Regioselective syntheses of 2,7-(Het)arylpyrido[2,3- d ]pyrimidines by an orthogonal cross-coupling strategy

Article abstract of DOI:10.1055/s-0032-1317180

An efficient and easy access to 2,7-disubstituted pyrido[2,3-d]pyrimidine derivatives is reported. These derivatives were obtained using two orthogonal palladium-catalyzed cross-coupling reactions via successive C-7 chlorine and C-2 methylsulfur releases.

Full text of DOI:10.1055/s-0032-1317180

LETTER
▌2449
lRetteergioselective Syntheses of 2,7-(Het)Arylpyrido[2,3-d]pyrimidines by an
Orthogonal Cross-Coupling Strategy
2,7-(Het)Arylpyrido[2,3-d]pyrimidines
Lucie Maingot,a Oussama Dehbi,a,b Frédéric Buron,a Mina Aadil,b Mohamed Akssira,b Sylvain Routier*a
Gérald Guillaumet*a
a
Institut de Chimie Organique et Analytique (ICOA), Université d’Orléans, UMR CNRS 7311, Rue de Chartres, BP 6759, 45067 Orléans,
France
Fax +33(2)38417281; E-mail: sylvain.routier@univ-orleans.fr
b
Laboratoire de Chimie Bioorganique et Analytique, URAC-22, FST-Université Hassan II-Mohammedia, BP 146, 20650 Mohammedia,
Morocco
Received: 10.06.2012; Accepted after revision: 15.08.2012
Table 1 Suzuki–Miyaura Cross-Coupling Using 7-Chloro-2-
methylsulfanylpyrido[2,3-d]pyrimidine (1)
Abstract: An efficient and easy access to 2,7-disubstituted pyri-
do[2,3-d]pyrimidine derivatives is reported. These derivatives were
obtained using two orthogonal palladium-catalyzed cross-coupling
reactions via successive C-7 chlorine and C-2 methylsulfur releases.
(Het)Ar1B(OH)2 (1.1 equiv)
N
N
Na2CO3 (2.0 equiv)
S
N
N
(Het)Ar1
Key words: cross-coupling, palladium, copper, alkylsulfur, regio-
selectivity, pyridopyrimidine
S
N
N
Cl
Pd(PPh3)4 (5 mol%)
reflux, 18 h
1
Me
Me
3a–j
Entry
(Het)Ar1
Solvent
A
Product Yield (%)b
In the search of new biocompatible nitrogen-containing
heterocycles, pyridopyrimidines seem to be useful scaf-
folds. Including this skeleton in more complex structures
has led to a wide range of bioactive molecules which
could be used as antimicrobial,1a antibacterial,1b–d anti-
folate,1e anti-inflammatory,1f insecticidal,1g antiviral,1i and
anticancer agents.1h This explains the interest of chemists
to develop straightforward strategies and versatile meth-
ods to obtain and functionalize them.2
3a
1
2
47
B
73
3a
OMe
OMe
3
4
B
3b
63
B
B
3c
69
73
Among the four pyridopyrimidines, we focused our ef-
forts on two rare [3,2-d] and [2,3-d] regioisomers and op-
timized experimental conditions to prepare C-2 and C-4
bis(het)arylated derivatives by a sequential route involv-
ing as leaving groups a C-4 chlorine atom and a C-2 iso-
propylsulfanyl group.3 Having in hands a general method
to introduce two substituents on the pyrimidine ring, we
thought that a double substitution onto the pyrimidine and
the pyridine rings could be useful to increase chemical
diversity.
OMe
5
6
3d
B
3e
77
CN
7
8
9
B
3f
68
79
63
CF3
To pursue our objectives, we envision now to functional-
ize the 7-chloro-2-methylsulfanylpyrido[2,3-d]pyrimi-
dine (1, Scheme 1) by a selective chlorine displacement at
C-7 followed by a alkylsulfanyl release at C-2 under two
palladium-catalyzed cross-coupling procedures.4,5
B
B
3g
3h
O
O
Starting material 1 was obtained after a six-step route
from commercially available 4-chloro-5-ethoxycarbonyl-
2-methylsulfanylpyrimidine (2) using a patent-published
procedure on a multigram scale in 12% overall yield.5
N
10
11
B
B
3i
3j
78
71
N
N
SYNLETT 2012, 23, 2449–2452
Advanced online publication: 13.09.2012
DOI: 10.1055/s-0032-1317180; Art ID: ST-2012-B0493-L
© Georg Thieme Verlag Stuttgart · New York
a Solvent mixture A: DME–H2O = 2:1; solvent mixture B: toluene–
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
EtOH = 2:1.
b Isolated yields.

2450
L. Maingot et al.
LETTER
O
2 selective
cross-coupling
reactions
N
N
N
OEt
6 steps
(Het)Ar2
N
N
(Het)Ar1
MeS
N
N
Cl
MeS
N
Cl
I
1
2
Scheme 1 General route for bis(het)aryl derivative I synthesis
Suzuki–Miyaura-type reactions were performed at C-7 of hour to furnish 4a in 79% yield (Table 2, entry 4). In order
the key intermediate 1 (Table 1).6 The first cross-coupling to explore the scope and limitation of our methodology,
attempt was performed with the p-methoxyphenylboronic we next modified the nature of the boronic acid (Table
acid using only 5% mol of Pd(PPh3)4 and Na2CO3 as base 3).10
in a refluxing mixture of DME and H2O (Table 1, entry 1)
Addition of a methoxy group onto the phenyl boronic acid
to furnish after 18 hours the product 3a in a promising
affected slowly the efficiency, and compounds 4b–d were
47% yield. Switching the solvent system to a dry toluene–
isolated in good yields ranging from 73–75% (Table 3, en-
EtOH mixture, the yield increased to 73% (Table 1, entry
tries 2–4). The same behavior was obtained with the
2). Whatever the class of the boronic acid used, the cross-
fluorine substituent (Table 3, entry 5) but using the 4-cyano-
coupling reaction led to the desired C-7 mono(het)arylat-
phenylboronic acid, the purification remained difficult,
ed pyridopyrimidines 3a–j in comparable yields.7 The re-
and 4f was always contaminated by a small amount of
starting material 3a. This effect was turned off by starting
from 3e, which led to 4g–i in good yields (Table 3, entries
7–9), synthesis of 4g is moreover the best assay we real-
action is fully compatible with electron-rich or electron-
poor aryl residues and representative heterocycles, each
reaction led to complete consumption of the starting ma-
terial and only one newly formed product.
ized.
To explore the feasibility of our sequence we then ex-
The use of 3i or 3j appeared as problematic. Only degra-
dation was observed which seems to indicate that the C-2
alkylsulfur release was affected by the electron deficiency
of the pyridine at C-7. In addition, the reaction between 3a
plored the C-alkylsulfanyl release using the multigram-
produced compound 3a (Table 2).8 Under standard condi-
tions, involving the use of 5% of catalyst and 2.2 equiva-
lents of CuTC, compound 4a was isolated after five hours
or 3e and the 4-pyridinylboronic acid always failed, indi-
in a low 37% yield (Table 2, entry 2), whereas the use of
cating the changeable comportment of this coupling
other copper(I) sources failed (Table 2, entry 1).
agent.
An increase of the reaction time indicated a stagnation of
Fortunately, using 2-thiophenylboronic acid (Table 3, en-
the turnover. Fortunately, when DME was used (Table 2,
tries 11 and 12), the efficiency of the reaction was partial-
entry 3), 66% of 4a was formed. In this case, during the
increase of the reaction time, a permanent consumption of
the starting material was observed. To reduce the reaction
ly recovered. Attempted compounds 4l and 4m were
formed and 4m was isolated in 55% yield. The low con-
version indicated that electron-poor heterocycles could be
time (3 d), we thought to take advantage of microwave ac-
smoothly introduced at C-7 of the pyridopyrimidine scaf-
tivation.9 The best conditions we report therein involved a
fold using alkylsulfur as the leaving group.
reaction carried out in DME, at 200 °C and in only one
Table 2 Optimization of the Pd-Catalyzed Cross-Coupling Conditions on Compound 3a
N
N
PhB(OH)2 (2.2 equiv)
Pd(PPh3)4 (5 mol%)
CuX (2.2 equiv)
N
N
S
N
N
Me
OMe
OMe
3a
4a
Entry
Solvent
CuX
Conditions
reflux
Time (h)
Yield (%)a
1
2
3
4
DME
THF
CuBr·SMe2
CuTC
16
5
–
50 °C
37
66
79
DME
DME
CuTC
reflux
72
1
CuTC
MW, 200 °C
a Isolated yields.
Synlett 2012, 23, 2449–2452
© Georg Thieme Verlag Stuttgart · New York

LETTER
2,7-(Het)Arylpyrido[2,3-d]pyrimidines
2451
Table 3 Synthesis of Derivatives 4a–m by Methylsulfur Release
(Het)Ar2B(OH)2 (2.2 equiv)
N
N
Pd(PPh3)4 (5 mol%)
(Het)Ar1
S
N
N
(Het)Ar2
N
N
(Het)Ar1
CuTC (2.2 equiv)
DME, MW, 200 °C, 1 h
Me
3a–j
4a–m
Entry
1
(Het)Ar1
(Het)Ar2
Product
Yield (%)
79
4a
OMe
OMe
OMe
2
4b
73
OMe
3
4c
4d
4e
4f
73
OMe
OMe
OMe
OMe
CN
4
75
OMe
F
5
85
6
80b (conv.)
CN
7
4g
4h
4i
84
8
72
CN
CN
9
75
OMe
CN
10
11
12
13
4j
n.d.a
N
4k
4l
n.d.a
N
S
S
75b (conv.)
OMe
CN
4m
55
a n.d. = not detected.
b Incomplete conversion was observed, compound was contaminated by a small amount of starting material, the amount of final compound
(conv.) was estimated by 1H NMR spectroscopy.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2449–2452

2452
L. Maingot et al.
LETTER
(6) (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett.
1979, 36, 3437. (b) Miyaura, N.; Suzuki, A. Chem. Rev.
1995, 36, 2457.
In conclusion, we have demonstrated the first preparation
of 2,7-disubstituted pyrido[2,3,d]pyrimidines by two
cross-coupling reactions with boronic acid derivatives.
The first reaction was realized at C-7 by a chlorine substi-
tution whereas at C-2 the release of a methylsulfur group
was preferred. The last reaction required a microwave ir-
radiation to reduce the reaction time and enhance the
yield. Some efforts are in progress to design a bioactive
compound from this study.11
(7) General Procedure for the Preparation of Compounds
3a–j. 7-Chloro-2-methylsulfanylpyrido[2,3-d]pyrimidine5
(1, 0.5 mmol), boronic acid (1.1 equiv), and Na2CO3 (2.0
equiv) were dissolved in a mixture of toluene–EtOH (6:3
mL). After argon bubbled, Pd(PPh3)4 (0.05 equiv) was
added, and the reaction mixture was refluxed for 18 h. The
reaction mixture was then cooled to r.t., and the solvent was
removed under reduced pressure. Desired compounds 3
were directly obtained after purification by flash silica gel
chromatography (eluent PE–EtOAc, 8:2 to 1:1).
7-(4-Methoxyphenyl)-2-methylsulfanylpyrido[2,3-
d]pyrimidine (3a)
Acknowledgment
This work was supported by grants from the Ligue Nationale contre
le Cancer (comités départementaux des régions Centre, Charentes-
Poitou, Pays de la Loire et Bretagne) and from the Cancéropôle
Grand Ouest (strand ‘Valorisation des produits de la mer’). We
thank the Hubert Curien Volubilis program for financial support.
Yield 73%; yellow solid; mp 163–165 °C. IR (ATR): 3051,
2929, 1584, 1512, 1462 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 2.73 (s, 3 H), 3.86 (s, 3 H), 6.99 (d, J = 8.0 Hz, 2 H), 7.84
(d, J = 8.0 Hz, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 8.19 (d, J = 8.0
Hz, 2 H), 9.06 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ =
14.7 (CH3), 55.6 (CH3), 114.4 (2 CH), 115.5 (Cq), 119.1
(CH), 130.1 (2 CH), 130.4 (Cq), 137.1 (CH), 158.9 (Cq),
160.4 (CH), 162.3 (Cq), 164.6 (Cq), 173.9 (Cq). HRMS (EI-
MS): m/z calcd for C15H13N3OS: 284.08558 [M + H+];
found: 284.08521.
References and Notes
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(10) General Procedure for the Preparation of Compounds
4a–m
In a sealed tube and under argon, 7-aryl-2-
methylsulfanylpyrido[2,3-d]pyrimidine 3 (0.3 mmol),
boronic acid (2.2 equiv), and CuTC (2.2 equiv) were
dissolved in dry DME (3 mL). Pd(PPh3)4 (0.05 equiv) was
added, and the reaction mixture was stirred under microwave
irradiation at 200 °C for 1 h. After cooling to r.t., the reaction
mixture was poured into a sat. aq NaHCO3 solution (20 mL)
and the aqueous layer extracted with CH2Cl2 (3 × 20 mL).
The combined organic phases were dried over MgSO4, and
the solvent was removed under reduced pressure. Desired
compounds 4 were purified by flash silica gel
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Ed.; Thieme: Stuttgart, 2004, 1155.
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C.; Guillaumet, G. Org. Lett. 2007, 9, 4673. (b) Tikad, A.;
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Bombrun, A.; Augustine, J. K.; Bernardinelli, G.;
chromatography (CH2Cl2–MeOH, 100:0 to 98:2).
7-(4-Methoxyphenyl)-2-phenylpyrido[2,3-d]pyrimidine
(4a)
Yield 79%; white solid; mp 313–314 °C. IR (ATR): 3061,
2990, 2834, 1517, 1435 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 3.89 (s, 3 H), 7.03 (d, J = 8.8 Hz, 2 H), 7.50–7.54 (m, 3
H), 7.97 (d, J = 8.5 Hz, 1 H), 8.24 (d, J = 8.5 Hz, 1 H), 8.28
(d, J = 8.8 Hz, 2 H), 8.70–8.73 (m, 2 H), 9.42 (s, 1 H). 13
NMR (100 MHz, CDCl3): δ = 55.6 (CH3), 114.5 (2 CH),
C
117.0 (Cq), 120.2 (CH), 128.7 (2 CH), 129.4 (2 CH), 130.2
(2 CH), 130.6 (Cq), 131.4 (CH), 136.7 (CH), 137.6 (Cq),
159.3 (Cq), 161.2 (CH), 162.4 (Cq), 164.8 (Cq), 165.1 (Cq).
HRMS (EI-MS): m/z calcd for C20H15N3O: 314.1288 [M +
H+]; found: 314.1292.
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Synlett 2012, 23, 2449–2452
© Georg Thieme Verlag Stuttgart · New York