One-pot chemoselective bis(suzuki-miyaura cross-coupling): Efficient access to 3,9-Bis[(hetero)aryl]-4H-pyrido[1,2-a]pyrimidin-4-one derivatives under microwave irradiation

Article abstract of DOI:10.1002/ejoc.201200748

A one-pot chemoselective bis(Suzuki-Miyaura cross-coupling) reaction under microwave irradiation is reported for the 4H-pyrido[1,2-a]pyrimidin-4-one series. First, we ascertained an initial coupling reaction that was selectively carried out at the C-3 position of (7,9-dichloro-3-iodo-4-oxo-4H-pyrido[1,2-a] pyrimidin-2-yl)methyl acetate (4). Next, we developed an extremely efficient one-pot chemoselective bis(Suzuki-Miyaura cross-coupling) reaction, allowing us to substitute successively at the 3-and then at the 9-position of compound 4 with various boronic acids.

Full text of DOI:10.1002/ejoc.201200748

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FULL PAPER
DOI: 10.1002/ejoc.201200748
One-Pot Chemoselective Bis(Suzuki–Miyaura Cross-Coupling): Efficient
Access to 3,9-Bis[(hetero)aryl]-4H-pyrido[1,2-a]pyrimidin-4-one Derivatives
Under Microwave Irradiation
[a]
[a]
[a]
[a]
Youssef Kabri, Maxime D. Crozet, Nicolas Primas, and Patrice Vanelle*
Keywords: Synthetic methods / Heterocycles / Cross-coupling / Chemoselectivity / Palladium / Microwave chemistry
A one-pot chemoselective bis(Suzuki–Miyaura cross-cou-
pling) reaction under microwave irradiation is reported for
the 4H-pyrido[1,2-a]pyrimidin-4-one series. First, we ascer-
tained an initial coupling reaction that was selectively car-
ried out at the C-3 position of (7,9-dichloro-3-iodo-4-oxo-4H-
pyrido[1,2-a]pyrimidin-2-yl)methyl acetate (4). Next, we de-
veloped an extremely efficient one-pot chemoselective
bis(Suzuki–Miyaura cross-coupling) reaction, allowing us to
substitute successively at the 3- and then at the 9-position of
compound 4 with various boronic acids.
Introduction
peared the most attractive. However, few examples of the
Suzuki–Miyaura cross-coupling reaction for the 4H-pyr-
The Suzuki–Miyaura reaction has become one of the
most significant palladium-catalyzed methods of forming
carbon–carbon bonds. Since the pioneering work of Suzuki
and Miyaura, a great number of studies have been devoted
[15]
ido[1,2-a] pyrimidin-4-one series have been reported.
Under our research program on the design and synthesis
[16]
of original molecules with pharmacological properties
and in connection with previous studies on the use of mi-
crowave heating in the Suzuki–Miyaura cross-coupling re-
[
1]
to the development of this cross-coupling reaction. The
H-pyrido[1,2-a]pyrimidin-4-one core has proved to be a
4
[17]
action, we recently reported on the reactivity of this het-
successful scaffold for the development of biologically inter-
esting molecules, and their pharmacological action has been
widely reported in various biological areas.[
These interesting biological properties make the prepara-
tion of such derivatives an important challenge. Our re-
search program investigated the synthesis of 4H-pyrido[1,2-
a]pyrimidin-4-one containing a chloromethyl group at the
[18]
erocycle in the Suzuki cross-coupling reaction. Using mi-
crowave heating with the 7-chloro-3-iodo-4H-pyrido[1,2-a]-
pyrimidin-4-one derivative, we found experimental Suzuki–
Miyaura conditions which led to the monoarylated com-
pound in the 3-position (see Scheme 1).
2–13]
2-position, which would be able to react under SRN1 condi-
tions with various nucleophiles. As a result of this study, we
report the first example of a SRN1 reaction of a non-
nitrated 4H-pyrido[1,2-a]pyrimidin-4-one.[ The study in-
volved various nucleophiles, and a mechanistic study
showed a C-alkylation followed by a radical chain mecha-
nism. Furthermore, only the chloromethyl group underwent
substitution. Thus, new substrates bearing various func-
tional groups at the 3-, 7-, and 9-positions needed to be
assessed to investigate the influence of the substituent on
the electron-transfer reactivity towards different nucleo-
philes. The Suzuki–Miyaura cross-coupling reaction ap-
14]
Scheme 1. Suzuki–Miyaura cross-coupling reaction.
In a continuation of our work on the synthesis of more
complex structures in the 4H-pyrido[1,2-a]pyrimidin-4-one
series, we report herein the first one-pot chemoselective
double Suzuki–Miyaura cross-coupling reaction for this
series using microwave irradiation.
[
a] Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de
Pharmacie, Aix-Marseille Univ-CNRS, UMR 7273, Institut de
Chimie radicalaire,
Results and Discussion
The required starting material, compound 4, for the Su-
zuki–Miyaura bis(cross-coupling) study was synthesized
from 5-chloropyridin-2-amine in four steps by the chlorin-
ation of 5-chloropyridin-2-amine with N-chlorosuccinimide
(NCS) in refluxing MeCN (acetonitrile), followed by a con-
2
7 Boulevard J. Moulin, CS30064, 13385 Marseille Cedex 05,
France
Fax: +33-4-86136822
E-mail: patrice.vanelle@univ-amu.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200748.
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Y. Kabri, M. D. Crozet, N. Primas, P. Vanelle
FULL PAPER
densation reaction with ethyl 4-chloroacetoacetate in polyp- Table 2. Suzuki–Miyaura monocoupling reaction of 4 with various
[
19]
boronic acids.
hosphoric acid (PPA) using the Ferrarini procedure,
which produced 7,9-dichloro-2-(chloromethyl)-4H-pyr-
ido[1,2-a]pyrimidin-4-one (2). Iodination of compound 2
with N-iodosuccinimide (NIS) in refluxing MeCN and sub-
sequent acetylation using potassium acetate in dimethyl-
formamide (DMF) provided (7,9-dichloro-3-iodo-4-oxo-
4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate (4) as de-
scribed in Scheme 2.
Scheme 2. Synthesis of the starting material 4.
Scheme 3. Chemoselective C-3 Suzuki–Miyaura cross-coupling re-
action.
Table 1. Suzuki–Miyaura reaction of 4 with phenyboronic acid.
Boronic
acid
%
Yield
4
%
Yield
5a
% Yield
Entry
Conditions
[equiv.]
6
0
Pd(PPh
Pd(PPh
Pd(PPh
3 4
) , MW, 100 °C,
1
2
3
1.5
1.5
1.1
41
0
45
40
70
2
h
3 4
) , MW, 110 °C,
25
9
2
h
3 4
) , MW, 110 °C,
0
[a] 9% of the dicoupled compound. [b] Trace amounts of dicoupled
compounds are present in the mixture, but are not isolated.
2
h
2
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One-Pot Chemoselective Bis(Suzuki–Miyaura Cross-Coupling)
Initial trials of the Suzuki–Miyaura cross-coupling reac-
This encouraging result for the chemoselective monocou-
tion were performed under similar experimental conditions pling of trihalogenated compound 4 led us to investigate the
to those recently described by our group. The reaction was possibility of a one-pot chemoselective bis(Suzuki–Miyaura
carried out using phenylboronic acid (1.5 equiv.), cross-coupling) reaction to substitute successively at the 3-
Pd(PPh ) (0.05 equiv.), K CO (1 n solution, 3 equiv.) in and then the 9-position with various boronic acids. Thus,
3
4
2
3
1,2-dimethoxyethane (DME)/EtOH (9:1) at 100 °C under starting material 4 was treated with 1.1 equiv. of phenyl-
microwave (MW) irradiation (see Scheme 3). After 2 h, we boronic acid in presence of Pd(PPh3)4 (0.05 equiv.) and
obtained a mixture of starting material 4 and compound 5a, K CO3 (1 n solution, 3 equiv.) in DME/EtOH (9:1, see
2
the monocoupled product, in only 45% yield (see Table 1, Scheme 4). After 2 h of heating at 110 °C under microwave
Entry 1). The structure of 5a was confirme 1, Entry 2) in- irradiation, 1.3 equiv. of 4-methoxyphenylboronic acid and
creased the conversion of 4 into the monocoupled product 3 equiv. of K CO were added to the reaction mixture. The
2
3
5a, however, this was accompanied by a considerable reaction mixture was again stirred for 2 h at 110 °C under
amount of the dicoupled compound 6. Next, the amount microwave irradiation, yielding 34% of the desired product
of phenylboronic acid was decreased to reduce the forma- 7a (see Table 3, Entry 1).
tion of the undesirable product 6. The use of 1.1 equiv. of
In addition to the desired compound 7a, the diphenyl
boronic acid minimized the formation of 6 (Ͻ10%, see product 6 was obtained in 19% yield and a mixture of com-
Table 1, Entry 3) and increased the yield of 5a (70%), which pound 8 and 9 in 15% yield. The increase in the yield of
demonstrates the higher reactivity of the C–I bond at the the undesired dicoupled compound 6 compared with the
3-position versus the C–Cl bond at the 9-position.
result from the optimal conditions in Scheme 3 could be
We then examined the scope and limitations of this explained by the difference in the reaction times (4 h vs 2 h).
chemoselective Suzuki–Miyaura cross-coupling reaction The presence of compounds 8 and 9 was because of cou-
procedure with 10 different aryl(heteroaryl) boronic acids pling occurring at the 7-position of products 6 and 7a,
(see Table 2). The results showed that the coupling process respectively, with the excess amount of 4-methoxyphenyl-
was tolerant towards the nature of the boronic acids (elec- boronic acid. Compounds 8 and 9 were not isolated because
tron-donating, electron-withdrawing, and bulky) and gen- of problems with purification, but nevertheless, their pres-
erally gave good isolated yields of the monocoupled prod- ence was confirmed by LC–MS analysis.
ucts (56–75%, see Table 2). Furthermore, under these ex-
Encouraged by this result and aiming to improve the
perimental conditions, cross-coupling reactions at the 3-po- chemoselectivity, we decided to optimize the previous reac-
sition of compound 4 were carried out with high selectivity. tion conditions. Interestingly, decreasing the proportion of
Scheme 4. One-pot chemoselective bis(Suzuki–Miyaura cross-coupling) reaction.
Table 3. Optimization study of the one-pot strategy.
Entry Conditions
I and II
equiv.]
% Yield 7a
% Yield 6
% Yield 8 and 9
[
1
2
3
4
Pd(PPh
Pd(PPh
3
3
)
)
4
, MW, 110 °C, 2 h step 1, 110 °C, 2 h step 2
, MW, 105 °C, 2 h step 1, 110 °C, 2 h step 2
1.1, 1.3
1, 1.1
1, 1.2
1, 1.1
34
44
46
61
19
15
17
15
Ͻ10
10
4
PdCl
PdCl
2
(PPh
(PPh
3
)
)
2
, MW, 110 °C, 2 h step 1, 110 °C, 2 h step 2
, MW, 105 °C, 2 h step 1, 110 °C, 2 h step 2
2
3
2
Ͻ10
trace
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Y. Kabri, M. D. Crozet, N. Primas, P. Vanelle
FULL PAPER
both boronic acids (1 equiv. of phenyboronic acid and Table 4. Scope of the one-pot chemoselective bis(Suzuki–Miyaura
cross-coupling) reaction.[
a]
1.1 equiv. of 4-methoxyphenylboronic acid) and the tem-
perature of the first step to 105 °C increased the yield of 7a
44%, see Table 3, Entry 2). We then investigated the effect
(
of the catalytic species. The use of PdCl (PPh )
2
3 2
(0.05 equiv.), 1 equiv. of phenyboronic acid (105 °C, 2 h),
and 1.1 equiv. of 4-methoxyphenylboronic acid (110 °C,
2
h) led to the formation of compound 7a in 61% yield (see
Table 3, Entry 4), showing a better chemoselectivity com-
pared to the use of Pd(PPh ) .
3
4
X-ray crystal structure analysis was performed to con-
firm the structure of compound 7a (see Figure 1). The other
structures were assigned by analogy and comparison of the
NMR spectroscopic data.
Figure 1. X-ray crystal structure of compound 7a.
After confirmation of the desired reactivity, we focused
on the scope of the one-pot bis(Suzuki–Miyaura cross-cou-
pling) reaction under the established optimal microwave
conditions. Simple and inexpensive phenylboronic acid was
chosen for the first cross-coupling reaction at the 3-posi-
tion, and a range of aryl and heteroaryl boronic acids were
used for the second cross-coupling reaction at the 9-posi-
tion. The results in Table 4 show that this method was ap-
plicable to all of the aryl boronic acid derivatives used in
our study. These reactions were tolerant of electron-poor,
electron-rich, and bulky boronic acid derivatives and gen-
erally gave moderate to good isolated yields of 3-phenyl-9-
(hetero)aryl-4H-pyrido[1,2-a]pyrimidin-4-ones over two
steps. LC–MS analysis showed the presence of diphenyl
product 6 and trace amounts of the corresponding tri-
coupled compounds.
The Suzuki–Miyaura reaction of 4 with an excess
amount of arylboronic acids (4.5 equiv.) afforded 3,7,9-tri-
aryl-4H-pyrido[1,2-a]pyrimidin-4-ones 11a–11c in moderate
yields (see Table 5). The preliminary reaction conditions
were carried out with Pd(PPh ) (0.05 equiv.) as the cata-
3
4
lytic species and K CO (1 n solution, 9 equiv.) as the base
2
3
in DME/EtOH (9:1, 110 °C, 4 h) under microwave irradia-
tion (see Scheme 5). In addition to the tricoupled com-
4
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One-Pot Chemoselective Bis(Suzuki–Miyaura Cross-Coupling)
Table 4. (continued)
Conclusions
We have described an efficient palladium-catalyzed
method to design new and rare asymmetrical 3,9-bis-
[(hetero)aryl]-4H-pyrido[1,2-a]pyrimidin-4-one derivatives
under microwave irradiation. This one-pot double Suzuki–
Miyaura cross-coupling reaction was adapted to achieve
high selectivity and creative synthetic design at each step.
We first ascertained an initial (hetero)arylation reaction
that was selectively carried out at the C-3 position of (7,9-
dichloro-3-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)meth-
yl acetate (4). Taking advantage of the greater reactivity
of the 3-position, we then developed an efficient one-pot
chemoselective double Suzuki–Miyaura cross-coupling re-
action based on the investigations of the catalytic species
and reaction temperature. This strategy allowed us to sub-
stitute successively at the 3- and then at the 9-position of
compound 4 with various boronic acids in one pot. This
original method should allow the efficient preparation of
chemical libraries of potentially bioactive compounds.
Experimental Section
[
a] One-pot reaction reagents and conditions: (step 1) phenyl-
boronic acid (1 equiv.), PdCl (PPh (0.05 equiv.), K CO (1 n
solution, 3 equiv.), DME/EtOH (9:1), MW 105 °C, 2 h; (step 2)
boronic acids (1.1 equiv.), CO (1 n solution, 3 equiv.),
PdCl (PPh (0.05 equiv.), DME/EtOH (9:1), MW 110 °C, 2 h.
b] Step 2 of these reactions were carried out in 3 h with 1.5 equiv.
of the corresponding boronic acid.
2
3
)
2
2
3
General: Melting points were measured with a Büchi B-540. Ele-
mental analyses and MS were carried out at the Spectropole, Fac-
ulté des Sciences et Techniques de Saint-Jérôme, Marseille.
K
2
3
1
H
2
3 2
)
1
3
[
NMR (200 MHz, reference CHCl
(50 MHz, reference CHCl , δ = 76.9 ppm) spectroscopic data were
recorded in CDCl with a Bruker ARX 200 spectrometer at the
Faculté de Pharmacie de Marseille. The solvents were dried by con-
3
, δ = 7.26 ppm) and C NMR
3
3
pound, the dicoupled product was isolated in minor yields ventional methods. For column chromatography, silica gel 60
(
16–27%). Increasing the temperature led to the hydrolysis (Merck, particle size 0.063–0.200 mm, 70–230 mesh ASTM) was
of the acetyl group, and a complex mixture was obtained.
used for the adsorbent. TLC was performed on 5 cmϫ10 cm alu-
minium plates coated with silica gel 60F-254 (Merck) in an appro-
priate eluent. MS spectra were recorded with a QStar Elite (Ap-
plied Biosystems SCIEX) spectrometer. PEG (polyethylene glycol)
was the matrix for HRMS. The microwave reactions were per-
formed with a Biotage Initiator Microwave oven using 10–20 mL
sealed vials. The temperatures were measured with an IF-senor, and
the reaction times are given as hold times. The X-ray crystal struc-
ture analyses were recorded with a Bruker-Nonius KappaCCD dif-
fractometer at 293(2) K. The structures were solved by using
SHELXL-97. LC–MS analyses were performed at the Faculty of
Table 5. Synthesis of 3,7,9-triaryl-4H-pyrido[1,2-a]pyrimidin-4-one.
Entry
Ar
% Yield
% Yield
1
2
3
4-methoxyphenyl
4-methylphenyl
3-nitrophenyl
10a, 27
10b, 16
10c, 24
11a, 46
11b, 52
11c, 40
®
Pharmacy of Marseille with an Accela High System chain U-
®
HPLC coupled with a Thermo MSQ Plus simple quadrupole. A
Thermo Hypersil Gold® 50ϫ2.1 mm chromatographic column was
2
used (SiO C18) with 1.9 μm diameter particles. The analysis ran
2
for 8 min, using a MeOH/H O eluent with a gradient from 50:50
to 95:05.
3
,5-Dichloropyridin-2-amine (1): A mixture of 5-chloropyridin-2-
amine (5 g, 38.9 mmol, 1 equiv.) and NCS (5.7 g, 42.8 mmol,
.1 equiv.) in MeCN (110 mL) was heated to reflux for 16 h. At
this time, the solution was cooled and evaporated under reduced
pressure. Flash chromatography (silica gel, CH Cl /petroleum
1
2
2
ether/ethyl acetate, 5:4.4:0.6) followed by recrystallization from pro-
pan-2-ol provided 1 (4.98 g, 79%) as a yellow solid. M.p. 88 °C;
ref.[ 85–86 °C. H NMR (200 MHz, CDCl
20]
1
, 24 °C): δ = 4.79 (br.
3
), 7.51 (d, JH,H = 2.2 Hz, 1 H, 4-H), 7.93 (d, 4JH,H
4
=
s, 2 H, NH
2
Scheme 5. Synthesis of 11a–11c. Reagents and conditions:
ArB(OH) (4.5 equiv.), Pd(PPh (0.05 equiv.), K CO (1 n solu-
tion, 9 equiv.), DME/EtOH (9:1), 110 °C, 4 h.
1
3
2
3
)
4
2
3
2.2 Hz, 1 H, 2-H) ppm. C NMR (50 MHz, CDCl
3
, 24 °C): δ =
115.2 (C), 120.3 (C), 136.7 (CH), 144.1 (CH), 153.2 (C) ppm.
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Y. Kabri, M. D. Crozet, N. Primas, P. Vanelle
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7
,9-Dichloro-2-(chloromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (2): 8-H), 9.00 (d, 4JH,H = 2.1 Hz, 1 H, 6-H) ppm. 13C NMR (50 MHz,
To a solution of 3,5-dichloropyridin-2-amine (1, 4 g, 24.5 mmol, CDCl , 24 °C): δ = 20.7 (CH ), 63.9 (CH ), 117.8 (C), 122.7 (C),
3
3
2
1
1
equiv.) in ethyl 4-chloroacetoacetate (4.7 mL, 34.4 mmol,
.4 equiv.) was added polyphosphoric acid (18 g). The reaction
124.4 (CH), 128.6 (CH), 128.8 (2 CH), 129.9 (2 CH), 132.0 (C),
132.1 (C), 135.9 (CH), 145.3 (C), 156.7 (C), 157.5 (C), 170.7
mixture was heated at 110 °C for 3 h. After cooling, water (500 mL)
was added, and the solution was neutralized by sodium carbonate.
The resulting precipitate was filtered, washed with water
(C) ppm. C17
found C 56.74, H 3.38, N 7.54.
2 2 3
H12Cl N O (363.19): calcd. C 56.22, H 3.33, N 7.71;
[
7,9-Dichloro-3-(4-methoxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimid-
(3ϫ100 mL), and dried in a vacuum drying oven (desiccator cabi-
in-2-yl]methyl Acetate (5b): Yellow solid (68% yield); m.p. 149 °C.
net). Recrystallization from propan-2-ol gave 2 (4.95 g, 77%) as a
1
H NMR (200 MHz, CDCl
s, 3 H, OCH ), 5.08 (s, 2 H, CH
Ј,5Ј-(4-methoxyphenyl)-H], 7.29 [d, JH,H = 8.9 Hz, 2 H, 2Ј,6Ј-(4-
3
, 24 °C): δ = 2.16 (s, 3 H, CH
3
), 3.86
1
brown solid; m.p. 172 °C. H NMR (200 MHz, CDCl
3
, 24 °C): δ =
3
(
3
3
2
), 7.00 [d, JH,H = 8.9 Hz, 2 H,
4
4
8
.58 (s, 2 H, CH ), 6.75 (s, 1 H, 3-H), 7.87 (d, JH,H = 2.0 Hz, 1 H,
2
3
4
13
-H), 8.98 (d, JH,H = 2.0 Hz, 1 H, 6-H) ppm. C NMR (50 MHz,
, 24 °C): δ = 45.4 (CH ), 104.0 (CH), 122.7 (C), 124.1 (CH),
31.7 (C), 136.6 (CH), 146.5 (C), 157.1 (C), 162.4 (C) ppm.
Cl O (263.51): calcd. C 41.02, H 1.91, N 10.63; found C
1.51, H 1.96, N 10.51.
4
methoxyphenyl)-H], 7.83 (d,
JH,H = 2.2 Hz, 1 H, 8-H), 8.99 (d,
CDCl
3
2
4
13
J
H,H = 2.2 Hz, 1 H, 6-H) ppm. C NMR (50 MHz, CDCl
4 °C): δ = 20.8 (CH ), 55.3 (OCH ), 63.9 (CH ), 114.3 (2 CH),
17.6 (C), 122.6 (C), 124.1 (C), 124.3 (CH), 131.2 (2 CH), 131.9
3
,
1
2
1
3
3
2
C
9
H
5
3 2
N
4
(
C), 135.6 (CH), 145.1 (C), 156.9 (C), 157.4 (C), 159.8 (C), 170.7
7
,9-Dichloro-2-(chloromethyl)-3-iodo-4H-pyrido[1,2-a]pyrimidin-4- (C) ppm. C H Cl N O (393.22): calcd. C 54.98, H 3.59, N 7.12;
1
8
14
2
2
4
one (3): A mixture of 7,9-dichloro-2-(chloromethyl)-4H-pyrido-
found C 55.07, H 3.59, N 7.05.
[
(
1,2-a] pyrimidin-4-one (2, 4 g, 15.2 mmol, 1 equiv.) and NIS
3.76 g, 16.7 mmol, 1.1 equiv.) in MeCN (100 mL) was heated to
[
7,9-Dichloro-3-(3-nitrophenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-
1
yl]methyl Acetate (5c): Brown solid (65% yield); m.p. 173 °C. H
NMR (200 MHz, CDCl , 24 °C): δ = 2.12 (s, 3 H, CH ), 5.02 (s, 2
H, CH ), 7.62–7.77 (m, 2 H, 3-nitrophenyl-H), 7.92 (d,
2.2 Hz, 1 H, 8-H), 8.27–8.31 (m, 2 H, 3-nitrophenyl-H), 9.00 (d,
reflux for 26 h. At this time, the solution was cooled and evapo-
rated under reduced pressure. Flash chromatography (silica gel,
CH
3
3
4
2
H,H
J =
2
Cl
2
) followed by recrystallization from propan-2-ol provided 3
1
(
5.1 g, 86%) as a yellow solid; m.p. 155 °C. H NMR (200 MHz,
4
13
4
J
H,H = 2.2 Hz, 1 H, 6-H) ppm. C NMR (50 MHz, CDCl
24 °C): δ = 20.6 (CH ), 63.9 (CH ), 115.5 (C), 123.4 (C), 123.5
CH), 124.4 (CH), 125.3 (CH), 129.7 (CH), 132.1 (C), 134.1 (C),
3
,
CDCl
8
3
, 24 °C): δ = 4.82 (s, 2 H, CH
2
), 7.91 (d, JH,H = 2.2 Hz, 1 H,
-H), 8.99 (d, JH,H = 2.2 Hz, 1 H, 6-H) ppm. 13C NMR (50 MHz,
4
3
2
(
CDCl
31.9 (C), 136.8 (CH), 146.0 (C), 155.3 (C), 163.2 (C) ppm.
Cl IN O (389.40): calcd. C 27.76, H 1.04, N 7.19; found C
8.04, H 1.04, N 7.37.
3 2
, 24 °C): δ = 50.1 (CH ), 80.9 (C), 123.9 (C), 124.6 (CH),
1
1
1
36.2 (CH), 136.6 (CH), 145.7 (C), 148.4 (C), 156.4 (C), 157.9 (C),
70.4 (C) ppm. C17 (408.19): calcd. C 50.02, H 2.72, N
0.29; found C 50.09, H 2.74, N 10.22.
1
C
2
2 3 5
H11Cl N O
9
H
4
3
2
[
7,9-Dichloro-3-(4-fluorophenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-
(
7,9-Dichloro-3-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl
Acetate (4): A solution of 7,9-dichloro-2-(chloromethyl)-3-iodo-
H-pyrido[1,2-a]pyrimidin-4-one (3, 3 g, 7.70 mmol, 1 equiv.) and
1
yl]methyl Acetate (5d): Yellow solid (66% yield); m.p. 166 °C. H
NMR (200 MHz, CDCl , 24 °C): δ = 2.14 (s, 3 H, CH ), 5.05 (s, 2
H, CH ), 7.13–7.22 (m, 2 H, 4-fluorophenyl-H), 7.31–7.38 (m, 2 H,
-fluorophenyl-H), 7.86 (d,
4
3
3
potassium acetate (0.91 g, 9.24 mmol, 1.2 equiv.) in DMF (90 mL)
was stirred at room temp. for 3 h. After this time, the DMF was
evaporated under reduced pressure. Flash chromatography (silica
2
4
4
JH,H = 2.2 Hz, 1 H, 8-H), 8.99 (d,
4
13
J
3
H,H = 2.2 Hz, 1 H, 6-H) ppm. C NMR (50 MHz, CDCl ,
3
2
4 °C): δ = 20.7 (CH
3 2
), 63.8 (CH ), 115.9 (d, JC,F = 21.6 Hz, 2
gel, CH
2 2
Cl ) followed by recrystallization from propan-2-ol pro-
1
CH-CF), 116.8 (C), 122.9 (C), 124.4 (CH), 128.0 (C), 131.8 (d,
vided 4 (2.13 g, 67%) as a yellow solid; m.p. 206 °C. H NMR
4
J
C,F = 8.4 Hz, 2 CH-CCF), 132.0 (C), 136.0 (CH), 145.3 (C), 156.7
(200 MHz, CDCl
3
, 24 °C): δ = 2.27 (s, 3 H, CH
3
4
), 5.23 (s, 2 H,
2
4
(C), 157.7 (C), 162.8 (d, JC,F = 248.5 Hz, C-F), 170.6 (C) ppm.
C H Cl FN O (381.19): calcd. C 53.57, H 2.91, N 7.35; found
C 53.70, H 2.90, N 7.30.
CH
1
2
), 7.89 (d, JH,H = 2.1 Hz, 1 H, 8-H), 8.99 (d, JH,H = 2.1 Hz,
H, 6-H) ppm. 13C NMR (50 MHz, CDCl
3
, 24 °C): δ = 20.7
17 11
2
2
3
(
(
C
3
CH ), 68.3 (CH
CH), 145.6 (C), 154.5 (C), 162.2 (C), 170.6 (C) ppm.
Cl IN (413.00): calcd. C 31.99, H 1.71, N 6.78; found C
1.34, H 1.67, N 6.93.
3
2
), 77.1 (C), 123.6 (C), 124.6 (CH), 131.7 (C), 136.6
[7,9-Dichloro-3-(4-chlorophenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-
11
H
7
2
2
O
3
1
yl]methyl Acetate (5e): Yellow solid (64% yield); m.p. 163 °C. H
NMR (200 MHz, CDCl , 24 °C): δ = 2.14 (s, 3 H, CH ), 5.04 (s, 2
2
H, CH ), 7.31 [d, JH,H = 8.4 Hz, 2 H, 3Ј,5Ј-(4-chlorophenyl)-H],
3
3
3
General Procedure of the Chemoselective Suzuki–Miyaura Mono-
coupling Reaction: A solution of (7,9-dichloro-3-iodo-4-oxo-4H-
pyrido[1,2-a]pyrimidin-2-yl)methyl acetate (4, 0.2 g, 0.48 mmol,
1
2
1
3
7.46 [d,
JH,H = 8.4 Hz, 2 H, 2Ј,6Ј-(4-chlorophenyl)-H], 7.86 (d,
4
4
J
H,H = 2.1 Hz, 1 H, 8-H), 8.99 (d, JH,H = 2.1 Hz, 1 H, 6-H) ppm.
1
3
equiv.), boronic acid (0.53 mmol, 1.1 equiv.), Pd(PPh
4 μmol, 0.05 equiv.), and K CO (1 n solution, 1.44 mL,
.44 mmol, 3 equiv.) in a mixture of DME/ethanol (9:1, 15 mL)
3
)
4
(28 mg,
3 3 2
C NMR (50 MHz, CDCl , 24 °C): δ = 20.7 (CH ), 63.8 (CH ),
116.6 (C), 123.0 (C), 124.4 (CH), 129.1 (2 CH), 130.6 (C), 131.3 (2
CH), 132.0 (C), 134.7 (C), 136.1 (CH), 145.4 (C), 156.5 (C), 157.6
2
3
under argon was heated at 110 °C under microwave irradiation for
h. After cooling, water (100 mL) was added, and the solution was
(C), 170.6 (C) ppm. C17
2.79, N 7.04; found C 50.89, H 2.74, N 7.02.
3 2 3
H11Cl N O (397.64): calcd. C 51.35, H
2
extracted with dichloromethane (3ϫ60 mL). The organic layer was
washed with water (3ϫ100 mL) and dried with sodium sulfate, and
the solvents were evaporated. The crude product was purified by
[
7,9-Dichloro-4-oxo-3-(3,4,5-trimethoxyphenyl)-4H-pyrido[1,2-a]-
pyrimidin-2-yl]methyl Acetate (5f): Beige solid (62 % yield); m.p.
1
1
3
6
92 °C. H NMR (200 MHz, CDCl
3
, 24 °C): δ = 2.16 (s, 3 H, CH
), 5.09 (s, 2 H, CH
3
),
),
2 2
column chromatography (silica gel, CH Cl /petroleum ether/ethyl
.85 (s, 6 H, 2 OCH ), 3.89 (s, 3 H, OCH
.57 (s, 2 H, trimethoxyphenyl-H), 7.85 (d, JH,H = 2.2 Hz, 1 H, 8-
3
3
4
2
acetate, 5:4.8:0.2) and then recrystallized from propan-2-ol.
4
13
(
7,9-Dichloro-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl
H), 9.00 (d, JH,H = 2.2 Hz, 1 H, 6-H) ppm. C NMR (50 MHz,
CDCl , 24 °C): δ = 20.7 (CH ), 56.1 (2 OCH ), 60.8 (OCH ), 63.7
(CH ), 107.0 (2 CH), 117.6 (C), 122.8 (C), 124.3 (CH), 127.4 (C),
131.9 (C), 135.9 (CH), 138.2 (C), 145.2 (C), 153.5 (2 C), 156.6 (C),
1
Acetate (5a): Yellow solid (70 % yield); m.p. 157 °C. H NMR
200 MHz, CDCl , 24 °C): δ = 2.14 (s, 3 H, CH ), 5.07 (s, 2 H,
), 7.34–7.53 (m, 5 H, phenyl-H), 7.85 (d, JH,H = 2.1 Hz, 1 H,
3
3
3
3
(
3
3
2
4
CH
2
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20748
/KAP1
Date: 21-08-12 15:35:23
Pages: 11
One-Pot Chemoselective Bis(Suzuki–Miyaura Cross-Coupling)
2 3 2 2 3
57.7 (C), 170.7 (C) ppm. C20 (453.27): calcd. C 53.00, 1 equiv.), PdCl (PPh ) (17 mg, 24 μmol, 0.05 equiv.), and K CO
1
H18Cl
2
N
2
O
6
H 4.00, N 6.18; found C 53.19, H 4.01, N 6.23.
(1 n solution, 1.45 mL, 1.45 mmol, 3 equiv.) in a mixture of DME/
ethanol (9:1, 15 mL) under argon was heated at 105 °C under mi-
crowave irradiation for 2 h. After cooling, boronic acid II
{
7,9-Dichloro-4-oxo-3-[3-(trifluoromethyl)phenyl]-4H-pyrido[1,2-a]-
pyrimidin-2-yl}methyl Acetate (5g): Beige solid (58% yield); m.p.
(
1.1 equiv.) and K
2 3
CO (1 n solution, 1.44 mL, 1.44 mmol,
1
1
5
7
6
6
1
3
1
1
5
41 °C. H NMR (200 MHz, CDCl
3 3
, 24 °C): δ = 2.10 (s, 3 H, CH ),
3
equiv.) were added. The mixture was heated at 110 °C under mi-
.02 (s, 2 H, CH ), 7.55–7.70 (m, 4 H, trifluoromethylphenyl-H),
2
crowave irradiation for 2 h. After cooling, water (100 mL) was
added, and the solution was extracted with dichloromethane
4
4
.89 (d, JH,H = 2.2 Hz, 1 H, 8-H), 9.00 (d, JH,H = 2.2 Hz, 1 H,
-H) ppm. 13C NMR (50 MHz, CDCl
3.9 (CH ), 116.4 (C), 123.1 (C), 123.9 (q, JC,F = 272.6 Hz, CF
24.3 (CH), 125.3 (q, JC,F = 3.7 Hz, CH-CCF
, 24 °C): δ = 20.5 (CH
),
),
=
3
3
3
(
3ϫ60 mL). The organic layer was washed with water (3ϫ100 mL)
2
2
and then dried with sodium sulfate, and the solvents were evapo-
rated. The crude product was purified by column chromatography
4
4
3
), 126.9 (q, JC,F
), 129.2 (CH), 131.1 (q, JC,F = 32.6 Hz, C-CF
32.0 (C), 133.1 (C), 133.4 (CH), 136.3 (CH), 145.5 (C), 156.5 (C),
57.8 (C), 170.4 (C) ppm. C18 (431.19): calcd. C
0.14, H 2.57, N 6.50; found C 50.08, H 2.65, N 6.37.
3
.7 Hz, CH-CCF
3
3
),
(
2 2
silica gel, CH Cl /petroleum ether/ethyl acetate, 5:4.8:0.2) and
recrystallized from propan-2-ol.
H
2 3 2 3
11Cl F N O
[7-Chloro-9-(4-methoxyphenyl)-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyr-
imidin-2-yl]methyl Acetate (7a): Yellow solid (61 % yield); m.p.
[
7,9-Dichloro-3-(furan-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl]-
1
1
3
64 °C. H NMR (200 MHz, CDCl
3
, 24 °C): δ = 1.90 (s, 3 H, CH
3
),
1
methyl Acetate (5i): Green solid (75% yield); m.p. 188 °C. H NMR
200 MHz, CDCl , 24 °C): δ = 2.24 (s, 3 H, CH ), 5.62 (s, 2 H,
CH ), 6.59–6.62 (m, 1 H, furanyl-H), 7.39 (d, JH,H = 3.4 Hz, 1 H,
furanyl-H), 7.58–7.59 (m, 1 H, furanyl-H), 7.80 (d, JH,H = 2.1 Hz,
3
.88 (s, 3 H, OCH
3
), 5.02 (s, 2 H, CH
2
), 7.01 [d, JH,H = 8.9 Hz, 2
(
3
3
H, 3Ј,5Ј-(4-methoxyphenyl)-H], 7.35–7.52 (m, 5 H, phenyl-H), 7.65
3
2
3
4
[
=
d, JH,H = 8.9 Hz, 2 H, 2Ј,6Ј-(4-methoxyphenyl)-H], 7.68 (d, JH,H
4
2.4 Hz, 1 H, 8-H), 9.10 (d, JH,H = 2.4 Hz, 1 H, 6-H) ppm. 13C
NMR (50 MHz, CDCl , 24 °C): δ = 20.7 (CH ), 55.4 (OCH ), 63.6
), 113.6 (2 CH), 116.2 (C), 124.0 (CH), 124.1 (C), 127.3 (C),
4
H, 8-H), 9.05 (d, 4
50 MHz, CDCl , 24 °C): δ = 20.9 (CH
12.0 (CH), 114.0 (CH), 123.1 (C), 124.1 (CH), 132.0 (C), 135.3
J
H,H = 2.1 Hz, 1 H, 6-H) ppm. C NMR
13
1
(
1
(
3
3
3
3
3
), 64.8 (CH ), 107.0 (C),
2
(
CH
2
1
1
1
6
28.3 (CH), 128.7 (2 CH), 130.0 (2 CH), 131.6 (2 CH), 132.7 (C),
35.8 (CH), 138.8 (C), 147.1 (C), 157.0 (C), 157.1 (C), 160.3 (C),
CH), 142.8 (CH), 143.3 (C), 146.7 (C), 154.4 (C), 155.7 (C), 171.0
C) ppm. C15 (353.16): calcd. C 51.01, H 2.85, N 7.93;
(
2 2 4
H10Cl N O
70.5 (C) ppm. C24
2 4
H19ClN O (434.87): calcd. C 66.29, H 4.40, N
found C 51.01, H 2.89, N 7.83.
.44; found C 66.31, H 4.44, N 6.46.
[
7,9-Dichloro-4-oxo-3-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl]-
[
7-Chloro-9-(3-nitrophenyl)-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyr-
1
methyl Acetate (5j): Yellow solid (65 % yield); m.p. 164 °C. H
NMR (200 MHz, CDCl , 24 °C): δ = 2.11 (s, 3 H, CH ), 5.06 (s, 2
H, CH ), 7.40–7.46 (m, 1 H, pyridinyl-H), 7.73–7.79 (m, 1 H, pyrid-
inyl-H), 7.89 (d,
pyridinyl-H), 9.00 (d, JH,H = 2.7 Hz, 1 H, 6-H) ppm. C NMR
50 MHz, CDCl , 24 °C): δ = 20.6 (CH ), 64.8 (CH ), 114.3 (C),
23.2 (C), 123.5 (CH), 124.4 (CH), 128.5 (C), 132.1 (C), 136.4
CH), 137.6 (CH), 145.6 (C), 149.7 (CH), 150.6 (CH), 156.6 (C),
58.1 (C), 170.5 (C) ppm. C16 (364.18): calcd. C 52.77,
H 3.04, N 11.54; found C 52.60, H 3.06, N 11.35.
imidin-2-yl]methyl Acetate (7b): Yellow solid (52 % yield); m.p.
3
3
1
1
4
8
53 °C. H NMR (200 MHz, CDCl
.98 (s, 2 H, CH ), 7.35–7.53 (m, 5 H, phenyl-H), 7.69 (t, JH,H
.0 Hz, 1 H, 3-nitrophenyl-H), 7.78 (d,
3 3
, 24 °C): δ = 1.83 (s, 3 H, CH ),
2
3
=
4
2
J
H,H = 2.7 Hz, 1 H, 8-H), 8.61–8.68 (m, 2 H,
4
JH,H = 2.3 Hz, 1 H, 8-
4
13
H), 8.02–8.06 (m, 1 H, 3-nitrophenyl-H), 8.32–8.38 (m, 1 H, 3-
(
1
(
1
3
3
2
4
nitrophenyl-H), 8.58–8.60 (m, 1 H, 3-nitrophenyl-H), 9.17 (d, JH,H
1
3
=
2
(
2.3 Hz, 1 H, 6-H) ppm. C NMR (50 MHz, CDCl
0.4 (CH ), 63.5 (CH ), 117.3 (C), 123.7 (CH), 123.8 (C), 125.2
CH), 125.6 (CH), 128.5 (CH), 128.7 (2 CH), 129.1 (CH), 129.9 (2
3
, 24 °C): δ =
3
2
2 3 3
H11Cl N O
CH), 132.3 (C), 136.2 (CH), 136.4 (C), 136.5 (C), 136.9 (CH), 146.4
(C), 148.0 (C), 156.7 (C), 157.2 (C), 170.3 (C) ppm. C H ClN O
5
[
7,9-Dichloro-4-oxo-3-(pyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl]-
2
3
16
3
1
methyl Acetate (5k): Yellow solid (56 % yield); m.p. 191 °C. H
NMR (200 MHz, CDCl , 24 °C): δ = 2.11 (s, 3 H, CH ), 5.06 (s, 2
H, CH ), 7.32–7.35 (m, 2 H, pyridinyl-H), 7.91 (d, JH,H = 2.2 Hz,
1
1
(
1
(
5
(449.84): calcd. C 61.41, H 3.59, N 9.34; found C 61.45, H 3.60, N
9.27.
3
3
4
2
[
7-Chloro-9-(4-fluorophenyl)-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyr-
4
H, 8-H), 8.73–8.76 (m, 2 H, pyridinyl-H), 9.01 (d, JH,H = 2.2 Hz,
H, 6-H) ppm. 13C NMR (50 MHz, CDCl
, 24 °C): δ = 20.6
), 63.7 (CH ), 114.9 (C), 123.4 (C), 124.4 (CH), 124.8 (2CH),
32.1 (C), 136.6 (CH), 140.7 (C), 145.7 (C), 150.3 (2 CH), 156.0
(364.18): calcd. C
2.77, H 3.04, N 11.54; found C 52.80, H 3.09, N 11.41.
imidin-2-yl]methyl Acetate (7c): Yellow solid (49 % yield); m.p.
3
1
1
5
7
7
6
61 °C. H NMR (200 MHz, CDCl
.01 (s, 2 H, CH ), 7.14–7.23 (m, 2 H, 4-fluorophenyl-H), 7.34–
.52 (m, 5 H, phenyl-H), 7.64–7.68 (m, 2 H, 4-fluorophenyl-H),
3 3
, 24 °C): δ = 1.87 (s, 3 H, CH ),
CH
3
2
2
2 3 3
C), 157.9 (C), 170.5 (C) ppm. C16H11Cl N O
4
4
.69 (d, JH,H = 2.2 Hz, 1 H, 6-H), 9.12 (d, JH,H = 2.2 Hz, 1 H,
1
3
-H) ppm. C NMR (50 MHz, CDCl
63.4 (CH ), 115.2 (d, J
2 C,F
3
, 24 °C): δ = 20.6 (CH
3
),
3
(7-Chloro-4-oxo-3,9-diphenyl-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl
= 21.6 Hz, 2 CH-CF), 116.4 (C), 124.0
Acetate (6): (Table 1, Entry 2). Yellow solid (25 % yield); m.p. (C), 124.7 (CH), 128.4 (CH), 128.8 (2 CH), 130.0 (2 CH), 130.9 (d,
1
5
4
1
5
2
=
30 °C. H NMR (200 MHz, CDCl
3
, 24 °C): δ = 1.83 (s, 3 H, CH
3
),
JC,F = 3.3 Hz, C-CCCF), 132.0 (d, J
C,F
= 8.4 Hz, 2 CH-CCF),
.01 (s, 2 H, CH
2
), 7.36–7.55 (m, 8 H, diphenyl-H), 7.64–7.69 (m,
132.5 (C), 136.4 (CH), 138.1 (C), 146.9 (C), 156.8 (C), 157.2 (C),
163.2 (d, J
4
4
2
H, diphenyl-H), 7.71 (d, JH,H = 2.3 Hz, 1 H, 8-H), 9.13 (d, JH,H
2.3 Hz, 1 H, 6-H) ppm. 13C NMR (50 MHz, CDCl
, 24 °C): δ = (422.84): calcd. C 65.33, H 3.81, N 6.63; found C 65.48, H 3.84, N
), 63.4 (CH ), 116.1 (C), 124.0 (C), 124.6 (CH), 128.2 (2 6.51.
CH), 128.4 (CH), 128.8 (2 CH), 128.9 (CH), 129.9 (2 CH), 130.1
2 CH), 132.6 (C), 135.0 (C), 136.5 (CH), 139.2 (C), 147.0 (C),
56.9 (C), 157.3 (C), 170.5 (C) ppm. C23 17ClN (404.85): calcd.
C,F 23 16 2 3
= 249.9 Hz, C-F), 170.4 (C) ppm. C H ClFN O
3
2
0.5 (CH
3
2
[
7-Chloro-9-(4-chlorophenyl)-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyr-
(
1
imidin-2-yl]methyl Acetate (7d): White solid (48 % yield); m.p.
1
5
H
2 3
O
1
51 °C. H NMR (200 MHz, CDCl
3 3
, 24 °C): δ = 1.86 (s, 3 H, CH ),
.01 (s, 2 H, CH ), 7.34–7.40 (m, 2 H, 4-chlorophenyl-H), 7.43–
C 68.23, H 4.23, N 6.92; found C 67.69, H 4.26, N 6.93.
2
General Procedure of the One-Pot Chemoselective Bis(Suzuki–
Miyaura Cross-Coupling) Reaction: A solution of (7,9-dichloro-3-
iodo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate (4, 0.2 g,
7.51 (m, 5 H, phenyl-H), 7.59–7.65 (m, 2 H, 4-chlorophenyl-H),
4
4
7.69 (d, JH,H = 2.3 Hz, 1 H, 8-H), 9.13 (d, JH,H = 2.3 Hz, 1 H,
1
3
6-H) ppm. C NMR (50 MHz, CDCl
3 3
, 24 °C): δ = 20.5 (CH ),
0
.48 mmol, 1 equiv.), phenylboronic acid (I, 0.06 g, 0.48 mmol,
63.4 (CH ), 116.5 (C), 123.9 (C), 124.8 (CH), 128.3 (2 CH), 128.4
2
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20748
/KAP1
Date: 21-08-12 15:35:23
Pages: 11
Y. Kabri, M. D. Crozet, N. Primas, P. Vanelle
FULL PAPER
3
(
(
(
CH), 128.8 (2 CH), 129.9 (2 CH), 131.5 (2 CH), 132.4 (C), 133.3
C), 135.2 (C), 136.4 (CH), 137.9 (C), 146.7 (C), 156.8 (C), 157.2
tolyl)-H], 7.35–7.51 (m, 5 H, phenyl-H), 7.58 [d, JH,H = 8.1 Hz, 2
4
H, 2Ј,6Ј-(p-tolyl)-H], 7.69 (d, JH,H = 2.4 Hz, 1 H, 8-H), 9.11 (d,
4
13
C), 170.4 (C) ppm. C23
H
16Cl
2
N
2
O
3
(439.29): calcd. C 62.88, H
J
H,H = 2.4 Hz, 1 H, 6-H) ppm. C NMR (50 MHz, CDCl
24 °C): δ = 20.5 (CH ), 21.3 (CH ), 63.6 (CH ), 116.2 (C), 124.1
C), 124.3 (CH), 128.3 (CH), 128.7 (2 CH), 128.9 (2 CH), 130.0 (2
3
,
3.67, N 6.38; found C 62.74, H 3.69, N 6.25.
3
3
2
(
[
[
7-Chloro-4-oxo-3-phenyl-9-(3,4,5-trimethoxyphenyl)-4H-pyrido-
CH), 130.1 (2 CH), 132.1 (C), 132.7 (C), 136.2 (CH), 139.0 (C),
139.2 (C), 147.0 (C), 156.9 (C), 157.2 (C), 170.5 (C) ppm.
O (418.87): calcd. C 68.82, H 4.57, N 6.69; found C
2 3
8.29, H 4.50, N 6.47.
1,2-a]pyrimidin-2-yl]methyl Acetate (7e): Yellow solid (46% yield);
1
m.p. 91 °C. H NMR (200 MHz, CDCl
3
, 24 °C): δ = 1.80 (s, 3 H,
), 3.94 (s, 6 H, 2 OCH ), 5.02 (s, 2 H,
), 6.86 (s, 2 H, trimethoxyphenyl-H), 7.34–7.53 (m, 5 H,
C
6
24
H
19ClN
CH
CH
phenyl-H), 7.70 (d,
2
2
1
3
), 3.92 (s, 3 H, OCH
3
3
2
4
4
J
H,H = 2.3 Hz, 1 H, 8-H), 9.13 (d,
J
H,H
=
(7-Chloro-4-oxo-3-phenyl-9-o-tolyl-4H-pyrido[1,2-a]pyrimidin-2-yl)-
1
3
1
.3 Hz, 1 H, 6-H) ppm. C NMR (50 MHz, CDCl
0.2 (CH ), 56.3 (2 OCH ), 60.8 (OCH ), 63.4 (CH
16.1 (C), 123.9 (C), 124.5 (CH), 128.4 (CH), 128.8 (2 CH), 129.9
3
, 24 °C): δ =
methyl Acetate (7k): Yellow solid (51 % yield); m.p. 170 °C. H
3
3
3
2
3 3
), 107.6 (2 CH), NMR (200 MHz, CDCl , 24 °C): δ = 1.60 (s, 3 H, CH ), 2.15 (s, 3
H, CH ), 5.01 (s, 2 H, CH ), 7.19–7.24 (m, 1 H, o-tolyl-H), 7.29–
3
2
(
1
C
6
2 CH), 130.4 (C), 132.5 (C), 136.3 (CH), 138.7 (C), 139.3 (C),
47.0 (C), 152.9 (2 C), 156.8 (C), 157.2 (C), 170.6 (C) ppm.
23ClN (494.92): calcd. C 63.10, H 4.68, N 5.66; found C
2.23, H 4.64, N 5.46. HRMS: calcd. for C26 23ClN [M +
7.39 (m, 5 H, phenyl-H), 7.42–7.52 (m, 3 H, o-tolyl-H), 7.60 (d,
4
4
J
H,H
= 2.4 Hz, 1 H, 8-H), 9.15 (d, J
H,H
= 2.4 Hz, 1 H, 6-H) ppm.
1
3
26
H
2
O
6
3 3 2
C NMR (50 MHz, CDCl , 24 °C): δ = 20.0 (2 CH ), 63.0 (CH ),
H
2
O
6
115.7 (C), 123.8 (C), 124.9 (CH), 125.7 (CH), 128.4 (CH), 128.8 (3
CH), 129.7 (CH), 129.9 (3 CH), 132.5 (C), 135.3 (C), 137.1 (CH),
+
H] 495.1317; found 495.1316.
7-Chloro-4-oxo-3-phenyl-9-[3-(trifluoromethyl)phenyl]-4H-pyrido-
1,2-a]pyrimidin-2-yl}methyl Acetate (7f): Yellow solid (52% yield);
137.2 (C), 140.3 (C), 147.0 (C), 156.8 (C), 157.5 (C), 170.5 (C) ppm.
{
[
C
24
H
19ClN (418.87): calcd. C 68.82, H 4.57, N 6.69; found C
2 3
O
1
68.50, H 4.56, N 6.57.
m.p. 163 °C. H NMR (200 MHz, CDCl
CH ), 4.98 (s, 2 H, CH ), 7.34–7.53 (m, 5 H, phenyl-H), 7.59–7.76
m, 3 H, trifluoromethylphenyl-H), 7.86–7.95 (m, 2 H, 8-H, trifluo-
3
, 24 °C): δ = 1.80 (s, 3 H,
3
2
General Procedure of the Synthesis of 3,7,9-Triaryl-4H-pyrido-
(
[
1,2-a]pyrimidin-4-one: A solution of (7,9-dichloro-3-iodo-4-oxo-
4
13
romethylphenyl-H), 9.15 (d, JH,H = 2.4 Hz, 1 H, 6-H) ppm.
NMR (50 MHz, CDCl , 24 °C): δ = 20.3 (CH ), 63.6 (CH ), 116.9
), 125.3 (CH), 125.7
), 126.9 (q, JC,F = 3.7 Hz, CH-CCF ),
28.5 (CH), 128.7 (CH), 128.8 (2 CH), 129.9 (2 CH), 130.7 (q, JC,F
32.6 Hz, C-CF ), 132.4 (C), 133.5 (CH), 135.7 (C), 136.8 (CH),
37.6 (C), 146.7 (C), 156.8 (C), 157.3 (C), 170.4 (C) ppm.
16ClF (472.84): calcd. C 60.96, H 3.41, N 5.92; found
C 60.75, H 3.41, N 5.84.
C
4
1
2
4
H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate (4, 0.2 g, 0.48 mmol,
equiv.), boronic acid (2.16 mmol, 4.5 equiv.), Pd(PPh (28 mg,
4 μmol, 0.05 equiv.), and K CO (1 n solution, 4.32 mL,
.32 mmol, 9 equiv.) in a mixture of DME/ethanol (9:1, 15 mL)
3
3
2
3 4
)
2
(
(
C), 123.9 (C), 124.0 (q, JC,F = 272.6 Hz, CF
3
q, JC,F = 3.7 Hz, CH-CCF
2
3
4
4
3
3
3
1
=
1
C
under argon was heated at 110 °C under microwave irradiation for
h. After cooling, water (100 mL) was added, and the solution was
3
4
extracted with dichloromethane (3ϫ60 mL). The organic layer was
washed with water (3ϫ100 mL) and dried with sodium sulfate, and
then the solvents were evaporated. The crude product was purified
24
H
3 2 3
N O
by column chromatography on silica gel (CH
2 2
Cl /petroleum ether/
[
2
7-Chloro-9-(furan-2-yl)-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyrimidin-
1
ethyl acetate, 5:4.9:0.1, for 11b; CH Cl /petroleum ether/ethyl acet-
-yl]methyl Acetate (7g): Brown solid (58% yield); m.p. 156 °C. H
, 24 °C): δ = 2.11 (s, 3 H, CH ), 5.10 (s, 2
), 6.60–6.63 (m, 1 H, furanyl-H), 7.38–7.53 (m, 5 H, phenyl-
2
2
ate, 5:4.5:0.5, for 11a and 11c] and then recrystallized from propan-
-ol.
NMR (200 MHz, CDCl
H, CH
H), 7.61–7.62 (m, 1 H, furanyl-H), 7.94 (d, JH,H = 3.4 Hz, 1 H,
3
3
2
2
3
[3,7,9-Tris(4-methoxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl]-
furanyl-H), 8.19 (d, 4
2
2
J
H,H = 2.4 Hz, 1 H, 8-H), 8.99 (d,
4
J
=
1
H,H
methyl Acetate (11a): Yellow solid (46% yield); m.p. 89 °C. H
NMR (200 MHz, CDCl , 24 °C): δ = 1.93 (s, 3 H, CH ), 3.86 (s, 3
H, OCH ), 3.87 (s, 3 H, OCH ), 3.89 (s, 3 H, OCH ), 5.06 (s, 2 H,
CH ), 6.99–7.05 [m, 6 H, tris(methoxyphenyl)-H], 7.34 [d, JH,H
.5 Hz, 2 H, tris(methoxyphenyl)-H], 7.60–7.72 [m, 4 H, tris-
13
.4 Hz, 1 H, 6-H) ppm. C NMR (50 MHz, CDCl
3
, 24 °C): δ =
3
3
0.8 (CH ), 64.1 (CH ), 112.6 (CH), 116.4 (CH), 117.4 (C), 122.9
3
2
3
3
3
(
CH), 124.2 (C), 127.2 (C), 128.4 (CH), 128.7 (2 CH), 130.1 (2
CH), 131.0 (CH), 132.6 (C), 144.0 (CH), 144.1 (C), 147.1 (C), 156.7
C), 156.9 (C), 170.4 (C) ppm. C21 15ClN (394.81): calcd. C
3.89, H 3.83, N 7.10; found C 63.86, H 3.86, N 6.93.
3
2
=
8
(
6
H
2
O
4
4
(
methoxyphenyl)-H], 7.98 (d, JH,H = 2.0 Hz, 1 H, 8-H), 9.25 (d,
J
4
13
H,H = 2.0 Hz, 1 H, 6-H) ppm. C NMR (50 MHz, CDCl
24 °C): δ = 20.8 (CH ), 55.3 (OCH ), 55.4 (OCH ), 55.5 (OCH
63.8 (CH ), 113.5 (2 CH), 114.2 (2 CH), 114.8 (2 CH), 115.1 (C),
122.7 (CH), 125.3 (C), 128.1 (2 CH), 128.2 (C), 128.7 (C), 129.0
), 7.35–7.53 (m, 5 H, phenyl-H), (C), 131.3 (2 CH), 131.6 (2 CH), 135.0 (CH), 137.5 (C), 147.2 (C),
.76 (d, JH,H = 2.2 Hz, 1 H, 8-H), 8.00 [s, 1 H, bis(trifluoromethyl)
156.8 (C), 158.1 (C), 159.4 (C), 159.9 (C), 160.3 (C), 170.6 (C) ppm.
phenyl-H], 8.18 [s, 2 H, bis(trifluoromethyl)phenyl-H], 9.18 (d,
3
,
{
9-[3,5-Bis(trifluoromethyl)phenyl]-7-chloro-4-oxo-3-phenyl-4H-pyr-
3
3
3
3
),
ido[1,2-a]pyrimidin-2-yl}methyl Acetate (7i): Beige solid (45 %
2
1
yield); m.p. 172 °C. H NMR (200 MHz, CDCl
s, 3 H, CH ), 4.94 (s, 2 H, CH
3
, 24 °C): δ = 1.82
(
7
3
2
4
28 2 6
H N O
[M + H]+ 537.2020; found
HRMS (ESI+): calcd. for C32
537.2014.
4
13
J
H,H = 2.2 Hz, 1 H, 6-H) ppm. C NMR (50 MHz, CDCl
4 °C): δ = 20.1 (CH ), 63.9 (CH ), 117.9 (C), 122.8 [m, CH(CCF
], 123.1 (q, JC,F = 273.0 Hz, 2 CF
CH), 128.8 (2 CH), 129.9 (2 CH), 130.4 (q, JC,F = 3.7 Hz, 2 CH-
3
,
)
2
3
2
3
[
4-Oxo-3,7,9-tris(p-tolyl)-4H-pyrido[1,2-a]pyrimidin-2-yl]methyl
2
2
3
), 123.7 (C), 126.0 (CH), 128.6
1
Acetate (11b): Yellow solid (52 % yield); m.p. 168 °C. H NMR
200 MHz, CDCl , 24 °C): δ = 1.89 (s, 3 H, CH ), 2.41 (s, 3 H,
CH ), 2.42 (s, 3 H, CH ), 2.45 (s, 3 H, CH ), 5.04 (s, 2 H, CH ),
.26–7.33 [m, 8 H, tris(p-tolyl)-H], 7.56–7.65 [m, 4 H, tris(p-tolyl)-
4
(
(
3
3
3
CCF
36.9 (C), 137.2 (CH), 146.4 (C), 156.8 (C), 157.3 (C), 170.3
C) ppm. C25 15ClF (540.84): calcd. C 55.52, H 2.80, N
.18; found C 55.43, H 2.73, N 5.25.
3 3
), 131.8 (q, JC,F = 33.3 Hz, 2 C-CF ), 132.3 (C), 136.0 (C),
3
3
3
2
1
(
5
7
H
6
N
2
O
3
4
4
H], 8.02 (d, JH,H = 2.1 Hz, 1 H, 8-H), 9.30 (d, JH,H = 2.1 Hz, 1
13
H, 6-H) ppm. C NMR (50 MHz, CDCl
21.2 (CH ), 21.3 (CH ), 21.4 (CH ), 63.8 (CH
methyl Acetate (7j): Yellow solid (56 % yield); m.p. 172 °C. H (CH), 126.8 (2 CH), 128.8 (2 CH), 129.2 (C), 129.4 (2 CH), 129.9
3
, 24 °C): δ = 20.6 (CH
3
),
(
7-Chloro-4-oxo-3-phenyl-9-p-tolyl-4H-pyrido[1,2-a]pyrimidin-2-yl)-
3
3
3
2
), 115.4 (C), 123.3
1
NMR (200 MHz, CDCl
3
, 24 °C): δ = 1.86 (s, 3 H, CH
3
), 2.44 (s, 3
(2 CH), 130.0 (2 CH), 130.1 (C), 130.2 (2 CH), 132.8 (C), 133.5
(C), 135.4 (CH), 137.9 (C), 138.0 (C), 138.4 (C), 138.9 (C), 147.4
3
H, CH
), 5.01 (s, 2 H, CH ), 7.29 [d, JH,H = 8.1 Hz, 2 H, 3Ј,5Ј-(p-
3 2
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20748
/KAP1
Date: 21-08-12 15:35:23
Pages: 11
One-Pot Chemoselective Bis(Suzuki–Miyaura Cross-Coupling)
(
C
C), 156.9 (C), 158.0 (C), 170.6 (C) ppm. HRMS (ESI+): calcd. for
280 variables and 0 restraint, were refined for 2193 reflections with
I Ն 2σ to R = 0.0478, GoF = 1.128.
l
H
28
N
2
O
3
[M + H]+ 489.2172; found 489.2173.
32
[
3,7,9-Tris(3-nitrophenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl]-
CCDC-883898 (for 7a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
1
methyl Acetate (11c): Yellow solid (40% yield); m.p. 195 °C.
NMR (200 MHz, CDCl , 24 °C): δ = 1.89 (s, 3 H, CH ), 4.98 (s, 2
H, CH ), 7.65–7.82 [m, 4 H, tris(nitrophenyl)-H], 8.04–8.13 [m, 2
H, tris(nitrophenyl)-H], 8.16 (d, JH,H = 2.2 Hz, 1 H, 8-H), 8.29–
.41 [m, 4 H, tris(nitrophenyl)-H], 8.56–8.58 [m, 1 H, tris(nitro-
H
3
3
2
4
8
Supporting Information (see footnote on the first page of this arti-
4
phenyl)-H], 8.65–8.67 [m, 1 H, tris(nitrophenyl)-H], 9.43 (d, JH,H
2.2 Hz, 1 H, 6-H) ppm. 13C NMR (50 MHz, CDCl
0.4 (CH ), 63.8 (CH ), 115.0 (C), 121.9 (CH), 123.4 (CH), 123.8
CH), 124.1 (CH), 125.3 (CH), 125.4 (CH), 125.7 (CH), 127.4 (C),
29.3 (CH), 129.7 (CH), 130.8 (CH), 132.8 (CH), 134.4 (C), 135.9
CH), 136.2 (CH), 136.4 (CH), 136.5 (C), 136.7 (C), 136.9 (C),
cle): General information, characterization data, selected crystallo-
=
2
(
1
3
, 24 °C): δ = graphic data, copies of H and C NMR spectra, reference.
1
13
3
2
Acknowledgments
(
1
1
5
47.6 (C), 148.2 (C), 148.5 (C), 149.1 (C), 157.4 (C), 158.0 (C),
70.3 (C) ppm. HRMS (ESI+): calcd. for C29
82.1255; found 582.1251.
This work was supported by the Centre National de la Recherche
Scientifique (CNRS) and Aix-Marseille Université. The authors
thank V. Remusat for the NMR spectra recording and the Spectro-
19 5 9
H N O
[M + H]+
[7-Chloro-3,9-bis(4-methoxyphenyl)-4-oxo-4H-pyrido[1,2-a]pyrimid- pole team for various analytical measurements.
in-2-yl]methyl Acetate (10a): Yellow solid (27% yield); m.p. 193 °C.
1
H NMR (200 MHz, CDCl
s, 3 H, OCH ), 3.88 (s, 3 H, OCH
.03 [m, 4 H, bis(methoxyphenyl)-H], 7.30 [d, JH,H = 8.9 Hz, 2 H,
3
, 24 °C): δ = 1.91 (s, 3 H, CH
3
), 3.85
[
1] a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457–2483;
b) A. Suzuki, J. Organomet. Chem. 1999, 576, 147–168; c) N.
Miyaura, in: Topics in Current Chemistry (Ed.: N. Miyaura),
Springer-Verlag, Berlin, 2002, vol. 219, pp. 11–59; d) S. Kotha,
K. Lahiri, D. Kashinath, Tetrahedron 2002, 58, 9633–9695; e)
F. Bellina, A. Carpita, R. Rossi, Synthesis 2004, 2419–2440; f)
N. T. S. Phan, M. Van Der Sluys, C. W. Jones, Adv. Synth. Ca-
tal. 2006, 348, 609–679.
(
7
3
3
), 5.04 (s, 2 H, CH ), 6.98–
2
3
3
bis(methoxyphenyl)-H], 7.65 [d, JH,H = 8.9 Hz, 2 H, bis(methoxy-
phenyl)-H], 7.67 (d, JH,H = 2.2 Hz, 1 H, 8-H), 9.08 (d, JH,H
2
2
1
4
4
=
13
.2 Hz, 1 H, 6-H) ppm. C NMR (50 MHz, CDCl
0.7 (CH ), 55.3 (OCH ), 55.4 (OCH ), 63.6 (CH
14.3 (2 CH), 115.9 (C), 123.9 (C), 124.0 (CH), 124.7 (C), 127.3
3
, 24 °C): δ =
3
3
3
2
), 113.6 (2 CH),
(
C), 131.2 (2 CH), 131.6 (2 CH), 135.6 (CH), 138.7 (C), 146.8 (C), [2] C. La Motta, S. Sartini, L. Mugnaini, F. Simorini, S. Taliani,
1
57.1 (C), 157.2 (C), 159.6 (C), 160.3 (C), 170.6 (C) ppm. HRMS
S. Salerno, A. M. Marini, F. Da Settimo, A. Lavecchia, E. Nov-
+
ellino, M. Cantore, P. Failli, M. Ciuffi, J. Med. Chem. 2007,
(
2 5
ESI+): calcd. for C25H21ClN O [M + H] 465.1211; found
50, 4917–4927.
4
65.1212.
[
3] a) W. Wang, R. N. Constantine, L. M. Lagniton, S. Pecchi,
M. T. Burger, M. C. Desai (Chiron Corporation, USA), WO
2004113335 A2, 2004 [Chem. Abstr. 2004, 142, 93843]; b) Z. A.
Knight, G. G. Chiang, P. J. Alaimo, D. M. Kenski, C. B. Ho,
K. Coan, R. T. Abraham, K. M. Shokat, Bioorg. Med. Chem.
2004, 12, 4749–4759; c) R. G. Griffin, G. Fontana, B. T. Gol-
ding, S. Guiard, I. R. Hardcastle, J. J. J. Leahy, N. Martin, C.
Richardson, L. Rigoreau, M. Stockley, G. C. M. Smith, J.
Med. Chem. 2005, 48, 569–585.
[
7-Chloro-4-oxo-3,9-bis(p-tolyl)-4H-pyrido[1,2-a]pyrimidin-2-yl]-
1
methyl Acetate (10b): Yellow solid (16% yield); m.p. 144 °C.
NMR (200 MHz, CDCl , 24 °C): δ = 1.87 (s, 3 H, CH ), 2.40 (s, 3
H, CH ), 2.44 (s, 3 H, CH ), 5.02 (s, 2 H, CH ), 7.27–7.31 [m, 6
H
3
3
3
3
2
3
H, bis(p-tolyl)-H], 7.57 [d, JH-H = 8.1 Hz, 2 H, bis(p-tolyl)-H], 7.67
4
H,H = 2.3 Hz, 1 H, 8-H), 9.10 (d, 4
(d,
J
J
H,H = 2.3 Hz, 1 H, 6-
), 21.3
), 116.2 (C), 124.0 (C), 124.3 (CH),
28.9 (2 CH), 129.5 (2 CH), 129.6 (C), 129.8 (2 CH), 130.1 (2 CH),
32.2 (C), 136.1 (CH), 138.2 (C), 139.0 (C), 139.2 (C), 146.9 (C),
13
H) ppm. C NMR (50 MHz, CDCl
CH ), 21.4 (CH ), 63.6 (CH
3 3
, 24 °C): δ = 20.6 (CH
(
3
3
2
[
4] D. Tworowski, R. Matsievitch (Atir Holding S. A., Luxem-
bourg), WO2007110868, 2007 [Chem. Abstr. 2007, 147,
427370].
1
1
1
57.0 (C), 157.1 (C), 170.5 (C) ppm. HRMS (ESI+): calcd. for [5] H. Fujita, Y. Shimoji, S. Kojima, H. Nishino, K. Kamoshita,
+
C
25
H21ClN
2
O
3
[M + H] 433.1313; found 433.1313.
K. Endo, S. Kobayashi, S. Kumakura, Y. Sato, Sankyo Kenkyu-
sho Nenpo 1977, 29, 75–98.
6] M. Van der Mey, A. D. Windhorst, R. P. Klok, J. D. M. Her-
scheid, L. E. Kennis, F. Bischoff, M. Bakker, X. Langlois, L.
Heylen, M. Jurzak, J. E. Leysen, Bioorg. Med. Chem. 2006, 14,
4526–4534.
[7-Chloro-3,9-bis(3-nitrophenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-
[
1
yl]methyl Acetate (10c): Yellow solid (24% yield); m.p. 177 °C. H
NMR (200 MHz, CDCl , 24 °C): δ = 1.87 (s, 3 H, CH ), 4.93 (s, 2
H,H
H, CH ), 7.63–7.79 (m, 3 H, nitrophenyl-H), 7.86 (d, J =
3
3
4
2
2
.3 Hz, 1 H, 8-H), 8.01–8.06 (m, 1 H, nitrophenyl-H), 8.26–8.39 [7] R. V. Hes, P. Smid, C. G. Kruse, M. Th. M. Tulp (Solvay Phar-
(
(
2
(
1
m, 3 H, nitrophenyl-H), 8.59–8.61 (m, 1 H, nitrophenyl-H), 9.17
maceuticals B. V., Neth.), U. S. Patent Appl. Publ.
20060122206, 2006 [Chem. Abstr. 2006, 145, 28008].
4
13
d, JH,H = 2.3 Hz, 1 H, 6-H) ppm. C NMR (50 MHz, CDCl
4 °C): δ = 20.3 (CH ), 63.7 (CH ), 115.1 (C), 123.4 (CH), 124.0
CH), 124.5 (C), 125.3 (CH), 125.4 (CH), 125.7 (CH), 129.3 (CH),
29.7 (CH), 134.3 (C), 136.0 (CH), 136.1 (C), 136.4 (CH), 136.7
C), 137.7 (CH), 146.9 (C), 148.1 (C), 148.4 (C), 159.5 (C), 157.7
3
,
[
[
[
8] K. Magyar, E. Satory, Z. Meszaros, J. Knoll, Med. Biol. 1974,
3
2
52, 384–389.
9] F. C. Colpaert, P. A. Janssen, Eur. J. Pharmacol. 1984, 103,
169–171.
(
(
10] a) K. Nakayama, H. Kawato, J. Watanabe, M. Ohtsuka, K.-I.
Yoshida, Y. Yokomizo, A. Sakamoto, N. Kuru, T. Ohta, K.
Hoshino, K. Yoshida, H. Ishida, A. Cho, M. H. Palme, J. Z.
Zhang, V. J. Lee, W. J. Watkins, Bioorg. Med. Chem. Lett. 2004,
+
C), 170.2 (C) ppm. HRMS (ESI ): calcd. for C23
H15ClN
4 7
O [M +
+
H] 495.0702, found 495.0702.
Crystal Data for Compound 7a: C24
H
19ClN
2 4
O , colorless prism
1
4, 475–479; b) K.-I. Yoshida, K. Nakayama, N. Kuru, S. Ko-
3
–1
(0.6ϫ0.1ϫ0.08 mm ), M = 434.87 gmol , orthorhombic, space
bayashi, M. Ohtsuka, M. Takemura, K. Hoshino, H. Kanda,
1 1 1
group P2 2 2 (T = 293 K), a = 7.0029(2) Å, b = 16.8565(4) Å, c
=
=
J. Z. Zhang, V. J. Lee, W. J. Watkins, Bioorg. Med. Chem. 2006,
3
17.5920(5) Å, α = 90°, β = 90°, γ = 90°, V = 2076.64(10) Å , Z
14, 1993–2004.
–1
–1
4, Dcalcd. = 13.91 gcm , μ = 0.219 mm , F(000) = 904, index
[11] H. Varma, C. Voisine, C. T. DeMarco, E. Cattaneo, D. C. Lo,
ranges 0 Յ h Յ 9, 0 Յ k Յ 21, 0 Յ l Յ 22, θ range = 1.67–27.40°,
A. C. Hart, B. R. Stockwell, Nat. Chem. Biol. 2007, 3, 99–100.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O20748
/KAP1
Date: 21-08-12 15:35:23
Pages: 11
Y. Kabri, M. D. Crozet, N. Primas, P. Vanelle
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Received: June 4, 2012
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20748
/KAP1
Date: 21-08-12 15:35:23
Pages: 11
One-Pot Chemoselective Bis(Suzuki–Miyaura Cross-Coupling)
Cross-Coupling Reaction
Y. Kabri, M. D. Crozet, N. Primas,
P. Vanelle* ...................................... 1–11
One-Pot
Chemoselective
Bis(Suzuki–
Miyaura Cross-Coupling): Efficient Access
to 3,9-Bis[(hetero)aryl]-4H-pyrido[1,2-a]-
pyrimidin-4-one Derivatives Under Micro-
wave Irradiation
A
one-pot chemoselective bis(Suzuki–
stitute successively at the 3- and then at the
9-position of (7,9-dichloro-3-iodo-4-oxo-
4H-pyrido[1,2-a]pyrimidin-2-yl)methyl
acetate (4) with various boronic acids.
Miyaura cross-coupling) reaction under
microwave irradiation is reported for the
4H-pyrido[1,2-a]pyrimidin-4-one
series.
Keywords: Synthetic methods / Hetero-
cycles / Cross-coupling / Chemoselectivity /
Palladium / Microwave chemistry
This reaction procedure allowed us to sub-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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