Biginelli reaction-carboxylic acids as catalysts

Article abstract of DOI:10.14233/ajchem.2013.14094

Mono and dicarboxylic acids were found to be excellent catalysts for the synthesis of dihydropyrimidones/thiones. These are presented as alternate and cheap catalysts for the multicomponent reactions.

Full text of DOI:10.14233/ajchem.2013.14094

Asian Journal of Chemistry; Vol. 25, No. 9 (2013), 4770-4772
http://dx.doi.org/10.14233/ajchem.2013.14094
Biginelli Reaction-Carboxylic Acids as Catalysts
1
2
3,*
1
1,2
SADIA NOREEN , SAIMA PERVEEN , MUHAMMAD NAEEM KHAN , AREESHA NAZEER , MISBAHUL AIN KHAN , MUNAWAR ALI
1
1
1
4
5
6
MUNAWAR , RABIA BABAR , FARAH SUHAIL , MUHAMMAD AZAD , ALICE M.R. BERNARDINO and MAURÍCIO S. DOS SANTOS
1Institute of Chemistry, University of the Punjab, Lahore, Pakistan
2Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
3Applied Chemistry Resarch Center, PCSIR Laboratories Complex, Lahore, Pakistan
4Government Polytechnic Institute for Printing and Graphic Arts, Lahore, Pakistan
5Programa de Pós-Graduação em Química, Universidade Federal Fluminense, Niterói-RJ, Brazil
6Departamento de Física e Química, Universidade Federal de Itajubá, Itajubá-MG, Brazil
*Corresponding author: E-mail: changwani_1@yahoo.com
(Received: 23 May 2012;
Accepted: 4 March 2013)
AJC-13067
Mono and dicarboxylic acids were found to be excellent catalysts for the synthesis of dihydropyrimidones/thiones. These are presented as
alternate and cheap catalysts for the multicomponent reactions.
Key Words: Multicomponent reactions, Dihydropyrimidone, Dihydropyrimidothione, Acid catalysts.
promoting Biginelli reaction. Here we would like to report
T
INTRODUCTION
our findings for the use of organic acids (both mono and
dicarboxylic acids) as catalysts in the Biginelli reaction. The
Pyrimidines are of vital importance in the life processes
and the system has received the attention as it deserves both
from the biological as well as from chemical field. It is evidenced
form the literature regarding the diazines1. One of the pyrimidine
derivatives i.e., 3,4-dihydropyrimidin-2-(1H)-ones/thiones*
(DHPM), also known as the Biginelli compounds2, are of parti-
cular biological importance due to their effectiveness as calcium
channel blockers and other properties3-5.
raw materials employed were aromatic aldehydes, β-dicarbonyl
compounds and urea or thiourea (Scheme-I). The list is by no
means exhaustive so are the conditions. Yields are good to
excellent. Better yields in many reactions can be obtained by
varying time and other factors. Other substrates, solvents may
also be gainfully employed.
These three component reactions, involving aldehydes,
methylenic component (CH) and urea/thiourea in the presence
of a catalyst/solvent have been extensively reviewed6.A number
of effective catalysts have been reported for this reaction.
Among these to cite a few are metal salts such as BiCl37, NiCl28,
ZrCl4 , Sr(NO3)210, Ln(OTf)311, solid support12, microwave
9
I a
assisted13, 1,3-dibromo-5,5-dimethylhydantoin14, iodine15,
CuCl2·2H2O in aqueous surfactant system16, DDQ17, SnCl218
,
triphenylphosphine19, ammonium carbonate20 and ionic
liquids21. Several Brönsted and Lewis acids have been used in
these reactions and in fact acetic acid was the original catalyst
used by Biginelli22. Hydrochloric acid has often been employed23.
Another organic acid catalyst, besides acetic acid reported is
chloroacetic acid24. A recent paper has described this reaction
carried out in low-melting tartaric acid-urea mixtures as a green
method25.
Scheme-I:Synthesis of dihydropyrimidin-2-(1H)-one/thiones Ia-d and
IIa-c
Although acetic acid has previously been used as combined
catalyst and the solvent in the Biginelli condensation26, it was,
however, interesting to see if this or other acids, in solvents
such as ethanol can also function as catalysts.
To our best of knowledge other organic acids, although a
large source of reagents/catalysts have not been explored for

Vol. 25, No. 9 (2013)
Biginelli Reaction-Carboxylic Acids as Catalysts 4771
TABLE-1
SYNTHESIS OF DIHYDROPYRIMIDIN-2-(1H)-ONES/THIONES USING MONOCARBOXYLIC ACIDS
Yield (%)/m.p. (ºC)a,b
S. No.
Acid catalyst
Ia
Ib
75 (220-222)
– (220-222)
25 (220-222)
55 (220-222)
–
IIa
60 (205)
20 (205)
15 (205)
71 (205)
–
IIb
25 (220-225)
25 (220-225)
25 (220-225)
69 (220-225)
–
1
2
3
4
5
6
7
8
Formic acid
Acetic acid
75 (203)
60 (203)
55 (203)
75 (203)
80 (188)
66 (187)
68 (190)
55 (203)
Propanoic acid
Butyric acid
Hexanoic acid
Palmitic acid
Oleic acid
–
–
–
–
–
–
Stearic acid
70 (220-222)
20 (205)
20 (220-225)
a Ic 72 %, m.p. 198 ºC; Id, 71 %, m.p. 183 ºC and IIc, 67 %, m.p. 181 oC. b100 mg monocarboxylic acid (n-hexanoic acid for Ic and butyric acid for
IIc).
When different dioic acids were used in these reactions
as catalysts (50 and 10 mg amounts), comparable yields of
the products were obtained (Table-2). These results demons-
trate the efficacy of dioic acids as catalysts of Biginelli
reaction. With the decrease in amount of the catalyst the
product yield in some cases were, however, lower as shown in
Table-2.
EXPERIMENTAL
All the chemicals and reagents used in the present study
were commercial products. These were purified by usual methods
of distillation (for liquids) and crystallization from appropriate
solvents (for solids). Melting points were determined on a
Gallenkamp melting point apparatus and are uncorrected. IR
spectra were recorded on Perkin-Elmer spectrum BX 1 and
NMR on a Brucker 400 MHz spectrometer using tetramethyl-
silane as an internal reference.
General procedure: A mixture of 40 mmol of benzalde-
hyde, 40 mmol β-diketo compound, 45 mmol urea or thiourea
and catalytic amount (a few drops of the liquid acid or a few
crystals (ranging from 5-100 mg of the mono- or dicarboxylic
acid as mentioned) in 10 mL of ethanol was heated under reflux
for a few hours. The reaction was monitored by TLC. After
cooling the reaction mixture was diluted with 100 mL of water,
kept for a few hours, the precipitates were filtered off, washed
with water and dried.A portion was recrystallized from ethanol
to give the expected dihydropyrimidone (or thione). Some
reactions were carried out by fusion on a hot plate (solvent
less condition) and the contents were dissolved in ethanol and
purified as usual. All the products of the reactions were com-
pared with the authentic samples prepared by the literature
methods and were found to be identical in all respects m.p.,
TABLE-2
SYNTHESIS OF DIHYDROPYRMIDIN-
2-(1H)-ONES USING DICARBOXYLIC ACIDS
Yield (%)a Ia
Yield (%)b Ia
S. No.
Acid catalyst
Oxalic acid
Malonic acid
Maleic acid
Adipic acid
Succinic acid
Fumaric acid
1
2
3
4
5
6
63
76
66
68
63
65
54
43
66
48
70
62
a50 mg dioic acid. b10 mg dioic acid.
Some of the reactions were also carried out by direct fusing
the components in the presence of slight amount of different
dioic acids (5 mg) and the results obtained are presented in
Table-3. The product yields are found to be little lower in all
these cases in general. Probably some of the components
escaped or decomposed during this "direct" fusion.
1
mixed m.p., FTIR or other spectra. Compound Ia: H NMR
(400 MHz, DMSO): δ = 1.06 (t, J = 7.2 Hz, 3H), 2.23 (s, 3H),
3.98 (q, J = 7.2 Hz, 2H), 5.12 (s, 1H), 7.21-7.32 (m, 5H), 7.60
(s, 1H), 9.14 (s, 1H). IR (KBr, νmax, cm-1): 3239, 3110, 1725,
1702, 1646. MS (EI): m/z calcd. (%) for C14H16N2O3: 260,
2884; found (%): 260,2879.
TABLE-3
SYNTHESIS OF DIHYDROPYRMIDIN-2-(1H)-
ONES/THIONES USING DIOIC ACIDS
S. No.
Acid catalysta
Oxalic acid
Malonic acid
Maleic acid
Adipic acid
Succinic acid
Fumaric acid
Yield (%) Ia
Yield (%) IIa
1
2
3
4
5
6
59
47
67
44
62
54
32
24
40
50
27
36
RESULTS AND DISCUSSION
A 10 mol % of the acid functioned well as a catalyst to
give the desired Ia and then even a tenfold decrease i.e., 1 mol
% was effective (Tables 1 and 2). However, the yields, in some
cases, where low, can be increased by using longer reaction
periods. This successful attempt encouraged us to explore the
use of other aliphatic carboxylic acids as catalysts in these
reactions. Formic acid has previously been employed for the
dihydropyrimidine synthesis but under microwave irradiation
conditions9 but with the present protocol comparable yield
(75 %) of Ia was isolated. Reactions with other acids also gave
reasonable yields of the products. Even the long chain fatty
acids including the unsaturated oleic acid proved to be efficient
catalysts. Table-1 lists the results of these reactions.
a5 mg dioic acid, without solvent.
Conclusion
The present method provides yet another series of catalysts
for the Biginelli reaction. The procedure is not only simple
but also a cheaper alternative for this three component reaction.
ACKNOWLEDGEMENTS
The authors thank Higher Education Commission (HEC)
of Pakistan for a scholarship to S. Noreen, S. Perveen and A.

4772 Noreen et al.
Asian J. Chem.
11. L. Wang, C. Qian, H. Tian andY. Ma, Synth. Commun., 33, 1459 (2003).
12. P. Salehi, M. Dabiri, M.A. Zolfigol and M.A.B. Fardi, Tetrahedron
Lett., 44, 2889 (2003).
13. M. Kidwai, S. Saxena, R. Mohan and R. Venkataramanan, J. Chem. Soc.
Perkin Trans. 1, 1845 (2002).
Nazeer. Thanks are also due to Coordenação deAperfeiçoamento
de Pessoal de Nível Superior (CAPES) and Conselho Nacional
de Desenvolvimento Científico e Tecnológico (CNPq) for their
continuous support.
14. M. Abdollahi and Z. Zaghaghi, Chem. Papers, 63, 97 (2009).
15. I. Saxena, D.C. Borah and J.C. Sarma, Tetrahedron Lett., 46, 1159
(2005).
16. X. Feng, J.-J. Wang and Y.-P. Tian, Synth. Commun., 38, 1299 (2008).
17. D. Shobha, M.A. Chari, P. Sadanandam and K. Mukkanti, J. Heterocycl.
Chem., 45, 1225 (2008).
REFERENCES
1. D.J. Brown, In eds.: A.R. Katritzky and C. W Rees, In Comprehensive
Heterocyclic Chemistry; Pergamon Press: Oxford (1984).
2. P. Biginelli, Gazz. Chim. Ital., 23, 360 (1893).
3. G.C. Rovnyak, S.D. Kimball, B. Beyer, G. Cucinotta, J.D. Dimarco, J.
Gougoutas, A. Hedberg, M. Malley, J.P. McCarthy, R. Zhang and S.
Moreland, J. Med. Chem., 38, 119 (1995).
4. G.C. Rovnyak, K.S. Atwal, A. Hedberg, S.D. Kimball, S. Moreland,
J.Z. Gougoutas, B.C. O' Reilly, J. Schwarz and M.F. Malley, J. Med.
Chem., 35, 3254 (1992).
18. D. Russowsky, F.A. Lopes, V.S.S. da Silva, K.F.S. Canto, M.G.M. D`
Oca and M.N. Godoi, J. Braz. Chem. Soc., 15, 165 (2004).
19. A. Debache, M. Amimour, A. Belfaitah, S. Rhouati and B. Carboni,
Tetrahedron Lett., 49, 6119 (2008).
20. F. Tamaddon, Z. Razmi and A.A. Jafar, Tetrahedron Lett., 51, 1187
(2010).
5. S.D. Sidler, R.D. Larsen, M. Chartrain, N. Ikemoto, C.M. Roberge,
C.S. Taylor, W. Li and G.F. Bills, PCT. Int. Appl. WO# 9906795 (1999).
6. C.O. Kappe and A. Stadler, Org. React. A, 65, 1 (2004).
7. K. Ramalinga, P.Vijayalakshmi and T.N.B. Kaimal, Synlett, 863 (2001).
8. J. Lu and Y. Bai, Synthesis, 466 (2002).
21. J. Peng and Y. Deng, Tetrahedron Lett., 42, 5917 (2001).
22. E.H. Hu, D.R. Sidler and U.H. Dolling, J. Org. Chem., 63, 3454 (1998).
23. J. Lu and H. Ma, Synlett, 63 (2000).
24. Y. Yu, D. Liu, C. Liu and G. Luo, Bioorg. Med. Chem. Lett., 17, 3508
(2007).
9. C.V. Reddy, M. Mahesh, P.V.K. Raju, T.R. Babu and V.V.N. Reddy,
Tetrahedron Lett., 43, 2657 (2002).
10. C. Liu, J. Wang and Y. Li, J. Mol. Catal. A, 258, 367 (2006).
25. S. Gore, S. Baskaran and B. Koenig, Green Chem., 13, 1009 (2011).
26. J. Wichmann, G. Adam, S. Kolczewski, V. Mutel and T. Woltering,
Bioorg. Med. Chem. Lett., 9, 1573 (1999).