New efficient route to dissymmetric 2,4-di(het)aryl-pyrido[3,2-d] pyrimidines via regioselective cross-coupling reactions

Article abstract of DOI:10.1021/ol7014434

(Chemical Equation Presented) The first access to dissymmetric 2,4-di(het)aryl-pyrido[3,2-d]pyrimidines III is reported. Two mild alternative routes led to the rarely targeted compounds from 2,4-dichloro- and 2-chloro-4-isopropylsulfanyl-pyrido[3,2-d]pyrimidine by two successive palladium-catalyzed reactions involving an original regioselective chlorine discrimination. Alternatively, type III compounds were elaborated from 2 by C-2 chlorine further displacement of the C-4 isopropylsulfanyl group, which acted as a temporary C-4 protecting group. These results open the way to innovative synthesis strategies of various bis-functionalized pyrimidine series.

Full text of DOI:10.1021/ol7014434

ORGANIC
LETTERS
2007
Vol. 9, No. 23
4673-4676
New Efficient Route to Dissymmetric
2,4-Di(het)aryl-pyrido[3,2-d]pyrimidines
via Regioselective Cross-Coupling
Reactions
Abdellatif Tikad,†,‡ Sylvain Routier,*,† Mohamed Akssira,‡ Jean-Michel Leger,§
Christian Jarry,§ and Ge´rald Guillaumet†
ICOA UMR 6005 CNRS, UniVersite´ d’Orle´ans, F-45067, Orle´ans, France,
LCBA UniVersite´ Hassan II-Mohammedia, BP 146, 20650 Mohammedia, Morocco,
and EA 2962, Pharmacochimie, UniVersite Victor Segalen Bordeaux II, France
sylVain.routier@uniV-orleans.fr
Received June 19, 2007
ABSTRACT
The first access to dissymmetric 2,4-di(het)aryl-pyrido[3,2-d]pyrimidines III is reported. Two mild alternative routes led to the rarely targeted
compounds from 2,4-dichloro- and 2-chloro-4-isopropylsulfanyl-pyrido[3,2-d]pyrimidine by two successive palladium-catalyzed reactions involving
an original regioselective chlorine discrimination. Alternatively, type III compounds were elaborated from 2 by C-2 chlorine further displacement
of the C-4 isopropylsulfanyl group, which acted as a temporary C-4 protecting group. These results open the way to innovative synthesis
strategies of various bis-functionalized pyrimidine series.
Palladium-catalyzed cross-coupling reactions represent an
important method for carbon-carbon bond formation of
heterocycles.1 In recent years, the regioselectivity of poly-
haloheteroaromatics as starting materials in such reactions
has been extensively studied.2 Some pyrido[d]pyrimidine
derivatives were recently developed as anticancer agents and
described as very promising PDGFs,3 MAP kinase inhibi-
tors,4 and adenosine kinase inhibitors.5 Hence, synthesis of
pyridopyrimidine derivatives provides an interesting chal-
lenge in medicinal chemistry, but the synthesis of pyrido-
[3,2-d]pyrimidines remains very complicated and is poorly
cited in the literature. In our group, we recently showed that
SNAr and palladium insertion occurred regioselectively at
the C-4 position of the 2,4-dichloro-pyrido[3,2-d]pyrimidine
1 giving access to the literature unknown 4-(O,S,N,H)-alkyl-
and 4-H-2-chloro-pyrido[3,2-d]pyrimidines.6
† University of Orle´ans.
(4) Natarajan, S. R.; Wisnoski, D. D.; Singh, S. B.; Stelmach, J. E.;
O’Neill, E. A.; Schwartz, C. D.; Thompson, C. M.; Fitzgerald, C. E.;
O’Keefe, S. J.; Kumar, S.; Hop, C. E. C. A.; Zaller, D. M.; Schmatz, D.
M.; Doherty, J. B. Bioorg. Med. Chem. Lett. 2003, 13, 273.
(5) Perner, R. J.; Lee, C. H.; Jiang, M.; Gu, Y. G.; DiDomenico, S.;
Bayburt, E. K.; Alexander, K. M.; Kohlhaas, K. L.; Jarvis, M. F.; Kowaluk,
E. L.; Bhagwat, S. S. Bioorg. Med. Chem. Lett. 2005, 15, 2803.
(6) Tikad, A.; Routier, S.; Akssira, M.; Le´ger, J. M.; Jarry, C.; Guillaumet,
G. Synlett 2006, 12, 1938.
‡ University of Mohammedia.
§ University of Bordeaux.
(1) Reviews: (a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic
Chemistry; Pergamon Press: Oxford, 2000. (b) Kalinin, V. N. Synthesis
1992, 413.
(2) Review: Schro¨ter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61,
2245.
(3) Hamby, J. M.; Showalter, H. D. H. Pharmacol. Ther. 1999, 82, 169.
10.1021/ol7014434 CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/20/2007

These results prompted us to explore selective and
sequential palladium-catalyzed reactions to prepare, by either
pathway A or B, compounds III from 1 and 2 (Scheme 1).
Table 1. Selective Suzuki and Stille Reactions on 1a
Scheme 1. Routes A and B to Design Derivatives I-III
So we performed a chlorine discrimination on 1 leading first
to 4-(het)Ar1-2-chloro derivatives I followed by dissymmetric
2,4-di(het)aryl compounds III.7 As an alternative, two
different (het)aryl moieties on III were introduced from
2 by sequential release of the 4-chlorine atom prior to the
2-SiPr group, which acted as a C-2 temporary protective
group during the palladium-catalyzed reactions. Those two
interesting, convergent, and efficient synthetic pathways
offered numerous dissymmetric 2,4-di(het)aryl-pyrido[3,2-
d]pyrimidines.
The first synthetic route A was achieved from 1 and the
2-chloro-4-(het)aryl-pyrido[3,2-d]pyrimidines I (Table 1).
The Suzuki reactions were first achieved with a near
stoichiometric amount of phenylboronic acid and only 5 mol
% of Pd(PPh3)4 and K2CO3 (1.5 equiv) in toluene at 100 °C.
After only 2 h, the regioselective C-4 arylation occurred,
and 3 was isolated in 84% yield (Table 1, entry 1). The
replacement of the catalyst with Pd(OAc)2/PPh3 tandem
affected neither the selectivity nor the reaction time, but the
yield of 3 slightly decreased to 79% (Table 1, entry 2). With
a near stoichiometric amount of reagents, no trace of biphenyl
compound 4 was observed, indicating the lack of reactivity
of the 2-Cl vs 4-Cl atom. On the other hand, treatment of
compound 1 with 2 equiv of phenylboronic acid and K2CO3
(3 equiv) afforded a separable mixture of products from
which monocoupled product 3 and dicoupled product 4 could
be isolated in 55 and 12% yield, respectively (Table 1, entry
4). Pd(PPh3)4 replacement with Pd(OAc)2/PPh3 gives in 1 h
the dicoupled product with 88% yield (Table 1, entry 5), as
the only compound.
To rationalize this unexpected result, we decided to study
the influence of diverse structural parameters. The chlorine
discrimination was then investigated using the bulk naph-
thalene ring and two electron-rich phenyl boronic acids in
the presence of the best catalyst Pd(PPh3)4, without any lack
of selectivity (entries 6-8).
The reaction time increased slightly to 24 h; however,
selectivity was preserved and compounds 5-7 were then
isolated in 72-89% yield as sole products.
a
Yields are given in isolated products. Reagents and conditions: (a)
(het)Ar1B(OH)2, 1.05 equiv; K2CO3, 1.5 equiv; Pd(PPh3)4, 0.05 equiv;
toluene, 100 °C. (b) Idem with Pd(OAc)2, 0.05 equiv; PPh3, 0.1 equiv. (c)
(het)Ar1SnBu3, 1.05 equiv; Pd(PPh3)4, 0.05 equiv; LiCl, 2.8 equiv; toluene,
100 °C. (d) Idem with (het)Ar1SnMe3.
yield, and starting material 1 subsisted. Change of the
catalytic system led to identical results (entries 9 and 10).
The lack of reactivity of the boronic acid and its degradation
were the main reasons for the decrease of yield.
As an alternative to Suzuki, Stille reactions were then
investigated with near stoichiometric amounts of tributyl-
stannylbenzene and 1, but the base was switched for LiCl
(2.8 equiv).8 The reaction afforded the 2-chloro-4-phenyl-
pyrido[3,2-d]pyrimidine 3 in 83% yield with no trace of 4
(entry 3). Interestingly, this selective Stille cross-coupling
was also successfully employed with other heteroaryls
(entries 11 and 12). Starting from the more bulky 2-tri-
methylstannyl-N-benzene-sulfonylindole, the selective het-
eroarylation yielded 10 in 34% yield (Table 1, entry 13).
The only inefficient assay was found with the unstable and
versatile 2-tributylstannylpyridine (Table 1, entry 14).
From type I compounds, the family III was immediately
attainable indiscriminately via a Suzuki or a Stille cross-
coupling, by the C-2 chlorine insertion of several aromatic
To maintain the selectivity, the 2-thiophene boronic acid
afforded after 24 h the attempted compound 8 in only 50%
(7) (a) Hocek, M.; Votruba, I.; Dvorakova, H. Tetrahedron 2003, 59,
607. (b) Hocek, M. Eur. J. Org. Chem. 2003, 245.
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Org. Lett., Vol. 9, No. 23, 2007

or heteroaromatic moieties. The Suzuki procedure was
achieved with a slight excess of boronic acids and Na2CO3
in a mixture of toluene/EtOH at 100 °C.5 The Stille reactions
were performed with a stoichiometric amount of stannanes
and required 2.8 equiv of LiCl in DMF at 90 °C.8 Each
reaction needed only 5 mol % of Pd(PPh3)4 and was stopped
as soon as starting material completely disappeared to afford
the expected products 11-21 (Table 2).
reaction time (1-24 h) appeared under Stille conditions.
Fortunately, the reaction with the versatile 2-tributylstan-
nylpyridine was achieved in 14 h and yielded 19 from 3 in
a 77% yield. Compounds 3 and 14, resulting, respectively,
from the chlorine differentiation and dissymmetrical bisary-
lations were clearly elucidated by X-ray analysis (Figure 1).
Table 2. First Synthesis of Compounds of Type III from
Type Ia
Figure 1. ORTEP view of compound 3 (left) and 14 (right).
The second synthetic route B offered alternative solutions
during the synthetic challenge designing compounds III.
Alternatively, such dissymmetric derivatives could be ob-
tained by the sequential use of the C-2 chlorine atom
followed by the elimination of the C-4 isopropylsulfanyl
group during palladium-catalyzed (het)arylations. The three
representative compounds 22-24 of type II were also
prepared from 2 under basic Suzuki conditions5 without
coupling in the C-4 position (Scheme 2).9
Scheme 2. Preparation of Derivatives of Type IIa
a For 22: (het)Ar2 ) Ph, 1 h, 90%. For 23: (het)Ar2 ) 3-MeOPh,
3 h, 81%. For 24: (het)Ar2 ) 2-thienyl, 3 h, 73%.
The second palladium cross-coupling reaction, which was
reported by Liebeskind et al.,10 required the presence of
copper(I) cofactors. On the basis of our knowledge,11 we
applied this strategy to our electron-deficient pyridopyrim-
idines 22-24. Suzuki related conditions were also first
a
SM: Starting Material. Yields are given in isolated products. Reagents
and conditions: (a) (het)Ar2B(OH)2, 1.2 equiv; Na2C03, 2 equiv; Pd(PPh3)4,
0.05 equiv; toluene, EtOH, 100 °C. (b) (het)Ar2SnBu3, 1.25 equiv; LiCl,
2.8 equiv; Pd(PPh3)4, 0.05 equiv; DMF, 90 °C.
All Suzuki reactions were achieved in 4-6 h and led to
the attempted products in excellent yields (89-98%).
Conversely, individual variations in yield (52-97%) or
(9) Kusturin, C.; Liebeskind, L. S.; Rahman, H.; Sample, K.; Schweitzer,
B.; Srogl, J.; Neumann, W. L. Org. Lett. 2003, 5, 4349.
(10) (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260.
(b) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2001, 3, 91. (c)
Savarin, C.; Liebeskind, L. S. Org. Lett. 2001, 3, 2149. (d) Kusturin, C. L.;
Liebeskind, L. S.; Neumann, W. L. Org. Lett. 2002, 4, 983.
(11) (a) Leconte, N.; Keromnes-Wuillaume, A.; Suzenet, F.; Guillaumet,
G. Synlett 2007, 2, 204. (b) Alphonse, F. A.; Susenet, F.; Keromnes, A.;
Lebret, B.; Guillaumet, G. Org. Lett. 2003, 5, 803.
(8) (a) Joseph, B.; Da Costa, H.; Me´rour, J. Y.; Le´once, S. Tetrahedron
2000, 56, 3189. (b) Busch, A.; Chapoulaud, V. G.; Audoux, J.; Ple´, N.;
Turch, A. Tetrahedron 2004, 60, 5373. (c) Aboul-Fadl, T.; Lo¨ber, S.;
Gmeiner, P. Synthesis 2000, 1727.
Org. Lett., Vol. 9, No. 23, 2007
4675

All aromatic Suzuki arylations were completed in a few
hours and with excellent yields (entries 1-4). Encouraged
by this result, similar sulfur releases were then achieved
following a Stille related procedure by using the organostan-
nane in the presence of CuBr‚Me2S as a soluble copper(I)
source and Pd(PPh3)4 in boiling DME. All examples were
achieved in only a few minutes in either aromatic or
heteroaromatic series (entries 5-8). The yields in isolated
products ranged between 89 and 96%.
Table 3. Synthesis of Compounds of Type III from Type IIa
Interestingly, the cross-coupling reaction using 2-trimeth-
ylstannyl-N-benzenesulfonylindole was carried out in only
30 min, and 21 was isolated in 75% yield (Table 3, entry
9), as a supplementary proof of the efficiency of the reaction.
As described in Table 3, the use of the versatile 2-tributyl-
stannylpyridine was again and inexplicably unsuccessful
(entry 10).
In this report, we developed two efficient palladium-
catalyzed routes A and B to design new and rare dissym-
metrical 2,4-bis(het)aryl-pyrido[3,2-d]pyrimidines. Suzuki-
and Stille-type reactions were accurately adapted to perform
each step with high selectivity and originality.
In the first route A, we showed that the first (het)arylation
occurred selectively in the C-4 position of the 2,4-dichloro-
pyrido[3,2-d]pyrimidine 1. The two chlorine atoms could also
be fully discriminated. The second route B involved two
sequential (het)aryl transfers from the 2-chloro-4-isopropyl-
sulfanyl-pyrido[3,2-d]pyrimidine 2 by palladium insertion
first in the C-Cl bond and then in the C-S bond. The two
original methods opened the way to a general synthesis of
bis-functionalized pyridopyrimidines, major skeletons for
designing biologically active compounds. Further studies are
currently in progress in our laboratory.
a
SM: Starting Material. Reagents and conditions: (a) (het)Ar1B(OH)2,
2.2 equiv; CuTC, 2.2 equiv; Pd(PPh3)4, 0.05 equiv; THF, 50 °C. (b)
(het)Ar1SnBu3, 2.2 equiv; CuBr‚Me2S, 2.2 equiv; Pd(PPh3)4, 0.05 equiv;
DME, reflux. (c) Idem with (het)Ar1SnMe3.
Supporting Information Available: Characterization
data for new compounds and experimental procedures are
included. Full crystallographic results have been deposited
as Supporting Information at the Cambridge Crystallographic
Data Centre, University Chemical Lab, 12 Union Road,
Cambridge CB2 1EZ, U.K., e-mail: deposit@ccdc.cam.ac.uk.
This material is available free of charge via the Internet at
http://pubs.acs.org.
carried out with a slight excess of (het)aryl boronic acids
and 2-thiophene copper(I) carboxylate12 as a cofactor. Each
reaction required only 5 mol % of Pd(PPh3)4 and the THF
temperature limited to 50 °C (Table 3).
(12) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748.
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