Efficient one-pot synthesis of 2,4-di(het)aryl and 2,4-diamino pyrido[3,2-d]pyrimidines involving regioselective SNAr and palladium-catalyzed reactions

Article abstract of DOI:10.1039/b913657f

An efficient and original synthesis of various 2,4-disubstituted pyrido[3,2-d]pyrimidines is reported. One-pot di(het)arylation and diamination approaches were used to obtain highly functionalized products in very good yields. The two one-pot processes we

Full text of DOI:10.1039/b913657f

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Efficient one-pot synthesis of 2,4-di(het)aryl and 2,4-diamino
pyrido[3,2-d]pyrimidines involving regioselective SNAr and
palladium-catalyzed reactions†
Abdellatif Tikad,a,b Sylvain Routier,*a Mohamed Akssirab and Ge´rald Guillaumeta
Received 9th July 2009, Accepted 10th September 2009
First published as an Advance Article on the web 15th October 2009
DOI: 10.1039/b913657f
An efficient and original synthesis of various 2,4-disubstituted pyrido[3,2-d]pyrimidines is reported.
One-pot di(het)arylation and diamination approaches were used to obtain highly functionalized
products in very good yields. The two one-pot processes were compared to their step-by-step related
synthesis. Both routes started from 2,4-dichloropyrido[3,2-d]pyrimidine 1 and included a chlorine
discrimination during the first reaction.
2,4-dichloropyrido[3,2-d]pyrimidine 1 as a common starting ma-
Introduction
terial. A double Suzuki cross-coupling achieved di(het)arylation,
and a double SNAr or SNAr/Buchwald combination completed
the amination reaction panel. The assays described herein were
either carried out in an oil bath by classical heating, or under
microwave irradiation. This new “one-pot” work offers a useful
perspective in heterocyclic functionalization and for the design of
original active drugs.
In anticancer chemotherapy, the pyridopyrimidine scaffold has
generated a great number of biologically active drugs and
very promising PDGF, DHFR, p38 MAP kinase, PI3 kinase,
tyrosine kinase, adenosine kinase and cyclin-dependant kinases
inhibitors.1–7 However, the pyrido[3,2-d]pyrimidine regioisomer is
the least described in the literature because of its difficult and
expensive syntheses. Recently, our group has developed an original
synthesis of 2,4-disubstituted pyrido[3,2-d]pyrimidines.8,9
We have previously demonstrated that a fully regioselective
palladium insertion or SNAr reaction occurred at the C-4 position
of the 2,4-dichloropyrido[3,2-d]pyrimidine 1 and also designed,
in two distinct steps, 2,4 disubstituted pyrido[3,2-d]pyrimidines
(Fig. 1).8,9 Nevertheless, one-pot syntheses including the same type
of reaction twice are quite rare.10
One-pot C-4 and C-2 diarylation by double Suzuki–Miyaura
cross-coupling
We initially envisaged the synthesis of 2,4-di(het)aryl-pyrido[3,2-
d]pyrimidines starting from 1 via Suzuki–Miyaura cross-coupling
reactions. We have thus recently shown that the 2,4-dichloro-
pyrido[3,2-d]pyrimidine 1 reacts with 1 equiv. of phenylboronic
acid and then with 2-thiopheneboronic acid to afford the
2,4-unsymmetrically substituted pyrido[3,2-d]pyrimidine
3
(Scheme 1, steps (a) and (b)).9
Fig. 1 Step-by-step and one-pot strategies leading to II from 1.
The realization of several reactions in one flask has been attract-
ing greater attention in recent years.11 However, as a matter of fact,
our previous results could be extrapolated to give chemists more
attractive methods to synthesize 2,4-di(het)aryl and 2,4-diamino
pyrido[3,2-d]pyrimidines II in a single step.12 To highlight the
usefulness and flexibility of this new process we have used our
Scheme 1 Optimized conditions for a double (het)arylation of 1. Reagents
and conditions: (a) PhB(OH)2 1.05 equiv., Pd(PPh3)4 0.05 equiv., K2CO3
1.5 equiv., toluene, 100 ◦C, 2 h; (b) 2-thiopheneboronic acid 1.2 equiv.,
Pd(PPh3)4 0.05 equiv., Na2CO3 2.0 equiv., toluene/EtOH (2 : 1), 100 ◦C,
4 h; (c) PhB(OH)2 1.05 equiv., K2CO3 2.0 equiv., Pd(OAc)2 0.05 equiv., PPh3
0.1 equiv., toluene, 100 ◦C, 2 h then 2-thiopheneboronic acid 1.2 equiv.,
EtOH (2 : 1), 100 ◦C, 15 min.
aInstitut de Chimie Organique et Analytique, (1) Universite´ d’Orle´ans, (2)
CNRS UMR 6005, B.P. 6759, 45067, Orle´ans Cedex 2, France. E-mail:
sylvain.routier@univ-orleans.fr; Fax: 33 2 38.41 72.81; Tel: 33 2384 94592
The difference in reactivity of the two chlorine atoms prompted
us to attempt an unprecedented one-pot Pd-catalyzed preparation
of 3 from 1. Each step has been independently optimized and un-
fortunately the conditions demonstrate incompatible differences
bLaboratoire de Chimie Bioorganique et Analytique, Universite´ Hassan
II-Mohammedia, BP 146, 20650, Mohammedia, Morocco
† Electronic supplementary information (ESI) available: Synthesis and 1H
and 13C NMR spectra of compounds 11–20. See DOI: 10.1039/b913657f
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 5113–5118 | 5113
©

View Article Online
Table 1 One-pot di(het)arylation of compound 113
Step-by-step sequence
Timea
One-pot synthesis
Entry
1
(het)Ar1BOH)2
(het)Ar2B(OH)2
Compound
Yield
82%
Timea
Yield
81%
6 h
2 h 15
2
3
28 h
8 h
47%
75%
18 h 20
2 h 15
40%
70%
4
5
9 h
82%
67%
2 h 15
75%
69%
29 h
12 h 15
6
7
6 h
82%
69%
2 h 15
3 h 15
78%
75%
12 h
b
8
9
—
—
4 h 10
4 h 30
86%
78%
b
a Global reaction times are reported. b Not performed.
(base and solvent) preventing the realization of the two steps in
a single flask. Thus, we propose modifications to pursue our new
one-pot strategy (Scheme 2, Table 1).
First, compound 2 was prepared using K2CO3 and 5 mol% of
Pd(PPh3)4 in toluene at 100 ◦C.9 After completion of the reaction
(monitored by TLC), the second boronic acid was added but the
derivative 3 was isolated after one day in only 42% yield.
Fortunately, introduction of the second boronic acid in EtOH
decreased the global reaction time to 3 h and enhanced the yield
of 3 to 64%. In each assay, compound 2 is the only other isolated
product and its yield fully completed the amount of organic
material. With a near stoichiometric amount of reagents, no trace
of biphenyl compound was observed, emphasizing the lack of
reactivity of the 2-Cl vs. the 4-Cl atom. As a last idea, we now
5114 | Org. Biomol. Chem., 2009, 7, 5113–5118
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
compound 12 after 12 h at room temperature in 87% yield whereas
the second SNAr reaction was achieved with 1.2 equiv. of PMBNH2
in refluxing dioxane to afford compound 13 after 24 h in a high
(92%) yield. Furthermore, the step-by-step synthesis of 13 from 1
required the purification of the intermediate 12.
Despite of the high yields, the development of an attractive
one-pot strategy would constitute a major advance in the poly
substitution of pyrido[3,2-d]pyrimidines (Scheme 4). After several
assays, we opted for dioxane as solvent. The first reaction was
also performed with PhNH2 at room temperature to preserve
the C-4 regioselectivity. After the complete disappearance of
1 on TLC (2 h), 1.2 equiv. of PMBNH2 was added and the
reaction mixture was refluxed. After nearly one additional day,
the expected product 13 was isolated in 78% yield. Our new one-
pot strategy greatly decreased the reaction time and this process
was generalized as demonstrated by the results summarized in
Table 2.
Scheme 2 Reagents and conditions: (het)Ar1B(OH)2 1.05 equiv., K2CO3
2.0 equiv., Pd(OAc)2 0.05 equiv., PPh3 0.1 equiv., toluene, 100 ◦C, then
(het)Ar2B(OH)2 1.2 equiv., EtOH (2 : 1), 100 ◦C.
switched the catalyst to the more simple Pd(OAc)2/PPh3 system
at the beginning of the one-pot sequence. The first reaction was
regioselectively achieved in only 2 h whereas the second reaction
required only a few minutes and compound 3 was isolated in the
best yield of 81%.
Other indicators in favour of our new green one-pot method-
ology include the diminishing of the global reaction time (6 h
to 2 h 15), the amount of the catalytic system required (2 ¥ 5%
for two independent steps versus 5% for a single step) and the
production of 3 in fairly good yield by a single purification. Thus,
we performed additional assays in order to complete our study
(Scheme 2, Table 1). In entries 1–7, we indicated the reaction times
and the yields of the two step-by-step and one-pot reactions.
Regardless of the chosen method, the attempted 2,4-disubstituted
pyrido[3,2-d]pyrimidines 3–9 were isolated in quite similar and
good yields (69–81%) except compound 4 does not exceed 40%
due to its degradation. Interestingly, the one-pot reactions are
3–4 times faster than the step-by-step syntheses.
During the one-pot synthesis, the second boronic acid was
added when starting material 1 fully disappeared (monitored by
TLC). Most of the first cross-coupling reactions were achieved
after 2–4 hours (entries 1, 3, 4, 6–9). The use of 2-thienyl and
3,4-methylenedioxyphenyl boronic acids (entries 2, 5) increased
the reaction time to 18 and 12 h respectively. In both aromatic
and heteroaromatic series, the second Suzuki reaction required
only a few minutes (10–30 mins). Our new one-pot method con-
stitutes easier access to 2,4-di(het)aryl-pyrido[3,2-d]pyrimidines,
independent of the nature of the (het)arylboronic acid.
Scheme 4 Reagents and conditions: R1NH2 1.01 equiv., Et3N 2.0 equiv.,
1,4-dioxane, r.t. then R2NH2 1.2 equiv., reflux or MW irradiation 140 ◦C.
The first SNAr reaction was mostly completed after 1 or 2 h
whatever the nature of the primary amine (aliphatic, benzylamine
or anilines, entries 1–7). With 6-aminoquinoline (entry 8), a
strongly deactivated nucleophile, completion occurred only after
12 h. Introduction of the second primary amines (alkyl, benzyl
and phenyl) and refluxing the mixture achieved the C-2 SNAr
reaction. Assays 1–8 were nearly quantitative on TLC but some
of the synthesized compounds were not easy to purify, explaining
why the diaminated derivatives 13–20 were isolated in the 63–89%
yield range.
In spite of the good yields obtained for compounds 13–20,
the second reaction times strongly increased (12–47 h). The
lack of reactivity of the residual C-2 chlorine atom may be
due to the presence of electron-donating groups on the C-4
position. This hypothesis was confirmed when the less nucleophilic
6-aminoquinoline was used. The desired product 21 was not
identified and only 81% of 12 was isolated. So we switched the
thermal conditions for microwave irradiation.14 After only one or
two hours, complete conversion was seen on TLC and compounds
13–20 were isolated in good yields (63–84%). Despite the change in
the activation mode, the use of 6-aminoquinoline (entry 9) failed
again and only 86% of 12 was recovered.
One-pot C-4 and C-2 diamination by double SNAr reaction
Alkyl amination of 1 regioselectively occurred at C-4.8 From
this point of view, we now considered the synthesis of C-2 and
C-4 bis-aminated pyrido[3,2-d]pyrimidines (Scheme 3). Under a
sequential route, compound 1 reacted first with aniline in the
presence of a stoichiometric amount of Et3N in THF to produce
In summary, we have proposed a straightforward one-pot
bisamination of pyrido[3,2-d]pyrimidines and successfully intro-
duced onto positions C-2 and C-4 alkyl, benzyl and aryl primary
amines.15 The two chlorine atoms of 1 were successfully and
regioselectively displaced after two successive SNAr reactions. The
first one was achieved on C-4 at room temperature, whereas the
second one on C-2 required harsh thermal conditions. Microwave
irradiation retrieved the situation and reduced the global reaction
time to a few hours. Nevertheless, the use of deactivated amines
remains unsolved.
Scheme 3 Reagents and conditions: (a) PhNH2 1.0 equiv., Et3N 1.0 equiv.,
THF, r.t., 12 h; (b) PMBNH2 1.2 equiv., 1,4-dioxane, reflux, 24 h; (c)
PhNH2 1.0 equiv., Et3N 2.0 equiv., 1,4-dioxane, r.t., 2 h then PMBNH2
1.2 equiv., reflux, 22 h, see also ref. 15.
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 5113–5118 | 5115
©

View Article Online
Table 2 One-pot diamination of compound 1
2nd SNAr under thermal
conditions
2nd SNAr under MW
irradiation
1st SNAr
Time
Entry
1
R1NH2
R2NH2
Compound
Time
22 h
Yield
Time
Yield
75%
2 h
78%
1 h
2
3
2 h
1 h
12 h
47 h
63%
83%
1 h
2 h
67%
78%
4
5
1 h
2 h
23 h
22 h
89%
60%
1 h
1 h
84%
67%
6
7
8
9
2 h
1 h
12 h
2 h
22 h
47 h
12 h
46 h
72%
64%
1 h
2 h
1 h
2 h
74%
63%
68%
70%
a
b
a 81% of 12 was isolated. b 86% of 12 was isolated.
One-pot C-4 and C-2 diamination by a SNAr/Buchwald
combination
tion mixture the 6-aminoquinoline and the Pd(OAc)2/Xantphos
catalytic system, which proved its efficiency in Buchwald
aminations.16
The poor reactivity of 2-chloro-4-aminopyrido[3,2-d]pyrimidine
and the use of deactivated amines led to disappointing failure in
the double SNAr one-pot strategy. So, we envisioned to perform
the second SNAr reaction via a Buchwald amination. To exemplify
our new proposal, we started with the compound 21 as the target
(Scheme 5).
After a nearly two-day period at reflux, compound 21 was
isolated in 82% yield.17 So we were able to restore the reactivity at
position C-2 with poor nucleophilic amines.
The great interest of a one-pot methodology intimately relies
on a fast turnover and good yields. In a final assay, we performed
the palladium-catalyzed reaction under microwave irradiation.
Interestingly, the reaction time decreased to only 2 h with
a minor impact on the global yield. Including this original
Starting from 1, we first realized the selective SNAr reaction
with aniline at room temperature and then we added to the reac-
5116 | Org. Biomol. Chem., 2009, 7, 5113–5118
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
S. McGaraughty, C. T. Wismer, J. Mikusa, K. C. Marsh, R. D. Snyder,
M. S. Diehl, E. A. Kowaluk, M. F. Jarvis and S. S. Bhagwat, Bioorg.
Med. Chem., 2005, 13, 3705–3709.
7 S. N. VanderWel, P. J. Harvey, D. J. McNamara, J. T. Repine, P. R.
Keller, J. Quin III, R. J. Booth, W. L. Elliott, E. M. Dobrusin, D. W.
Fry and P. L. Toogood, J. Med. Chem., 2005, 48, 2371–87.
8 A. Tikad, S. Routier, M. Akssira, J. M. Le´ger, C. Jarry and G.
Guillaumet, Synlett., 2006, 1938–1942.
9 A. Tikad, S. Routier, M. Akssira, J. M. Le´ger, C. Jarry and G.
Guillaumet, Org. Lett., 2007, 9, 4673–4676.
Scheme 5 One pot SNAr/Buchwald synthesis. Reagents and conditions:
PhNH2 1.0 equiv., Et3N 2.0 equiv., 1,4-dioxane, r.t., 2 h; then 6-amino-
quinoline 1.2 equiv., Pd(OAc)2 0.05 equiv., Xantphos 0.1 equiv., (reflux,
46 h, 82% or MW irradiation 140 ◦C, 2 h, 78%).
10 (a) F. Beaumard, P. Dauban and R. H. Dodd, Org. Lett., 2009, 11,
1801–1804; (b) S. T. Handy, T. Wilson and A. Muth, J. Org. Chem.,
2007, 72, 8496–8500; (c) S. T. Handy and J. J. Sabatini, Org. Lett., 2006,
8, 1537–1539; (d) S. T. Handy and D. Mayi, Tetrahedron Lett., 2007, 48,
8108–8110; (e) G. Langli, L.-L. Gundersen and F. Rise, Tetrahedron,
1996, 52, 5625–5638.
11 (a) Q. Xiao and P. E. Floreancig, Org. Lett., 2008, 10, 1139–1142;
(b) Y. H. Kim, H. Lee, Y. J. Kim, B. T. Kim and J.-N. Heo, J. Org.
Chem., 2008, 73, 495–501; (c) L. B. Sun, J. Yang, J. H. Kou, F. N. Gu,
Y. Chun, Y. Wang, J. H. Zhu and Z. G. Zou, Angew. Chem., Int. Ed.,
2008, 47, 3418–3421; (d) H. Wang, A. Wang, X. Wang and T. Zhang,
Chem. Commun., 2008, 2565–2567; (e) A. W. Franz and T. J. J. Mueller,
Synthesis, 2008, 1121–1125; (f) S. Song, L. Song, B. Dai, H. Yi, G. Jin,
S. Zhu and M. Shao, Tetrahedron, 2008, 64, 5728–5735; (g) S. Hajra, S.
Bar, D. Sinha and B. Maji, J. Org. Chem., 2008, 73, 4320–4322; (h) L.
Zhu, M. Patel and M. Zhang, Tetrahedron Lett., 2008, 49, 2734–2737.
12 J. Koubachi, S. El Kazzouli, S. Berteina-Raboin, A. Mouaddib and G.
Guillaumet, J. Org. Chem., 2007, 72, 7650–7665.
13 General procedure for the one-pot double Suzuki–Miyaura cross-
coupling reactions (compounds 3–11): To an argon degassed solution of
2,4-dichloropyrido[3,2-d]pyrimidine 1 (100 mg, 0.5 mmol) in toluene
(6 mL), the desired (het)Ar boronic acid (1.05 equiv.), K2CO3 (138 mg,
2 equiv.), Pd(OAc)2 (6.0 mg, 0.05 equiv.) and PPh3 (13 mg, 0.1 equiv.)
were successively added. The reaction mixture was heated at 100 ◦C
under vigorous stirring. After complete disappearance of 1 on TLC, the
second (het)aryl boronic acid (1.2 equiv.) in EtOH (3 mL) was added.
After complete conversion of the C-4 monoarylated non-isolated
intermediate, the reaction mixture was cooled to room temperature
and concentrated under reduced pressure. Water (10 mL) and CH2Cl2
(10 mL) were successively added. After extraction of the aqueous
phase with CH2Cl2 (3 ¥ 10 mL), the combined organic layers were
dried over MgSO4, filtered and evaporated under reduced pressure.
The crude material was purified by flash chromatography to afford
the attempted compounds 3–11. 4-(3-Methoxyphenyl)-2-(thien-2-yl)-
pyrido[3,2-d]pyrimidine (10). Compound 10 was isolated after a flash
chromatography (petroleum ether/EtOAc, 9/1) as a pale yellow solid
in 86% yield. Mpt 119–120 ◦C; IR (ATR-Ge, cm-1) n 3063, 2832, 1594,
1532, 1451, 1323, 1256, 1036, 867, 790; 1H NMR (400 MHz, CDCl3) d
3.88 (s, 3H, CH3), 7.10 (dd, 1H, J = 2.1 Hz, J = 7.8 Hz), 7.18 (dd, 1H,
J = 3.8 Hz, J = 5.0 Hz), 7.43 (t, 1H, J = 8.0 Hz), 7.56 (dd, 1H, J =
1.0 Hz, J = 5.0 Hz), 7.70 (dd, 1H, J = 4.1 Hz, J = 8.6 Hz, H7), 8.03-8.04
(m, 1H), 8.07 (d, 1H, J = 7.8 Hz), 8.37 (d, 1H, J = 3.8 Hz), 8.46 (dd,
1H, J = 1.6 Hz, J = 8.6 Hz, H8), 8.92 (dd, 1H, J = 1.6 Hz, J = 4.1 Hz,
H6); 13C NMR (100 MHz, CDCl3) d 55.4 (CH3), 117.2 (CH), 117.3
(CH), 124.8 (CH), 128.4 (CH), 129.0 (CH), 129.2 (CH), 131.4 (CH),
132.2 (CH), 134.9 (CH), 136.7 (Cq), 137.2 (Cq), 141.6 (Cq), 146.3 (Cq),
150.7 (CH), 156.3 (Cq), 159.3 (Cq), 167.0 (Cq); HRMS (EI-MS) : m/z
calcd for C18H14N3OS: 320.0858, found: 320.0867.
microwave irradiation step, we efficiently performed a double one-
pot amination of pyrido[3,2-d]pyrimidine 1 using successive SNAr
and Buchwald-type reactions to get around the lack of reactivity
of strongly deactivated amines.
Conclusion
Herein, we have described three original one-pot proce-
dures to generate 2,4-disubstituted pyrido[3,2-d]pyrimidines from
2,4-dichloropyrido[3,2-d]pyrimidine 1 using SNAr and palladium-
catalyzed reactions. This unprecedented work included a double
Suzuki–Miyaura cross-coupling, a double SNAr reaction and an
SNAr/Buchwald combination, which proved to be very efficient.
The C-4 versus C-2 chlorine discrimination under Suzuki or
SNAr conditions is the key to achieving the first steps in only a
few hours. The second C-2 arylations were realized in a few minutes
under thermal activation, whereas the second C-2 aminations
required microwave irradiation to be achieved in a few hours. The
C-2 aminations were mostly performed by SNAr reactions and,
last but not least, the deactivated amines were introduced under
Buchwald-type conditions. This strategy has also proved to be
very useful in the double substitution of pyrido[3,2-d]pyrimidine.
Efforts are already in progress to broaden the methodology to
other heterocycles.
Acknowledgements
SR acknowledges the Canceropoˆle Grand Ouest and the Ligue
contre le Cancer (Re´gion Centre) for their financial support. The
authors thank the PHC Volubilis grant.
Notes and references
1 J. M. Hamby and H. D. H. Showalter, Pharmacol. Ther., 1999, 82,
169–193.
14 (a) B. U. W. Maes, K. T. J. Loones, S. Hostyn, G. Diels and G. Rombouts,
Tetrahedron Lett., 2004, 60, 11559–11564; (b) T. A. Jensen, X. Liang, D.
Tanner and N. Skjaerbaek, J. Org. Chem., 2004, 69, 4936–4947; (c) C. O.
Kappe and M. Larhed, Angew. Chem., Int. Ed., 2005, 44, 7666–7669;
(d) A. P. Skoumbourdis, S. Moore, M. Landsman and C. J. Thomas,
Tetrahedron Lett., 2007, 48, 9140–43.
15 General procedure for the one-pot double SNAr (compounds 13–20): To a
solution of 2,4-dichloropyrido[3,2-d]pyrimidine 1 (100 mg, 0.5 mmol)
in dry 1,4-dioxane (5 mL), the first primary amine R1NH2 (1.01 equiv.)
and Et3N (130 mL, 2.1 equiv.) were successively added. The reaction
mixture was stirred at room temperature and after the complete disap-
pearance of 1, the second amine R2NH2 (1.2 equiv.) was added and the
reaction was subject to microwave irradiation at 140 ◦C. After complete
conversion of the non-isolated C-4 monoaminated intermediate, the
reaction mixture was cooled to room temperature and the solvent was
evaporated under reduced pressure. The crude residue was purified
by silica gel column chromatography or by triturating with Et2O to
2 A. Gangjee, O. Adair and S. F. Queener, J. Med. Chem., 1999, 42,
2447–2455.
3 S. R. Natarajan, D. D. Wisnoski, S. B. Singh, J. E. Stelmach, E. A.
O’Neill, C. D. Schwartz, C. M. Thompson, C. E. Fitzgerald, S. J.
O’Keefe, S. Kumar, C. E. C. A. Hop, D. M. Zaller, Schmatz and
D. M. J. B. Doherty, Bioorg. Med. Chem. Lett., 2003, 13, 273–276.
4 M. Hayakawa, H. Kaizawa, H. Moritomo, T. Koizumi, T. Ohishi, M.
Okada, M. Ohta, S.-I. Tsukamoto, P. Parker, P. Workman and M.
Waterfield, Bioorg. Med. Chem., 2006, 14, 6847–6858.
5 S. R. Klutchko, H. Zhou, R. T. Winters, T. P. Tran, A. J. Bridges,
I. W. Althaus, D. M. Amato, W. L. Elliott, P. A. Ellis, M. A. Meade,
B. J. Roberts, D. W. Fry, A. J. Gonzales, P. J. Harvey, J. M. Nelson, V.
Sherwood, H.-K. Han, G. Pace, J. B. W. A. Smaill, H. D. Denny and
Hollis Showalter, J. Med. Chem., 2006, 49, 1475–1485.
6 M. A. Matulenko, C.-H. Lee, M. Jiang, R. R. Frey, M. D. Cowart, E. K.
Bayburt, S. DiDomenico, G. A. Gfesser, A. Gomtsyan, G. Z. Zheng,
J. A. McKie, A. O. Stewart, H. Yu, K. L. Kohlhaas, K. M. Alexander,
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 5113–5118 | 5117
©

View Article Online
afford the expected compounds 13–20. 2-(4-Methoxybenzylamino)-4-
phenylaminopyrido[3,2-d]pyrimidine (13). Compound 13 was isolated
after flash chromatography (DCM/MeOH, 98/2) as a yellow solid in
2.1 equiv.) were added. The reaction mixture was stirred for 2 h at room
temperature. 6-Aminoquinoline (86 mg, 1.2 equiv.), Pd(OAc)2 (6 mg,
0.05 equiv.), Xantphos (29 mg, 0.1 equiv.) were successively added to
the reaction mixture and the reaction was refluxed for 46 h or subjected
to microwave irradiation (140 ◦C) for 2 h. Whereas in the chosen
method, the purification steps were similar. The reaction mixture was
cooled to room temperature and the solvent was evaporated under
reduced pressure. Water (10 mL) and CH2Cl2 (10 mL) were added.
After extraction of the aqueous phase with CH2Cl2 (3 ¥ 10 mL),
the combined organic layers were dried over MgSO4, filtered and
evaporated under reduced pressure. The crude residue was purified
by silica gel column chromatography (DCM/MeOH 98/2) to afford
compound 21 in 82% yield with thermal activation and 78% including
the microwave irradiation step. 4-Phenylamino-2-(6-quinolinamino)-
pyrido[3,2-d]pyrimidine (21). Compound 21 was isolated after flash
chromatography (petroleum ether/EtOAc, 98/2) as a beige solid in
◦
78% yield. Mpt 157–158 C; IR (ATR-Ge, cm-1) n 3360, 3247, 2833,
1622, 1546, 1453, 1339, 1227, 1041, 811; 1H NMR (250 MHz, CDCl3)
d 3.77 (s, 3H, OCH3), 4.66 (d, 2H, J = 5.6 Hz, CH2), 5.62 (sl, 1H, NH),
6.85 (d, 2H, J = 8.8 Hz), 7.08 (t, 1H, J = 7.5 Hz), 7.30-7.37 (m, 4H),
7.45 (dd, 1H, J = 4.1 Hz, 8.5 Hz, H7), 7.73 (d, 1H, J = 8.5 Hz, H8), 7.84
(d, 2H, J = 7.5 Hz), 8.36 (dd, 1H, J = 1.6 Hz, J = 4.1 Hz, H6), 9.05
(sl, 1H, NH); 13C NMR (62.5 MHz, CDCl3) d 45.4 (CH2), 55.4 (CH3),
114.0 (3CH), 120.2 (3CH), 123.5 (CH), 126.0 (Cq), 127.8 (CH), 129.0
(3CH), 131.5 (Cq), 133.0 (Cq), 138.7 (Cq), 143.3 (CH), 147.1 (Cq),
157.6 (Cq), 158.9 (Cq); HRMS (EI-MS): m/z calcd for C21H20N5O:
358.1668, found: 358.1673.
16 (a) E. Garnier, J. Audoux, E. Pasquinet, F. Suzenet, D. Poullain, B.
Lebret and G. Guillaumet, J. Org. Chem., 2004, 69, 7809–1815; (b) A.
Salcedo, L. Neuville, C. Rondot, P. Retailleau and J. Zhu, Org. Lett.,
2008, 10, 857–860; (c) R. Lira and J. P. Wolfe, J. Am. Chem. Soc.,
2004, 126, 13906–13907; (d) J. Ji, T. Li and W. H. Bunnelle, Org. Lett.,
2003, 5, 4611–14; (e) J. Yin, M. M. Zhao, M. A. Huffman and J. M.
McNamara, Org. Lett., 2002, 4, 3481–84; (f) S. Cacchi, G. Fabrizi, A.
Goggiamani, E. Licandro, S. Maiorana and D. Perdicchia, Org. Lett.,
2005, 7, 1497–1500; (g) A. Ghosh, J. E. Sieser, M. Riou, W. Cai and
L. Rivera-Ruiz, Org. Lett., 2003, 5, 2207–2210; (h) A. Kuwahara, K.
Nakano and K. Nozaki, J. Org. Chem., 2005, 70, 413–419.
◦
82% yield. Mpt 198–199 C; IR (ATR-Ge, cm-1) n 3043, 2285, 1599,
1563, 1486, 1420, 1348, 1297, 1102, 831; 1H NMR (400 MHz, CDCl3)
d 7.16 (t, 1H, J = 7.3 Hz), 7.38-7.42 (m, 2H), 7.45 (dd, 1H, J = 4.2 Hz,
J = 8.3 Hz), 7.76 (dd, 1H, J = 4.2 Hz, J = 8.5 Hz, H7), 7.94 (d, 1H,
J = 9.1 Hz), 8.00 (dd, 1H, J = 1.2 Hz, J = 8.4 Hz), 8.09-8.18 (m, 4H),
8.61 (dd, 1H, J = 1.5 Hz, J = 4.2 Hz), 8.73 (dd, 1H, J = 1.6 Hz, J =
4.1 Hz, H6), 8.76 (sl, 1H), 9.82 (s, 1H, NH), 10.06 (s, 1H, NH); 13C
NMR (100 MHz, CDCl3) d 113.6 (CH), 121.5 (CH), 121.6 (CH), 123.5
(CH), 124.2 (CH), 128.4 (2CH), 128.6 (2CH). 128.9 (CH), 129.1 (Cq),
133.5 (CH), 134.9 (CH), 138.8 (Cq), 138.9 (Cq), 144.1 (Cq), 144.7 (CH),
146.2 (Cq), 147.9 (CH), 156.4 (2Cq), 157.6 (Cq); HRMS (EI-MS) : m/z
calcd for C22H17N6: 365.1515, found: 365.1510.
17 Synthesis of 21 by a one-pot SNAr/Buchwald sequence. To a solu-
tion of 2,4-dichloropyrido[3,2-d]pyrimidine 1 (100 mg, 0.5 mmol) in
1,4-dioxane (5 mL), aniline (47 mg, 1.01 equiv.) and Et3N (130 mL,
5118 | Org. Biomol. Chem., 2009, 7, 5113–5118
This journal is
The Royal Society of Chemistry 2009
©