An efficient one-pot three-component synthesis of functionalized pyrimido[4,5-b]quinolines and indeno fused pyrido[2,3-d]pyrimidines in water

Article abstract of DOI:10.1016/j.tetlet.2011.11.047

A simple, efficient, and high yielding one-pot protocol for the synthesis of pyrimido[4,5-b]quinolines and indeno[2′,1′:5,6]pyrido[2,3-d] pyrimidines has been developed by three-component domino coupling of 6-amino-1,3-dimethyluracil, aldehydes, and cycli

Full text of DOI:10.1016/j.tetlet.2011.11.047

Tetrahedron Letters 53 (2012) 399–402
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient one-pot three-component synthesis of functionalized
pyrimido[4,5-b]quinolines and indeno fused pyrido[2,3-d]pyrimidines in water
⇑
Girijesh K. Verma, Keshav Raghuvanshi, Ram Kumar, Maya Shankar Singh
Department of Chemistry (Centre of Advanced Study), Faculty of Science, Banaras Hindu University, Varanasi 221 005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, efficient, and high yielding one-pot protocol for the synthesis of pyrimido[4,5-b]quinolines and
indeno[20,10:5,6]pyrido[2,3-d]pyrimidines has been developed by three-component domino coupling of
6-amino-1,3-dimethyluracil, aldehydes, and cyclic 1,3-diketones in ecofriendly solvent water promoted
by PTSA. The protocol avoids the use of expensive catalysts, toxic solvents, and chromatographic separa-
tion. The generality and functional tolerance of this convergent and environmentally benign method is
demonstrated.
Received 18 October 2011
Revised 7 November 2011
Accepted 10 November 2011
Available online 18 November 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
One-pot three-component coupling
Pyrimido[4,5-b]quinolines
Indeno fused pyrido[2,3-d]pyrimidines
PTSA
In recent years, the key constraints for the synthetic chemists are
the use of hazardous solvents, expensive, and toxic reagents, multi-
step protocols, and generation of unwanted side-products.1 Now a
days, green chemistry has attained the status of a major scientific
discipline, and it now encompasses wide areas of chemical enter-
prise and is an alternative way to reduce drastic requirements for
reactions.2 To find new alternatives for simple and eco-compatible
protocols, chemists have adopted water as the solvent of choice in
organic synthesis.3 Water offers several practical advantages over
conventional organic solvents4 such as easy availability, cheap,
non-toxic, non-corrosive, non-flammable, and environmentally
acceptable.5 Furthermore, besides having a unique reactivity and
selectivity, water also offers an easy separation.6 The above advan-
tages have been attributed to many factors, including the hydro-
phobic effect,7 enhanced hydrogen bonding in the transition
state,8 and the high cohesive energy density of water.9,10
Due to growing environmental concerns, carrying out organic
reactions in water has become highly desirable, and several reports
of organic synthesis in water have appeared during the past dec-
ade.11 Recently, a variety of organic transformations such as aldol
reaction, allylation reaction, Diels–Alder reaction, Henry reaction,
Michael reaction, Mannich reaction, and Pd-catalyzed coupling
reactions have been reported in aqueous media.12 Indeed, industry
prefers to use water as a solvent rather than organic solvents. In
the past decade there have been tremendous development in mul-
ti-component reactions and great efforts are being made to devel-
op new multicomponent reactions13 (MCRs) in water. They have
become an increasingly powerful tool14 in organic, combinatorial,
and medicinal chemistry because of their convergence, atom-
economy, multiple bond forming efficiency,15 and other suitable
characteristics from the green chemistry point of view.16 These fea-
tures make MCRs well-suited for the easy construction of diversi-
fied heterocyclic scaffolds.17
Organic compounds containing pyrimidine scaffold as a core
unit are important targets and are known to exhibit various biolog-
ical and pharmaceutical activities.18 6-Amino-1,3-dimethyluracil
and its fused derivatives19 are versatile building blocks for the syn-
thesis of several bioactive heterocycles.20 Pyrido[2,3-d]pyrimidines
are a class of naturally occurring fused uracils occupying a special
place in synthetic and medicinal chemistry due to their wide range
of pharmacological activities.21 5-(3-Bromophenyl)-1,3-dimethyl-
5,11-dihydro-1H-indeno [20,10:5,6]pyrido[2,3-d]pyrimidine-2,4,6-
trione (BPIPP) was identified as new potent inhibitor of STa
induced cyclic nucleotide synthesis, and as a promising lead for
the treatment of acute diarrhea.22a,b Moreover, appropriately func-
tionalized pyrido[2,3-d]pyrimidines have also been identified as a
new class of fibroblast growth factor receptor (FGFR3) tyrosine ki-
nase inhibitors.22c,d Quinolines an important class of heterocyclic
alkaloids, are important synthetic targets both in pharmaceutical
industries and in academic laboratories displaying rich chemistry
and various useful biological activities.23 They are widely present
as key structural motifs in a large number of bioactive drugs such
as Quinine, Chloroquine, Luotonine-A, and Camptothecin. Further-
more, quinoline derivatives find applications in flavoring agents24a
and in luminescence chemistry.24b In addition quinolines are
valuable synthons for the preparation of nano-and meso-structures
with enhanced electronic as well as photonic functions.25
⇑
Corresponding author. Fax: +91 542 2368127.
E-mail address: mssinghbhu@yahoo.co.in (M.S. Singh).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.047

400
G. K. Verma et al. / Tetrahedron Letters 53 (2012) 399–402
In view of the immense biological significance of these heterocycles,
gave the desired product in low yield along with octahydroxanth-
ene-1,8-dione as a side product (Table 1, entries 3–10). To our de-
light, PTSA gave the desired product in good yield under above two
conditions. However, the reaction in water showed superiority
over the solvent-free conditions in terms of yield (Table 1, entries
11 and 12). PTSA loading was subsequently examined and it was
found that 20 mol % of PTSA provided the maximum yield in min-
imum time (Table 1, entry 13). We immediately undertook a study
to examine the effect of temperature on this transformation, and
the results demonstrated that 90 °C appeared to be the optimum
temperature. Thus, the best yield, cleanest reaction, and most facile
work-up was achieved employing 20 mol % of PTSA in water at
90 °C. The starting materials were completely consumed to afford
the desired product that was highly visible on TLC under UV
light.30 Furthermore, simple work-up in water opened the route
for an entirely green and highly efficient one-pot reaction in water.
Encouraged by the remarkable results obtained with the above
reaction conditions, and in order to show the generality and scope
of this new protocol, we used various aldehydes and cyclic 1,3-
diketones (Scheme 1). Notably, a wide range of aldehydes (aro-
matic, heteroaromatic, and aliphatic) were well tolerated under
the reaction conditions (Table 2). However, in comparison to aro-
matic aldehydes, heteroaromatic, and aliphatic aldehydes gave
somewhat lower yields. In order to further investigate the scope
of this reaction with indane-1,3-dione, the reaction of 1 and 2 with
5 was examined under the above optimized conditions, and found
to produce tetracyclic indeno fused pyrido[2,3-d]pyrimidines 6a–h
in good yields (Table 2). This is particularly attractive because com-
pounds with indeno fused pyrido[2,3-d]pyrimidine motif show a
wide range of biological activities. Table 2 clearly demonstrates
that PTSA is an excellent catalyst for this one-pot three-component
reaction in water. Notably, the reactions were clean and all the
products were easily isolated simply by filtration and washing
with water. The structures of compounds 4 and 6 were established
by their satisfactory elemental analyses and spectral (1H, 13C NMR,
IR, and Mass) studies,30 and by comparison with known com-
pounds reported in the literature.26,27
many synthetic protocols involving multicomponent strategies have
been developed.26,27 However, despite the potential utility of the meth-
ods published so far, they exhibit varying degrees of successes as well
as limitations such as harsh reaction conditions, expensive catalysts/
reagents, toxic organic solvents, cumbersome experimental proce-
dures, and long reaction time. Therefore, to overcome these problems
development of more general, efficient, eco-compatible, and viable
protocols are highly desirable. In this context, in recent years, much
attention has been focused on acid catalyzed organic reactions in
water. p-Toluenesulfonic acid (PTSA) is environmentally benign, inex-
pensive, and economically feasible catalyst that offers several advanta-
ges.28 Therefore, organic reactions that exploit PTSA catalyst in water
could prove ideal for industrial synthetic organic chemistry applica-
tions provided that the catalyst shows high catalytic activity in water.
In continuation of our efforts for the development of one-pot three-
component protocols29 under solvent-free conditions to synthesize
biologically important heterocycles, we have explored a straightfor-
ward convergent one-pot synthesis of pyrimido[4,5-b]quinoline-
2,4,6-triones and indeno fused pyrido[2,3-d] pyrimidine-2,4,6-triones
in water promoted by PTSA.30
Our literature survey at this stage revealed that, there is no re-
port yet available on the synthesis of pyrimido[4,5-b]quinolines
and indeno fused pyrido[2,3-d]pyrimidines in one-pot via three-
component coupling of 6-amino-1,3-dimethyluracil, aldehydes,
and cyclic-1,3-diketones in water promoted by PTSA. The utility
of multicomponent reactions has been significantly expanded if
they are conducted in water or under solvent-free conditions.
The aim of this present protocol is to highlight the synergistic ef-
fect of the combined use of MCRs and water for the development
of new eco-compatible strategy for heterocyclic synthesis.
Initially, the three-component coupling reaction of 6-amino-
1,3-dimethyluracil 1, 4-nitrobenzaldehyde 2a, and dimedone 3a
under solvent-free conditions and in water, separately was exam-
ined without any catalyst. It was found that only trace amount of
the desired product 4a was observed on TLC plate even after 14 h
of reflux, while undesired Knoevenagel condensation product
was formed as a major one (Table 1, entries 1 and 2) under above
two conditions. Subsequently, various acidic catalysts such as
SiO2–H2SO4, SiO2–HClO4, InCl3, P2O5, and PTSA were tested in
water and under solvent-free conditions, separately. SiO2–H2SO4
and SiO2–HClO4 could trigger the reaction providing only trace
amount of the product after 12 h of heating, while InCl3 and P2O5
A probable mechanistic rationale portraying sequence of events for
this domino coupling is postulated in Scheme 2. The first step is be-
lieved to be the acid-catalyzed Knoevenagel condensation between
the aldehyde and cyclic 1,3-diketone to generate adduct A, which acts
as Michael acceptor. The 6-amino-1,3-dimethyl uracil 1 attacks to ad-
duct A in a Michael-type fashion to produce an open chain intermedi-
ate B. Intermediate B undergoes intramolecular cyclization by the
reaction of nucleophilic amino function to carbonyl group followed
by dehydration to form pyrimido[4,5-b]quinoline 4.
Table 1
Optimization of reaction conditionsa
In conclusion, we have developed a simple one-pot three-
component synthesis of pyrimido[4,5-b]quinoline-2,4,6-triones
and indeno fused pyrido[2,3-d]pyrimidines by the coupling of
6-amino-1,3-dimethyluracil, aldehydes, and cyclic 1,3-dicarbonyl
compounds in water promoted by PTSA. This protocol is endowed
with several advantages such as convergent nature, improved
Entry
Catalyst (mol %)
Solvent
Time (h)
Temp (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
None
None
None
H2O
None
H2O
None
H2O
None
H2O
None
H2O
None
H2O
H2O
H2O
14
14
12
12
12
12
4
4
4
4
3
90
90
90
90
90
90
90
90
90
90
90
90
90
90
80
70
Tracec
Tracec
Tracec
Tracec
Tracec
Tracec
55d
SiO2–H2SO4 (10)
SiO2–H2SO4 (10)
SiO2–HClO4 (10)
SiO2–HClO4 (10)
InCl3 (10)
InCl3 (10)
P2O5 (10)
P2O5 (10)
p-TSA (10)
p-TSA (10)
p-TSA (20)
p-TSA (30)
p-TSA (20)
p-TSA (20)
46d
O
O
O
R1
O
9
25d
p-TSA
Me
Me
O
10
11
12
13
14
15
16
40d
N
N
R1CHO
(20 mol %)
R2
R2
R2
R2
+
+
O
62
77
94
90
80
72
H2O, 90 0C O
N
Me
O
N
H
4
2
N
Me
1
NH2
3
3
2.5
2.5
4
O
R1
O
O
H2O
H2O
p-TSA
(20 mol %)
Me
O
N
6
2
1
+
+
a
H2O, 90 0
C
All the reactions were carried out using 6-amino-1,3-dimethyluracil
(1.0 mmol), 4-nitrobenzaldehyde 2a (1.0 mmol), and dimedone 3a (1.0 mmol).
1
N
N
6
5
Me
b
Isolated pure yields.
Knoevenagel condensation product was obtained as a major one.
Xanthene as side product was formed.
c
Scheme 1. Synthesis of pyrimido[4,5-b]quinolines 4a–t and indeno fused pyr-
ido[2,3-d]pyrimidines 6a–h.
d

G. K. Verma et al. / Tetrahedron Letters 53 (2012) 399–402
401
Table 2
2. (a) Clark, J. H.; Macquarrie, D. In Handbook of Green Chemistry and Technology;
Blackwell Publishers: Oxford, 2002; (b) Anastas, P.; Eghbali, N. Chem. Soc. Rev.
2010, 39, 301; (c) Anastas, P. T.; Warner, J. C. In Green Chemistry: Theory and
Practice; Oxford University Press: New York, 1998; (d) Leitner, W. Green Chem.
2009, 11, 603.
Exploration of the substrate scope for the synthesis of 4 and 6
Productsa 4,6 Aldehyde 2 (R1)
Diketones 3,5 Time (h) Yieldb (%)
4a
4-NO2C6H4 (2a)
4-BrC6H4 (2b)
4-ClC6H4 (2c)
4-CH3C6H4 (2d)
3-OHC6H4 (2e)
4-OMeC6H4 (2f)
2-NO2C6H4 (2g)
3-NO2C6H4 (2h)
C6H5 (2i)
R2 = CH3 (3a)
2.5
3.0
2.5
2.5
3.0
3.0
3.0
3.0
3.0
3.0
3.5
3.5
2.5
2.0
2.5
2.5
2.5
2.5
3.0
3.0
3.0
2.5
2.5
3.0
3.0
3.0
3.5
3.5
94
91
89
85
86
84
90
86
85
82
66
62
95
87
90
88
86
86
87
84
88
86
90
82
86
76
72
60
3. (a) Breslow, R. In Green Chemistry; Anastas, P. T., Williamson, T. C., Eds.; Oxford
Press: New York, 1998. Chapter 13; (b) DeSimone, J. M. Science 2002, 297, 799;
(c) Horvath, I. T.; Anastas, P. T. Chem. Rev. 2007, 107, 2167; (d) Kumar, B. S. P. A.;
Madhav, B.; Reddy, K. H. V.; Nageswar, Y. V. D. Tetrahedron Lett. 2011, 52, 2862.
4. (a) Otto, S.; Engberts, J. B. F. N. Pure Appl. Chem. 2000, 72, 1365; (b) Narayan, S.;
Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. Angew. Chem.,
Int. Ed. 2005, 44, 3275; (c) Chanda, A.; Fokin, V. V. Chem. Rev. 2009, 109, 725.
5. (a) Aplander, K.; Hidestal, O.; Katebzadeh, K.; Lindstorm, U. M. Green Chem.
2006, 8, 22; (b) Liu, R.; Dong, C.; Liang, X.; Wang, X.; Hu, X. J. Org. Chem. 2005,
70, 729; (c) Stavber, G.; Zupan, M.; Jereb, M.; Stavber, S. Org. Lett. 2004, 6, 4973;
(d) Lindstrom, U. M. In Organic Reactions in Water: Principles, Strategies and
Applications; Wiley-Blackwell: Oxford, UK, 2007; (e) Hailes, H. C. Org. Process
Res. Dev. 2007, 11, 114.
6. (a) Lindstrom, U. M. Chem. Rev. 2002, 102, 2751; (b) Butler, R. N.; Coyne, A. G.
Chem. Rev. 2010, 110, 6302; (c) Polshettiwar, V.; Varma, R. S. Green Chem. 2010,
12, 743; (d) Khatik, G. L.; Kumar, R.; Chakraborti, A. K. Org. Lett. 2006, 8, 2433;
(e) Azizi, N.; Aryanasab, F.; Torkiyan, L.; Ziyaei, A.; Saidi, M. R. J. Org. Chem.
2006, 71, 3634.
7. (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159; (b) Otto, S.; Engberts, J. B. F. N. Org.
Biomol. Chem. 2003, 1, 2809; (c) Lindstrom, U. M.; Andersson, F. Angew. Chem.,
Int. Ed. 2006, 45, 548.
4b27a
4c27a
4d27a
4e
3a
3a
3a
3a
3a
3a
3a
3a
4f27a
4g
4h
4i27e
4j27a
4k
2-Thienyl (2j)
i-Propyl (2k)
3a
3a
3a
4l
Cyclohexyl (2l)
4-NO2C6H4 (2a)
3-NO2C6H4 (2h)
2,4-Cl2C6H3 (2m)
4-CH3C6H4 (2d)
C6H5 (2i)
4m26b
4n
R2 = H (3b)
3b
3b
3b
3b
3b
3b
3b
5
5
5
5
5
4o
4p26b
4q
4r26b
4s
4-FC6H4 (2n)
2-ClC6H4 (2o)
2-OMeC6H4 (2p)
4-BrC6H4 (2b)
4-ClC6H4 (2c)
4-FC6H4 (2n)
3-NO2C6H4 (2h)
4-CH3C6H4 (2d)
5-Br-2-OHC6H3 (2q)
2-Thienyl (2j)
i-Propyl (2k)
4t
6a27a
6b27a
6c27a
6d27a
6e27a
6f
8. Chandrasekhar, J.; Shariffskul, S.; Jorgensen, W. L. J. Phys. Chem. B 2002, 106,
8078.
9. (a) Lubineau, A.; Auge, J. Top. Curr. Chem. 1999, 206, 1; (b) Lubineau, A.; Auge, J.;
Queneau, Y. Synthesis 1994, 741.
10. Sheldon, R. A. J. Mol. Catal. A 1996, 107, 75.
11. (a) Li, C.-J. Chem. Rev. 2005, 105, 3095; (b) Fringuelli, F.; Pizzo, F.; Tortoioli, S.;
Vaccaro, L. Org. Lett. 2005, 7, 4411; (c) Pirrung, M. C.; Das Sarma, K. J. Am. Chem.
Soc. 2004, 126, 444; (d) Azoulay, S.; Manabe, K.; Kobayashi, S. Org. Lett. 2005, 7,
4593; (e) Manabe, K.; Limura, S.; Sun, X.-M.; Kobayashi, S. J. Am. Chem. Soc.
2002, 124, 11971; (f)Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie
Academic and Professional: London, 1998; (g) Li, C.-J.; Chen, L. Chem. Soc. Rev.
2006, 35, 68; (h) Breslow, R. Acc. Chem. Res. 2004, 37, 471; (i) Pirrung, M. C.
Chem. -Eur. J. 2006, 12, 1312.
5
5
5
6g
6h
a
Literature reference.
Isolated yields.
b
12. (a) Virkutyte, J.; Baruwati, B.; Varma, R. S. Nano Scale 2010, 2, 1109; (b)
Polshettiwar, V.; Varma, R. S. Tetrahedron 2010, 66, 1091; (c) Liu, X.-L.; Zhang,
X.-M.; Yuan, W.-C. Tetrahedron Lett. 2011, 52, 903; (d) Azizi, N.; Torkiyan, L.;
Saidi, M. R. Org. Lett. 2006, 8, 2079; (e) Wu, H.; Lin, W.; Wan, Y.; Xin, H.-Q.; Shi,
D.-Q.; Shi, Y.-H.; Yuan, R.; Bo, R.-C.; Yin, W. J. Comb. Chem. 2010, 12, 31; (f)
Krasovskaya, V.; Krasovskiy, A.; Bhattacharjya, A.; Lipshutz, B. H. Chem.
Commun. 2011, 47, 5717.
13. (a) Gogoi, S.; Dutta, M.; Gogoi, J.; Boruah, R. C. Tetrahedron Lett. 2011, 52, 813;
(b) Kumar, D.; Kumar, N. M.; Patel, G.; Gupta, S.; Varma, R. S. Tetrahedron Lett.
2011, 52, 1983; (c) Xie, J.-W.; Li, P.; Wang, T.; Zhou, F.-T. Tetrahedron Lett. 2011,
52, 2379; (d) Ramesh, K.; Murthy, S. N.; Nageswar, Y. V. D. Tetrahedron Lett.
2011, 52, 2362; (e) El Kaïm, L.; Grimaud, L.; Purumandla, S. R. Tetrahedron Lett.
2010, 51, 4962; (f) Palasz, A. Synthesis 2010, 4021; (g) Kolla, S. R.; Lee, Y. R.
Tetrahedron 2010, 66, 8938; (h) Shi, L.; Tu, Y.-Q.; Wang, M.; Zhang, F.-M.; Fan,
C.-A. Org. Lett. 2004, 6, 1001; (i) Ma, N.; Jiang, B.; Zhang, G.; Tu, S.-J.; Wever, W.;
Li, G. Green Chem. 2010, 12, 1357; (j) Adib, M.; Sheikhi, E.; Kavoosi, A.;
Bijanzadeh, H. R. Tetrahedron 2010, 66, 9263.
O
N
Me
1
R1
O
O
Me
N
Knoevenagel
R2
R2
+ R1CHO
R2
R2
condensation
O
O
H2N
O
2
A
3
Michael
addition
O
R1
O
R1
O
O
H
Me
cyclization
Me
O
N
R2
R2
N
−H2O R2
N
H
N
Me
O
N
Me
R2
O
HN
4
B
14. (a) Zhu, J.; Bienayme, H. In Multicomponent Reactions; Wiley-VCH Weinheim:
Germany, 2005; (b) Malacria, M. Chem. Rev. 1996, 96, 289; (c) Schwier, T.;
Sromek, A. W.; Yap, D. M.; Chernyak, D.; Gevorgyan, V. J. Am. Chem. Soc. 2007,
129, 9868; (d) Barluenga, J.; Jimenez-Aquino, A.; Valdes, C.; Aznar, F. Angew.
Chem., Int. Ed. 2007, 46, 1529; (e) Waldmann, H.; Kuhn, M.; Liu, W.; Kumar, K.
Chem. Commun. 2008, 1211; (f) de Meijere, A.; von Zezschwitz, P.; Braese, S.
Acc. Chem. Res. 2005, 38, 413; (g) Tietze, L. F.; Brasche, G.; Gericke, K. In Domino
Reactions in Organic Synthesis; Wiley-VCH Weinheim: Germany, 2006; (h)
Diguez-Vzquez, A.; Tzschucke, C. C.; Lam, W. Y.; Ley, S. V. Angew. Chem., Int. Ed.
2008, 47, 209; (i) Arya, A. K.; Kumar, M. Green Chem. 2011, 13, 1332.
15. (a) Tietze, L. F. Chem. Rev. 1996, 96, 115; (b) Trost, B. M. Acc. Chem. Res. 2002, 35,
695; (c) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res.
2008, 41, 40.
Scheme 2. Plausible mechanism for the formation of 4.
yields, clean reaction, easy operation, and simple purification. Fur-
thermore, it can be considered as environmental friendly, since it
uses water as the reaction medium, and purification is done by
simple filtration and washing, avoiding the use of organic solvents
at any point of the experimental procedure. No extraction or sepa-
ration by column chromatography is necessary.
16. (a) Döemling, A. Chem. Rev. 2006, 106, 17; (b) D’Souza, D. M.; Mueller, T. J. J.
Chem. Soc. Rev. 2007, 36, 1095; (c) Polshettiwar, V.; Varma, R. S. Chem. Soc. Rev.
2008, 37, 1546; (d) Shore, G.; Yoo, W.-J.; Li, C.-J.; Organ, M. G. Chem. -Eur. J.
2010, 16, 126; (e) Ganem, B. Acc. Chem. Res. 2009, 42, 463; (f) Padwa, A. Chem.
Soc. Rev. 2009, 38, 3072.
17. (a) Zhu, J. Eur. J. Org. Chem. 2003, 1133; (b) Willy, B.; Mueller, T. J. J. Curr. Org.
Chem. 2009, 13, 1777; (c) Bello, D.; Ramon, R.; Lavilla, R. Curr. Org. Chem. 2010,
14, 332; (d) Jiang, B.; Rajale, T.; Wever, W.; Tu, S.-J.; Li, G. Chem. Asian J. 2010, 5,
2318.
18. (a) Kappe, C. O. Tetrahedron 1993, 49, 6937; (b) Ibrahim, D. A.; El-Metwally, A.
M. Eur. J. Med. Chem. 2010, 45, 1158; (c) Deshmukh, M. B.; Salunkhe, S. M.; Patil,
D. R.; Anbhule, P. V. Eur. J. Med. Chem. 2009, 44, 2651; (d) Gasse, C.; Douguet,
D.; Huteau, V.; Marchal, G.; Munier-Lehmann, H.; Pochet, S. Bioorg. Med. Chem.
2008, 16, 6075; (e) 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; (f) Falcao, E. P. S.; Melo, S. J.; Srivastava, R. M.; Catanho, M. T. J. A.; Do
Acknowledgements
We are grateful to the Council of Scientific and Industrial Re-
search (CSIR) and the Department of Science and Technology
(DST), New Delhi for the financial support. G.K.V. is thankful to
the University Grant Commission (UGC), New Delhi, for Junior Re-
search Fellowship. We also thank Professor H. Ila (JNCASR, Banga-
lore) for her timely valuable advice and suggestions.
References and notes
1. (a) Breslow, R.; Maitra, U. Tetrahedron Lett. 1984, 25, 1239; (b) Breslow, R.;
Maitra, U.; Rideout, D. Tetrahedron Lett. 1983, 24, 1901; (c) Rideout, D. C.;
Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816.

402
G. K. Verma et al. / Tetrahedron Letters 53 (2012) 399–402
Nascimento, S. C. Eur. J. Med. Chem. 2006, 41, 276; (g) Chen, Q.; Zhu, X.-L.; Jiang,
3698; (h) Verma, R. K.; Verma, G. K.; Raghuvanshi, K.; Singh, M. S. Tetrahedron
2011, 67, 584; (i) Chowdhury, S.; Nandi, G. C.; Samai, S.; Singh, M. S. Org. Lett.
2011, 13, 3762; (j) Shukla, G.; Verma, R. K.; Verma, G. K.; Singh, M. S.
Tetrahedron Lett. 2011, 52, 7195.
L.-L.; Liu, Z.-M.; Yang, G.-F. Eur. J. Med. Chem. 2008, 43, 595; (h) Hassan Hilmy,
K. M.; Khalifa, M. M. A.; Allah Hawata, M. A.; AboAlzeen Keshk, R. M.; El-
Torgman, A. A. Eur. J. Med. Chem. 2010, 45, 5243; (i) Aliaga, M. J.; Ramon, D. J.;
Yus, M. Org. Biomol. Chem. 2010, 8, 43.
30. General procedure for the synthesis of compounds 4 and 6: To a mixture of 6-
amino-1,3-dimethyluracil (1.0 mmol), aldehyde (1.0 mmol), and cyclic 1,3-
diketone (1.0 mmol) in distilled water (10 mL) 20 mol % of PTSA was added.
The reaction mixture was heated at 90 °C for the stipulated period of time till
the full consumption of the starting materials (monitored by TLC). After
completion of the reaction, the reaction mixture was allowed to cool to room
temperature. The solid obtained was filtered and washed with water to get the
pure product in good yield. However, in some cases they were recrystallized
from ethanol. Data of some selected new compounds: 5-(4-Nitrophenyl)-1,3,8,8-
tetramethyl-7,8,9,10-tetrahydropyrimido[4,5-b]quinoline-2,4,6-trione (4a): 1H
NMR (300 MHz, DMSO-d6): d 9.12 (s, 1H, NH, D2O exchangeable), 8.07 (d,
J = 8.7 Hz, 2H, ArH), 7.46 (d, J = 8.7 Hz, 2H, ArH), 4.97 (s, 1H, CH), 3.45 (s, 3H,
NCH3), 3.07 (s, 3H, NCH3), 2.59 (d, J = 6.9 Hz, 2H, CH2), 2.23 (d, J = 16.2 Hz, 1H,
CH), 2.03 (d, J = 15.9 Hz, 1H, CH), 1.07 (s, 3H, CH3), 0.87 (s, 3H, CH3). 13C NMR
(75 MHz, DMSO-d6): d 194.5, 160.6, 153.7, 150.4, 150.2, 145.7, 144.1, 129.0,
122.9, 110.5, 89.0, 56.0, 49.8, 34.6, 32.0, 30.2, 28.9, 27.6, 26.4, 18.5. IR (KBr):
19. (a) Hirota, K.; Kuki, H.; Maki, Y. Heterocycles 1994, 37, 563; (b) Griengl, H.;
Wanek, E.; Schwarz, W.; Streicher, W.; Rosenwirth, B.; De Clercq, E. J. Med.
Chem. 1987, 30, 1199; (c) Srivastava, P.; Saxena, A. S.; Ram, V. J. Synthesis 2000,
541; (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) Walsh, E. B.; Wamhoff, H. Chem.
Ber. 1989, 122, 1673.
20. (a) Lunt, E.; Newton, C. G. In Comprehensive Heterocyclic Chemistry; Katritzky, A.
R., Rees, C. W., Boulton, A. J., Mckillop, A., Eds.; Permgamon Press: Oxford,
1984; Vol. 3, p 199–232, 260–262; (b) Bradshaw, T. K.; Hutchinson, D. W.
Chem. Soc. Rev. 1977, 6, 43.
21. (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) Grivsky, E. M.; Lee, S.; Sigel, C. W.;
Duch, D. S.; Nichol, C. A. J. Med. Chem. 1980, 23, 327; (c) Bennett, L. R.; Blankley,
C. J.; Fleming, R. W.; Smith, R. D.; Tessman, D. K. J. Med. Chem. 1981, 24, 382.
22. (a) Hughes, J. M.; Murad, F.; Chang, B.; Guerrant, R. L. Nature 1978, 271, 755; (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) 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; (d) Kammasud, N.; Boonyarat, C.; Sanphanya, K.; Utsintong, M.;
Tsunoda, S.; Sakurai, H.; Saiki, I.; André, I.; Grierson, D. S.; Vajragupta, O. Bioorg.
Med. Chem. Lett. 2009, 19, 745.
23. (a) Perzyna, A.; Klupsch, F.; Houssin, R.; Pommery, N.; Lemoine, A.; Henichart,
J.-P. Bioorg. Med. Chem. Lett. 2004, 14, 2363; (b) Joshi, A. A.; Viswanathan, C. L.
Bioorg. Med. Chem. Lett. 2006, 16, 2613; (c) Klingenstein, R. M. P.; Leliveld, S. R.;
Ryckebusch, A.; Korth, C. J. Med. Chem. 2006, 49, 5300; (d) Benkovic, S. J.; Baker,
S. J.; Alley, M. R. K.; Woo, Y.-H.; Zhang, Y.-K.; Akama, T.; Mao, W.; Baboval, J.;
Rajagopalan, P. T. R.; Wall, M.; Kahng, L. S.; Tavassoli, A.; Shapiro, L. J. Med.
Chem. 2005, 48, 7468; (e) El-Gazzar, A. B. A.; Youssef, M. M.; Youssef, A. M. S.;
Abu-Hashem, A. A.; Badria, F. A. Eur. J. Med. Chem. 2009, 44, 609; (f) Benedetti,
P.; Mannhold, R.; Cruciani, G.; Ottaviani, G. Bioorg. Med. Chem. 2004, 12, 3607.
24. (a) Holla, B. S.; Mahalinga, M.; Karthikeyan, M. S.; Akberali, P. M.; Shetty, N. S.
Bioorg. Med. Chem. 2006, 14, 2040; (b) Całus, S.; Gondek, E.; Danel, A.; Jarosz, B.;
Pokładko, M.; Kityk, A. V. Mater. Lett. 2007, 61, 3292.
m
= 3468, 3272, 3095, 2960, 1700, 1644, 1511, 1378, 1244, 1081 cmꢀ1. ESI MS
(m/z): 411 (M++1); Anal. Calcd for C21H22N4O5: C, 61.45; H, 5.40; N, 13.65%.
Found C, 61.13; H, 5.62; N, 13.80%. 5-(3-hydroxyphenyl)-1,3,8,8-tetramethyl-
7,8,9,10-tetrahydropyrimido [4,5-b]quinoline-2,4,6-trione (4e): 1H NMR
(300 MHz, DMSO-d6): d 9.09 (s, 1H, NH, D2O exchangeable), 8.97 (s, 1H, OH,
D2O exchangeable), 7.42–7.35 (m, 2H, ArH), 7.18–7.10 (m, 2H, ArH), 4.83 (s, 1H,
CH), 3.44 (s, 3H, NCH3), 3.08 (s, 3H, NCH3), 2.56 (d, J = 6.9 Hz, 2H, CH2), 2.21 (d,
J = 15.6 Hz, 1H, CH), 2.03 (d, J = 16.2 Hz, 1H, CH), 1.03 (s, 3H, CH3), 0.89 (s, 3H,
CH3). 13C NMR (75 MHz, DMSO-d6): d 198.5, 165.3, 161.0, 156.2, 154.2, 148.0,
149.9, 133.2, 121.0, 118.5, 96.4, 55.6, 45.3, 38.9, 35.1, 34.0, 33.6, 18.7. IR (KBr):
m
= 3397, 3279, 3220, 3098, 2963, 1701, 1658, 1623, 1495, 1455, 1382, 1246,
1213, 1147, 1052, 962, 869, 785 cmꢀ1. ESI MS (m/z): 382 (M++1); Anal. Calcd
for C21H23N3O4: C, 66.13; H, 6.08; N, 11.02%. Found C, 66.30; H, 6.26; N, 11.34%.
5-(3-Nitrophenyl)-1,3-dimethyl-7,8,9,10-tetrahydropyrimido[4,5-b]
quinoline-
2,4,6-trione (4n): 1H NMR (300 MHz, CDCl3): d 8.00–7.93 (m, 3H, ArH), 7.42
(t, J = 8.4 Hz, 1H, ArH), 6.30 (s, 1H, NH, D2O exchangeable), 5.24 (s, 1H, CH), 3.56
(s, 3H, NCH3), 3.25 (s, 3H, NCH3), 2.62 (m, 2H, CH2), 2.39 (m, 2H, CH2), 2.07 (m,
2H, CH2). 13C NMR (75 MHz, CDCl3): 194.2, 160.9, 151.4, 150.8, 148.2, 147.8,
144.5, 135.2, 128.7, 122.4, 121.8, 113.5, 91.2, 36.3, 34.3, 27.4, 26.4, 20.4. IR
(KBr):
m = 3451, 3275, 3219, 3087, 2960, 2875, 1691, 1666, 1643, 1498, 1379,
25. (a) Agarwal, A. K.; Jenekhe, S. A. Macromolecules 1991, 24, 6806; (b) Zhang, X.;
Shetty, A. S.; Jenekhe, S. A. Macromolecules 1999, 32, 7422; (c) Jenekhe, S. A.; Lu,
L.; Alam, M. M. Macromolecules 2001, 34, 7315; (d) Kim, J. I.; Shin, I.-S.; Kim, H.;
Lee, J.-K. J. Am. Chem. Soc. 2005, 127, 1614.
26. (a) Quiroga, J.; Insuasty, B.; Insuasty, H.; Abonia, R.; Ortiz, A.; Sanchez, A.;
Nogueras, M. J. Heterocycl. Chem. 2001, 38, 339; (b) Hassan, N. A.; Hegab, M. I.;
Hashem, A. I.; Abdel-Motti, F. M.; Hebah, S. H. A.; Abdel-Megeid, F. M. E. J.
Heterocycl. Chem. 2007, 44, 775; (c) Jiang, B.; Cao, L.-J.; Tu, S.-J.; Zheng, W.-R.;
Yu, H.-Z. J. Comb. Chem. 2009, 11, 612; (d) Quiroga, J.; Acosta, P. A.; Cruz, S.;
Abonia, R.; Insuasty, B.; Nogueras, M.; Cobo, J. Tetrahedron Lett. 2010, 51, 5443;
(e) Aknin, K.; Desbene-Finck, S.; Helissey, P.; Giorgi-Renault, S. Mol. Divers.
2010, 14, 123.
27. (a) Shi, D.-Q.; Ni, S.-N.; Yang, F.; Shi, J.-W.; Dou, G.-L.; Li, X.-Y.; Wang, X.-S.; Ji,
S.-J. J. Heterocycl. Chem. 2008, 45, 693; (b) Quiroga, J.; Trilleras, J.; Insuasty, B.;
Abonia, R.; Nogueras, M.; Marchal, A.; Cobo, J. Tetrahedron Lett. 2010, 51, 1107;
(c) Kumar, A.; Maurya, R. A. Tetrahedron 2007, 63, 1946; (d) Tanifum, E. A.; Kots,
A. Y.; Choi, B.-K.; Murad, F.; Gilbertson, S. R. Bioorg. Med. Chem. Lett. 2009, 19,
3067; (e) Mosslemin, M. H.; Nateghi, M. R. Ultrasonics Sonochem. 2010, 17, 162.
28. (a) Quiroga, J.; Portillo, S.; Pérez, A.; Gálvez, J.; Abonia, R.; Insuasty, B.
Tetrahedron Lett. 2011, 52, 2664; (b) Ghahremanzadeh, R.; Sayyafi, M.; Ahadi,
S.; Bazgir, A. J. Comb. Chem. 2009, 11, 393; (c) Ahadi, S.; Mirzaei, P.; Bazgir, A.
Synth. Commun. 2010, 40, 1224; (d) Ghahremanzadeh, R.; Shakibaei, G. I.;
Ahadi, S.; Bazgir, A. J. Comb. Chem. 2010, 12, 191.
1348, 1257, 1198, 1168, 1134, 1084, 1050, 946, 873, 817, 745 cmꢀ1. ESI MS (m/
z): 383 (M++1); Anal. Calcd for C19H18N4O5: C, 59.68; H, 4.74; N, 14.65%. Found:
C, 59.87; H, 4.85; N, 14.78%. 5-(2-Methoxyphenyl)-1,3-dimethyl-7,8,9,10-
tetrahydropyrimido[4,5-b]quinoline-2,4,6-trione (4t): 1H NMR (300 MHz,
CDCl3): d 9.02 (s, 1H, NH, D2O exchangeable), 7.22–6.75 (m, 4H, ArH), 4.95
(s, 1H, CH), 3.68 (s, 3H, NCH3), 3.46 (s, 3H, NCH3), 3.04 (s, 3H, OCH3), 2.68–2.66
(m, 2H, CH2), 2.46–2.43 (m, 2H, CH2), 2.17–2.14 (m, 2H, CH2). 13C NMR
(75 MHz, CDCl3): d 194.8, 160.7, 150.9, 150.4, 147.8, 147.5, 143.2, 134.5, 128.0,
121.9, 120.7, 112.6, 90.2, 56.4, 39.3, 38.3, 28.2, 27.6, 21.4. IR (KBr):
m = 3245,
3159, 2972, 1698, 1668, 1656, 1349, 1247, 1178, 1064, 986, 867, 765 cmꢀ1. ESI
MS (m/z): 368 (M++1); Anal. Calcd for C20H21N3O4: C, 65.38; H, 5.76; N, 11.44%.
Found: C, 65.51; H, 5.52; N, 11.60%. 1,3-Dimethyl-5-(5-bromo-2-
hydroxyphenyl)indeno[20,10:5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione (6f): 1H
NMR (300 MHz, CDCl3):
d 9.03 (s, 1H, OH, D2O exchangeable), 7.95 (d,
J = 7.5 Hz, 1H, ArH), 7.68–7.64 (m, 2H, ArH), 7.56–7.52 (m, 1H, ArH), 7.44 (d,
J = 8.7 Hz, 1H, ArH), 7.18(s, 1H, ArH), 6.84 (d, J = 8.7 Hz, 1H, ArH), 3.90 (s, 3H,
NCH3), 3.38 (s, 3H, NCH3). 13C NMR (75 MHz, DMSO-d6): d 185.3, 172.5, 170.3,
160.4, 158.4, 151.7, 132.5, 131.6, 130.4, 129.9, 128.1, 128.0, 125.7, 119.5, 118.7,
113.0, 35.2, 30.0. IR (KBr):
m
.
= 3409, 3063, 2965, 1730, 1670, 1578, 1436, 1362,
1245, 1160, 1089. cmꢀ1
ESI MS (m/z): 465 (M++1); Anal. Calcd for
C
22H14BrN3O4: C, 56.91; H, 3.04; N, 9.05%. Found C, 57.23; H, 2.85; N, 9.23%.
1,3-Dimethyl-5-(iso-propyl)indeno[20,10:5,6] pyrido[2,3-d] pyrimidine-2,4,6-trione
(6h): 1H NMR (300 MHz, CDCl3):
7.93 (d, J = 7.2 Hz, 1H, ArH), 7.80 (d,
d
29. (a) Nandi, G. C.; Samai, S.; Kumar, R.; Singh, M. S. Tetrahedron 2009, 65, 7129;
(b) Nandi, G. C.; Samai, S.; Kumar, R.; Singh, M. S. Tetrahedron Lett. 2009, 50,
7220; (c) Samai, S.; Nandi, G. C.; Kumar, R.; Singh, M. S. Tetrahedron Lett. 2009,
50, 7096; (d) Kumar, R.; Raghuvanshi, K.; Verma, R. K.; Singh, M. S. Tetrahedron
Lett. 2010, 51, 5933; (e) Nandi, G. C.; Samai, S.; Singh, M. S. Synlett 2010, 1133;
(f) Nandi, G. C.; Samai, S.; Singh, M. S. J. Org. Chem. 2010, 75, 7785; (g) Verma, G.
K.; Raghuvanshi, K.; Verma, R. K.; Dwivedi, P.; Singh, M. S. Tetrahedron 2011, 67,
J = 7.2 Hz, 1H, ArH), 7.67 (t, J = 7.5 Hz, 1H, ArH), 7.56 (t, J = 7.5 Hz, 1H, ArH), 3.86
(s, 3H, NCH3), 3.50 (s, 3H, NCH3), 2.49–2.38 (m, 1H, CH), 0.87 (s, 6H, CH3). 13C
NMR (75 MHz, DMSO-d6): d 180.2168.5, 165.3, 164.6, 159.4, 155.3, 146.2,
130.7, 129.1, 128.5, 125.3, 122.6, 107.5, 37.5, 30.4, 28.3, 28.2, 22.4. IR (KBr):
m
= 2987, 1755, 1700, 1555, 1510, 1400, 1398, 1330, 1250, 1185, 1040 cmꢀ1. ESI
MS (m/z) 365(M+ + 1); Anal. Calcd for C19H17N3O3: c, 68.05; H, 5.11; N, 12.53%.
Found C, 68.26; H, 5.43; N, 12.29%.