Oxalic acid as a versatile catalyst for one pot facile synthesis of 3,4-dihydropyrimidin-2-(1H)-ones and their thione analogues

Article abstract of DOI:10.1002/jhet.5570450440

(Chemical Equation Presented) 3,4-Dihydropyrirnidin-2-(1H)-ones and their thione analogues are synthesized from the condensation of aromatic aldehydes, β-dicarbonyl compound and urea or thiourea in presence of 5 mol% of oxalic acid in ethanol-water (1:2 ;

Full text of DOI:10.1002/jhet.5570450440

Jul-Aug 2008
1191
Oxalic Acid as a versatile catalyst for one pot facile synthesis of 3,4-
dihydropyrimidin-2-(1H)-ones and their thione Analogues
Jaiprakash N. Sangshetti1, Nagnnath D. Kokare1, 2, Devanand B. Shinde*1
1Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad-431004 (MS), India
2New Drug Discovery, Wockhardt Research Centre, Aurangabad-431210 (MS), India
E-mail: dbshinde.2007@rediffmail.com
Received March 1, 2007
O
X
O
O
H
+
+
O
H2N
NH2
N
x = O,
x = S
5 mol%, oxalic acid,
ethanol-water
N
O
O
NH
N
H
X
x = O,
x = S
3,4-Dihydropyrimidin-2-(1H)-ones and their thione analogues are synthesized from the condensation of
aromatic aldehydes, ꢀ-dicarbonyl compound and urea or thiourea in presence of 5 mol% of oxalic acid in
ethanol-water (1:2 ; v/v) under mild reaction conditions. The yields obtained are better and also the use of
very inexpensive catalyst, environmentally benign solvent and easy work-up are the advantageous aspects
of the present method.
J. Heterocyclic Chem., 45, 1191 (2008).
INTRODUCTION
reagents or catalysts, unsatisfactory yields, incompat-
ibility with other functional groups and involve tedious
work-up. Some of methods are applicable for aromatic
aldehydes only [8]. Thus, there is still need of a simple
and general procedure for one-pot synthesis of DHPMs
and their thione analogues under mild conditions. In
continuation with our research for the development of
simple and novel methods for synthesis of different
heterocycles [9], we have developed a convenient method
for the synthesis of DHPMs and their thione analogues
using 5 mol% oxalic acid as a catalyst in ethanol-water.
The interest of dihydropyrimidones (DHPMs) and their
derivatives stem from their widespread activities like
calcium channel blockers, ꢁ-1a-antagonists and
neuropeptide-Y (NPY) antagonists [1]. Recently, some
alkaloids are reported containing dihydropyrimidones,
which are potent HIV gp 120-CD4 inhibitors [2]. DHPMs
and their sulphur analogues are pharmacologically
important because of their antibacterial, antitumour and
anti-inflammatory properties [3]. The literature reveals a
number of methods for the synthesis of DHPMs and their
derivatives. Biginelli [4] reported the first synthesis of
dihydropyrimidines by a simple one-pot condensation
reaction of ethyl acetoacetate, benzaldehyde and urea.
Later, different modifications are reported for the
synthesis of array of substituted DHPMs. The use of
different Lewis acid has attempted such as FeCl3, BF3-
ethrate, LaCl3, ZnCl2, ZrCl4, BiCl3 etc [5]. Some metal-
triflates like Yb (OTf)3, Bi(OTf)3, La(OTf)3 are also
reported [6]. We have recently reported sulphamic acid as
a catalyst for preparing DHPMs [7]. However, most of
these methods are associated with expensive and toxic
Oxalic acid is the only possible compound in which two
carboxylic groups are joined directly; and hence supposed
to be one of the strongest organic acid. The use of oxalic
acid as a catalyst was reported for the de-protection of
ketal to give the corresponding aldehydes or ketones [10].
It was also used for isomerization of ꢂ5-cholesten-3-one
to ꢂ4-cholesten-3-one [11] and oxalic acid is also used for
the dealumination of zeolite [12]. To our knowledge,
further use of the strong acidic property of oxalic acid is
not explored. We have used oxalic acid (5 mol%) as a
catalyst for synthesis of array of substituted DHPMs and

1192
J. N. Sangshetti, N. D. Kokare, D. B. Shinde
Vol 45
heterocyclic aldehydes and results are summarized in
Table 2. Better yields were obtained for the synthesis of
all the DHPM derivatives. All synthesized derivatives
their thione analogues in ethanol-water under mild
conditions.
1
were characterized using mass and H NMR. The present
RESULTS AND DISCUSSION
method was found to be effective for both electron-
donating and electron-withdrawing substituted aromatic
aldehydes as well as aliphatic aldehydes. Using similar
reaction conditions, the thione analogues of DHPMs were
also synthesized from thiourea, ꢀ-dicarbonyl compound
and aromatic or aliphatic aldehydes. The easy work-up of
the reaction was also an advantageous aspect of this
method. It includes pouring the reaction mass in ice-water
to precipitate the solid, which could be collected by
filtration to give the corresponding DHPM with better
yield.
Firstly, we studied the catalytic property of oxalic acid
for the synthesis of ethyl-6-methyl-2-oxo-4-phenyl-
1,2,3,4-tetrahydropyridimidine-5-carboxylate (4a) using
benzaldehyde, urea, ethyl acetoacetate substrates in
various solvents like THF, acetonitrile, ethanol, benzene.
Among the results obtained, use of 5 mol% oxalic acid in
ethanol-water gave the better yield (98%) for the
synthesis of 4a (Table 1). The use of environmental
benign solvent such as water has received very much
attention in ‘Green Chemistry’. To study this aspect, the
Table 1
Optimization of reaction conditions and the quantity of oxalic acid for the synthesis of ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-
tetrahydropyridimidine-5 carboxylate (4a).
Solvent
Mol % of oxalic acid
Reaction time (min)
Yield* ( %)
THF
Acetonitrile
Ethanol
THF-water (1:1)
Acetonitrile-water (1:1)
Ethanol-water (1:2)
Ethanol-water (1:2)
Ethanol-water (1:2)
Ethanol-water (1:2)
Ethanol-water (1:2)
20
20
20
20
20
20
15
10
5
60
90
30
70
70
45
45
45
45
80
85
85
90
85
92
98
98
98
98
90
2.5
* Yields refer to isolated pure products.
Although, the detailed mechanism of this reaction is not
clear, probably as proposed for Lewis acid, the reaction
involves the in situ formation of acylimine intermediate
by the reaction of urea or thiourea and aldehyde, which
undergoes the subsequent addition to the ꢀ-carbonyl
compounds followed by cyclization and dehydration to
yield corresponding DHPM [13].
In conclusion, DHPMs and their thione derivatives
were efficiently synthesized with better yields using 5
mol% oxalic acid. For all the presented reactions, the
ethanol-water solvent was used which is relatively
environmentally benign and supporting to Green
Chemistry. The advantages of the reported method are the
use of cheap catalyst, easy work-up, and better yields.
Hence the utility of oxalic acid catalyst for synthesis
DHPMs and their thione derivatives would be precious
addition to available methods.
reaction was carried out for synthesis of 4a using 5 mol%
oxalic acid and corresponding substrates in water. The
reaction was found to be sluggish and it may be due to
lower solubility of substrates. To avoid this problem, the
ethanol-water (1:2; v/v) solvent was used and found to be
effective for synthesis of 4a (98% in 45 min). The
methodology was extended for synthesis of array of
DHPMs using different aliphatic, aromatic and
Scheme 1
X
O
O
R1-CHO
+
R2
H2N
NH2
+
1
2
3a; x = O
3b; x = S
5 mol%, oxalic acid,
ethanol-water
R1
O
EXPERIMENTAL
H
X
R2
N
Typical experimental procedure for the synthesis of Ethyl
6-Methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyridimidine-5-
carboxylate (4a). A mixture of ethyl acetoacetate (1.3 g m, 10
mmol), benzaldehyde (1.1 gm, 10 mmol), urea (0.72 gm, 12
N
H
4a - 4v

Jul-Aug 2008
Oxalic Acid as a versatile catalyst for one pot facile synthesis
1193
of 3,4-dihydropyrimidin-2-(1H)-ones
Table 2
Oxalic Acid-catalyzed synthesis of DHPM and thione derivatives at 70°C.
Entry
R1
R2
X
Time
(min)
45
30
30
40
40
40
45
40
40
45
40
45
30
40
35
45
40
40
45
40
Yield
(%)
98
95
95
95
89
93
90
89
95
90
90
88
88
90
90
95
93
93
95
93
M.P. (°C)
Reported [ref.]
Found
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
CH3O
CH3O
CH3O
CH3O
CH3
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
200-201
204-206
211-213
230
200-202 [14]
205-207 [14]
210-212 [5a]
228 [14]
157-158 [5a]
225-227 [5a]
216-218 [14]
203-205 [5a]
209-216 [14]
235-237 [14]
240-241(d) [14]
226-229 [16]
233-235 [16]
230 [16]
267-269 [5c]
208-210 16]
208-210 [16]
208-210 [16]
208-210 [16]
-
4-NO2C6H4
4-ClC6H4
4-OHC6H4
CH3CH2CH2CH2
3-NO2C6H4
2-ClC6H4
2- furyl
159-161
227-229
218-220
203-205
212-214
238-240
239-240(d)
225-227
232-235
231-233
267-268(d)
210-212
210-212
210-212
210-212
209-211
C6H5
4j
4k
4l
4-NO2C6H4
3-NO2C6H4
2-ClC6H4
4-ClC6H4
4-OHC6H4
3-NO2C6H4
C6H5
3-NO2C6H4
4-OHC6H4
C6H5
4m
4n
4o
4p
4q
4r
4s
4t
CH3
CH3
C2H5O
CH3
CH3
S
S
S
O
C2H5O
C2H5O
Quinoline
3-carbaldehyde
Quinoline
3-carbaldehyde
CH3
4u
4v
C2H5O
C2H5O
S
40
06
89
85
231-233
189-191
-
O
194-195 [5c]
* Yields refer to isolated pure products.
mmol) and oxalic acid (46 mg, 0.5 mmol) in water-ethanol (9
ml, 2:1; v/v) was heated at 70 °C till completion of reaction
[TLC, ethyl acetate - hexane (8:2; v/v)]. Then, the reaction
mixture was poured in ice water and the precipitated solid was
collected by filtration, washed with water and dried. The crude
product was recrystallized from ethanol to give the
corresponding pure product 4a. White solid, mp 200 - 201 °C;
1H NMR (DMSO-d6): ꢀ=9.18(s, 1H), 7.74(s, 1H,), 7.22(m, 5H),
5.14 (d, J = 3.6 Hz, 1H), 3.4(q, J=6.9 Hz, 2H), 2.24(s, 3H), 1.09
(t, J=6.9 Hz, 3H); mass (ES/MS): m/z 260 (M - H).
Ethyl-6-methyl-2-oxo-4-(quinolin-3-yl)-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate(4t). White solid, mp 209 - 211 °C;
1H NMR (DMSO-d6): ꢀ = 8.8(s, 1H), 8.1(d, 1H), 7.8(s, 1H), 7.5-
7.6(m, 2H), 7.42 (t, 1H), 5.8 (bs, 2H), 5.32(s, 1H), 4.1(q, 2H),
1.71(s, 3H), 1.3 (t, 3H); mass (ES/MS): m/z 310(M - H); anal.
Cald for C17H17N3O3: C, 65.58; H, 5.50; N, 13.50. Found: C,
65.61; H, 5.48; N, 13.52.
Ethyl-6-methyl-4-(quinolin-3-yl)-2-thioxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (4u). White solid, mp 231 – 233 °C;
1H NMR (DMSO-d6): ꢀ = 8.8(s, 1H), 8.1(d, 1H), 7.8(s, 1H), 7.5-
7.6(m, 2H), 7.42 (t, 1H), 5.2(bs, 2H), 4.71(s, 1H), 4.1(q, 2H),
1.70(s, 3H), 1.3 (t, 3H); mass (ES/MS): m/z 326(M - H); anal.
Cald for C17H17N3O2S: C, 62.36; H, 5.23; N, 12.83. Found: C,
62.41; H, 5.24; N, 12.81.
Acknowledgements. The authors are thankful to the Head,
Department of Chemical Technology, Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad - 431004 (MS), India for
providing the laboratory facility.
REFERENCES AND NOTES
[1] [a] Atwal, K. S.; Rovnyak, G. C.; Kimball, S. D.; Floyd, D.
M.; Moreland, S.; Swanson, B. N.; Gougoutas, J. Z.; Schwartz, J.;
Smille, K. M.; Mallary, M. F. J. Med. Chem., 1990, 33, 2629; [b]
Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.; Moreland, S.;
Hedberg, A.; O’Reilly, B. C. J. Med. Chem., 1991, 34, 806.
[2] [a] Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.;
Freyer, 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;
[b] Snider, B. B.; Chen, J.;
Patil, A. D.; Freyer, A. J. Tetrahedron Lett., 1996, 37, 6977.
[3] (a) Kappe, C. O. Tetrahedron, 1993, 49, 6937; (b) Kappe,
C. O.; Fabian, W. M. F. Tetrahedron, 1997, 53, 2803; (c) Kappe, C.
O. Eur. J. Med. Chem., 2000, 35, 1043.
[4] Biginelli, P. Gazz. Chim. Ital., 1893, 23, 360.
[5] [a]Ma, Y.; Qian, C.; Wang, L.; Yang, M. J. Org. Chem.,
2000, 65, 3864; [b] Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem.,
2000, 65, 6270; [c] Fu, N. Y.; Yuan, Y. F.; Cao, Z.; Wang, S. W.;
Wang, J. T.; Peppe, C. Tetrahedron, 2002, 58, 4801; [d] Reddy, C. V.;
Mahesh, M.; Raju, P. V. K.; Babu, T. R.; Reddy, V. V. N. Tetrahedron
Lett., 2002, 43, 2657; [e] Ramalinga, K.; Vijayalakshmi, P.; Kamial,T.
N. B. Synlett, 2001, 863; [f] Maiti, G.; Kundu, P.; Guin, C. Tetrahedron
Lett., 2003, 44, 2757; [g] Yadav, J. S.; Reddy, B. V. S.; Srinivas, R.;
Venugopal, C.; Ramalingam, T. Synthesis , 2001, 1341; [h] Yadav, J.
S.; Reddy, B. V. S.; Reddy, K. B.; Raj, K. S.; Prasad, A. R. J. Chem.
Soc., Perkin Trans. 1, 2001,1939; [i] Lu, J.; Bai, Y. Synthesis, 2002,
Using similar procedure other DHPMs and their thione
derivatives were synthesized [Table 2]. All the synthesized
1
compounds were characterized using mass, and H NMR. Also
the melting points of synthesized compounds were compared
with the corresponding reported melting points in literature
[9d,5a,14,15].

1194
J. N. Sangshetti, N. D. Kokare, D. B. Shinde
Vol 45
ed., John Wiley & Sons, 1990; [b] Meyers, A. I. And Flanagan, M. E.
Org. Synthesis, Collect. Vol. 9, pp 258 N. Rabjan, ed., John Wiley &
Sons, 1993; [c] Politzer, I. R. and Meyers, A. I. Org. Synthesis, Collect.
Vol. 6, pp 905 N. Rabjan, ed., John Wiley & Sons, 1988.
[11] Fieser, L. F. Org. Synthesis, Collect. Vol. 4, pp195-201 N.
Rabjan, ed., John Wiley & Sons, 1963.
[12] Apelian, M. R.; Fung, A. S.; Kennedy, G. J. and Degnan, T.
F. J. Phys. Chem., 1996, 100, 16577.
[13] Kappe, C. O. J. Org. Chem. 1997, 62, 7201.
[14] Shaabani, A.; Teimouri, F.; Bazgir, A. Tetrahedron Lett.
2003, 44, 857.
[15] Reddy, K. R.; Reddy, C. V.; Mahesh, M.; Raju, P. V. K.;
Reddy, V. V. N. Tetrahedron Lett., 2003, 44, 8173.
[16] Qi Sun; Yi-qiang Wang, Ze-mei Ge, Tie-mig Cheng, Run-tao
Li, Synthesis, 2004, 7, 1047.
466; [j] Sabhita, G.; Reddy, G. S. K. K.; Reddy, K. B. ; Yadav, J. S.
Tetrahedron Lett., 2003, 44, 6497.
[6] [a] Varala, R.; Alam, M. M.; Adapa, S. R. Synlett, 2003, 67;
[b] Paraskar A. S.; Dewkar, G. K. and Sundalai, A. Tetrohedron
Letters, 2003, 44, 3305.
[7]
S.S. and Shinde D.B.
[8] Kappe, C. O.; Kumar, D. Synthesis, 1999, 1799.
Kotharkar S. A.; Jadhav M. R.; Nagawade, R. R.; Bahekar
Letters in Organic Chemistry, 2005, 2, 398.
[9] [a] Kokare, N. D.; Nagawade, R. R.; Rane V. P. and Shinde D.
B. Synthesis, 2007, 5, 766; [b] Nagawade R. R. ; Khanna V. V.; Bhagwat S.
S.; Shinde D. B. Euro. J. Med. Chem., 2005, 40, 1325; [c] Bahekar, S. S. and
Shinde, D. B. Tetrahedron Lett., 2004, 45, 7999; [d] Bahekar, S. S.; Kotharkar,
S.A. and Shinde, D. B. Mendeleev Commun., 2004, 210.
[10] [a] Smith, A. B.; Branca S. J.; Guaciaro, M. A.; Wovkulich,
P. M. and Korn, A. Org. Synthesis, Collect. Vol. 7, pp 271 N. Rabjan,