Sonochemical synthesis of Biginelli compounds

Article abstract of DOI:10.1023/B:RUCB.0000012380.78140.26

The ultrasound effect accelerates the Biginelli reaction 40 and more times. A sonochemical method for the synthesis of ethyl 4-R-6-methyl-2-oxo- and 4-R-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates was developed. The target products were

Full text of DOI:10.1023/B:RUCB.0000012380.78140.26

Russian Chemical Bulletin, International Edition, Vol. 52, No. 11, pp. 2527—2528, November, 2003
2527
Sonochemical synthesis of Biginelli compounds
M. S. Zhidovinova,ꢀ O. V. Fedorova, G. L. Rusinov, and I. G. Ovchinnikova
Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
2
0 ul. S. Kovalevskoi, 620219 Ekaterinburg, Russian Federation.
Fax: +7 (343 2) 74 1189. Eꢀmail: rusinov@ios.uran.ru
The ultrasound effect accelerates the Biginelli reaction 40 and more times. A sonochemical
method for the synthesis of ethyl 4ꢀRꢀ6ꢀmethylꢀ2ꢀoxoꢀ and 4ꢀRꢀ6ꢀmethylꢀ2ꢀthioxoꢀ1,2,3,4ꢀ
tetrahydropyrimidineꢀ5ꢀcarboxylates was developed. The target products were obtained within
2
to 5 min in 90—95% yields.
Key words: Biginelli reactions, ethyl 4ꢀRꢀ6ꢀmethylꢀ2ꢀoxoꢀ and 4ꢀRꢀ6ꢀmethylꢀ2ꢀthioxoꢀ
1
,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀcarboxylates, ultrasound effect.
Multicomponent reactions leading to a variety of moꢀ
lecular structures are of special interest for combinatorial
chemistry. For instance, the Biginelli reaction (condenꢀ
sation between aldehyde 1, ethyl acetoacetate (2), and
urea or thiourea (3)) affords a broad range of substituted
reaction time from 8—12 to 3—7 h, with ammonium
cerium nitrate as a neutral catalyst.
7
We discovered that the classical Biginelli reaction
(ethanol, HCl as a catalyst) is accelerated by ultrasound
40 and more times. After the reaction mixture was exꢀ
posed to ultrasound for 2 to 5 min and the solvent was
removed, the target compounds 4—8 were obtained in
90—95% yields, irrespective of the aldehyde nature. In
most cases, no additional purification (recrystallization)
is needed because of high selectivity of the reaction which
reduces the quantity of byꢀproducts (Scheme 1).
2
ꢀoxoꢀ and 2ꢀthioxoꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀ
carboxylates 4—8, which are known as calcium channel
blockers of the nifedipine type.1 Biginelli compounds are
conventionally synthesized either by prolonged (2—3 days)
,2
3
stirring of the reactants in EtOH in the presence of HCl
4
or by refluxing them for 3—4 h. Microwave radiation
with an active carrier reduces the Biginelli reaction time
5
to several minutes; however, the target products are more
Experimental
difficult to isolate and, moreover, urea has been reported6
to decompose by microwave rays.
The ultrasound effect on the Biginelli reaction has
been described in only one paper and found to reduce the
Melting points were determined on a combined Boetius miꢀ
croscope stage and are given uncorrected. H NMR spectra
were recorded on a Bruker DRXꢀ400 instrument in CDCl or
1
3
DMSOꢀd with Me Si as the internal standard. Elemental analyꢀ
6
4
Scheme 1
sis was carried out on a Carlo Erba 1108 instrument; TLC
was performed on Silufol UVꢀ254 plates (ethanol—chloroform,
1
: 9). The domestic UZDNꢀA ultrasound disperser was used
(
20 kHz, 80 W).
Synthesis of compounds 4—8 (general procedure). The emitꢀ
ter of the ultrasound disperser was immersed in a suspension of
ethyl acetoacetate 2 (10 mmol), urea (thiourea) 3 (10 mmol),
and a corresponding aldehyde 1 (10 mmol) in 20 mL of EtOH
acidified with conc. HCl (1—2 drops). The emitter was on until
the reaction was completed (2—5 min). The solvent was reꢀ
moved, and the residue was washed with water or acetonitrile.
While isolating compound 5, the solvent was removed, and the
residue was triturated with water, filtered off, and recrystallized
from dioxane.
Ethyl 6ꢀmethylꢀ2ꢀoxoꢀ4ꢀphenylꢀ1,2,3,4ꢀtetrahydropyrimꢀ
idineꢀ5ꢀcarboxylate (4). Yield 95%, m.p. 202—204 °C (cf. Ref. 8:
R
Ph
Me
X
O
S
O
S
R
X
R
Me
CH=CH—Ph
2ꢀthienyl
2
02—204 °C). Found (%): C, 64.80; H, 6.15; N, 10.79.
1a
1b
1c
1d
3a
3b
4
—
—
Ph
Ph
6
7
8
O
O
O
C H N O . Calculated (%): C, 64.60; H, 6.20; N, 10.76.
14 16
2
3
1
CH=CH—Ph
2ꢀthienyl
H NMR (DMSOꢀd ), δ: 1.14 (t, 3 H, MeCH J = 7.0 Hz);
6 2,
5
2.26 (s, 3 H, Me); 3.91 (q, 2 H, MeCH , J = 7.0 Hz); 5.12 (d,
2
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2389—2390, November, 2003.
066ꢀ5285/03/5211ꢀ2527 $25.00 © 2003 Plenum Publishing Corporation
1

2528
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003
Zhidovinova et al.
1
1
H, C(4)H, J = 4.5 Hz); 7.30 (s, 5 H, Ph); 7.67 (d, 1 H, NH,
H NMR (DMSOꢀd ), δ: 1.21 (t, 3 H, MeCH , J = 7.2 Hz);
6
2
J = 4.5 Hz); 9.09 (br.s, 1 H, NH).
2.22 (s, 3 H, Me); 4.04 (q, 2 H, MeCH , J = 7.2 Hz); 5.40 (d,
2
Ethyl 6ꢀmethylꢀ4ꢀphenylꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydropyrimꢀ
idineꢀ5ꢀcarboxylate (5). Yield 90%, m.p. 203—205 °C (cf. Ref. 5:
1 H, C(4)H, J = 3.6 Hz); 7.17 (m, 3 H, thiophene); 7.76 (d, 1 H,
NH, J = 3.6 Hz); 9.18 (s, 1 H, NH).
2
05—206 °C). Found (%): C, 60.76; H, 5.86; N, 9.93.
C H N O S. Calculated (%): C, 60.85; H, 5.84; N, 10.14.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 02ꢀ03ꢀ
32332ꢀa) and the State Program for Supporting Leading
Scientific Schools of the Russian Federation (Grant
14
16
2
2
1
H NMR (DMSOꢀd ), δ: 1.18 (t, 3 H, MeCH , J = 4.0 Hz);
6
2
2
.30 (s, 3 H, Me); 4.00 (m, 2 H, MeCH ); 5.18 (d, 1 H, C(4)H,
2
J = 3.6 Hz); 7.25 (m, 5 H, Ph); 9.50 (d, 1 H, NH, J = 3.6 Hz);
1
0.15 (s, 1 H, NH).
Ethyl 4,6ꢀdimethylꢀ2ꢀoxoꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀ
1
766.2003.3).
carboxylate (6). Yield 91.5%, m.p. 181—182 °C (cf. Refs. 8, 9:
81—184 °C). Found (%): C, 54.33; H, 7.73; N, 14.59.
References
1. C. O. Kappe, Eur. J. Med. Chem., 2000, 35, 1043.
1
C H N O . Calculated (%): C, 54.54; H, 7.12; N, 14.14.
9
14
2
3
1
H NMR (CDCl ), δ: 1.26 (d, 3 H, MeCH, J = 10.2 Hz); 1.28
3
2
3
4
5
. C. O. Kappe, Molecules, 1998, 3, 1.
(
t, 3 H, MeCH , J = 6.2 Hz); 2.29 (s, 3 H, Me); 4.02 (m, 2 H,
2
. C. O. Kappe, J. Org. Chem., 1997, 62, 7201.
. C. O. Kappe, Heterocycles, 1997, 45, 1976.
. C. O. Kappe, D. Kumar, and R. S. Varma, Synthesis,
MeCH ); 4.07 (m, 1 H, C(4)H); 5.59 (br.s, 1 H, NH); 7.89
2
(
s, 1 H, NH).
Ethyl 6ꢀmethylꢀ2ꢀoxoꢀ4ꢀstyrylꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ
1
999, 1799.
. A. Stadler and O. C. Kappe, J. Chem. Soc., Perkin Trans. 2,
000, 1363.
5
2
ꢀcarboxylate (7). Yield 94.5%, m.p. 238—240 °C (cf. Ref. 7:
41—243 °C). Found (%): C, 67.14; H, 6.48; N, 9.47.
6
2
C
16H18N O . Calculated (%): C, 67.13; H, 6.34; N, 9.78.
2 3
1
7. J. S. Yadav, B. V. S. Reddy, K. B. Reddy, K. S. Raj, and A. R.
Prasad, J. Chem. Soc., Perkin Trans. 1, 2001, 1939.
H NMR (CDCl ), δ: 1.30 (t, 3 H, MeCH , J = 7.2 Hz); 2.48 (s,
3
2
3
1
6
8
H, Me); 4.20 (m, 2 H, MeCH ); 6.40 (d, 1 H, C(4)H, J =
2
8
9
. K. Folkers, H. J. Harwood, and T. B. Jonson, J. Am. Chem.
Soc., 1932, 54, 3751.
. K. Singh, J. Singh, P. K. Deb, and H. Singh, Tetrahedron,
5.0 Hz); 6.01 (dd, 1 H, CH=CHPh, J = 7.0 Hz, J = 15.0 Hz);
.47 (d, 1 H, CH=CHPh, J = 7.0 Hz); 7.25 (m, 5 H, Ph); 7.36,
.91 (both s, 1 H each, NH).
1
999, 55, 12873.
Ethyl 6ꢀmethylꢀ2ꢀoxoꢀ4ꢀ(2ꢀthienyl)ꢀ1,2,3,4ꢀtetrahydroꢀ
pyrimidineꢀ5ꢀcarboxylate (8). Yield 92.5%, m.p. 205—207 °C
cf. Ref. 7: 206—208 °C). Found (%): C, 54.25; H, 5.94; N, 10.70.
C H N O S. Calculated (%): C, 54.13; H, 5.30; N, 10.52.
(
Received April 11, 2003;
in revised form July 1, 2003
12
14
2
3