New catalysts of Biginelli reaction

Article abstract of DOI:10.1134/S1070428007100181

A synthesis was developed of new imidazole derivatives catalyzing three-component condensation of ethyl acetoacetate, aromatic aldehydes, and urea(or thiourea) by Biginelli reaction.

Full text of DOI:10.1134/S1070428007100181

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 10, pp. 1512−1515. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © F. Makaev, E. Styngach, V. Muntyanu, S. Pogrebnoi, Z. Rybkovskaya, A. Barba, 2007, published in Zhurnal Organicheskoi
Khimii, 2007, Vol. 43, No. 10, pp. 1518−1520.
New Catalysts of Biginelli Reaction
F. Makaev, E. Styngach, V. Muntyanu, S. Pogrebnoi, Z. Rybkovskaya, and A. Barba
Institute of Chemistry, Academy of Sciences of Moldova, Kishenev, MD-2028, Moldova
e-mail: flmacaev@cc.acad.md
Received November15, 2006
Abstract—A synthesis was developed of new imidazole derivatives catalyzing three-component condensation of
ethyl acetoacetate, aromatic aldehydes, and urea(or thiourea) by Biginelli reaction.
DOI: 10.1134/S1070428007100181
and one-proton singlet belonging to H3 of imidazole at
9.06, 9.26 ppm.
3,4-Dihydropyrimidin-2(1H)-ones(thiones), among
them also those with biological action [1] are convenient-
ly prepared by a one-pot synthesis catalyzed with mineral,
organic, or Lewis acids involving ureas (thioureas),
aldehydes, and β-dicarbonyl compounds under standard
conditions or under microwave irradiation [2, 3]. Two
examples of synthesis of the said compounds were
described performed by Biginelli reaction involving ionic
fluids [4, 5]. No published data exist on application of
monochloroacetic acid and N-substituted imidazoles to
the synthesis of imidazolium salts, catalysts for organic
reactions [6–8].
Analogously an oily mixture of compounds IIIb and
IVb was synthesized using acid II and nitrile Ib.
In the IR spectrum of the mixture of compounds IIIb
and IVb appear bands characteristic of carboxylates
(1610–1550 and 1400 cm–1), ammonium (2700–2250
cm–1), cyano (2245 cm–1), and chloromethyl (775 cm–1),
groups. In the 1H NMR spectrum a multiplet set of signals
from three methylene groups is observed in the region
3.13–4.71 ppm, and the signals from imidazole structural
fragment are present in the region 7.44–9.42 ppm.
The synthesis of new imidazole derivatives involved
mixing in MeCN solution equimolar quantities of
N-methylimidazole (Ia) and monochloroacetic acid (II)
(Scheme 1). The reaction product obtained at room
temperature is an oily fluid whose composition and
structure are confirmed by elemental analysis, IR and
It was established that 0.6 mol% of the mixture of
compounds IIIb and IIIb catalyzed the condensation of
ethyl acetoacetate, aromatic aldehydes, and urea (or
thiourea) (Scheme 2).
Syntheses of target products Va, Vb–IXa, IXb was
performed at elevated temperature without solvent like
described in [4, 5]. The replacement of catalyst IIIa, IIIb
by IVa, IVb increased the yield of reaction products by
10%, in particular, compared to method [5]. It should be
noted that in most cases the yield of 3,4-dihydro-
pyrimidine-2(1H)-thiones is higher than that of their
1
1H NMR spectra. The specific feature of the H NMR
spectrum of the product is a double set of signals (1:1)
due to the presence of salts IIIa and IVa mixture. For
instance. in the downfield region appear three-proton
singlets of the methyl groups (3.84, 3.88 ppm), singlet
of the methylene group (5.07 ppm), two-proton
multiplet of protons H4, H5 of imidazole (7.50–7.80 ppm),
oxygen-containing analogs.
.
Scheme 1.
_
R
R
R
Cl
N
OH
N
N
+
N
N
Cl
Cl
+
+
+
+
NH
O
_
O
OH
O
O
Ia, Ib
II
IIIa, IIIb
IVa, IVb
1512

NEW CATALYSTS OF BIGINELLI REACTION
1513
Scheme 2.
Ar
X
IIIa, IIIb or IVa, IVb
O
CO2Et
_
(0.6 mol%), 100 125oC
HN
CO2Et
H2N
NH2
+
ArCHO +
X
N
H
_
Va, Vb Xa, Xb
1075, 980, 825, 750, 700, 630. 1H NMR spectrum, δ,
ppm: 3.21 t (2H, CH2CN, J 6.4 Hz), 3.28 t (2H, CH2CN,
J 5.98 Hz), 4.24-4.71 m (4H, N–CH2CH2), 5.14 s (4H,
2CH2CO2), 7.44–8.01 m (4H, 2H4, 2H5), 8.82 s, 9.43 s
(2H, 2H3).
The catalytic action of the melts of the synthesized
imidazole salts is apparently due to the activity of the
free carboxy group of acetic acid [9] together with
probable generation of trace amounts of HCl that also
initiate the reaction [4].
3,4-Dihydropyrimidin-2(1H)-ones(thiones).
General procedure. To a mixture of 1.3 g (0.01 mol) of
ethyl acetoacetate, 0.76 g (0.01 mol) of thiourea and
(0.01 mol) of an appropriate aldehyde was added
0.6 mol% of a mixture of compounds IIIa and IIIb
(method a) or IVa and IVb (method b). The reaction
mixture was heated for 2–5 h at 100–125°C. On
completion of the reaction (TLC monitoring) the mixture
was dispersed in ethanol, the residue was filtered off and
washed with H2O. A sample was recrystallized for
analysis from EtOH.
Thus we demonstrated that the melts of the N-sub-
stituted imidazoles monochloroacetates catalyzed the
Biginelly reaction.
EXPERIMENTAL
IR spectra were recorded on a spectrophotometer
Specord 75IR from mulls in mineral oil. Melting points
..
were measured on a Boetius heating block and were not
1
corrected. H NMR spectra were registered from solu-
tions in DMSO-d6 on spectrometers Bruker AC-E 200
and Bruker AC-80, chemical shifts are reported with
respect to TMS (internal reference). TLC was carried
out on Silufol plates (Czechia), spots were visualized by
5% solution of phosphomolybdic acid in EtOH followed
by heating, or with acidified 2% water solution of
KMnO4.
Ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (Va). Yield 56 (a),
61% (b), mp 213–214°C. IR spectrum, ν, cm–1: 3250,
1
2940, 2900, 1720, 1690, 1630, 1210, 750. H NMR
spectrum, δ, ppm: 1.14 t (3H, MeCH2, J 7.0 Hz), 2.26 s
(3H, Me), 3.91 q (2H, MeCH2, J 7.0 Hz), 5.12 d (1H,
H4, J 4.5 Hz), 7.30 s (5H, Ph), 7.67 d (1H, NH, J 4.5 Hz),
9.09 s (1H, NH). Found, %: C 64.60; H 6.20; N 10.76.
C14H16N2O3. Calculated, %: C 64.55; H 6.10; N 10.52.
Synthesis of IIIa and IIIb mixture. To a vigorously
stirred solution of 4.53 g (0.048 mol) of monochloro-
acetic acid in 2 ml of anhydrous MeCN at 20°C was
added dropwise a solution of 4 g (0.048 mol) of N-methyl-
imidazole in 2 ml of anhydrous MeCN. The reaction
mixture was stirred for 6 h at 20°C, left overnight. After
distilling off the solvent we obtained 8.4 g (99%) of oily
mixture. IR spectrum, ν, cm–1: 3390, 3150, 1730, 1630,
1575, 1550, 1400, 1275, 1165, 1080, 825, 775, 700, 625.
1H NMR spectrum, δ, ppm: 3.84 s, 3.88 s (6H, 2CH3),
5.07 s (4H, 2CH2), 7.50–7.80 m (4H, 2H4, 2H5), 9.06 s,
9.26 s (2H, 2H3).
Ethyl 6-methyl-2-thioxo-4-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (Vb). Yield 55
(a), 67% (b), mp 212–213°C. IR spectrum, ν, cm–1: 2940,
1
1980, 1940, 1810, 1650, 1240, 1050, 790. H NMR
spectrum, δ, ppm: 1.18 t (3H, MeCH2, J 7.0 Hz), 2.30 s
(3H, Me), 4.00 q (2H, MeCH2, J 7.0 Hz), 5.19 d (1H,
H4, J 3.6 Hz), 7.25–7.56 m (5H, Ph), 7.67 d (1H, NH,
J 3.6 Hz), 10.15 C (1H, NH). Found, %: C 60.88;
H 5.78; N 10.35. C14H16N2O2S. Calculated, %: C 60.85;
H 5.84; N 10.40.
Mixture IVa and IVb was similarly obtained from
3.12 g (0.033 mol) of monochloroacetic acid and 4 g
(0.033 mol) of cyanide Ib. Yield 7 g (99%). Oily light-
yellow substance. IR spectrum, ν, cm–1: 3400, 3150,
2700–2250, 2245, 1730, 1630, 1560, 1400, 1275, 1165,
Ethyl 4-(3,4-dimethoxyphenyl)-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (VIa).
Yield 41 (a), 50% (b), mp 195–198°C. IR spectrum, ν,
cm–1: 3260, 2960, 2920, 1710–1550, 1550, 780. 1H NMR
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007

MAKAEV et al.
1514
spectrum, δ, ppm: 1.11 t (3H, MeCH2, J 7.2 Hz), 2.24 s
(3H, Me), 3.36 s, 3.71 s (6H, 2 MeO), 3.99 q (2H, MeCH2,
J 7.1 Hz), 5.10 d (1H, H4, CH, J 3.7 Hz), 6.64–6.95 m
(3Harom), 7.66 d (1H, NH, J 3.6 Hz), 9.14 c (1H, NH).
Found, %: C 60.06; H 6.22; N 8.59. C16H20N2O5.
Calculated, %: C 59.99; H 6.29; N 8.74.
Yield 68 (a), 82% (b), mp 92–93°C. IR spectrum, ν, cm–1:
1
3200, 1710, 1575, 1090, 1030, 740, 620. H NMR
spectrum, δ, ppm: 1.02 t (3H, MeCH2, J 7.02 Hz), 2.32 s
(3H, Me), 3.93 q (2H, MeCH2), J 6.99 Hz), 5.62 d (1H,
H4, CH, J 2.9 Hz), 7.24–7.59 m (3Harom), 9.62 d (1H,
NH, J 3.1 Hz), 10.40 s (1H, NH). Found, %: C 48.52;
H 4.07; N 8.22. C14H14Cl2N2O2S. Calculated, %: C 48.70;
H 4.09; N 8.11.
Ethyl 4-(3,4-dimethoxyphenyl)-6-methyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (VIb).
Yield 63 (a), 69% (b), mp 177–178°C. IR spectrum, ν,
Ethyl 6-methyl-4-(4-methoxyphenyl)-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (IXa).
Yield 72 (a), 69% (b), mp 209–211°C. IR spectrum, ν,
cm-1: 3250, 2900, 1690, 1640, 1605, 1500, 1270, 1160,
1070, 775. 1H NMR spectrum, δ, ppm: 1.09 t (3H,
MeCH2, J 7.04 Hz), 2.23 s (3H, Me), 3.71 s (3H, MeO),
4.00 q (2H, MeCH2, J 6.54 Hz), 5.09 d (1H, H4, CH,
J 3.39 Hz), 6.85 d, 6.94 d (4Harom, J 6.45, J 19.74 Hz),
7.65 d (1H, NH, J 3.7 Hz), 9.13 s (1H, NH). Found, %:
C 62.22; H 6.22; N 9.56. C15H18N2O4. Calculated, %:
C 62.06; H 6.25; N 9.65.
1
cm–1: 3320, 2960–2900, 1680, 1580, 1190, 750. H NMR
spectrum, δ, ppm: 1.12 t (3H, MeCH2, J 7.1 Hz), 2.28 s
(3H, Me), 3.36 s, 3.71 s (6H, 2MeO), 4.02 q (2H, MeCH2,
J 7.03 Hz), 5.12 d (1H, H4, CH, J 3.67 Hz), 6.72–6.97 m
(3Harom), 9.58 d (1H, NH, J 3.5 Hz), 10.29 s (1H, NH).
Found, %: C 57.22; H 5.78; N 8.39. C16H20N2O4S.
Calculated, %: C 57.12; H 5.99; N 8.33.
Ethyl 4-(2,4-dimethoxyphenyl)-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (VIIa).
Yield 80 (a), 77% (b), mp 221–222°C. IR spectrum, ν,
cm–1: 3240, 2920, 1710, 1680, 1500, 1210, 1090, 740.
1H NMR spectrum, δ, ppm: 1.04 t (3H, MeCH2, J 7.1 Hz),
2.27 s (3H, Me), 3.72 s, 3.77 s (6H, 2 MeO), 3.91 q (2H,
MeCH2, J 7.1 Hz), 5.4 d (1H, H4, CH, J 2.98 Hz), 6.36–
6.99 m (3Harom), 7.20 d (1H, NH, J 3.3 Hz), 9.07 s (1H,
NH). Found, %: C 59.77; H 6.12; N 8.71. C16H20N2O5.
Calculated, %: C 59.99; H 6.29; N 8.74.
Ethyl 6-methyl-4-(4-methoxyphenyl)-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (IXb).
Yield 69 (a), 68% (b), mp 156–157°C. IR spectrum, ν,
cm–1: 3310, 2900, 1660, 1615, 1500, 1165, 760. 1H NMR
spectrum, δ, ppm: 1.1 t (3H, MeCH2, J 6.96 Hz), 2.28 s
(3H, Me), 3.72 s (3H, MeO), 4.00 q (2H, MeCH2,
J 7.12 Hz), 5.10 d (1H, H4, CH, J 3.4 Hz), 7.30–6.80 d,
6.97 d (4Harom, J 6.3, J 12.4 Hz), 9.59 d (1H, NH,
J 3.81 Hz), 10.28 s (1H, NH). Found, %: C 58.67; H 5.85;
N 9.10. C15H18N2O3S. Calculated, %: C 58.80; H 5.92;
N 9.14.
Ethyl 4-(2,4-dimethoxyphenyl)-6-methyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (VIIb).
Yield 67 (a), 68% (b), mp 155–157°C. IR spectrum, ν,
cm–1: 3320, 2980, 1700, 1560, 1180, 1125, 750. 1H NMR
spectrum, δ, ppm: 1.05 t (3H, MeCH2, J 7.08 Hz), 2.27 s
(3H, Me), 3.73 s, 3.77 s (6H, 2OMe), 3.94 q (2H, MeCH2,
J 7.01 Hz), 5.39 d (1H, H4, CH, J 3.5 Hz), 6.38–6.98 m
(3Harom), 9.16 d (1H, NH, J 3.4 Hz), 10.54 s (1H, NH).
Found, %: C 57.31; H 5.82; N 8.24. C16H20N2O4S.
Calculated, %: C 57.12; H 5.99; N 8.33.
Ethyl 4-(4-dimethylaminophenyl)-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (Xa).
Yield 68 (a), 63% (b), mp 257–258°C. IR spectrum, ν,
cm–1: 3250, 1725, 1700, 1360, 1220, 1160, 1085, 780.
1H NMR spectrum, δ, ppm: 1.11 t (3H, MeCH2,
J 7.02 Hz), 2.23 s (3H, Me), 2.84 c (6H, NMe2), 3.97 q
(2H, MeCH2, J 7.05 Hz), 5.03 d (1H, H4, CH, J 3.26 Hz),
6.63 d, 6.78 d (4Harom, J 8.76, J 32 Hz), 7.58 d (1H, NH,
J 3.66 Hz), 9.08 s (1H, NH). Found, %: C 63.04; H 7.03;
N 13.81. C16H21N3O3. Calculated, %: C 63.35; H 6.98;
N 13.85.
Ethyl 4-(2,4-dichlorophenyl)-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (VIIIa).
Yield 50 (a), 44% (b), mp 247–249°C. IR spectrum, ν,
cm–1: 3350, 1690, 1160, 1090, 645. 1H NMR spectrum,
δ, ppm: 1.00 t (3H, MeCH2, J 7.14 Hz), 2.30 s (3H, Me),
3.90 q (2H, MeCH2, J 7.04 Hz), 5.60 d (1H, H4, CH,
J 2.15 Hz), 7.25–7.75 m (3Harom), 7.75 d (1H, NH,
J 2.8 Hz), 9.31 s (1H, NH). Found, %: C 51.32; H 4.11;
N 8.64. C14H14Cl2N2O3. Calculated, %: C 51.08; H 4.29;
N 8.51.
Ethyl 4-(4-dimethylaminophenyl)-6-methyl-2-
thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(Xb). Yield 53 (a), 64% (b), mp 211–213°C. IR spectrum,
1
ν, cm–1: 3300, 1370, 1170, 1660, 1100, 750. H NMR
spectrum, δ, ppm: 1.12 t (3H, MeCH2, J 6.94 Hz), 2.27 s
(3H, Me), 2.86 s (6H, NMe2), 3.97 q (2H, MeCH2,
J 7.24 Hz), 5.03 d (1H, H4, CH, J 3.65 Hz), 6.65 d,
Ethyl 4-(2,4-dichlorophenyl)-6-methyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (VIIIb).
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NEW CATALYSTS OF BIGINELLI REACTION
1515
4. Putilova, E.S., Kryshtal’, G.V., Zhdankina, G.M., Troits-
kii, N.A., and Zlotin, S.G., Zh. Org. Khim., 2005, vol. 41,
p. 524.
5. Peng, J. and Deng, Y., Tetrahedron Lett., 2001, vol. 42,
p. 5917.
6.78 d (4Harom, J 8.08, J 29.3 Hz), 9.53 d (1H, NH,
J 3.89 Hz), 10.51 s (1H, NH). Found, %: C 60.44; H 6.57;
N 13.11. C16H21N3O2S. Calculated, %: C 60.16; H 6.63;
N 13.16.
6. Jain, N., Kumar, A., Chauhan, S., and Chauhan, S.M.S.,
Tetrahedron, 2005, vol. 61, p. 1015.
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