Efficient and original microwave-assisted Suzuki-Miyaura cross-coupling reaction in the 4 H-pyrido[1,2-a ]pyrimidin-4-one series

Article abstract of DOI:10.1055/s-0030-1260197

An efficient synthesis of new series of various 3-aryl, 3-heteroaryl, and 3-styryl-4H-pyrido[1,2-a]pyrimidin-4-ones by palladium-catalyzed Suzuki-Miyaura cross-coupling reactions using microwave irradiation is described. The coupling process is tolerant o

Full text of DOI:10.1055/s-0030-1260197

PAPER
3115
Efficient and Original Microwave-Assisted Suzuki–Miyaura Cross-Coupling
Reaction in the 4H-Pyrido[1,2-a]pyrimidin-4-one Series
C
ross-Coupling Re
o
action in the
u
4
H
-Pyrido[
s
1,2-
a
]pyr
i
s
midin-4-o
e
ne Serie
s
f Kabri, Maxime D. Crozet, Rémi Szabo, Patrice Vanelle*
Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Universités d¢Aix-Marseille I, II et III – CNRS, UMR 6264,
Laboratoire Chimie Provence, 27 Boulevard J. Moulin, 13385 Marseille Cedex 05, France
Fax +33(4)86136822; E-mail: patrice.vanelle@univmed.fr
Received 18 May 2011; revised 12 July 2011
The choice of starting material was dictated by the intend-
Abstract: An efficient synthesis of new series of various 3-aryl, 3-
ed use of the derivatives, which required the presence of
heteroaryl, and 3-styryl-4H-pyrido[1,2-a]pyrimidin-4-ones by pal-
ladium-catalyzed Suzuki–Miyaura cross-coupling reactions using
microwave irradiation is described. The coupling process is tolerant
Csp2–Cl and Csp3–Cl moieties. Indeed, in continuation of
our study on the reactivity in electron transfer reactions,
of electron-poor, electron-rich, and bulky boronic acid derivatives, and as a part of our program directed toward the prepara-
and leads to the desired products in good yields.
tion of more complex structures of pharmacological inter-
est in heterocyclic series,18 we recently developed a new
Key words: cross-coupling,
4H-pyrido[1,2-a]pyrimidin-4-one,
palladium, Suzuki reaction, arylation
non-nitrated substrate capable of reacting under SRN1 con-
ditions.18a The study involved various nucleophiles, and a
mechanistic study showed that C-alkylations followed a
radical chain mechanism. Furthermore, only the chloro-
methyl group reacted by substitution. Thus, new substrates
bearing various functional groups at the 3-position needed
to be accessed in order to investigate the influence of the
substituent on electron-transfer reactivity toward different
nucleophiles. Finally, in order to increase the selectivity
of the cross-coupling reaction between the 3- and 7-posi-
tions, we decided to investigate the 7-chloro-3-iodo-4H-
pyrido[1,2-a]pyrimidin-4-one derivative.
4H-Pyrido[1,2-a]pyrimidin-4-one derivatives are current-
ly the object of renewed interest in the pharmacological
field, and many publications have reported their pharma-
cological activities in various biological areas.1–12 In con-
tinuation of our studies, and directed by an interest in the
use of microwave heating in Suzuki–Miyaura cross-
coupling reactions,13 we prepared the 7-chloro-2-(chloro-
methyl)-3-iodo-4H-pyrido[1,2-a]pyrimidin-4-one (2) and
studied its reactivity with a range of aryl, heteroaryl, and
styrylboronic acids under Suzuki–Miyaura conditions.
The Suzuki–Miyaura cross-coupling reaction is known to
be an extremely efficient synthetic route for the synthesis
of functionalized heterocycles.14
The required starting material for the Suzuki–Miyaura
cross-coupling study was obtained by condensing 2-ami-
no-5-chloropyridine with ethyl 4-chloroacetoacetate in
polyphosphoric acid (PPA) using the Ferrarini proce-
dure,19 providing 7-chloro-2-(chloromethyl)-4H-pyri-
do[1,2-a]pyrimidin-4-one (1), which reacted with N-
iodosuccinimide in acetonitrile at reflux to give 7-chloro-
2-(chloromethyl)-3-iodo-4H-pyrido[1,2-a]pyrimidin-4-one
(2; Scheme 1).
Microwave irradiation has recently become a possible
way to improve reaction yields and reduce reaction
times15 compared to conventional heating. It has already
been shown that microwave irradiation can significantly
promote the Suzuki–Miyaura cross-coupling reaction.16
Initial trials of the Suzuki–Miyaura cross-coupling reac-
tion were tested under similar experimental conditions to
those described by Barbeau et al. (Scheme 2).20 The reac-
tion was carried out by using 4-methoxyphenylboronic
acid (1.5 equiv), tetrakis(triphenylphosphine)palladi-
um(0) (0.05 equiv), and potassium carbonate (3 equiv) in
Only a few examples of Suzuki–Miyaura cross-coupling
reactions in 4H-pyrido[1,2-a]pyrimidin-4-one series have
been reported,17 and none of them involve microwave ir-
radiation. Herein, we report an efficient synthesis of new
3-aryl, 3-heteroaryl, and 3-styryl-4H-pyrido[1,2-a]pyrim-
idin-4-one derivatives under microwave irradiation.
NH2
N
N
N
Cl
Cl
Cl
PPA
NIS
+
N
N
Cl
Cl
I
MeCN
80 °C, 16 h
110 °C, 3 h
CO2Et
Cl
O
O
O
1 90%
2 75%
Scheme 1 Preparation of the starting material 2
SYNTHESIS 2011, No. 19, pp 3115–3122
x
x.
x
x
.
2
0
1
1
Advanced online publication: 01.09.2011
DOI: 10.1055/s-0030-1260197; Art ID: Z52711SS
© Georg Thieme Verlag Stuttgart · New York

3116
Y. Kabri et al.
PAPER
dioxane at 100 °C (Table 1, entry 1). After three hours, tate (3) after acetylation of the chloromethyl group. The
only a mixture of the starting material 2 and the reduced acetylation reaction was carried out in N,N-dimethyl-
compound 1 were obtained (Table 1, entry 1). The forma- formamide, using potassium acetate at room temperature
tion of compound 1 suggested that a palladium-catalyzed for 12 hours, which gave 3 in 76% yield (Scheme 3).
reduction of aromatic halides took place, as previously
We then investigated the reactivity of 3 in the Suzuki–
observed in the literature.21 The use of microwave irradi-
Miyaura reaction. The initial conditions used to carry out
ation and 1,2-dimethoxyethane–ethanol (9:1) as solvent
the cross-coupling reaction involved Pd(PPh3)4 (5 mol%)
did not result in any selectivity, and also led to a mixture
as a catalyst, potassium carbonate (3 equiv) as the base,
of 1 and 2 (Table 1, entries 2 and 3).
and 4-(methoxyphenyl)boronic acid (1.5 equiv) in diox-
With the chloromethyl group in the 2-position of com- ane–ethanol (9:1), as shown in Scheme 4. Under these
pound 2, the 3-position was apparently too reactive. We conditions, the reaction led to the formation of the desired
therefore investigated the reactivity of the (7-chloro-3- product 5 after eight hours, in moderate yield (19%;
iodo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl ace- Table 2, entry 1). In addition to the desired compound, the
reduced product 4 was also obtained in 58% yield.
N
Cl
We then decided to evaluate the influence of microwave
N
irradiation on this cross-coupling reaction according to
Cl
I
our previous studies. Three reaction parameters were ex-
amined: solvent, temperature, and reaction times
(Table 2). Indeed, the crucial role played by the solvent in
determining the reaction rate of Suzuki–Miyaura reac-
tions is well established.22
O
N
O
2
Cl
Pd(PPh3)4, (0.05 equiv)
K2CO3 (1 N, 3 equiv)
+
N
Cl
H
B(OH)2
1
As a result, optimized microwave-assisted experimental
conditions were established that permitted the synthesis of
OMe
1.5 equiv
Table 2 Suzuki–Miyaura Coupling Reaction of 3 with 4-Methoxy-
phenylboronic Acida
Scheme 2 Suzuki–Miyaura reaction of 2
Table 1 Suzuki–Miyaura Reaction of 2a
Entry Solvent (9:1)
Conditions
Yield 4/5 (%)
58:19
50:10
18:20
0:39
1
2
3
4
5
6
7
8
dioxane–EtOH K2CO3, 100 °C, 8 h
Entry Solvent
Conditions
Yield 1/2 (%)
38:55
dioxane–EtOH K2CO3, MW, 100 °C, 5 h
1
2
3
dioxane
dioxane
K2CO3, 100 °C, 3 h
DMF–EtOH
DME–EtOH
DME–EtOH
DME–EtOH
H2O–EtOH
DME–EtOH
K2CO3, MW, 120 °C, 4 h
K2CO3, MW, 80 °C, 5 h
Na2CO3, MW, 80 °C, 3 h
K2CO3, MW, 100 °C, 2 h
K2CO3, MW, 100 °C, 2 h
K2CO3, 100 °C, 9 h
K2CO3, MW, 100 °C, 3 h
37:42
DME–EtOH K2CO3, MW, 80 °C, 2 h
43:33
10:28
0:79
a Reaction conditions: 2 (1 equiv), 4-methoxyphenyl boronic acid (1.5
equiv), [Pd(PPh3)4] (0.05 equiv), K2CO3 (3 equiv).
0:0b
O
0:40
N
O
N
KOAc
Cl
O
a Reaction conditions: 4-methoxyphenylboronic acid (1.5 equiv),
[Pd(PPh3)4] (0.05 equiv), K2CO3 (3 equiv), solvent/EtOH (9:1).
b The experimental conditions furnished 7-chloro-2-(hydroxymethyl)-
3-(4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one (5¢) from the
one-pot cross-coupling reaction and hydrolysis of the acetyl group in
33% yield.
N
N
DMF
r.t., 12 h
Cl
I
Cl
I
O
2
3 76%
Scheme 3 Acetylation of the chloromethyl group of 2
N
B(OH)2
OAc
N
Cl
H
O
4
MeO
N
1.5 equiv
OAc
+
N
Pd(PPh3)4 (0.05 equiv)
base (1 N, 3 equiv)
N
O
Cl
I
OAc
O
3
N
Cl
OMe
5
Scheme 4 Suzuki–Miyaura cross-coupling reaction
Synthesis 2011, No. 19, 3115–3122 © Thieme Stuttgart · New York

PAPER
Cross-Coupling Reaction in the 4H-Pyrido[1,2-a]pyrimidin-4-one Series
3117
[7-chloro-3-(4-methoxyphenyl)-4-oxo-4H-pyrido[1,2-a]- action is applicable to all aryl, heteroaryl, and styryl
pyrimidin-2-yl] methyl acetate (5) in 79% yield in two boronic acid derivatives used in our study.
hours (Table 2, entry 6). Furthermore, no trace of the re-
duced compound 4 was detected. Using conventional
heating, the same reaction took place after nine hours in
40% yield. Thus, the use of microwave irradiation reduces
These experimental conditions allowed compounds 18–
20 to be synthesized by reaction of 3 with (E)-4-(trifluo-
romethyl)styrylboronic acid, (E)-styrylboronic acid, and
(E)-4-methylstyrylboronic acid in excellent yields
the reaction time up to four-fold and gives higher yields
(Table 3, entries 14–16), which constitutes an interesting
compared to classical heating methodology (Table 2, en-
alternative to the Heck reaction. The reaction was 100%
tries 6 and 8).
stereoselective, and the E-configuration of the alkene unit
To evaluate the scope and the limitations of this proce- of (E)-18, (E)-19, and (E)-20 was clear from their respec-
dure, we performed coupling reactions with 16 variously tive 1H NMR spectra (3J = 16.0 Hz), which confirmed the
substituted boronic acid derivatives (Scheme 5). The re- presence of the E-isomer exclusively.
sults show, as illustrated in Table 3, that this coupling re-
N
RB(OH)2 (1.5 equiv)
Pd(PPh3)4 (0.05 equiv)
N
OAc
OAc
N
N
Cl
I
Cl
R
K2CO3 (1 N, 3 equiv)
DME–EtOH (9:1)
MW, 100 °C, 2 h
O
3
O
5–20
Scheme 5 Suzuki–Miyaura cross-coupling reaction under the optimized conditions
Table 3 Suzuki–Miyaura Coupling Reaction of 3 with Aryl, Heteroaryl, and Styrylboronic Acid Derivatives under the Optimized Conditionsa
Boronic acid
Product
Yield (%)
N
B(OH)2
OAc
OAc
OAc
1
2
3
5
79
73
70
N
N
N
Cl
O
N
MeO
OMe
B(OH)2
6
7
Cl
Cl
O
N
B(OH)2
NO2
O
N
NO2
B(OH)2
OAc
OAc
4
5
8
9
82
84
N
N
N
Cl
Cl
Cl
O
N
F
F
B(OH)2
O
N
MeO
Cl
B(OH)2
OMe
OAc
OMe
OMe
6
10
63
MeO
MeO
O
OMe
Synthesis 2011, No. 19, 3115–3122 © Thieme Stuttgart · New York

3118
Y. Kabri et al.
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Table 3 Suzuki–Miyaura Coupling Reaction of 3 with Aryl, Heteroaryl, and Styrylboronic Acid Derivatives under the Optimized Conditionsa
(continued)
Boronic acid
Product
Yield (%)
N
OAc
B(OH)2
N
N
7
8
Cl
11
65
89
O
N
F3C
CF3
OAc
B(OH)2
Cl
12
O
N
OAc
O
B(OH)2
O
9
13
14
90
53
N
N
Cl
Cl
O
N
B(OH)2
B(OH)2
OAc
10
O
N
N
N
OAc
11
12
15
16
71
73
N
Cl
N
O
N
N
B(OH)2
OAc
N
N
Cl
Cl
O
N
OAc
B(OH)2
CF3
13
17
62
O
N
F3C
CF3
CF3
B(OH)2
OAc
14
15
16
N
N
N
18
19
20
83
75
80
Cl
Cl
Cl
O
N
CF3
F3C
B(OH)2
OAc
OAc
O
N
B(OH)2
O
a Reaction conditions: boronic acid derivative (1.5 equiv), [Pd(PPh3)4] (0.05 equiv), K2CO3 (3 equiv), DME–EtOH (9:1), MW, 100 °C, 2 h.
Synthesis 2011, No. 19, 3115–3122 © Thieme Stuttgart · New York

PAPER
Cross-Coupling Reaction in the 4H-Pyrido[1,2-a]pyrimidin-4-one Series
3119
7-Chloro-2-(chloromethyl)-3-iodo-4H-pyrido[1,2-a]pyrimidin-
4-one (2)
To conclude, we have developed a general operating
procedure for an efficient synthesis of new 3-aryl, 3-
heteroaryl, and 3-styryl-4H-pyrido[1,2-a]pyrimidin-4-one
derivatives from the microwave-assisted palladium-medi-
ated coupling reactions of aryl, heteroaryl, and styryl bo-
ronic acid derivatives with (7-chloro-3-iodo-4-oxo-4H-
pyrido[1,2-a]pyrimidin-2-yl)methyl acetate (3). Finally, a
wide array of electron-withdrawing, electron-donating,
and sterically bulky groups has been shown to be well tol-
erated under these microwave-assisted conditions. These
results constitute the first example of a Suzuki–Miyaura
cross-coupling reaction of a 4H-pyrido[1,2-a]pyrimidin-
4-one series under microwave irradiation. Furthermore,
replacement of the acetyl group at the 2-position gave ac-
cess to a large variety of analogues and also to derivatives
that could, after hydrolysis of the acetyl group and chlori-
nation, constitute promising candidates for SRN1 reac-
tions.
A mixture of 7-chloro-2-(chloromethyl)-4H-pyrido[1,2-a]pyrimi-
din-4-one (1; 1 g, 4.36 mmol, 1 equiv) and NIS (1.08 g, 5.24 mmol,
1.2 equiv) was heated at reflux in MeCN (60 mL) for 16 h. At this
time, the solution was cooled and evaporated under reduced pres-
sure. Flash chromatography (silica gel; CH2Cl2–EtOAc, 9:1) pro-
vided, after recrystallization from propan-2-ol, pure 2.
Yield: 1.16 g (75%); yellow solid; mp 190 °C.
1H NMR (CDCl3, 200 MHz): d = 4.78 (s, 2 H), 7.66 (d, J = 9.4 Hz,
1 H), 7.76 (dd, J = 9.4, 2.2 Hz, 1 H), 9.05 (d, J = 2.2 Hz, 1 H).
13C NMR (CDCl3, 50 MHz): d = 50.1, 79.2, 125.5, 125.6, 127.1,
138.2, 148.6, 155.2, 163.2.
Anal. Calcd for C9H5Cl2IN2O: C, 30.45; H, 1.42; N, 7.89. Found: C,
30.97; H, 1.35; N, 7.74.
(7-Chloro-3-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)meth-
yl Acetate (3)
A solution of 7-chloro-2-(chloromethyl)-3-iodo-4H-pyrido[1,2-
a]pyrimidin-4-one (2; 1 g, 2.82 mmol, 1 equiv) and potassium ace-
tate (0.33 g, 3.38 mmol, 1.2 equiv) in DMF (70 mL) was stirred at
r.t. for 5 h. At this point, the DMF was evaporated under reduced
pressure. Flash chromatography (silica gel; CH2Cl2–EtOAc,
9.5:0.5) provided, after recrystallization from propan-2-ol, pure 3.
Melting points were determined with a Büchi B-540 and are uncor-
rected. Elemental and MS analyses were carried out at the Spectro-
pole, Faculté des Sciences et Techniques de Saint-Jérôme. 200 MHz
1H NMR (CHCl3: d = 7.26 ppm) and 50 MHz 13C NMR (CHCl3:
d = 76.9 ppm) spectra were recorded with a Bruker ARX 200 spec-
trometer in CDCl3 solvent at the Faculté de Pharmacie de Marseille.
Solvents were dried by conventional methods. Silica gel 60 (Merck,
particle size 0.063–0.200 mm, 70–230 mesh ASTM) was used for
column chromatography. TLC was performed with 5 × 10 cm alu-
minum plates coated with silica gel 60F-254 (Merck) in an appro-
priate solvent. MS spectra were recorded with a QStar Elite
(Applied Biosystems SCIEX) spectrometer; PEG was used as the
matrix for HRMS.
Yield: 0.81 g (76%); yellow solid; mp 156 °C.
1H NMR (CDCl3, 200 MHz): d = 2.23 (s, 3 H), 5.24 (s, 2 H), 7.62
(d, J = 9.4 Hz, 1 H), 7.73 (dd, J = 9.4, 2.2 Hz, 1 H), 9.06 (d,
J = 2.2 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 20.8, 68.8, 76.6, 125.3, 125.6,
127.2, 137.9, 148.4, 154.7, 162.3, 170.5.
Anal. Calcd for C11H8ClIN2O3: C, 34.90; H, 2.13; N, 7.40. Found:
C, 35.09; H, 2.10; N, 7.42.
Microwave-assisted reactions were performed in a multimode mi-
crowave oven of a ETHOS Synth Lab station and MicroSYNTH
Lab terminal 1024 (Ethos start, Milestone Inc.) or a Biotage Initia-
tor Microwave oven. The multimode microwave was fitted with a
twin magnetron (2 × 800 W, 2.45 GHz) with a maximum delivered
power of 1000 W in 10 W increments (pulsed irradiation). Built-in
magnetic stirring (Teflon-coated stirring bar) was used in all opera-
tions. During experiments, the time, temperature and power were
measured with the “easy WAVE“ software package. The tempera-
ture was measured throughout the reaction and recorded with either
an infrared detector or an optical fiber (ATC-FO 300). The micro-
wave reactions were performed with a Biotage Initiator Microwave
oven using 10–20 mL sealed vials; temperatures were measured
with an IR-sensor and reaction times are given as hold times.
Suzuki–Miyaura Reaction; General Procedure
A solution of (7-chloro-3-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidin-
2-yl)methyl acetate (3; 0.3 g, 0.79 mmol, 1 equiv), boronic acid (1.5
equiv, 1.19 mmol), and [Pd(PPh3)4] (45 mg, 39 mmol, 0.05 equiv),
and a 1N solution of K2CO3 (2.37 mL, 2.37 mmol, 3 equiv) in a
DME–EtOH mixture (9:1, 15 mL) was heated at 100 °C under mi-
crowave irradiation for 2 h. At this time, H2O (100 mL) was added
and the solution was extracted with CH2Cl2 (3 × 60 mL). The organ-
ic layer was washed with H2O (3 × 100 mL), dried over Na2SO4 and
evaporated. The crude product was purified by column chromatog-
raphy (silica gel; CH2Cl2–EtOAc, 9:1) and recrystallized from pro-
pan-2-ol.
(7-Chloro-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl Ace-
tate (4) (Table 2, Entry 1)
Yield: 58%; yellow solid; mp 137 °C.
1H NMR (CDCl3, 200 MHz): d = 2.21 (s, 3 H), 5.10 (s, 2 H), 6.51
(s, 1 H), 7.56 (d, J = 9.5 Hz, 1 H), 7.69 (dd, J = 9.5, 2.3 Hz, 1 H),
9.05 (d, J = 2.3 Hz, 1 H).
7-Chloro-2-(chloromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one
(1)
To a solution of 5-chloropyridin-2-amine (5 g, 38.9 mmol, 1 equiv)
in ethyl 4-chloroacetoacetate (7.4 mL, 54.5 mmol, 1.4 equiv), PPA
(25 g) was added. The reaction mixture was heated at 110 °C for
3 h. After cooling, H2O (500 mL) was added and the solution was
neutralized with Na2CO3. A precipitate appeared and was filtered,
washed with H2O (3 × 100 mL) and dried in a vacuum drying oven
(desiccator cabinet). Recrystallization from propan-2-ol gave pure
1.
13C NMR (CDCl3, 50 MHz): d = 20.8, 65.1, 101.3, 124.2, 125.1,
127.1, 137.8, 149.5, 157.0, 162.5, 170.2.
Anal. Calcd for C11H9ClN2O3: C, 52.29; H, 3.59; N, 11.09. Found:
C, 52.50; H, 3.56; N, 10.87.
Yield: 8.0 g (90%); brown solid; mp 155 °C (Lit.23 156 °C).
1H NMR (CDCl3, 200 MHz): d = 4.50 (s, 2 H), 6.65 (s, 1 H), 7.56–
7.71 (m, 2 H), 9.04 (s, 1 H).
[7-Chloro-3-(4-methoxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimi-
din-2-yl]methyl Acetate (5)
Yield: 79%; yellow solid; mp 126 °C.
1H NMR (CDCl3, 200 MHz): d = 2.10 (s, 3 H), 3.84 (s, 3 H), 5.00
(s, 2 H), 6.98 (d, J = 8.7 Hz, 2 H), 7.28 (d, J = 8.7 Hz, 2 H), 7.62–
7.64 (m, 2 H), 9.04–9.06 (m, 1 H).
13C NMR (CDCl3, 50 MHz): d = 44.9, 102.7, 123.8, 124.5, 126.5,
137.3, 148.8, 156.4, 161.7.
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3120
Y. Kabri et al.
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13C NMR (CDCl3, 50 MHz): d = 20.7, 55.3, 64.4, 114.1, 114.1,
117.5, 124.3, 124.6, 125.2, 127.5, 131.3, 131.3, 136.9, 148.0, 156.9,
157.3, 159.6, 170.5.
Anal. Calcd for C17H12Cl2N2O3: C, 56.22; H, 3.33; N, 7.71. Found:
C, 56.26; H, 3.30; N, 7.58.
[7-Chloro-4-oxo-3-(3,4,5-trimethoxyphenyl)-4H-pyrido[1,2-
a]pyrimidin-2-yl]methyl Acetate (10)
Yield: 63%; yellow solid; mp 186 °C.
Anal. Calcd for C18H15ClN2O4: C, 60.26; H, 4.21; N, 7.81. Found:
C, 60.27; H, 4.34; N, 7.65.
7-Chloro-2-(hydroxymethyl)-3-(4-methoxyphenyl)-4H-pyri-
do[1,2-a]pyrimidin-4-one (5¢) (Table 2, Entry 7)
Yield: 33%; yellow solid; mp 163 °C.
1H NMR (CDCl3, 200 MHz): d = 2.13 (s, 3 H), 3.86 (s, 6 H), 3.90
(s, 3 H), 5.02 (s, 2 H), 6.59 (s, 2 H), 7.61–7.73 (m, 2 H), 9.08–9.09
(m, 1 H).
1H NMR (CDCl3, 200 MHz): d = 3.86 (s, 3 H), 4.55 (s, 2 H), 7.00
(d, J = 8.7 Hz, 2 H), 7.26 (d, J = 8.7 Hz, 2 H), 7.66–7.77 (m, 2 H),
9.12 (s, 1 H).
13C NMR (CDCl3, 50 MHz): d = 20.7, 56.1, 56.1, 60.8, 64.4, 77.2,
107.2, 107.2, 117.6, 124.5, 125.3, 127.5, 128.0, 137.3, 148.2, 153.4,
153.4, 156.7, 157.7, 170.4.
13C NMR (CDCl3, 50 MHz): d = 55.3, 61.8, 114.3, 114.3, 114.7,
123.9, 124.6, 125.6, 126.6, 131.1, 131.1, 137.7, 147.8, 156.3, 159.6,
160.7.
Anal. Calcd for C20H19ClN2O6: C, 57.35; H, 4.57; N, 6.69. Found:
C, 57.24; H, 4.54; N, 6.71.
{7-Chloro-4-oxo-3-[3-(trifluoromethyl)phenyl]-4H-pyrido[1,2-
a]pyrimidin-2-yl}methyl Acetate (11)
Yield: 65%; yellow solid; mp 141 °C.
Anal. Calcd for C16H13ClN2O3: C, 60.67; H, 4.14; N, 8.84. Found:
C, 60.32; H, 4.18; N, 8.57.
(7-Chloro-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyrimidin-
2-yl)methyl Acetate (6)
1H NMR (CDCl3, 200 MHz): d = 2.08 (s, 3 H), 4.96 (s, 2 H), 7.57–
7.75 (m, 6 H), 9.09 (s, 1 H).
Yield: 73%; beige solid; mp 110 °C.
1H NMR (CDCl3, 200 MHz): d = 2.09 (s, 3 H), 5.00 (s, 2 H), 7.34–
7.47 (m, 5 H), 7.66–7.67 (m, 2 H), 9.07 (s, 1 H).
13C NMR (CDCl3, 50 MHz): d = 20.5, 64.5, 116.3, 123.9 (q, JC–F
=
273.0 Hz, CF3), 124.9, 125.2 (q, JC–F = 3.7 Hz, CHCF3), 125.3,
127.1 (q, JC–F = 3.7 Hz, CHCF3), 127.6, 129.2, 131.0 (q, JC–F =
32.1 Hz, CCF3), 133.5, 133.6, 137.7, 148.5, 156.5, 157.8, 170.3.
13C NMR (CDCl3, 50 MHz): d = 20.7, 64.4, 117.7, 124.5, 125.3,
127.5, 128.4, 128.7, 128.7, 130.1, 130.1, 132.6, 137.3, 148.2, 156.7,
157.4, 170.4.
Anal. Calcd for C18H12ClF3N2O3: C, 54.49; H, 3.05; N, 7.06. Found:
C, 54.16; H, 3.17; N, 6.89.
Anal. Calcd for C17H13ClN2O3: C, 62.11; H, 3.99; N, 8.52. Found:
C, 62.27; H, 3.99; N, 8.42.
{7-Chloro-3-(naphthalen-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimi-
din-2-yl}methyl Acetate (12)
Yield: 89%; yellow solid; mp 160 °C.
[7-Chloro-3-(3-nitrophenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-
2-yl]methyl Acetate (7)
Yield: 70%; beige solid; mp 167 °C.
1H NMR (CDCl3, 200 MHz): d = 2.09 (s, 3 H), 4.95 (s, 2 H), 7.61–
7.79 (m, 4 H), 8.24–8.29 (m, 2 H), 9.07–9.08 (m, 1 H).
13C NMR (CDCl3, 50 MHz): d = 20.5, 64.5, 115.3, 123.3, 125.1,
125.3, 125.4, 127.6, 129.5, 134.6, 136.5, 138.0, 148.3, 148.6, 156.4,
157.9, 170.2.
1H NMR (CDCl3, 200 MHz): d = 1.90 (s, 3 H), 4.85 (s, 2 H), 7.41–
7.60 (m, 4 H), 7.68–7.78 (m, 3 H), 7.90–7.96 (m, 2 H), 9.11 (s,
1 H).
13C NMR (CDCl3, 50 MHz): d = 20.4, 64.4, 115.7, 124.6, 124.8,
125.5, 125.6, 126.1, 126.6, 127.6, 128.1, 128.7, 129.2, 130.2, 131.9,
133.9, 137.5, 148.8, 156.5, 159.3, 170.3.
HRMS-FAB: m/z [M + H]+ calcd for C18H15ClN2O3: 379.0844;
found: 379.0843.
Anal. Calcd for C17H12ClN3O5: C, 54.63; H, 3.24; N, 11.24. Found:
C, 54.86; H, 3.30; N, 11.04.
[7-Chloro-3-(furan-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-
yl]methyl Acetate (13)
Yield: 90%; brown solid; mp 147 °C.
1H NMR (CDCl3, 200 MHz): d = 2.17 (s, 3 H), 5.51 (s, 2 H), 6.59
(m, 1 H), 7.28 (d, J = 3.4 Hz, 1 H), 7.56–7.68 (m, 3 H), 9.12 (s,
1 H).
[7-Chloro-3-(4-fluorophenyl)-4-oxo-4H-pyrido[1,2-a]pyrimi-
din-2-yl]methyl Acetate (8)
Yield: 82%; yellow solid; mp 132 °C.
1H NMR (CDCl3, 200 MHz): d = 2.07 (s, 3 H), 4.96 (s, 2 H), 7.08–
7.19 (m, 2 H), 7.29–7.38 (m, 2 H), 7.59–7.71 (m, 2 H), 9.03–9.04
(m, 1 H).
13C NMR (CDCl3, 50 MHz): d = 20.6, 64.2, 115.7 (d, JC–F
21.6 Hz, 2 × CHCF), 116.6, 124.5, 125.2, 127.4, 128.5 (d, JC–F
3.7 Hz, C-CF), 131.9 (d, JC–F = 8.1 Hz, 2 × CHCF), 137.3, 148.2,
156.6, 157.6, 162.6 (d, JC–F = 248.1 Hz, CF), 170.3.
13C NMR (CDCl3, 50 MHz): d = 20.8, 65.3, 106.8, 111.8, 113.4,
124.9, 125.1, 127.6, 136.8, 142.5, 146.7, 146.8, 154.6, 156.4, 170.8.
=
=
Anal. Calcd for C15H11ClN2O4: C, 56.53; H, 3.48; N, 8.79. Found:
C, 55.83; H, 3.52; N, 8.66.
[7-Chloro-4-oxo-3-(pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-2-
yl]methyl Acetate (14)
Yield: 53%; yellow solid; mp 140 °C.
Anal. Calcd for C17H12ClFN2O3: C, 58.89; H, 3.49; N, 8.08. Found:
C, 58.81; H, 3.61; N, 7.95.
[7-Chloro-3-(4-chlorophenyl)-4-oxo-4H-pyrido[1,2-a]pyrimi-
din-2-yl]methyl Acetate (9)
Yield: 84%; beige solid; mp 136 °C.
1H NMR (CDCl3, 200 MHz): d = 2.06 (s, 3 H), 4.99 (s, 2 H), 7.34
(d, J = 5.7 Hz, 2 H), 7.64–7.78 (m, 2 H), 8.72 (d, J = 5.7 Hz, 2 H),
9.07–9.08 (m, 1 H).
1H NMR (CDCl3, 200 MHz): d = 2.09 (s, 3 H), 4.98 (s, 2 H), 7.31
(d, J = 8.4 Hz, 2 H), 7.44 (d, J = 8.4 Hz, 2 H), 7.61–7.73 (m, 2 H),
9.07 (s, 1 H).
13C NMR (CDCl3, 50 MHz): d = 20.6, 64.2, 114.7, 125.0, 125.1,
125.1, 125.4, 127.6, 138.0, 141.3, 148.7, 150.1, 150.1, 156.1, 157.9,
170.3.
13C NMR (CDCl3, 50 MHz): d = 20.7, 64.3, 116.5, 124.7, 125.3,
127.5, 128.9, 128.9, 131.1, 131.5, 131.5, 134.5, 137.5, 148.3, 156.6,
157.6, 170.4.
HRMS-FAB: m/z [M + H]+ calcd for C16H12ClN3O3: 330.0640;
found: 330.0642.
Synthesis 2011, No. 19, 3115–3122 © Thieme Stuttgart · New York

PAPER
Cross-Coupling Reaction in the 4H-Pyrido[1,2-a]pyrimidin-4-one Series
3121
[7-Chloro-4-oxo-3-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-2-
yl]methyl Acetate (15)
Yield: 71%; yellow solid; mp 145 °C.
(E)-[7-Chloro-3-(4-methylstyryl)-4-oxo-4H-pyrido[1,2-a]pyri-
midin-2-yl]methyl Acetate (20)
Yield: 80%; yellow solid; mp 205 °C.
1H NMR (CDCl3, 200 MHz): d = 2.05 (s, 3 H), 4.96 (s, 2 H), 7.35
(dd, J = 4.8, 7.8 Hz, 1 H), 7.62–7.70 (m, 2 H), 7.72–7.78 (m, 1 H),
8.59 (d, J = 1.6 Hz, 1 H), 8.62 (dd, J = 1.6, 4.8 Hz, 1 H), 9.05–9.06
(m, 1 H).
1H NMR (CDCl3, 200 MHz): d = 2.18 (s, 3 H), 2.37 (s, 3 H), 5.38
(s, 2 H), 7.08 (d, J = 16.0 Hz, 1 H), 7.18 (d, J = 8.1 Hz, 2 H), 7.44
(d, J = 8.1 Hz, 2 H), 7.60 (m, 2 H), 8.01 (d, J = 16.0 Hz, 1 H), 9.11–
9.12 (m, 1 H).
13C NMR (CDCl3, 50 MHz): d = 20.5, 64.3, 114.1, 123.3, 124.8,
125.3, 127.5, 129.0, 137.7, 137.7, 148.5, 149.4, 150.7, 156.6, 158.1,
170.2.
13C NMR (CDCl3, 50 MHz): d = 20.8, 21.3, 64.7, 113.1, 117.9,
124.7, 124.9, 126.7, 126.7, 127.5, 129.4, 129.4, 135.1, 135.4, 136.4,
138.1, 146.4, 155.5, 156.3, 170.6.
HRMS-FAB: m/z [M + H]+ calcd for C16H12ClN3O3: 330.0640;
found: 330.0641.
Anal. Calcd for C20H17ClN2O3: C, 65.13; H, 4.65; N, 7.60. Found:
C, 65.13; H, 4.69; N, 7.72.
(7-Chloro-4-oxo-3-o-tolyl-4H-pyrido[1,2-a]pyrimidin-
2-yl)methyl Acetate (16)
Acknowledgment
Yield: 73%; yellow solid; mp 148 °C.
This work was supported by the CNRS and the Universities of Aix-
Marseille. The authors thank V. Remusat for recording the NMR
spectra and the Spectropole team for performing various analytical
measurements.
1H NMR (CDCl3, 200 MHz): d = 2.07 (s, 3 H), 2.17 (s, 3 H), 4.86
(s, 2 H), 7.11–7.15 (m, 1 H), 7.31–7.33 (m, 3 H), 7.62–7.72 (m,
2 H), 9.09 (s, 1 H).
13C NMR (CDCl3, 50 MHz): d = 19.6, 20.7, 63.9, 117.2, 125.0,
125.5, 126.3, 127.0, 129.0, 130.0, 130.5, 131.7, 137.5, 138.0, 148.3,
155.6, 157.4, 170.4.
References
HRMS-FAB: m/z [M + H]+ calcd for C18H15ClN2O3: 343.0844;
found: 343.0843.
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{3-[3,5-Bis(trifluoromethyl)phenyl]-7-chloro-4-oxo-4H-pyri-
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Yield: 62%; yellow solid; mp 139 °C.
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(q, JC–F = 33.7 Hz, 2 × CCF3), 135.2, 138.3, 148.7, 156.4, 158.2,
170.1.
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(E)-{7-Chloro-4-oxo-3-[4-(trifluoromethyl)styryl]-4H-pyri-
do[1,2-a]pyrimidin-2-yl}methyl Acetate (18)
Yield: 83%; yellow solid; mp 209 °C.
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=
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3122
Y. Kabri et al.
PAPER
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Synthesis 2011, No. 19, 3115–3122 © Thieme Stuttgart · New York