Thiourea dioxide in water as a recyclable catalyst for the synthesis of structurally diverse dihydropyrido[2,3-d]pyrimidine-2,4-diones

Article abstract of DOI:10.1016/j.tetlet.2012.03.037

A series of dihydropyrido[2,3-d]pyrimidine-2,4-diones derivatives were synthesized by the three-component reaction of 6-amino-1,3-dimethyl uracil, aromatic aldehydes, and 1,3-dicarbonyl compound catalyzed by thiourea dioxide in aqueous media. Importantly, the aqueous layer containing thiourea dioxide could be reused for several runs without significant loss in catalytic activity. This method provided several advantages such as inexpensive, recyclable catalyst, easier work-up, milder reaction conditions and environmental benign nature.

Full text of DOI:10.1016/j.tetlet.2012.03.037

Tetrahedron Letters 53 (2012) 2595–2600
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Thiourea dioxide in water as a recyclable catalyst for the synthesis of
structurally diverse dihydropyrido[2,3-d]pyrimidine-2,4-diones
⇑
Sanny Verma, Suman L. Jain
Chemical Sciences Division, CSIR-Indian Institute of Petroleum, Mohkampur, Dehradun 248005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of dihydropyrido[2,3-d]pyrimidine-2,4-diones derivatives were synthesized by the three-compo-
nent reaction of 6-amino-1,3-dimethyl uracil, aromatic aldehydes, and 1,3-dicarbonyl compound cata-
lyzed by thiourea dioxide in aqueous media. Importantly, the aqueous layer containing thiourea
dioxide could be reused for several runs without significant loss in catalytic activity. This method pro-
vided several advantages such as inexpensive, recyclable catalyst, easier work-up, milder reaction condi-
tions and environmental benign nature.
Received 11 October 2011
Revised 7 March 2012
Accepted 10 March 2012
Available online 16 March 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Organocatalysis
Multicomponent coupling
Heterocycle
Thiourea dioxide
Recyclable catalyst
Catalysis promoted by organic molecules termed as ‘Organoca-
talysis’ is a novel concept in synthetic organic chemistry which is
gaining particular interest in recent decades.1 Despite of their low
cost, low toxicity organocatalysts are less sensitive to moisture
and, more importantly in many cases, the efficiency and selectivity
of reactions remain similar to the established organic reactions.
Owing to their environmental and economical benefits, organocat-
alytic reactions can be considered as green processes,2 however,
recovery and recycling of organocatalysts are still a challenging
task. Nevertheless, a number of heterogeneous and heterogenized
homogeneous organocatalysts3 have been developed; most of them
suffer from the drawbacks of lower efficiency, expensive nature, and
use of organic solvents as reaction media. During the course of our
investigations, we have established the use of thiourea dioxide
(TUD) 1,4 (Fig. 1) easily prepared by the oxidation of thiourea with
hydrogen peroxide as an efficient organocatalyst for developing
new methodologies in organic reactions.5 In continuation of our
work on multidisciplinary synthetic approach, herein we wish to
report TUD in water as an efficient recyclable combination for the
synthesis of structurally diverse dihydropyrido[2,3-d]pyrimidine-
2,4-diones via one-pot condensation of 6-amino-1,3-dimethyl ura-
cil, 1,3-dicarbonyl compound, and aromatic aldehyde (Scheme 1).
Dihydropyrido[2,3-d]pyrimidines are highly versatile uracil
derivatives, which have been extensively used for the synthesis of
a number of nitrogen-containing heterocyclic building blocks of bio-
logical importance.6 These compounds show the diverse range of
pharmacological activities7 including adenosine kinase inhibitor,8
AbI kinase inhibitor,9 tyrosine phosphatase inhibitor,10 antiviral,
and calcium channel antagonist activities.11 Conventionally these
compounds are synthesized via Hantzsch-type reaction, however
most of the known methods suffer from certain drawbacks such as
longer time, tedious synthetic pathways, expensive catalysts, and
use of volatile organic solvents. Thus the development of more con-
venient, cheaper, and environmentally benign synthetic methods
for these compounds still remains a challenging task. Although a
few organocatalytic systems such as p-toluenesulfonic acid,12
2,4,6-trichloro-1,3,5-triazine,13 -proline14 have been reported for
L
this transformation, however, most of them are homogeneous in
nature. Thus the development of more convenient, environmentally
benign, and recyclable catalytic system for these compounds is
highly desired.
Initially, we studied the reaction between 6-amino-1,3-dimethyl
uracil 2, benzaldehyde 3a, and ethyl acetoacetate 4 by using TUD
(2 mol %) as catalyst in various solvents such as acetonitrile, meth-
anol, dichloromethane, and water. As shown in the Table 1, entry 1,
water was found to be an optimum reaction media for this transfor-
mation. Thiourea dioxide played a crucial role in this reaction and
no reaction occurred in the absence of catalyst under described
reaction conditions (entry 1). Further, we studied the reaction
between 6-amino-1,3-dimethyl uracil 2, aromatic aldehyde 3, and
1,3-dicarbonyl compound 4 in the presence of catalytic amount of
TUD in water at 50 °C under nitrogen atmosphere which afforded
corresponding dihydropyrido[2,3-d]pyrimidine-2,4-diones
5 in
moderate to good yields.15 The results are summarized in Table 1.
All the substrates underwent reaction efficiently and no noticeable
⇑
Corresponding author. Tel.: +91 135 2525788; fax: +91 135 2660202.
E-mail address: suman@iip.res.in (S.L. Jain).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.037

2596
S. Verma, S. L. Jain / Tetrahedron Letters 53 (2012) 2595–2600
O
O
S
H2N
NH2
Figure 1. Thiourea dioxide (TUD) 1.
R
O
O
CHO
O
N
O
O
N
1 (2 mol%)
H2O,500C
R'
O
N
R
O
R'
H2N
N
O
R'=H, CH3
N
H
O
3
4
2
5
R
O
O
N
Prolonged heating at 80 oC
without N2
R'
O
N
N
O
6
Scheme 1. TUD catalyzed synthesis of dihydropyrido[2,3-d]pyrimidines.
Table 1
TUD-catalyzed synthesis of dihydropyrido[2,3-d]pyrimidine-2,4-dionesa
Entry
Reactants
Product
Reaction time (h)
8.0 18,c 24,d 12e-f
Yieldb (%)
O
CHO
N
O
O
N
H2N
N
O
1
O
N
92 55, 40, 60 -
N
H
O
O
O
O
O
N
CHO
N
N
O
O
O
N
H2N
O
O
N
2
8.0
94
N
H
O
O
O
O
CHO
O
O
O
N
H2N
N
O
O
3
8.0
94
N
N
H
O
O
O
Cl
CHO
Cl
O
N
O
N
H2N
4
N
O
O
8.0
94
N
O
N
H

S. Verma, S. L. Jain / Tetrahedron Letters 53 (2012) 2595–2600
2597
Table 1 (continued)
Entry
Reactants
Product
Reaction time (h)
Yieldb (%)
CHO
Cl
Cl
O
N
O
O
N
H2N
N
O
5
6
7
8.0
93
O
O
N
O
O
N
H
O
O
CHO
CH3
CH
3
O
N
N
N
O
N
H2N
O
8.0
92
N
O
O
N
O
O
CHO
CH3
CH
3
O
N
O
N
H2N
O
8.0
94
O
O
N
O
O
N
O
O
CHO
CH3
CH3
O
N
N
O
N
H2N
O
8
8.0
95
O
N
O
O
N
H
O
N
O
CHO
OCH3
O
N
N
O
O
O
H2N
9
8.5
90
OCH3
O
O
N
H
N
N
O
O
O
O
CHO
OCH3
O
N
N
O
H2N
O
O
10
8.5
90
OCH3
O
O
O
N
H
N
N
O
O
CHO
OCH3
O
N
O
H2N
N
O
O
11
10.0
90
OCH3
N
H
N
O
O
(continued on next page)

2598
S. Verma, S. L. Jain / Tetrahedron Letters 53 (2012) 2595–2600
Table 1 (continued)
Entry
Reactants
Product
Reaction time (h)
Yieldb (%)
CHO
OH
OH
O
N
O
O
N
N
O
H2N
12
10.0
92
O
O
N
O
O
N
H
O
O
CHO
OH
OH
O
N
N
O
H2N
O
13
10.0
92
O
N
O
O
N
H
N
O
N
O
CHO
NO2
NO2
O
N
N
O
O
N
O
H2N
14
10.0
90
O
O
O
O
N
N
O
O
CHO
NO2
NO2
O
N
O
N
H2N
O
15
10.0
90
O
O
N
N
O
O
O
O
CHO
NO2
O
N
N
O
N
16
H2N
O
10.0
86
NO2
O
N
O
N
O
a
Reaction mixture: 6-Amino-1,3-dimethyl uracil (3 mmol), aldehyde (3.5 mmol), 1,3-dicarbonyl compound (3.5 mmol), TUD (2 mol %) in water (2 ml) at 50 °C under
nitrogen atmosphere.
b
Isolated yields.
Using acetonitrile.
Using dichloromethane.
Using methanol as solvent.
c
d
e
f
Blank experiment without using TUD.
effect of the substituents on the aromatic ring was observed under
similar reaction conditions. The identity of the compounds was
ascertained by comparing their physical and spectroscopic data
with those of the reported compounds. The use of acetyl acetone
in the place of ethyl or methyl acetoacetate also provided better
yields of the product (Table 1, entries 3, 4, 6, 11 and 16).
It was reported that the dihydropyrido[2,3-d]pyrimidine-2,4-
dione derivatives were unstable to air and could be easily oxidized
to corresponding aromatization products 6.16 Thus, prolonged
heating of the reaction mixture in the absence of nitrogen could
afford the corresponding pyrido[2,3-d]pyrimidine-2,4-diones
exclusively (Scheme 1). Further we studied the recyclability and
reusability of the TUD in water by choosing the reaction between
6-amino-1,3-dimethyl uracil, benzaldehyde, and ethyl acetoace-
tate under described reaction conditions. After completion of the
reaction, the reaction mixture was diluted with water and the
product was isolated by simple filtration. The residual aqueous
layer containing TUD was concentrated under reduced pressure
and reused for the subsequent run (8 runs). The results of these
recycling experiments are shown in Table 2. It is worthy to men-
tion that TUD is insoluble in organic solvents, while readily soluble
in water. Thus, the product could easily be isolated by filtration and
aqueous phase containing TUD was successfully reused with con-
sistent catalytic activity. Some control experiments using known
acid/base catalysts, and to compare the efficiency to that of TUD
were performed. 6-Amino-1,3-dimethyl uracil 2, benzaldehyde

S. Verma, S. L. Jain / Tetrahedron Letters 53 (2012) 2595–2600
2599
Table 2
Results of recycling experiments
R
O
O
N
CHO
O
N
O
O
N
TUD, H2O
500C, 8 h
R'
O
N
O
H2N
O
N
H
O
Run
1
2
3
4
5
6
7
8
Yield (%)
92
92
92
92
92
90
90
90
Table 3
Comparison of TUD with other acid/base catalysts for the synthesis of dihydropyrido[2,3-d]pyrimidine-2,4-dione
O
CHO
O
O
N
O
O
N
O
H2N
N
O
O
N
N
H
O
Entry
Reaction conditions
Reaction time (h)
Yielda (%)
1
2
3
4
5
AcOH, 50 °C
HCl, 50 °C
Et3N, 50 °C
Pyridine, 50 °C
TUD, 50 °C
8
8
8
8
8
57
72
55
20
94
a
Isolated yield.
H2N
N
O
O
N
Ar
O
H
O
Ar
O
N
H
O
R1
R1
2
O
Ar
H
+
O
R1
N
Aldol condensation
O
O
O
O
O
O
HN
7
4
3
O
Ar
O
N
8
Ar
O
N
R1
O
H
O
N
R1
O
N
Dehydration
-H2O
Intramolecular
cyclisation
N
H
O
N
H
O
HO
5
Scheme 2. Probable mechanistic pathway.
3a, and ethyl acetoacetate 4 were reacted by using different acid/
base such as acetic acid, HCl, triethyl amine, and pyridine as cata-
lysts in water at 50 °C for 8 h. The results of these experiments are
summarized in Table 3. As shown, among the various catalysts TUD
was found to be most promising and afforded excellent product
yield (94%) under described reaction conditions.
catalyzed by TUD in aqueous media. The milder reaction condi-
tions, simple workup, environmental friendly, and good yields
are the most significant advantages of this new procedure in the
synthesis of these potential biologically active compounds.
Acknowledgments
The exact mechanistic pathway for this reaction is not known at
this stage; however, the possible mechanism is shown in Scheme 2.
The reaction between 3 and 4 in the presence of TUD could readily
give the intermediate 7 by aldol condensation, which on subse-
quent reaction with 2 followed by intramolecular cyclization and
dehydration results in the formation of the desired product 5.
In conclusion, we have described a convenient, highly efficient,
and environmentally benign procedure for the preparation of
structurally diverse dihydropyrido[2,3-d]pyrimidine derivatives
by the one step three-component coupling of aromatic aldehyde,
malononitrile, and 6-amino-4-hydroxyl-2-mercaptoprimidine
We are thankful to the Director, IIP for his kind permission to
publish these results. S.V. acknowledges the CSIR, New Delhi for
the award of his Research Fellowship.
References and notes
1. For reviews on organocatalysis, see: Special issue on organocatalysis, Acc.
Chem. Res. 2004, 37, 631.; (b) Dalko, P. I. Enantioselective Organocatalysis;
Wiley-VCH: Weinheim, Germany, 2007; (c) Bertelsen, S.; Jorgensen, K. A. Chem.
Soc. Rev. 2009, 38, 2178; (d) Barbas, C. F., III Angew. Chem. 2008, 120, 44. Angew.
Chem., Int. Ed. 2008, 47, 42..

2600
S. Verma, S. L. Jain / Tetrahedron Letters 53 (2012) 2595–2600
2. (a) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638; (b) Palomo, C.;
Oiarbide, M.; López, R. Chem. Soc. Rev. 2009, 38, 632; (c) Houk, K. N.; List, B. Acc.
Chem. Res. 2004, 37, 487; (d) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew.
Chem. 2007, 119, 1590. Angew. Chem., Int. Ed. 2007, 46, 1570.; (e) Melchiorre,
P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem. 2008, 120, 6232. Angew.
Chem. Int. Ed. 2008, 47, 6138..
3. (a) Liang, B.; Wang, X.; Wang, J. X.; Du, Z. Tetrahedron 1981, 2003, 63; (b)
Narsaiah, A. V.; Basak, A. K.; Nagaiah, K. Synthesis 2004, 1253; (c) Xiaoyan, H.;
Fan, X.; Yiqin, L.; Qi, S. Eur. J. Org. Chem. 2005, 1500; (d) Singh, O. M.; Devi, N. S.
J. Org. Chem. 2009, 74, 3141; (e) Xin, J.; Chang, L.; Hou, Z.; Shang, D.; Liu, X.;
Feng, X. Chem. Eur. J. 2008, 14, 3177; (f) Debache, A.; Amimour, M.; Belfaitah, A.;
Rhouati, S.; Carboni, B. Tetrahedron Lett. 2008, 49, 6119; (g) Hassani, Z.; Islami,
M. R.; Kalantari, M. Bioorg. Med. Chem. Lett. 2006, 16, 4479; (h) Rafiee, E.; Jafari,
H. Bioorg. Med. Chem. Lett. 2006, 16, 2463; (i) Heravi, M. M.; Bakhtiari, K.;
Bamoharram, F. F. Catal. Commun. 2006, 7, 373; (j) Yu, Y.; Liu, D.; Liu, C.; Luo, G.
Bioorg. Med. Chem. Lett. 2007, 17, 3508; (k) Schauble, J. H.; Trauffer, E. A.;
Deshpande, P. P.; Evans, R. D. Synthesis 2005, 1333; (l) De, S. K.; Gibbs, R. A.
Synthesis 2005, 1748; (m) Rodrıguez-Domınguez, J. C.; Bernardi, D.; Kirsch, G.
Tetrahedron Lett. 2007, 48, 5777.
8. Zheng, G. Z.; Lee, C.-H.; Pratt, J. K.; Perner, R. J.; Jiang, M. Q.; Gomtsyan, A.;
Matulenko, M. A.; Mao, Y.; Koenig, J. R.; Kim, K. H.; Muchmore, S.; Yu, H.;
Kohlhaas, K.; Alexander, K. M.; McGaraughty, S. K.; Chu, L.; Wismer, C. T.;
Mikusa, J.; Jarvis, M. F.; Marsh, K. E.; Kowaluk, A.; Bhagwat, S. S.; Stewart, A. O.
Bioorg. Med. Chem. Lett. 2001, 11, 2071.
9. Huron, D. R.; Gorre, M. E.; Kraker, A. J.; Sawyers, C. L.; Rosen, N.; Moasser, M. M.
Clin. Cancer Res. 2003, 9, 1267.
10. Thakkar, K. C.; Berthel, S. J.; Cheung, A. W. -H.; Kim, K.; Li, S.; Yun, W. US
Applications. Patent No. 20070021445.
11. Wang, X. S.; Zeng, Z. S.; Shi, D. Q.; Wei, X. Y.; Zong, Z. M. Synth Commun. 2004,
34, 4331.
12. Kumar, A.; Maurya, R. A. Synlett 2008, 883.
13. Sharma, G. V. M.; Reddy, K. L.; Lakshmi, P. S.; Krishna, P. R. Synthesis 2006, 55.
14. (a) Suri, J. T.; Mitsumori, S.; Albertshofer, K.; Tanaka, F.; Barbas, C. F., III J. Org.
Chem. 2006, 71, 3822; (b) Northrup, A. B.; Mangion, I. K.; Hettche, F.;
MacMillan, D. W. C. Angew. Chem., Int. Ed. 2004, 43, 2152; (c) Allemann, C.;
Gordillo, R.; Clemente, F. R.; Cheong, P. H.-Y.; Houk, K. N. Acc. Chem. Res. 2004,
37, 558; (d) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423; (e)
Sabitha, G.; Fatima, N.; Reddy, E. V.; Yadav, S. Adv. Synth. Catal. 2005, 347, 1353;
(e) Utsumi, N.; Zhang, H.; Tanaka, F.; Barbas, C. F. Angew. Chem., Int. Ed. 2007,
46, 1878 and references cited therein..
4. Ohura,O; Fujimoto,O. U. S. Patent 4,233238, 1980.
5. (a) Verma, S.; Kumar, S.; Jain, S. L.; Sain, B. Org. Biomol. Chem. 2011, 9, 6943; (b)
Verma, S.; Jain, S. L.; Sain, B. Tetrahedron Lett. 2010, 51, 6897.
15. General experimental procedure: A mixture containing 6-amino-1,3-dimethyl
6. (a) Kappe, C. O. Tetrahedron 1993, 49, 6937; (b) Kappe, C. O. In Multicomponent
Reactions In Zhu, J., Bienaymie, H., Eds.; Wiley-VHC: Weinheim, 2005; pp 95–
120; (c) Kappe, C. O.; Roschger, P. J. Heterocycl. Chem. 1989, 26, 55; (d) Chitra, S.;
Devanathan, D.; Pandiarajan, K. Eur. J. Med. Chem. 2010, 45, 367 and references
cited therein.
7. (a) Stadler, A.; Kappe, C. O. J. Comb. Chem. 2001, 3, 624; (b) Valverde, M. G.;
Dallinger, D.; Kappe, C. O. Synlett 2001, 741; (c) Rovnyak, G. C.; Atwal, K. S.;
Hedberg, A.; Kimball, S. D.; Moreland, S.; Gougoutas, J. Z.; O’Reilly, B. C.;
Schwartz, J.; Malley, M. F. J. Med. Chem. 1992, 35, 3254; (c) Patil, A. D.; Kumar,
N. V.; Kokke, W. C.; Bean, M. F.; Freyer, A. J.; De Brosse, C.; Mai, S.; Truneh, A.;
Faulkner, D. J.; Carte, B.; Breen, A. L.; Hertzberg, R. P.; Johnson, R. K.; Westley, J.
W.; Potts, B. C. M. J. Org. Chem. 1995, 60, 1182; (d) Zorkun, I. S.; Sarac, S.; Celebi,
S.; Erol, K. Bioorg. Med. Chem. 2006, 14, 8582.
uracil 2 (3.0 mmol), aromatic aldehyde 3 (3.5 mmol), 1,3-dicarbonyl
compound 4 (3.5 mmol) and TUD (2 mol %) in water was heated at 50 °C for
8–10 h to obtain dihydropyrido[2,3-d]pyrimidine-2,4-diones 5. The reaction
progress was monitored by TLC (SiO2). After completion of the reaction, the
mixture was allowed to cool and water (5 mL) was added. The precipitated
solid was separated by filtration and washed with water and dried.
Recrystallization from ethanol gave light yellow or white crystals of the
desired compound. The aqueous layer was concentrated under reduced
pressure and reused for subsequent experiment. The products were
identified by comparing their physical and spectral data with the reported
compound.
16. (a) Subba, R. A.; Mitra, R. B. Indian J. Chem. 1981, 20B, 159; (b) Wawzonek, S. J.
Org. Chem. 1976, 41, 3149.