α-chlorobenzyl isocyanates in a new synthesis of 3,4- dihydropyrimidin-2(1H)-ones

Full text of DOI:10.1007/s11178-005-0328-2

Russian Journal of Organic Chemistry, Vol. 41, No. 8, 2005, pp. 1240−1241. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 8, 2005,
pp. 1261−1262.
Original Russian Text Copyright © 2005 by Vovk, Sukach.
SHORT
COMMUNICATIONS
α-Chlorobenzyl Isocyanates in a New Synthesis
of 3,4-Dihydropyrimidin-2(1H)-ones
M.V. Vovk and V.A. Sukach
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev, 02094 Ukraine
e-mail: mvovk@i.com.ua
Received March 17, 2005
5
-Functionally substituted 3,4-dihydropyrimidin-2(1H)-
α-Chlorobenzyl isocyanates Ia–If were prepared by
ones constitute a unique heterocyclic system possessing
versatile pharmacological properties [1–3]. The three-
component cyclocondensation of 1,3-dicarbonyl com-
pounds with aldehydes and urea discovered by Biginelli
procedure [8].
(
2-Fluorophenyl)chloromethyl isocyanate (Ib).
Yield 59%, bp 120–124°C (12 mm Hg). IR spectrum
–1
1
(
(
CH Cl ), cm : 2265 (N=C=O). H NMR spectrum
2 2
[
4] in 1893 is a traditional procedure for preparation of
CDCl ), δ, ppm: 6.70 s (1H, CH), 7.10–7.65 m (4Harom).
3
these compounds that is successfully used up till now.
The other synthetic methods described [5–7] as a rule
are modifications of this reaction.
Found, %: C 51.60; H 2.79; N 7.64. C H ClFN.
8
5
Calculated, %: C 51.78; H 2.72; N 7.55.
3-Bromophenyl))chloromethyl isocyanate (Ic).
Yield 81%, bp 141–146°C (0.2 mm Hg). IR spectrum
(
We developed a new synthetic approach to compounds
of the 3,4-dihydropyrimidine series based on the con-
densation of sufficiently accessible reagents: α-chloro-
benzyl isocyanates Ia–If [8] and enamines IIa–IIc. We
demonstrated that isocyanates Ia–If reacted with
enamines IIa–IIc in toluene at room temperature
affording in good yields 3,4-dihydropyrimidin-2(1H)-ones
IIIa–IIIf. The discovered reaction is a new [C=N−C] +
–
1
1
(
(
CH Cl ), cm : 2270 (N=C=O). H NMR spectrum
2 2
CDCl ), δ, ppm: 6.61 s (1H, CH), 7.12–7.68 m (4Harom).
3
Found, %: C 38.75; H 1.99; N 5.60. C H BrClN.
8
5
Calculated, %: C 38.98; H 2.04; N 5.68.
4-Chlorophenyl)chloromethyl isocyanate (Id).
Yield 72%, bp 126–130°C (0.3 mm Hg). IR spectrum
(
–
1
1
(
(
CH Cl ), cm : 2265 (N=C=O). H NMR spectrum
2 2
[
C=C−N] method [9, 10] of building up the pyrimidine
CDCl ), δ, ppm: 6.45 s (1H, CH), 7.36–7.50 m (4Harom).
3
ring. Compounds III might form via two alternative path-
ways; however taking into account previous results on
reaction of 1-aryl-1-chloro-2,2,2-trifluoroethyl isocyanates
with ethyl β-N-methylaminocrotonate [11] it is presum-
able that the reaction occurs through an intermediate
formation of isocyanatealkylated products A.
Found, %: C 47.73; H 2.55; N 6.87. C H Cl N.
8
5
2
Calculated, %: C 47.56; H 2.49; N 6.93.
3,4-Dihydropyrimidin-2(1H)-ones IIIa–IIIf. To
a solution of 5 mmol of α-chlorobenzylisocyanate Ia–If
in 20 ml of anhydrous toluene was added 5 mmol of
Ar
O
O
Ar
O
Ar
Cl
NCO
R
R
NCO
NH2
R
NH
+
Toluene,
HCl
Me
NH2
Me
Me
N
H
_
O
_
_
_
Iа If
IIа IIc
A
IIIа IIIf
I,Ar = C H (a), 2-F-C H (b), 3-Br-C H (c), 4-Cl-C H (d), 4-Br-C H (e), 4-NO -C H (f); II, R = Me (a), MeO (b), EtO (c); III,
6
5
6
4
6
4
6
4
6
4
2
6 4
R = Me,Ar = 2-F-C H (a), 3-Br-C H (b); R = MeO,Ar = 4-Cl-C H (c), 4-NO -C H (d); R = EtO,Ar = C H (e), 4-Br-C H (f).
6
4
6
4
6
4
2
6
4
6
5
6 4
1070-4280/05/4108-1240©2005 Pleiades Publishing, Inc.

α-CHLOROBENZYL ISOCYANATES IN ANEWSYNTHESIS
1241
enamine IIa–IIc, and the mixture was stirred for 1 h at
room temperature. Then the precipitate was filtered off
and recrystallized from ethanol.
4-(4-Bromophenyl)-6-methyl-5-ethoxycarbonyl-
3,4-dihydropyrimidin-2(1H)-one (IIIf). Yield 73%,
mp 195–197°C [13].
1
5
-Acetyl-6-methyl-4-(2-fluorophenyl)-3,4-di-
IR spectra were recorded on UR-20 instrument. H
NMR spectra were registered on spectrometer Varian-
Gemini (300 MHz), internal reference TMS.
hydropyrimidin-2(1H)-one (IIIa). Yield 68%, mp 235–
–1
2
37°C. IR spectrum (KBr), cm : 3200 (NH), 1690, 1650
1
(
C=O). H NMR spectrum (DMSO-d ), δ, ppm: 2.12 s
6
REFERENCES
(3H, CH ), 2.29 s (3H, CH ), 5.23 d (1H, CH, J 2.1 Hz),
3
3
7
9
.22–7.40 m (4Harom), 7.81 d (1H, NH, J 2.1 Hz),
.21 s (1H, NH). Found, %: C 50.39; H 4.17; N 9.01.
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2. Kappe, C.O., Tetrahedron, 1993, vol. 49, p. 6937.
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p. 1185.
C H BrN O . Calculated, %: C 50.51; H 4.24; N 9.06.
13
13
2
2
5
-Acetyl-4-(3-bromophenyl)-6-methyl-3,4-di-
hydropyrimidin-2(1H)-one (IIIb).Yield 65%, mp 248–
–1
250°C. IR spectrum (KBr), cm : 3190 (NH), 1690, 1660
1
(
(
C=O). H NMR spectrum (DMSO-d ), δ, ppm: 2.06 s
3H, CH ), 2.29 s (3H, CH ), 5.51 d (1H, CH, J 2.0 Hz),
6
6. Atwal, K.S., O’Reilly, B. C., Gougoutas, J.Z., and
Malley, M.F., Heterocycles, 1987, vol. 26, p. 1189.
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tsov,A.Yu., Molecules, 1998, vol. 3, p. 100.
3
3
7
9
.12–7.48 m (4Harom), 7.68 d (1H, NH, J 2.0 Hz),
.20 s (1H, NH). Found, %: C 62.95; H 5.33; N 11.34.
8. Sinitsa,A.D., Bonadyk, S.V., and Markovskii, L.N. , Zh. Org.
Khim., 1978, vol. 14, p. 1107.
C H FN O . Calculated, %: C 62.90; H 5.28; N 11.28.
13
13
2
2
6
-Methyl-5-methoxycarbonyl-4-(4-chloro-
9. Vovk, M.V., Lebed’, P.S., Sukach, V.A., and Kornilov, M.Yu.,
Zh. Org. Khim., 2003, vol. 39, p. 1852.
phenyl)-3,4-dihydropyrimidin-2(1H)-one (IIIc).
Yield 66%, mp 178–180°C [12].
10. Vovk, M.V., Lebed’, P.S., Pirozhenko, V.V., andTsymbal, I.F.,
Zh. Org. Khim., 2004, vol. 40, p. 1715.
6
-Methyl-5-methoxycarbonyl-4-(4-nitrophenyl)-
,4-dihydropyrimidin-2(1H)-one (IIId). Yield 69%,
mp 213–215°C [12].
-Methyl-4-phenyl-5-ethoxycarbonyl-3,4-di-
hydropyrimidin-2(1H)-one (IIIe). Yield 71%, mp 202–
04°C [12].
1
1. Vovk, M.V. and Pirozhenko, V.V., Khim. Geterotsikl. Soed.,
994, p. 96.
3
1
1
2. Fu, N.-Y., Yuan, Y.-F, Cao, Z., Wang, S.-W., Wang, J.-T., and
Peppe, C., Tetrahedron, 2002, vol. 58, p. 4801.
13. Reddy, K.R., Reddy, C.V., Manesh, M., Raju, P.V.K., and
6
2
Reddy, V.V.N., Tetrahedron Lett., 2003, vol. 44, p. 8173.
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 8 2005