A new one-step route for the synthesis of fused pyrido[1,2-a]pyrimidin-4- ones

Article abstract of DOI:10.1055/s-2008-1066988

The cyclization of 3-formylchromone with a variety of 2-methylpyrimidin- 4(3H)-ones promoted by chlorotrimethylsilane was investigated. A simple and flexible general procedure for the synthesis of a series of fused pyrido[1,2-a]pyrimidin-4-ones is proposed. A set of functionally and structurally diverse pyrido[1,2-a]pyrimidin-4-ones were obtained in high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1066988

PAPER
1069
A New One-Step Route for the Synthesis of Fused Pyrido[1,2-a]pyrimidin-4-
ones
A
N
ew One-Ste
p
R
n
oute for the
d
S
ynthesis of
r
Fused P
e
yrido[1, 2-
ay
]pyrimidin-4-onesS. Plaskon,a,b Sergey V. Ryabukhin,a,b Dmitriy M. Volochnyuk,*a,c Andrey A. Tolmachevb
a
Enamine Ltd., 23 Alexandra Matrosova Str., 01103 Kiev, Ukraine
Fax +380(44)5373253; E-mail: D.Volochnyuk@enamine.net
b
c
National Taras Shevchenko University, 62 Volodymyrska Str., 01033 Kiev, Ukraine
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska Str., 02094 Kiev, Ukraine
Received 20 November 2007; revised 11 December 2007
The main methods for the synthesis of derivatives of 11H-
pyrido[2,1-b]quinazolin-11-one (I) are the reactions of
pyridine-2-amines IV with 2-chlorobenzoic acid (V,
Hal = Cl; X = H)5 or 2-fluorobenzoyl chloride (V, Hal = F;
Abstract: The cyclization of 3-formylchromone with a variety of 2-
methylpyrimidin-4(3H)-ones promoted by chlorotrimethylsilane
was investigated. A simple and flexible general procedure for the
synthesis of a series of fused pyrido[1,2-a]pyrimidin-4-ones is pro-
posed. A set of functionally and structurally diverse pyrido[1,2- X = Cl) (Scheme 1, route 1),5e the interaction of anthra-
nilic acid (VI) with 2-halopyridines VII (route 2),1,3,5d,6
a]pyrimidin-4-ones were obtained in high yields.
and the reactions of quinazolin-2-ylacetonitrile VIII with
pyrimidine derivative IX (route 3)7a or 2-halobenzalde-
hydes X (route 4).7b,c Another approach involves the
palladium-mediated interaction of N-(2-bromophenyl)py-
ridin-2-amine (XI) with carbon monoxide (route 5).8
Analogous methods are used to obtain 4H-pyrido[1,2-
a]thieno[2,3-d]pyrimidin-4-one (II) and 10H-pyrido[1,2-
a]thieno[3,2-d]pyrimidin-10-one (III); these compounds
can be synthesized by the reaction of ethyl 2-ami-
nothiophene-3-carboxylate (XII) and 2-halopyridines
VII,9,10a,b or by the reaction of pyridine-2-amine (IV) with
ethyl 3-bromo-1-benzothiophene-2-carboxylate (XIII) in
Key words: 3-formylchromone, 2-methylpyrimidin-4(3H)-ones,
fused-ring systems, cyclizations, chlorotrimethylsilane
Among the derivatives of 11H-pyrido[2,1-b]quinazolin-
11-one (I), substances exhibiting a diverse spectrum of bi-
ological activity, such as antiallergic,1,2 analgesic,2a,3 anti-
inflammatory,3 antipyretic,2a and antitumor,4 are known.
The search for antiallergic agents in this series of com-
pounds has been particularly intensive. Pyrido[1,2-
a]thienopyrimidones II and III, being sulfur isosteres of
pyridoquinazolone I, display antiallergic activity as well.
O
O
Hal
ClOC
Cl
N
SO2Me
NH
NH
+
+
N
N
VIII
N
CHO
route 3
route 4
IX
VIII
X
CN
CN
Br
O
route 2
route 1
route 5
COOH
NH2
N
N
+
N
N
Hal
N
H
VI
VII
XI
I
this work
O
O
O
N
O
CHO
NH
X
+
+
R'
N
NH2
Hal
XV
XIV
V
IV
R
O
O
Br
COOEt
S
N
N
+
+
COOEt
N
NH2
S
NH2
N
N
Hal
S
N
S
II
XII
VII
III
XIII
IV
Scheme 1
SYNTHESIS 2008, No. 7, pp 1069–1077
x
x
.
x
x
.2
0
0
8
Advanced online publication: 06.03.2008
DOI: 10.1055/s-2008-1066988; Art ID: P13607SS
© Georg Thieme Verlag Stuttgart · New York

1070
A. S. Plaskon et al.
PAPER
the presence of palladium(II) acetate, xantphos, and cesi- We have demonstrated in our earlier studies that chloro-
um carbonate.10
trimethylsilane (TMSCl) is a convenient promoter for the
cyclization of 3-formylchromones, which results in the re-
gioselective formation of 2-hydroxybenzoyl derivatives
of nitrogen heterocycles,12 as well as for other condensa-
tions of carbonyl compounds.13 Therefore, we decided to
use TMSCl as a promoter and water scavenger in the re-
action with various 2-methylpyrimidin-4(3H)-ones.
During the course of our 3-formylchromone11 cyclization
studies, involving the [3+3] cyclocondensation of 3-
formylchromone (XIV) (1,3-CCC-bielectrophilic compo-
nents) with substituted acetamides,12a amino heterocycles,
donor anilines,12b and various benzimidazoles12c bearing a
methylene (CH2) moiety at the 2-position, we had the op-
portunity to explore the formation of 2-hydroxybenzoyl- 3-Formylchromone (1) reacted with (4-oxo-3,4-dihydro-
substituted fused pyrido[1,2-a]pyrimidines by coupling 3- quinazolin-2-yl)acetonitrile (2a) in N,N-dimethylform-
formylchromone (XIV) with various 2-methylpyrimidin- amide (DMF) solution at 100 ° in the presence of 4
4(3H)-ones XV. Such an approach to the synthesis of equivalents of TMSCl giving pyrido[2,1-b]quinazoline 3a
fused pyrido[1,2-a]pyrimidin-4-ones had not been used as a single product of cyclization in 98% yield (Scheme 2,
previously.
Table 1). This synthesis is a general one: not only does 2-
cyanomethyl-substituted quinazolone 2a take part in the
HMBC
O
H
O
OH
O
O
O
N
TMSCl
DMF
N
O
NH
R2
R2
+
R1
N
R1
1
3a–n
2a–n
R1
N
O
O
N
OH
R2
XVI
Scheme 2
Table 1 Chlorotrimethylsilane-Promoted Synthesis of 11H-Pyrido[2,1-b]quinazolin-11-ones 3a–n
Product
3a
R1
R2
Time (h)
12
Yielda,b (%)
Mpc (°C)
Crystallization solvent
DMF–EtOH
DMF–MeOH
DMF–EtOH
DMF–MeOH
DMF–MeOH
DMF–MeOH
DMF–MeOH
DMF–EtOH
DMF–EtOH
EtOH
CN
H
98
80
88
81
84
92
85
84
82
59
68
71
78
73
229–230
175
3b
3c
H
H
15
Cl
H
18
234
3d
3e
Cl
2-Cl
18
239–240
>300
Cl
3-Cl
18
3f
Cl
3-CO2H
15
288–289
246–247
177–178
283
3g
Cl
3-CO2Me
15
3h
3i
Cl
4-Me
18
Cl
2,3-(OMe)2
20
3j
CH2CO2H
(CH2)2CO2H
N(CH2)4NH
N(CH2)4NMe
N(CH2)4O
H
H
H
H
H
24
190
3k
3l
24
206–207
257
EtOH
30
MeCN
3m
3n
30
195
MeCN–i-PrOH
MeCN–EtOH
30
230–231
a Yields refer to the pure isolated products.
b Satisfactory microanalyses were obtained: C 0.33; H 0.45; N 0.25.
c Melting points are uncorrected.
Synthesis 2008, No. 7, 1069–1077 © Thieme Stuttgart · New York

PAPER
A New One-Step Route for the Synthesis of Fused Pyrido[1,2-a]pyrimidin-4-ones
1071
reaction, but also quinazolones containing any substituent trogen atoms. The latter reaction may lead to the forma-
on the CH2 moiety at the 2-position, such as chloromethyl tion of pyrido[1,2-a]quinazolin-6-ones XVI instead of
derivatives 2c–i, acids 2j and 2k, and amines 2l–n, react structures 3a–n. However, the 2D heteronuclear multiple
as well to give the corresponding 11H-pyrido[2,1- bond correlation (HMBC) NMR spectra of compounds 3
b]quinazolin-11-ones 3b–n (Scheme 2, Table 1). The re- showed correlation between H-9 and the two carbon at-
placement of a strong acceptor (nitrile) by a weaker one oms C-11 and in the carbonyl moiety at C-8 providing ev-
influences the reaction time and yields of the target 11H- idence for the exclusive formation of structures 3.
pyrido[2,1-b]quinazolin-11-ones, but does not limit the
reaction itself.
Similarly, performing the cyclization using 2-methyl-
thieno[2,3-d]pyrimidin-4(3H)-ones 4a–f, 6a–g, and 8a–d,
It should be noted that 2-methylquinazolin-4(3H)-ones which are sulfur isosteres of 2-methylquinazolones 2a–n,
2a–n can undergo cyclization at both the N-1 and N-3 ni- leads to the formation of the corresponding 4H-pyri-
HMBC
O
N
H
O
OH
R3
O
R3
TMSCl
DMF
N
NH
R2
+
1
R2
R1
S
S
N
TMSCl
DMF
R1
4a–f, 6a–g, 8a–d
TMSCl
DMF
6b
100 °C
12 h
5a–f, 7a–g, 9a–d
100 °C
24 h
O
NH
O
S
N
10 (82%)
O
Scheme 3
Table 2 Chlorotrimethylsilane-Promoted Synthesis of 4H-Pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-ones 5a–f, 7a–g, and 9a–d
Product
5a
R1
R2
R3
Time (h)
12
Yielda,b (%)
Mpc (°C)
205
Crystallization solvent
DMF–EtOH
DMF–EtOH
DMF–EtOH
DMF–EtOH
DMF–EtOH
DMF–EtOH
DMF–MeOH
DMF–EtOH
DMF–MeOH
DMF–EtOH
MeCN
CN
Me
Me
Me
Me
Me
Me
Me
95
89
92
79
77
73
95
89
92
73
75
70
79
68
77
80
69
5b
5c
CO2Me
Me
12
210
CON(CH2)4
Me
12
263–264
229
5d
5e
Cl
Me
28
SMe
Me
32
265
5f
SCH(Me)CO2H
Me
32
>300
7a
CN
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
CO2H
CO2H
CO2H
CO2H
12
146–147
176–177
262
7b
7c
H
36
Cl
30
7d
7e
SMe
32
263–264
183–184
246–247
232
SCH2CO2H
32
7f
S(CH2)2CO2H
32
DMF–MeOH
DMF
7g
2-py
H
20
9a
Me
Me
Me
Me
12
274
DMF–EtOH
DMF–MeOH
DMF–EtOH
DMF
9b
9c
Cl
24
>300
SMe
Ph
28
>300
9d
24
>300
a Yields refer to the pure isolated products.
b Satisfactory microanalyses were obtained C 0.33; H 0.45; N 0.25.
c Melting points are uncorrected.
Synthesis 2008, No. 7, 1069–1077 © Thieme Stuttgart · New York

1072
A. S. Plaskon et al.
PAPER
do[1,2-a]thieno[2,3-d]pyrimidin-4-ones 5a–f, 7a–g, and with 3-formylchromone (1); the reaction resulted in the
9a–d in high yields (Scheme 3, Table 2). Their structures regioselective formation of compound 14 (Scheme 5).
were also confirmed by 2D HMBC NMR spectroscopy.
In summary, we have developed a new efficient route for
2-Methylthieno[2,3-d]pyrimidin-4(3H)-ones 4, 6, and 8
the preparation of fused pyrido[1,2-a]pyrimidin-4-ones
were less reactive toward 3-formylchromone (1) com-
from 2-methylpyrimidin-4(3H)-ones and 3-formyl-
chromone using chlorotrimethylsilane as a promoter and
water scavenger. The methodology is applicable to a wide
variety of 2-methylpyrimidin-4(3H)-ones and delivers the
target products in good yields. The procedure is very sim-
ple and can be easily adapted to the semiautomated solu-
tion-phase parallel synthesis of pyrido[1,2-a]pyrimidin-4-
pared with their benzo analogues 2. This resulted in a de-
crease in the reaction rate and led to an increase in the
required substrate heating time. In addition, the reactivity
of substrates 4a–f, 6a–g, and 8a–d is greatly influenced
by the substituent R1 on the CH2 moiety. Thus, in the case
of R1 = dialkylamino no reaction was observed, even after
heating for 48 hours, unlike the corresponding reaction of
one libraries.
amines 2l–n. The introduction of a carboxy group on the
thiophene ring (compounds 8a–d) increases the activity of
All chemicals were obtained from commercially available sources
(Aldrich, Fluka, Enamine Ltd.) and were used without further puri-
fication. DMF was freshly distilled and dried by standard methods;
the monitoring of H2O in solvents (the solvents contained <0.05,
the substrate in comparison with the dimethyl 4a–f and
cyclohexyl 6a–g derivatives. This is confirmed by the fact
that heating thieno[2,3-d]pyrimidine-6-carboxylic acid 8a
and 3-formylchromone (1) for 12 hours leads to the for-
mation of compound 9a, while thieno[2,3-d]pyrimidin-
4(3H)-one 6b under the same conditions converts into the
corresponding condensation product 10. With subsequent
heating (up to 24 h), the latter transforms into the target
compound 7b (Scheme 3). The result suggests that the re-
action of 2-methylpyrimidin-4(3H)-ones with 3-formyl-
chromone (1) proceeds via the intermediate formation of
a benzylidene analogue, which undergoes cyclization to
give the target fused pyrido[1,2-a]pyrimidin-4-ones. Only
in the case of amines 2l–n do we consider the reaction to
start with the nitrogen atom; this is indirectly confirmed
by the fact that these substrates do not react with the usual
aromatic aldehydes under analogous conditions.13f
usually 0.02%, of H2O) was performed using a Mettler Toledo
DL31 KF titrator. All crystallization solvents were used without ad-
ditional purification. All procedures were carried out under open at-
mosphere with no precautions taken to exclude ambient moisture.
Melting points were measured with a Büchi melting point apparatus
and are uncorrected. Infrared spectra were recorded on a Nexus-470
spectrometer using KBr discs. 1H NMR spectra (400 and 500 MHz)
were recorded on Varian Mercury-400 and Bruker Avance DRX
500 spectrometers with TMS as an internal standard. 13C NMR
spectra (125 MHz) were recorded on a Bruker Avance DRX 500
spectrometer with TMS as an internal standard. Liquid chromatog-
raphy/mass spectrometry was performed using a system comprising
HPLC apparatus, Agilent 1100 Series, equipped with the diode-ma-
trix and mass-selective detector Agilent LC/MSD SL. According to
HPLC/MS data, all the synthesized compounds had a purity >95%.
Microanalyses were performed by the Microanalytical Laboratory
of the Institute of Organic Chemistry, National Academy of Sci-
ences of Ukraine. A Branson 2510E-MT ultrasonic bath was used.
2-(Chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (11)
also reacted with 3-formylchromone (1) affording the cor-
responding chloro derivative 12 (Scheme 4). The struc-
ture of 10H-pyrido[1,2-a]thieno[3,2-d]pyrimidin-10-one
12 was confirmed by 2D HMBC NMR spectroscopy. We
failed to perform the similar reaction of 2-(piperazin-1-yl-
methyl)thieno[3,2-d]pyrimidin-4(3H)-one, i.e. amine de-
rivatives were again the limiting case for the reactions of
this set of compounds.
Pyrido[1,2-a]pyrimidin-4-ones 3, 5, 7, 9, 12, and 14; General
Procedure
2-Methylpyrimidin-4(3H)-one 2, 4, 6, 8, 10, 11, or 13 (2 mmol) and
3-formylchromone (1) (2 mmol) were placed in a 15-mL pressure
tube and were dissolved in DMF (3–5 mL). Then, TMSCl (869 mg,
8 mmol) was added dropwise to the solution. The tube was thor-
oughly sealed and heated using a water bath for 12–36 h. After cool-
ing, the flask was opened (caution: excessive pressure inside), and
the mixture was poured into H2O (15 mL) and allowed to stand at
20 °C in an ultrasonic bath for 1 h. The precipitate that formed was
filtered and washed with i-PrOH (2 mL). Recrystallization using the
appropriate solvent (see also Tables 1 and 2) yielded the corre-
sponding target compound.
Monocyclic 3-(2,4-dimethyl-6-oxo-1,6-dihydropyrimi-
din-5-yl)propanoic acid (13) also successfully reacted
HMBC
O
N
H
O
OH
O
S
S
TMSCl
N
NH
8-(2-Hydroxybenzoyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-6-
carbonitrile (3a)
IR (KBr): 3650–3100 (br, OH), 2958, 2926, 2200 (C≡N), 1707
(C=OC-11), 1635 (C=O), 1601, 1576, 1558, 1462, 1335, 1255, 1221,
1153, 1122, 997, 764 cm–1.
1
+
Cl
DMF, 28 h
N
Cl
11
12 (85%)
Scheme 4
HMBC
O
OH
O
N
H
O
HOOC
TMSCl
DMF, 24 h
HOOC
NH
N
+
1
N
13
14 (68%)
Scheme 5
Synthesis 2008, No. 7, 1069–1077 © Thieme Stuttgart · New York

PAPER
A New One-Step Route for the Synthesis of Fused Pyrido[1,2-a]pyrimidin-4-ones
1073
3
1H NMR (400 MHz, DMSO-d6): d = 7.01 (t, JH,H = 8.3 Hz, 1 H,
CH), 7.06 (d, 3JH,H = 8.3 Hz, 1 H, CH), 7.48 (d, 3JH,H = 8.3 Hz, 1 H,
CH), 7.52 (t, 3JH,H = 8.3 Hz, 1 H, CH), 7.65 (t, 3JH,H = 8.4 Hz, 1 H,
CH), 7.86 (d, 3JH,H = 8.4 Hz, 1 H, CH), 8.02 (t, 3JH,H = 8.4 Hz, 1 H,
CH), 8.31 (d, 3JH,H = 8.4 Hz, 1 H, CH), 8.66 (d, 4JH,H = 1.7 Hz, 1 H,
CH), 9.11 (d, 4JH,H = 1.7 Hz, 1 H, CH), 10.49 (s, 1 H, OH).
13C NMR (125 MHz, DMSO-d6): d = 115.4, 117.4, 119.9, 122.4,
124.5, 127.0, 127.4, 129.6, 129.7, 130.7, 132.1, 132.4, 134.2, 141.3,
145.3, 148.5, 156.7, 158.5, 191.9.
APSI-MS: m/z = 385 [M+ + 1].
6-Chloro-8-(2-hydroxybenzoyl)-11-oxo-11H-pyrido[2,1-
b]quinazoline-3-carboxylic Acid (3f)
13C NMR (125 MHz, DMSO-d6): d = 109.9, 115.4, 117.1, 117.4,
120.0, 121.9, 124.2, 127.4, 127.72, 127.74, 131.0, 134.5, 136.7,
136.9, 142.7, 145.1, 147.4, 156.8, 158.6, 191.2.
3
1H NMR (400 MHz, DMSO-d6): d = 7.00 (t, JH,H = 8.1 Hz, 1 H,
CH), 7.05 (d, 3JH,H = 8.1 Hz, 1 H, CH), 7.45 (d, 3JH,H = 8.1 Hz, 1 H,
3
3
CH), 7.51 (t, JH,H = 8.1 Hz, 1 H, CH), 8.03 (dd, JH,H = 8.3 Hz,
4JH,H = 1.0 Hz, 1 H, CH), 8.18 (d, 4JH,H = 2.0 Hz, 1 H, CH), 8.27 (d,
4JH,H = 1.0 Hz, 1 H, CH), 8.36 (d, 3JH,H = 8.3 Hz, 1 H, CH), 8.96 (d,
4JH,H = 2.0 Hz, 1 H, CH), 10.40 (s, 1 H, OH), 13.63 (br s, 1 H,
CO2H).
APSI-MS: m/z = 342 [M+ + 1].
8-(2-Hydroxybenzoyl)-11H-pyrido[2,1-b]quinazolin-11-one
(3b)
IR (KBr): 3650–3110 (br, OH), 2926, 1709 (C=OC-11), 1641 (C=O),
1622, 1605, 1552, 1470, 1458, 1421, 1340, 1309, 1246, 1153, 928,
771, 748, 660 cm–1.
13C NMR (125 MHz, DMSO-d6): d = 115.4, 117.4, 119.9, 122.4,
124.5, 127.0, 127.4, 129.6, 129.7, 130.7, 132.1, 132.4, 134.2, 141.3,
145.3, 148.5, 156.7, 158.5, 191.9.
3
1H NMR (500 MHz, DMSO-d6): d = 6.99 (t, JH,H = 8.2 Hz, 1 H,
3
CH), 7.04 (d, JH,H = 8.2 Hz, 1 H, CH), 7.42–7.51 (m, 2 H, CH),
APSI-MS: m/z = 395 [M+ + 1], 393 [M– – 1].
7.52–7.57 (m, 2 H, CH), 7.77 (d, 3JH,H = 8.1 Hz, 1 H, CH), 7.91–7.97
(m, 2 H, CH), 8.27 (d, 3JH,H = 8.1 Hz, 1 H, CH), 9.01 (s, 1 H, CH),
10.32 (s, 1 H, OH).
Methyl 6-Chloro-8-(2-hydroxybenzoyl)-11-oxo-11H-pyri-
do[2,1-b]quinazoline-3-carboxylate (3g)
1H NMR (500 MHz, DMSO-d6): d = 3.94 (s, 3 H, OCH3), 7.00 (t,
3JH,H = 8.3 Hz, 1 H, CH), 7.05 (d, 3JH,H = 8.3 Hz, 1 H, CH), 7.45 (d,
3JH,H = 8.3 Hz, 1 H, CH), 7.50 (t, 3JH,H = 8.3 Hz, 1 H, CH), 8.01 (d,
3JH,H = 8.3 Hz, 1 H, CH), 8.17 (d, 4JH,H = 1.7 Hz, 1 H, CH), 8.25 (s,
1 H, CH), 8.35 (d, 3JH,H = 8.3 Hz, 1 H, CH), 8.94 (d, 4JH,H = 1.7 Hz,
1 H, CH), 10.40 (s, 1 H, OH).
13C NMR (125 MHz, DMSO-d6): d = 116.5, 117.3, 119.8, 123.4,
125.0, 126.26, 126.28, 127.4, 127.5, 130.6, 132.7, 133.3, 133.8,
136.1, 147.3, 148.3, 156.6, 158.8, 193.0.
APSI-MS: m/z = 317 [M+ + 1].
6-Chloro-8-(2-hydroxybenzoyl)-11H-pyrido[2,1-b]quinazolin-
11-one (3c)
IR (KBr): 3650–3120 (br, OH), 3097, 2924, 1705 (C=OC-11), 1637
(C=O), 1599, 1552, 1468, 1458, 1348, 1244, 1151, 1119, 1007, 804,
768, 731 cm–1.
13C NMR (125 MHz, DMSO-d6): d = 53.3, 117.4, 119.4, 119.9,
122.5, 124.5, 126.0, 128.4, 129.0, 129.1, 129.7, 130.7, 132.1, 134.2,
136.3, 144.9, 147.2, 156.7, 158.7, 165.7, 191.8.
APSI-MS: m/z = 409 [M+ + 1].
1H NMR (400 MHz, DMSO-d6): d = 7.00 (t, JH,H = 8.3 Hz, 1 H,
3
6-Chloro-8-(2-hydroxybenzoyl)-4-methyl-11H-pyrido[2,1-
b]quinazolin-11-one (3h)
CH), 7.06 (d, 3JH,H = 8.3 Hz, 1 H, CH), 7.46 (d, 3JH,H = 8.3 Hz, 1 H,
CH), 7.50 (t, 3JH,H = 8.3 Hz, 1 H, CH), 7.62 (t, 3JH,H = 8.1 Hz, 1 H,
CH), 7.85 (d, 3JH,H = 8.1 Hz, 1 H, CH), 7.99 (t, 3JH,H = 8.1 Hz, 1 H,
CH), 8.14 (d, 4JH,H = 1.7 Hz, 1 H, CH), 8.28 (d, 3JH,H = 8.1 Hz, 1 H,
CH), 8.97 (d, 4JH,H = 1.7 Hz, 1 H, CH), 10.41 (br s, 1 H, OH).
1H NMR (400 MHz, DMSO-d6): d = 2.62 (s, 3 H, CH3), 7.00 (t,
3JH,H = 8.3 Hz, 1 H, CH), 7.05 (d, 3JH,H = 8.3 Hz, 1 H, CH), 7.38–
7.53 (m, 3 H, CH), 7.80 (d, 3JH,H = 8.0 Hz, 1 H, CH), 8.06 (d, 3JH,H
=
8.0 Hz, 1 H, CH), 8.10 (s, 1 H, CH), 8.91 (s, 1 H, CH), 10.38 (s, 1
H, OH).
13C NMR (125 MHz, DMSO-d6): d = 17.4, 116.3, 117.3, 119.8,
122.0, 124.7, 125.1, 126.7, 130.0, 130.6, 131.0, 132.3, 134.0, 136.2,
136.5, 143.0, 145.8, 156.6, 159.1, 192.0.
13C NMR (125 MHz, DMSO-d6): d = 116.6, 117.3, 119.9, 122.0,
124.6, 127.2, 127.6, 128.0, 129.7, 130.7, 131.5, 132.5, 134.0, 136.6,
144.2, 147.4, 156.6, 159.0, 192.0.
APSI-MS: m/z = 351 [M+ + 1].
APSI-MS: m/z = 365 [M+ + 1].
2,6-Dichloro-8-(2-hydroxybenzoyl)-11H-pyrido[2,1-b]quinazo-
lin-11-one (3d)
6-Chloro-8-(2-hydroxybenzoyl)-2,3-dimethoxy-11H-pyri-
do[2,1-b]quinazolin-11-one (3i)
3
1H NMR (500 MHz, DMSO-d6): d = 7.00 (t, JH,H = 8.0 Hz, 1 H,
CH), 7.05 (d, 3JH,H = 8.0 Hz, 1 H, CH), 7.44 (d, 3JH,H = 8.0 Hz, 1 H,
CH), 7.49 (t, 3JH,H = 8.0 Hz, 1 H, CH), 7.84 (d, 3JH,H = 8.8 Hz, 1 H,
CH), 7.97 (dd, JH,H = 8.8 Hz, JH,H = 2.2 Hz, 1 H, CH), 8.16 (d,
4JH,H = 1.5 Hz, 1 H, CH), 8.19 (d, 4JH,H = 2.2 Hz, 1 H, CH), 8.93 (d,
4JH,H = 1.5 Hz, 1 H, CH), 10.40 (s, 1 H, OH).
13C NMR (125 MHz, DMSO-d6): d = 117.4, 117.6, 119.9, 122.5,
124.5, 126.2, 129.7, 130.2, 130.7, 131.2, 131.9, 132.1, 134.2, 136.5,
144.4, 146.1, 156.7, 158.1, 191.8.
1H NMR (500 MHz, DMSO-d6): d = 3.90 (s, 3 H, OCH3), 3.98 (s, 3
H, OCH3), 6.99 (t, 3JH,H = 8.3 Hz, 1 H, CH), 7.03 (d, 3JH,H = 8.3 Hz,
1 H, CH), 7.25 (s, 1 H, CH), 7.46 (d, 3JH,H = 8.3 Hz, 1 H, CH), 7.44–
3
4
7.51 (m, 2 H, CH), 8.07 (d, 4JH,H = 1.5 Hz, 1 H, CH), 8.98 (d, 4JH,H
1.5 Hz, 1 H, CH), 10.34 (s, 1 H, OH).
13C NMR (125 MHz, DMSO-d6): d = 56.3, 56.8, 105.5, 108.1,
109.5, 117.3, 119.8, 121.9, 124.6, 129.3, 130.4, 130.8, 132.1, 134.0,
142.8, 144.1, 149.5, 156.7, 156.8, 157.4, 192.0.
=
APSI-MS: m/z = 385 [M+ + 1].
APSI-MS: m/z = 411 [M+ + 1].
3,6-Dichloro-8-(2-hydroxybenzoyl)-11H-pyrido[2,1-b]quinazo-
[8-(2-Hydroxybenzoyl)-11-oxo-11H-pyrido[2,1-b]quinazolin-6-
yl]acetic Acid (3j)
lin-11-one (3e)
3
1H NMR (500 MHz, DMSO-d6): d = 6.99 (t, JH,H = 8.1 Hz, 1 H,
1H NMR (500 MHz, DMSO-d6): d = 3.99 (s, 2 H, CH2), 6.99 (t,
3JH,H = 8.5 Hz, 1 H, CH), 7.04 (d, 3JH,H = 8.5 Hz, 1 H, CH), 7.48 (d,
3JH,H = 8.5 Hz, 1 H, CH), 7.52 (t, 3JH,H = 8.5 Hz, 1 H, CH), 7.57 (t,
3JH,H = 8.3 Hz, 1 H, CH), 7.72 (d, 3JH,H = 8.3 Hz, 1 H, CH), 7.98 (t,
3JH,H = 8.3 Hz, 1 H, CH), 8.22 (d, 4JH,H = 1.5 Hz, 1 H, CH), 8.28 (d,
CH), 7.06 (d, 3JH,H = 8.1 Hz, 1 H, CH), 7.44 (d, 3JH,H = 8.1 Hz, 1 H,
CH), 7.49 (t, 3JH,H = 8.1 Hz, 1 H, CH), 7.59 (d, 3JH,H = 8.6 Hz, 1 H,
CH), 7.85 (s, 1 H, CH), 8.16 (s, 1 H, CH), 8.23 (d, 3JH,H = 8.6 Hz, 1
H, CH), 8.93 (s, 1 H, CH), 10.43 (br s, 1 H, OH).
Synthesis 2008, No. 7, 1069–1077 © Thieme Stuttgart · New York

1074
A. S. Plaskon et al.
PAPER
3
3JH,H = 8.3 Hz, 1 H, CH), 8.99 (d, 4JH,H = 1.5 Hz, 1 H, CH), 10.34
(br s, 1 H, OH), 12.48 (br s, 1 H, CO2H).
13C NMR (125 MHz, DMSO-d6): d = 37.1, 116.5, 117.3, 119.0,
119.8, 120.8, 125.1, 126.2, 126.6, 127.4, 130.7, 133.4, 133.9, 134.7,
136.3, 145.9, 147.6, 157.7, 159.1, 176.0, 193.3.
(dd, 3JH,H = 8.0 Hz, 4JH,H = 1.5 Hz, 1 H, CH), 7.47 (td, JH,H = 8.0
Hz, 4JH,H = 1.5 Hz, 1 H, CH), 7.56 (t, 3JH,H = 8.3 Hz, 1 H, CH), 7.77
(d, 3JH,H = 8.3 Hz, 1 H, CH), 7.93 (td, 3JH,H = 8.0 Hz, 4JH,H = 1.5 Hz,
1 H, CH), 8.24 (dd, 3JH,H = 8.0 Hz, 4JH,H = 1.5 Hz, 1 H, CH), 8.76
(d, 4JH,H = 1.7 Hz, 1 H, CH), 10.25 (s, 1 H, OH).
13C NMR (125 MHz, DMSO-d6): d = 51.1, 66.6, 113.8, 116.4,
117.2, 119.7, 122.9, 125.2, 126.6, 127.0, 127.3, 128.1, 130.4, 133.5,
136.0, 143.4, 145.0, 146.8, 156.5, 159.4, 193.6.
APSI-MS: m/z = 375 [M+ + 1], 373 [M– – 1].
3-[8-(2-Hydroxybenzoyl)-11-oxo-11H-pyrido[2,1-b]quinazolin-
6-yl]propanoic Acid (3k)
APSI-MS: m/z = 402 [M+ + 1].
IR (KBr): 3650–3120 (br, OH), 3103, 2924, 1719 (C=Oacid), 1695
(C=OC-11¢), 1639 (C=O), 1606, 1564, 1537, 1471, 1406, 1335, 1248,
1157, 1120, 995, 904, 768 cm–1.
7-(2-Hydroxybenzoyl)-2,3-dimethyl-4-oxo-4H-pyrido[1,2-
a]thieno[2,3-d]pyrimidine-9-carbonitrile (5a)
IR (KBr): 3650–3110 (br, OH), 3097, 3059, 2926, 2198 (CN), 1716
(C=OC-4), 1624 (C=O), 1606, 1529, 1456, 1419, 1396, 1281, 1246,
1186, 1151, 1117, 1034, 958, 870, 760, 729 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.43 (s, 3 H, CH3), 2.44 (s, 3
H, CH3), 7.01 (t, 3JH,H = 8.1 Hz, 1 H, CH), 7.05 (d, 3JH,H = 8.1 Hz, 1
H, CH), 7.48 (d, 3JH,H = 8.1 Hz, 1 H, CH), 7.52 (t, 3JH,H = 8.1 Hz, 1
H, CH), 8.71 (d, 4JH,H = 2.0 Hz, 1 H, CH), 9.24 (d, 4JH,H = 2.0 Hz, 1
H, CH), 10.49 (s, 1 H, OH).
13C NMR (125 MHz, DMSO-d6): d = 13.4 (C-2, C-3, observed as
singlet with ca. double the intensity of the other signals), 109.3,
115.1, 117.4, 120.0, 123.0, 124.2, 125.8, 129.4, 131.0, 131.3, 134.5,
136.5, 142.0, 145.2, 153.7, 156.8, 162.9, 191.3.
3
1H NMR (500 MHz, DMSO-d6): d = 2.76 (t, JH,H = 7.2 Hz, 2 H,
CH2), 3.21 (t, 3JH,H = 7.2 Hz, 2 H, CH2), 6.99 (t, 3JH,H = 8.1 Hz, 1 H,
CH), 7.04 (d, 3JH,H = 8.1 Hz, 1 H, CH), 7.43 (d, 3JH,H = 8.1 Hz, 1 H,
CH), 7.47 (t, 3JH,H = 8.1 Hz, 1 H, CH), 7.54 (t, 3JH,H = 8.1 Hz, 1 H,
CH), 7.78 (d, 3JH,H = 8.1 Hz, 1 H, CH), 7.86 (s, 1 H, CH), 7.92 (t,
3JH,H = 8.1 Hz, 1 H, CH), 8.24 (d, 3JH,H = 8.1 Hz, 1 H, CH), 8.94 (s,
1 H, CH), 10.27 (br s, 1 H, OH), 12.13 (br s, 1 H, CO2H).
13C NMR (125 MHz, DMSO-d6): d = 27.0, 32.7, 116.3, 117.3,
119.8, 122.6, 125.0, 126.4, 127.3, 127.9, 129.6, 130.5, 132.1, 133.7,
136.1, 136.3, 146.7, 147.7, 156.5, 159.1, 174.3, 193.2.
APSI-MS: m/z = 389 [M+ + 1], 387 [M– – 1].
8-(2-Hydroxybenzoyl)-6-piperazin-1-yl-11H-pyrido[2,1-
b]quinazolin-11-one Hydrochloride (3l)
APSI-MS: m/z = 376 [M+ + 1].
1H NMR (400 MHz, DMSO-d6): d = 3.35–3.41 (m, 4 H, 2 CH2),
3.59–3.66 (m, 4 H, 2 CH2), 6.99 (t, 3JH,H = 8.1 Hz, 1 H, CH), 7.06
(d, 3JH,H = 8.1 Hz, 1 H, CH), 7.31 (d, 4JH,H = 1.0 Hz, 1 H, CH), 7.41
(d, 3JH,H = 8.1 Hz, 1 H, CH), 7.47 (t, 3JH,H = 8.1 Hz, 1 H, CH), 7.58
(t, 3JH,H = 8.0 Hz, 1 H, CH), 7.82 (d, 3JH,H = 8.0 Hz, 1 H, CH), 7.96
(t, 3JH,H = 8.0 Hz, 1 H, CH), 8.25 (d, 3JH,H = 8.0 Hz, 1 H, CH), 8.79
(d, 4JH,H = 1.0 Hz, 1 H, CH), 9.28 (br s, 1 H, NH2), 10.30 (s, 1 H,
OH).
Methyl 7-(2-Hydroxybenzoyl)-2,3-dimethyl-4-oxo-4H-pyri-
do[1,2-a]thieno[2,3-d]pyrimidine-9-carboxylate (5b)
IR (KBr): 3640–3100 (br, OH), 2956, 2924, 1747 (C=Oester), 1709
(C=OC-4), 1630 (C=O), 1608, 1520, 1454, 1437, 1398, 1286, 1269,
1246, 1088, 1036, 968, 769 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.41 (s, 3 H, CH3), 2.44 (s, 3
H, CH3), 3.93 (s, 3 H, OCH3), 7.01 (t, 3JH,H = 8.5 Hz, 1 H, CH), 7.04
(d, 3JH,H = 8.5 Hz, 1 H, CH), 7.45–7.53 (m, 2 H, CH), 8.29 (d, 4JH,H
= 2.2 Hz, 1 H, CH), 9.24 (d, 4JH,H = 2.2 Hz, 1 H, CH), 10.41 (s, 1 H,
OH).
13C NMR (125 MHz, DMSO-d6): d = 43.3, 47.3, 114.7, 116.4,
117.2, 119.6, 122.7, 125.2, 126.7, 127.3, 127.5, 128.2, 130.3, 133.5,
136.1, 143.2, 144.1, 146.8, 156.5, 159.3, 193.5.
13C NMR (125 MHz, DMSO-d6): d = 13.4, 13.5, 53.4, 116.9, 117.3,
119.9, 122.9, 124.6, 128.5, 129.2, 130.7, 130.8, 133.7, 134.2, 135.0,
144.1, 153.9, 156.6, 163.1, 165.0, 192.3.
APSI-MS: m/z = 401 [M+ + 1].
8-(2-Hydroxybenzoyl)-6-(4-methylpiperazin-1-yl)-11H-pyri-
do[2,1-b]quinazolin-11-one Hydrochloride (3m)
APSI-MS: m/z = 409 [M+ + 1].
IR (KBr): 3650–3100 (br, OH, NH), 2954, 2926, 1695 (C=OC-11),
1632 (C=O), 1606, 1564, 1539, 1470, 1456, 1406, 1342, 1296,
1250, 1149, 1130, 1007, 920, 769 cm–1.
7-(2-Hydroxybenzoyl)-2,3-dimethyl-9-(pyrrolidin-1-ylcarbon-
yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one (5c)
1H NMR (500 MHz, DMSO-d6): d = 1.73–1.82 (m, 2 H, CH2), 1.85–
1.93 (m, 2 H, CH2), 2.41 (s, 3 H, CH3), 2.45 (s, 3 H, CH3), 3.18 (t,
3JH,H = 6.4 Hz, 2 H, CH2), 3.53 (t, 3JH,H = 6.4 Hz, 2 H, CH2), 7.00 (t,
3JH,H = 8.3 Hz, 1 H, CH), 7.03 (d, 3JH,H = 8.3 Hz, 1 H, CH), 7.44–
1H NMR (400 MHz, DMSO-d6): d = 2.88 (s, 3 H, CH3), 3.24 (t,
3JH,H = 7.9 Hz, 2 H, CH2), 3.38–3.45 (m, 2 H, CH2), 3.54–3.64 (m,
3
2 H, CH2), 4.10–4.20 (m, 2 H, CH2), 6.98 (t, JH,H = 8.1 Hz, 1 H,
CH), 7.07 (d, 3JH,H = 8.1 Hz, 1 H, CH), 7.33 (d, 4JH,H = 1.3 Hz, 1 H,
CH), 7.40 (d, 3JH,H = 8.1 Hz, 1 H, CH), 7.47 (t, 3JH,H = 8.1 Hz, 1 H,
CH), 7.58 (t, 3JH,H = 8.1 Hz, 1 H, CH), 7.79 (d, 3JH,H = 8.1 Hz, 1 H,
CH), 7.96 (t, 3JH,H = 8.1 Hz, 1 H, CH), 8.25 (d, 3JH,H = 8.1 Hz, 1 H,
CH), 8.78 (d, 4JH,H = 1.3 Hz, 1 H, CH), 10.33 (s, 1 H, OH), 10.94 (br
s, 1 H, NH).
7.52 (m, 2 H, CH), 7.95 (d, JH,H = 2.0 Hz, 1 H, 4-py), 9.20 (d,
4
4JH,H = 2.0 Hz, 1 H, 2-py), 10.36 (s, 1 H, OH).
13C NMR (125 MHz, DMSO-d6): d = 13.4, 13.5, 24.5, 25.9, 45.9,
47.7, 116.8, 117.3, 119.9, 123.8, 124.8, 129.2, 130.3, 130.7, 130.9,
133.2, 134.05, 134.12, 144.1, 154.2, 156.6, 163.4, 163.8, 192.7.
APSI-MS: m/z = 448 [M+ + 1].
13C NMR (125 MHz, DMSO-d6): d = 42.5, 47.3, 52.7, 114.8, 116.4,
117.2, 119.7, 122.7, 125.2, 126.8, 127.3, 127.6, 128.1, 130.3, 133.5,
136.2, 143.3, 143.7, 146.8, 156.5, 159.3, 193.4.
9-Chloro-7-(2-hydroxybenzoyl)-2,3-dimethyl-4H-pyrido[1,2-
a]thieno[2,3-d]pyrimidin-4-one (5d)
IR (KBr): 3650–3120 (br, OH), 3105, 3051, 2924, 1705 (C=OC-4),
1622 (C=O), 1519, 1466, 1389, 1350, 1244, 1221, 1186, 1034, 964,
949, 769, 760 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.42 (s, 3 H, CH3), 2.43 (s, 3
H, CH3), 7.00 (t, 3JH,H = 8.0 Hz, 1 H, CH), 7.04 (d, 3JH,H = 8.0 Hz, 1
H, CH), 7.45 (d, 3JH,H = 8.0 Hz, 1 H, CH), 7.49 (t, 3JH,H = 8.0 Hz, 1
APSI-MS: m/z = 415 [M+ + 1].
8-(2-Hydroxybenzoyl)-6-morpholin-4-yl-11H-pyrido[2,1-
b]quinazolin-11-one (3n)
1H NMR (400 MHz, DMSO-d6): d = 2.48–2.52 (m, 4 H, 2 NCH2),
3.85–3.90 (m, 4 H, 2 CH2), 6.98 (t, 3JH,H = 8.3 Hz, 1 H, CH), 7.03
(d, 3JH,H = 8.3 Hz, 1 H, CH), 7.25 (d, 4JH,H = 1.7 Hz, 1 H, CH), 7.41
Synthesis 2008, No. 7, 1069–1077 © Thieme Stuttgart · New York

PAPER
A New One-Step Route for the Synthesis of Fused Pyrido[1,2-a]pyrimidin-4-ones
1075
H, CH), 8.21 (d, 4JH,H = 1.7 Hz, 1 H, CH), 9.11 (d, 4JH,H = 1.7 Hz, 1
APSI-MS: m/z = 377 [M+ + 1].
H, CH), 10.36 (s, 1 H, OH).
7-Chloro-9-(2-hydroxybenzoyl)-1,2,3,4-tetrahydro-12H-
[1]benzothieno[2,3-d]pyrido[1,2-a]pyrimidin-12-one (7c)
13C NMR (125 MHz, DMSO-d6): d = 13.3, 13.4, 117.4, 119.0,
119.9, 123.1, 124.5, 125.9, 129.2, 130.7, 131.1, 131.7, 134.1, 135.3,
143.9, 154.0, 156.7, 163.0, 192.0.
1H NMR (500 MHz, DMSO-d6): d = 1.73–1.85 (m, 4 H, 2 CH2),
2.75–2.82 (m, 2 H, CH2), 2.89–2.93 (m, 2 H, CH2), 6.99 (t, 3JH,H
8.5 Hz, 1 H, CH), 7.03 (d, 3JH,H = 8.5 Hz, 1 H, CH), 7.44 (d, 3JH,H
8.5 Hz, 1 H, CH), 7.49 (t, 3JH,H = 8.5 Hz, 1 H, CH), 8.22 (d, 4JH,H
=
=
=
APSI-MS: m/z = 385 [M+ + 1].
1.8 Hz, 1 H, CH), 9.10 (d, 4JH,H = 1.8 Hz, 1 H, CH), 10.37 (s, 1 H,
7-(2-Hydroxybenzoyl)-2,3-dimethyl-9-(methylsulfanyl)-4H-py-
rido[1,2-a]thieno[2,3-d]pyrimidin-4-one (5e)
IR (KBr): 3650–3100 (br, OH), 2924, 1693 (C=OC-4), 1622 (C=O),
1603, 1514, 1470, 1246, 1186, 1153, 1117, 1036, 982, 862, 758
cm–1.
OH).
13C NMR (125 MHz, DMSO-d6): d = 22.1, 22.8, 25.2, 25.6, 115.7,
117.3, 119.9, 123.1, 124.5, 129.1, 130.8, 131.3, 131.8, 132.1, 134.0,
134.1, 144.0, 153.7, 156.7, 163.6, 192.0.
1H NMR (400 MHz, DMSO-d6): d = 2.39 (s, 3 H, CH3), 2.41 (s, 3
APSI-MS: m/z = 411 [M+ + 1].
3
H, CH3), 2.55 (s, 3 H, SCH3), 7.00 (t, JH,H = 8.3 Hz, 1 H, CH), 7.04
(d, 3JH,H = 8.3 Hz, 1 H, CH), 7.45 (d, 3JH,H = 8.3 Hz, 1 H, CH), 7.49
(td, 3JH,H = 8.3 Hz, 4JH,H = 1.7 Hz, 1 H, CH), 7.66 (s, 1 H, CH), 8.91
(s, 1 H, CH), 10.30 (s, 1 H, OH).
9-(2-Hydroxybenzoyl)-7-(methylsulfanyl)-1,2,3,4-tetrahydro-
12H-[1]benzothieno[2,3-d]pyrido[1,2-a]pyrimidin-12-one (7d)
1H NMR (400 MHz, DMSO-d6): d = 1.74–1.86 (m, 4 H, 2 CH2),
2.56 (s, 3 H, SCH3), 2.75–2.81 (m, 2 H, CH2), 2.89–2.94 (m, 2 H,
CH2), 7.00 (t, 3JH,H = 8.2 Hz, 1 H, CH), 7.03 (d, 3JH,H = 8.2 Hz, 1 H,
CH), 7.44 (d, 3JH,H = 8.2 Hz, 1 H, CH), 7.49 (t, 3JH,H = 8.2 Hz, 1 H,
CH), 7.68 (s, 1 H, CH), 8.91 (s, 1 H, CH), 10.31 (s, 1 H, OH).
13C NMR (125 MHz, DMSO-d6): d = 13.3, 13.4, 14.2, 116.8, 117.3,
119.8, 123.3, 123.6, 124.9, 128.7, 129.1, 130.2, 130.6, 133.8, 137.7,
144.0, 154.1, 156.6, 162.5, 193.1.
APSI-MS: m/z = 397 [M+ + 1].
13C NMR (125 MHz, DMSO-d6): d = 14.2, 22.2, 22.8, 25.2, 25.7,
116.0, 117.3, 119.8, 123.5, 123.7, 124.8, 128.5, 130.7, 131.2, 133.2,
133.9, 137.7, 144.2, 153.8, 156.8, 163.1, 193.2.
2-{[7-(2-Hydroxybenzoyl)-2,3-dimethyl-4-oxo-4H-pyrido[1,2-
a]thieno[2,3-d]pyrimidin-9-yl]sulfanyl}propanoic Acid (5f)
1H NMR (400 MHz, DMSO-d6): d = 1.55 (d, 3JH,H = 7.1 Hz, 3 H,
CHCH3), 2.39 (s, 3 H, CH3), 2.41 (s, 3 H, CH3), 4.23 (q, 3JH,H = 7.1
APSI-MS: m/z = 423 [M+ + 1].
Hz, 1 H, CHCH3), 6.99 (t, 3JH,H = 8.5 Hz, 1 H, CH), 7.03 (d, 3JH,H
8.5 Hz, 1 H, CH), 7.43 (d, 3JH,H = 8.5 Hz, 1 H, CH), 7.48 (t, 3JH,H
=
=
{[9-(2-Hydroxybenzoyl)-12-oxo-1,2,3,4-tetrahydro-12H-[1]ben-
zothieno[2,3-d]pyrido[1,2-a]pyrimidin-7-yl]sulfanyl}acetic
Acid (7e)
8.5 Hz, 1 H, CH), 7.98 (s, 1 H, CH), 8.94 (s, 1 H, CH), 10.33 (br s,
1 H, OH), 12.97 (br s, 1 H, CO2H).
13C NMR (125 MHz, DMSO-d6): d = 13.2, 13.5, 16.4, 31.2, 117.3,
119.3, 119.9, 122.4, 124.6, 126.4, 128.3, 129.1, 130.7, 132.3, 134.1,
137.8, 144.9, 147.4, 156.6, 158.9, 166.8, 191.9.
1H NMR (400 MHz, DMSO-d6): d = 1.74–1.86 (m, 4 H, 2 CH2),
2.75–2.79 (m, 2 H, CH2), 2.88–2.92 (m, 2 H, CH2), 4.03 (s, 2 H,
SCH2), 6.99 (td, 3JH,H = 8.3 Hz, 4JH,H = 1.7 Hz, 1 H, CH), 7.03 (d,
3JH,H = 8.3 Hz, 1 H, CH), 7.43 (dd, 3JH,H = 8.3 Hz, 4JH,H = 1.7 Hz, 1
H, CH), 7.48 (td, 3JH,H = 8.3 Hz, 4JH,H = 1.7 Hz, 1 H, CH), 7.80 (d,
4JH,H = 1.8 Hz, 1 H, CH), 8.91 (d, 4JH,H = 1.8 Hz, 1 H, CH), 10.33
(br s, 1 H, OH), 12.79 (br s, 1 H, CO2H).
APSI-MS: m/z = 455 [M+ + 1], 453 [M– – 1].
9-(2-Hydroxybenzoyl)-12-oxo-1,2,3,4-tetrahydro-12H-[1]ben-
zothieno[2,3-d]pyrido[1,2-a]pyrimidine-7-carbonitrile (7a)
1H NMR (400 MHz, DMSO-d6): d = 1.78–1.88 (m, 4 H, 2 CH2),
13C NMR (125 MHz, DMSO-d6): d = 22.1, 22.8, 25.2, 25.7, 33.7,
116.0, 117.3, 119.8, 123.5, 124.5, 124.9, 129.4, 130.6, 131.2, 133.3,
133.8, 135.6, 144.0, 153.8, 156.6, 163.1, 170.4, 192.9.
2.80–2.85 (m, 2 H, CH2), 2.93–2.98 (m, 2 H, CH2), 7.01 (t, 3JH,H
8.3 Hz, 1 H, CH), 7.06 (d, 3JH,H = 8.3 Hz, 1 H, CH), 7.48 (d, 3JH,H
8.3 Hz, 1 H, CH), 7.52 (t, 3JH,H = 8.3 Hz, 1 H, CH), 8.69 (d, 4JH,H
=
=
=
APSI-MS: m/z = 467 [M+ + 1], 465 [M– – 1].
1.8 Hz, 1 H, CH), 9.26 (d, 4JH,H = 1.8 Hz, 1 H, CH), 10.42 (s, 1 H,
3-{[9-(2-Hydroxybenzoyl)-12-oxo-1,2,3,4-tetrahydro-12H-
[1]benzothieno[2,3-d]pyrido[1,2-a]pyrimidin-7-yl]sulfa-
nyl}propanoic Acid (7f)
IR (KBr): 3650–3100 (br, OH), 2926, 1741 (C=Oacid), 1697 (C=OC-12¢),
1624 (C=O), 1508, 1466, 1390, 1333, 1244, 1159, 1120, 1028, 974,
860, 764, 729 cm–1.
OH).
13C NMR (125 MHz, DMSO-d6): d = 22.1, 22.8, 25.2, 25.7, 109.4,
115.1, 116.4, 117.5, 120.0, 123.1, 124.2, 131.0, 131.5, 134.3, 134.5,
136.4, 142.0, 145.2, 153.4, 156.9, 163.6, 191.3.
APSI-MS: m/z = 402 [M+ + 1].
1H NMR (400 MHz, DMSO-d6): d = 1.74–1.86 (m, 4 H, 2 CH2),
2.70 (t, 3JH,H = 6.8 Hz, 2 H, CH2), 2.75–2.80 (m, 2 H, CH2), 2.89–
9-(2-Hydroxybenzoyl)-1,2,3,4-tetrahydro-12H-[1]ben-
zothieno[2,3-d]pyrido[1,2-a]pyrimidin-12-one (7b)
IR (KBr): 3650–3000 (br, OH), 2955, 2924, 1701 (C=OC-12), 1630
(C=O), 1605, 1522, 1466, 1439, 1404, 1335, 1242, 1155, 1126,
1036, 764, 727 cm–1.
2.93 (m, 2 H, CH2), 3.25 (t, 3JH,H = 6.8 Hz, 2 H, CH2), 6.99 (t, 3JH,H
8.3 Hz, 1 H, CH), 7.03 (d, 3JH,H = 8.3 Hz, 1 H, CH), 7.45 (d, 3JH,H
8.3 Hz, 1 H, CH), 7.48 (t, 3JH,H = 8.3 Hz, 1 H, CH), 7.74 (d, 4JH,H
=
=
=
1.5 Hz, 1 H, CH), 8.92 (d, 4JH,H = 1.5 Hz, 1 H, CH), 10.35 (br s, 1
1H NMR (500 MHz, DMSO-d6): d = 1.73–1.84 (m, 4 H, 2 CH2),
H, OH).
2.73–2.79 (m, 2 H, CH2), 2.88–2.94 (m, 2 H, CH2), 6.99 (t, 3JH,H
=
13C NMR (125 MHz, DMSO-d6): d = 22.1, 22.8, 25.2, 25.7, 25.9,
32.8, 116.0, 117.3, 119.8, 123.7, 124.2, 124.8, 128.9, 130.7, 131.2,
133.3, 133.9, 135.8, 144.2, 153.9, 156.7, 163.1, 173.0, 193.0.
8.0 Hz, 1 H, CH), 7.02 (d, 3JH,H = 8.0 Hz, 1 H, CH), 7.44 (dd, 3JH,H
= 8.0 Hz, 4JH,H = 1.8 Hz, 1 H, CH), 7.48 (td, 3JH,H = 8.0 Hz, 4JH,H
=
1.8 Hz, 1 H, CH), 7.61 (d, 3JH,H = 9.3 Hz, 1 H, CH), 8.04 (dd, 3JH,H
= 9.3 Hz, 4JH,H = 2.0 Hz, 1 H, CH), 9.14 (d, 4JH,H = 2.0 Hz, 1 H, CH),
10.31 (s, 1 H, OH).
APSI-MS: m/z = 481 [M+ + 1], 479 [M– – 1].
9-(2-Hydroxybenzoyl)-7-pyridin-2-yl-1,2,3,4-tetrahydro-12H-
[1]benzothieno[2,3-d]pyrido[1,2-a]pyrimidin-12-one (7g)
1H NMR (500 MHz, DMSO-d6): d = 1.75–1.85 (m, 4 H, 2 CH2),
13C NMR (125 MHz, DMSO-d6): d = 22.2, 22.8, 25.1, 25.7, 115.5,
117.3, 119.9, 124.5, 125.0, 125.6, 128.3, 130.6, 131.2, 132.7, 133.0,
133.9, 147.3, 153.8, 156.6, 164.5, 193.1.
2.72–2.78 (m, 2 H, CH2), 2.90–2.96 (m, 2 H, CH2), 7.01 (t, 3JH,H
=
Synthesis 2008, No. 7, 1069–1077 © Thieme Stuttgart · New York

1076
A. S. Plaskon et al.
PAPER
2-[(E)-2-(4-Oxo-4H-chromen-3-yl)vinyl]-5,6,7,8-tetrahy-
dro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one (10)
Mp >300 °C (DMF–EtOH).
1H NMR (500 MHz, DMSO-d6): d = 1.72–1.77 (m, 2 H, CH2), 1.77–
1.83 (m, 2 H, CH2), 2.70–2.75 (m, 2 H, CH2), 2.84–2.89 (m, 2 H,
CH2), 7.54 (t, 3JH,H = 8.5 Hz, 1 H, CH), 7.67 (d, 3JH,H = 15.6 Hz, 1
H, CH), 7.70 (d, 3JH,H = 8.5 Hz, 1 H, CH), 7.82 (d, 3JH,H = 15.6 Hz,
1 H, CH), 7.84 (t, 3JH,H = 8.5 Hz, 1 H, CH), 8.16 (d, 3JH,H = 8.5 Hz,
1 H, CH), 8.85 (s, 1 H, CH), 12.40 (s, 1 H, NH).
8.1 Hz, 1 H, CH), 7.04 (d, 3JH,H = 8.1 Hz, 1 H, CH), 7.44–7.52 (m,
3 H, CH), 7.94 (td, 3JH,H = 8.0 Hz, 4JH,H = 1.7 Hz, 1 H, CH), 8.24 (d,
3JH,H = 8.1 Hz, 1 H, CH), 8.44 (d, 4JH,H = 2.0 Hz, 1 H, CH), 8.73 (d,
3JH,H = 4.8 Hz, 1 H, CH), 9.28 (d, 4JH,H = 2.0 Hz, 1 H, CH), 10.35 (s,
1 H, OH).
13C NMR (125 MHz, DMSO-d6): d = 22.1, 22.8, 25.1, 25.7, 115.3,
117.3, 119.9, 123.7, 124.1, 124.9, 126.3, 130.7, 131.2, 131.5, 133.1,
133.9, 134.0, 134.1, 136.5, 145.7, 150.0, 153.1, 153.8, 156.6, 163.7,
193.0.
APSI-MS: m/z = 454 [M+ + 1].
13C NMR (125 MHz, DMSO-d6): d = 22.3, 23.0, 25.0, 25.7, 118.9,
119.3, 121.2, 122.8, 124.0, 125.9, 126.4, 130.9, 131.4, 132.2, 134.8,
152.2, 155.4, 158.8, 160.0, 163.7, 175.7.
7-(2-Hydroxybenzoyl)-3-methyl-4-oxo-4H-pyrido[1,2-
a]thieno[2,3-d]pyrimidine-2-carboxylic Acid (9a)
IR (KBr): 3650–3120 (br, OH), 3103, 2958, 2926, 1716 (C=Oacid),
1703 (C=OC-4), 1637 (C=O), 1531, 1464, 1377, 1335, 1306, 1242,
1149, 951, 768 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.86 (s, 3 H, CH3), 7.00 (t,
3JH,H = 8.3 Hz, 1 H, CH), 7.04 (d, 3JH,H = 8.3 Hz, 1 H, CH), 7.46 (d,
3JH,H = 8.3 Hz, 1 H, CH), 7.49 (t, 3JH,H = 8.3 Hz, 1 H, CH), 7.66 (d,
3JH,H = 9.0 Hz, 1 H, CH), 8.15 (dd, 3JH,H = 9.0 Hz, 4JH,H = 1.7 Hz, 1
H, CH), 9.16 (d, 4JH,H = 1.7 Hz, 1 H, CH), 10.40 (br s, 1 H, OH).
APSI-MS: m/z = 377 [M+ + 1].
5-Chloro-7-(2-hydroxybenzoyl)-10H-pyrido[1,2-a]thieno[3,2-
d]pyrimidin-10-one (12)
Mp 222 °C (DMF–MeOH).
IR (KBr): 3650–3290 (br, OH), 3076, 3024, 2980, 1709 (C=OC-10),
1643 (C=O), 1601, 1539, 1481, 1458, 1298, 1255, 1219, 1163, 802,
783, 758, 671 cm–1.
3
1H NMR (400 MHz, DMSO-d6): d = 6.99 (t, JH,H = 8.4 Hz, 1 H,
13C NMR (125 MHz, DMSO-d6): d = 15.3, 116.8, 117.3, 119.9,
123.4, 124.77, 124.88, 125.5, 130.7, 133.0, 134.1, 135.1, 143.0,
149.4, 154.9, 156.7, 164.0, 166.4, 192.9.
CH), 7.09 (d, 3JH,H = 8.4 Hz, 1 H, CH), 7.43–7.52 (m, 2 H, CH), 7.61
(d, 3JH,H = 5.3 Hz, 1 H, CH), 8.23 (d, 4JH,H = 1.4 Hz, 1 H, CH), 8.47
(d, 3JH,H = 5.3 Hz, 1 H, CH), 9.09 (d, 4JH,H = 1.4 Hz, 1 H, CH), 10.48
(s, 1 H, OH).
APSI-MS: m/z = 381 [M+ + 1], 379 [M– – 1].
13C NMR (125 MHz, DMSO-d6): d = 116.2, 117.4, 119.8, 123.2,
124.5, 126.0, 129.6, 130.8, 131.5, 132.0, 134.2, 139.7, 146.0, 154.3,
156.8, 157.3, 192.0.
9-Chloro-7-(2-hydroxybenzoyl)-3-methyl-4-oxo-4H-pyrido[1,2-
a]thieno[2,3-d]pyrimidine-2-carboxylic Acid (9b)
1H NMR (500 MHz, DMSO-d6): d = 2.86 (s, 3 H, CH3), 7.00 (t,
3JH,H = 8.3 Hz, 1 H, CH), 7.05 (d, 3JH,H = 8.3 Hz, 1 H, CH), 7.45 (d,
3JH,H = 8.3 Hz, 1 H, CH), 7.50 (t, 3JH,H = 8.3 Hz, 1 H, CH), 8.32 (d,
4JH,H = 1.5 Hz, 1 H, CH), 9.10 (d, 4JH,H = 1.5 Hz, 1 H, CH), 10.43 (s,
1 H, OH), 13.55 (br s, 1 H, CO2H).
APSI-MS: m/z = 357 [M+ + 1].
3-[7-(2-Hydroxybenzoyl)-2-methyl-4-oxo-4H-pyrido[1,2-a]py-
rimidin-3-yl]propanoic Acid (14)
Mp 198 °C (EtOH).
13C NMR (125 MHz, DMSO-d6): d = 15.2, 117.0, 117.4, 119.9,
123.6, 124.0, 124.4, 129.0, 130.8, 132.0, 133.8, 134.3, 143.2, 146.3,
154.8, 156.8, 163.7, 165.7, 191.8.
IR (KBr): 3650–3000 (br, OH), 2962, 2926, 1735 (C=Oacid), 1705
(C=OC-4), 1635 (C=O), 1558, 1456, 1443, 1340, 1248, 1228, 1120,
1036, 955, 731 cm–1.
APSI-MS: m/z = 415 [M+ + 1], 413 [M– – 1].
3
1H NMR (500 MHz, DMSO-d6): d = 2.43 (t, JH,H = 7.9 Hz, 2 H,
CH2), 2.46 (s, 3 H, CH3), 2.80 (t, 3JH,H = 7.9 Hz, 2 H, CH2), 6.98 (t,
3JH,H = 8.3 Hz, 1 H, CH), 7.01 (d, 3JH,H = 8.3 Hz, 1 H, CH), 7.44 (d,
3JH,H = 8.3 Hz, 1 H, CH), 7.48 (t, 3JH,H = 8.3 Hz, 1 H, CH), 7.60 (d,
3JH,H = 9.2 Hz, 1 H, CH), 8.07 (dd, 3JH,H = 9.2 Hz, 4JH,H = 1.7 Hz, 1
H, CH), 9.05 (d, 4JH,H = 1.7 Hz, 1 H, CH), 10.32 (s, 1 H, OH), 12.13
(br s, 1 H, CO2H).
7-(2-Hydroxybenzoyl)-3-methyl-9-(methylsulfanyl)-4-oxo-4H-
pyrido[1,2-a]thieno[2,3-d]pyrimidine-2-carboxylic Acid (9c)
1H NMR (400 MHz, DMSO-d6): d = 2.56 (s, 3 H, SCH3), 2.83 (s, 3
H, CH3), 7.00 (t, 3JH,H = 8.3 Hz, 1 H, CH), 7.04 (d, 3JH,H = 8.3 Hz, 1
H, CH), 7.45 (dd, 3JH,H = 8.3 Hz, 4JH,H = 1.7 Hz, 1 H, CH), 7.50 (td,
3JH,H = 8.3 Hz, 4JH,H = 1.7 Hz, 1 H, CH), 7.75 (d, 4JH,H = 1.8 Hz, 1
H, CH), 8.89 (d, 4JH,H = 1.8 Hz, 1 H, CH), 10.36 (s, 1 H, OH).
13C NMR (125 MHz, DMSO-d6): d = 14.2, 15.2, 117.2, 117.3,
119.8, 123.4, 124.0, 124.7, 125.1, 128.5, 130.7, 134.0, 137.8, 143.2,
146.2, 154.8, 156.7, 163.8, 165.1, 192.9.
13C NMR (125 MHz, DMSO-d6): d = 22.7, 22.8, 32.3, 114.7, 117.3,
119.9, 124.8, 125.6, 125.9, 130.7, 132.3, 133.9, 134.1, 148.5, 156.6,
157.5, 162.4, 174.4, 193.1.
APSI-MS: m/z = 353 [M+ + 1], 351 [M– – 1].
APSI-MS: m/z = 427 [M+ + 1], 425 [M– – 1].
Acknowledgment
7-(2-Hydroxybenzoyl)-3-methyl-4-oxo-9-phenyl-4H-pyri-
do[1,2-a]thieno[2,3-d]pyrimidine-2-carboxylic Acid (9d)
1H NMR (500 MHz, DMSO-d6): d = 2.87 (s, 3 H, CH3), 7.01 (t,
3JH,H = 8.3 Hz, 1 H, CH), 7.05 (d, 3JH,H = 8.3 Hz, 1 H, CH), 7.44–
The authors acknowledge V. V. Polovinko (Enamine Ltd.) and S. A.
Alekseev (Department of Chemistry of Kyiv National Taras Shev-
chenko University) for spectral measurements, and D. Dontsova for
helpful discussions and suggestions upon preparation of the manus-
cript.
7.54 (m, 5 H, CH), 7.68 (d, 3JH,H = 8.1 Hz, 2 H, CH), 8.04 (d, 4JH,H
=
1.7 Hz, 1 H, CH), 9.24 (d, 4JH,H = 1.7 Hz, 1 H, CH), 10.42 (br s, 1
H, OH), 13.47 (br s, 1 H, CO2H).
13C NMR (125 MHz, DMSO-d6): d = 15.3, 116.5, 117.3, 119.9,
123.3, 124.2, 124.7, 128.6, 129.0, 130.3, 130.9, 132.3, 134.2, 134.3,
136.2, 136.4, 143.2, 148.3, 155.1, 156.7, 163.9, 166.0, 192.8.
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Synthesis 2008, No. 7, 1069–1077 © Thieme Stuttgart · New York

PAPER
A New One-Step Route for the Synthesis of Fused Pyrido[1,2-a]pyrimidin-4-ones
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Synthesis 2008, No. 7, 1069–1077 © Thieme Stuttgart · New York