Regiocontroled SNAr and palladium cross-coupling reactions of 2,4,7-trichloropyrido[3,2-d]pyrimidine

Article abstract of DOI:10.1002/ejoc.201200521

An efficient and original synthesis of various 2,4,7-trisubstituted pyrido[3,2-d]pyrimidines is reported. The first access to and the chemical interest of 2,4,7-trichloropyrido[3,2-d]pyrimidine is described. Double arylations and S_NAr reactions occurred selectively at the C4 and C2 positions of 2,4,7-trichloropyrido[3,2-d]pyrimidine. The reactions at the C7 position were achieved under microwave irradiation in a few minutes. A one-step synthesis of a 2,4,7-tris(aminated) derivative was achieved as a highly efficient alternative. An efficient and original synthesis of 2,4,7-trisubstituted pyrido[3,2-d]pyrimidines is reported. Arylations and S _NAr reactions occurred regioselectively at the C4 and C2 positions of 2,4,7-trichloropyrido[3,2-d]pyrimidine. Reactions at the C7 position were achieved under microwave irradiation in a few minutes. A one-step synthesis of a 2,4,7-tris(aminated) derivative was achieved as an efficient alternative. Copyright

Full text of DOI:10.1002/ejoc.201200521

Job/Unit: O20521
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Date: 03-07-12 15:43:40
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FULL PAPER
DOI: 10.1002/ejoc.201200521
Regiocontroled SNAr and Palladium Cross-Coupling Reactions of
2,4,7-Trichloropyrido[3,2-d]pyrimidine
Abdellatif Tikad,[a,b] Mohamed Akssira,[b] Stéphane Massip,[c] Jean-Michel Léger,[c]
Christian Jarry,[c] Gérald Guillaumet,*[a] and Sylvain Routier*[a]
Keywords: Arylation / Aromatic substitution / Cross-coupling / Amination / Heterocycles
An efficient and original synthesis of various 2,4,7-trisubsti-
chloropyrido[3,2-d]pyrimidine. The reactions at the C7 posi-
tuted pyrido[3,2-d]pyrimidines is reported. The first access to tion were achieved under microwave irradiation in a few
and the chemical interest of 2,4,7-trichloropyrido[3,2-d]pyr-
imidine is described. Double arylations and SNAr reactions
occurred selectively at the C4 and C2 positions of 2,4,7-tri-
minutes. A one-step synthesis of a 2,4,7-tris(aminated) deriv-
ative was achieved as a highly efficient alternative.
tive examples of inhibitors of CDK and GSK3 kinases are
polyarylated and/or polyaminated,[12] we designed a flexible
method to synthesize such compounds from the novel 2,4,7-
trichloropyrido[3,2-d]pyrimidine (3). At the 2-, 4- and 7-
positions, tris(arylation) remains unknown, and one patent
reports two tris(aminated) structures.[13]
We report herein the preparation of novel trichloro deriv-
ative 3 and its regioselective functionalization by reactions
of two different classes. Several (het)arylations and amina-
tions were achieved in the order C4, then C2, then C7 to
give compounds of types I and II (Figure 1). Complete dis-
crimination between the chlorinated positions was observed
in each reaction, and a single-step strategy for tris(amin-
ation) was also developed.
Introduction
The pyridopyrimidine scaffold has generated a great
number of biologically active compounds, and has recently
been used to design effective and original drugs, including
an MEK inhibitor,[1] a bacterial topoisomerase inhibitor,[2]
an HCV inhibitor,[3] a p38 MAP kinase inhibitor,[4] gluco-
cerebrosidase inhibitors,[5] and antimalarial[6] and cytotoxic
agents.[7]
A recent review surveyed the efforts undertaken to build
and functionalize this heterocyclic skeleton. Most substitu-
ents are introduced in advance of or during heterocycle gen-
eration.[8] In the general pyridopyrimidine field, the [3,2-d]
regioisomer is the least well described because of its difficult
and costly synthesis. Over the past decade, the regioselecti-
vity of substitution reactions of polyhaloheteroaromatics
has been extensively studied.[9]
At the beginning of our research, we reported an original
synthesis of 2,4-dichloro derivative 2 (Table 1), and used it
in sequential or one-pot reactions, substituting first at the
C4 position and then at C2.[10] We then used our methodol-
ogy to modulate the biological activity of reference mo-
lecules, and to synthesize original drug-like molecules,
mainly using original heterocyclic skeletons and previously
unknown synthetic sequences.[11] As important representa-
Figure 1. General strategy.
Results and Discussion
[a] Institut de Chimie Organique et Analytique, (1) Université
d’Orléans, (2) CNRS UMR 6005,
B. P. 6759, 45067 Orléans Cedex 2, France
Fax: +33-2-38417281
Selective chlorination of heterocycles in the position β to
a nitrogen atom has been observed with [1,10]phen-
anthroline,[14] quinoline,[15] 1,6-naphthyridine,[16] and 7-
bromo-2H-isoquinolin-1-one;[17] but to the best of our
knowledge, the direct trichlorination of pyrido[3,2-d]pyr-
imidine in a single step has not yet been described. The sole
reported trichlorinated [3,2-d]pyridopyrimidine is methyl
2,4,8-trichloropyrido[3,2-d]pyrimidine-6-carboxylate, which
was used recently by Quattropani et al.[18]
E-mail: sylvain.routier@univ-orleans.fr
gerald.guillaumet@unv-orleans.fr
[b] Laboratoire de Chimie Bioorganique et Analytique, Université
Hassan II-Mohammedia,
B. P. 146, 20650 Mohammedia, Morocco
[c] Laboratoire de Chimie Physique et minérale, FRE CNRS 3396,
UFR de Pharmacie, Université Bordeaux Segalen,
146 rue Léo Saignat, 33076 Bordeaux Cedex, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200521.
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During the multigram synthesis of 2, we observed the Table 2. Selective C2 arylations of compound 4.
formation of the trichloro derivative 3 in a very low 2%
yield (Table 1, Entry 1). Prolonging the reaction time to
24 h gave no significant effect. Fortunately, switching from
thermal activation to microwave irradiation at 160 °C for
2 h improved the yield of 3 to 39% (Table 1, Entry 3). In-
creasing the amount of PCl5 to 6.0 equiv. provided 2,4,7-
trichloropyrido[3,2-d]pyrimidine (3) in 62% isolated yield,
with no trace of any other compound (Table 1, Entry 4). It
is noteworthy that the POCl3/PCl5 system is required for
the formation of 3. When either reagent was used alone,
only starting material was detected.
Entry
C2 substitution
Compound
Time
[h]
Yield[a,b]
[%]
1
2
3
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
6
7
8
5
4
5
84
81
83
[a] Reaction conditions: ArB(OH)2 (1.05 equiv.), Na2CO3
(2.0 equiv.), Pd(PPh3)4 (5.0 mol-%), toluene/EtOH (2:1), 100 °C.
[b] Isolated yields.
Table 1. Trichlorination of compound 1.
The structures of compounds 4 and 8, resulting from tri-
ple 2,4,7 and double 2,7 chlorine differentiation, respec-
tively, were clearly elucidated by single-crystal X-ray crys-
tallography. The two ORTEP representations in Figure 2
clearly show the positions of the chlorine atoms and the
aryl insertions.
Entry Chlorination system
(equiv.)
T
[°C]
Time
[h]
Yield[a] [%]
2
3
1
2
3
4
POCl3/PCl5 (4.0)
POCl3/PCl5 (4.0)
POCl3/PCl5 (4.0)
POCl3/PCl5 (6.0)
130[b]
6
24
2
58
49
2
5
39
62
130[b]
160 (MW)[c]
160 (MW)[c]
20
2
n.d.[d]
[a] Isolated yields. [b] The reaction was performed in a sealed tube
under thermal conditions. [c] Microwave irradiation. [d] Not de-
tected.
Tris[(het)arylation] of 2,4,7-Trichloropyrido[3,2-d]pyrimidine
Having obtained the trichloro derivative 3, we first per-
formed regioselective arylation at C4. Using a near stoi-
chiometric amount of phenylboronic acid in the presence
of potassium carbonate and Pd(PPh3)4 (5 mol-%) in toluene
at 100 °C, we observed complete consumption of 3 and the
Figure 2. ORTEP views of compound 4 (left) and 8 (right).
Some conformational differences were observed between
formation of the monophenyl derivative 4 in a good 77% compounds 4 and 8. Firstly, the rms deviation of the pyr-
yield (Scheme 1). The small amount of diarylated by-prod- idopyrimidine bicycles have similar values (0.06 Å and
uct 5 (2%) that was subsequently formed was separated by 0.02 Å, respectively). But a slight torsion of the bicycle for
flash chromatography.
compound 4 was observed, with deviations from the least-
We then envisioned an arylation at the C2 position with- squares plane of around 0.1 Å for atoms C-7, N-13 and C-
out any effect on the chlorine atom at C7. The best condi- l1 [–0.109(5), 0.094(5), –0.094(3) Å, respectively]. Secondly,
tions were obtained by adding ethanol as co-solvent and the angles between these planes and the benzene groups
using sodium carbonate as base (Table 2). The three (meth- were found to be 28.9(2)° and 45.8(1)° for the respective
oxyphenyl)boronic acids reacted with 4 in a few hours to compounds. In addition, for compound 8, the angle be-
give the bis(arylated) compounds 6–8 in good yields. Com- tween the bicycle and the methoxyphenyl substituent shows
plete C2 vs. C7 regioselectivity was obtained, and no obvi- a quasi-planar geometry with a value of 2.4(1) (see Table S1
ous steric effect of the 2-methoxy group was observed.
in the Supporting Information).
Scheme 1. Selective C4 arylation of 3. Reaction conditions: ArB(OH)2 (1.05 equiv.), K2CO3 (1.5 equiv.), Pd(PPh3)4 (5.0 mol-%), toluene,
100, 2 h, 77% (4), 2% (5).
2
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Regiocontroled Reactions of 2,4,7-Trichloropyrido[3,2-d]pyrimidine
By starting from 7, the last (het)arylations were first at- to synthesise unknown C2-monoaminated, 2,4-bis(amin-
tempted in the presence of a slight excess of boronic acid ated) and finally 2,4,7-tris(aminated) pyrido[3,2-d]pyrimid-
and K2CO3 (Na2CO3 gave lower yields) as base (Table 3).
ines.
By applying a sequential route, compound 3 was treated
first with a stoichiometric amount of benzylamine in the
presence of Et3N in THF at room temperature. C4 amin-
ation occurred after a few hours, and compound 17 was
isolated in 90% yield (Scheme 2). The second reaction re-
quired thermal activation (refluxing dioxane) and the pres-
ence of a slight excess of nucleophilic agent to achieve the
C2 chlorine displacement by an SNAr mechanism. Com-
pound 18 was isolated after 12 h in a high 92% yield
(Scheme 2), indicating that the SNAr reactions tolerate
base-sensitive functionalities (NH, OH).
Table 3. Heteroarylation of compound 7.
Scheme 2. Regioselective double amination of 3 by sequential SNAr
reactions. Reaction conditions: 1st SNAr: Et3N (1.05 equiv.), THF,
room temp., 4 h, 90%; 2nd SNAr: ethanolamine (1.2 equiv.), Et3N
(2.0 equiv.), 1,4-dioxane, reflux, 12 h, 92%.
During the first step, no trace of bis(amination), and
during the second step, no trace of tris(amination) was ob-
served, emphasizing the lack of reactivity of the 7-Cl vs. 2-
Cl and of the 2-Cl vs. 4-Cl atoms. In order to formally es-
tablish the regioselectivity of the first SNAr reaction at the
C4 position, an X-ray analysis of the monoaminated deriva-
tive 17 was performed. The ORTEP representation (Fig-
ure 3) confirms the C4 amination.
[a] Isolated yields. [b] Reaction conditions: (Het)ArB(OH)2
(1.2 equiv.), K2CO3 (2.0 equiv.), Pd(PPh3)4 (5.0 mol-%), toluene/
EtOH (2:1), microwave irradiation, 150 °C. [c] Reaction conditions:
(Het)ArB(OH)2 (1.2 equiv.), K2CO3 (2.0 equiv.), Pd(PPh3)4
(5.0 mol-%), toluene/EtOH (2:1), 100 °C.
After 12 h, the trisubstituted derivative 9 was isolated in
a best yield of 95%. To diminish the reaction time, micro-
wave irradiation was used. After only 5 min at 150 °C, com-
plete reaction was observed, and purification afforded 9 in
a similar yield (Table 3, Entries 1a,b).
We then used aryl-, naphthyl-, furyl-, pyridinyl-, thienyl-
and (benzothienyl)boronic acids to synthesise the corre-
sponding desired compounds in excellent yields. Generally,
a slight increase in the reaction time to 10 (Table 3, En-
tries 3, 5, 6) or 15 min (Table 3, Entry 4) was required for
complete reaction to be reached. A decrease in yield was
observed in only one case (Table 3, Entry 8), which was
mainly due to difficulties during the purification of com-
pound 16.
Figure 3. ORTEP view of compound 17.
In summary, this method enabled us to discriminate be-
tween the three chlorine atoms of 2,4,7-trichloro[3,2-d]pyr-
imidine (3) using highly efficient successive Suzuki cross-
coupling reactions, which were carried out successively in
the sequence C4, C2 and finally C7.
The structural conformation of compound 17 could be
compared to that of compound 4. The bicycle shows a tor-
sion for compound 4, whereas it is very close to planar for
compound 17 (the latter compound having an rms devia-
tion of 0.01 Å). This is due to less steric hindrance for this
latter compound due to the presence of the linker between
the pyridopyrimidine core and the phenyl group. For this
reason, and also due to a hydrogen bond of the chelate type
Tris(amination) of 2,4,7-Trichloropyrido[3,2-d]pyrimidine
In the light of this step-by-step discrimination, the versa- (see Table S2 in the Supporting Information) between N8-
tility of 3 as a building block was next explored through a H and N15, the two planes defined by bicycle and phenyl
wide range of SNAr and Pd-catalyzed N-arylations in order moieties are angled at 89.6(1)°.
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In addition, the C–Cl bond of 18 was reduced under mi-
The scope and limitations of the C7 reactions were found
crowave-assisted palladium dechlorination (Scheme 3). The by using various amines (Table 5). Only a few minutes were
1H and COSY NMR spectra of product 19 clearly indicate necessary to achieve the reactions of 18 with (het)aryl-
the presence of three adjacent pyridinyl H atoms. This sup- amines, and compounds 20–27 were isolated in good yields
plementary analysis confirms the regioselectivity of the sec- (Table 5, Entries 1–8). All the reactions led to a complete
ond nucleophilic attack on C2.
conversion of the starting material into a single product,
but difficulties with purification lowered the isolated yields.
Table 5. N-Arylation of compound 18 with various amines.
Scheme 3. Dechlorination of compound 18. Reaction conditions:
HCO2H (2.0 equiv.), Et3N (3.0 equiv.), Pd(OAc)2 (10 mol-%),
Xantphos (20 mol-%), THF, 150 °C under microwave irradiation,
15 min, 57%.
To perform the C7 amination of compound 18, we de-
cided to study the Pd-catalyzed N-arylation as an alterna-
tive route, because the starting material was fully recovered
from the SNAr reactions. Our initial experiment focused on
the C–N bond formation between compound 18 and p-
anisidine (Table 4) under Buchwald conditions,[19] which
had been used in our previous report. Thus, by using
Pd(OAc)2/Xantphos as a catalytic system with K2CO3 in
refluxing 1,4-dioxane,[20] the target compound 20 was iso-
lated in a modest 49% yield after 24 h (Table 4, Entry 1).
[a] Isolated yields. [b] Compound 18 was recovered. [c] Reaction
conditions: (Het)ArNH2 (1.2 equiv.), K2CO3 (2.0 equiv.), Pd-
(OAc)2 (0.1 equiv.), Xantphos (0.2 equiv.), 140 °C, microwave irra-
diation.
Table 4. N-Arylation of compound 18 with p-anisidine.
One-Pot Reaction of 2,4,7-Trichloropyrido[3,2-d]pyrimidine
Entry Catalytic system[a]
Base
(equiv.)
Temp.
Activating
mode
Time Yield[a,b]
[%]
Small differences in reaction conditions were found to
increase efficiency and selectivity during the tris(arylations).
Despite varying the reaction conditions, such as the nature
of the base, the solvent, and the activation mode (thermal
reaction/microwave irradiation), we were unable to find ex-
perimental conditions for successful one-pot tris(aryl-
ations).
In the case of tris(aminated) pyrido[3,2-d]pyrimidines,
the larger difference between the reactivity of the three
chlorine atoms prompted us to attempt an unprecedented
one-pot synthesis of these substrates by tandem double
SNAr/Buchwald N-arylation.
1
2
3
4
5
Pd(OAc)2/
Xantphos
Pd(OAc)2/
Xantphos
Pd(OAc)2/
Xantphos
Pd(OAc)2/
Xantphos
none
K2CO3
(20.0)
K2CO3
(20.0)
K2CO3
(2.0)
Cs2CO3
(2.0)
K2CO3
(2.0)
reflux
thermal
140 °C
MW
140 °C
MW
140 °C
MW
140 °C
MW
24 h
40 min
50 min
1 h
49
68
72
70
2 h
n.d.[c]
After a careful screening of experimental conditions, we
found that the first two reactions could be achieved in diox-
ane in the presence of an excess of triethylamine in a sealed
vial. The first SNAr was achieved at room temperature in
[a] Isolated yields. [b] Reaction conditions: Pd(OAc)2 (0.1 equiv.),
Xantphos (0.2 equiv.), 1,4-dioxane, p-anisidine (1.2 equiv.). [c] Not
detected; compound 18 was fully recovered.
The use of microwave irradiation and a decrease of the the presence of a stoichiometric amount of BnNH2 to pre-
amount of base to 2 equiv. provided 20 in the best 72% serve the C4 regioselectivity. After complete disappearance
yield (Table 4, Entries 2–3). Any change of base resulted in of 3 (observed in 5 min), ethanolamine was added, and the
a less efficient reaction, and in the absence of the catalytic reaction mixture was placed under microwave irradiation
system, only starting material was observed; therefore, the at 140 °C until the disappearance of intermediate 17 was
possibility of nucleophilic attack at C7 may be excluded observed. The completion of the second amination at C2
(Table 4, Entries 4 and 5).
occurred after 1 h, and led to the in situ formation of 18.
4
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Regiocontroled Reactions of 2,4,7-Trichloropyrido[3,2-d]pyrimidine
After cooling, a Buchwald pre-mix [i.e., p-anisidine, K2CO3,
Pd(OAc)2 and Xantphos] was added to the vial. The cross-
coupling reaction was activated under microwave irradia-
tion at 140 °C for an additional 1 h. After a single purifica-
tion step, the expected 2,4,7-tris(triaminated) derivative 20
was isolated in 64% yield.
This new green one-pot tris(amination) methodology di-
minished the global reaction time and afforded 20 in fairly
good yield after a single purification. Having developed
such an innovative alternative method, we were now able to
apply the procedure to the synthesis of compounds 21–27.
As shown in Table 6, the target 2,4,7-trisubstituted pyr-
ido[3,2-d]pyrimidines 21–27 were isolated in similarly good
yields (64–72%), whatever the aniline or the heterocyclic
amine used, and whatever the method chosen.
Experimental Section
1
General Methods: H and 13C NMR spectra were recorded with a
250 MHz or a 400 MHz spectrometer by using CDCl3 or [D6]-
DMSO as the solvent. The chemical shifts are reported in parts per
million (δ scale), and all coupling constant (J) values are in Hertz
(Hz). The following abbreviations were used to explain the multi-
plicities: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet)
and dd (doublet of doublets). IR spectra were recorded with an
FTIR spectrometer with a diamond ATR accessory by using the
thin-film method. HRMS data were recorded with a mass spec-
trometer by the “Fédération de Recherche” ICOA/CBM (FR2708)
platform. Reactions were monitored by TLC on silica [alu-plates
(0.2 mm)]. Spots were visualized by UV light at 254 and 356 nm.
Column chromatography was performed by using silica gel 60
(0.063–0.200 mm). Microwave irradiation was carried out in sealed
2–5 mL vessels placed in a Biotage Initiator system by using a stan-
dard absorbance level (300 W maximum power). The temperature
was measured externally by an IR probe that determined the tem-
perature on the surface of the vial and could be read directly from
the instrument screen. The reaction time was measured from when
the reaction mixture reached the stated temperature for tempera-
ture-controlled experiments. Pressure was measured by a non-in-
vasive sensor integrated into the cavity lid.
Table 6. Triple amination of compound 3 by a one-pot double
SNAr/Buchwald sequence.
2,4,7-Trichloropyrido[3,2-d]pyrimidine (3): A suspension of 1H,3H-
pyrido[3,2-d]pyrimidine-2,4-dione (1) (1.0 g, 6.13 mmol) in a mix-
ture of POCl3 (10 mL) and PCl5 (7.65 g, 36.7 mmol) was heated in
a sealed vial under microwave irradiation at 160 °C. After 2 h, ex-
cess POCl3 was removed under reduced pressure, and the crude
residue was dissolved in CH2Cl2 (20 mL) at 0 °C. The crude mix-
ture was poured into an iced-water bath (20 mL) with vigorous
stirring, and the organic layer was extracted with CH2Cl2 (20 mL).
After drying with MgSO4, filtration, and removal of the volatiles
under reduced pressure, the residue was purified by flash
chromatography using silica gel (petroleum ether/CH2Cl2, 40:60) to
afford 3 (891 mg, 62%) as a white solid. M.p. 165–166 °C. IR (ATR
Entry
Compound
Global yield[a] [%]
Three steps
One pot[b]
1
2
3
4
5
6
7
8
20
21
22
23
24
25
26
27
60
63
59
64
60
67
53
64
64
75
68
70
71
67
72
69
[a] Isolated yields. [b] Reaction conditions: 1st SNAr: BnNH2
(1.0 equiv.), Et3N (3.0 equiv.), 1,4-dioxane, room temp., 5 min; 2nd
SNAr: ethanolamine (5.0 equiv.), 140 °C, microwave irradiation,
1 h, then (het)ArNH2 (1.2 equiv.), K2CO3 (2.0 equiv.), Pd(OAc)2
(0.1 equiv.), Xantphos (0.2 equiv.), 140 °C, microwave irradiation,
1 h.
Diamond): ν = 3048, 2167, 1579, 1531, 1430, 1324, 1253, 1136,
˜
1001, 872 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.31 (d, J =
2.2 Hz, 1 H, 8-H), 9.03 (d, J = 2.2 Hz, 1 H, 6-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 134.2 (CH), 135.1 (Cq), 138.5 (Cq), 148.8
(Cq), 152.7 (CH), 157.0 (Cq), 166.0 (Cq) ppm. HRMS (EI-MS+):
calcd. for C7H235Cl3N3 [M]+ 232.9314; found 232.9323.
Conclusions
2,7-Dichloro-4-phenylpyrido[3,2-d]pyrimidine (4): Compound
3
(2.14 g, 9.13 mmol) was dissolved in anhydrous toluene (7 mL) un-
der argon. Phenylboronic acid (1.17 g, 9.596 mmol, 1.05 equiv.),
K2CO3 (1.989 g, 14.394 mmol, 1.5 equiv.) and Pd(PPh3)4 (527 mg,
0.457 mmol, 0.05 equiv.) were successively added, and the reaction
mixture was heated at 100 °C for 2 h. After cooling, water (30 mL)
was added, and extractions were performed with CH2Cl2 (2ϫ
20 mL). The combined organic layers were dried with MgSO4, fil-
tered and concentrated under reduced pressure. The crude residue
was purified by flash chromatography using silica gel (petroleum
ether/CH2Cl2, 90:10) to afford 4 (1.942 g, 77%) as a white solid.
In this paper, we have described the first access to 2,4,7-
trichloropyrido[3,2-d]pyrimidine 3 and its use to build two
2,4,7-tris(het)aryl- and -aminopyrido[3,2-d]pyrimidine li-
braries using a novel and highly efficient strategy. Aryl-
ations were performed selectively by fine-tuning of the ex-
perimental conditions.
The first two aminations were SNAr reactions and oc-
curred selectively at the C4 and then at the C2 positions of
3. The chlorine atom at C7 was substituted during (het)-
arylations, (het)aryl aminations and reduction by using
palladium catalysis and microwave irradiation. A one-pot
tris(amination) including a double SNAr reaction and a mi-
crowave-assisted Buchwald reaction completed this unprec-
edented work. With this robust route leading to 3, and re-
gioselective conditions for the chlorine substitution, we
have opened an interesting method that may be used to de-
sign new active drugs, in particular protein kinase inhibi-
tors.
1
M.p. 140–141 °C. H NMR (400 MHz, CDCl3): δ = 7.53–7.62 (m,
3 H, HPh), 8.29 (d, J = 2.2 Hz, 1 H, 8-H), 8.36–8.40 (m, 2 H, HPh),
8.97 (d, J = 2.2 Hz, 1 H, 6-H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 128.5 (2 CH), 132.1 (3 CH), 134.1 (CH), 134.4 (Cq), 135.6
(Cq), 136.7 (Cq), 149.6 (Cq), 151.2 (CH), 158.7 (Cq), 169.6 (Cq)
ppm. IR (ATR Diamond): ν = 3043, 2167, 1584, 1527, 1439, 1268,
˜
1124, 1080, 933, 852 cm–1. HRMS (EI-MS+): calcd. for
C13H835Cl2N3 [M + 1]+ 276.0095; found 276.0098.
7-Chloro-2,4-diphenylpyrido[3,2-d]pyrimidine (5): Compound
(58 mg, 2%) was isolated as a yellow solid as a by-product during
5
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20521
/KAP1
Date: 03-07-12 15:43:41
Pages: 11
G. Guillaumet, S. Routier et al.
1027, 846 cm–1. HRMS (EI-MS+): calcd. for C20H1535ClN3O [M +
FULL PAPER
the synthesis of 4. M.p. 120–122 °C. 1H NMR (400 MHz, CDCl3):
δ = 7.54–7.63 (m, 6 H, HPh), 8.38 (d, J = 2.2 Hz, 1 H, 8-H), 8.44– 1]+ 348.0904; found 348.0908.
8.48 (m, 2 H, HPh), 8.68–8.72 (m, 2 H, HPh), 8.90 (d, J = 2.2 Hz,
2-(3-Methoxyphenyl)-7-(4-methoxyphenyl)-4-phenylpyrido[3,2-d]-
1 H, 6-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 128.4 (2 CH),
128.8 (2 CH), 129.1 (2 CH), 131.1 (CH), 131.4 (CH), 131.8 (2 CH),
135.2 (CH), 135.5 (Cq), 136.0 (Cq), 136.2 (Cq), 137.4 (Cq), 148.5
(Cq), 150.2 (CH), 161.8 (Cq), 166.6 (Cq) ppm. IR (ATR Dia-
pyrimidine (9): Under argon, in a sealed vial, compound 7 (70 mg,
0.201 mmol) was dissolved in a mixture of toluene/EtOH (1.4/
0.7 mL), and (4-methoxyphenyl)boronic acid (37 mg, 0.241 mmol,
1.2 equiv.), K2CO3 (56 mg, 0.402 mmol, 2 equiv.) and Pd(PPh3)4
(12 mg, 10 μmol, 0.05 equiv.) were successively added. The reaction
mixture was heated under microwave irradiation at 150 °C for
5 min. After cooling, water (15 mL) was added, and extractions
were performed with CH2Cl2 (2ϫ 15 mL). The combined organic
layers were dried with MgSO4 and filtered, and the volatiles were
removed under reduced pressure. The crude residue was purified by
flash chromatography by using silica gel (petroleum ether/CH2Cl2,
80:20) to afford 9 (79 mg, 94%) as a yellow solid. M.p. 147–148 °C.
1H NMR (250 MHz, CDCl3): δ = 3.75 (s, 3 H, OCH3), 3.84 (s, 3
H, OCH3), 6.92–6.98 (m, 3 H, HAr), 7.34 (t, J = 8.0 Hz, 1 H, HAr),
7.46–7.50 (m, 3 H, HPh), 7.59 (d, J = 8.8 Hz, 2 H, HAr), 8.16–8.18
(m, 1 H, HAr), 8.21 (d, J = 7.8 Hz, 1 H, HAr), 8.32 (d, J = 2.3 Hz,
1 H, 8-H), 8.38–8.42 (m, 2 H, HPh), 9.11 (d, J = 2.3 Hz, 1 H, 6-H)
ppm. 13C NMR (62.5 MHz, CDCl3): δ = 55.5 (CH3), 55.5 (CH3),
mond): ν = 3043, 2167, 1584, 1527, 1439, 1268, 1124, 1080, 933,
˜
852 cm–1. HRMS (EI-MS+): calcd. for C19H1335ClN3 [M + 1]+
318.0798; found 318.0799.
7-Chloro-2-(2-methoxyphenyl)-4-phenylpyrido[3,2-d]pyrimidine (6):
A
solution of 2,7-dichloro-4-phenylpyrido[3,2-d]pyrimidine (4)
(100 mg, 362 μmol) in toluene (6 mL) and EtOH (3 mL) was de-
gassed and placed under argon, and (2-methoxyphenyl)boronic
acid (58 mg, 380 μmol, 1.05 equiv.), Na2CO3 (77 mg, 724 μmol,
2 equiv.), and Pd(PPh3)4 (21 mg, 18 μmol, 0.05 equiv.) were success-
ively added. The reaction mixture was heated at 100 °C with vigor-
ous stirring. After 5 h, the solvent was removed under reduced
pressure. The crude material was purified by flash chromatography
(EtOAc/petroleum ether, 5:95) to afford compound 6 (84%) as a
1
yellow solid. M.p. 116–117 °C. H NMR (250 MHz, CDCl3): δ =
3.93 (s, 3 H, OCH3), 7.07–7.15 (m, 2 H, HAr), 7.44–7.51 (m, 1 H, 113.7 (CH), 114.9 (2 CH), 117.1 (CH), 121.5 (CH), 128.2 (2 CH),
HAr), 7.54–7.58 (m, 3 H, HPh), 7.93 (dd, J = 1.7, J = 7.5 Hz, 1 H, 128.6 (Cq), 128.8 (2 CH), 129.7 (CH), 130.7 (CH), 131.8 (2 CH),
Ar), 8.36–8.40 (m, 2 H, HPh), 8.43 (d, J = 2.4 Hz, 1 H, 8-H), 8.95 132.2 (CH), 136.4 (Cq), 136.6 (Cq), 139.3 (Cq), 139.8 (Cq), 148.3
(d, J = 2.4 Hz, 1 H, 6-H) ppm. 13C NMR (62.5 MHz, CDCl3): δ (Cq), 150.2 (CH), 160.0 (Cq), 160.7 (Cq), 160.9 (Cq), 165.9 (Cq)
H
= 56.2 (CH3), 112.4 (CH), 120.9 (CH), 128.3 (2 CH), 128.4 (Cq),
131.0 (CH), 131.5 (CH), 131.8 (2 CH), 132.2 (CH), 135.2 (CH),
135.4 (Cq), 135.5 (Cq), 136.1 (Cq), 148.1 (Cq), 150.5 (CH), 158.2
ppm. IR (ATR Diamond): ν = 3002, 2828, 1604, 1543, 1451, 1333,
˜
1230, 1169, 1021, 836 cm–1. HRMS (EI-MS+): calcd. for
C27H22N3O2 [M + 1]+ 420.1712; found 420.1717.
(Cq), 163.5 (Cq), 166.7 (Cq) ppm. IR (ATR Diamond): ν = 3068,
˜
7-(4-Acetylphenyl)-2-(3-methoxyphenyl)-4-phenylpyrido[3,2-d]pyr-
imidine (10): Compound 10 was obtained as described for 9 by
using (4-acetylphenyl)boronic acid in 5 min. Flash chromatography
by using silica gel (petroleum ether/EtOAc, 85:15) afforded com-
pound 10 (97 %) as a yellow solid. M.p. 133–134 °C. 1H NMR
(250 MHz, CDCl3): δ = 3.75 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3),
6.92–6.98 (m, 3 H, HAr), 7.34 (t, J = 8.0 Hz, 1 H, HAr), 7.46–7.50
(m, 3 H, HPh), 7.59 (d, J = 8.8 Hz, 2 H, HAr), 8.16–8.18 (m, 1 H,
2267, 1584, 1538, 1445, 1379, 1292, 1113, 1077, 887 cm–1. HRMS
(EI-MS+): calcd. for C20H1535ClN3O [M + 1]+ 348.0904; found
348.0900.
7-Chloro-2-(3-methoxyphenyl)-4-phenylpyrido[3,2-d]pyrimidine (7):
Compound 7 was obtained as described for 6 by using (3-meth-
oxyphenyl)boronic acid in 4 h. Flash chromatography by using sil-
ica gel (petroleum ether/EtOAc, 98:2) afforded compound 7 (81%)
1
as a yellow solid. M.p. 112–113 °C. H NMR (250 MHz, CDCl3): HAr), 8.21 (d, J = 7.8 Hz, 1 H, HAr), 8.32 (d, J = 2.3 Hz, 1 H, 8-
δ = 3.92 (s, 3 H, OCH3), 7.06 (ddd, J = 0.8, J = 2.6, J = 8.2 Hz, 1
H, HAr), 7.42 (t, J = 8.0 Hz, 1 H, HAr), 7.55–7.58 (m, 3 H, HPh), 13C NMR (62.5 MHz, CDCl3): δ = 26.7 (CH3), 55.4 (CH3), 113.7
8.20 (dd, J = 1.6, J = 2.6 Hz, 1 H, HAr), 8.25 (d, J = 8.0 Hz, 1 H, (CH), 117.1 (CH), 121.4 (CH), 127.7 (2 CH), 128.2 (2 CH), 129.3
H), 8.38–8.42 (m, 2 H, HPh), 9.11 (d, J = 2.3 Hz, 1 H, 6-H) ppm.
HAr), 8.32 (d, J = 2.4 Hz, 1 H, 8-H), 8.40–8.44 (m, 2 H, HPh), 8.85 (2 CH), 129.6 (CH), 130.9 (CH), 131.8 (2 CH), 133.9 (CH), 136.3
(d, J = 2.4 Hz, 1 H, 6-H) ppm. 13C NMR (62.5 MHz, CDCl3): δ (Cq), 137.0 (Cq), 137.2 (Cq), 138.7 (Cq), 138.9 (Cq), 140.5 (Cq),
= 55.5 (CH3), 113.8 (CH), 117.5 (CH), 121.6 (CH), 128.3 (2 CH),
147.8 (Cq), 149.6 (CH), 159.9 (Cq), 160.9 (Cq), 165.8 (Cq), 197.3
129.7 (CH), 131.1 (CH), 131.8 (2 CH), 135.1 (CH), 135.4 (Cq), (Cq) ppm. IR (ATR Diamond): ν = 2935, 1681, 1604, 1536, 1454,
˜
135.9 (Cq), 136.1 (Cq), 138.7 (Cq), 148.3 (Cq), 150.1 (CH), 160.0
1340, 1265, 1047, 908, 830 cm–1. HRMS (EI-MS+): calcd. for
C28H22N3O2 [M + 1]+ 432.1712; found 432.1709.
(Cq), 161.5 (Cq), 166.4 (Cq) ppm. IR (ATR Diamond): ν = 3053,
˜
2828, 1589, 1536, 1456, 1334, 1248, 1179, 1047, 836 cm–1. HRMS
(EI-MS+): calcd. for C20H1535ClN3O [M + 1]+ 348.0904; found
348.0905.
2-(3-Methoxyphenyl)-7-(4-methylsulfonyl)-4-phenylpyrido[3,2-d]pyr-
imidine (11): Compound 11 was obtained as described for 9 by
using [4-(methylsulfonyl)phenyl]boronic acid in 10 min. Flash
chromatography by using silica gel (petroleum ether/EtOAc, 80:20)
afforded compound 11 (97%) as a yellow solid. M.p. 215–216 °C.
1H NMR (250 MHz, CDCl3): δ = 3.33 (s, 3 H, CH3), 3.87 (s, 3 H,
7-Chloro-2-(4-methoxyphenyl)-4-phenylpyrido[3,2-d]pyrimidine (8):
Compound 8 was obtained as described for 6 by using (4-meth-
oxyphenyl)boronic acid in 5 h. Flash chromatography by using sil-
ica gel (petroleum ether/EtOAc, 95:5) afforded compound 8 (83%) OCH3), 7.14 (dd, J = 2.5, J = 8.1 Hz, 1 H, HAr), 7.49 (t, J = 8.0 Hz,
1
as a yellow solid. M.p. 193–194 °C. H NMR (400 MHz, CDCl3): 1 H, HAr), 7.60–7.64 (m, 3 H, HPh), 8.09–8.13 (m, 3 H, HAr), 8.21
δ = 3.90 (s, 3 H, OCH3), 7.03 (d, J = 9.0 Hz, 2 H, HAr), 7.57–7.59
(m, 3 H, HPh), 8.32 (d, J = 2.4 Hz, 1 H, 8-H), 8.41–8.44 (m, 2 H,
HPh), 8.64 (d, J = 9.0 Hz, 2 H, HAr), 8.84 (d, J = 2.4 Hz, 1 H, 6-
(d, J = 7.8 Hz, 1 H, HAr), 8.28 (d, J = 8.4 Hz, 2 H, HAr), 8.43–
8.47 (m, 2 H, HPh), 8.78 (d, J = 2.2 Hz, 1 H, 8-H), 9.46 (d, J =
2.2 Hz, 1 H, 6-H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 43.4
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.6 (CH3), 114.1 (2 (CH3), 55.2 (CH3), 113.3 (CH), 116.9 (CH), 120.8 (CH), 127.8 (2
CH), 128.3 (2 CH), 130.1 (Cq), 130.9 (2 CH), 131.0 (CH), 131.8 (2
CH), 134.9 (CH), 135.4 (Cq), 135.8 (Cq), 136.3 (Cq), 148.6 (Cq),
149.6 (CH), 161.6 (Cq), 162.5 (Cq), 166.5 (Cq) ppm. IR (ATR
CH), 128.1 (2 CH), 128.8 (2 CH), 129.9 (CH), 130.8 (CH), 131.6
(2 CH), 134.0 (CH), 135.9 (Cq), 136.6 (Cq), 138.0 (Cq), 138.4 (Cq),
140.4 (Cq), 141.3 (Cq), 147.4 (Cq), 150.6 (CH), 159.7 (Cq), 159.8
Diamond): ν = 3053, 2167, 1604, 1538, 1443, 1317, 1249, 1164,
(Cq), 165.5 (Cq) ppm. IR (ATR Diamond): ν = 2920, 1594, 1535,
˜
˜
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20521
/KAP1
Date: 03-07-12 15:43:41
Pages: 11
Regiocontroled Reactions of 2,4,7-Trichloropyrido[3,2-d]pyrimidine
1460, 1301, 1225, 1148, 1034, 956, 852 cm–1. HRMS (EI-MS+):
calcd. for C27H22N3O3S [M + 1]+ 468.1382; found 468.1384.
CDCl3): δ = 3.96 (s, 3 H, OCH3), 7.09 (ddd, J = 0.9, J = 2.6, J =
8.2 Hz, 1 H, HAr), 7.43–7.51 (m, 3 H, HAr and HHet), 7.61–7.64
(m, 3 H, HPh), 7.70 (s, 1 H, HHet), 7.95–7.99 (m, 1 H, HHet), 8.04–
8.08 (m, 1 H, HHet), 8.30–8.32 (m, 1 H, HAr), 8.36 (d, J = 7.8 Hz,
1 H, HAr), 8.54–8.58 (m, 3 H, HPh and 8-H), 9.24 (d, J = 2.2 Hz,
1 H, 6-H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 55.5 (CH3),
113.7 (CH), 117.2 (CH), 121.6 (CH), 122.4 (CH), 123.3 (CH), 125.2
(2 CH), 126.8 (CH), 128.3 (2 CH), 129.7 (CH), 130.9 (CH), 131.9
(2 CH), 133.2 (Cq), 134.8 (CH), 135.7 (Cq), 136.5 (Cq), 136.9 (Cq),
137.0 (Cq), 139.2 (Cq), 140.9 (Cq), 148.2 (Cq), 151.2 (CH), 160.0
2-(3-Methoxyphenyl)-7-(2-naphthyl)-4-phenylpyrido[3,2-d]pyrimid-
ine (12): Compound 12 was obtained as described for 9 by using
2-naphthylboronic acid in 15 min. Flash chromatography by using
silica gel (petroleum ether/CH2Cl2, 80:20) afforded compound 12
(98%) as a yellow solid. M.p. 166–167 °C. 1H NMR (250 MHz,
CDCl3): δ = 3.82 (s, 3 H, OCH3), 6.95 (dd, J = 2.6, J = 8.1 Hz, 1
H, HAr), 7.33 (t, J = 8.0 Hz, 1 H, HAr), 7.40–7.43 (m, 2 H, HNaph),
7.47–7.50 (m, 3 H, HPh), 7.68–7.86 (m, 4 H, HNaph), 8.06 (s, 1 H,
(Cq), 161.0 (Cq), 166.2 (Cq) ppm. IR (ATR Diamond): ν = 2920,
˜
HNaph), 8.16–8.17 (m, 1 H, HAr), 8.22 (d, J = 7.8 Hz, 1 H, HAr),
1599, 1538, 1505, 1448, 1334, 1226, 1039, 908, 831 cm–1. HRMS
(EI-MS+): calcd. for C28H20N3OS [M + 1]+ 446.1327; found
446.1329.
8.40–8.45 (m, 3 H, HPh and 8-H), 9.23 (d, J = 2.3 Hz, 1 H, 6-H)
ppm. 13C NMR (62.5 MHz, CDCl3): δ = 55.5 (CH3), 113.7 (CH),
117.2 (CH), 121.6 (CH), 124.8 (CH), 126.9 (CH), 127.1 (CH), 127.2
(CH), 127.8 (CH), 128.2 (2 CH), 128.6 (CH), 129.4 (CH), 129.7
(CH), 130.8 (CH), 131.9 (2 CH), 133.4 (Cq), 133.5 (CH), 133.6
(Cq), 136.6 (Cq), 136.8 (Cq), 139.2 (Cq), 140.1 (Cq), 148.2 (Cq),
150.4 (CH), 160.0 (2Cq), 160.9 (Cq), 166.0 (Cq) ppm. IR (ATR
2-(3-Methoxyphenyl)-4-phenyl-7-(2-thienyl)pyrido[3,2-d]pyrimidine
(16): Compound 16 was obtained as described for 9 by using 2-
thienylboronic acid in 5 min. Flash chromatography by using silica
gel (CH2Cl2/MeOH, 99.5:0.5) afforded compound 16 (67%) as a
1
Diamond): ν = 3063, 2833, 1584, 1532, 1445, 1338, 1276, 1220,
˜
yellow solid. M.p. 140–141 °C. H NMR (250 MHz, CDCl3): δ =
1046, 826 cm–1. HRMS (EI-MS+): calcd. for C30H22N3O [M + 1]+
440.1763; found 440.1766.
3.85 (s, 3 H, OCH3), 6.98 (dd, J = 2.0, J = 8.2 Hz, 1 H, HAr), 7.09
(dd, J = 3.7, J = 5.0 Hz, 1 H, HHet), 7.32–7.39 (m, 2 H, HAr and
H
Het), 7.46–7.52 (m, 4 H, HPh and HHet), 8.15–8.17 (m, 1 H, HAr),
7-(2-Furyl)-2-(3-methoxyphenyl)-4-phenylpyrido[3,2-d]pyrimidine
(13): Compound 13 was obtained as described for 9 by using 2-
furylboronic acid in 10 min. Flash chromatography by using silica
gel (petroleum ether/CH2Cl2, 80:20) afforded compound 13 (97%)
8.21 (d, J = 7.8 Hz, 1 H, HAr), 8.35 (d, J = 2.3 Hz, 1 H, 8-H), 8.37–
8.41 (m, 2 H, HPh), 9.17 (d, J = 2.3 Hz, 1 H, 6-H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 55.6 (CH3), 113.7 (CH), 117.3 (CH), 121.6
(CH), 126.3 (CH), 128.1 (CH), 128.3 (2 CH), 128.9 (CH), 129.7
(CH), 130.8 (CH), 130.9 (CH), 131.8 (2 CH), 133.9 (Cq), 136.5
(Cq), 136.7 (Cq), 139.2 (Cq), 139.3 (Cq), 148.3 (Cq), 148.8 (CH),
1
as a yellow solid. M.p. 131–132 °C. H NMR (250 MHz, CDCl3):
δ = 3.85 (s, 3 H, OCH3), 6.48 (dd, J = 1.8, J = 3.4 Hz, 1 H, HHet),
6.90 (d, J = 3.4 Hz, 1 H, HHet), 6.97 (dd, J = 1.9, J = 8.1 Hz, 1 H,
HAr), 7.34 (t, J = 8.0 Hz, 1 H, HAr), 7.47–7.52 (m, 4 H, HPh and
160.1 (Cq), 161.2 (Cq), 165.9 (Cq) ppm. IR (ATR Diamond): ν =
˜
3073, 2203, 1599, 1537, 1452, 1335, 1274, 1218, 1042, 894 cm–1.
HRMS (EI-MS+): calcd. for C24H18N3OS [M + 1]+ 396.1171;
found 396.1181.
HHet), 8.15–8.17 (m, 1 H, HAr), 8.21 (d, J = 7.8 Hz, 1 H, HAr),
8.35–8.40 (m, 3 H, HPh and 8-H), 9.16 (d, J = 2.2 Hz, 1 H, 6-H)
ppm. 13C NMR (62.5 MHz, CDCl3): δ = 55.6 (CH3), 109.7 (CH),
112.5 (CH), 113.7 (CH), 117.2 (CH), 121.6 (CH), 128.2 (2 CH),
128.9 (CH), 129.7 (CH), 130.1 (Cq), 130.8 (CH), 131.8 (2 CH),
136.4 (Cq), 136.5 (Cq), 139.2 (Cq), 144.7 (CH), 147.4 (CH), 148.3
(Cq), 150.2 (Cq), 160.0 (Cq), 161.1 (Cq), 165.9 (Cq) ppm. IR (ATR
4-(Benzylamino)-2,7-dichloropyrido[3,2-d]pyrimidine (17): A solu-
tion of compound 3 (2.0 g, 8.53 mmol), benzylamine (914 mg,
8.53 mmol, 1 equiv.) and triethylamine (863 mg, 7.76 mmol,
1.05 equiv.) in dry THF (100 mL) was stirred at room temperature
for 4 h. The solvent was evaporated, and water (20 mL) was added.
The organic material was extracted with CH2Cl2 (3ϫ 30 mL), and
the combined organic layers were dried with MgSO4 and filtered,
and the solvents were evaporated under vacuum. Flash chromatog-
raphy by using silica gel (petroleum ether/CH2Cl2, 1:1) afforded
product 17 (2.341 g, 90%) as a white solid. M.p. 169–171 °C. 1H
NMR (250 MHz, CDCl3): δ = 4.85 (d, J = 5.8 Hz, 2 H, CH2),
7.33–7.39 (m, 5 H, HPh), 7.48 (br., 1 H, NH), 8.00 (d, J = 2.1 Hz, 1
H, 8-H), 8.56 (d, J = 2.1 Hz, 1 H, 6-H) ppm. 13C NMR (62.5 MHz,
CDCl3): δ = 45.3 (CH2), 128.1 (CH), 128.2 (2 CH), 128.8 (Cq),
129.1 (2 CH), 133.6 (CH), 136.3 (Cq), 136.9 (Cq), 146.1 (Cq), 147.8
Diamond): ν = 2956, 1599, 1531, 1451, 1340, 1229, 1176, 1034,
˜
897, 825 cm–1. HRMS (EI-MS+): calcd. for C24H18N3O2 [M + 1]+
380.1399; found 380.1416.
2-(3-Methoxyphenyl)-4-phenyl-7-(3-pyridyl)pyrido[3,2-d]pyrimidine
(14). Compound 14 was obtained as described for 9 by using 3-
pyridylboronic acid in 10 min. Flash chromatography by using sil-
ica gel (CH2Cl2/MeOH, 99.5:0.5) afforded compound 14 (88%) as
a yellow solid. M.p. 134–135 °C. 1H NMR (250 MHz, CDCl3): δ =
3.92 (s, 3 H, OCH3), 7.05 (ddd, J = 0.9, J = 2.6, J = 8.2 Hz, 1 H,
HAr), 7.39–7.48 (m, 2 H, HAr and HPyr), 7.57–7.60 (m, 3 H, HPh),
8.02 (d, J = 7.9 Hz, 1 H, HPyr), 8.22–8.24 (m, 1 H, HAr), 8.28 (d,
J = 7.8 Hz, 1 H, HAr), 8.47–8.52 (m, 3 H, HPh and 8-H), 8.75 (br.,
1 H, HPyr), 9.04 (br., 1 H, HPyr), 9.18 (d, J = 2.3 Hz, 1 H, 6-H)
ppm. 13C NMR (62.5 MHz, CDCl3): δ = 55.5 (CH3), 113.7 (CH),
117.3 (CH), 121.5 (CH), 128.3 (2 CH), 129.7 (CH), 130.9 (CH),
131.8 (2 CH), 134.0 (CH), 134.8 (CH), 136.3 (Cq), 137.1 (Cq),
137.2 (Cq), 138.9 (Cq), 147.9 (Cq), 148.5 (CH), 149.5 (2 CH), 150.3
(CH), 160.0 (2Cq), 161.1 (Cq), 166.2 (Cq) ppm. IR (ATR Dia-
(CH), 159.7 (Cq), 160.4 (Cq) ppm. IR (ATR Diamond): ν = 3036,
˜
2156, 1601, 1572, 1524, 1438, 1297, 1130, 1045, 880 cm–1. HRMS
(EI-MS+): calcd. for C14H1135Cl2N4 [M + 1]+ 305.0361; found
305.0365.
4-(Benzylamino)-7-chloro-2-[(2-hydroxyethyl)amino]pyrido[3,2-d]-
pyrimidine (18): A solution of compound 17 (1.5 g, 4.91 mmol),
ethanolamine (360 mg, 5.90 mmol, 1.2 equiv.) and Et3N (994 mg,
9.83 mmol, 2 equiv.) in dry 1,4-dioxane (100 mL) was heated at re-
flux for 12 h. After cooling, the volatiles were evaporated, and
water (20 mL) was added. The organic material was extracted with
CH2Cl2 (3ϫ 30 mL), and the combined organic layers were dried
with MgSO4 and filtered, and the solvents were evaporated under
vacuum. Flash chromatography by using silica gel (MeOH/CH2Cl2,
5:95) afforded product 18 (1.489 g, 92%) as a yellow solid. M.p.
mond): ν = 3048, 2162, 1589, 1533, 1453, 1394, 1341, 1230, 1026,
˜
841 cm–1. HRMS (EI-MS+): calcd. for C25H19N4O [M + 1]+
391.1559; found 391.1565.
7-(3-Benzothienyl)-2-(3-methoxyphenyl)-4-phenylpyrido[3,2-d]pyrim-
idine (15): Compound 15 was obtained as described for 9 by using
3-benzothienylboronic acid in 5 min. Flash chromatography by
using silica gel (CH2Cl2/MeOH, 99.5:0.5) afforded compound 15
(96%) as a yellow solid. M.p. 112–113 °C. 1H NMR (250 MHz,
1
106–107 °C. H NMR (250 MHz, CDCl3): δ = 3.57–3.63 (m, 2 H,
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G. Guillaumet, S. Routier et al.
FULL PAPER
CH2), 3.81–3.84 (m, 2 H, CH2), 4.58 (br., 1 H, OH), 4.71 (d, J =
5.9 Hz, 1 H, CH2Ph), 5.74 (br., 1 H, NH), 7.26–7.35 (m, 6 H, HPh NMR (250 MHz, [D6]DMSO): δ = 3.57–3.61 (m, 2 H, CH2), 3.80–
64 % yield by using general procedure B. M.p. 126–127 °C. 1H
and NH), 7.63 (d, J = 2.0 Hz, 1 H, 8-H), 8.16 (d, J = 2.0 Hz, 1 H,
3.83 (m, 5 H, CH2 et OCH3), 4.73 (d, J = 5.9 Hz, 2 H, CH2Ph),
6-H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 44.6 (CH2), 44.9 5.48 (br., 1 H, OH), 5.84 (br., 1 H, NH), 6.88–6.94 (m, 3 H, HAr
(CH2), 63.7 (CH2), 127.3 (Cq), 127.7 (2 CH), 127.8 (2 CH), 128.8 and 8-H), 7.06 (br., 1 H, NH), 7.14 (d, J = 8.9 Hz, 2 H, HAr), 7.29–
(CH), 130.6 (CH), 135.5 (Cq), 137.9 (Cq), 142.3 (CH), 146.5 (Cq),
7.37 (m, 5 H, HPh), 7.93 (d, J = 2.5 Hz, 1 H, 6-H) ppm. 13C NMR
(100 MHz, 80 °C, [D6]DMSO): δ = 43.0 (CH2), 43.5 (CH2), 55.1
(CH3), 60.4 (CH2), 107.8 (CH), 114.6 (2 CH), 120.6 (Cq), 122.4 (2
CH), 126.3 (CH), 127.1 (2 CH), 127.8 (2 CH), 133.7 (Cq), 134.6
(CH), 139.5 (Cq), 145.4 (Cq), 146.8 (Cq), 155.2 (Cq), 158.8 (Cq),
159.6 (Cq), 160.9 (Cq) ppm. IR (ATR Diamond): ν = 3406, 2843,
˜
1609, 1568, 1515, 1445, 1312, 1159, 1067, 893 cm–1. HRMS (EI-
MS+): calcd. for C16H1735ClN5O [M + 1]+ 330.1122; found
330.1107.
159.1 (Cq) ppm. IR (ATR Diamond): ν = 3247, 2926, 1564, 1503,
˜
4-(Benzylamino)-2-[(2-hydroxyethyl)amino]pyrido[3,2-d]pyrimidine
(19): Compound 18 (100 mg, 0.303 mmol) was dissolved in dry
THF (2 mL), and Et3N (92 mg, 0.91 mmol, 3 equiv.) and formic
acid (28 mg, 0.606 mmol, 2 equiv.) were successively added. After
5 min of stirring at room temperature, Pd(OAc)2 (7 mg, 30.3 μmol,
0.1 equiv.) and Xantphos (35 mg, 60.6 μmol, 0.2 equiv.) were
added, and the reaction mixture was heated at 150 °C under micro-
wave irradiation for 15 min. After cooling, the volatiles were evapo-
rated, and water (20 mL) was added. The organic material was ex-
tracted with CH2Cl2 (2ϫ 10 mL), and the combined organic layers
were dried with MgSO4 and filtered, and the solvents were evapo-
rated under vacuum. Flash chromatography by using silica gel
(EtOAc/MeOH, 95:5) afforded product 19 (51 mg, 57%) as a white
1454, 1414, 1326, 1237, 1175, 1028, 816 cm–1. HRMS (EI-MS+):
calcd. for C23H25N6O2 [M + 1]+ 417.2039; found 417.2033.
4-(Benzylamino)-2-[(2-hydroxyethyl)amino]-7-[(3-methoxyphenyl)-
amino]pyrido[3,2-d]pyrimidine (21): Compound 21 was obtained af-
ter flash chromatography by using silica gel (EtOAc/MeOH, 95:5)
as a yellow solid in 76% yield by using general procedure A and in
75 % yield by using general procedure B. M.p. 110–111 °C. 1H
NMR (250 MHz, [D6]DMSO): δ = 3.33–3.37 (m, 2 H, CH2), 3.47–
3.52 (m, 2 H, CH2), 3.75 (s, 3 H, OCH3), 4.65 (d, J = 6.3 Hz, 2 H,
CH2Ph), 6.50 (t, J = 6.3 Hz, 1 H, NH), 6.58 (dd, J = 2.0, J =
8.1 Hz, 1 H, HAr), 6.71–6.73 (m, 1 H, HAr), 6.80 (d, J = 8.1 Hz, 1
H, HAr), 7.06 (d, J = 2.0 Hz, 1 H, HAr), 7.18–7.39 (m, 6 H, HPh
and 8-H), 8.09 (d, J = 2.4 Hz, 1 H, 6-H), 8.27 (br., 1 H, NH), 8.75
(br., 1 H, NH) ppm. 13C NMR (100 MHz, 80 °C, [D6]DMSO): δ
= 42.9 (CH2), 43.5 (CH2), 54.7 (CH3), 60.4 (CH2), 104.8 (CH),
107.2 (CH), 110.9 (CH), 111.1 (CH), 121.6 (Cq), 126.2 (CH), 127.1
(2 CH), 127.7 (2 CH), 129.7 (CH), 135.1 (CH), 139.5 (Cq), 142.6
(Cq), 143.5 (Cq), 147.4 (Cq), 158.8 (Cq), 159.6 (Cq), 160.1 (Cq)
1
solid. M.p. 87–88 °C. H NMR (250 MHz, CDCl3): δ = 3.59–3.64
(m, 2 H, CH2), 3.82–3.86 (m, 2 H, CH2), 4.74 (d, J = 5.9 Hz, 1 H,
CH2Ph), 5.79 (br., 1 H, NH), 7.26–7.36 (m, 6 H, HPh and NH),
7.42 (dd, J = 4.2, J = 8.5 Hz, 1 H, H7), 7.68 (dd, J = 1.4, J =
8.5 Hz, 1 H, 8-H), 8.29 (dd, J = 1.4, J = 4.2 Hz, 1 H, 6-H) ppm.
13C NMR (62.5 MHz, CDCl3): δ = 44.4 (CH2), 44.8 (CH2), 63.3
(CH2), 127.4 (CH), 127.6 (CH), 127.7 (2 CH), 128.6 (2 CH), 129.0
(Cq), 132.0 (CH), 138.1 (Cq), 143.1 (CH), 145.8 (Cq), 159.7 (Cq),
ppm. IR (ATR Diamond): ν = 3252, 2930, 2290, 1568, 1490, 1320,
˜
1230, 1152, 1048, 846 cm–1. HRMS (EI-MS+): calcd. for
C23H25N6O2 [M + 1]+ 417.2039; found 417.2042.
160.1 (Cq) ppm. IR (ATR Diamond): ν = 3247, 2930, 1604, 1563,
˜
1507, 1415, 1323, 1118, 1056, 821 cm–1. HRMS (EI-MS+): calcd.
for C16H18N5O [M + 1]+ 296.1511; found 296.1504.
4-(Benzylamino)-7-[(3,4-dimethoxyphenyl)amino]-2-[(2-hydroxyeth-
yl)amino]pyrido[3,2-d]pyrimidine (22): Compound 22 was obtained
after flash chromatography by using silica gel (EtOAc/MeOH,
99.5:0.5) as a yellow solid in 71 % yield by using general pro-
cedure A and in 68% yield by using general procedure B. M.p. 149–
150 °C. 1H NMR (250 MHz, CDCl3): δ = 3.56 (br., 2 H, CH2),
3.77–3.82 (m, 5 H, CH2 and OCH3), 3.85 (s, 3 H, OCH3), 4.69 (d,
J = 5.9 Hz, 2 H, CH2Ph), 5.58 (br., 1 H, NH), 6.30 (br., 1 H, NH),
6.69–6.81 (m, 3 H, HPh and HAr), 6.97 (d, J = 2.4 Hz, 1 H, 8-H),
7.06 (t, J = 5.9 Hz, 1 H, NH), 7.29–7.34 (m, 5 H, HPh and HAr),
7.92 (d, J = 2.4 Hz, 1 H, 6-H) ppm. 13C NMR (100 MHz, 80 °C,
[D6]DMSO): δ = 44.5 (CH2), 45.3 (CH2), 56.1 (CH3), 56.3 (CH3),
64.8 (CH2), 107.1 (CH), 110.3 (CH), 112.1 (CH), 114.6 (CH), 121.9
(Cq), 127.5 (CH), 127.8 (2 CH), 128.8 (2 CH), 133.3 (Cq), 135.2
(CH), 138.5 (Cq), 145.7 (Cq), 146.3 (Cq), 146.9 (Cq), 149.8 (Cq),
General Procedure A Leading to the Tris(aminated) Derivatives 20–
27 from 18: In a sealed vial, compound 18 (0.2 mmol scale,
1.0 equiv.) and the required amine (2.0 equiv.) were dissolved in
anhydrous dioxane (2 mL). K2CO3 (2.0 equiv.), Pd(OAc)2
(0.1 equiv.) and Xantphos (0.2 equiv.) were successively added, and
the reaction mixture was heated under microwave irradiation at
140 °C. After cooling, the solvent was evaporated, water (10 mL)
was added, and extractions were performed with CH2Cl2 (2 ϫ
20 mL). The combined organic layers were dried with MgSO4, fil-
tered, and concentrated under reduced pressure. The crude residue
was purified by flash chromatography by using silica gel to afford
the 2,4,7-tris(aminated) derivatives 20–27.
General Procedure B Leading to the Tris(aminated) Derivatives 20–
27 from 3: Under argon, in a sealed vial, compound 3 (0.3 mmol
scale, 1.0 equiv.), triethylamine (3.0 equiv.) and benzylamine
(1.0 equiv.) were dissolved in dry dioxane (2 mL). After 5 min of
stirring, ethanolamine (5.0 equiv.) was introduced prior to heating
the vial at 140 °C under microwave irradiation for 1 h. After cool-
ing, a Buchwald pre-mix containing the required amine (1.2 equiv.),
K2CO3 (2.0 equiv.), Pd(OAc)2 (0.1 equiv.) and Xantphos
(0.2 equiv.) was added. The resulting suspension was placed under
microwave irradiation at 140 °C for 1 h. After cooling, the same
purification as described in general procedure A led to the 2,4,7-
tris(aminated) derivatives 20–27.
159.5 (Cq), 160.9 (Cq) ppm. IR (ATR Diamond): ν = 3837, 1585,
˜
1504, 1504, 1449, 1235, 1172, 1058, 800, 733 cm–1. HRMS (EI-
MS+): calcd. for C24H27N6O3 [M + 1]+ 447.2145; found 447.2146.
7-[(4-Acetylphenyl)amino]-4-(benzylamino)-2-[(2-hydroxyethyl)amino]-
pyrido[3,2-d]pyrimidine (23): Compound 23 was obtained after flash
chromatography by using silica gel (CH2Cl2/MeOH, 99.5:0.5) as a
yellow solid in 78% yield by using general procedure A and in 70%
yield by using general procedure B. M.p. 125–126 °C. 1H NMR
(250 MHz, [D6]DMSO): δ = 2.50 (s, 3 H, CH3), 3.33–3.39 (m, 2 H,
CH2), 3.48–3.50 (m, 2 H, CH2), 4.66 (d, J = 6.3 Hz, 2 H, CH2Ph),
4.93 (br., 1 H, OH), 6.59 (t, J = 6.3 Hz, 1 H, NH), 7.19–7.40 (m,
4-(Benzylamino)-2-[(2-hydroxyethyl)amino]-7-[(4-methoxyphenyl)- 8 H, HPh, HAr and 8-H), 7.92 (d, J = 8.6 Hz, 1 H, HAr), 8.17 (d, J
amino]pyrido[3,2-d]pyrimidine (20): Compound 20 was obtained af-
ter flash chromatography by using silica gel (CH2Cl2/MeOH, 95:5)
as a yellow solid in 72% yield by using general procedure A and in
= 2.4 Hz, 1 H, 6-H), 8.36 (br., 1 H, NH), 9.26 (br., 1 H, NH) ppm.
13C NMR (100 MHz, 80 °C, [D6]DMSO): δ = 25.6 (CH3), 43.1
(CH2), 43.5 (CH2), 60.2 (CH2), 116.0 (CH), 126.3 (CH), 127.2
8
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Regiocontroled Reactions of 2,4,7-Trichloropyrido[3,2-d]pyrimidine
(CH), 127.8 (CH), 129.6 (Cq), 129.7 (CH), 136.1 (CH), 139.2 (Cq),
69% yield by using general procedure B. M.p. 203–204 °C. 1H
141.9 (Cq), 145.9 (Cq), 146.2 (Cq), 158.7 (2Cq), 158.9 (Cq), 195.3 NMR (400 MHz, [D6]DMSO): δ = 3.35–3.40 (m, 2 H, CH2), 3.51
(Cq) ppm. IR (ATR Diamond): ν = 1645, 1570, 1511, 1467, 1342,
(br., 2 H, CH2), 4.67 (d, J = 6.3 Hz, 2 H, CH2Ph), 6.67 (br., 1 H,
NH), 7.23 (t, J = 7.2 Hz, 1 H, HAr), 7.29–7.33 (m, 3 H, HPh), 7.38–
7.40 (m, 2 H, HPh), 7.45 (dd, J = 4.2, J = 8.3 Hz, 1 H, HQuin), 7.62
(dd, J = 2.3, J = 9.0 Hz, 1 H, HQuin), 7.70 (d, J = 2.2 Hz, 1 H, 8-
H), 7.98 (d, J = 9.0 Hz, 1 H, HQuin), 8.24 (d, J = 2.2 Hz, 1 H, 6-
H), 8.27 (d, J = 8.3 Hz, 1 H, HQuin), 8.31 (br., 1 H, NH), 8.72 (dd,
J = 1.4, J = 4.2 Hz, 1 H, HQuin), 9.19 (br., 1 H, NH) ppm. 13C
NMR (100 MHz, 80 °C, [D6]DMSO): δ = 43.0 (CH2), 43.5 (CH2),
60.3 (CH2), 111.2 (CH), 111.8 (CH), 121.2 (CH), 121.9 (Cq), 123.6
(CH), 126.3 (CH), 127.1 (2 CH), 127.8 (2 CH), 128.7 (Cq), 129.9
(CH), 134.1 (CH), 135.5 (CH), 139.3 (Cq), 139.5 (Cq), 143.1 (Cq),
144.0 (Cq), 146.6 (Cq), 147.7 (CH), 158.8 (Cq), 159.1 (Cq) ppm.
˜
1287, 1180, 1062, 829, 726 cm–1. HRMS (EI-MS+): calcd. for
C24H25N6O2 [M + 1]+ 429.2039; found 429.2047.
4-(Benzylamino)-2-[(2-hydroxyethyl)amino]-7-(2-pyrimidinylamino)-
pyrido[3,2-d]pyrimidine (24): Compound 24 was obtained after flash
chromatography by using silica gel (EtOAc/MeOH, 90:10) as a yel-
low solid in 73% yield by using general procedure A and in 71%
yield by using general procedure B. M.p. 141–142 °C. 1H NMR
(250 MHz, [D6]DMSO): δ = 3.62–3.63 (m, 2 H, CH2), 3.84–3.88
(m, 2 H, CH2), 4.54 (br., 1 H, OH), 4.70 (d, J = 5.9 Hz, 2 H,
CH2Ph), 5.86 (br., 1 H, NH), 6.75 (t, J = 4.8 Hz, 1 H, HHet), 7.23
(br., 1 H, NH), 7.27–7.34 (m, 5 H, HPh), 8.21 (br., 1 H, NH), 8.31
(d, J = 2.3 Hz, 1 H, 8-H), 8.34 (d, J = 2.3 Hz, 1 H, 6-H), 8.42 (d,
J = 4.8 Hz, 2 H, HHet) ppm. 13C NMR (100 MHz, 80 °C, [D6]-
DMSO): δ = 43.0 (CH2), 43.5 (CH2), 60.4 (CH2), 113.1 (CH), 116.3
(CH), 122.8 (Cq), 126.3 (CH), 127.1 (2 CH), 127.8 (2 CH), 136.1
(CH), 139.4 (Cq), 140.0 (Cq), 146.6 (Cq), 157.6 (2 CH), 158.9 (Cq),
IR (ATR Diamond): ν = 3427, 2915, 2172, 1614, 1565, 1503, 1382,
˜
1243, 1026, 846 cm–1. HRMS (EI-MS+): calcd. for C25H24N7O [M
+ 1]+ 438.2042; found 438.2047.
X-ray Crystallography. Crystallographic details are available in the
Supporting Information. CCDC-720326 (for 4), -720327 (for 8)
and -720333 (for 17) contain the supplementary crystallographic
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.
159.4 (Cq), 159.5 (Cq) ppm. IR (ATR Diamond): ν = 3247, 2935,
˜
2290, 1566, 1517, 1407, 1343, 1200, 1051, 882 cm–1. HRMS (EI-
MS+): calcd. for C20H21N8O [M + 1]+ 389.1838; found 389.1841.
4-(Benzylamino)-2-[(2-hydroxyethyl)amino]-7-(1,3,5-triazinylamino)-
pyrido[3,2-d]pyrimidine (25): Compound 25 was obtained after flash
chromatography by using silica gel (EtOAc/MeOH/Et3N, 94:5:1) as
a yellow solid in 81% yield by using general procedure A and in
67 % yield by using general procedure B. M.p. 202–203 °C. 1H
NMR (250 MHz, [D6]DMSO): δ = 3.37–3.41 (m, 2 H, CH2), 3.50–
3.52 (m, 2 H, CH2), 4.68 (d, J = 5.9 Hz, 2 H, CH2Ph), 6.71 (br., 1
H, NH), 7.21–7.40 (m, 5 H, HPh), 8.22 (br., 1 H, 8-H), 8.45 (br., 1
H, NH), 8.56 (d, J = 2.3 Hz, 1 H, 6-H), 8.87 (s, 2 H, HHet), 10.70
(br., 1 H, NH) ppm. 13C NMR (100 MHz, 80 °C, [D6]DMSO): δ
= 43.0 (CH2), 43.5 (CH2), 60.2 (CH2), 119.5 (CH), 124.1 (Cq),
126.2 (CH), 127.1 (2 CH), 127.7 (2 CH), 136.3 (CH), 138.1 (Cq),
139.2 (Cq), 146.6 (Cq), 158.8 (Cq), 159.6 (Cq), 163.0 (Cq), 165.8
Supporting Information (see footnote on the first page of this arti-
cle): Crystallographic details, characterization data and copies of
1H and 13C NMR spectra for all new compounds.
Acknowledgments
This work was supported by grants from the Ligue Nationale con-
tre le Cancer (Comités du Nord, du Loiret et du Grand Ouest) and
the Cancéropôle Grand Ouest (strand “Valorisation des produits
de la mer”). We thank the Hubert Curien Volubilis program for
financial support.
(2 CH) ppm. IR (ATR Diamond): ν = 3416, 2904, 2280, 1619,
˜
1573, 1430, 1307, 1205, 1067, 811 cm–1. HRMS (EI-MS+): calcd.
for C19H20N9O [M + 1]+ 390.1791; found 390.1807.
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4-(Benzylamino)-2-[(2-hydroxyethyl)amino]-7-(3-quinolinylamino)-
pyrido[3,2-d]pyrimidine (26): Compound 26 was obtained after flash
chromatography by using silica gel (EtOAc/MeOH, 99.5:0.5) as a
yellow solid in 64% yield by using general procedure A and in 72%
yield by using general procedure B. M.p. 154–155 °C. 1H NMR
(250 MHz, [D6]DMSO): δ = 3.60–3.64 (m, 2 H, CH2), 3.83–3.85
(m, 2 H, CH2), 4.75 (d, J = 5.9 Hz, 2 H, CH2Ph), 5.49 (br., 1 H,
OH), 6.42 (br., 1 H, NH), 7.11 (t, J = 5.9 Hz, 1 H, NH), 7.28–7.32
(m, 2 H, HPh), 7.34–7.40 (m, 4 H, HPh and HAr), 7.52 (t, J = 7.0 Hz,
1 H, HAr), 7.60 (dt, J = 1.4, J = 7.0 Hz, 1 H, HAr), 7.72 (d, J =
8.0 Hz, 1 H, HAr), 7.93 (d, J = 2.4 Hz, 1 H, 8-H), 8.05 (d, J =
8.4 Hz, 1 H, HAr), 8.13 (d, J = 2.4 Hz, 1 H, 6-H), 8.75 (d, J =
2.6 Hz, 1 H, HAr) ppm. 13C NMR (100 MHz, 80 °C, [D6]DMSO):
δ = 43.1 (CH2), 43.5 (CH2), 60.1 (CH2), 118.8 (CH), 121.4 (Cq),
126.3 (CH), 126.51 (CH), 126.54 (2 CH), 126.58 (CH), 127.2 (2
CH), 127.8 (2 CH), 127.9 (Cq), 128.2 (CH), 135.0 (Cq), 135.5 (CH),
139.1 (Cq), 143.2 (Cq), 143.3 (Cq), 145.4 (CH), 158.2 (Cq), 158.7
(2Cq) ppm. IR (ATR Diamond): ν = 3242, 2924, 1645, 1565, 1452,
˜
1345, 1234, 1123, 1046, 826 cm–1. HRMS (EI-MS+): calcd. for
C25H24N7O [M + 1]+ 438.2042; found 438.2044.
4-(Benzylamino)-2-[(2-hydroxyethyl)amino]-7-(6-quinolinylamino)-
pyrido[3,2-d]pyrimidine (27): Compound 27 was obtained after flash
chromatography by using silica gel (EtOAc/MeOH/Et3N, 94:5:1) as
a yellow solid in 77% yield by using general procedure A and in
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Eur. J. Org. Chem. 0000, 0–0
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G. Guillaumet, S. Routier et al.
FULL PAPER
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Received: April 20, 2012
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20521
/KAP1
Date: 03-07-12 15:43:41
Pages: 11
Regiocontroled Reactions of 2,4,7-Trichloropyrido[3,2-d]pyrimidine
Pyridopyrimidines
An efficient and original synthesis of 2,4,7-
trisubstituted pyrido[3,2-d]pyrimidines is
reported. Arylations and SNAr reactions
occurred regioselectively at the C4 and C2
positions of 2,4,7-trichloropyrido[3,2-d]-
pyrimidine. Reactions at the C7 position
were achieved under microwave irradiation
in a few minutes. A one-step synthesis of
A. Tikad, M. Akssira, S. Massip,
J.-M. Léger, C. Jarry, G. Guillaumet,*
S. Routier* ...................................... 1–11
Regiocontroled SNAr and Palladium
Cross-Coupling Reactions of 2,4,7-Tri-
chloropyrido[3,2-d]pyrimidine
a
2,4,7-tris(aminated) derivative was
Keywords: Arylation / Aromatic substi-
achieved as an efficient alternative.
tution
/
Cross-coupling
/
Amination
/
Heterocycles
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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