Biginelli condensations of fluorinated 3-oxo esters and 1,3-diketones

Article abstract of DOI:10.1016/S0022-1139(99)00216-X

Condensation of fluorinated 3-oxo esters or 1,3-diketones with benzaldehyde and (thio)urea results in the diastereoselective formation of 4-fluoroalkyl-4-hydroxy-2-oxo(thioxo)-6-phenyl-hexahydropyrimidine-5- carboxylates from which by dehydration under acidic conditions the corresponding 6-fluoroalkyl-2-oxo(thioxo)-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates were obtained. Under the same conditions, hexafluoroacetylacetone furnishes 4,6-dihydroxy-4,6-di(trifluoromethyl)-hexahydropyrimidin-2-one. Some further reactions of these pyrimidine derivatives leading to fused heterocycles are described.

Full text of DOI:10.1016/S0022-1139(99)00216-X

Journal of Fluorine Chemistry 103 (2000) 17±23
Biginelli condensations of ¯uorinated 3-oxo esters and 1,3-diketones [1]
V.I. Saloutina,*, Ya.V. Burgarta, O.G. Kuzuevaa, C.O. Kappeb, O.N. Chupakhina
aInstitute of Organic Synthesis, UD RAS, 20, S. Kovalevskoy Str., 620219, Ekaterinburg, GSP-147, Russia
bInstitute of Organic Chemistry, Karl-Franzens-University Graz, A-8010 Graz, Austria
Received 13 September 1999; accepted 16 September 1999
Abstract
Condensation of ¯uorinated 3-oxo esters or 1,3-diketones with benzaldehyde and (thio)urea results in the diastereoselective formation of
4-¯uoroalkyl-4-hydroxy-2-oxo(thioxo)-6-phenyl-hexahydropyrimidine-5-carboxylates from which by dehydration under acidic conditions
the corresponding 6-¯uoroalkyl-2-oxo(thioxo)-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates were obtained. Under the same
conditions, hexa¯uoroacetylacetone furnishes 4,6-dihydroxy-4,6-di(tri¯uoromethyl)-hexahydropyrimidin-2-one. Some further reactions of
these pyrimidine derivatives leading to fused heterocycles are described. # 2000 Elsevier Science S.A. All rights reserved.
Keywords: Fluoroalkyl 3-oxo esters and 1,3-diketones; Biginelli reaction; Hexahydropyrimidines
1. Introduction
recorded on a Tesla BS-587A instrument (1H: 80 MHz,
using TMS as an internal standard, 19F: 75 MHz, using
C6F6 as an internal standard). Microanalyses were per-
formed with a Carlo Erba CHNS-O EA 1108 elemental
analyzer. Thin-layer chromatography was performed on
`Silufol-UV 254' plates.
The cyclocondensation of acetoacetic esters with aro-
matic aldehydes and (thio)urea, known as the Biginelli
reaction, has attracted considerable attention in recent years
[2]. The resulting 1,2,3,4-tetrahydropyrimidine derivatives
have been shown to possess a variety of interesting phar-
macological properties and therefore many synthetic meth-
ods for the synthesis of this heterocyclic scaffold are now
available [3]. Recently, we have discovered that using a
¯uorinated acetoacetic ester derivative (i.e. ethyl tri¯uor-
oacetoacetate) the reaction takes a different course and a
hexahydropyrimidine is obtained [4]. The structure and
relative stereochemistry of this material was established
unequivocally by X-ray analysis [4]. In this article we show
that this reaction is rather general and that a number of
¯uorinated 3-oxo esters or 1,3-dicarbonyl compounds can be
employed in this novel three-component condensation lead-
ing to ¯uorine-containing heterocycles of potential biologi-
cal activity.
2.1. Materials
3-Oxo esters 1a±e were prepared by the methods
described previously [5]. 1,3-Diketones 2a±d were prepared
via a known procedure [6].
2.2. Synthesis of hexahydropyrimidines 3a±h, 4a±g, i, 7
A mixture of benzaldehyde (0.21 g, 2.0 mmol), 1,3-dicar-
bonyl compound (1a±e, 2a±d) (2.0 mmol) (Scheme 1),
(thio)urea (3.0 mmol) and 8 ml of ethanol, containing two
drops of concentrated HCl, was re¯uxed for 6 h. The reac-
tion mixture was stored at 48C overnight. The precipitate
was ®ltered and recrystallized from ethanol to give hexahy-
dropyrimidines 3a±h, 4a±g, i, 7 as white solids.
2. Experimental details
Melting points were measured in open capillaries and are
reported uncorrected. Infrared spectra were measured on a
Specord 75 IR spectrometer. 1H- and 19F-NMR spectra were
2.2.1. Ethyl ester of 4-difluoromethyl-4-hydroxy-2-oxo-6-
phenylhexahydropyrimidine-5-carboxylic acid (3a)
1
Yield, 75%; m.p., 204±2058C. H NMR (DMSO-d6) d:
0.87 (3H, t, CH3, J(H±H) ˆ 7.0 Hz); 2.92 (1H, d, H5, J(H5±H6)
ˆ 11.6 Hz); 3.82 (2H, q, CH2, J(H±H) ˆ 7.0 Hz); 4.80 (1H, d,
* Corresponding author. Fax: ‡7-3432-745954.
E-mail addresses: fc@ios.uran.ru (V.I. Saloutin),
kappeco@balu.kfunigraz.ac.at (C.O. Kappe).
H6, J(H6±H5) ˆ 11.6 Hz); 5.88 (1H, t, HCF2, J(H±F)
ˆ
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 2 1 6 - X

18
V.I. Saloutin et al. / Journal of Fluorine Chemistry 103 (2000) 17±23
Scheme 1.
55.2 Hz); 7.33 (5H, s, C6H5); 6.67, 7.00, 7.15 (3H, 3 ws,
2NH, OH) ppm. 19F NMR (DMSO-d6) d: 30.38 (2F, m,
2.2.4. Ethyl ester of 4-hydroxy-4-nonafluorobutyl-2-oxo-6-
phenyl-hexahydropyrimidine-5-carboxylic acid (3d)
Yield, 80%; m.p., 191±1928C. 1H NMR (DMSO-d6)
d: 0.78 (3H, t, CH3, J(H±H) ˆ 7.1 Hz); 3.03 (1H, d, H5,
J(H5±H6) ˆ 11.1 Hz); 3.74 (2H, q, CH2, J(H±H) ˆ 7.1 Hz);
4.81 (1H, d, H6, J(H6±H5) ˆ 11.1 Hz); 7.33 (5H, s, C6H5);
5.39, 7.11, 7.48 (3H, 3 ws, 2NH, OH) ppm. 19F NMR
(DMSO-d6) d: 37.25 (2F, m, CF2); 44.66±43.51 (4F, m,
2CF2); 82.42 (3F, m, CF3) ppm. IR: 3420, 3190, 1620 (NH,
OH); 3075 (CH); 1720 (CO2Et); 1675 (C ˆ O); 1530
(C ˆ C); 1220±1090 (C±F) cm 1. Analysis: Found: C,
42.34; H, 3.13; F, 35.45; N, 5.81. Calc. for C17H15F9N2O4:
C, 42.29; H, 3.21; F, 35.53; N, 5.96%.
HCF2, AB-system, Dv ˆ 236.0, J(F±F) ˆ 274.9, J(F±H)
ˆ
55.2 Hz) ppm. IR: 3315, 3200, 1585 (NH, OH); 3090
(CH); 1720 (CO2Et); 1665 (C=O); 1500 (C=C); 1170±
1070 (C±F) cm 1. Analysis: Found: C, 53.39; H, 5.17; F,
12.44; N, 8.65. Calc. for C14H16F2N2O4: C, 53.50; H, 5.13;
F, 12.09; N, 8.91%.
2.2.2. Methyl ester of 4-hydroxy-2-oxo-6-phenyl-4-
(1,1,2,2-tetrafluoroethyl)-hexahydropyrimidine-5-
carboxylic acid (3b)
1
Yield, 79%; m.p., 190±1928C. H NMR (DMSO-d6) d:
3.00 (1H, d, H5, J(H5±H6) ˆ 11.1 Hz); 3.27 (3H, s, OCH3);
4.79 (1H, d, H6, J(H6±H5) ˆ 11.1 Hz); 6.70 (1H, t.t, H(CF2)2,
2.2.5. Methyl ester of 4-hydroxy-6-phenyl-4-(1,1,2,2-
tetrafluoroethyl)-2-thioxohexahydro-pyrimidine-5-
carboxylic acid (3e)
3
2J(H±F) ˆ 51.4, J(H±F) ˆ 5.1 Hz); 7.32 (5H, s, C6H5); 7.10
(H, ws, OH); 7.20 (2H, ws, 2NH) ppm. 19F NMR (DMSO-
d6) d: 27.57 (2F, m, HCF2CF2); 35.14 (2F, m, HCF2CF2,
Yield, 50%; m.p., 212±2138C. 1H NMR (DMSO-d6)
d: 3.09 (1H, d, H5, J(H5±H6) ˆ 11.7 Hz); 3.28 (3H, s,
OCH3); 4.81 (1H, d, H6, J(H6±H5) ˆ 11.7 Hz); 6.79 (1H,
AB-system, Dv ˆ 166.12, 2J(F±F) ˆ 266.0, 3J(F±H)
ˆ
5.1 Hz) ppm. IR: 3440, 3220, 1585 (NH, OH); 3055
(CH); 1740 (CO2Me); 1660 (C ˆ O); 1500 (C ˆ C);
1160±1090 (C±F) cm 1. Analysis: Found: C, 48.13; H,
4.16; F, 22.14; N, 8.06. Calc. for C14H14F4N2O4: C,
48.00; H, 4.03; F, 21.70; N, 8.00%.
2
3
t.t, H(CF2)2, J(H±F) ˆ 51.4, J(H±F) ˆ 6.6 Hz); 7.33 (5H, s,
C6H5); 7.73, 8.31, 9,19 (3H, ws, OH, 2NH) ppm. 19F NMR
(DMSO-d6) d: 27.46 (2F, m, HCF2CF2); 35.14 (2F, m,
HCF2CF2) ppm. IR: 3400, 3200, 1600 (NH, OH); 3090
(CH); 1735 (CO2Me); 1580, 1565, 1500 (C ˆ C); 1220±
1100 (C±F) cm 1. Analysis: Found: C, 46.21; H, 4.12; F,
20.38; N, 7.65; S, 8.65. Calc. for C14H14F4N2O3S: C, 45.90;
H, 3.85; F, 20.74; N, 7.65; S, 8.75%.
2.2.3. Methyl ester of 4-heptafluoropropyl-4-hydroxy-2-
oxo-6-phenyl-hexahydropyrimidine-5-carboxylic acid (3c)
1
Yield, 73%; m.p., 204±2058C. H NMR (DMSO-d6) d:
3.04 (1H, d, H5, J(H5±H6) ˆ 11.0 Hz); 3.28 (3H, s, OCH3);
4.81 (1H, d, H6, J(H6±H5) ˆ 11.0 Hz); 7.33 (5H, s, C6H5);
7.17, 7.53, 7.61 (3H, 3 ws, OH, 2NH) ppm. 19F NMR
(DMSO-d6) d: 40.39 (2F, m, CF2); 43.76 (2F, m, CF2);
82.26 (2F, m, CF3) ppm. IR: 3450, 3205, 1630 (NH, OH);
3080 (CH); 1740 (CO2Me); 1670 (C ˆ O); 1490 (C ˆ C);
1230±1100 (C±F) cm 1. Analysis: Found: C, 43.25; H,
3.14; F, 31.91; N, 6.70. Calc. for C15H13F7N2O4: C,
43.07; H, 3.13; F, 31.80; N, 6.70%.
2.2.6. Methyl ester of 4-heptafluoropropyl-4-hydroxy-6-
phenyl-2-thioxo-hexahydropyrimidine-5-carboxylic acid
(3f)
1
Yield, 47%; m.p., 215±2178C. H NMR (DMSO-d6) d:
3.14 (1H, d, H5, J(H5±H6) ˆ 11.3 Hz); 3.30 (3H, s, OCH3);
4.83 (1H, d, H6, J(H6±H5) ˆ 11.3 Hz); 7.34 (5H, s, C6H5);
8.13 (1H, ws, OH); 9.35 (2H, ws, 2NH) ppm. 19F NMR
(DMSO-d6) d: 40.38 (2F, m, CF2); 44.05 (2F, m, CF2); 82.35

V.I. Saloutin et al. / Journal of Fluorine Chemistry 103 (2000) 17±23
19
(2F, m, CF3) ppm. IR: 3440, 3200, 1600 (NH, OH); 3100
(CH); 1740 (CO2Me); 1585, 1565, 1490 (C=C); 1280±1170
(C±F) cm 1. Analysis: Found: C, 41.45; H, 3.23; F, 30.62;
N, 6.68; S, 7.34. Calc. for C15H13F7N2O3S: C, 41.48; H,
3.02; F, 30.62; N, 6.42; S, 7.38%.
Analysis: Found: C, 59.23; H, 4.05; F, 15.69; N, 7.54. Calc.
for C18H15F3N2O3: C, 59.34; H, 4.15; F, 15.64; N, 7.69%.
2.2.11. 5-Acetyl-4-hydroxy-6-phenyl-4-(1,1,2,2-
tetrafluoroethyl)-hexahydropyrimidin-2-one (4c)
1
Yield, 33%; m.p., 184±1858C. H NMR (DMSO-d6) d:
2.2.7. Ethyl ester of 4-hydroxy-4-nonafluorobutyl-6-
phenyl-2-thioxo-hexahydropyrimidine-5-carboxylic acid
(3g)
1.80 (3H, s, CH3); 3.10 (1H, d, H5, J(H5±H6) ˆ 11.4 Hz); 4.82
(1H, d, H6, J(H6±H5) ˆ 11.4 Hz); 6.71 (1H, t.t, H(CF2)2,
3
2J(H±F) ˆ 51.5 Hz, J(H±F) ˆ 6.8 Hz); 7.34 (5H, s, C6H5);
Yield, 45%; m.p., 212±2138C. 1H NMR (DMSO-d6)
d: 0.81 (3H, t, CH3, J(H±H) ˆ 7.1 Hz); 3.13 (1H, d, H5,
J(H5±H6) ˆ 11.5 Hz); 3.78 (2H, q, CH2, J(H±H) ˆ 7.1 Hz);
4.84 (1H, d, H6, J(H6±H5) ˆ 11.5 Hz); 7.35 (5H, s, C6H5);
7.90, 7.98, 9.24 (3H, 3 ws, 2NH, OH) ppm. 19F NMR
(DMSO-d6) d: 37.08 (2F, m, CF2); 43.73 (2F, m, CF2);
44.86 (2F, m, CF2); 82.33 (3F, m, CF3) ppm. IR: 3440, 3185,
1600 (NH, OH); 3100 (CH); 1730 (CO2Et); 1580, 1500
(C=C); 1230±1130 (C±F) cm 1. Analysis: Found: C, 40.98;
H, 3.13; F, 34.26; N, 5.67; S, 6.48. Calc. for
C17H15F9N2O3S: C, 40.97; H, 3.03; F, 34.21; N, 5.62; S,
6.43%.
7.21, 7.28 (3H, 2 ws, 2NH, OH) ppm. 19F NMR (DMSO-d6)
d: 27.64 (2F, m, HCF2CF2); 36.69 (2F, m, HCF2CF2, AB-
system, Dv ˆ 116.83, 2J(F±F) ˆ 267.0 Hz, 3J(F±H) ˆ 6.8 Hz)
ppm. IR: 3450, 3390, 3210, 1590 (NH, OH); 3090 (CH);
1700 (COMe); 1690 (C=O); 1480 (C=C); 1160±1110 (C±F)
cm 1. Analysis: Found: C, 50.39; H, 4.27; F, 22.74; N, 8.43.
Calc. for C14H14F4N2O3: C, 50.30; H, 4.22; F, 22.73; N,
8.38%.
2.2.12. 5-Benzoyl-4-hydroxy-6-phenyl-4-(1,1,2,2-
tetrafluoroethyl)-hexahydropyrimidin-2-one (4d)
1
Yield, 38%; m.p., 233±2348C. H NMR (DMSO-d6) d:
4.65 (2H, m, H5, H6, AB-system, Dv ˆ 41.45, J(H5±H6)
ˆ
2
2.2.8. Ethyl ester of 4-hydroxy-6-phenyl-2-thioxo-4-
trifluoromethylhexahydropyrimidine-5-carboxylic acid
(3h)
11.0 Hz); 6.72 (1H, t.t, H(CF2)2, J(H±F) ˆ 51.3 Hz,
3J(H±F) ˆ 6.7 Hz); 7.04±7.46 (10H, m, 2C6H5); 7.54, 7.62
(3H, 2 ws, 2NH, OH) ppm. 19F NMR (DMSO-d6) d: 27.79
1
2
Yield, 43%; m.p., 190±1918C (lit. mp. 1908C [7]). H
(2F, m, HCF2CF2, AB-system, Dv ˆ 159.34, J(F±F)
ˆ
2
NMR (DMSO-d6) d: 0.81 (3H, t, CH3, J(H±H) ˆ 7.1 Hz);
3.02 (1H, d, H5, J(H5±H6) ˆ 11.8 Hz); 3.79 (2H, q, CH2,
J(H±H) ˆ 7.1 Hz); 4.79 (1H, d, H6, J(H6±H5) ˆ 11.8 Hz); 7.34
(5H, s, C6H5); 7.88, 8.89, 9.09 (3H, 3 ws, 2NH, OH) ppm.
19F NMR (DMSO-d6) d: 82.30 (3F, m, CF3) ppm. IR: 3430,
3190, 1600 (NH, OH); 3100 (CH); 1735 (CO2Et); 1570
(C=C); 1260±1170 (C±F) cm 1. Analysis: Found: C, 48.18;
H, 4.32; F, 16.34; N, 8.01. Calc. for C14H15F3N2O3S: C,
48.27; H, 4.34; F, 16.36; N, 8.04%.
300.0 Hz, J(F±H) ˆ 51.3 Hz); 38.11 (2F, m, HCF2CF2,)
ppm. IR: 3430, 3190, 1590 (NH, OH); 3050 (CH); 1675
.
1
(COPh); 1660 (C=O); 1490 (C=C); 1140±1100 (C±F) cm
Analysis: Found: C, 57.44; H, 4.12; F, 19.12; N, 7.04.
Calc. for C19H16F4N2O3: C, 57.58; H, 4.07; F, 19.17; N,
7.07%.
2.2.13. 5-Acetyl-4-hydroxy-6-phenyl-4-trifluoromethyl-
hexahydropyrimidine-2-thione (4e)
1
Yield, 22%; m.p., 211±2128C. H NMR (DMSO-d6) d:
2.2.9. 5-Acetyl-4-hydroxy-6-phenyl-4-trifluoromethyl-
hexahydropyrimidin-2-one (4a)
Yield, 32%; m.p., 180±1828C. H NMR (DMSO-d6) d:
1.89 (3H, s, CH3); 3.19 (1H, d, H5, J(H5±H6) ˆ 11.8 Hz); 4.86
(1H, d, H6, J(H6±H5) ˆ 11.8 Hz); 7.35 (5H, s, C6H5); 8.02,
8.96, 9.09 (3H, 3 ws, 2NH, OH) ppm. 19F NMR (DMSO-d6)
d : 82.90 (3F, m, CF3) ppm. IR: 3380, 3260, 1580 (NH, OH);
3050 (CH); 1690 (COMe); 1550, 1500 (C=C); 1240±1160
(C±F) cm 1. Analysis: Found: C, 49.05; H, 4.14; F, 17.83;
N, 8.78; S, 10.14. Calc. for C13H13F3N2O2S: C, 49.05; H,
4.12; F, 17.91; N, 8.80; S, 10.07%.
1
1.88 (3H, s, CH3); 3.11 (1H, d, H5, J(H5±H6) ˆ 11.7 Hz); 4.84
(1H, d, H6, J(H6±H5) ˆ 11.7 Hz); 7.35 (5H, s, C6H5); 7.19,
7.52, 7.61 (3H, 3 ws, 2NH, OH) ppm. 19F NMR (DMSO-d6)
d: 82.04 (3F, m, CF3) ppm. IR: 3400, 3390, 3220, 1610 (NH,
OH); 3080, 3050 (CH); 1720, 1705 (COMe); 1680, 1660
(C=O); 1500 (C=C); 1190±1170 (C±F) cm 1. Analysis:
Found: C, 51.49; H, 4.28; F, 18.85; N, 9.28. Calc. for
C13H13F3N2O3: C, 51.66; H, 4.34; F, 18.86; N, 9.27%.
2.2.14. 5-Benzoyl-4-hydroxy-6-phenyl-4-trifluoromethyl-
hexahydropyrimidine-2-thione (4f)
1
Yield, 30%; m.p., 229±2308C. H NMR (DMSO-d6) d:
2.2.10. 5-Benzoyl-4-hydroxy-6-phenyl-4-trifluoromethyl-
hexahydropyrimidin-2-one (4b)
4.75 (2H, m, H5, H6, AB-system, Dv ˆ 38.80, J(H5±H6)
ˆ
11.5 Hz); 7.15±7.70 (10H, m, 2C6H5); 7.75, 8.95, 9.09 (3H,
1
Yield, 42%; m.p., 204±2058C. H NMR (DMSO-d6) d:
3 ws, 2NH, OH) ppm. 19F NMR (DMSO-d6) d: 83.61 (3F, s,
CF3) ppm. IR: 3430, 3180, 1585 (NH, OH); 3090 (CH);
4.68 (2H, m, H5, H6, AB-system, Dv ˆ 41.94, J(H5±H6)
2NH, OH) ppm. 19F NMR (DMSO-d6) d: 82.71 (3F, s, CF3)
ppm. IR: 3430, 3190, 1590 (NH, OH); 3060 (CH); 1675
ˆ
1
11.1 Hz); 7.10±7.40 (10H, m, 2C6H5); 7.60, 7.72 (3H, 3 ws,
1665 (COPh); 1560, 1500 (C=C); 1250±1120 (C±F) cm
.
Analysis: Found: C, 56.95; H, 3.84; F, 14.76; N, 7.36; S,
8.47. Calc. for C18H15F3N2O2S: C, 56.84; H, 3.97; F, 14.98;
N, 7.36; S, 8.43%.
1
(COPh); 1660 (C=O); 1500 (C=C); 1200±1175 (C±F) cm
.

20
V.I. Saloutin et al. / Journal of Fluorine Chemistry 103 (2000) 17±23
2.2.15. 5-Benzoyl-4-hydroxy-6-phenyl-(1,1,2,2-
tetrafluoroethyl)-hexahydropyrimidine-2-thione (4g)
4.88 (1H, d, H6, J(H6±H5) ˆ 11.5 Hz); 7.34 (5H, m, C6H5);
7.44, 7.95, 8.09 (3H, 3 ws, 2NH, OH) ppm. 19F NMR
(DMSO-d6) d: 81.17 (3F, q, CF3, J ˆ 5.3 Hz); 84.03 (3F,
q, CF3, J ˆ 5.3 Hz) ppm. IR: 3390, 3200, 1610 (NH, OH);
3060 (CH); 1745 (COCF3); 1660 (C=O); 1480 (C=C);
1200±1100 (C±F) cm 1. Analysis: Found: C, 43.74; H,
2.82; F, 32.14; N, 7.93. Calc. for C13H10F6N2O3: C,
43.83; H, 2.83; F, 32.00; N, 7.86%.
1
Yield, 36%; m.p., 233±2348C. H NMR (DMSO-d6) d:
4.72 (2H, m, H5, H6, AB-system, Dv ˆ 41.79, J(H5±H6)
ˆ
2
3
11.5 Hz); 6.84 (1H, t.t, H(CF2)2, J(H±F) ˆ 51.5 Hz, J(H±F)
ˆ 6.0 Hz); 7.09±7.58 (10H, m, 2C6H5); 7.66, 8.30, 9.20
(3H, 3 ws, 2NH, OH) ppm. 19F NMR (DMSO-d6) d: 27.50
(2F, m, HCF2CF2); 38.65 (2F, m, HCF2CF2, AB-system,
Dv ˆ 80.22, 2J(F±F) ˆ 264.4 Hz, 3J(F±H) ˆ 6.0 Hz) ppm. IR:
3440, 3190, 1595 (NH, OH); 3100 (CH); 1680 (COPh);
1560, 1500 (C=C); 1220±1150 (C±F) cm 1. Analysis:
Found: C, 55.25; H, 4.06; F, 18.54; N, 6.69; S, 7.70. Calc.
for C19H16F4N2O2S: C, 55.34; H, 3.91; F, 18.43; N, 6.79; S,
7.77%.
2.4. Synthesis of tetrahydropyrimidines 5a,b and 6a,b
To a solution of hexahydropyrimidine 3d,g, 4d,g
(2.0 mmol) (Scheme 1) in 15 ml of toluene, 0.1 g of p-
toluenesulfonic acid was added. The mixture was re¯uxed
for 6 h with azeotropic removal of water. The reaction
mixture was cooled to room temperature and ®ltered from
a small amount of solid material. Reprecipitation of this
residue from ethanol/water gave compounds 5a,b, 6a,b.
2.2.16. 4-Hydroxy-6-phenyl-5-trifluoroacetyl-4-
trifluoromethylhexahydropyrimidine-2-thione (4i)
Yield, 20%; m.p., 215±2168C. 1H NMR (DMSO-d6)
d: 3.97 (1H, d, H5, J(H5±H6) ˆ 11.5 Hz); 4.89 (1H, d, H6,
J(H6±H5) ˆ 11.5 Hz); 7.35 (5H, m, C6H5); 8.38, 9.29, 9.46
(3H, 3 ws, 2NH, OH) ppm. 19F NMR (DMSO-d6) d: 82.59
(3F, q, CF3, J ˆ 5.4 Hz); 84.59 (3F, q, CF3, J ˆ 5.4 Hz)
ppm. IR: 3160, 1580 (NH, OH); 3100 (CH); 1740 (COCF3);
1560, 1510 (C=C); 1200±1170 (C±F) cm 1. Analysis:
Found: C, 41.99; H, 2.75; F, 30.74; N, 7.56; S, 8.35. Calc.
for C13H10F6N2O2S: C, 41.94; H, 2.71; F, 30.62; N, 7.52; S,
8.61%.
2.4.1. Ethyl ester of 6-nonafluorobutyl-2-oxo-4-phenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (5a)
Yield, 56%; m.p., 154±1558C. 1H NMR (DMSO-d6)
d: 1.03 (3H, t, CH3, J(H±H) ˆ 7.1 Hz); 4.00 (2H, q, CH2,
J(H±H) ˆ 7.1 Hz); 5.25 (1H, s, H4); 7.34 (5H, s, C6H5); 7.96,
9.60 (2H, 2 ws, 2NH) ppm. 19F NMR (DMSO-d6) d : 36.92
(2F, m, CF2); 42.85 (2F, m, CF2); 52.62 (2F, m, CF2); 82.25
(3F, m, CF3) ppm. IR: 3270, 3210, 1650 (NH); 3080 (CH);
1730 (CO2Et); 1670 (C=O); 1560 (C=C); 1240±1140 (C±F)
cm 1. Analysis: Found: C, 43.93; H, 2.86; F, 36.91; N, 6.14.
Calc. for C17H13F9N2O3: C, 43.98; H, 2.82; F, 36.83; N
6.03%.
2.2.17. 4,6-Di(hydroxy)-4,6-di(trifluoromethyl)-
hexahydropyrimidin-2-one (7)
1
Yield, 44%; m.p., 211±2128C. H NMR (DMSO-d6) d:
2.15 (2H, m, H5a, H5e, AB-system, Dv ˆ 18.28, J(H±H)
ˆ
13.7 Hz); 6.94, 7.97 (4H, 2s, 2NH, 2OH) ppm. 19F NMR
(DMSO-d6) d: 78.60 (6F, s, CF3) ppm. IR: 3290, 3130, 1590
(NH, OH); 1680 (COPh); 1560, 1500 (C=C); 1220±1150
(C±F) cm 1. Analysis: Found: C, 55.25; H, 4.06; F, 18.54;
N, 6.69; S, 7.70. Calc. for C19H16F4N2O2S: C, 55.34; H,
3.91; F, 18.43; N, 6.79; S, 7.77%.
2.4.2. Ethyl ester of 6-nonafluorobutyl-4-phenyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (5b)
Yield, 48%; m.p., 137±1388C. 1H NMR (DMSO-d6)
d: 1.08 (3H, t, CH3, J(H±H) ˆ 7.1 Hz); 4.07 (2H, q, CH2,
J(H±H) ˆ 7.1 Hz); 5.25 (1H, d, H4, 3J(H±H) ˆ 3.1 Hz); 7.21±
3
7.46 (5H, m, C6H5); 9.20 (1H, d, NH, J(H±H) ˆ 3.1 Hz);
Method B: A mixture of 1,3-diketone 2e (0.42 g,
2.0 mmol) and urea (0.18 g, 3.0 mmol) was re¯uxed in
8 ml of ethanol containing two drops of concentrated
HCl for 2 h. The solvent was removed under reduced
pressure. The residue was washed with chloroform
(10 ml). Recrystallization of the mixture from ethanol±
water (1:1) gave 7 (0.39 g, 72%). The physical data were
identical to those listed above.
10.71 (1H, ws, NH) ppm. 19F NMR (DMSO-d6) d: 36.85
(2F, m, CF2); 42.88 (2F, m, CF2); 52.86 (2F, m, CF2); 82.19
(3F, m, CF3) ppm. IR: 3295, 3180, 1580 (NH); 3100 (CH);
1710 (CO2Et); 1670 (C=C); 1560 (C=C); 1220±1130 (C±F)
cm 1. Analysis: Found: C, 43.93; H, 2.86; F, 36.91; N, 6.14.
Calc. for C17H13F9N2O3: C, 43.98; H, 2.82; F, 36.83; N,
6.03%.
2.4.3. 5-Benzoyl-4-phenyl-6-(1,1,2,2-tetrafluoroethyl)-
1,2,3,4-tetrahydropyrimidin-2-one (6a)
Yield, 44%; m.p., 152±1538C. H NMR (DMSO±d6) d:
2.3. 4-Hydroxy-6-phenyl-5-trifluoroacetyl-4-
trifluoromethyl-hexahydropyrimidin-2-one (4h)
1
2
5.13 (1H, ws, H4); 6.65 (1H, t.t, H(CF2)2, J(H±F1,2)
ˆ
3
3
A mixture of benzaldehyde (0.21 g, 2.0 mmol), 1,3-dike-
tone 2e (0.42 g, 2.0 mmol), urea (0.18 g, 3.0 mmol) and
p-toluenesulfonic acid (0.09 g, 1.5 mmol) in 8 ml of tetra-
hydrofuran was re¯uxed for 2 h. Precipitation by water gave
4g (0.21 g, 30%) as a white powder (m.p., 200±2018C). 1H
NMR (DMSO-d6) d: 3.83 (1H, d, H5, J(H5±H6) ˆ 11.5 Hz);
52.0 Hz, J(H±F3) ˆ 7.4 Hz, J(H±F4) ˆ 4.6 Hz); 7.18±7.65
(10H, m, 2C6H5); 7.86, 9.43 (2H, 2 ws, 2NH) ppm. 19F
2
NMR (DMSO-d6) d: 25.08 (2F, d.t, HCF2CF2, J(F1,2±H)
ˆ
3
52.0 Hz, J(F1,2±F3,4) ˆ 7.9 Hz); 46.04 (2F, m, HCF2CF2,
2
3
AB-system, Dv ˆ 363.3, J(F3±F4) ˆ 269.6 Hz, J(F3,4±F1,2)
3
3
ˆ 7.9 Hz, J(F3±H) ˆ 7.4 Hz, J(F4±H) ˆ 4.6 Hz) ppm. IR:

V.I. Saloutin et al. / Journal of Fluorine Chemistry 103 (2000) 17±23
21
3235, 1600 (NH); 3100 (CH); 1710 (COPh); 1675 (C=O);
1660 (C=C); 1490 (C=C); 1170±1100 (C±F) cm 1. Analy-
sis: Found: C, 60.07; H, 3.68; F, 19.85; N, 7.50. Calc. for
C19H14F4N2O2: C, 60.32; H, 3.73; F, 20.09; N, 7.40%.
that an earlier report on the condensation of ethyl tri¯uor-
oacetoacetate with thiourea and benzaldehyde postulated
the formation of the corresponding ureidopropionate B
(Rf ˆ CF3, R ˆ OEt, X ˆ S) under essentially similar reac-
tion conditions [7]. Based on comparison of melting points
and spectral data we assume that the identical material has
been isolated. However, we assign the structure of the
corresponding hexahydropyrimidine of type A (3h) to this
product based on the detailed spectroscopic characterization
that we have carried out.
2.4.4. 5-Benzoyl-4-phenyl-6-(1,1,2,2-tetrafluoroethyl)-
1,2,3,4-tetrahydropyrimidine-2-thione (6b)
1
Yield, 40%; m.p., 123±1248C. H NMR (DMSO-d6) d:
5.10 (1H, ws, H4); 6.76 (1H, t.t, H(CF2)2, 2J(H±F) ˆ 51.9 Hz,
3J(H±F) ˆ 6.0 Hz); 7.20±7.67 (10H, m, 2C6H5); 9.70, 10.67
(2H, 2 ws, 2NH) ppm. 19F NMR (DMSO-d6) d: 24.75 (2F,
m, HCF2CF2,); 46.90 (2F, m, HCF2CF2) ppm. IR: 3150,
1590 (NH); 3090 (CH); 1665 (COPh); 1650 (C=C); 1570
(C=C); 1210±1100 (C±F) cm 1. Analysis: Found: C, 57.70;
H, 3.52; F, 19.04; N, 7.04. Calc. for C19H14F4N2OS: C,
57.86; H, 3.58; F, 19.27; N, 7.10%.
2.5. Ethyl ester of 7-nonafluorobutyl-5-phenyl-2,3-
dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid,
hydrobromide salt (9)
To a re¯uxing solution of tetrahydropyrimidine 5b
(0.96 g, 2.0 mmol) in 5 ml of DMF, dibromoethane
(0.39 g, 2.1 mmol) was added. The mixture was re¯uxed
for 25 min. After cooling, the resulting precipitate was
collected by ®ltration. Recrystallization from ethanol gave
9 (0.49 g, 42%) as a white powder (m.p., 200±2018C).
1H NMR (CF3COOD) d: 1.11 (3H, t, CH3, J(H±H) ˆ 7.0 Hz);
3.71 (2H, m, H2a,H2e, J(H±H) ˆ 6.5 Hz); 4.17 (2H, q, CH2,
J(H±H) ˆ 7.0 Hz); 4.58 (2H, m, H3a,H3e, J(H±H) ˆ 6.5 Hz);
5.92 (1H, s, H5); 7.50 (5H, m, C6H5) ppm. IR: 2770, 2745,
2700 (NH‡); 3060 (CH); 1730 (CO2Et); 1660, 1500 (C=C,
C=N); 1240±1140 (C±F) cm 1. Analysis: Found: C, 38.85;
H, 2.74; F, 29.13; N, 4.75; S, 5.48. Calc. for C19H15F9N2O2S
HBr: C, 38.86; H, 2.75; F, 29.11; N, 4.77; S, 5.46%.
Spectral examination (1H and 19F NMR) of products 3a±
h, 4a±g con®rms the formation of one single isomer in all
cases. The IR spectra of products 3a±h, 4a±g are character-
ized by the absence of two narrow absorption bands corre-
sponding to the asymmetric and symmetric vibration of the
NH2-groups in structures B. However, sharp and intense
signals for the OH functionality in structure A are present in
1
all cases. In the H NMR spectra of compounds 3a±h, and
4a±g, the most characteristic signals are two doublets
corresponding to the two trans-axial methine protons in
A (H5±H6). The observed coupling constants (J ˆ 11.0±
11.8 Hz) agree very well with the values previously found
for our reference compound A (Rf ˆ CF3, R ˆ OEt, X ˆ O)
[4]. It is therefore reasonable to assume that the same
relative stereochemistry as shown in A and ring orientation
is observed in all cases.
3. Results and discussion
In addition, the cyclic nature of compound 3h was
con®rmed by 13C NMR spectroscopy. In the spectrum, a
quartet for the carbon atom connected with the tri¯uoro-
In the present work, the Biginelli-type cyclocondensa-
tions of a number of ¯uorine-containing 3-oxo esters 1a±e
and 1,3-diketones 2a±e have been studied. In analogy to the
reaction with ethyl tri¯uoroacetoacetate 1e with benzalde-
hyde and urea [4], we ®nd that both ¯uorinated 3-oxo esters
1a±e and ¯uorinated 1,3-diketones 2a±d in general react
with (thio)urea and benzaldehyde to furnish hexahydropyr-
imidines 3a±h, and 4a±g, respectively (Scheme 1). These
reactions were conveniently carried out in re¯uxing ethanol
in the presence of a catalytic amount of concentrated HCl
for 5±6 h providing hexahydropyrimidine products in mod-
erate to good yields.
In principle, one has to consider two isomeric structures
for these condensation products, namely the hexahydropyr-
imidine structure of type A, or the isomeric acyclic urei-
dopropionate structure of type B (which may exist as
mixture of keto- and enol tautomers). It has to be mentioned
methyl substituent is located at 79.61 ppm (3J(C±F)
ˆ
31.13 Hz) (Table 1) which is typical for a quarternary
carbon rather than a carbonyl carbon atom [8]. Therefore,
all the spectroscopic data clearly con®rm the cyclic struc-
ture of type A for the products obtained, in agreement with
the X-ray analysis obtained previously for a single analog
[4].
When non-symmetrical 1,3-diketones are employed in
the above Biginelli-type cyclocondensation process two
isomeric products may possibly be formed. Cyclization
of the pyrimidine nucleus may occur on the carbonyl group
at the ¯uorinated substituent or the carbonyl group con-
nected with the non-¯uorinated substituent to form the
corresponding heterocycles C or D, respectively, or a mix-
ture of both isomers. Literature data indicate that condensa-
tion of amines with non-symmetrical 1,3-diketones having

22
V.I. Saloutin et al. / Journal of Fluorine Chemistry 103 (2000) 17±23
Table 1
13C NMR spectra of compounds 3h, 4a (dC, ppm; J(13C±19F), Hz) in DMSO-d6
N
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
3h
4a
177.17
164.22
79.61 (31.13)
80.69 (30.52)
54.30
53.21
60.37
57.21
122.84 (288)
123.21 (288)
166.40
203.89
49.36
30.58
13.36
153.72
136.89
127.97
128.06
128.52
128.31
138.04
128.55
one ¯uorinated substituent preferably occurs at the carbonyl
group attached to the non-¯uorinated radical [9].
di(tri¯uoromethyl)-hexahydropyrimidin-2-one 7 (Scheme
2). The formation of the latter evidently proceeds without
the participation of the aldehyde component, and is com-
petitive to the Biginelli condensation (see below). The
addition of water or alcohols on both carbonyl groups with
the formation of stable adducts (tetraols and bis-semiketals)
is typical for hexa¯uoroacetylacetone [9]. Under the reac-
tion conditions in an ethanol/water medium, hexa¯uoroa-
cetylacetone probably spontaneously forms bis-semiketal or
tetraol E, which do not have an activated methylene group
and therefore cannot react with the N-acyliminium ion
intermediate formed from the benzaldehyde and urea com-
ponents [10].
Hexahydropyrimidine 7 may exist in two diastereoiso-
meric forms (cis- and trans-isomers). The character of the
non-equivalent methylene proton signals as an AB-system
In the NMR spectra of compounds 4a±g, signals for only
one isomer are observable. The distinction between struc-
tures C and D was easily made on the basis of 13C NMR
spectroscopic data, as the quartet signal of the carbon atom
attached to the tri¯uoromethyl group (3JC±F ˆ 30.52 Hz) is
located at 80.69 ppm, which is typical for a quarternary
carbon atom (structure C, O±C±N) rather than a carbonyl
carbon in structure D [8]. Thus, the above cyclocondensa-
tion occurs regioselectively on the carbonyl group at the
¯uorinated substituent.
1
(J(H±H) ˆ 13.7 Hz) in the H NMR spectrum of 7 and one
single signal for the tri¯uoromethyl group in the 19F NMR
spectrum suggests that the cis-isomer is the only one
formed. This was further supported by semiempirical
AM1 calculations, showing that the cis-isomer is ca.
4 kcal/mol more stable than the trans-isomer. A representa-
tion of the AM1 optimized geometry is given in Fig. 1.
The formation of the originally anticipated hexahydro-
pyrimidine 4h is only possible using anhydrous conditions
in the three-component reaction and an aprotoic solvent
such as THF in the presence of a catalytic amount of p-
toluenesulfonic acid (Scheme 3). In contrast to the reaction
In contrast to the reactions of 3-oxo esters 1a±d and 1,3-
diketones 2a±d described above, hexa¯uoroacetylacetone
2e reacts with urea and benzaldehyde (under identical
reaction conditions) in a different manner yielding 4,6-
Scheme 2.

V.I. Saloutin et al. / Journal of Fluorine Chemistry 103 (2000) 17±23
23
Fig. 1. AM1 optimized geometry of cis-hexahydropyrimidine 7 (sche-
matic representation).
Scheme 4.
pyrimidines may be used as precursors for the synthesis of
fused heterocyclic systems. For example, tetrahydropyrimi-
dine 5b on re¯uxing with dibromoethane in DMF affords the
substituted thiazolopyrimidine 9 as hydrobromide salt
(Scheme 4) [14].
In conclusion, we have shown that a family of novel
¯uoroalkyl substituted hexahydropyrimidines is readily
available by Biginelli-type three-component cycloconden-
sation reaction of ¯uorinated 1,3-dicarbonyl compounds
with benzaldehyde and (thio)urea. The biological properties
of these substances are currently under investigation.
Scheme 3.
with urea, interaction of hexa¯uoroacetylacetone 2e with
thiourea and benzaldehyde results in the formation of
hexahydropyrimidine 4i even under classical reaction con-
ditions (EtOH/HCl). In this case, the Biginelli-type three-
component condensation apparently occurs faster than the
competitive addition of thiourea on both carbonyl groups of
the 1,3-diketone. Probably, this is a result of the greater
basicity of thiourea (pKb ˆ 11.97) as compared to urea
(pKb ˆ 13.82).
References
[1] Synthesis and reactions of biginelli compounds, part 18. For part 17,
see: C.O. Kappe, Bioorg. Med. Chem. Lett. in press.
[2] C.O. Kappe, Synthesis (1999) 1799.
[3] C.O. Kappe, D. Kumar, R.S. Varma, Synthesis (1999), in press.
[4] C.O. Kappe, S.F. Falsone, W.M.F. Fabian, F. Belaj, Heterocycles 51
(1999) 77.
[5] A.M. Lovelace, D.A. Rausch, M. Postelnek, Aliphatic Fluorine-
Containing Compounds, Inostrannaya Literatura, Moscow, 1961,
p. 225.
The experimental data obtained herein allow us to con-
clude that the replacement of non-¯uorinated 3-oxo ester
components in the Biginelli reaction by 1,3-dicarbonyl
compounds containing partially or completely ¯uorinated
substituents results in the formation of hexahydropyrimi-
dine derivatives in a diastereoselective fashion. The forma-
tion of stable hydrated heterocycles due to the presence of a
strong electron-withdrawing group is typical for the reac-
tions of ¯uorinated 1,3-dicarbonyl compounds with nucleo-
philic reagents [11±13].
We were also able to show that e.g. hexahydropyrimi-
dines 3d,f and 4d,f underwent successful dehydration in
re¯uxing toluene in the presence of p-toluenesulfonic acid
with azeotropic removal to form 1,2,3,4-tetrahydropyrimi-
dines 5a,b and 6a,b (see Scheme 1) [4]. Such tetrahydro-
[6] A.L. Henne, M.S. Newman, L.L. Quill, R.A. Staniforth, J. Amer.
Chem. Soc. 69 (1947) 1819.
[7] M.S. Akhtar, M. Seth, A.P. Bhaduri, Indian J. Chem. 26B (1987)
556.
[8] G.C. Levy, R.L. Lichter, G.L. Nelson, Carbon-13 Nuclear Magnetic
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(1981) 325.
[10] C.O. Kappe, J. Org. Chem. 62 (1997) 7201.
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(1987) 2527.
[12] Z.E. Skryabina, Ya.V. Burgart, V.I. Saloutin, Russ. J. Org. Chem. 33
(1997) 442.
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Saloutin, J. Fluor. Chem. 92 (1998) 101.
[14] C.O. Kappe, P. Roschger, J. Heterocycl. Chem. 26 (1989) 55.