L-Proline catalyzed synthesis of densely functionalized pyrido[2,3-d]pyrimidines via three-component one-pot domino Knoevenagel aza-Diels-Alder reaction

Article abstract of DOI:10.1016/j.tet.2011.06.051

Highly functionalized hitherto unreported pyrido[2,3-d]pyrimidines have been concisely synthesized in good yields via l-proline catalyzed one-pot three-component domino coupling of 6-amino-1,3-dimethyluracil, aldehydes, and dialkyl acetylenedicarboxylates

Full text of DOI:10.1016/j.tet.2011.06.051

Tetrahedron 67 (2011) 5935e5941
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
L
-Proline catalyzed synthesis of densely functionalized pyrido[2,3-d]pyrimidines
via three-component one-pot domino Knoevenagel aza-DielseAlder reaction
*
Subhasis Samai, Ganesh Chandra Nandi, Sushobhan Chowdhury, Maya Shankar Singh
Department of Chemistry (Centre of Advanced Study), Faculty of Science, Banaras Hindu University, Varanasi 221005, U.P., India
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly functionalized hitherto unreported pyrido[2,3-d]pyrimidines have been concisely synthesized in
Received 22 March 2011
Received in revised form 30 May 2011
Accepted 14 June 2011
good yields via
L-proline catalyzed one-pot three-component domino coupling of 6-amino-1,3-
dimethyluracil, aldehydes, and dialkyl acetylenedicarboxylates under mild conditions for the first time.
The MCR process involves Knoevenagel condensation followed by [4þ2] cycloaddition reaction. No co-
catalyst or activator is required for this MCR. The molecular structures of two representative pyrido
[2,3-d]pyrimidines 4a and 4h were confirmed by single crystal X-ray diffraction.
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 22 June 2011
Keywords:
One-pot three-component reaction
L-Proline
Pyrido[2,3-d]pyrimidine
Knoevenagel condensation
Aza-DielseAlder reaction
1. Introduction
inhibitors of adenosine kinase (AK).6 Therefore, much effort has
been directed toward the synthetic manipulation of uracil for the
Organic compounds containing pyrimidine scaffold as a core unit
are known to exhibit various biological and pharmaceutical
activities,1aec such as antiviral,1d antibacterial,1e,f antitumor,1g anti-
inflammatory,1h antifungal,1i,j and antileishmanial agent.1k Conse-
quently, the synthesis of such heterocyclic scaffolds is assigned as
one of the most fertile areas for both synthetic and medicinal
chemists. Uracil derivatives2 are versatile building blocks for the
synthesis of nitrogen-containing heteroaromatic species of bi-
ological importance.3 Pyrido[2,3-d]pyrimidines are a class of natu-
rally occurring fused uracils occupying a special place in synthetic
organic as well as in medicinal chemistry. They have received
enormous interest over the past years due to their wide range of
pharmacological activities, such as antibacterial,4a antitumor,4b,c
antihypertensive,4d cardiotonic,4d,e bronchiodilator,4f vasodilator,4g
antialergic,4h antimalarial,4i analgesic,4j,k antifungal,4l and CNS
depressant4m properties. Moreover, appropriately functionalized
pyrido[2,3-d]pyrimidines (Chart 1) exhibit variety of promising
pharmacological activities, such as potent inhibitor of dihydrofolate
reductase(I),5a in treatment of diarrhea (II),5b specific inhibitor of
cyclin dependent kinase 4 (III),5c and induces apoptosis of K562
cells.5d Compounds having pyrido[2,3-d]pyrimidine as a central core
unit have also been identified as a new class of fibroblast growth
factor receptor (FGFR3) tyrosine kinase inhibitors.5e,f 4-Amino-5,7-
disubstituted pyridopyrimidines are potent non-nucleoside
preparation of these bioactive molecules.
Due to environmental and economically positive implications,
one-pot multicomponent coupling reactions7 (MCRs) have been
proven to be a very elegant and rapid way to access complex
structures in a single synthetic operation from simple building
blocks. They also address fundamental principles of synthetic effi-
ciency and reaction design, and show atom-economy and selec-
tivity. MCRs are important tools for both combinatorial chemistry
and diversity-oriented synthesis (DOS), and thus play a significant
role in the development of methodology for drug discovery.8,9
MCRs can be considered as an interesting topic for academic re-
search, which also satisfies a practical interest of applied science.
Among the variety of methods documented in the literature, the
widely exploited DielseAlder (DA) reaction10 is the most favorite
protocol to synthesize six-membered carbocycles and/or hetero-
cycles. The hetero-DielseAlder (HAD) reaction represents one of the
most effective methods for the synthesis of six-membered hetero-
cycles,10i,11 because of their atom economical and stereocontrolled
nature.12 Among catalytic asymmetric hetero-DielseAlder re-
actions,12 the aza-DielseAlder version12m has received much less
attention, despite its potential utility to afford optically active
dihydropyridines.
The synthesis of pyrido[2,3-d]pyrimidines is mainly by twoways,
i.e., annulation of pyrimidine ring over pyridine or vice versa.13a In
spite of the importance of pyrido[2,3-d]pyrimidines, exemplified by
the derivatives (Chart 1), there are limited methods13 that allow
* Corresponding author. E-mail address: mssinghbhu@yahoo.co.in (M.S. Singh).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.051

5936
S. Samai et al. / Tetrahedron 67 (2011) 5935e5941
Earlier works:13
CH3
N
N
Br
OH Ar
OH
N
OMe
KF/Al2O3
HN
N
O
CN
CN
OMe
N
O
N
ArCHO +
O
NH2 CH3
+
EtOH reflux
CN
Me
N
HO
N
N
NH2
5-8h
HO
NH2
N
N
OMe
H
(67-95%)
O
N
Me
N
H2N
N
N
H
N
I
R2
II
III
R1
R2
CO2Me
NH
NH2
R1
O
MW
1400c
CN
N
Anti-diarrhea
+
CDK-4 Inhibitor
Inhibitor of Dihydrofolate
Reductases
+
H2N
CO2Me
H2N
N
N
H
Chart 1. Some biologically active pyrido[2,3-d]pyrimidine frameworks.
(53-98%)
OH
N
OH Ar
sodium lauryl
sulfate/H2O
CN
CN
CN
N
N
their preparation. Further, they suffer from drawbacks, such as long
reaction time, relatively expensive or harmful catalysts, cumber-
some experimental procedures, and lacking generality. Therefore,
more general, efficient, and viable routes are very much desirable in
view of their broad array of biological activity, and would be of great
+
ArCHO
+
900c
NH2
HS
HS
N
N
NH2
(28-81%)
O
O
N
R
Me
Me
COMe
Me
O
O
AcOH
N
N
relevance to both synthetic and medicinal chemists. L-Proline has
+
NH2
RCHO +
heat, 8h
drawn much interest in different organic reactions due to its ex-
perimental simplicity, non toxicity, ease of handling, cost effec-
tiveness, and excellent solubility in water and organic solvents.
O
N
O
N
H
Me
Me
(high yields)
L
-Proline being bifunctional molecule, has been found to be very
effective in direct catalytic asymmetric reactions,14 including the
synthesis of 1,4-dihydropyridines.15 Recently, we reported
-proline
This work:
L
O
R
catalyzed synthesis of highly substituted imidazoles via multicom-
ponent one-pot reaction.16 In the course of our research aimed at the
synthesis of bioactive heterocycles utilizing multicomponent re-
O
COOR'
COOR'
L-Proline (10 mol %)
EtOH, reflux, 4-6 h
Me
O
COOR'
COOR'
Me
N
N
R
CHO
+
+
NH2
N
N
H
actions,17 in this paper, we report the first example of
L-proline
One-pot
[3+1+2] Annulation
O
N
Me
Me
catalyzed efficient synthesis of highly functionalized pyrido[2,3-d]
pyrimidines via one-pot three-component domino Knoevenagel
aza-DielseAlder reaction.
Scheme 1. Synthesis of pyrido[2,3-d]pyrimidines.
percentages (5 mol %, 10 mol %, and 15 mol %, Table 1, entries 6e8).
It was observed that 10 mol % loading of the -proline provided the
2. Results and discussion
L
maximum yield (Table 1, entry 7). Higher percentage loading of the
catalyst neither increased the yield nor reduced the reaction time
(Table 1, entry 8). Secondly, to find the most suitable solvent for
Our literature survey at this stage revealed that, despite the
potent and diverse biological activities of pyrido[2,3-d]pyrimidines,
there are only limited publications13 devoted to the synthesis of
pyrido[2,3-d]pyrimidines (Scheme 1). However, to the best of our
knowledge, there was no report yet available on the synthesis of
pyrido[2,3-d]pyrimidines in one-pot via three-component coupling
reaction utilizing 6-amino-1,3-dimethyluracil, aldehyde, and dia-
lkyl acetylenedicarboxylate as the versatile templates in the pres-
L-proline, various non-polar (CH2Cl2, CHCl3, toluene), polar-aprotic
(CH3CN, DMF, DMSO), and polar-protic (MeOH, EtOH, and i-PrOH)
solvents were used but the best result was obtained in ethanol
(Table 1, entry 7). Finally, the reaction temperature was also ex-
amined and 80 ꢀC was found to be the optimum temperature. Re-
ducing the temperature from 80 ꢀC led to a significant decrease in
the yield of the desired product 4. The reactions usually completed
within 4e6 h (monitored by TLC).
ence of L-proline as catalyst. We therefore became interested in
devising more general synthetic strategy for the construction of
pyrido[2,3-d]pyrimidines (Scheme 1).
Subsequently, with optimal condition in hand, the generality and
synthetic scope of this coupling protocol was demonstrated by
synthesizing a series of pyrido[2,3-d]pyrimidines 4aer. A wide
range of aldehydes (aromatic, heteroaromatic, and aliphatic) and
methyl/ethyl acetylenedicarboxylates were well tolerated under the
reaction conditions and furnished the corresponding pyrido[2,3-d]
pyrimidines in good yields (Table 2). However, in comparison to
aromatic aldehydes, aliphatic aldehydes gave lower yields (Table 2,
entries 4len) thus, limiting the scope of this reaction to some extent.
The structures of all the compounds were ascertained by their
satisfactory elemental analyses and spectral (IR, 1H, 13C NMR, and
MS) studies. The 1H NMR spectra showed the absence of C-5 proton
of the uracil moiety in all the synthesized compounds, which
supported the involvement of a cycloaddition process. The dihy-
dropyridine ring exhibited a sharp singlet for the chiral 5-CH about
4.98e5.29 ppm when aromatic ring was attached to this chiral
carbon, while it appeared around 3.90e4.00 ppm when aliphatic
substituent was attached to this carbon. The sharp singlet around
6.66e6.90 ppm for the NH proton (D2O exchangeable) was ob-
served. 13C NMR spectra showed distinct resonances in agreement
In our initial studies, 6-amino-1,3-dimethyluracil (1.0 mmol),
benzaldehyde (1.0 mmol), and diethyl acetylenedicarboxylate
(1.3 mmol) were refluxed in ethanol for 24 h without catalyst. The
reaction gave an unexpected Knoevenagel condensation product 5
as the major one in 78% yield, while the expected cascade HDA
cycloadduct 4 was detected in the trace amount only (Table 1, entry
1). TLC of the above reaction mixture showed the non-consumption
of diethyl acetylenedicarboxylate. Subsequently, various acid cata-
lysts, such as InCl3, SiO2eH2SO4, SiO2eHClO4, and p-TSA were
tested for the above reaction to promote condensation and cyclo-
addition. InCl3 could not trigger the reaction, while SiO2eH2SO4,
SiO2eHClO4, and p-TSA gave a mixture of 4 and 5 in almost equal
amounts (Table 1, entries 3e5). Encouraged by this result, various
organocatalysts, such as
L-proline, trans-4-hydroxyproline,
L-leu-
cine, and phenyl glycine were used, and to our delight
L-proline
provided satisfactory results (Table 1, entries 6e11).
Confident that the method would tolerate structural diversity,
focus then shifted to optimization. To optimize the catalyst loading,
above model reaction was carried out under different L-proline

S. Samai et al. / Tetrahedron 67 (2011) 5935e5941
5937
Table 1
Optimization of the reaction conditions for the synthesis of 4a
O
O
O
Ph
O
Ph
Me
Me
O
COOEt
Me
N
N
Reaction Me
condition
COOEt
N
N
+
+ Ph CHO
O
+
N
N
O
N
NH2
O
N
N
H
COOEt
2
H2N
NH2
COOEt
Me
Me
Me
1
Me
3
5
4
Entry
Solvent
Catalyst (mol %)
Time (h)
Yieldb (%) 4
Yieldc (%) 5
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
i-PrOH
CH2Cl2
CHCl3
Toluene
CH3CN
DMF
No catalyst
InCl3 (10)
SiO2eH2SO4
SiO2eHClO4
p-TSA (10)
24
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
Trace
Nil
42
40
35
62
84
84
58
55
46
52
65
20
18
24
29
36
32
78
90
44
45
40
14
7
L-Proline (5)
L-Proline (10)
L-Proline (15)
8
9
trans-4-Hydroxyproline (10)
-Leucine (10)
Phenylglycine (10)
16
16
14
30
19
52
62
51
44
16
12
10
11
12
13
14
15
16
17
18
19
L
L-Proline (10)
L-Proline (10)
L-Proline (10)
L-Proline (10)
L-Proline (10)
L-Proline (10)
L-Proline (10)
L-Proline (10)
DMSO
a
Reaction of 6-amino-1,3-dimethyluracil 1 (1.0 mmol), benzaldehyde 2 (1.0 mmol), and diethyl acetylenedicarboxylate 3 (1.3 mmol).
Isolated yields.
Yields based upon the starting material aldehyde.
b
c
Table 2
Synthesis of pyrido[2,3-d]pyrimidines 4
O
R
O
COOR'
Me
O
COOR'
COOR'
Me
O
N
N
L-Proline
+
R
CHO +
N
N
H
EtOH
reflux
N
Me
1
NH2
2
COOR'
Me
4
3
Entry
R
R0
Time (h)
Yielda (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
C6H5
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
4
4
4.5
4
4
4
4
4
4
4
5
5.5
6
6
4
5
5
4.5
84
74
75
76
74
85
78
88
69
70
80
48
54
46
76
70
72
70
4-MeC6H4
4-ClC6H4
4-NO2C6H4
4-OMeC6H4
2-Furyl
2-Thienyl
2,4-Cl2C6H3
4-BrC6H4
4-FC6H4
3-ClC6H4
CH3
Cyclohexyl
CH3CH2
C6H5
2-ClC6H4
4-MeC6H4
2-Furyl
a
Isolated yields.
with the proposed structures. The mass spectra of these com-
pounds displayed molecular ion peaks at the appropriate m/z
values. Finally, the single crystal X-ray diffraction analyses of two
representative compounds 4a and 4h were used unambiguously to
corroborate the formation of racemic mixture, which was sup-
ported by X-ray diffraction data of compound 4h, where both
the optical isomers have co-crystallized in the same lattice (Fig. 1,
Table 3). The CCDC numbers are available in the website.18
Fig. 1. ORTEP diagrams for 4a and 4h.

5938
S. Samai et al. / Tetrahedron 67 (2011) 5935e5941
Table 3
pyrimidines via three-component one-pot reaction of 1,3-
dimethyl-6-amino uracil, aldehydes, and dialkyl acetylenedi-
Crystal data of compounds 4a and 4h
carboxylates through domino Knoevenagel condensation/[4þ2]
4a
4h
cycloaddition in the presence of
L-proline for the first time. The
Empirical formula
Formula weight
C21H23N3O6
413.42
C21H21Cl2N3O6
482.31
advantages of operational simplicity, economic viability, generality,
atom-economy, together with ecologically benign nature make this
protocol a very efficient alternative to literature methods, which
could be directly used for biological assays. Further, library gener-
ation and biological evaluation of these compounds is currently
under investigation in our research group.
Crystal system, space group
Monoclinic
7.8659 (5)
19.4927 (15)
12.9732 (9)
91.237 (9)
1988.7 (2)
4
1.1381
0.103
872
Triclinic
8.9113 (7)
11.8263 (10)
23.2535 (13)
92.442 (5)
2270.8 (3)
4
1.411
0.328
1000
ꢀ
a/A
ꢀ
b/A
ꢀ
c/A
ꢀ
b
/
3
ꢀ
Volume/A
Z
Calculated density/g cmꢁ3
Absorption coefficient/mmꢁ1
F(000)
4. Experimental section
4.1. General
O
O
All the chemicals used were reagent grade purchased from
Merck, Aldrich, CDH, and Fluka, and were used as received without
further purification. The products were purified by column chro-
matography over silica gel. 1H and 13C NMR spectra were recorded
at 300 MHz and 75 MHz, respectively, on JEOL AL 300 FT-NMR
N
O
O
N
H
-H2O
O
H
H
H
R
Me
O
N
R
H2N
N
Me
1
O
spectrometer. Chemical shifts are given as
d (ppm) values with
2
reference to tetramethylsilane (TMS) as the internal standard. IR
spectra (KBr) were recorded on Varian 3100 FT-IR spectropho-
tometer in the range of 400e4000 cmꢁ1. Mass spectra were
recorded at 70 eV ionizing voltage on a JEOL-D300 MS instrument.
The CHN analyses were performed from microanalytical laboratory
with an Exeter Analytical Inc. ‘Model CE-400 CHN Analyzer’. X-ray
diffraction was measured on Xcalibur Oxford CCD Diffractometer.
All the reactions were monitored by TLC using precoated sheets of
silica gel G/UV-254 of 0.25 mm thickness (Merck 60F254). Melting
O
N
OH
H
O
N
R
O
R
CO2R'
Me
CO2R'
CO2R'
Me
O
N
N
O
N
H
N
CO2R'
NH
Me
Me
A
3
4
€
points were determined with Buchi B-540 melting point in-
Scheme 2. A plausible mechanism for the synthesis of pyrido[2,3-d]pyrimidines.
strument and are uncorrected.
4.2. General procedure for the synthesis of 1,3-dimethyl-2,4-
dioxo-5-aryl/alkyl-1,2,3,4,5,8-hexadihydro[2,3-d]pyrimidine-
6,7-dicarboxylic acid dimethyl/diethylester (4)
The preceding examples nicely highlight how adduct obtained
from three-component reaction involving aldehydes, 1,3-dimethyl-
6-amino uracil, and dialkyl acetylenedicarboxylate can be readily
transformed by cascade reactions to generate heterocycles that are
endowed with useful functionality for further manipulation and
diversification. This new pyrido[2,3-d]pyrimidine synthesis can be
viewed as an alternative to some previously known pyrido[2,3-d]
pyrimidine synthesis. One of the benefits of this class of trans-
formations is that it takes advantage of the large number of com-
mercially available aldehyde derivatives. The economical factors
(time, money, waste etc.) for these three-component reactions hold
promise for the future of organic synthesis.
A tentative mechanistic rationale portraying the probable se-
quence of events is given in Scheme 2. It is conceivable that initially
the 1,3-dimethyl-6-amino uracil 1 undergoes proline catalyzed
Knoevenagel condensation with aldehyde 2 to give the ortho-imi-
nemethide intermediate A. Once the intermediate A is formed, it
underwent spontaneous [4þ2] cycloaddition with dialkyl acetyle-
nedicarboxylate 3 to form the desired pyrido[2,3-d]pyrimidine 4.
The intermediate A is quite reactive and not isolable, although its
intermediacy has been confirmed by the formation of product 5 via
the attack of second molecule of 1,3-dimethyl-6-amino uracil
(Table 1). The condensation and cycloaddition proceeded well
without the electronic and steric effect of the substituents. Thus, by
this strategy, two new carbonecarbon bonds and one carbon-
enitrogen bond could be formed in a single stroke with the efficient
assembly of two rings from readily available starting materials.
In a 50 mL round bottom flask 6-amino-1,3-dimethyluracil
(1.0 mmol), aldehyde (1.0 mmol), and ethyl or methyl acetylene-
dicarboxylate (1.3 mmol) were taken in 4 mL ethanol, and 11.5 mg
(10 mol %) of L-proline was added to it. The reaction mixture was
stirred at reflux temperature for the stipulated period of time. The
progress of the reaction was monitored by TLC. After completion of
the reaction, the solvent was removed under reduced pressure. The
residue was diluted with water and extracted with diethyl ether
(3ꢂ15 mL). The combined organic phase was washed with brine
and dried over anhydrous MgSO4. The solvent was removed under
vacuum and the crude product was purified by silica gel column
chromatography using methanol and dichloromethane (1:49) as
eluent to afford the desired product in excellent purity. The physical
and spectral data of the synthesized compounds are as follows:
4.2.1. 1,3-Dimethyl-2,4-dioxo-5-phenyl-1,2,3,4,5,8-hexahydro pyrido
[2,3-d]pyrimidine-6,7-dicarboxylic acid diethylester (4a). Colorless
solid; mp 224e225 ꢀC; IR (KBr, nmax, cmꢁ1): 3191, 1743, 1704, 1660,
1610; 1H NMR (300 MHz, CDCl3,
d ppm): 7.32e7.20 (m, 5H), 6.76 (s,
1H), 5.01 (s, 1H), 4.33 (q, J¼5.1 Hz, 2H), 4.12 (q, J¼7.2 Hz, 2H), 3.51 (s,
3H), 3.25 (s, 3H), 1.33 (t, J¼7.2 Hz, 3H), 1.12 (t, J¼7.8 Hz, 3H); 13C
NMR (75 MHz, CDCl3, d ppm): 166.3, 162.3, 161.0, 150.8, 143.3, 143.1,
128.4, 127.9, 127.2, 126.5, 118.0, 88.4, 63.1, 61.2, 40.7, 28.6, 28.0, 13.7;
ESI-MS: m/z¼436.2 (Mþþ23); Anal. Calcd for C21H23N3O6: C, 61.01;
H, 5.61; N, 10.16. Found: C, 61.29; H, 5.85; N, 10.02.
3. Conclusion
4.2.2. 1,3-Dimethyl-2,4-dioxo-5-p-tolyl-1,2,3,4,5,8-hexahydro pyrido
[2,3-d]pyrimidine-6,7-dicarboxylic acid diethylester (4b). Pale yel-
low solid; mp 236e237 ꢀC; IR (KBr, nmax, cmꢁ1): 3266, 1744, 1707,
In conclusion, we have devised a versatile, convenient, and ef-
ficient approach to construct the structurally diverse pyrido[2,3-d]

S. Samai et al. / Tetrahedron 67 (2011) 5935e5941
5939
1617; 1H NMR (300 MHz, CDCl3,
d
ppm): 7.21 (d, J¼7.8 Hz, 2H), 7.09
m/z¼442.2 (Mþþ23); Anal. Calcd for C19H21N3O6S: C, 54.41; H,
(d, J¼7.5 Hz, 2H), 6.90 (s,1H), 4.97 (s,1H), 4.34 (q, J¼7.2 Hz, 2H), 4.13
(q, J¼7.5 Hz, 2H), 3.47 (s, 3H), 3.25 (s, 3H), 2.27 (s, 3H), 1.33 (t,
J¼7.2 Hz, 3H), 1.16 (t, J¼6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3,
5.05; N, 10.02. Found: C, 54.66; H, 5.27; N, 9.86.
4.2.8. 5-(2,4-Dichlorophenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,8-
hexahydropyrido[2,3-d]pyrimidine-6,7-dicarboxylic acid diethylester
(4h). Colorless solid; mp 237e238 ꢀC; IR (KBr, nmax, cmꢁ1): 3222,
d
ppm): 166.8, 162.5, 161.0, 150.2, 142.7, 140.4, 137.0, 129.3, 127.4,
126.8, 118.1, 88.5, 63.6, 62.4, 40.0, 29.6, 28.6, 13.8; ESI-MS:
m/z¼428.2 (Mþþ1); Anal. Calcd for C22H25N3O6: C, 61.82; H, 5.90;
N, 9.83. Found: C, 61.59; H, 6.23; N, 9.98.
1746,1705,1643,1619; 1H NMR (300 MHz, CDCl3,
d ppm): 7.33 (s,1H),
7.23e7.17 (m, 2H), 6.80 (s,1H), 5.50 (s,1H), 4.32 (q, J¼6.9 Hz, 2H), 4.14
(q, J¼6.9 Hz, 2H), 3.54 (s, 3H), 3.24 (s, 3H),1.32 (t, J¼6.9 Hz, 3H),1.17 (t,
4.2.3. 5-(4-Chlorophenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,8-
hexahydropyrido[2,3-d]pyrimidine-6,7-dicarboxylic acid diethylester
(4c). White solid; mp 234e235 ꢀC; IR (KBr, nmax, cmꢁ1): 3219, 1747,
J¼6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3,
d ppm): 165.9, 161.6, 160.8,
150.7, 143.7, 139.4, 133.8, 133.6, 131.6, 129.2, 127.5, 124.9, 118.0, 86.9,
63.3, 61.6, 38.5, 28.7, 28.0, 13.7; ESI-MS: m/z¼482.0 (Mþþ1); Anal.
Calcd for C21H21Cl2N3O6:C, 52.29; H, 4.39; N, 8.71. Found: C, 52.01; H,
4.65; N, 8.56.
1702, 1640, 1607; 1H NMR (300 MHz, CDCl3,
d ppm): 7.41 (d,
J¼8.1 Hz, 2H), 7.21 (d, J¼8.1 Hz, 2H), 6.76 (s, 1H), 4.98 (s, 1H), 4.37 (q,
J¼7.2 Hz, 2H), 4.13 (q, J¼7.2 Hz, 2H), 3.51 (s, 3H), 3.25 (s, 3H), 1.34 (t,
J¼7.2 Hz, 3H), 1.15 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3,
4.2.9. 5-(4-Bromophenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,8-
hexahydropyrido[2,3-d]pyrimidine-6,7-dicarboxylic acid diethylester
(4i). White solid; mp 266e267 ꢀC; IR (KBr, nmax, cmꢁ1) 3207, 1742,
d
ppm): 166.2, 162.0, 160.9, 150.7, 143.0, 141.7, 133.1, 129.3, 128.6,
126.0, 118.2, 87.9, 63.3, 61.4, 40.5, 28.6, 28.1, 14.0, 13.7; ESI-MS:
m/z¼448.3 (Mþþ1); Anal. Calcd for C21H22ClN3O6: C, 56.32; H,
4.95; N, 9.38. Found: C, 56.10; H, 5.20; N, 9.65.
1706,1610; 1H NMR (300 MHz, CDCl3,
d
ppm): 7.41 (d, J¼8.1 Hz, 2H),
7.21 (d, J¼8.1 Hz, 2H), 6.75 (s, 1H), 4.98 (s, 1H), 4.37 (q, J¼7.2 Hz, 2H),
4.13 (q, J¼7.5 Hz, 2H), 3.51 (s, 3H), 3.25 (s, 3H), 1.34 (t, J¼7.2 Hz, 3H),
4.2.4. 1,3-Dimethyl-5-(4-nitrophenyl)-2,4-dioxo-1,2,3,4,5.8-
hexahydropyrido[2,3-d]pyrimidine-6,7-dicarboxylic acid diethylester
(4d). White solid; mp 275e276 ꢀC; IR (KBr, nmax, cmꢁ1): 3220, 1742,
1.15 (t, J¼6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3,
d ppm): 166.2,162.0,
160.9, 150.7, 143.0, 142.2, 131.5, 129.7, 126.1, 121.3, 118.1, 87.9, 63.3,
61.4, 40.6, 28.6, 28.1, 13.8, 13.7; ESI-MS: m/z¼492.1 (Mþþ1); Anal.
Calcd for C21H22BrN3O6: C, 51.23; H, 4.50; N. 8.54. Found: C, 51.40;
H, 4.25; N, 8.22.
1702, 1635, 1619, 1378; 1H NMR (300 MHz, CDCl3,
d ppm): 8.16 (d,
J¼8.4 Hz, 2H), 7.52 (d, J¼8.4 Hz, 2H), 6.84 (s,1H), 5.14 (s,1H), 4.39 (q,
J¼7.2 Hz, 2H), 4.11 (q, J¼7.5 Hz, 2H), 3.54 (s, 3H), 3.25 (s, 3H), 1.35 (t,
J¼7.2 Hz, 3H), 1.14 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3,
4.2.10. 5-(4-Fluorophenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,8-
hexahydropyrido[2,3-d]pyrimidine-6,7-dicarboxylic acid diethylester
(4j). White solid; mp 254e255 ꢀC; IR (KBr, nmax, cmꢁ1): 3212, 1746,
d
ppm): 165.8, 161.9, 160.9, 150.6, 150.2, 147.0, 143.2, 129.0, 127.2,
123.7, 116.6, 87.4, 63.5, 61.6, 40.9, 28.7, 28.1, 13.8, 13.7; ESI-MS:
m/z¼459.2 (Mþþ1); Anal. Calcd for C21H22N4O8: C, 55.02; H, 4.84;
N, 12.22. Found: C, 55.29; H, 5.17; N, 12.45.
1704, 1612; 1H NMR (300 MHz, CDCl3,
d ppm): 7.30e7.28 (m, 1H),
6.99e6.93 (m, 3H), 6.78 (s, 1H), 5.00 (s, 1H), 4.34 (q, J¼6.9 Hz, 2H),
4.12 (q, J¼7.2 Hz, 2H), 3.53 (s, 3H), 3.25 (s, 3H), 1.35 (t, J¼7.2 Hz, 3H),
4.2.5. 5-(4-Methoxyphenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,8-
hexahydropyrido[2,3-d]pyrimidine-6,7-dicarboxylic acid diethylester
(4e). Pale yellow solid; mp 241e242 ꢀC; IR (KBr, nmax, cmꢁ1): 3225,
1.14 (t, J¼6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3,
d ppm): 165.8, 161.9,
160.9, 150.2, 147.0, 143.2, 133.7, 129.0, 127.2, 123.7, 116.6, 87.4, 63.5,
61.6, 40.9, 28.7, 28.1, 13.8, 13.7; ESI-MS: m/z¼454.2 (Mþþ23); Anal.
Calcd for C21H22FN3O6: C, 58.46; H, 5.14; N, 9.74. Found: C, 58.22; H,
5.36; N, 9.40.
1745, 1701, 1609; 1H NMR (300 MHz, CDCl3,
d ppm): 7.24 (d,
J¼8.7 Hz, 2H), 6.82 (d, J¼8.7 Hz, 2H), 6.75 (s, 1H), 4.96 (s, 1H), 4.32
(q, J¼5.7 Hz, 2H), 4.13 (q, J¼7.2 Hz, 2H), 3.74 (s, 3H), 3.49 (s, 3H),
3.25 (s, 3H), 1.33 (t, J¼7.2 Hz, 3H), 1.15 (t, J¼7.2 Hz, 3H); 13C NMR
4.2.11. 5-(3-Chlorophenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,8-
hexahydropyrido[2,3-d]pyrimidine-6,7-dicarboxylic acid diethylester
(4k). White solid; mp 188e189 ꢀC; IR (KBr, nmax, cmꢁ1): 3196, 1746,
(75 MHz, CDCl3,
d ppm): 166.5, 162.2, 161.0, 158.7, 150.8, 142.9,
135.5, 129.0, 125.4, 119.0, 113.8, 88.4, 63.1, 61.3, 55.1, 40.3, 28.6, 28.1,
13.8, 13.7; ESI-MS: m/z¼444.1 (Mþþ1); Anal. Calcd for C22H25N3O7:
C, 59.59; H, 5.68; N, 9.48. Found: C, 59.80; H, 5.36; N, 9.72.
1709, 1664, 1611; 1H NMR (300 MHz, CDCl3,
d ppm): 7.25e7.20 (m,
4H), 6.76 (s,1H), 5.00 (s,1H), 4.37 (q, J¼7.2 Hz, 2H), 4.14 (q, J¼6.9 Hz,
2H), 3.53 (s, 3H), 3.26 (s, 3H), 1.34 (t, J¼6.9 Hz, 3H), 1.15 (t, J¼7.2 Hz,
4.2.6. 5-Furan-2-yl-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,8-
hexahydropyrido[2,3-d]pyrimidine-6,7-dicarboxylic acid diethylester
(4f). White solid; mp 175e176 ꢀC; IR (KBr, nmax, cmꢁ1): 3207, 1746,
3H); 13C NMR (75 MHz, CDCl3,
d ppm): 166.1, 162.1, 160.9, 150.7,
145.2, 143.2, 134.3, 129.5, 128.0, 127.5, 126.7, 126.3, 117.4, 87.8, 63.2,
61.3, 40.6, 28.6, 28.1, 13.8, 13.7; ESI-MS: m/z¼448.3 (Mþþ1); Anal.
Calcd for C21H22ClN3O6: C, 56.32; H, 4.95; N, 9.38. Found: C, 56.19;
H, 4.89; N, 9.50.
1703, 1656, 1612; 1H NMR (300 MHz, CDCl3,
d ppm): 7.27 (s, 1H),
7.00 (s, 1H), 6.26e6.19 (m, 2H), 5.18 (s, 1H), 4.33 (q, J¼7.2 Hz, 2H),
4.20 (q, J¼6.9 Hz, 2H), 3.50 (s, 3H), 3.30 (s, 3H),1.34 (t, J¼7.2 Hz, 3H),
1.24 (t, J¼6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3,
d
ppm): 166.1, 162.1,
4.2.12. 1,3,5-Trimethyl-2,4-dioxo-1,2,3,4,5,8-hexahydropyrido [2,3-d]
pyrimidine-6,7-dicarboxylic acid diethylester (4l). Yellow jelly; IR
(KBr, nmax, cmꢁ1): 1740, 1702, 1661, 1597; 1H NMR (300 MHz, CDCl3,
160.9, 154.1, 150.8, 143.5, 142.0, 127.0, 115.2, 110.5, 106.7, 85.3, 63.2,
61.4, 34.3, 28.6, 28.1, 13.9, 13.7; ESI-MS: m/z¼404.2 (Mþþ1); Anal.
Calcd for C19H21N3O7: C, 56.57; H, 5.25; N, 10.42. Found: C, 56.80; H,
5.02; N, 10.19.
d
ppm): 6.66 (s, 1H), 4.36e4.22 (m, 4H), 3.94 (q, J¼6.6 Hz, 1H), 3.47
(s, 3H), 3.42 (s, 3H), 1.35e1.28 (m, 9H); 13C NMR (75 MHz, CDCl3,
d
ppm): 166.8, 161.8, 161.1, 150.8, 143.5, 125.7, 120.5, 88.3, 62.9, 61.4,
4.2.7. 1,3-Dimethyl-2,4-dioxo-5-thiophen-2-yl-1,2,3,4,5.8-
hexahydropyrido[2,3-d]pyrimidine-6,7-dicarboxylic acid diethylester
(4g). Pale yellow solid; mp 181e182 ꢀC; IR (KBr, nmax, cmꢁ1): 3193,
30.1, 28.4, 28.0, 21.2, 14.0, 13.8; ESI-MS: m/z¼352.2 (Mþþ1); Anal.
Calcd for C16H21N3O6: C, 54.69; H, 6.02; N, 11.96. Found: C, 54.52; H,
5.90; N, 11.80.
1746, 1704, 1660, 1612; 1H NMR (300 MHz, CDCl3,
d ppm): 7.15 (d,
J¼8.1 Hz, 1H), 6.95 (s, 1H), 6.90e6.85 (m, 2H), 5.36 (s, 1H), 4.37 (q,
J¼6.9 Hz, 2H), 4.20 (q, J¼7.2 Hz, 2H), 3.50 (s, 3H), 3.30 (s, 3H), 1.35 (t,
J¼7.2 Hz, 3H), 1.23 (t, J¼7.2 Hz, 3H); 13C NMR(75 MHz, CDCl3,
4.2.13. 5-Cyclohexyl-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,8-
hexahydropyrido[2,3-d]pyrimidine-6,7-dicarboxylic acid diethylester
(4m). Yellow jelly; IR (KBr, nmax, cmꢁ1): 1743, 1707, 1662, 1599; 1H
d
ppm): 165.8, 162.6, 161.0, 150.7, 147.0, 142.9, 128.4, 126.7, 124.8,
NMR (300 MHz, CDCl3,
d
ppm): 6.73 (s, 1H), 4.33 (q, J¼7.2 Hz, 2H),
124.5, 115.5, 88.5, 63.2, 61.4, 34.7, 28.7, 27.2, 13.9, 13.7; ESI-MS:
4.27 (q, J¼7.2 Hz, 2H), 3.94 (s, 1H), 3.48 (s, 3H), 3.35 (s, 3H),

5940
S. Samai et al. / Tetrahedron 67 (2011) 5935e5941
1.41e1.25 (m, 17H); 13C NMR (75 MHz, CDCl3,
d
ppm): 165.8, 163.4,
is thankful to the University Grant Commission (UGC), New Delhi, for
160.1,151.0,140.5,119.1,110.4,83.1, 62.6, 62.1, 30.0,29.6, 28.7, 25.6, 23.6,
14.1, 13.9; ESI-MS: m/z¼420.2 (Mþþ1); Anal. Calcd for C21H29N3O6: C,
60.13; H, 6.97; N, 10.02. Found: C, 60.30; H, 6.70; N, 10.28.
the financialassistanceintheformofJuniorResearchFellowship(JRF).
Supplementary data
4.2.14. 5-Ethyl-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,8-hexahydropyrido
[2,3-d]pyrimidine-6,7-dicarboxylic acid diethylester (4n). Yellow
jelly; IR (KBr, nmax, cmꢁ1): 1747, 1706, 1660, 1612; 1H NMR
X-ray structures and crystallographic information files (CIF) for
compounds 4a and 4h have been attached. Supplementary data
associated with this article can be found, in the online version, at
doi:10.1016/j.tet.2011.06.051.
(300 MHz, CDCl3,
d ppm): 6.59 (s, 1H), 4.35e4.23 (m, 4H), 4.02 (t,
J¼3.3 Hz, 1H), 3.47 (s, 3H), 4.34 (s, 3H), 1.34e1.20 (m, 8H), 0.88 (t,
J¼6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3,
d ppm): 166.9, 161.7, 161.3,
References and notes
150.9, 144.5, 126.6, 119.1, 85.9, 62.9, 61.4, 35.7, 28.5, 28.1, 26.8, 13.9,
8.8; ESI-MS: m/z¼366.2 (Mþþ1); Calcd for C21H23N3O6: C, 55.88; H,
6.34; N, 11.50. Found: C, 55.94; H, 6.12; N, 11.57.
1. (a) Kappe, C. O. Tetrahedron 1993, 49, 6937 and references cited therein; (b)
Sasaki, S.; Cho, N.; Nara, Y.; Harada, M.; Endo, S.; Suzuki, N.; Furuya, S.; Fujino,
M. J. Med. Chem. 2003, 46, 113; (c) Ibrahim, D. A.; El-Metwally, A. M. Eur. J. Med.
Chem. 2010, 45, 1158; (d) Jones, A. S.; Sayers, J. R.; Walker, R. T.; Clercq, E. D. J.
Med. Chem. 1988, 31, 268; (e) Deshmukh, M. B.; Salunkhe, S. M.; Patil, D. R.;
Anbhule, P. V. Eur. J. Med. Chem. 2009, 44, 2651; (f) Gasse, C.; Douguet, D.;
Huteau, V.; Marchal, G.; Munier-Lehmann, H.; Pochet, S. Bioorg. Med. Chem.
2008, 16, 6075; (g) Lin, R.; Johnson, S. G.; Connolly, P. J.; Wetter, S. K.; Binnun, E.;
Hughes, T. V.; Murray, W. V.; Pandey, N. B.; Moreno-Mazza, S. J.; Adams, M.;
Fuentes-Pesquera, A. R.; Middleton, S. A. Bioorg. Med. Chem. Lett. 2009, 19, 2333;
(h) Falcao, E. P. S.; Melo, S. J.; Srivastava, R. M.; Catanho, M. T. J. A.; Nascimento,
S. C. Eur. J. Med. Chem. 2006, 41, 276; (i) Chen, Q.; Zhu, X.-L.; Jiang, L.-L.; Liu, Z.-
M.; Yang, G.-F. Eur. J. Med. Chem. 2008, 43, 595; (j) Hilmy, K. M. H.; Khalifa, M.
M. A.; Hawata, M. A. A.; Keshk, R. M. A.; El-Torgman, A. A. Eur. J. Med. Chem.
2010, 45, 5243; (k) Aliaga, M. J.; Ramon, D. J.; Yus, M. Org. Biomol. Chem. 2010, 8,
43.
4.2.15. 1,3-Dimethyl-2,4-dioxo-5-phenyl-1,2,3,4,5,8-hexahydropyrido
[2,3-d]pyrimidine-6,7-dicarboxylic acid dimethylester (4o). Yellow
solid; mp 234e235 ꢀC; IR (KBr, nmax, cmꢁ1): 3195, 1746, 1702, 1656,
1607; 1H NMR (300 MHz, CDCl3,
d
ppm): 7.30e7.20 (m, 5H), 6.78 (s,
1H), 5.03 (s, 1H), 3.88 (s, 3H), 3.64 (s, 3H), 3.50 (s, 3H), 3.25 (s, 3H);
13C (75 MHz, CDCl3,
ppm): 166.8, 162.7, 161.0, 150.8, 143.2, 142.9,
d
128.5, 127.8, 127.4, 127.2, 117.7, 88.6, 53.6, 52.3, 40.6, 28.6, 28.1; ESI-
MS: m/z¼386.2 (Mþþ1); Anal. Calcd for C19H19N3O6: C, 59.22; H,
4.97; N, 10.90. Found: C, 59.07; H, 4.70; N, 10.68.
2. (a) Marumoto, R.; Furukawa, Y. Chem. Pharm. Bull. 1977, 25, 2974; (b) Griengl,
H.; Wack, E.; Schwarz, W.; Streicher, W.; Rosenwirth, B.; De Clercq, E. J. Med.
Chem. 1987, 30, 1199; (c) De Clercq, E.; Bernaerts, R. J. Biol. Chem. 1987, 262,
14905; (d) Mitsuya, H.; Yarchoan, R.; Broder, S. Science 1990, 249, 1533; (e)
Pontikis, R.; Monneret, C. Tetrahedron Lett. 1994, 35, 4351; (f) Wamhoff, H.;
Schupp, W. J. Org. Chem. 1986, 51, 2787; (g) Hirota, K.; Banno, K.; Yamada, Y.;
Senda, S. J. Chem. Soc., Perkin Trans. 1 1985, 1137; (h) Walsh, E. B.; Wamho, H.
Chem Ber. 1989, 122, 1673.
3. (a) Lunt, E.; Newton, C. G. In Pyridodiazines and Their Benzo Derivatives; Ka-
tritzky, A. R., Rees, C. W., Boulton, A. J., Mckillop, A., Eds.; Comprehensive
Heterocyclic Chemistry; Pergamon: Oxford, 1984; Vol. 3, pp 199, 232, 260; (b)
Bradshaw, T. K.; Hutchinson, D. W. Chem. Soc. Rev. 1977, 6, 43.
4. (a) Kanth, S. R.; Reddy, G. V.; Kishore, K. H.; Rao, P. S.; Narsaiah, B.; Murthy, U. S.
N. Eur. J. Med. Chem. 2006, 41, 1011; (b) Broom, A. D.; Shim, J. L.; Anderson, G. L. J.
Org. Chem. 1976, 41, 1095; (c) Grivsky, E. M.; Lee, S.; Sigel, C. W.; Duch, D. S.;
Nichol, C. A. J. Med. Chem. 1980, 23, 327; (d) Furuya, S.; Ohtaki, T. Pyridopyr-
imidine derivatives, their production and use. Eur. Pat. Appl. EP0 608565 A1,
Aug 3, 1994; Chem. Abstr. 1994, 121, 205395; (e) Heber, D.; Heers, C.; Ravens, U.
Pharmazie 1993, 48, 537; (f) Sakuma, Y.; Hasegawa, M.; Kataoka, K.; Hoshina, K.;
Yamazaki, N.; Kadota, T.; Yamaguchi, H. 1,10-Phenanthroline Derivatives. PCT
Int. Appl. WO 91/05785, May 2, 1989; Chem. Abstr. 1991, 115, 71646; (g) Coates,
W. Pyrimidopyrimidine Derivatives. J. Eur. Pat. 0351058 A1, Jan 17, 1990; Chem.
Abstr. 1990, 113, 40711; (h) Bennett, L. R.; Blankley, C. J.; Fleming, R. W.; Smith,
R. D.; Tessman, D. K. J. Med. Chem. 1981, 24, 382; (i) Davoll, J.; Clarke, J.; Elslager,
E. F. J. Med. Chem. 1972, 15, 837; (j) Kretzschmer, E. Pharmazie 1980, 35, 253; (k)
Shigo, S.; Hiroshi, I. Yakugaku Zasshi 1969, 89, 266; (l) Ahluwalia, V. K.; Bhatla,
R.; Khurana, A.; Kumar, R. Indian J. Chem. Sect. B 1990, 29, 1141; (m) Hasan, M. F.;
Madkour, A. M.; Saleem, I.; Rahman, J. M. A.; Mohammed, E. A. Z. Heterocycles
1994, 38, 57.
4.2.16. 5-(2-Chlorophenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,8-
hexahydropyrido[2,3-d]pyrimidine-6,7-dicarboxylic acid dimethy-
lester (4p). White solid; mp 224e225 ꢀC; IR (KBr, nmax, cmꢁ1): 3226,
1747, 1704, 1654, 1612; 1H NMR (300 MHz, CDCl3,
d
ppm): 7.33e7.28
(m, 2H), 7.20e7.14 (m, 2H) 6.83 (s,1H), 5.54 (s, 1H), 3.84 (s, 3H), 3.65
(s, 3H), 3.53 (s, 3H), 3.34 (s, 3H); 13C NMR (75 MHz, CDCl3,
ppm):
d
166.5, 162.3, 160.8, 150.8, 143.7, 140.7, 135.1, 133.3, 129.8, 117.6, 87.5,
53.6, 52.4, 29.6, 29.3; ESI-MS: m/z¼420.3 (Mþþ1); Anal. Calcd for
C19H18ClN3O6: C, 54.36; H, 4.32; N, 10.01. Found: C, 54.20; H, 4.58;
N, 10.28.
4.2.17. 1,3-Dimethyl-2,4-dioxo-5-p-tolyl-1,2,3,4,5,8-hexahydropyrido
[2,3-d]pyrimidine-6,7-dicarboxylic acid dimethylester (4q). Pale
yellow solid; mp 220e221 ꢀC; IR (KBr, nmax, cmꢁ1): 3260,1746,1704,
1629; 1H NMR (300 MHz, CDCl3,
d
ppm): 7.21 (d, J¼8.1 Hz, 2H), 7.09
(d, J¼7.8 Hz, 2H), 6.80 (s, 1H), 4.98 (s, 1H), 3.87 (s, 3H), 3.65 (s, 3H),
3.49 (s, 3H), 3.25 (s, 3H), 2.28 (s, 3H); 13C NMR (75 MHz, CDCl3,
d
ppm): 166.8, 162.7, 161.0, 150.8, 142.8, 140.3, 137.0, 129.2, 127.6,
126.8,118.0, 88.7, 53.6, 52.3, 40.0, 28.6, 28.1, 21.1; ESI-MS: m/z¼400.1
(Mþþ1); Anal. Calcd for C20H21N3O6: C, 60.14; H, 5.30; N, 10.52.
Found: C, 60.39; H, 5.14; N, 10.69.
5. (a) Gangjee, A.; Vasudevan, A.; Queener, S. F.; Kisliuk, R. L. J. Med. Chem. 1996,
39, 1438; (b) Kots, A. Y.; Choi, B.-K.; Estrella-Jimenez, M. E.; Warren, C. A.;
Gilbertson, S. R.; Guerrant, R. L.; Murad, F. Proc. Natl. Acad. Sci. U. S. A. 2008, 105,
8440; (c) VanderWel, S. N.; Harvey, P. J.; McNamara, D. J.; Repine, J. T.; Keller, P.
R.; Quin, J., III; Booth, R. J.; Elliott, W. L.; Dobrusin, E. M.; Fry, D. W.; Toogood, P.
L. J. Med. Chem. 2005, 48, 2371; (d) Dorsey, J. F.; Jove, R.; Kraker, A. J.; Wu, J.
Cancer Res. 2000, 60, 3127; (e) Le Corre, L.; Girard, A.-L.; Aubertin, J.; Radvanyi,
F.; Benoist-Lasselin, C.; Jonquoy, A.; Mugniery, E.; Legeai-Mallet, L.; Busca, P.; Le
Merrer, Y. Org. Biomol. Chem. 2010, 8, 2164; (f) Kammasud, N.; Boonyarat, C.;
4.2.18. 5-Furan-2-yl-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,8-
hexahydropyrido[2,3-d]pyrimidine-6,7-dicarboxylic acid dimethy-
lester (4r). Pale brown solid; mp 188e189 ꢀC; IR (KBr, nmax, cmꢁ1):
3197, 1702, 1656, 1596; 1H NMR (300 MHz, CDCl3,
d ppm): 7.27 (d,
J¼4.2 Hz, 1H), 6.92 (s, 1H), 6.20e6.19 (m, 2H), 5.18 (s, 1H), 3.87 (s,
3H), 3.72 (s, 3H), 3.50 (s, 3H), 3.30 (s, 3H); 13C NMR (75 MHz, CDCl3,
d
ppm): 166.4, 162.7, 160.9, 154.1, 150.8, 143.4, 142.0, 128.5, 113.9,
ꢁ
Sanphanya, K.; Utsintong, M.; Tsunoda, S.; Sakurai, H.; Saiki, I.; Andre, I.;
110.5, 106.6, 85.6, 53.6, 52.4, 33.7, 28.7, 28.2; ESI-MS: m/z¼398.2
(Mþþ23) Anal. Calcd for C17H17N3O7: C, 54.40; H, 4.57; N, 11.20.
Found: C, 54.65; H, 4.32; N, 11.42.
Grierson, D. S.; Vajragupta, O. Bioorg. Med. Chem. Lett. 2009, 19, 745.
6. Matulenko, M. A.; Lee, C.-H.; Jiang, M.; Frey, R. R.; Cowart, M. D.; Bayburt, E. K.;
DiDomenico, S., Jr.; Gfesser, G. A.; Gomtsyan, A. G.; Zheng, Z.; McKie, J. A.;
Stewart, A. O.; Yu, H.; Kohlhaas, K. L.; Alexander, K. M.; McGaraughty, S.;
Wismer, C. T.; Mikusa, J.; Marsh, K. C.; Snyder, R. D.; Diehl, M. S.; Kowaluk, E. A.;
Jarvisa, M. F.; Bhagwat, S. S. Bioorg. Med. Chem. 2005, 13, 3705.
Acknowledgements
7. For recent reviews, see: (a) Domling, A. Chem. Rev. 2006, 106, 17; (b) Guillena,
G.; Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry 2007, 18, 693; (c) D’Souza, D.
M.; Muller, T. J. J. Chem. Soc. Rev. 2007, 36, 1095; (d) Tietze, L. F.; Kinzel, T.;
Brazel, C. C. Acc. Chem. Res. 2009, 42, 367; (e) Sunderhaus, J. D.; Martin, S. F.
Chem.dEur. J. 2009, 15, 1300; (f) Scheffelaar, R.; Paravidino, M.; Znabet, A.;
Schmitz, R. F.; de Kanter, F. J. J.; Lutz, M.; Spek, A. L.; Guerra, C. F.; Bickelhaupt, F.
M.; Groen, M. B.; Ruijter, E.; Orru, R. V. A. J. Org. Chem. 2010, 75, 1723; (g) Marek,
I. Tetrahedron 2005, 61, 11309; (h) Basso, A.; Banfi, L.; Riva, R.; Guanti, G. J. Org.
Chem. 2005, 70, 575; (i) For a monograph, see:Multicomponent Reactions; Zhu, J.,
This work was carried out under financial support from the
Council of Scientific and Industrial Research (Grant 01(2260)/08/
EMR-II) and the Department of Science and Technology (Grant SR/
S1/OC-66/2009), New Delhi. S.S and G.C.N. are thankful to Council
of Scientific and Industrial Research (CSIR), New Delhi, for the fi-
nancial assistanceinthe form ofSeniorResearchFellowship(SRF). S.C.

S. Samai et al. / Tetrahedron 67 (2011) 5935e5941
5941
Bienayme, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005; (j) Cariou, C. C. A.;
Clarkson, G. J.; Shipman, M. J. Org. Chem. 2008, 73, 9762; (k) Shaterian, H. R.;
Yarahmadi, H.; Ghashang, M. Tetrahedron 2008, 64, 1263; (l) Znabet, A.; Ruijter,
E.; de Kanter, F. J. J.; Kohler, V.; Helliwell, M.; Turner, N. J.; Orru, R. V. A. Angew.
Chem., Int. Ed. 2010, 49, 5289.
8. (a) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51; (b) Sunderhaus, J. D.;
Dockendorff, C.; Martin, S. F. Org. Lett. 2007, 9, 4223; (c) Armstrong, R. W.;
Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Chem. Res. 1996, 29, 123;
(d) Lieby-Muller, F.; Constantieux, T.; Rodriguez, J. J. Am. Chem. Soc. 2005, 127,
17176; (e) Chebanov, V. A.; Saraev, V. E.; Desenko, S. M.; Chernenko, V. N.;
Knyazeva, I. V.; Groth, U.; Glasnov, T. N.; Kappe, C. O. J. Org. Chem. 2008, 73,
5110.
M. M.; Lemos, A.; Pinho e Melo, T. M. V. D. Tetrahedron Lett. 2010, 51, 6756; (j)
Wang, X.-S.; Zhou, J.; Yang, K.; Yao, C.-S. Tetrahedron Lett. 2010, 51, 5721; (k)
Baruah, B.; Bhuyan, P. J. Tetrahedron 2009, 65, 7099; (l) Matiychuk, V. S.; Lesyk,
R. B.; Obushak, M. D.; Gzella, A.; Atamanyuk, D. V.; Ostapiuk, Y. V.; Kryshchy-
shyn, A. P. Tetrahedron Lett. 2008, 49, 4648; (m) Sunden, H.; Ibrahem, I.;
Eriksson, L.; Cordova, A. Angew. Chem., Int. Ed. 2005, 44, 4877.
13. (a) Comprehensive Heterocyclic Chemistry-II; Kataritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; 1996; Vol. 7, p 591; (b) Agarwal, A.; Chauhan, P. M. S.
Synth. Commun. 2004, 34, 4447; (c) Wang, X.-S.; Zeng, Z.-S.; Shi, D.-Q.; Wei, X.-
Y.; Zong, Z.-M. Synth. Commun. 2004, 34, 4331; (d) Mont, N.; Teixido, J.; Borrella,
J. I.; Kappe, C. O. Tetrahedron Lett. 2003, 44, 5385; (e) Agarwal, A.; Ramesh;
Ashutosh; Goyal, N.; Chauhan, P. M. S.; Gupta, S. Bioorg. Med. Chem. 2005, 13,
6678; (f) Li, S.-H.; Shen, Y.-H.; Gao, N.; Li, J.-T. E. J. Chem. 2010, 7, 779; (g) Al-
Sehemi, A. G. Der Pharma Chemica 2010, 2, 336; (h) Rana, P. B.; Patel, J. A.;
Mistry, B. D.; Desai, K. R. J. Indian Chem. Soc. 2010, 87, 365; (i) Bagley, M. C.;
Glover, C.; Merritt, E. A. Synlett 2007, 2459; (j) Saini, A.; Kumar, S.; Sandhu, J. S.
Synth. Commun. 2007, 37, 2317; (k) Chan, J.; Faul, M. Tetrahedron Lett. 2006, 47,
3361; (l) Shi, D.; Ji, S.; Niu, L.; Shi, J.; Wang, X. J. Heterocycl. Chem. 2007, 44, 1083.
14. For representative recent examples of proline-catalyzed reactions, see: (a) List,
B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc 2000, 122, 2395; (b) Sakthivel,
K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260; (c) Hahn,
9. (a) Dax, S. L.; McNally, J. J.; Youngman, M. A. Curr. Med. Chem. 1999, 6, 255; (b)
Willy, B.; Muller, T. J. Eur. J. Org. Chem. 2008, 4157; (c) Heravi, M. M.; Ba-
ghernejad, B.; Oskooie, H. A.; Hekmatshoar, R. Tetrahedron Lett. 2008, 49, 6101;
€
(d) Domling, A. Comb. Chem. High Throughput Screening 1998, 1, 1; (e) Evdoki-
mov, N. M.; Kireev, A. S.; Yakovenko, A. A.; Antipin, M. Y.; Magedov, I. V.;
Kornienko, A. J. Org. Chem. 2007, 72, 3443.
10. (a) Wessig, P.; Muller, G. Chem. Rev. 2008, 108, 2051; (b) Hilt, G.; Danz, M.
Synthesis 2008, 2257; (c) Dai, M.; Sarlah, D.; Yu, M.; Danishefsky, S. J.; Jones, G.
O.; Houk, K. N. J. Am. Chem. Soc. 2007, 129, 645; (d) Zhang, Z.; Peng, Z.-W.; Hao,
M.-F.; Gao, J.-G. Synlett 2010, 2895; (e) Shea, K. J.; Wada, E. J. Am. Chem. Soc.
1982, 104, 5715; (f) Shea, K. J.; Fruscella, W. M.; Carr, R. C.; Burke, L. D.; Cooper,
D. K. J. Am. Chem. Soc. 1987, 109, 447; (g) Schmidt, R. R. Acc. Chem. Res. 1986, 19,
250; (h) Hwang, Y. C.; Fowler, F. W. J. Org. Chem. 1985, 50, 2719; (i) Corey, E. J.
Angew. Chem. Int. Ed. 2002, 41, 1650; (j) Maier, M. E.; Perez, C. Synlett 1998, 159;
(k) Gharagozloo, P.; Miyauchi, M.; Birdshall, B.; Birdshall, N. J. M. J. Org. Chem.
1998, 63, 1974; (l) Magnuson, S. R.; Sepp-Lorenzino, L.; Rosen, N.; Danishefsky,
S. J. J. Am. Chem. Soc. 1998, 120, 1615; (m) Nakashima, D.; Yamamoto, H. J. Am.
Chem. Soc. 2006, 128, 9626; (n) Murase, T.; Horiuchi, S.; Fujita, M. J. Am. Chem.
Soc. 2010, 132, 2866; (o) Gelman, D. M.; Forsyth, C. M.; Perlmutter, P. Org. Lett.
2009, 11, 4958.
11. (a) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew.
Chem., Int. Ed. 2002, 41,1668 and references cited therein; (b) Jorgensen, K. A. Eur.
J. Org. Chem. 2004, 2093; (c) Palacios, F.; Herran, E.; Rubiales, G.; Ezpeleta, J. M. J.
Org. Chem. 2002, 67, 2131; (d) Behforouz, M.; Ahmadian, M. Tetrahedron 2000, 56,
5259; (e) Devi, I.; Bhuyan, P. J. Tetrahedron Lett. 2004, 45, 7727; (f) Pellissier, H.
Tetrahedron 2009, 65, 2839; (g) Osborn, H. M. I.; Coisson, D. Mini Rev. Org. Chem.
2004, 1, 41; (h) Kende, A. S.; Fan, J.; Chen, Z. Org. Lett. 2003, 5, 3205; (i) Crimmins,
M. T.; Smith, A. C. Org. Lett. 2006, 8, 1003; (j) Hughes, R. A.; Thompson, S. P.;
Alcaraz, L.; Moody, C. J. J. Am. Chem. Soc. 2005, 127, 15644; (k) Chao, W.; Mahajan,
Y. R.; Weinreb, S. M. Tetrahedron Lett. 2006, 47, 3815; (l) Khoshkholgh, M. J.;
Balalaie, S.; Gleiter, R.; Rominger, F. Tetrahedron 2008, 64, 10924.
€
B. T.; Frohlich, R.; Harms, K.; Glorius, F. Angew. Chem., Int. Ed. 2008, 47, 9985; (d)
Chandler, C.; Galzerano, P.; Michrowska, A.; List, B. Angew. Chem., Int. Ed. 2009,
48, 1978; (e) Kotrusz, P.; Toma, S.; Schmalz, H.-G.; Adler, A. Eur. J. Org. Chem.
2004, 1577; (f) Luo, S.; Mi, X. L.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P. Angew.
Chem., Int. Ed. 2006, 45, 3093; (g) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F.,
III. Angew. Chem., Int. Ed. 2003, 42, 4233; (h) List, B. J. Am. Chem. Soc. 2002, 124,
5656; (i) Baumann, T.; Vogt, H.; Brase, S. Eur. J. Org. Chem. 2007, 266; (j) Hayashi,
Y.; Yamaguchi, J.; Sumiya, T.; ShoJi, M. Angew. Chem., Int. Ed. 2004, 43, 1112; (k)
ꢁ
ꢁ
Bogevig, A.; Sunden, H.; Cordova, A. Angew. Chem., Int. Ed. 2004, 43, 1109; (l)
Davies, H. J.; Ruda, A. M.; Tomkinson, N. C. O. Tetrahedron Lett. 2007, 48, 1461;
(m) Utsumi, N.; Zhang, H.; Tanaka, F.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2007,
46, 1878.
15. (a) Kumar, A.; Maurya, R. A. Tetrahedron 2008, 64, 3477; (b) Kumar, A.; Maurya,
R. A. Tetrahedron 2007, 63, 1946; (c) Karade, N. N.; Budhewar, V. H.; Shinde, S.
V.; Jadhav, W. N. Lett. Org. Chem. 2007, 4, 16; (d) Sivamurugan, V.; Suresh Kumar,
R.; Palanichamy, M.; Murugesan, V. J. Heterocycl. Chem. 2005, 42, 969; (e) Jiang,
H.; Mai, R.; Cao, H.; Zhu, Q.; Liu, X. Org. Biomol. Chem. 2009, 7, 4943.
16. Samai, S.; Nandi, G. C.; Singh, P.; Singh, M. S. Tetrahedron 2009, 65, 10155.
17. (a) Samai, S.; Nandi, G. C.; Kumar, R.; Singh, M. S. Tetrahedron Lett. 2009, 50,
7096; (b) Nandi, G. C.; Samai, S.; Kumar, R.; Singh, M. S. Tetrahedron 2009, 65,
7129; (c) Nandi, G. C.; Samai, S.; Kumar, R.; Singh, M. S. Tetrahedron Lett. 2009,
50, 7220; (d) Kumar, R.; Nandi, G. C.; Verma, R. K.; Singh, M. S. Tetrahedron Lett.
2010, 51, 442; (e) Nandi, G. C.; Samai, S.; Singh, M. S. Synlett 2010, 1133; (f)
Samai, S.; Nandi, G. C.; Singh, M. S. Tetrahedron Lett. 2010, 51, 5555; (g) Kumar,
R.; Raghuvanshi, K.; Verma, R. K.; Singh, M. S. Tetrahedron Lett. 2010, 51, 5933;
(h) Nandi, G. C.; Samai, S.; Singh, M. S. J. Org. Chem. 2010, 75, 7785.
18. Crystallographic data for compounds 4a and 4h have been deposited with the
Cambridge Crystallographic Data Center as supplementary publication num-
bers CCDC 794380 and CCDC 794336, respectively. These data can be obtained
free of charge at www.ccdc.cam.ac.uk.
12. (a) Amos, D. T.; Renslo, A. R.; Danheiser, R. L. J. Am. Chem. Soc. 2003, 125, 4970;
(b) Bland, D. C.; Raudenbush, B. C.; Weinreb, S. M. Org. Lett. 2000, 2, 4007; (c)
Ho, T.-L.; Kung, L.-R.; Chein, R.-J. J. Org. Chem. 2000, 65, 5774; (d) Snyder, S. A.;
Vosburg, D. A.; Jarvis, M. G.; Markgraf, J. H. Tetrahedron 2000, 56, 5329; (e)
Thomas, E. J. Acc. Chem. Res. 1991, 24, 229; (f) Tanaka, N.; Suzuki, T.; Hosoya, Y.;
Nakada, M. Tetrahedron Lett. 2007, 48, 6488; (g) Dentel, H.; Chataigner, I.;
Cavelier, F. L.; Gulea, M. Tetrahedron Lett. 2010, 51, 6014; (h) Gould, E.; Lebl, T.;
Slawin, A. M. Z.; Reid, M.; Smith, A. D. Tetrahedron 2010, 66, 8992; (i) Lopes, S.