Convenient synthesis of 2,4-disubstituted pyrido[2,3-d]pyrimidines via regioselective palladium-catalyzed reactions

Article abstract of DOI:10.1016/j.tet.2012.04.051

A novel and effective route for the synthesis of 2,4-disubstituted pyrido[2,3-d]pyrimidines III is reported starting from the corresponding 2,4-dichloropyridopyrimidine 1 through regioselective functionalization palladium-catalyzed C-C coupling reactions, by two successive palladium-catalyzed reactions involving an original regioselective chlorine discrimination. Alternatively, type III compounds were elaborated from 2 by C-2 chlorine further displacement of the C-4 isopropylsulfanyl group, which acted as a temporary C-4 protecting group. Further Suzuki-Miyaura cross-coupling reactions led to C-2 and C-4 disubstituted compounds.

Full text of DOI:10.1016/j.tet.2012.04.051

Tetrahedron 68 (2012) 5018e5024
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Convenient synthesis of 2,4-disubstituted pyrido[2,3-d]pyrimidines via
regioselective palladium-catalyzed reactions
,
Yassine Riadi a b, Stephane Massip c, Jean-Michel Leger c, Christian Jarryc, Saïd Lazar b,
a
,
*
ꢀ
Gerald Guillaumet
a
ꢀ
ꢀ
ꢀ
Institut de Chimie Organique & Analytique, Universite d’Orleans, UMR CNRS 7311, BP 6759, 45067 Orleans Cedex 2, France
Laboratoire de Biochimie, Environnement & Agroalimentaire, UARC 36, Universite Hassan II Mohammedia-Casablanca, BP 146, 20650 Mohammedia, Morocco
Pharmacochimie, Universite de Bordeaux, CNRS FRE 3396, 33000 Bordeaux, France
b
c
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and effective route for the synthesis of 2,4-disubstituted pyrido[2,3-d]pyrimidines III is reported
starting from the corresponding 2,4-dichloropyridopyrimidine 1 through regioselective functionalization
palladium-catalyzed CeC coupling reactions, by two successive palladium-catalyzed reactions involving
an original regioselective chlorine discrimination. Alternatively, type III compounds were elaborated
from 2 by C-2 chlorine further displacement of the C-4 isopropylsulfanyl group, which acted as a tem-
porary C-4 protecting group. Further SuzukieMiyaura cross-coupling reactions led to C-2 and C-4 di-
substituted compounds.
Received 13 February 2012
Received in revised form 10 April 2012
Accepted 13 April 2012
Available online 21 April 2012
Keywords:
Pyrido[2,3-d]pyrimidines
SuzukieMiyaura
Cross-coupling
Ó 2012 Elsevier Ltd. All rights reserved.
Palladium-catalyzed
1. Introduction
aryl-pyrido[2,3-d]pyrimidines via regioselective cross-coupling
reactions. In the present paper, we describe the selective and se-
Palladium-catalyzed cross-coupling reactions represent a pow-
erful method for the formation of highly substituted heterocycles.1
The regioselective functionalization of polyhalogenated hetero-
aromatics in such reactions has been extensively studied and can
provide a versatile means for the synthesis of libraries containing
functionalized substituents in specific positions of the heterocyclic
scaffold.2
The pyridopyrimidine scaffold is present in a great number of
biologically active drugs, e.g., PDGF, EGFR, DMFR, P38 MAP kinase,3
P13 kinase,4 tyrosine kinase,5 adenosine kinase,6,7 cyclin-
dependent kinase inhibitors,8,9 and pro-apoptotic agents.10 Hence,
the synthesis of pyridopyrimidine derivatives provides an in-
teresting challenge in medicinal chemistry.
In connection with our research program focusing on the
preparation of new therapeutic agents, our group previously
reported an example of the selective bifunctionalization of pyrido
[2,3-d]pyrimidines in positions 2 and 411 and has recently de-
veloped original strategies to design 2,4-disubstituted pyrido[3,2-
d]pyrimidines.12 Encouraged by these results, we decided to extend
this methodology to the synthesis of isomeric position 2,4-di(het)
quential palladium-catalyzed reactions used to prepare compounds
III from 1 and 2 (Scheme 1).
(het)Ar
1
N
(het)Ar
1
Route A
N
N
Cl
X
I
N
N
2
r
N
N
Cl
N
N
A
)
t
III
e
h
(
1; X = Cl
2; X = SiPr
SiPr
N
Route B
2
r
N
N
A
)
II
t
e
h
(
Scheme 1. Routes A and B to design derivatives IeIII.
As shown in Scheme 1 we first performed a chlorine discrimi-
nation on 1 leading first to 4-(het)Ar1-2-chloro derivatives I fol-
lowed by dissymmetric 2,4-di(het)aryl compounds III. As an
alternative, two different het(aryl) were introduced on III via de-
rivatives II by sequential release of the 2-chlorine atom prior to the
4-Si-Pr group, which acted as a C-2 temporary protective group
during palladium-catalyzed reactions. These two interesting,
* Corresponding author. Tel.: þ33 238 417 073; fax: þ33 238 417 281; e-mail
address: gerald.guillaumet@univ-orleans.fr (G. Guillaumet).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.051

Y. Riadi et al. / Tetrahedron 68 (2012) 5018e5024
5019
convergent and efficient synthetic pathways offer numerous dis-
symmetric 2,4-di(het)aryl-pyrido[2,3-d]pyrimidines.
used a near stoichiometric amount of boronic acid and 2,4-
dichloropyrido[2,3-d]pyrimidine 1, under these conditions no
trace of bisubstituted compound was observed, indicating the lack
of reactivity of the 2-Cl versus the 4-Cl atom.
2. Results and discussion
The C-4 arylations via Suzuki reaction were similarly performed
and led to type I products (Table 1, entries 1e6) in very good yields
(69e83%) starting from phenyl-, hetaryl-, and arylboronic acids
with the aromatic ring substituted by electron-donating groups.
However, when using pyridinylboronic acid and arylboronic acids
functionalized by electron-withdrawing groups (NO2, CN), only
starting material was recovered.
An X-ray analysis performed with compound 3 formally estab-
lished the regioselectivity of arylation in position C-4 of the 2,4-
dichloropyrido[2,3-d]pyrimidine (Fig. 1).
The first synthetic route A was achieved from 2,4-dichloro-
pyrido[2,3-d]pyrimidine 1, prepared from 2-aminonicotinic acid
according to the procedure described in the literature.11
The SuzukieMiyaura cross-coupling reactions were first per-
formed with a slight excess of boronic acid and only 0.05 mol % of
Pd(PPh3)4 and K2CO3 (1.5 equiv) in toluene at 110 ꢀC. After 2e4 h,
the regioselective C-4 arylation occurred, and derivatives of type I
were isolated in 69e83% yields (Table 1). On the basis of pro-
portions implemented by Wipf et al.,2 and Tikad et al.12b we have
Table 1
Selective Suzuki reactions on 1
(het)Ar
1
Cl
(het)Ar B(OH)
1
2
N
N
Pd(PPh ) , K CO
3
Toluene, 110 °C
3 4
2
N
N
Cl
N
N
Cl
1
3 - 8
Entry
(het)Ar1
Products
Yieldsa (time)
O
O
1
3
83% (2 h)
N
N
N
Cl
O
O
2
3
4
4
5
6
80% (3 h)
81% (2 h)
83% (2 h)
N
O
Fig. 1. ORTEP view of compound 3.
N
N
Cl
In the next step we explored the reactivity of compounds 3e8
through Suzuki cross-coupling. All the reactions required 1.2 equiv
of boronic acid and only 5 mol % of catalyst, and 2.0 equiv of Na2CO3
in a mixture of toluene/ethanol (6/2 mL) at 110 ꢀC.
The reactions were stopped when the starting material com-
pletely disappeared. The second aryl or hetaryl was successfully
introduced by C-2 chlorine displacement and the expected
products 9e18 were obtained after purification by flash silica gel
chromatography. The isolated products yields oscillated be-
tween 61% and 86% for a fixed reaction time of only a few hours
(Table 2).
The influence of cosolvent on the Suzuki cross-coupling reaction
has been previously reported in the literature.13 Herein, the high
efficiency of the EtOH cosolvent may be due to the increased sol-
ubility of the reagents.14
The structure of compound 17 was clearly elucidated by X-ray
analysis (Fig. 2).
In the route B, the idea was based on the protection of the C-4
position by the isopropylsulfanyl group. Hence, thioether 2 was
readily accessed by treatment of 2,4-dichloropyrido[2,3-d]-pyrim-
idine 1 with 1.05 equiv of isopropyl mercaptan and sodium hydride
in tetrahydrofuran.12a
Substitution occurred exclusively at the electrophilic C-4 posi-
tion. Subsequent regioselective C-2 arylation of 1 proceeded in very
good yields with most arylboronic acids in the presence of 5 mol %
of Pd(PPh3)4 in a mixture of 1,2-dimethoxyethane/water (6/2 mL)
at 75 ꢀC.
O
S
N
N
N
Cl
N
S
N
Cl
Cl
N
5
7
8
81% (2 h)
N
N
O
N
N
O
O
6
69% (4 h)
O
N
Cl
N
a
Yields are given for isolated products.

5020
Y. Riadi et al. / Tetrahedron 68 (2012) 5018e5024
Table 2
Synthesis of type III compounds from type I
(het)Ar
(het)Ar
1
1
(het)Ar B(OH)
2
2
N
N
2
r
Pd(PPh ) , Na CO
3
Toluene/EtOH, 110 °C
3 4
2
N
N
Cl
A
)
N
N
9 - 18
t
e
3 - 8
h
(
Entry
1
(het)Ar1
(het)Ar2
Products
Yieldsa (time)
83% (2 h)
O
O
9
O
O
O
O
Fig. 2. ORTEP view of compound 17.
2
3
4
5
10
11
12
13
80% (2 h)
71% (2 h)
73% (3 h)
76% (2 h)
Table 3
Synthesis of type II compounds from 2
S
S
S
Cl
N
(het)Ar2B(OH)2
iPrSH
N
N
N
Pd(PPh3)4, Na2CO3
DME/H2O, 75 °C
NaH, THF
2
r
A
N
N
Cl
N
N
N
Cl
)
t
e
19 - 22
h
(
2 (92%)
1
Entry
(het)Ar2
Products
Yieldsa (time)
83% (2 h)
O
O
O
O
S
N
1
19
N
N
O
O
O
S
6
7
8
14
15
16
73% (3 h)
61% (3 h)
86% (2 h)
S
N
O
2
3
20
21
79% (3 h)
81% (3 h)
N
O
S
N
S
S
O
N
N
N
S
O
O
S
N
9
17
18
70% (2 h)
71% (2 h)
4
22
81% (3 h)
N
N
O
a
Yields are given for isolated products.
10
O
copper(I) cofactors. On the basis of the coupling conditions repor-
ted by Liebeskind et al.15 and on our knowledge,16 we applied this
strategy to our electron deficient pyridopyrimidines 19e22.
Suzuki related conditions were also first carried out with a slight
excess of (het)arylboronic acid with 2.2 equiv of 2-thiophene cop-
per(I) carboxylate.17 Each reaction required only 5 mol % of
Pd(PPh3)4 and THF at 50 ꢀC (Table 4).
Interestingly, the cross-coupling reaction using copper(I) as
a cofactor was rapidly carried out, and all products were isolated in
good yields (71e86%) (Table 4, entries 1e4). These results show the
efficiency of the reaction pathway.
a
Yields are given for isolated products.
The yields of isolated products ranged between 79% and 83%.
The substitution of the starting material by the S-isopropyl group
did not affect the yield of the coupling reactions, which were very
homogeneous (Table 3, entries 1e4).
To access type III compounds from type II compounds, the
second palladium cross-coupling reaction required the presence of

Y. Riadi et al. / Tetrahedron 68 (2012) 5018e5024
5021
Table 4
chromatography was performed on silica gel 60 (40e63 mesh).
Thin layer chromatography (TLC) was carried out on Merck silica
gel 60F254 precoated plates. Visualization was made with ultravi-
olet light. Reactions requiring anhydrous conditions were per-
formed under argon. All solvents were freshly distilled under argon
prior to use. Chemicals products were obtained from the following
sources: Aldrich and Acros organics. Copper(I) thiophene-2-
carboxylate was prepared from procedure described in the
literature.18
Synthesis of type III compounds from type II
(het)Ar1
S
(het)Ar1B(OH)2
N
N
N
2
r
2
r
A
Pd(PPh3)4, CuTC
THF, 50 °C
N
N
A
N
)
t
)
t
e
e
h
(
h
9, 11, 12, 16
(
19 - 22
Yieldsa (time)
75% (1 h)
The data of 3 and 17 were collected with an R-Axis Rapid Rigaku
MSC and the data of 17 were collected with a CAD4 Enraf Nonius
Entry
1
(het)Ar2
(het)Ar1
Products
O
diffractometer, both using the Cu Ka radiation and a graphite
O
monochromator. On the R-axis, all reflections were used for unit
cell refinement whereas 25 reflections were used with the CAD4.
The program PLATON19 was used for analysis and drawing figures.
The structures were solved by direct methods and refined using
SHELX 97 suite of programs20 integrated in WinGX 1.80 version.21
The positions of the H atoms were deduced from coordinates of
the non-H atoms and confirmed by Fourier synthesis. The non-H
atoms were refined with anisotropic temperature parameters. H
atoms were included for structure factor calculations but not
refined.
9
O
S
2
3
11
71% (1 h)
O
12
16
75% (2 h)
86% (1 h)
4.2. General procedures
O
S
4.2.1. General procedure for synthesis of 2. A solution of compound
1, the desired nucleophile (1.0 equiv) and NaH (1.05 equiv) in dry
THF at 0 ꢀC was stirred under Argon for 12 h. After fully disap-
pearance of the starting material, dried from THF, water was added.
After three extractions (CH2Cl2), the combined organic layers were
dried with MgSO4, filtered and dried under reduced pressure. The
crude residue was next purified by flash chromatography. This
procedure was used for the synthesis of compounds 2.
4
a
Yields are given for isolated products.
3. Conclusion
In this report, we developed two efficient palladium-catalyzed
routes A and B to design new and rare dissymmetrical 2,4-
bis(het)aryl-pyrido[2,3-d]pyrimidines.
4.2.2. General procedure A: synthesis of 2-chloro-4-(het)aryl-pyrido
[2,3-d]pyrimidine (I) via Suzuki cross-coupling reaction. To a argon
degassed solution of 2,4-dichloropyrido[2,3-d]pyrimidine
1
Suzuki reactions were accurately adapted to perform each step
with high selectivity and originality. In the first route A, we
showed that the first (het)arylation occurred selectively in the C-4
position of the 2,4-dichloropyrido[2,3-d]pyrimidine 1. The two
chlorine atoms could be fully discriminated. The second route B
involved two sequential (het)aryl transfers from the 2-chloro-4-
(100 mg, 0.5 mmol) in toluene (6 mL) were successively added the
desired (het)aryl boronic acid (1.05 equiv), potassium carbonate
(1.5 equiv), and Pd(PPh3)4 (29 mg, 0.05 equiv). The reaction mixture
was heated at 110 ꢀC under vigorous stirring for the desired time.
After complete disappearance of 1, water (10 mL) was added. After
extraction with CH2Cl2 (3ꢁ10 mL), the combined organic layers
were dried over MgSO4 and the solvent was removed under re-
duced pressure. The crude material was purified by column chro-
matography to afford compounds of type I.
isopropylsulfanyl-pyrido[2,3-d]pyrimidine
2 by palladium in-
sertion first on the CeCl bond and then on the CeS bond.
This simple and efficient sequential coupling route to highly
substituted pyrido[2,3-d]pyrimidines enables the orchestration of
regioselective palladium-catalyzed cross-coupling reactions for the
preparation of focused libraries of biologically active compounds.
4.2.3. General procedure B. Compounds III were obtained via
a Suzuki reaction from I (0.5 mmol) by modification of the pro-
cedure A and also using (het)aryl boronic acid (1.2 equiv), Na2CO3
(1.5 equiv), and Pd(PPh3)4 (0.05 equiv) in a mixture of toluene/EtOH
(3/1) at 110 ꢀC. After complete disappearance of I, water (10 mL)
and CH2Cl2 (10 mL) were added. After extraction with CH2Cl2
(3ꢁ10 mL), the combined organic layers were dried over MgSO4
and the solvent was removed under reduced pressure. The crude
material was purified by flash chromatography to afford com-
pounds of type III.
4. Experimental section
4.1. General remarks and methods
4.1.1. Instrumentation and materials. 1H NMR and 13C NMR were
recorded on a Bruker Avance DPX250 spectrometer (400 MHz 1H,
62.89 MHz 13C) using tetramethylsilane as the internal standard,
multiplicities were determined by the DEPT 135 equivalence,
chemical shifts were reported in parts per million (ppm,
d
units).
4.2.4. General procedure C: synthesis of 2-(het)aryl-4-isopropyl-
Coupling constants were reported in units of hertz (Hz) if appli-
cable. Infrared (IR) spectra were obtained on PerkineElmer Paragon
1000 PC FT-IR. Infrared spectra recorded using an ATR-Ge equip-
ment. Low-resolution mass spectra (MS) were recorded on a Per-
kineElmer SCIEX API 3000 spectrometer. Exact mass were
performed in CRMPO, Rennes and Orleans, France. Melting points
were determined in open capillary tubes and are uncorrected. Flash
sulfanylpyrido[2,3-d]pyrimidine (II). To a solution containing 2
(0.5 mmol) in a mixture of DME/H2O (3/1) were successively added
the desired (het)aryl boronic acid (1.2 equiv), sodium carbonate
(2.0 equiv), and Pd(PPh3)4 (0.05 equiv). The reaction mixture was
heated at 75 ꢀC under vigorous stirring for the desired time. After
complete disappearance of 2, water (10 mL) and CH2Cl2 (10 mL) were
added. After extraction with CH2Cl2 (3ꢁ10 mL), the combined organic

5022
Y. Riadi et al. / Tetrahedron 68 (2012) 5018e5024
layers were dried over MgSO4 and the solvent was removed under
reduced pressure. The crude material was purified by flash chroma-
tography to afford compounds of type II.
1320,1275,1096, 926, 866, 798; 1H NMR (400 MHz, CDCl3)
d 7.58 (d,
1H, J¼8.0 Hz, HHet), 7.62 (dd, 1H, J¼4.0, 8.0 Hz, H6), 7.66 (d, 1H,
J¼8.0 Hz, HHet), 8.03 (d, 1H, J¼4.0 Hz, HHet), 8.69 (d, 1H, J¼8.0 Hz,
H5), 9.27 (d, 1H, J¼4.0 Hz, H7); 13C NMR (62.5 MHz, CDCl3)
d 116.55
4.2.5. General procedure D: synthesis of compounds type (III) via
a Suzuki cross-coupling reaction in the presence of CuTC. A solution
containing 2-(het)aryl-4-isopropylsulfanylpyrido[2,3-d]pyrimidine
II (0.35 mmol), the (het)aryl boronic acid (2.2 equiv), CuTC
(2.2 equiv), and Pd(PPh3)4 (0.05 equiv) in dry THF (6 mL) was
flushed with argon for 15 min. The brown suspension was stirred
under argon at 50 ꢀC for 3 h. After complete disappearance of
starting material II, a saturated aqueous solution of NaHCO3 was
added, and the mixture was extracted with dichloromethane
(3ꢁ15 mL). The combined organic layers were washed with
saturated NaHCO3 (2ꢁ10 mL). The solvent was evaporated under
reduced pressure the residue was next purified by flash chroma-
tography to give the attempted products of type III.
(Cq),123.60 (CH),127.59 (CH),128.86 (CH),130.91 (CH),136.52 (CH),
136.96 (Cq), 158.66 (CH), 160.46 (Cq), 160.68 (Cq), 167.40 (Cq);
HRMS (EIMS): m/z calcd for C11H6N3ClS: 246.9971, found: 246.9978.
4.3.6. 2-Chloro-4-phenylpyrido[2,3-d]pyrimidine 7. Compound
was isolated after flash chromatography (DCM 100%) as a white
solid. Mp 143e144 ꢀC; IR (ATR-Ge, cmꢂ1
1523, 1465, 1279, 1135,
884, 811, 761, 682; 1H NMR (400 MHz, CDCl3)
7.62 (m, 4H, J¼4.0,
7
)
n
d
8.0 Hz, HAr, H6), 7.77 (dd, 2H, J¼4.0, 8.0 Hz, HAr), 8.52 (d, 1H,
J¼8.0 Hz, H5), 9.26 (d, 1H, J¼4.0 Hz, H7); 13C NMR (62.5 MHz, CDCl3)
d
116.68 (Cq), 123.55 (CH), 129.15 (2ꢁCH), 130.37 (2ꢁCH), 131.46
(CH), 135.06 (CH), 137.08 (Cq), 158.71 (CH), 160.34 (Cq), 160.50 (Cq),
173.23 (Cq); HRMS (EIMS): m/z calcd for C13H8N3Cl: 241.0407,
found: 241.0413.
4.3. Experimental data
4.3.7. 2-Chloro-4-(2,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidine
4.3.1. 4-Isopropylsulfanylpyrido[2,3-d]pyrimidine 2. Compound
was isolated after flash chromatography (PE/EtOAc: 8/2) as a white
solid. IR (ATR-Ge, cmꢂ1
1556, 1475, 1438, 1366, 1244, 1011, 841,
712; 1H NMR (400 MHz, CDCl3)
2
8. Compound 8 was isolated after flash chromatography (DCM
100%) as a yellow solid. Mp 127e128 ꢀC; IR (ATR-Ge, cmꢂ1
)
n
1576,
)
n
1489, 1464, 1273, 1043, 889, 776, 692; 1H NMR (250 MHz, CDCl3)
d
1.58 (d, 6H, J¼8.0 Hz, 2ꢁCH3), 4.33
d
3.71 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 6.62 (d, 1H, J¼2.5 Hz, HAr),
(m, 1H, J¼4.0, 8.0 Hz, CH), 7.50 (dd, 2H, J¼4.0, 8.0 Hz, HAr), 8.38 (dd,
6.72 (dd, 1H, J¼2.5,7.5 Hz, HAr), 7.52 (dd, 2H, J¼2.5, 7.5 Hz, HAr, H6),
1H, J¼4.0, 8.0 Hz, H5), 9.14 (d, 1H, J¼4.0 Hz, H7); 13C NMR
8.17 (d, 1H, J¼7.5 Hz, H5), 9.21 (d, 1H, J¼2.5 Hz, H7); 13C NMR
(62.5 MHz, CDCl3)
(CH), 133.54 (CH), 157.66 (Cq), 158.19 (CH), 159.63 (Cq), 176.81 (Cq).
d
22.73 (2ꢁCH3), 36.76 (CH), 117.29 (Cq), 122.68
(62.5 MHz, CDCl3) d 55.52 (CH3), 55.58 (CH3), 114.54 (CH), 116.34
(Cq), 118.14 (CH), 123.13 (Cq), 129.11 (Cq), 129.46 (CH), 132.23 (CH),
136.34 (CH), 138.94 (Cq), 158.29 (CH), 160.38 (Cq), 162.4 (Cq), 172.16
(Cq); HRMS (EIMS): m/z calcd for C13H8N3Cl: 303.0408, found:
303.0415.
4.3.2. 2-Chloro-4-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine 3. Com-
pound 3 was isolated after flash chromatography (DCM 100%) as
a white solid. Mp 116e118 ꢀC; IR (ATR-Ge, cmꢂ1
)
n
1536, 1478, 1452,
1262, 1019, 895, 769, 689; 1H NMR (400 MHz, CDCl3)
d
3.92 (s, 3H,
4.3.8. 2-(3-Methoxyphenyl)-4-(4-methoxyphenyl)pyrido[2,3-d]py-
OCH3), 7.11 (d, 2H, J¼8.0 Hz, HAr), 7.58 (dd,1H, J¼4.0, 8.0 Hz, H6), 7.79
(d, 2H, J¼8.0 Hz, HAr), 8.55 (d,1H, J¼8.0 Hz, H5), 9.25 (d,1H, J¼4.0 Hz,
rimidine 9. Compound 9 was isolated after flash chromatography
(DCM/PE: 9/1) as a yellow solid. Mp 119e120 ꢀC; IR (ATR-Ge, cmꢂ1
)
H7); 13C NMR (62.5 MHz, CDCl3)
d
55.73 (CH3), 114.69 (2ꢁCH), 116.51
n
1611, 1552, 1469, 1457, 1361, 1255, 1038, 821, 747, 692; 1H NMR
(Cq), 123.28 (CH), 127.61 (Cq), 132.38 (2ꢁCH), 137.15 (CH), 158.44
(CH), 160.54 (Cq), 162.55 (2ꢁCq), 172.50 (Cq); HRMS (EIMS): m/z
calcd for C14H10N3OCl: 271.0514, found: 271.0512.
(400 MHz, CDCl3)
d
3.93 (s, 6H, CH3), 7.13 (d, 2H, J¼8.0 Hz, HAr), 7.44
(t, 2H, J¼8.0 Hz, HAr), 7.44 (dd, 2H, J¼4.0, 8.0 Hz, H6), 7.87 (d, 2H,
J¼8.0 Hz, HAr), 8.37 (s, 1H, HAr), 8.42 (d, 1H, J¼8.0 Hz, HAr), 8.53 (d,
1H, J¼8.0 Hz, H5), 9.23 (d, 1H, J¼4.0 Hz, H7); 13C NMR (62.5 MHz,
4.3.3. 2-Chloro-4-(3-methoxyphenyl)pyrido[2,3-d]pyrimidine 4. Com-
pound 4 was isolated after flash chromatography (DCM 100%) as
CDCl3)
d
55.53 (2ꢁCH3), 113.29 (CH), 114.30 (2ꢁCH), 116.38 (Cq),
118.16 (CH), 121.97 (CH), 122.25 (CH), 129.11 (Cq), 129.46 (CH),
132.02 (2ꢁCH), 136.55 (CH), 138.93 (Cq), 157.4 (CH), 159.94 (2ꢁCq),
161.78 (Cq), 163.17 (Cq), 169.36 (Cq); HRMS (EIMS): m/z calcd for
C21H17N3O2: 344.1399, found: 344.1402.
a white solid. Mp 121e122 ꢀC; IR (ATR-Ge, cmꢂ1
)
n
1554, 1488, 1432,
1259, 1042, 895, 769, 663; 1H NMR (400 MHz, CDCl3)
d
3.89 (s, 3H,
OCH3), 7.15 (d, 1H, J¼8.0 Hz, HAr), 7.28 (m, , 2H, J¼4.0, 8.0 Hz, HAr),
7.49 (dd, 1H, J¼4.0, 8.0 Hz, H6), 7.59 (dd, 1H, J¼4.0, 8.0 Hz, HAr), 8.53
(d, 1H, J¼8.0 Hz, H5), 9.25 (d, 1H, J¼4.0 Hz, H7); 13C NMR (62.5 MHz,
4.3.9. 2,4-Bis(4-methoxyphenyl)pyrido[2,3-d]pyrimidine 10. Com-
pound 10 was isolated after flash chromatogꢂra1phy (DCM 100%) as
CDCl3)
d 55.56 (OCH3),115.4 (CH), 116.57 (Cq), 117.09 (CH), 122.63
(CH), 123.39 (CH), 130.01 (CH), 136.12 (Cq), 136.97 (CH), 158.6 (CH),
160.02 (Cq), 160.19 (Cq), 160.33 (Cq), 172.93 (Cq); HRMS (EIMS): m/z
calcd for C14H10N3OCl: 271.0514, found: 271.0511.
a white solid. Mp 127e128 ꢀC; IR (ATR-Ge, cm
) n 1582,1463,1320,
1275, 1096, 926, 866, 798; 1H NMR (250 MHz, CDCl3)
d 3.93 (s, 3H,
OCH3), 3.95 (s, 3H, OCH3), 7.09 (dd, 1H, J¼4.0, 8.0 Hz, HAr), 7.12 (d,
2H, J¼8.0 Hz, HAr), 7.43 (t, 1H, J¼8.0 Hz, HAr), 7.49 (dd, 1H, J¼4.0,
8.0 Hz, H6), 7.87 (d, 2H, J¼8.0 Hz, HAr), 8.37 (d, 1H, J¼4.0 Hz, HAr),
8.42 (d, 1H, J¼8.0 Hz, H5), 8.52 (dd, 1H, J¼4.0, 8.0 Hz, HAr), 9.23 (d,
4.3.4. 2-Chloro-4-(3-furyl)pyrido[2,3-d]pyrimidine 5. Compound 5
was isolated after flash chromatography (DCM 100%) as a white
solid. Mp 146e147 ꢀC; IR (ATR-Ge, cmꢂ1
)
n
1567, 1523, 1475, 1444,
1H, J¼4.0 Hz, H7); 13C NMR (62.5 MHz, CDCl3)
d 55.66 (CH3), 55.70
1278, 1162, 1046, 991, 834, 696; 1H NMR (400 MHz, CDCl3)
d
7.06 (s,
(CH3), 113.43 (CH), 114.42 (2ꢁCH), 116.48 (Cq), 118.28 (CH), 122.09
(CH), 122.37 (CH), 129.35 (Cq), 129.60 (CH), 132.15 (2ꢁCH), 136.68
(CH), 139.07 (Cq), 157.53 (CH), 160.09 (Cq), 160.12 (Cq), 161.81 (Cq),
163.29 (Cq), 169.48 (Cq); HRMS (EIMS): m/z calcd for C21H17N3O2:
344.1399, found: 344.1396.
1H, HHet), 7.62 (dd, 1H, J¼4.0, 8.0 Hz, H6), 7.65 (dd, 1H, J¼4.0, 8.0 Hz,
HHet), 8.19 (d, 1H, J¼4.0 Hz, HHet), 8.68 (d, 1H, J¼8.0 Hz, H5), 9.26 (d,
1H, J¼4.0, H7); 13C NMR (62.5 MHz, CDCl3)
d
111.03 (2ꢁCH), 122.94
(Cq), 123.62 (Cq), 135.64 (CH), 144.72 (CH), 145.76 (CH), 158.70 (CH),
160.18 (Cq), 160.72 (Cq), 165.34 (Cq); HRMS (EIMS): m/z calcd for
C11H6N3OCl: 231.0199, found: 231.0209.
4.3.10. 4-(4-Methoxyphenyl)-2-(3-thienyl)pyrido[2,3-d]pyrimidine
11. Compound 11 was isolated after flash chromatography (DCM/
4.3.5. 2-Chloro-4-(3-thienyl)pyrido[2,3-d]pyrimidine 6. Compound
6 was isolated after flash chromatography (DCM 100%) as a white
PE: 9/1) as a white solid. Mp 179e180 ꢀC; IR (ATR-Ge, cmꢂ1
)
n
1600,
1525, 1423, 1371, 1322, 1214, 950, 752; 1H NMR (250 MHz, CDCl3)
3.91 (s, 3H, OCH3), 7.10 (d, 2H, J¼8.0 Hz, HAr), 7.39 (d, 1H, J¼8.0 Hz,
solid. Mp 158e159 ꢀC; IR (ATR-Ge, cmꢂ1
)
n
3376, 2963, 1582, 1463,
d

Y. Riadi et al. / Tetrahedron 68 (2012) 5018e5024
5023
HHet), 7.44 (dd,1H, J¼4.0, 8.0 Hz, H6), 7.82 (d, 2H, J¼8.0 Hz, HAr), 8.18
(d, 1H, J¼4.0 Hz, HHet), 8.46 (d, 1H, J¼8.0 Hz, H5), 8.60 (dd, 1H, J¼4.0,
8.0 Hz, HHet), 9.17 (d, 1H, J¼4.0 Hz, H7); 13C NMR (62.5 MHz, CDCl3)
100%) as a white solid. Mp 133e134 ꢀC; IR (ATR-Ge, cmꢂ1
)
n
1601,
1473, 1332, 1221, 1113, 962, 878, 799; 1H NMR (400 MHz, CDCl3)
d
3.90 (s, 3H, OCH3), 7.03 (d, 1H, J¼8.0 Hz, HAr), 7.47 (dd, 1H, J¼4.0,
d
55.62 (CH3), 114.37 (2ꢁCH), 116.18 (Cq), 122.08 (CH), 126.02 (CH),
8.0 Hz, H6), 7.56 (d, 1H, J¼4.0 Hz, HHet), 7.73 (d, 1H, J¼4.0 Hz, HHet),
7.99 (d, 1H, J¼4.0 Hz, HHet), 8.61 (d, 1H, J¼8.0 Hz, H5), 8.75 (d, 2H,
J¼8.0 Hz, HAr), 9.19 (d, 1H, J¼4.0 Hz, H7); 13C NMR (62.5 MHz,
128.31 (CH), 129.08 (Cq), 130.06 (CH), 132.02 (2ꢁCH), 136.62 (CH),
141.93 (Cq),157.42 (CH),160.09 (Cq),160.58 (Cq),161.83 (Cq),169.63
(Cq); HRMS (EIMS): m/z calcd for C18H13N3OS: 320.0858, found:
320.0855.
CDCl3)
d
55.53 (OCH3), 114.00 (2ꢁCH), 116.10 (Cq), 122.16 (CH),
126.87 (CH), 129.12 (CH), 129.33 (CH), 130.09 (Cq), 131.13 (2ꢁCH),
136.02 (CH), 138.67 (Cq), 157.61 (CH), 160.15 (Cq), 162.58 (Cq),
163.48 (Cq), 164.50 (Cq); HRMS (EIMS): m/z calcd for C18H13N3OS:
320.0858, found: 320.0867.
4.3.11. 2-Phenyl-4-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine 12. Co-
mpound 12 was isolated after flash chromatography (DCM/PE: 9/1)
as a white solid. Mp 122e123 ꢀC; IR (ATR-Ge, cmꢂ1
)
n
1582, 1463,
1320, 1275, 1096, 926, 866, 798; 1H NMR (250 MHz, CDCl3)
d
3.94 (s,
4.3.16. 4-Phenyl-2-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine
3H, OCH3), 7.14 (d, J¼7.5 Hz, 2H, HAr), 7.52 (m, 4H, J¼2.5, 7.5 Hz, HAr,
H6), 7.88 (dd, 2H, J¼2.5, 7.5 Hz, HAr), 8.53 (d, 1H, J¼7.5 Hz, H5), 8.82
(dd, 2H, J¼2.5, 7.5 Hz, HAr), 9.23 (d, 1H, J¼2.5 Hz, H7); 13C NMR
17. Compound 17 was isolated after flash chromatography (DCM/
PE: 9/1) as a white solid. Mp 120e121 ꢀC; IR (ATR-Ge, cmꢂ1
) n
1579, 1451, 1349, 1291, 1084, 934, 832, 792; 1H NMR (400 MHz,
CDCl3)
(62.5 MHz, CDCl3)
d
55.68 (CH3), 114.45 (2ꢁCH), 116.44 (Cq), 122.35
d
3.88 (s, 3H, OCH3), 7.02 (d, J¼8.0 Hz, 2H, HAr), 7.42 (dd, 1H,
(CH), 128.65 (2ꢁCH), 129.32 (Cq), 129.40 (2ꢁCH), 131.40 (CH), 132.15
(2ꢁCH), 136.66 (CH), 137.60 (Cq), 157.56 (CH), 160.20 (Cq), 161.90
(Cq), 163.51 (Cq), 169.58 (Cq); HRMS (EIMS): m/z calcd for
C20H15N3O: 314.1287, found: 314.1288.
J¼4.0, 8.0 Hz, H6), 7.60 (dd, 3H, J¼4.0, 8.0 Hz, HAr), 7.83 (m, 2H,
J¼4.0, 8.0 Hz, HAr), 8.41 (d, 1H, J¼8.0 Hz, H5), 8.76 (d, 2H, J¼8.0 Hz,
HAr), 9.18 (d, 1H, J¼4 Hz, H7); 13C NMR (62.5 MHz, CDCl3)
d 55.48
(OCH3), 113.96 (2ꢁCH), 116.10 (Cq), 122.02 (CH), 128.83 (2ꢁCH),
130.10 (Cq), 130.27 (2ꢁCH), 130.52 (CH), 131.16 (2ꢁCH), 136.49
(CH), 136.80 (Cq), 157.58 (CH), 160.03 (Cq), 162.53 (Cq), 163.33 (Cq),
169.95 (Cq); HRMS (EIMS): m/z calcd for C20H15N3O: 314.1293,
found: 314.1294.
4.3.12. 2-(4-Methoxyphenyl)-4-(3-methoxyphenyl)pyrido[2,3-d]py-
rimidine 13. Compound 13 was isolated after flash chromatography
(DCM/PE: 9/1) as a white solid. Mp 131e132 ꢀC; IR (ATR-Ge, cmꢂ1
) n
1579, 1469, 1352, 1275, 1011, 942, 834, 779; 1H NMR (400 MHz,
CDCl3)
d
3.87 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 7.01 (d, 2H, J¼8.0 Hz,
4.3.17. 4-(2,5-Dimethoxyphenyl)-2-(4-methoxyphenyl)pyrido[2,3-d]
pyrimidine 18. Compound 18 was isolated after flash chromatog-
raphy (DCM/PE: 9/1) as a yellow solid. Mp 144e145 ꢀC; IR (ATR-Ge,
HAr), 7.11 (d, 1H, J¼8.0 Hz, HAr), 7.36 (m, 2H, J¼4.0, 8.0 Hz, HAr), 7.42
(dd, 1H, J¼4.0, 8.0 Hz, H6), 7.47 (dd, 1H, J¼4, 8 Hz, HAr), 8.42 (d, 1H,
J¼8.0 Hz, H5), 8.75 (d, 2H, J¼8.0 Hz, HAr), 9.09 (d, 1H, J¼4.0 Hz, H7);
cmꢂ1
) n
1589, 1477, 1343, 1292, 1082, 950, 853, 775; 1H NMR
13C NMR (62.5 MHz, CDCl3)
d
55.45 (CH3), 55.58 (CH3), 113.93
(250 MHz, CDCl3) d 3.67 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.90 (s,
(2ꢁCH), 115.71 (CH), 116.02 (CH), 116.09 (Cq), 122.00 (CH), 122.64
(CH), 129.80 (CH), 130.04 (Cq), 131.14 (2ꢁCH), 136.48 (CH), 138.04
(Cq), 157.58 (CH), 159.93 (Cq), 159.97 (Cq), 162.51 (Cq), 163.26 (Cq),
169.76 (Cq); HRMS (EIMS): m/z calcd for C21H17N3O2: 344.1399,
found: 314.1403.
3H, OCH3), 7.03 (d, 3H, J¼7.5 Hz, HAr), 7.08 (d,1H, J¼7.5 Hz, HAr), 7.12
(s, 1H, HAr), 7.39 (dd,1H, J¼2.5, 7.5 Hz, H6), 8.07 (d, 1H, J¼7.5 Hz, H5),
8.76 (d, 2H, J¼7.5 Hz, HAr), 9.16 (dd, 1H, J¼2.5 Hz, H7); 13C NMR
(62.5 MHz, CDCl3)
d 55.67 (OCH3), 55.75 (OCH3), 56.79 (OCH3),
113.52 (CH), 114.51 (2ꢁCH), 116.57 (Cq), 118.37 (CH), 122.46 (CH),
129.34 (Cq), 129.69 (CH), 132.24 (2ꢁCH), 136.71 (CH), 139.16 (Cq),
157.62 (CH), 160.18 (Cq), 160.21 (2ꢁCq), 161.98 (Cq), 163.38 (Cq),
169.57 (Cq); HRMS (EIMS): m/z calcd for C22H19N3O3: 374.1299,
found: 374.1304.
4.3.13. 4-(3-Furyl)-2-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine
14. Compound 14 was isolated after flash chromatograꢂp1hy (DCM
100%) as a white solid. Mp 129e130 ꢀC; IR (ATR-Ge, cm
) n 1591,
1472, 1334, 1288, 1046, 922, 862, 771; 1H NMR (250 MHz, CDCl3)
d
3.91 (s, 3H, OCH3), 7.01 (d, 2H, J¼7.5 Hz, HAr), 7.16 (d, 1H, J¼2.5 Hz,
4.3.18. 4-Isopropylsulfanyl-2-(4-methoxyphenyl)pyrido[2,3-d]pyrim-
idine 19. Compound 19 was isolated after flash chromatography
(PE/EtOAc: 9/1) as a yellow solid. Mp 123e124 ꢀC; IR (ATR-Ge,
HHet), 7.51 (dd, 1H, J¼2.5, 7.5 Hz, H6), 7.68 (d, 1H, J¼2.5 Hz, HHet),
8.19 (s, 1H, HHet), 8.63 (d, 1H, J¼7.5 Hz, H5), 8.76 (d, 2H, J¼7.5 Hz,
HAr), 9.22 (d, 1H, J¼2.5 Hz, H7); 13C NMR (62.5 MHz, CDCl3)
d
55.57
cmꢂ1
) n
1636, 1539, 1432, 1382, 1326, 1217, 1012, 867, 749; 1H NMR
(CH3), 111.35 (2ꢁCH), 114.04 (CH), 116.07 (Cq), 122.18 (CH), 124.17
(Cq), 130.08 (2ꢁCH), 131.14 (Cq), 135.26 (CH), 144.21 (CH), 144.74
(CH), 157.70 (CH), 159.99 (Cq), 162.35 (Cq), 162.63 (Cq), 163.62 (Cq);
HRMS (EIMS): m/z calcd for C18H13N3O2: 304.0721, found:
304.0724.
(250 MHz, CDCl3)
d
1.59 (d, 6H, J¼8.0 Hz, 2ꢁCH3), 3.90 (s, 3H,
OCH3), 4.47 (m, 1H, J¼4.0, 8.0 Hz, CH), 7.04 (dd, 2H, J¼4.0, 8.0 Hz,
HAr), 7.40 (dd, 1H, J¼4.0, 8.0 Hz, H6), 8.36 (d, 1H, J¼8.0 Hz, H5),
8.68 (dd, 2H, J¼4.0, 8.0 Hz, HAr), 9.16 (d, 1H, J¼8 Hz, H7); 13C NMR
(62.5 MHz, CDCl3)
d
22.94 (2ꢁCH3), 36.02 (CH), 55.56 (CH3),
114.02 (2ꢁCH), 117.13 (Cq), 121.42 (CH), 130.17 (Cq), 131.04 (2ꢁCH),
133.30 (CH), 157.40 (CH), 157.83 (Cq), 162.15 (Cq), 162.54 (Cq),
173.11 (Cq); HRMS (EIMS): m/z calcd for C17H17N3OS: 311.1108,
found: 311.1105.
4.3.14. 4-(3-Furyl)-2-(3-thienyl)pyrido[2,3-d]pyrimidine 15. Compou-
nd 15 was isolated after flash chromatography (DCM/PE: 9/1) as
a white solid. Mp 172e173 ꢀC; IR (ATR-Ge, cmꢂ1
)
n
1595, 1436,
1337, 1283, 1086, 962, 882, 796; 1H NMR (400 MHz, CDCl3)
d
7.12
(d, 1H, J¼4.0 Hz, HHet), 7.42 (d, 1H, J¼8.0 Hz, HHet), 7.51 (dd, 1H,
J¼4.0, 8.0 Hz, H6), 7.67 (d, 1H, J¼4.0 Hz, HHet), 8.18 (d, 2H, J¼4.0 Hz,
HHet), 8.62 (m, 2H, J¼4.0, 8.0 Hz, HHet, H5), 9.22 (d, 1H, J¼4.0 Hz,
4.3.19. 4-Isopropylsulfanyl-2-(3-methoxyphenyl)pyrido[2,3-d]pyrim-
idine 20. Compound 20 was isolated after flash chromatography
(PE/EtOAc: 9/1) as a yellow solid. Mp 116e117 ꢀC; IR (ATR-Ge, cmꢂ1
n
)
H7); 13C NMR (62.5 MHz, CDCl3)
d
111.29 (CH), 116.20 (Cq), 122.42
1602, 1533, 1443, 1328, 1254, 1036, 1011, 821, 742; 1H NMR
(CH), 123.94 (Cq), 126.15 (CH), 128.27 (CH), 130.13 (CH), 135.26
(CH), 141.76 (Cq), 144.25 (CH), 144.79 (CH), 157.77 (CH), 159.91
(Cq), 160.92 (Cq), 162.64 (Cq); HRMS (EIMS): m/z calcd for
C18H13N3OS: 280.0545, found: 280.0549.
(400 MHz, CDCl3)
d
1.57 (d, 6H, J¼8.0 Hz, 2ꢁCH3), 3.89 (s, 3H,
OCH3), 4.43 (m, 1H, J¼4.0, 8.0 Hz, CH), 7.15 (d, 1H, J¼8.0 Hz , HAr),
7.28 (m, 2H, J¼4.0, 8.0 Hz, HAr), 7.49 (dd, 1H, J¼4.0, 8.0 Hz, H6), 7.58
(dd, 1H, J¼4.0, 8.0 Hz, HAr), 8.52 (d, 1H, J¼8.0 Hz, H5), 9.25 (d, 1H,
J¼4.0 Hz, H7); 13C NMR (62.5 MHz, CDCl3)
d
22.77 (2ꢁCH3), 35.86
4.3.15. 2-(4-Methoxyphenyl)-4-(3-thienyl)pyrido[2,3-d]pyrimidine
16. Compound 16 was isolated after flash chromatography (DCM
(CH), 55.39 (OCH3), 113.85 (2ꢁCH), 116.96 (Cq), 121.25 (CH), 130.00
(Cq), 130.87 (2ꢁCH), 133.13 (CH), 157.23 (CH), 157.66 (Cq), 161.98

5024
Y. Riadi et al. / Tetrahedron 68 (2012) 5018e5024
€
2. (a) Pereira, R.; Iglesias, B.; de Lera, A. R. Tetrahedron 2001, 57, 7871; (b) Schroter,
S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245; (c) Wipf, P.; George, K. M.
(Cq), 162.37 (Cq), 172.94 (Cq); HRMS (EIMS): m/z calcd for
C17H17N3OS: 311.1092, found: 311.1088.
ꢀ
Synlett 2010, 644; (d) Roy, D.; Mom, S.; Beauperin, M.; Doucet, H.; Hierso, J. C.
Angew. Chem., Int. Ed. 2010, 49, 6650.
3. Natarajan, S. R.; Wisnoski, D. D.; Singh, S. B.; Stelmach, J. E.; O’Neill, E. A.;
Schwartz, C. D.; Thompson, C. M.; Fitzgerald, C. E.; O’Keefe, S. J.; Kumar, S.; Hop,
C. E. C. A.; Zaller, D. M.; Schmatz, D. M.; Doherty, J. B. Bioorg. Med. Chem. Lett.
2003, 13, 273.
4. Hayakawa, M.; Kaizawa, H.; Moritomo, H.; Koizumi, T.; Ohishi, T.; Okada, M.;
Ohta, M.; Tsukamoto, S. I.; Parker, P.; Workman, P.; Waterfield, M. Bioorg. Med.
Chem. 2006, 14, 6847.
5. Klutchko, S. R.; Zhou, H.; Winters, R. T.; Tran, T. P.; Bridges, A. J.; Althaus, I. W.;
Amato, D. M.; Elliott, W. L.; Ellis, P. A.; Meade, M. A.; Roberts, B. J.; Fry, D. W.;
Gonzales, A. J.; Harvey, P. J.; Nelson, J. M.; Sherwood, V.; Han, H. K.; Pace, G.;
Smaill, J. B. W. A.; Denny, H. D.; Showalter, H. J. Med. Chem. 2006, 49, 1475.
6. Matulenko, M. A.; Lee, C. H.; Jiang, M.; Frey, R. R.; Cowart, M. D.; Bayburt, E. K.;
DiDomenico, S.; Gfesser, G. A.; Gomtsyan, A.; Zheng, G. Z.; McKie, J. A.; Stewart,
A. O.; Yu, H.; Kohlhaas, K. L.; Alexander, K. M.; McGaraughty, S.; Wismer, C. T.;
Mikusa, J.; Marsh, K. C.; Snyder, R. D.; Diehl, M. S.; Kowaluk, E. A.; Jarvis, M. F.;
Bhagwat, S. S. Bioorg. Med. Chem. 2005, 13, 3705.
4.3.20. 4-Isopropylsulfanyl-2-(3-thienyl)pyrido[2,3-d]pyrimidine
21. Compound 21 was isolated after flash chromatography ꢂ(1PE/
EtOAc: 9/1) as a beige solid. Mp 128e129 ꢀC; IR (ATR-Ge, cm
) n
1636, 1539, 1432, 1382, 1326, 1217, 1012, 867, 749; 1H NMR
(400 MHz, CDCl3)
d
1.58 (d, 6H, J¼8.0 Hz, 2ꢁCH3), 4.43 (m, 1H,
J¼4.0, 8.0 Hz, CHAr), 7.41 (m, 2H, J¼4.0, 8.0 Hz, HHet, H6), 8.11 (d, 1H,
J¼8.0 Hz, HHet), 8.36 (d, 1H, J¼8.0 Hz, H5), 8.52 (d, 1H, J¼4.0 Hz,
HHet), 9.12 (d, 1H, J¼4.0 Hz, H7); 13C NMR (62.5 MHz, CDCl3)
d 23.02
(2ꢁCH3), 36.32 (CH), 113.85 (Cq), 117.42 (Cq), 121.81 (CH), 126.26
(CH),128.38 (CH),130.07 (CH), 133.47 (CH),142.00 (Cq), 157.59 (CH),
159.63 (Cq), 173.61 (Cq); HRMS (EIMS): m/z calcd for C14H13N3OS2:
288.0629, found: 288.0632.
7. (a) Palmer, B. D.; Smaill, J. F.; Rewcastle, G. W.; Dobrusin, E. M.; Kraker, A.;
Moore, C. W.; Steinkempf, R. W.; Denny, W. A. Bioorg. Med. Chem. Lett. 2005, 15,
1931; (b) Perner, R. J.; Lee, C. H.; Gu, Y.-G.; Didomenico, S.; Baybut, E. K.;
Alexender, K. M.; Kohlhaas, H. L.; Jarvis, M. F.; Kowaluk, E. L.; Bhagawat, S. S.
Bioorg. Med. Chem. Lett. 2005, 15, 2803.
8. Vander Wel, S. N.; Harvey, P. J.; McNamara, D. J.; Repine, J. T.; Keller, P. R.; Quin,
J., III; Booth, R. J.; Elliott, W. L.; Dobrusin, E. M.; Fry, D. W.; Toogood, P. L. J. Med.
Chem. 2005, 48, 2371.
4.3.21. 4-Isopropylsulfanyl-2-phenylpyrido[2,3-d]pyrimidine
22. Compound 22 was isolated after flash chromatographyꢂ(1PE/
EtOAc: 9/1) as a beige solid. Mp 113e114 ꢀC; IR (ATR-Ge, cm
) n
1549, 1465, 1447, 1379, 1322, 1244, 1009, 851, 714; 1H NMR
(400 MHz, CDCl3)
d
1.58 (d, 6H, J¼8.0 Hz, 2ꢁCH3), 4.51 (m, 1H,
J¼4.0, 8.0 Hz, CH), 7.66 (m, 4H, J¼4.0, 8.0 Hz, HAr, H6), 7.82 (dd, 2H,
J¼4.0, 8.0 Hz, HAr), 8.56 (d, 1H, J¼8.0 Hz, H5), 9.31 (d, 1H, J¼4.0 Hz,
9. Zhang, J.; Yang, P. L.; Gray, N. S. Nat. Rev. Cancer 2009, 9, 28.
ꢀ
10. Font, M.; Gonzalez, A.; Palop, J. A.; Sanmartín, C. Eur. J. Med. Chem. 2011, 46,
H7); 13C NMR (62.5 MHz, CDCl3)
d
23.25 (2ꢁCH3), 36.34 (CH), 117.00
3887.
11. Lavecchia, G.; Berteina-Raboin, S.; Guillaumet, G. Tetrahedron Lett. 2005, 46,
5851.
(Cq), 123.87 (CH), 129.47 (2ꢁCH), 130.69 (2ꢁCH), 131.77 (CH),
135.38 (CH), 137.40 (Cq), 159.03 (CH), 160.66 (Cq), 160.82 (Cq),
173.54 (Cq); HRMS (EIMS): m/z calcd for C16H15N3S: 282.1060,
found: 282.1058.
12. (a) Tikad, A.; Routier, S.; Akssira, M.; Leger, J. M.; Jarry, C.; Guillaumet, G. Synlett
2006, 1938; (b) Tikad, A.; Routier, S.; Akssira, M.; Leger, J. M.; Jarry, C.; Guil-
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M.; Jarry, C.; Guillaumet, G. Synthesis 2009, 2379; (d) Tikad, A.; Routier, S.;
Akssira, M.; Guillaumet, G. Org. Biomol. Chem. 2009, 7, 5113.
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Acknowledgements
Authors thank the ‘Volubilis’ Hubert Curien Program for finan-
cial support.
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.04.051.
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