A three-component synthesis of pyrido[2,3-d]pyrimidines

Article abstract of DOI:10.1016/S0040-4039(03)01306-6

A new, high yield multicomponent reaction providing multifunctionalized pyrido[2,3-d]pyrimidines in a microwave-assisted one-pot cyclocondensation of α,β-unsaturated esters, amidine systems and malononitrile (or ethyl cyanoacetate) is described (the 'Victory' reaction).

Full text of DOI:10.1016/S0040-4039(03)01306-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5385–5387
A three-component synthesis of pyrido[2,3-d]pyrimidines
Nu´ria Mont,a Jordi Teixido´,a Jose´ I. Borrella,* and C. Oliver Kappeb,*
aGrup d’Enginyeria Molecular, Institut Qu´ımic de Sarria`, Universitat Ramon Llull, Via Augusta, 390, E-08017 Barcelona, Spain
bInstitute of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria
Received 24 April 2003; revised 25 April 2003; accepted 27 May 2003
Abstract—A new, high yield multicomponent reaction providing multifunctionalized pyrido[2,3-d]pyrimidines in a microwave-
assisted one-pot cyclocondensation of a,b-unsaturated esters, amidine systems and malononitrile (or ethyl cyanoacetate) is
described (the ‘Victory’ reaction). © 2003 Elsevier Science Ltd. All rights reserved.
Multicomponent reactions (MCRs) are of increasing
importance in organic and medicinal chemistry. In
times where a premium is put on speed, diversity, and
efficiency in the drug discovery process, MCR strategies
offer significant advantages over conventional linear-
type syntheses.1 MCRs leading to interesting hetero-
cyclic scaffolds are particularly useful for the creation
of diverse chemical libraries of ‘drug-like’ molecules for
biological screening, since the combination of three or
more small molecular weight building blocks in a single
operation leads to high combinatorial efficacy. Herein
we report a novel three-component synthesis of multi-
dones 3 renders these heterocycles excellent substrates
for further nucleophilic substitution or condensation
pathways. Along those lines we have reported general
protocols for the synthesis of bicyclic heterocycles such
as pyrazolo[3,4-b]pyridines, 1,6-naphthyridines, and 4-
amino-pyrido[2,3-d]pyrimidines 6 (R3=NH2) by treat-
ment of pyridones 3 with amidine systems 5 (R4=NH2,
H, Me, Ph).4 More recently, we described an acyclic
variation of the above protocol for the synthesis of
pyridopyrimidines 6 (R3=NH2) based on the isolation
of the corresponding Michael adduct 4 (G=CN), that
also allowed us to obtain 4-oxopyrido[2,3-d]pyrimidines
6 (R3=OH) by treatment of intermediates 4 (G=
CO2Me), synthesized by Michael addition of acrylate 1
and methyl cyanoacetate 2 (G=CO2Me), with an
amidine building block 5 (Scheme 1).5,6 We now report
that pyrido[2,3-d]pyrimidines 6 can be rapidly obtained
in one-pot by a microwave-assisted cyclocondensation
of a,b-unsaturated ester, amidine and malononitrile/
cyanoacetate building blocks.
functionalized
pyrido[2,3-d]pyrimidine
scaffolds
employing one-pot condensations of a,b-unsaturated
ester, amidine and malononitrile/cyanoacetate building
blocks.
Pyrido[2,3-d]pyrimidines represent a heterocyclic ring
system of considerable interest because of several bio-
logical activities associated with this scaffold. Some
analogues have been found to act as antitumor agents
inhibiting dihydrofolate reductases or tyrosine kinases,2
while others are known antiviral agents.3 Some time
ago it was discovered by Victory and co-workers that
this heterocyclic system can be prepared in a multistep
Our initial investigations involved treatment of a mix-
ture of methyl acrylate (1, R1=R2=H), malononitrile
(2, G=CN) and guanidine (5, R4=NH2) in a variety of
different solvents under microwave irradiation condi-
tions. Preliminary experiments with conventional reflux
conditions in e.g. MeOH or THF indicated that reflux
for 24 h in an oil-bath were required in order for this
multi-step sequence to be completed. Using sealed ves-
sel microwave heating technology7 at temperatures of
100–140°C full conversions were generally achieved
within 10 minutes. A variety of different solvents such
as MeOH, EtOH, THF and MeCN were utilized in our
early optimization studies. In general the strongly
microwave absorbing MeOH provided the highest
yields of the desired products. After considerable exper-
sequence
from
2-methoxy-6-oxo-1,4,5,6-tetra-
hydropyridin-3-carbonitrile intermediates 3 (Scheme 1),
obtained by reaction of an a,b-unsaturated ester 1 and
malononitrile 2 (G=CN) in NaOMe/MeOH.4 The
presence of a highly reactive methoxy group in pyri-
Keywords: multicomponent reactions; pyrido[2,3-d]pyrimidines;
microwave synthesis.
* Corresponding authors. Tel.: ++43-316-3805352; fax: ++43-316-
3809840; e-mail: oliver.kappe@uni-graz.at
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01306-6

5386
N. Mont et al. / Tetrahedron Letters 44 (2003) 5385–5387
Scheme 1.
imentation with respect to the molar equivalents of
reagents we arrived at conditions that utilized a 1:1.2:3
molar ratio of building blocks 1/2/5 and gave the most
satisfactory results in terms of product yields and
purity. The reaction was initially conducted in the
absence of additional base. However, it was observed
that, although guanidine is a base itself, a catalytic
amount of a stronger base was necessary to obtain the
desired product in high yield. Therefore, 5% of NaOMe
was used to perform all cyclocondensation reactions.
In conclusion, we have developed a new, rapid and
simple multicomponent cyclocondensation protocol
(‘Victory’ reaction) for the synthesis of biologically
active pyridopyrimidines in high yields. The full explo-
ration of this three-component process taking advan-
tage of all four possible diversity points R1–R4 around
the heterocyclic pyrido[2,3-d]pyrimidine core and fur-
ther scaffold decoration are currently in progress and
results will be reported in due course.
Using those conditions a variety of different a,b-unsat-
urated esters 1 were employed for the synthesis of a
small library of pyrido[2,3-d]pyrimidines (Table 1). In
all cases using guanidine as amidine building block (5,
R4=NH2) the products simply crystallized in high yield
after cooling of the reaction mixture to room tempera-
ture and were collected by filtration. The purity of all
pyridopyrimidines was higher than 98% based on
Acknowledgements
This work was supported by a grant from Generalitat
de Catalunya (grant 2001FI 00540, Borsa de Viatge-
BV: 2003BV 00013). N.M. is grateful to Generalitat de
Catalunya for a fellowship. We also thank Personal
Chemistry AB for the use of their instrument.
1
HPLC and H NMR measurements. For those exam-
ples involving benzamidine (5, R4=Ph) purification by
flash chromatography was required and the isolated
yields were somewhat lower.
References
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2455; (b) Gangjee, A.; Vasudevan, A.; Queener, S. F. J.
Med. Chem. 1996, 39, 1438–1446. Tyrosine kinase
inhibitors: (c) Hamby, J. M.; Connolly Cleo, J. C.;
Schroeder, M. C.; Winters, R. T.; Showalter, H. D. H.;
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Table 1. Isolated yields of pyrido[2,3-d]pyrimidines 6
(Scheme 1)a
Entry
R1
R2
R3
R4
Yield (%)
1
2
3
4
5
6
7
8
9
H
H
Me
H
H
H
Me
H
H
H
H
Me
H
Ph
H
Me
H
Ph
H
Me
NH2
NH2
NH2
NH2
OH
OH
OH
OH
NH2
OH
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
Ph
>98
>98
>98
96
97
>98
87
88
59
53
3. Nasr, M. N.; Gineinah, M. M. Arch. Pharm. 2002, 335,
289–295.
10
Ph
4. (a) Victory, P.; Diago, J. Afinidad 1978, 35, 154–158; (b)
Victory, P.; Diago, J. Afinidad 1978, 35, 161–165; (c)
Victory, P.; Nomen, R.; Colomina, O.; Garriga, M.;
a Sealed vessel monomode microwave irradiation (10 min, 100–
140°C), for details, see Ref. 8.

N. Mont et al. / Tetrahedron Letters 44 (2003) 5385–5387
5387
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8. All microwave experiments were performed using the
Emrys Synthesizer (Personal Chemistry AB). Typical pro-
cedure (Entry 2, Table 1): Guanidine carbonate (180 mg,
3.0 mmol) was added to a fresh solution of NaOMe
prepared by addition of 3.0 ml of MeOH to Na (70 mg,
3.05 mmol). The mixture was heated at reflux for 15 min.
After cooling to rt the mixture was filtered to remove
Na2CO3. The so prepared solution of guanidine in MeOH
was placed in a microwave process vial containing a stir
bar. After addition of methyl crotonate (100 mg, 1.0
mmol) and malononitrile (79 mg, 1.2 mmol), the vial was
sealed and subjected to microwave irradiation for 10 min
at 140°C. After gas jet cooling to rt (2 min) the formed
precipitate was collected by filtration and washed thor-
oughly with water, EtOH and Et2O providing an off-white
powder (193 mg, 98%) that had >98% purity by HPLC
5. Borrell, J. I.; Teixido´, J.; Mart´ınez-Teipel, B.; Serra, B.;
Matallana, J. L.; Costa, M.; Batllori, X. Collect. Czech.
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7. (a) Hayes, B. L. Microwave Synthesis: Chemistry at
the Speed of Light; CEM Publishing: Matthews, NC,
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www.maos.net.
1
and H NMR. Recrystallization from AcOH produced the
pyridopyrimidine 6 (R1=H, R2=Me, R3=R4=NH2) in
analytical purity. The spectral and analytical data were in
agreement with authentic material.4c,6