59
171
186
3-Cl
4-Cl
179-180
222-224
9-Cl
8-Cl
148
156-157
193-
6
13f
5-Cl
84
195
17f
7-Cl
81
124
121-12320
127-13020
19420
7
8
13g
13h
3-Br
4-Br
95
90
165-166
228
17g
17h
9-Br
8-Br
84
63
180-181
184-185
192-
9
13i
5-Br
99
188
17i
7-Br
76
125-127
19320
10
11
13j
3-I
5-I
75
69
180
189
17j
9-I
7-I
71
66
194-196
157-15821
13k
17k
O
N
N
R
EtOH, 80-85 oC, 3-5 h
61 - 88%
R
O
N
N
H
O
O
R = SMe, Me, Ph
18
Scheme 2
In contrast with what was reported by Ye et al.,23 who have obtained 4-oxo-4H-pyrido[1,2-a]pyrimidine-
3-carboxylic acids (19) when 18 was heated under reflux in EtOH, we did not observed the formation of
any 4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (19, R = H) from 13h under similar conditions, even
after a longer reaction time (8 h) (Scheme 2).
R3
R6
N
N CH
H
CO2Et

O
20
R3
N
O

N
R6
N
R3
21
N
H
R6
22
Scheme 3
The thermal cyclization of 3-(6-substituted-2-pyridyl)acrylates (20) gave 6-substituted-4H-pyrido-
[1,2-a]pyrimidin-4-ones (21) or 7-substituted-1,4-dihydro-1,8-naphthyridin-4-ones (22), or their mixture,
depending on the nature of the 2-substituent in the acrylates (R3) and on the reaction conditions.24
(Scheme 3) 6-Substituted-4H-pyrido[1,2-a]pyrimidin-4-ones (21) were transformed into the

HETEROCYCLES, Vol. 78, No. 10, 2009
2481
thermodynamically more stable 7-substituted-1,4-dihydro-1,8-naphthyridin-4-ones (22) by heating at
higher temperature or for a longer period.25
Me
Me
N
O
O
N
O
Me
Ph2O
Dowtherm A
~ 240 oC
3
O
O
260 oC
N
Me
N
N
Me
N
H
H
Me
23
25
24
O
Scheme 4
De Silva et al.26 obtained 5,7-dimethyl-1,4-dihydro-1,8-naphthyridin-4-one (24) by refluxing
isopropylidene [N-(4,6-dimethyl-2-pyridyl)aminomethylene]malonate (23) in Ph2O, but
4,6-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (25) was the product when the ring closure was carried
out in Dowtherm A at a lower temperature, ~240 oC.18 (Scheme 4).
O
O
Ar
N
O
O
- MeCOMe, - CO2
260 oC
+
C16H10N4O2X2
R
N
N
H
X
N
N
H
O
13l
13m
R = Cl
R = Br
27
O
26
Ar = 6-halo-2-pyridyl
Scheme 5
From the 6-chloro and 6-bromo derivatives of aminomethylenemalonates (13l, m) in boiling Ph2O we
expected to obtain 7-halo-1,4-dihydro-1,8-naphthyridin-4-ones (27, X = Cl, Br), as the Cl and Br atoms
exhibit similar bulkiness27 to that of the Me group. From the reaction mixtures besides the expected
1,8-naphthyridines 27, we could isolated by-products, too (Scheme 5). In both cases LC-MS
investigations have indicated a dimer formation with brutto formula C16H10N4O2X2. (At the thermal
cyclization of 13a dimer formation could not be detetected by LC-MS investigations.) Naphthyridines 27
and dimers 29 could be separated by fractional crystallization from EtOH. Dimers exhibited lower
solubility, than naphthyridines. According to our knowledge, these are the first cases when dimeric
products were detected and isolated in the case of the thermal cyclization of (6-substituted
2-pyridylamino)methylenemalonates.
Ar
Ar
N
Ar
N
O
N
O
N
O
[4+2]
+
H
N
Ar
O
N
O
O
H
Ar
Ar
28
26
+
26
29
Ar = 6-halo-2-pyridyl
Scheme 6

2482
HETEROCYCLES, Vol. 78, No. 10, 2009
Dimers 29 would be formed in a “head-to-tail” [4+2] cyclodimerization of the iminoketene 26, which
would probably take place in a pseudopericyclic manner, initiated by the attack of an imino lone pair on
the carbonyl carbon of a second molecule of iminoketene (Scheme 6). The initial dimer (28) thus formed
would tautomerizes by 1,3 hydrogen shift to the isolated product 29. A similar dimer formation was
earlier described by Wentrup et al. in the case of 2-pyridylketene.28 1H and 13C NMR data are consistent
with the dimer structure 29, and have indicated that the products are present as a 1:2 E-Z isomeric
mixtures in DMSO-d6 (see Figure 2).
Cl
Cl
120.6
120.6
7.79**d (7.9)
141.4
7.59*d (7.9)
141.4
N
142.3
N
141.6
7.91d
109.1
108.2
7.98d
150.5
150.5
8.05t
5.89d (7.4)
8.07t
5.87d (8.3)
180.7
N
N
DMSO-d6
1
2
3
.
123.4
183.6
164.3
163.9
7.77*d (7.9)
7.61**d
(7.9)
O
H
O
O
O
Z : E = ~ 2 : 1
13.53d (12.3)
105.2
105.2
151.3
H
151.3
H
4
12.29
(13.2)
N
N
H
9.23d
9.23d
149.7
N
149.7
N
121.6
121.6
7.42d (7.7)
7.41d (7.7)
7.96dd
Cl
Cl
7.96dd
E
Z
113.1
113.1
7.67d (8.0)
7.64d (8.1)
Figure 2. 1H (coupling constant in parenthesis) and identified 13C NMR (bold) data of compound 29a
determined by HSQC, COSY, HBMC experiments in DMSO-d6. (* and ** indicate that a reverse
assignment of these protons is also possible)
Table 2. Syntheses of aminomethylenemalonates 13l,m and 7-halo-1,4-dihydro-1,8-naphthyridin-
4-ones 27
Aminomethylenemalonate (13)
1,4-dihydro-1,8-naphthyridin-4-ones (27)
Entry
Compound
X
Yield %
Mp oC
Compound
X
Yield %
Mp oC
1
2
13l
6-Cl
6-Br
61
72
199-200
205
27a
27b
7-Cl
7-Br
75
69
> 300
> 300
13m
N
N
N
NBX
CCl4
N
X
17a
O
30
O
Scheme 7
3-Chloro-, 3-bromo- and 3-iodo-4H-pyrido[1,2-a]pyrimidin-4-ones (30) were obtained from 17a in
76-86% yields by reaction with the respective N-halosuccinimide in CCl4 (Scheme 7).

HETEROCYCLES, Vol. 78, No. 10, 2009
2483
CONCLUSION
In conclusion, a productive “one-pot” synthesis was extended for the preparation of halogenated
4H-pyrido[1,2-a]pyrimidin-4-one (17b-k) from Meldrum’s acid, trimethyl orthoformate and the
appropriate 2-aminopyridine via methoxymethylenemalonates (13). From the 6-chloro and 6-bromo
derivatives 13m, l a mixture of 7-halo-1,4-dihydro-1,8-naphthyridin-4-ones (27) and, in the first case,
tetrahydropyridine-2,4-diones 29 were obtained. The latters formed in a “head-to-tail” [4+2]
cyclodimerization from the common intermediates 26 of 4H-pyrido[1,2-a]pyrimidin-4-ones and
1,8-naphthyridin-4-ones. The 3-halo derivatives 30 were obtained from 4H-pyrido[1,2-a]-
pyrimidin-4-one (17a) with N-halosuccinimides. The structures of the new compounds were
characterized by means of 1H and 13C NMR spectroscopy.
Table 3. 1H NMR data on 4H-pyrido[1,2-a]pyrimidin-4-ones 17 and 30 in DMSO-d6
Compd.
H-2
H-3
H-6
H-7
H-8
H-9
Coupling constants (Hz)
17a
8.31d
6.34d
8.98dd 7.30dd 7.97ddd
8.78d 7.32ddd 7.89ddd
7.70d
J
2,3 = 6.2; J6,7 = 7.0; J7,8 = 6.9; J8,9 = 9.0;
4J6,8 = 1.6
2
17b
17c
8.32d
8.32d
6.48d
6.42d
-
J2,3 = 6.3; J6,7 = 7.1; J7,8 = 7.6; J8,9F
9.3; 4J6,8 = 1.2; 3J7,9F = 7.6
=
=
4
8.94dd
-
8.10ddd 7.80dd J2,3 = 6.2; J6,7F = 4.8; J6,8 = 2.8; J7F,8
7.2; J8,9 = 9.8; 4J7F,9 = 5.4
17d
17e
17f
17g
17h
17i
8.36d
8.26d
8.31d
8.37d
8.27d
8.32d
8.36d
8.29d
8.60s
6.48d
6.40d
6.44d
6.46d
6.41d
6.45d
6.34d
6.42d
-
8.91dd
8.92d
8.95d
8.96dd
8.82d
9.02d
8.97d
9.08d
7.30t
7.40dd
-
8.20dd
-
-
J
J
J
J
J
J
J
J
J
2,3 = 6.4; J6,7 = J7,8 = 7.3; 4J6,8 = 1.3
2,3 = 6.4; J6,7 = 7.8; 4J7,9 = 2.2
2,3 = 6.2; J8,9 = 9.0; 4J6,8 = 2.4
2,3 = 6.4; J6,7 = J7,8 = 7.2; 4J6,8 = 1.4
2,3 = 6.4; J6,7 = 7.6; 4J7,9 = 1.8
2,3 = 6.2; J8,9 = 9.6; 4J6,8 = 2.0
7.85d
7.71d
-
8.02dd
8.38dd
-
7.23t
7.50dd
-
8.04d
7.64d
-
8.08dd
8.57dd
8.12dd
17j
17k
30a
7.08dd
-
2,3 = 6.4; J6,7 = 7.0; J7,8 = 7.2; 4J6,8 = 2.0
2,3 = 6.2; J8,9 = 9.4; 4J6,8 = 2.2
7.47d
9.00dd 7.46ddd 8.02ddd 7.78dd
9.00dd 7.45ddd 8.03ddd 7.75dd
8.97dd 7.43ddd 8.03ddd 7.72dd
6,7 = 6.8; J7,8 = 7.0; J8,9 = 9.0; 4J6,8 = 1.6;
4J7,9 = 1.4
30b
30c
8.65s
8.72s
-
-
J
6,7 = 7.2; J7,8 = 7.0; J8,9 = 9.0; 4J6,8 = 1.4;
4J7,9 = 1.2
J
6,7 = 6.7; J7,8 = 7.6; J8,9 = 8.8; 4J6,8 = 1.6;
4J7,9 = 1.4

2484
HETEROCYCLES, Vol. 78, No. 10, 2009
EXPERIMENTAL
1
13
Melting points are uncorrected and yields were not maximized. H and C NMR spectra were recorded
in DMSO-d6 on a Bruker DRX instrument at 400 and 100 MHz, respectively). Coupling constants are
reported in Hz and chemical shifts in ppm (δ, ppm) downfield from TMS, which was used as internal
standard. The following abbreviations are used: singlet (s), doublet (d), triplet (t), broad (br). LC-MS
investigations were carried out by an Alliance 2695 HPLC system (Waters Co.) equipped with a
quaternary pump, an auto-sampler, Waters 2996 PDA detector and a Waters ZQ-2000 single quadruple
mass spectrometer with ESCi source. Chromatographic separation was carried out at 30 °C on an
Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 μm). The mobile phases consisted of 0.05%
CF3CO2H in H2O (A) and 0.03% CF3CO2H acid in MeCN (B) using a gradient elution of 5–5% (v/v) B
at 0–0.5 min; 5–95% B at 0.5–4.5 min; 95–95% B at 4.5–6.0 min. The flow rate was 0.5 mL/min, and the
injection volume was 0.5 μL.
Table 4. 13C NMR data on 4H-pyrido[1,2-a]pyrimidin-4-ones 17 and 30 in DMSO-d6
Compd.
17a
17ba)
17cb)
17d
17e
X
H
C-2
C-3
C-4
C-6
C-7
C-8
C-9
C-9a
151.8
144.8
149.9
148.5
151.6
150.3
148.8
151.6
150.3
149.5
150.2
150.3
150.8
151.2
155.1
104.0
105.5
103.7
105.1
104.7
104.7
104.9
104.8
104.8
104.3
104.7
110.8
100.6
75.6
157.2
156.7
156.8
157.1
156.9
156.3
157.2
157.0
156.2
157.4
156.0
154.3
154.3
155.2
127.4
123.5
124.9
126.8
129.0
127.0
127.5
128.6
127.9
128.1
131.7
127.8
127.9
128.1
116.8
114.9
154.3
115.4
117.6
123.7
116.1
120.0
110.9
117.1
82.3
137.7
119.6
129.8
136.7
142.9
138.0
140.5
132.2
140.1
147.5
144.6
137.8
138.0
138.3
126.4
153.8
127.9
129.7
124.6
127.9
120.4
128.1
127.0
98.7
9-F 154.1
7-F 154.6
9-Cl 154.4
8-Cl 155.6
7-Cl 154.9
9-Br 154.7
8-Br 155.5
7-Br 154.9
9-I 154.9
7-I 154.9
3-Cl 152.7
3-Br 155.2
3-I 160.1
17f
17g
17h
17i
17j
17k
30a
127.4
126.5
126.4
126.0
117.7
117.8
117.9
30b
30c
a) 1JC-9,F = 253,9 Hz; 2JC-9a,F = 20.7 Hz; 2JC-8,F = 17.9 Hz; 3JC-7,F = 7.4 Hz; 4JC-6,F = 4.8 Hz;
b) 1JC-9,F = 242,4 Hz; 2JC-6,F = 41.5 Hz; 2JC-8,F = 25.4 Hz; 3JC9,F = 7.9 Hz;
Synthesis of Isopropylidene (2-Pyridylamino)methylenemalonate (13). General Method. A 1:2
mixture of Meldrum’s acid (17.6 g, 0.12 mol) and trimethyl orthoformate (30 mL, 0.25 mol) was heated
under reflux for 4 h, and the reaction mixture was then evaporated to dryness at 100 mbar. The residue
11 was dissolved in EtOH (200 mL) and a 2-aminopyridine (0.1 mol) was added, and the reaction
mixture was stirred at ambient temperature overnight. The precipitated 13 was filtered off, washed with

HETEROCYCLES, Vol. 78, No. 10, 2009
2485
EtOH and used in cyclization reaction without further purification. Yields and mp are listed in Table 1,
and the results of the elemental analysis are listed in Table 5.
Table 5. Elemental analyses for new aminomethylenemalonates 13 and 4H-pyrido[1,2-a]pyrimidin-4-ones 17
Calcd
H
Found
H
Compound Anal. Calcd for
C
N
C
N
13b
13c
13d
13e
13g
13h
13j
C12H11FN2O4
C12H11FN2O4
54.14 4.16 10.52 53.92 4.15 10.44
54.14 4.16 10.52 54.20 4.11 10.57
C12H11ClN2O4 50.99 3.92 9.91 51.09 3.99 10.07
C12H11ClN2O4 50.99 3.92 9.91 50.85 3.87
C12H11BrN2O4 44.06 3.39 8.56 43.89 3.40
C12H11BrN2O4 44.06 3.39 8.56 44.00 3.38
9.95
8.52
8.68
7.38
7.50
9.98
8.74
C12H11IN2O4
C12H11IN2O4
38.52 2.96 7.49 38.69 2.89
38.52 2.96 7.49 38.38 2.99
13k
13l
C12H11ClN2O4 50.99 3.92 9.91 51.91 4.14
C12H11BrN2O4 44.06 3.39 8.56 43.85 3.51
13m
17b
17c
17d
17e
17g
17h
17j
C8H5FN2O
C8H5FN2O
C8H5ClN2O
C8H5ClN2O
C8H5BrN2O
C8H5BrN2O
C8H5IN2O
C8H5IN2O
58.54 3.07 17.07 58.72 2.98 17.21
58.54 3.07 17.07 58.52 3.10 17.15
53.21 2.79 15.51 53.34 2.70 15.41
53.21 2.79 15.51 53.30 2.80 15.28
42.70 2.24 12.45 42.91 2.31 12.53
42.70 2.24 12.45 42.66 2.20 12.38
35.32 1.85 10.30 35.51 1.91 10.22
35.32 1.85 10.30 35.26 1.86 10.43
17k
Synthesis of 4H-Pyrido[1,2-a]pyrimidin-4-ones (17). General Method. Isopropylidene
o
(2-pyridylamino)methylenemalonate (13) (20 g) was added to Ph2O (180 g) preheated to 260 C. The
reaction mixture was heated at 260 oC for 10 min, then quickly cooled to room temperature, diluted with
n-hexane (200 mL) and extracted with 2 N HCl. The pH of the separated aqueous phase was adjusted to
8 with 40% aqueous NaOH, and the precipitated 4H-pyrido[1,2-a]pyrimidin-4-one (17) was filtered off,
washed with water, and recrystallized from EtOH. Yields and mp are given in Table 1, and results of the
elemental analysis are listed in Table 5.
Cyclization of Isopropylidene (6-halo-2-pyridylamino)methylenemalonates (27). 6-Halo derivative
13l, or m (2 g) was added to Ph2O (40 g) preheated at 260 oC, the reaction mixture was heated at 260 oC
for ~2 min, then quickly cooled to room temperature and diluted with n-hexane (80 mL). The
precipitated crystals were filtered off, and 27 and 29 were separated by fractional crystallization from
EtOH.

2486
HETEROCYCLES, Vol. 78, No. 10, 2009
1
7-Chloro-1,4-dihydro-1,8-naphthyridin-4-one (27a). Yield and mp are given in Table 2. H NMR δ
12.34 (brd, 1H, J = 5.9 Hz, NH), 8.44 (d, 1H, J = 8.3 Hz, 5-H), 7.94 (dd, 1H, J = 7.6 Hz and 5.9 Hz, 2-H),
7.44 (d, 1H, J = 8.3 Hz, 6-H), 6.12 (d, 1H, J = 7.6 Hz, 3-H); 13C NMR δ 111.0 (C-3), 119.5 (C-4a), 120.3
(C-5), 138.7 (C-6), 140.8 (C-7), 150.4 (C-8a), 152.9 (C-2), 177,1 (C-4). Anal. Calcd for C8H5ClN2O: C,
53.21; H, 2.79; N, 15.51. Found: C 53.34; H 2.63; N 15.70
7-Bromo-1,4-dihydro-1,8-naphthyridin-4-one (27b). Yield and mp are given in Table 2. Anal. Calcd
for C8H5BrN2O: C, 42.70; H, 2.24; N 12.45. Found: C, 42.58; H, 2.31; N, 12,56.
1-(6-Chloro-2-pyridyl)-3-[(6-chloro-2-pyridylamino)methylene]-1,2,3,4-tetrahydropyridine-2,4-
dione (29a). Yield 8%, its purity was cca 95%, mp > 300 °C. HRMS m/z: (ESI+) calcd for
C16H10Cl2N4O2 +H: 361.0253. Found: 361.0246 .
1-(6-Bromo-2-pyridyl)-3-[(6-bromo-2-pyridylamino)methylene]-1,2,3,4-tetrahydropyridine-2,4-
dione (29b). Yield cca 6%, its purity was cca 80%, mp > 300 °C. HRMS m/z: (ESI+) calcd for
C16H10Br2N4O2 +H: 448.9249. Found: 448.9253.
Synthesis of 3-Halo-4H-pyrido[1,2-a]pyrimidin-4-ones (30). The respective N-halosuccinimide (0.11
mol) was added to a solution of 4H-pyrido[1,2-a]pyrimidin-4-one 17a (14.6 g, 0.1 mol) in CCl4 (200
mL), and the mixture was heated under reflux for 30 min, then filtered hot and cooled to ambient
temperature, and the precipitated yellow crystals were filtered off and recrystallized from EtOH.
3-Chloro-4H-pyrido[1,2-a]pyrimidin-4-one (28a). Yield 86%, mp 159-160 °C. Anal. Calcd for
C8H5ClN2O: C, 53.21; H, 2.79; N, 15.51. Found: C, 53.45; H, 2.86; N, 15.35.
3-Bromo-4H-pyrido[1,2-a]pyrimidin-4-one (28b). Yield 76%, mp 137-138 oC, lit.,29 mp 133-134 oC.
3-Iodo-4H-pyrido[1,2-a]pyrimidin-4-one (28c). Yield 86%, mp 142 °C. Anal. Calcd for C8H5IN2O: C,
35.32; H, 1.85; N, 10.30. Found: C, 35.40; H, 1.69; N, 10.42.
ACKNOWLEDGMENTS
We are grateful Dr. Durham David for the linguistic improvement of the manuscript. One of the authors
(A.M.) expresses her thanks for support through a sanofi-aventis fellowship.
REFERENCES
1. Nitrogen Bridgehead Compounds Part 94. Part 93: Á. Kiss, J. Kökösi, R. Rotter, and I. Hermecz,
Tetrahedron, 2000, 56, 7987.
2. I. Hermecz and Z. Mészáros, Med. Res. Rev., 1988, 8, 203.
3. C. A. Lipinski, F. Lombardo, B. W. Dominy, and P. J. Feeney, Adv. Drug Deliv. Rev., 1997, 23, 3.
4. (a) C. Fenton and L. J. Scott, CNS Drug, 2005, 19, 429. (b) idem., Pharmaceut. Exec., 2008, (5), 74.
5. (a) P. Revill, N. Serradell, and J. Bolós, Drug Fut., 2006, 31, 579. (b) L. P. H. Yang and G. L.
Plosker, CNS Drug, 2007, 21, 417.

HETEROCYCLES, Vol. 78, No. 10, 2009
2487
6. D. G. Shulman, L. Amdahl, C. Washington, and A. Graves, Clin. Ther., 2003, 25, 1096.
7. S. Fürst, K. Gyires, and J. Knoll, Arzneim. Forsch., 1988, 38, 552.
8. S. Matsutani and Y. Mizushima, Eur. Pat. Appl., 329126, 1989 (Chem. Abstr., 1990, 112, 98557).
9. R. L. Smith, R. J. Barrett, and E. J. Sanders-Bush, J. Pharmacol. Exp. Ther., 1995, 275, 1050.
10. F. Awouters, J. Vermeire, F. Smeyers, P. Vermote, R. van Beek, and C. J. E. Niemegeers, Drug.
Dev. Res., 1986, 8, 95.
11. A. Petterson, K. Gradin, T. Hedner, and B. Persson, Naunyn-Schiedeberg’s Arch. Pharmacol., 1985,
329, 394.
12. L. E. J. Kennis, F. P. Bischoff, C. J. Mertens, C. J. Love, F. A. F. Van den Keybus, S. Pieters, M.
Braeken, A. A. H. P. Megens, and J. E. Leysen, Bioorg. Med. Chem. Lett., 2002, 10, 71.
13. (a) F. Alonso, I. P. Beletskaya, and M. Yus, Tetrahedron, 2008, 64, 3047. (b) R. Chinchilla and C.
Nájera, Chem. Rev., 2007, 107, 874. (c) L. Yin and J. Liebscher, Chem. Rev., 2007, 107, 133. (d) I. J.
S. Fairlamb, Chem. Soc. Rev., 2007, 36, 1036. (e) B. H. Yang and S. L. Buchwald, J. Organomet.
Chem., 1999, 576, 125 (1999) and references cited therein.
14. (a) K. Yoshida, K. Nakayama, Y. Yokomizo, M. Ohtsuka, M. Takemura, K. Hoshino, H. Kanda, K.
Namba, H. Nitanai, J. Z. Zhang, V. J. Lee, and W. J. Watkins, Bioorg. Med. Chem., 2006, 14, 8506.
(b) K. Yoshida, K. Nakayama, N. Kuru, S. Kobayashi, M. Ohtsuka, M. Takemura, K. Hoshino, H.
Kanda, J. Z. Zhang, V. J. Lee, and W. J. Watkins, Bioorg. Med. Chem., 2006, 14, 1993. (c) Z. A.
Knight, G. G. Chiang, P. J. Alaimo, D. M. Kenski, C. H. Ho, K. Coan, R. T. Abraham, and K. M.
Shokat, Bioorg. Med. Chem., 2004, 12, 4749. (d) A. M. Venkatesan, J. I. Levin, J. S. Baker, P. S.
Chan, T. Bailey, and J. Coupet, Bioorg. Med. Chem. Lett., 1994, 4, 183. (e) M. J. O’Mahony, P. J.
West, S. D. Lindell, and J. A. Macritchie, Brit Patent 2,307,177, 1997 (Chem. Abstr., 1997, 127,
132147). (f) A. D. Robertson, S. Jackson, V. Kenche, C. Yaip, H. Parbaharan, and P. Thompson,
PCT Int. Appl. WO 01/053,266, 2001 (Chem. Abstr., 2001, 135, 122509). (g) G. L. Bundy, F. L.
Ciske, M. J. Genin, S. E. Heasley, S. D. Larsen, B. H. Lee, P. D. May, J. R. Palmer, M. E. Schnute,
V. E. Vaillancourt, A. Thorarensen, A. J. Wolf, N. A. Wicnienski, and D. Wilhite, PCT Int. Appl.
WO 02/04,444, 2002 (Chem. Abstr., 2002, 136, 118476). (h) H.-J. Zhou, A. McDonald, G. Bergnes,
D. J. Morgans Jr., J. C. Chabala, S. D. Knigth, and D. Dhanak, PCT Int. Appl. WO 04/064,741,
2004 (Chem. Abstr., 2004, 141, 174179). (i) W. Wang, R. N. Constantine, L. M. Lagniton, S. Pecchi,
M. T. Burger, and M. C. Desai, PCT Int. Appl. WO 04/113,335, 2004 (Chem. Abstr., 2005, 142,
93843). (j) W. Wang, R. N. Constantine, and L. M. Lagniton, U.S. Patent 02/28,002, 2002 (Chem.
Abstr., 2005, 143, 387057). (k) E. D. Jones, J. A. V. Coates, D. I. Rhodes, J. J. Deadman, N. A.
Degraff, L. J. Winfield, N. Thienthong, W. Issa, N. Choi, and K. Macfarlane, PCT Int. Appl. WO
08/077,188, 2008 (Chem. Abstr., 2008, 149, 128851). (l) S. Liu, J. Fu, R. Kamboj, Q. Jia, M. Wood,
S. Chowdhury, and J. Sun, PCT Int. Appl. WO 08/097,991, 2008 (Chem. Abstr., 2008, 149, 268064).

2488
HETEROCYCLES, Vol. 78, No. 10, 2009
(m) A.-R. Li, M. G. Johnson, J. Liu, X. Chen, X. Du, J. T. Mihalic, J. Deignan, D. J. Gustin, J.
Duquette, Z. Fu, L. Zhu, A. P. Marcus, P. Bergeron, L. R. McGee, J. Danao, B. Lemon, T. Carabeo,
T. Sullivan, J. Ma, L. Tang, G. Tonn, T. L. Collins, and J. C. Medina, Bioorg. Med. Chem. Lett.,
2008, 18, 688.
15. (a) A. S. Ivanov, Chem. Soc. Rev., 2008, 37, 789. (b) A. E.-A. M. Gaber and H. McNab, Synthesis,
2001, 2059. (c) I. Hermecz, G. Keresztúri, and L.Vasvári-Debreczy, Adv. Heterocycl. Chem., 1992,
54, 108 and 252. (d) B.-C. Chen, Heterocycles, 1991, 32, 529. e) H. McNab, Chem. Soc. Rev., 1991,
7, 345.
16. (a) E. M. Arnett and J. A. Harrelson Jr., J. Am. Chem Soc., 1987, 109, 809. (b) X. Wang and K. N.
Houk, J. Am. Chem Soc., 1988, 110, 1870.
17. R. Adams and I. J. Pachter, J. Am. Chem Soc., 1952, 74, 5491.
18. G. Y. Lesher, U.S. Patent 3,907,798, 1975 (Chem. Abstr., 1976, 84, 49967).
19. (a) I. Hermecz, Á. Horváth, L. Vasvári-Debreczy, and Z. Mészáros, Synthesis, 1984, 152. (b) R.
Westwood, P. Miller, I. R. Ager, and D. P. Kay, Eur. Pat. Appl. 86.723, 1983 (Chem. Abstr., 1984,
100, 6552).
20. I. Ravina, D. Zicane, M. Petrova, E. Gudriniece, and U. Kalejs, Chem. Heterocycl. Compd., 2002,
38, 836.
21. W.-C. Lee, L. Sun, F. Shan, C. Chuaqui, M. Cornebise, T. W. Pontz, M. Carter, J. Singh, P. A.
Boriaci-Sjodin, L. Ling, and R. C. Setter, PCT WO 04/072033, 2004 (Chem. Abstr., 2004, 141,
225504).
22. N. Katagiri, R. Niwa, and T. Kato, Heterocycles, 1983, 20, 597.
23. F.-C Ye, B.-C. Chen, and X. Huang, Synthesis, 1989, 317.
24. (a) G. R. Lappin, J. Am. Chem. Soc., 1948, 70, 3348. (b) I. Hermecz, Z. Mészáros, L. Vasvári-
Debreczy, Á. Horváth, G. Horváth, and M. Pongor-Csákvári, J. Chem. Soc., Perkin Trans. 1, 1977,
789.
25. (a) Z. Mészáros and I. Hermecz, Tetrahedron Lett., 1975, 16, 1019. (b) I. Hermecz, Z. Mészáros, K.
Simon, L. Szabó, and Z. Pál, J. Chem. Soc., Perkin Trans. 1, 1984, 1795. (c) I. Hermecz, L.
Vasvári-Debreczy, and K. Simon, J. Chem. Soc., Perkin Trans. 2, 1988, 1287.
26. L. E. da Silva, A. C. Joussef, R. J. Nunes, and K. N. de Oliveira, Synth. Commun., 2008, 38, 15.
27. (a) A. Bondi, J. Phys. Chem., 1964, 68, 441. (b) A. Verloop, W. Hoogenstraaten, and J. Tipker, in
Drug Design; ed. by E. J. Ariëns; Academic Press: New York, 1976; Vol. 7, pp. 165-207.
28. A. Khun, C. Plüg, and C.Wentrup, J. Am. Chem. Soc., 2000, 122, 1945.
29. R. Adams and I. J. Pachter, J. Am. Chem. Soc., 1954, 76, 1845.