Efficient synthesis of 2-substituted pyrido[3,2-d]pyrimidines involving SNAr and palladium-catalyzed cross-coupling reactions

Article abstract of DOI:10.1055/s-0029-1216854

The efficient and original synthesis of various 2-substituted pyrido[3,2-d]pyrimidines is reported. Starting from 2,4-dichloropyrido [3,2-d]pyrimidine, a regioselective pallado-dehalogenation led to 2-chloropyrido[3,2-d]pyrimidine, which was used in SNAr and palladium-catalyzed cross-coupling reactions in order to afford highly functionalized products in very good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216854

PAPER
2379
Efficient Synthesis of 2-Substituted Pyrido[3,2-d]pyrimidines Involving SNAr
and Palladium-Catalyzed Cross-Coupling Reactions
Efficient
S
ynthesis
b
of 2-Substit
d
uted
P
yrido[
e
3,2-
d
]pyrim
l
idineslatif Tikad,a,b Sylvain Routier,*a Mohamed Akssira,b Jean-Michel Léger,c Christian Jarry,c Gérald Guillaumeta
a
Institut de Chimie Organique et Analytique, Université d’Orléans, UMR CNRS 6005,
rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France
Fax +33(2)38417281; E-mail: sylvain.routier@univ-orleans.fr
b
c
Laboratoire de Chimie Bioorganique et Analytique, Université Hassan II-Mohammedia, BP 146, 20650 Mohammedia, Morocco
EA 2962, Pharmacochimie, Université Victor Segalen Bordeaux II, 33076 Bordeaux, France
Received 4 February 2009; revised 27 March 2009
tetrakis(triphenylphosphine)palladium(0) in toluene at
100 °C (Scheme 2).10
Abstract: The efficient and original synthesis of various 2-substi-
tuted pyrido[3,2-d]pyrimidines is reported. Starting from 2,4-
dichloropyrido[3,2-d]pyrimidine, a regioselective pallado-dehalo-
genation led to 2-chloropyrido[3,2-d]pyrimidine, which was used in
SNAr and palladium-catalyzed cross-coupling reactions in order to
afford highly functionalized products in very good yields.
We are now able to crystallize this starting material and an
X-ray crystal structure analysis of 2 formally established
its structure (Figure 1).12
Key words: arylations, amination, palladium
selective
dechlorination
N
Cl
N
Cl
N
N
N
N
Pyridopyrimidine moieties are scaffolds present in a great
number of biologically active drugs and very promising
PDGF, EGFR, DHFR, p38 MAP kinase, PI3 kinase,
tyrosine kinase, adenosine kinase, and cyclin-dependant
kinases inhibitors.1–8 Hence, the synthesis of pyridopyri-
midine derivatives provides an interesting challenge in
medicinal chemistry. Nevertheless, synthetic methods
leading to pyrido[3,2-d]pyrimidine regioisomers are
scarcely reported.
Cl
1
2
Scheme 2 Reagents and conditions: Bu3SnH (1.1 equiv), Pd(PPh3)4
(0.05 equiv), toluene, 100 °C, 1 h, 86%.
Our group has recently developed original strategies to
design 2,4-disubstituted pyrido[3,2-d]pyrimidines.9,10
Starting from 1 (Scheme 1), we have shown that SNAr,
Stille and Suzuki palladium-catalyzed reactions occurred
regioselectively at C4 and then at C2, indicating a strong
electronic difference between the two halogenated cen-
ters.11 Interestingly, the chlorine differentiation led to 2,4-
disubstituted pyrido[3,2-d]pyrimidines.
Figure 1 ORTEP representation of compound 2
1) selective
In order to study the versatility of 2 as a building block,
we carried out a wide range of SNAr and cross-coupling
reactions. The first SNAr was a direct amination (Table 1).
Reaction of 2 with a mixture of aqueous ammonia and tet-
rahydrofuran in a sealed tube at 80 °C led after 12 hours
to the desired derivative 3a in 69% yield (entry 1). Con-
densations of alkyl- and arylamines were then performed
in refluxing 1,4-dioxane (entries 2–7).
N
2
R
N
Cl
2
dechlorination
N
N
2) SNAr or "Pd"
cross-coupling
reactions
N
N
4
R = NHalkyl, NHaryl,
aryl, hetaryl, NHCOalkyl,
NHCOhetaryl, NHCOaryl
Cl
1
Scheme 1
In this paper, we report efficient methods affording 2-sub-
stituted pyrido[3,2-d]pyrimidines from 2-chloropyri-
do[3,2-d]pyrimidine (2). In a first step, we engaged
compound 1 in a regioselective reduction of the C4–Cl
bond by using tributyltin hydride in the presence of
Derivatives 3b and 3c were easily obtained from butyl-
amine and 4-methoxybenzylamine in 80% and 92%
yields, respectively. Starting indiscriminately from
aniline and 4-methoxy- or 4-chloroaniline, the reactions
gave the desired compounds 3d–f in high yields in few
hours (entries 2–6).
Nevertheless, the use of 2-chloroaniline proved to be
more tricky. In fact, compound 3g was isolated after 48
hours in only 65% yield (entry 7). The increase in the re-
SYNTHESIS 2009, No. 14, pp 2379–2384
x
x.
x
x
.
2
0
0
9
Advanced online publication: 02.06.2009
DOI: 10.1055/s-0029-1216854; Art ID: T02509SS
© Georg Thieme Verlag Stuttgart · New York

2380
A. Tikad et al.
PAPER
Table 1 Amination of 2-Chloropyrido[3,2-d]pyrimidine (2)a
Table 2 (Het)Arylation of 2-Chloropyrido[3,2-d]pyrimidine (2)a
H
N
N
Cl
N
(het)Ar
N
Cl
N
Suzuki
SNAr amination
R
N
N
or Stille
R = H, alkyl,
aryl, hetaryl
N
N
N
N
N
N
2
4
2
3
Entry Reactant
Product (Het)Ar
Time Yieldb
Entry
Product
3a
R
Time (h) Yieldb (%)
(h)
(%)
1
2
3
4
5
6
7
H
12
4
69
80
92
79
84
81
65
1
4a
4b
4c
4a
4b
4c
4d
Ph
3
86
B(OH)2
3b
Bu
3c
4-MeOC6H4CH2
Ph
4
2
2-thienyl
2-furyl
Ph
2
3
85
87
56
46
69
B(OH)2
B(OH)2
SnBu3
S
3d
4
3
3e
4-MeOC6H4
4-ClC6H4
2-ClC6H4
3
O
3f
3
4
24
24
24
24
3g
48
a Reaction conditions: for R = H, NH4OH, THF, sealed tube, 80 °C;
for R ºH, RNH2 (1.2 equiv), 1,4-dioxane, reflux.
b Yields are given for isolated product after flash chromatography.
5
2-thienyl
2-furyl
2-pyridyl
SnBu3
SnBu3
SnBu3
S
6
O
action time is due to steric hindrance, which affects direct-
ly the C2 SNAr.
N
c
7
–
The second aim of this work was the use of 2 in Suzuki
and Stille palladium-catalyzed reactions (Table 2).9,10 All
reactions were quenched after full disappearance of the
starting material 2 and were carried out with only 5 mol%
of tetrakis(triphenylphosphine)palladium(0). Other com-
ponents were fitted to the nature of the coupling process.
a Reaction conditions: Suzuki reaction (het)ArB(OH)2 (1.2 equiv),
Na2CO3 (2 equiv), Pd(PPh3)4 (0.05 equiv), toluene–EtOH (2:1), 100
°C; Stille reaction (het)ArSnBu3 (1.25 equiv), Pd(PPh3)4 (0.05 equiv),
LiCl (2.8 equiv), DMF, 90 °C.
b Yields are given for isolated products.
c Starting material was recovered.
Our previous report proved the efficiency of Suzuki reac-
tions between 2 and (het)arylboronic acids in nonaqueous
conditions to give 2-(het)arylpyrido[3,2-d]pyrimidines
4a–c (entries 1–3). Alternatively, we used the correspond-
ing tributylstannyl derivatives in order to achieve Stille re-
actions to give 4a–c (entries 4–6). To prevent degradation,
the amount of stannyl derivatives was slightly increased
and lithium chloride addition proved to be necessary.
Table 3 Amidation of 2-Chloropyrido[3,2-d]pyrimidine (2)a
H
N
N
R
N
Cl
amidation
N
O
N
R = alkyl, aryl,
N
N
hetaryl, OBn, OEt
2
5
Unfortunately, the reaction time increased to 24 hours and
the product yield of 2-(het)arylpyrido[3,2-d]pyrimidines
4a–c decreased notably compared to the Suzuki coupling
reactions. Using the sensitive 2-(tributylstannyl)pyridine,
no reaction occurred and the starting material 2 was fully
recovered (entry 7). Whatever the chosen Suzuki or Stille
conditions, 2-(het)arylpyrido[3,2-d]pyrimidines 4 were
obtained independently of electronic and steric effects. In
our hands, Stille-type reactions proved to be less efficient.
Entry
Product
5a
R
Time (min) Yieldb (%)
1
2
3
4
5
6
7
Ac
15
15
15
10
20
15
45
88
81
68
74
92
71
72
5b
Ph
5c
4-ClC6H4
3-pyridyl
pyrazin-2-yl
OBn
5d
5e
The last palladium-catalyzed reaction investigated was
the unusual Buchwald-type reaction. The great interest of
this method is to prepare new 2-amidopyrido[3,2-d]pyri-
midines in one step. Reactions were also carried out with
5 mol% of palladium(II) acetate and 10 mol% of Xant-
phos as a catalytic system13 in refluxing 1,4-dioxane
(Table 3).
5f
5g
OEt
a Reaction conditions: RCONH2 (1.2 equiv), K2CO3 (2 equiv),
Pd(OAc)2 (0.05 equiv), Xantphos (0.1 equiv), 1,4-dioxane, reflux.
b Yields are given for isolated products.
In this study, the alkyl, aryl, and hetaryl primary amides
(Table 3, entries 1–5) were successfully introduced by C2
chlorine displacement after a few minutes and compounds
5a–e were isolated in good yields. These reactions were
also independent of the amide substitution.
Synthesis 2009, No. 14, 2379–2384 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of 2-Substituted Pyrido[3,2-d]pyrimidines
2381
al was purified by column chromatography to afford the desired
compounds 3b–g.
To complete this work, we employed 2 in reaction with
benzylcarbamate. The reaction was achieved in a few
minutes and compound 5f was isolated in 71% yield. With
the very electron-rich ethylcarbamate, the reaction time
slightly increased to 45 minutes, but without any inci-
dence on the yield of 5g.
2-(Butylamino)pyrido[3,2-d]pyrimidine (3b)
From 2, flash chromatography (CH2Cl2–MeOH, 99:1) gave 3b
(80% yield) as a yellow solid; mp 85–86 °C.
IR (ATR-Ge): 3242, 2853, 1609, 1584, 1404, 1348, 1174, 1087,
934, 811 cm–1.
Herein, we have described the original regioselective
dechlorination procedure of 2,4-dichloropyrido[3,2-d]py-
rimidine (1) using palladium-catalyzed Stille-type cou-
pling reaction with tributyltin hydride. Furthermore, we
have studied the reactivity of 2-chloropyrido[3,2-d]pyri-
midine (2) via aminations (SNAr), (het)arylations, and
amidations, cross-coupling reactions (Suzuki, Stille, and
Buchwald), and found it to act as a versatile building
block for the direct introduction of the pyrido[3,2-d]pyri-
midin-2-yl moiety.
1H NMR (250 MHz, CDCl3): d = 0.97 (t, J = 7.2 Hz, 3 H, CH3),
1.38–1.53 (m, 2 H, CH2), 1.61–1.73 (m, 2 H, CH2), 3.51–3.59 (m, 2
H, CH2), 5.88 (s, 1 H, NH), 7.53 (dd, J = 4.1, 8.5 Hz, 1 H, H7), 7.88
(d, J = 8.5 Hz, 1 H, H8), 8.60 (dd, J = 1.6, 4.1 Hz, 1 H, H6), 9.17 (s,
1 H, H4).
13C NMR (62.5 MHz, CDCl3): d = 13.9 (CH3), 20.2 (CH2), 31.6
(CH2), 41.6 (CH2), 128.2 (CH), 133.5 (CH), 136.8 (Cq), 146.6 (CH),
148.5 (Cq), 159.6 (Cq), 163.2 (CH).
HRMS (EI): m/z [M + H]+ calcd for C11H15N4: 203.1297; found:
203.1294.
1H NMR and 13C NMR were recorded on Bruker Avance DPX250
(250.19 MHz 1H, 62.89 MHz 13C) or Bruker Avance II (400 MHz
1H, 100 MHz 13C) spectrometers using tetramethylsilane as the in-
ternal standard, chemical shifts are reported in parts par million
(ppm, d units). Coupling constants are reported in units of hertz
(Hz) if applicable. Infrared spectra were recorded using a Ge ATR
instrument. Low-resolution mass spectra (MS) were recorded on a
Perkin-Elmer SCIEX API 3000 spectrometer. Exact mass were per-
formed in CRMPO, Rennes, France. Melting points were deter-
mined in open capillary tubes and are uncorrected. Flash chroma-
tography was performed on silica gel 60 (40–63 mesh). Thin layer
chromatography (TLC) was carried out on Merck silica gel 60F254
precoated plates. Visualization was done with ultraviolet light. Re-
actions requiring anhydrous conditions were performed under ar-
gon. All solvents were freshly distilled under argon prior to use.
Chemical reagents and solvents were obtained from either Aldrich
or Acros Organics. PE = petroleum ether (boiling range 40–60 °C).
2-(4-Methoxybenzylamino)pyrido[3,2-d]pyrimidine (3c)
From 2, flash chromatography (CH2Cl2–MeOH, 98:2) gave 3c
(92% yield) as a yellow solid; mp 143–144 °C.
IR (ATR-Ge): 1607, 1585, 1541, 1508, 1246, 1180, 1021, 818, 726
cm–1.
1H NMR (250 MHz, DMSO-d6): d = 3.79 (s, 3 H, OCH3), 4.69 (d,
J = 5.6 Hz, 2 H, CH2), 6.03 (s, 1 H, NH), 6.86 (d, J = 8.5 Hz, 2 H,
Harom), 7.33 (d, J = 8.5 Hz, 2 H, Harom), 7.54 (dd, J = 4.1, 8.5 Hz, 1
H, H7), 7.89 (d, J = 8.5 Hz, 1 H, H8), 8.62 (dd, J = 1.5, 4.1 Hz, 1 H,
H6), 9.11 (s, 1 H, H4).
13C NMR (62.5 MHz, DMSO-d6): d = 45.5 (CH2), 55.4 (CH3), 114.2
(2 CH), 128.3 (CH), 129.2 (2 CH), 130.8 (Cq), 133.7 (CH), 137.1
(Cq), 147.0 (CH), 148.5 (Cq), 159.1 (Cq), 159.4 (Cq), 163.5 (CH).
HRMS (EI): m/z [M + H]+ calcd for C15H15N4O: 267.1246; found:
267.1242.
2-(Phenylamino)pyrido[3,2-d]pyrimidine (3d)
From 2, flash chromatography (CH2Cl2–MeOH, 99:1) gave 3d
(79% yield) as a white solid; mp 166–167 °C.
2-Aminopyrido[3,2-d]pyrimidine (3a); Typical Procedure
A soln of 2 (100 mg, 0.6 mmol) in THF (5 mL) and aq NH3 soln (5
mL) was heated at 80 °C in a sealed tube for 12 h. The mixture was
cooled to r.t. and the solvent was evaporated under reduced pres-
sure. After extraction with CH2Cl2 (3 × 10 mL), the combined or-
ganic layers were dried (MgSO4) and the solvent was removed
under reduced pressure. The crude material was purified by flash
chromatography (CH2Cl2–MeOH, 95:5) to give 3 (69% yield) as a
yellow solid; mp 214–215 °C.
IR (ATR-Ge): 1604, 1585, 1545, 1449, 1393, 1250, 818, 745 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.10 (t, J = 7.5 Hz, 1 H, Harom),
7.39 (t, J = 7.5 Hz, 2 H, Harom), 7.62 (dd, J = 4.1, 8.5 Hz, 1 H, H7),
7.72 (s, 1 H, NH), 7.80–7.84 (m, 2 H, Harom), 8.02–8.06 (m, 1 H,
H8), 8.73 (dd, J = 1.6, 4.1 Hz, 1 H, H6), 9.30 (s, 1 H, H4).
13C NMR (62.5 MHz, CDCl3): d = 119.4 (2 CH), 123.3 (CH), 128.6
(CH), 129.1 (2 CH), 134.4 (CH), 137.4 (Cq), 139.3 (Cq), 147.9 (Cq),
148.2 (CH), 156.9 (Cq), 163.4 (CH).
IR (ATR-Ge): 3329, 3160, 2290, 1659, 1581, 1465, 1364, 1174,
939, 816 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 7.11 (br s, 2 H, NH2), 7.66 (dd,
J = 4.1, 8.6 Hz, 1 H, H7), 7.82 (d, J = 8.6 Hz, 1 H, H8), 8.59 (dd,
J = 1.4, 4.1 Hz, 1 H, H6), 9.13 (s, 1 H, H4).
HRMS (EI): m/z [M + H]+ calcd for C13H11N4: 223.0984; found:
223.0981.
13C NMR (62.5 MHz, DMSO-d6): d = 128.6 (CH), 132.7 (CH),
135.9 (Cq), 146.4 (CH), 148.0 (Cq), 160.8 (Cq), 163.0 (CH).
2-(4-Methoxyphenylamino)pyrido[3,2-d]pyrimidine (3e)
From 2, flash chromatography (PE–EtOAc, 98:2) gave 3e (84%
yield) as a yellow solid; mp 179–180 °C.
HRMS (EI): m/z [M + H]+ calcd for C7H7N4: 147.0671; found:
147.0667.
IR (ATR-Ge): 1615, 1541, 1449, 1231, 1172, 1036, 818, 719 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.83 (s, 3 H, OCH3), 6.95 (d,
J = 8.8 Hz, 2 H, Harom), 7.59 (dd, J = 4.1, 8.6 Hz, 1 H, H7), 7.67–
7.71 (m, 3 H, NH, Harom), 7.98 (d, J = 8.6 Hz, 1 H, H8), 8.69 (m, 1
H, H6), 9.27 (s, 1 H, H4).
2-(Alkylamino)- or 2-(Arylamino)pyrido[3,2-d]pyrimidines 3b–
g; General Procedure
To a soln of 2 (100 mg, 0.6 mmol) in 1,4-dioxane (6 mL) was added
the amine (1.2 equiv). The reaction was refluxed for the desired
time (Table 1). The mixture was cooled to r.t. and the solvent was
evaporated under reduced pressure. After extraction with CH2Cl2
(3 × 10 mL), the combined organic layers were dried (MgSO4) and
the solvent was removed under reduced pressure. The crude materi-
13C NMR (62.5 MHz, CDCl3): d = 55.7 (OCH3), 114.4 (2 CH),
121.7 (2 CH), 128.5 (CH), 132.3 (Cq), 134.2 (CH), 137.3 (Cq), 147.8
(CH), 148.1 (Cq), 156.0 (Cq), 157.2 (Cq), 163.4 (CH).
Synthesis 2009, No. 14, 2379–2384 © Thieme Stuttgart · New York

2382
A. Tikad et al.
PAPER
HRMS (EI): m/z [M + H]+ calcd for C14H13N4O: 253.1089; found:
253.1084.
1H NMR (250 MHz, CDCl3): d = 7.51–7.55 (m, 3 H, HPh), 7.75 (dd,
J = 4.1, 8.5 Hz, 1 H, H7), 8.34 (dd, J = 1.5, 8.5 Hz, 1 H, H8), 8.59–
8.63 (m, 2 H, HPh), 8.98 (dd, J = 1.5, 4.1 Hz, 1 H, H6), 9.67 (s, 1 H,
H4).
2-(4-Chlorophenylamino)pyrido[3,2-d]pyrimidine (3f)
From 2, flash chromatography (PE–EtOAc, 98:2) gave 3f (81%
yield) as a yellow solid; mp 179–180 °C.
13C NMR (62.5 MHz, CDCl3): d = 128.5 (CH), 128.8 (2 CH), 128.9
(2 CH), 131.1 (CH), 136.6 (CH), 137.3 (Cq), 139.4 (Cq), 146.9 (Cq),
151.8 (CH), 161.6 (Cq), 161.9 (CH).
IR (ATR-Ge): 1589, 1537, 1489, 1456, 1405, 1239, 818, 722 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 7.39 (d, J = 8.8 Hz, 2 H, Harom),
7.80 (dd, J = 4.1, 8.5 Hz, 1 H, H7), 8.00–8.10 (m, 3 H, NH, Harom),
8.74–8.76 (m, 1 H, H8), 9.35 (s, 1 H, H6), 10.26 (s, 1 H, H4).
MS (IS): m/z = 208.0 [M + H]+.
2-(2-Thienyl)pyrido[3,2-d]pyrimidine (4b)
From 2, flash chromatography (PE–EtOAc, 80:20) gave 4b as a
beige solid; mp 131–132 °C.
13C NMR (62.5 MHz, DMSO-d6): d = 120.2 (2 CH), 125.3 (Cq),
128.3 (2 CH), 129.0 (CH), 133.5 (CH), 136.5 (Cq), 139.1 (Cq), 146.9
(Cq), 148.1 (CH), 156.4 (Cq), 162.9 (CH).
IR (ATR-Ge): 3084, 1570, 1527, 1449, 1421, 1385, 1261, 1210,
964, 823 cm–1.
HRMS (EI): m/z [M + H]+ calcd for C13H1035ClN4: 257.0594; found:
257.0598.
1H NMR (250 MHz, CDCl3): d = 7.16–7.19 (m, 1 H, Hhet), 7.53 (dd,
J = 1.2, 5.0 Hz, 1 H, Hhet), 7.73 (dd, J = 4.1, 8.8 Hz, 1 H, H7), 8.14
(dd, J = 1.2, 3.8 Hz, 1 H, Hhet), 8.26 (dd, J = 1.6, 8.8 Hz, 1 H, H8),
8.93 (dd, J = 1.6, 4.1 Hz, 1 H, H6), 9.55 (s, 1 H, H4).
2-(2-Chlorophenylamino)pyrido[3,2-d]pyrimidine (3g)
From 2, flash chromatography (PE–EtOAc, 98:2) gave 3g (65%
yield) as a yellow solid; mp 90–91 °C.
13C NMR (62.5 MHz, CDCl3): d = 128.6 (2 CH), 130.2 (CH), 130.8
(CH), 136.0 (CH), 139.0 (Cq), 143.0 (Cq), 146.9 (Cq), 151.4 (CH),
158.3 (Cq), 161.9 (CH).
IR (ATR-Ge): 3411, 2920, 2357, 1584, 1528, 1439, 1302, 1223,
1032, 934, 816 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.00 (dt, J = 1.5, 7.6 Hz, 1 H,
Harom), 7.31–7.43 (m, 2 H, Harom), 7.63 (dd, J = 4.1, 8.6 Hz, 1 H,
H7), 7.96 (br s, 1 H, NH), 8.05 (d, J = 8.6 Hz, 1 H, H8), 8.75 (dd,
J = 1.5, 4.1 Hz, 1 H, H6), 8.85 (dd, J = 1.3, 8.3 Hz, 1 H, Harom), 9.31
(s, 1 H, H4).
MS (IS): m/z = 214.0 [M + H]+.
2-(2-Furyl)pyrido[3,2-d]pyrimidine (4c)
From 2, flash chromatography (PE–EtOAc, 70:30) gave 4c as a
brown solid; mp 110–111 °C.
13C NMR (62.5 MHz, CDCl3): d = 120.1 (CH), 122.6 (Cq), 123.2
(CH), 127.6 (CH), 128.6 (CH), 129.2 (CH), 134.4 (CH), 135.9 (Cq),
137.5 (Cq), 147.6 (Cq), 148.6 (CH), 156.4 (Cq), 163.4 (CH).
IR (ATR-Ge): 3073, 1582, 1533, 1452, 1417, 1359, 1267, 1199,
953, 821 cm–1.
1H NMR (250 MHz, CDCl3): d = 6.54 (dd, J = 1.8, 3.5 Hz, 1 H,
Hhet), 7.42 (d, J = 3.5 Hz, 1 H, Hhet), 7.62 (d, J = 0.7 Hz, 1 H, Hhet),
7.69 (dd, J = 4.1, 8.6 Hz, 1 H, H7), 8.29 (d, J = 8.6 Hz, 1 H, H8),
8.89 (dd, J = 1.5, 4.1 Hz, 1 H, H6), 9.51 (s, 1 H, H4).
HRMS (EI): m/z [M + H]+ calcd for C13H1035ClN4: 257.0594; found:
257.0593.
2-Phenyl- and 2-Hetarylpyrido[3,2-d]pyrimidines 4; General
Procedures
13C NMR (62.5 MHz, CDCl3): d = 112.7 (CH), 115.4 (CH), 128.9
(CH), 136.4 (CH), 139.2 (Cq), 146.1 (CH), 147.0 (Cq), 151.8 (CH),
152.1 (Cq), 154.6 (Cq), 162.4 (CH).
Suzuki cross-coupling: To an argon-degassed soln of 2 (100 mg, 0.6
mmol) in toluene (6 mL) and EtOH (3 mL) was added successively
(het)arylboronic acid (1.2 equiv), Na2CO3 (2 equiv), and Pd(PPh3)4
(35 mg, 0.05 equiv). The reaction was heated at 100 °C under vig-
orous stirring for the time given in Table 2. After complete disap-
pearance of 2, H2O (10 mL) was added. After extraction with
CH2Cl2 (3 × 10 mL), the combined organic layers were dried
(MgSO4) and the solvent was removed under reduced pressure. The
crude material was purified by column chromatography to afford
the expected compound.
MS (IS): m/z = 198.0 [M + H]+.
2-(Acylamino)pyrido[3,2-d]pyrimidines 5a–g; General Proce-
dure
To an argon-degassed soln of 2 (100 mg, 0.6 mmol) in 1,4-dioxane
(5 mL) was added successively the amide or carbamate (1.2 equiv),
K2CO3 (2.0 equiv), Pd(OAc)2 (0.05 equiv), and Xantphos (0.1
equiv), the mixture was heated at reflux for 15 to 45 min (Table 3).
The mixture was cooled to r.t. and the solvent was evaporated under
reduced pressure. The crude residue was purified by column chro-
matography (silica gel) to afford the desired compounds 5a–g.
Stille cross-coupling: A soln of 2 (100 mg, 0.6 mmol), the
(het)ArSnBu3 (1.25 equiv) and LiCl (2.8 equiv) in DMF (7 mL) was
degassed with argon (bubbling) over 15 min. Pd(PPh3)4 (34 mg,
0.05 equiv) was added in 1 portion and the mixture was immerged
in a pre-heated oil bath (90 °C) for the time given in Table 2. After
the disappearance of 2, the mixture was cooled to r.t. and the vola-
tiles were concentrated under reduced pressure. The crude residue
was dissolved in CH2Cl2 (10 mL) and sat. KF soln (20 mL) was add-
ed. After filtration and extraction, the aqueous layer was extracted
with CH2Cl2 (3 × 10 mL). The combined organic layers were dried
(MgSO4) and evaporated under reduced pressure. The crude mate-
rial was purified by flash chromatography to afford the compounds.
N-(Pyrido[3,2-d]pyrimidin-2-yl)acetamide (5a)
From 2, flash chromatography (EtOAc–MeOH, 99:1) gave 5a (88%
yield) as a white solid; mp 200–201 °C.
IR (ATR-Ge): 1678, 1604, 1530, 1449, 1320, 1014, 826, 726 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.66 (s, 3 H, CH3), 7.76 (dd,
J = 4.1, 8.6 Hz, 1 H, H7), 8.23 (d, J = 8.6 Hz, 1 H, H8), 8.94 (dd,
J = 1.4, 4.1 Hz, 1 H, H6), 9.31 (s, 1 H, NH), 9.56 (s, 1 H, H4).
13C NMR (62.5 MHz, CDCl3): d = 25.8 (CH3), 129.3 (CH), 135.7
(CH), 138.7 (Cq), 147.8 (Cq), 151.0 (CH), 154.7 (Cq), 164.2 (CH),
172.0 (Cq).
2-Phenylpyrido[3,2-d]pyrimidine (4a)
From 2, flash chromatography (PE–EtOAc, 80:20) gave 4a as a
beige solid; mp 99–100 °C.
HRMS (EI): m/z [M + H]+ calcd for C9H9N4O: 189.0776; found:
189.0774.
IR (ATR-Ge): 3022, 2367, 1563, 1447, 1385, 1261, 1169, 1067,
934, 797 cm–1.
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Efficient Synthesis of 2-Substituted Pyrido[3,2-d]pyrimidines
2383
N-(Pyrido[3,2-d]pyrimidin-2-yl)benzamide (5b)
From 2, flash chromatography (PE–EtOAc, 50:50) gave 5b (81%
yield) as a white solid; mp 170–171 °C.
1H NMR (250 MHz, CDCl3): d = 5.31 (s, 2 H, CH2), 7.35–7.48 (m,
5 H, Harom), 7.73 (dd, J = 4.1, 8.5 Hz, 1 H, H7), 8.26 (dd, J = 1.5, 8.5
Hz, 1 H, H8), 8.32 (br s, 1 H, NH), 8.91 (dd, J = 1.5, 4.1 Hz, 1 H,
H6), 9.49 (s, 1 H, H4).
IR (ATR-Ge): 1703, 1604, 1515, 1467, 1397, 1235, 833, 730 cm–1.
13C NMR (62.5 MHz, CDCl3): d = 67.7 (CH2), 128.6 (CH), 128.7 (2
CH), 128.8 (2 CH), 128.9 (CH), 135.5 (CH), 135.6 (Cq), 138.1 (Cq),
147.7 (Cq), 150.7 (CH), 151.6 (Cq), 154.3 (Cq), 163.9 (CH).
1H NMR (250 MHz, CDCl3): d = 7.48–7.63 (m, 3 H, HPh), 7.74–
7.79 (m, 1 H, H7), 8.01 (d, J = 7.1 Hz, 2 H, HPh), 8.30 (d, J = 8.6 Hz,
1 H, H8), 8.93–8.95 (m, 1 H, H6), 9.08 (s, 1 H, NH), 9.51 (s, 1 H,
H4).
HRMS (EI): m/z [M + H]+ calcd for C15H13N4O2: 281.1039; found:
281.1032.
13C NMR (62.5 MHz, CDCl3): d = 127.7 (2 CH), 128.9 (CH), 129.0
(2 CH), 132.7 (CH), 134.2 (Cq), 135.7 (CH), 138.3 (Cq), 147.6 (Cq),
151.0 (CH), 154.5 (Cq), 163.8 (CH), 165.1 (Cq).
Ethyl N-(Pyrido[3,2-d]pyrimidin-2-yl)carbamate (5g)
From 2, flash chromatography (CH2Cl2–acetone, 95:5) gave 5g
(72% yield) as a white solid; mp 204–205 °C.
HRMS (EI): m/z [M + H]+ calcd for C14H11N4O: 251.0933; found:
251.0937.
IR (ATR-Ge): 3206, 2976, 1752, 1604, 1534, 1481, 1402, 1206,
1066, 827 cm–1.
4-Chloro-N-(pyrido[3,2-d]pyrimidin-2-yl)benzamide (5c)
From 2, flash chromatography (EtOAc–MeOH, 98:2) gave 5c (68%
yield) as a yellow solid; mp 196–197 °C.
1H NMR (250 MHz, CDCl3): d = 1.39 (t, J = 7.2 Hz, 3 H, CH3), 4.36
(q, J = 7.2 Hz, 2 H, CH2), 7.75 (dd, J = 4.1, 8.6 Hz, 1 H, H7), 8.29
(d, J = 8.6 Hz, 1 H, H8), 8.73 (br s, 1 H, NH), 8.92 (dd, J = 1.4, 4.1
Hz, 1 H, H6), 9.53 (s, 1 H, H4).
IR (ATR-Ge): 1707, 1585, 1464, 1250, 1095, 925, 833, 748 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.50 (d, J = 8.4 Hz, 2 H, Harom),
7.78 (dd, J = 4.1, 8.6 Hz, 1 H, H7), 7.95 (d, J = 8.4 Hz, 2 H, Harom),
8.30 (d, J = 8.6 Hz, 1 H, H8), 8.95–8.98 (m, 2 H, NH, H6), 9.52 (s,
1 H, H4).
13C NMR (62.5 MHz, CDCl3): d = 14.7 (CH3), 62.1 (CH2), 128.9
(CH), 135.6 (CH), 138.1 (Cq), 147.8 (Cq), 150.6 (CH), 151.8 (Cq),
154.4 (Cq), 163.8 (CH).
HRMS (EI): m/z [M + H]+ calcd for C10H11N4O2: 219.0882; found:
219.0876.
13C NMR (62.5 MHz, CDCl3): d = 129.0 (CH), 129.2 (2 CH), 129.3
(2 CH), 132.5 (Cq), 135.7 (CH), 138.3 (Cq), 139.1 (Cq), 147.6 (Cq),
151.0 (CH), 154.4 (Cq), 163.8 (CH), 164.2 (Cq).
HRMS (EI): m/z [M + H]+ calcd for C14H1035ClN4O: 285.0543;
found: 285.0548.
Acknowledgment
We thank the Cancéropôle Grand Ouest and the Ligue Contre le
Cancer Region Centre for the financial support.
N-(Pyrido[3,2-d]pyrimidin-2-yl)nicotinamide (5d)
From 2, flash chromatography (CH2Cl2–MeOH, 99:1) gave 5d
(74% yield) as a yellow solid; mp 211–212 °C.
References
IR (ATR-Ge): 1711, 1585, 1471, 1408, 1298, 1257, 1099, 826, 722
cm–1.
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HHet), 7.96 (dd, J = 4.1, 8.6 Hz, 1 H, H7), 8.27–8.36 (m, 2 H, Hhet,
H8), 8.78 (d, J = 3.8 Hz, 1 H, Hhet), 9.01 (dd, J = 1.4, 4.1 Hz, 1 H,
H6), 9.14 (s, 1 H, Hhet), 9.62 (s, 1 H, H4), 11.62 (s, 1 H, NH).
13C NMR (62.5 MHz, DMSO-d6): d = 123.5 (CH), 129.5 (CH),
130.0 (Cq), 134.9 (CH), 136.0 (CH), 137.7 (Cq), 146.8 (Cq), 149.2
(CH), 151.3 (CH), 152.6 (CH), 154.9 (Cq), 163.2 (CH), 164.5 (Cq).
HRMS (EI): m/z [M + H]+ calcd for C13H10N5O: 252.0885; found:
252.0885.
N-(Pyrido[3,2-d]pyrimidin-2-yl)pyrazine-2-carboxamide (5e)
From 2, flash chromatography (CH2Cl2–MeOH, 98:2) gave 5e
(92% yield) as a beige solid; mp 263–264 °C.
IR (ATR-Ge): 1718, 1515, 1460, 1401, 1231, 1135, 1021, 888, 722
cm–1.
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1H NMR (250 MHz, DMSO-d6): d = 7.99 (dd, J = 4.1, 8.6 Hz, 1 H,
H7), 8.33 (d, J = 8.6 Hz, 1 H, H8), 8.84–8.85 (m, 1 H, Hhet), 8.99 (d,
J = 2.5 Hz, 1 H, Hhet), 7.99 (dd, J = 1.4, 4.1 Hz, 1 H, H6), 9.34 (d,
J = 1.3 Hz, 1 H, Hhet), 9.64 (s, 1 H, H4), 10.90 (br s, 1 H, NH).
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HRMS (EI): m/z [M + H]+ calcd for C12H9N6O: 253.0838; found:
253.0833.
Benzyl N-(Pyrido[3,2-d]pyrimidin-2-yl)carbamate (5f)
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yield) as a white solid; mp 161–162 °C.
IR (ATR-Ge): 3186, 2986, 1756, 1604, 1538, 1454, 1399, 1212,
1060, 826 cm–1.
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Synthesis 2009, No. 14, 2379–2384 © Thieme Stuttgart · New York

2384
A. Tikad et al.
PAPER
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an Enraf-Nonius CAD-4 diffractometer using the CuKa
radiation and a graphite monochromator up to q = 45°. The
data were collected to relatively low resolution, i.e. no
reflections were observed for q > 45° with lCu. The data were
corrected for Lorentz and polarization effects and for
empirical absorption correction.14a The structure was solved
by direct methods SHELX 862 and refined using SHELX 972
suite of programs.14b,c Crystallographic data for the structure
2 in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
(CCDC 718788): Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; E-mail:
deposit@ccdc.cam.ac.uk.
McGaraughty, S.; Wismer, C. T.; Mikusa, J.; Marsh, K. C.;
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dimensions were determined using the least-squares fit from
Synthesis 2009, No. 14, 2379–2384 © Thieme Stuttgart · New York