Fluorocontaining 1,3-dicarbonyl compounds in the synthesis of pyrimidine derivatives

Article abstract of DOI:10.1023/A:1012473901354

Hexafluoroacetylacetone reacts with urea (thiourea) to yield respectively 4,6-bis(hydroxy)-4,6-bis(trifluoromethyl)hexahydropyrimidin-2-one(thione). The dehydration of the products and also reaction of nonsymmetrical fluoroalkyl-containing 1,3-diketones w

Full text of DOI:10.1023/A:1012473901354

Russian Journal of Organic Chemistry, Vol. 37, No. 6, 2001, pp. 869 880. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 6, 2001,
pp. 915 926.
Original Russian Text Copyright 2001 by Burgart, Kuzueva, Pryadeina, Kappe, Saloutin.
Fluorocontaining 1,3-Dicarbonyl Compounds in the Synthesis
of Pyrimidine Derivatives
Ya. V. Burgart1, O. G. Kuzueva1, M. V. Pryadeina1, C. O. Kappe2, and V. I. Saloutin1
1Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences, Yekaterinburg, 620219 Russia
2Institue of Organic Chemistry, Graz University, Austria
Received July 9, 1999
Abstract Hexafluoroacetylacetone reacts with urea (thiourea) to yield respectively 4,6-bis(hydroxy)-4,6-
bis(trifluoromethyl)hexahydropyrimidin-2-one(thione). The dehydration of the products and also reaction of
nonsymmetrical fluoroalkyl-containing 1,3-diketones with urea (thiourea) afford substituted pyrimidines. The
condensation of fluorinated 3-oxoesters and 1,3-diketones with benzaldehyde and urea (thiourea) results in
5-alkoxycarbonyl(acyl)-4-hydroxy-2-oxo(thioxo)-6-phenyl-4-fluoroalkylhexahydropyrimidines that on de-
hydration furnish 5-alkoxycarbonyl(acyl)-2-oxo(thioxo)-4-phenyl-6-fluoroalkyltetrahydropyrimidines. Ethyl
7-nonafluorobutyl-5-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidine-6-carboxylate hydrobromide forms in reac-
tion of dibromoethane with ethyl ether of 2-thioxo-4-phenyl-6-nonafluorobutyltetrahydropyrimidine.
Pyrimidines and their derivatives play important
part in the functions of the human body. Pyrimidine
structural fragment is included into quite a number of
natural substances (nucleic acids, vitamin B1), into
synthetic medicinals (barbiturates), into chemo-
therapeutic preparations (fluorouracil) [1]. The
biological activity of pyrimidine derivatives attracts
great interest to their synthesis. In preparation of
pyrimidines are widely used reactions of 1,3-di-
carbonyl compounds (e.g. ethyl acetoacetate, acetyl-
acetone) with urea, thiourea, guanidine etc [1]. An
alternative way of building up pyrimidine molecules
proceeding from 1,3-dicarbonyl compounds is
Biginelli reaction, cyclocondensation of 3-oxoester
with aldehydes and compounds of urea type [2].
processes occur both in the presence of catalytic
quantities of hydrochloric acid and with no acid
catalyst. Formerly in [8] was stated that no reaction
between hexafluoroacetylacetone with urea was
possible.
Hexahydropyrimidines IIIa, b can exist as two
diastereomers (cis- and trans-isomers).
1
The character of the resonance in the H NMR
spectrum of compound IIIa of nonequivalent dia-
stereotopic methylene protons appearing as an
AB-system with the geminal coupling constant
13.7 Hz (Table 2) and a single singlet peak of the
trifluoromethyl group in the 19F NMR spectrum
evidence that heterocycle IIIa is present exclusively
as cis-isomer.
We report here on the synthesis of pyrimidine
derivatives proceeding from fluoroalkyl-containing
1,3-diketones (I) and 3-oxoesters (II). Whereas the
reactions of fluorinated 3-oxoesters with compounds
of urea type are relatively well studied [3], the data
on such processes involving 1,3-diketones are limited
to interactions of nonsimmetrical trifluoromethyl-
substituted 1,3-diketones with urea [4]. In [5] the
isolation of pyrimidines from the reaction products
of fluoroalkyl-containing 1,3-diketones and urea was
considered impossible. In Biginelli condensation was
tested only ethyl trifluoroacetoacetate [6, 7].
1
In the H and 19F NMR spectra of compound IIIb
appear two sets of signals indicating the presence of
two isomers (Table 2). The methylene protons signals
in the H NMR spectrum (AB-system with the coupl-
ing constant 13.9 Hz for the cis-isomer and a
broadened singlet for the trans-isomer) distinguish
the isomers and permit evaluation of their ratio. Thus
unlike the carbonyl analog IIIa hexahydropyrimidine-
2-thione (IIIb) exists as cis- and trans-isomers mix-
ture in 3: 1 ratio. We failed to separate the isomers
and isolate them in a pure state.
1
We found that at boiling in ethanol hexafluoro-
acetylacetone (Ia) reacted with urea and thiourea to
afford the corresponding hexahydropyrimidines
IIIa, b (Scheme 1, Tables 1, 2). Note that these
To establish the position of the fluoroalkyl group
in the cis-isomer we take into account the known fact
that the substituent of higher conformational energy
displaces the neighboring group into the axial position
1070-4280/01/3706-0869$25.00 2001 MAIK Nauka/Interperiodica

870
BURGART et al.
Table 1. Elemental analysis of compounds IIIa, b, IVa d, Va h, VIa i, VIIIa, b, IXa, b, X
Found, %
F
Calculated, %
Compd.
no.
Formula
C
H
N
S
C
H
F
N
S
IIIa
IIIb
IVa
IVb
IVc
IVd
Va
Vb
Vc
Vd
Ve
26.98
25.28
31.05
29.21
52.91
37.20
59.39
48.13
43.25
42.34
46.21
41.45
40.98
48.18
57.44
50.39
51.49
59.23
55.25
49.05
56.95
43.74
41.99
43.93
2.31
2.05
0.83
1.09
2.67
2.76
5.17
4.16
3.14
3.13
4.12
3.23
3.13
4.32
4.12
4.27
4.28
4.05
4.06
4.14
3.84
2.82
2.75
2.86
2.79
3.68
3.52
2.74
42.62 10.45
40.16 10.17 11.28
49.32 11.90
45.91 11.36
27.73 10.00
C6H6F6N2O3
C6H6F6N2O2S
C6H2F6N2O
C6H2F6N2S
C12H8F4N2O
C7H6F4N2S
C14H16F2N2O4
C14H14F4N2O4
C15H13F7N2O4
26.88 2.26
25.36 2.13
31.05 0.87
29.04 0.81
52.95 2.96
37.17 2.67
53.50 5.13
48.00 4.03
43.07 3.13
42.29 3.21
45.90 3.85
41.48 3.02
40.97 3.03
48.27 4.34
57.58 4.07
50.30 4.22
51.66 4.34
59.34 4.15
55.34 3.91
49.05 4.12
56.84 3.97
43.83 2.83
41.94 2.71
43.98 2.82
42.51 2.73
60.32 3.73
57.86 3.58
42.51 10.45
40.11 9.86 11.28
49.11 12.07
45.94 11.29
27.92 10.29
33.17 12.20 13.95
33.60 12.38 14.17
12.44
22.14
31.91
35.45
20.38
30.62
34.26
16.34
19.12
22.74
18.85
15.69
18.54
17.83
14.76
32.14
30.74
36.91
35.62
19.85
19.04
29.13
8.65
8.06
6.70
5.81
7.65
6.68
5.67
8.01
7.04
8.43
9.28
7.54
6.69
12.09
21.70
31.80
35.53
20.74
30.62
34.21
16.36
19.17
22.73
18.86
15.64
18.43
17.91
14.98
32.00
30.62
36.83
35.60
20.09
19.27
29.11
8.91
8.00
6.70
5.96
7.65
6.42
5.62
8.04
7.07
8.38
9.27
7.69
6.79
C17H15F9N2O4
8.65 C14H14F4N2O3S
7.34 C15H13F7N2O3S
6.48 C17H15F9N2O3S
C14H15F3N2O3S
C19H16F4N2O3
8.75
7.38
6.43
Vf
Vg
Vh
VIa
VIb
VIc
VId
VIe
VIf
VIg
VIh
VIi
VIIIa
C14H14F4N2O3
C13H13F3N2O3
C18H15F3N2O3
7.70 C19H16F4N2O2S
7.77
8.78 10.14
C13H13F3N2O2S
8.47 C18H15F3N2O2S
C13H10F6N2O3
8.35 C13H10F6N2O2S
C17H13F9N2O3
6.67 C17H13F9N2O2S
C19H14F4N2O2
8.80 10.07
7.36
7.93
7.56
6.14
5.87
7.50
7.04
4.75
7.36
7.86
7.52
6.03
5.83
7.40
7.10
4.77
8.43
8.61
6.67
VIIIb 42.68
IXa
IXb
X
60.07
57.70
38.85
C19H14F4N2OS
5.48 C19H15F9N2O2S HBr 38.86 2.75
5.46
[9].
Therefore
trifluoromethyl
group
( G
fluorinated substituent Ib, c react with urea and
thiourea at boiling in ethanol in the presence or in
the absence of acid catalyst to afford pyrimidines
IVc, d (Scheme 1, Tables 1, 2).
1
8.8 kJ mol ) takes the equatorial position, and the
hydroxy group ( G 2.2 kJ mol ) the axial one
(Figs. 1, 2).
1
Both literature data [4] and our own experiments
show that unlike hexafluoroacetylacetone (Ia) the
Pyrimidines IVa, b with two trifluoromethyl
substituents can only be obtained from the, cor-
responding hexahydropyrimidines IIIa, b by boil-
nonsymmetrical 1,3-diketones with
a
single
Fig. 1. Conformational structure of 4,6-bis(hydroxy)-4,6-
bis(trifluoromethyl)hexahydropyridin-2-one (IIIa).
Fig. 2. Conformational structure of 4,6-bis(hydroxy)-4,6-
bis(trifluoromethyl)hexahydropyridine-2-thione (IIIb).
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FLUOROCONTAINING 1,3-DICARBONYL COMPOUNDS
871
Table 2. Yields, melting points, and spectral characteristics of compounds IIIa, b, IVa d, Va h, VIa i, VIIIa, b,
IXa, b, X)
1
Compd. mp,
no.
Yield,
%
IR spectrum, , cm
C
IIIa
211 212 82(a), 3290, 3130, 1590 (NH, OH), 1660 (C=O amide), 1200 1140 (C F)
44(b),
36(c)
IIIb
IVa
IVb
IVc
164 165 56 3290, 3180, 1555 (NH, OH), 3080 (C H stretch.), 1230 1150 (C F)
133 135 68 3290, 3210, 3120, 1620 (NH), 1665 (C= amide), 1580 (C=C, C=N conjug.), 1290 1150
62 (C F) 3090 (C H stretch.), 1580, 1555 (C=N, C=C conjug.), 1300 1100 (C F)
178 179 34 3320, 3140, 1600 (NH), 3070 (C H stretch.), 1660 (C=O amide.), 1570 (C=C conjug.),
1240 1080 (C F)
136 137 32 3170 2870 (SH, C H stretch.), 1585, 1560 (C=N, C=C conjug.)
204 205 75 3315, 3200, 1585 (NH, OH), 3090 (C H stretch.), 1720 (CO2Et), 1665 (C=O), 1500
(C= conjug.), 1170 1070 (C F)
50 51
IVda
Va
Vb
Vc
190 192 79 3440, 3220, 1585 (NH, OH), 3055 (C H stretch.), 1740 (CO2CH3), 1660 (C=O), 1500 (C=C
conjug.), 1160 1090 (C F)
204 205 73 3450, 3205, 1630 sh. (NH, OH), 3080 (C H stretch.), 1740 (CO2CH3), 1670 (C=O), 1490
(C=C conjug.), 1230 1100 (C F)
Vd
191 192 80 3420, 3190, 1620 sh. (NH, OH), 3075 (C H stretch.), 1720 (CO2Et), 1675 (C=O), 1630 sh
(C=C conjug.), 1220 1090 (C F)
Ve
212 213 50 3400, 3200, 1600 (NH, OH), 3090 (C H stretch.), 1735 (CO2CH3), 1580, 1565, 1500 (C=C
conjug.), 1220 1100 (C F)
Vf
215 217 47 3440, 3200, 1600 (NH, OH), 3100 (C H stretch.), 1740 (CO2CH3), 1585, 1565, 1490
(C=C conjug.), 1280 1170 (C F)
Vg
212 213 45 3440, 3185, 1600 (NH, OH), 3100 (C H stretch.), 1730 (CO2Et), 1580, 1500 (C=C conjug.),
1230 1130 (C F)
Vh
190 191 43 3430, 3190, 1600 (NH, OH), 3100 (C H stretch.), 1735 (CO2Et), 1570 (C=C conjug.),
1260 1170 (C F)
VIa
VIb
VIc
VId
VIe
VIf
VIg
VIh
VIi
233 234 38 3430, 3190, 1590 (NH, OH), 3050 (C H stretch.), 1675 (C=O ket.), 1660 (C=O amide.),
1490 (C=C conjug.), 1140 1100 (C F)
184 185 33 3450, 3390, 3210, 1590 (NH, OH), 3090 (C H stretch.), 1700 (C=O ket.), 1690 (C=O
amide), 1480 C=C conjug.), 1160 1110 (C F)
180 182 32 3400, 3390, 3220, 1610 (NH, OH), 3080, 3050 (C H stretch.), 1720, 1705 (C=O ket.), 1680,
1660 (C=O amide), 1500 (C=C conjug.), 1190 1170 (C F)
204 205 42 3430, 3190, 1590 (NH, OH), 3060 (C H stretch.), 1675 (C=O ket.), 1660 (C=O amide),
1500 (C=C conjug.), 1200 1175 (C F)
233 234 36 3440, 3190, 1595 (NH, OH), 3100 (C H stretch.), 1680 (C=O ket.), 1560, 1500
(C=C conjug.), 1220 1150 (C F)
211 212 22 3380, 3260, 3160, 1580 (NH, OH), 3050 (C H stretch.), 1690 (C=O ket.), 1550, 1500
(C=C conjug.), 1240 1160 (C F)
229 230 30 3430, 3180, 1585 (NH, OH), 3090 (C H stretch.), 1665 (C=O ket.), 1560, 1500
(C=C conjug.), 1250 1120 (C F)
200 201 30 3390, 3200, 1610 (NH, OH), 3060 (C H stretch.), 1745 (C=O ket.), 1660 (C=O amide),
1480 (C=C conjug.), 1200 1100 (C F)
215 216 20 3160, 1580 (NH, OH), 3100 (C H stretch.), 1740 (C=O ket.), 1560, 1510 (C=C conjug.),
1200 1170 (C F)
VIIIa 154 155 56 3270, 3210, 1650 sh. (NH), 3080 (C H stretch.), 1730 (CO2Et), 1690 (C=O ket.), 1670
(C=C conjug.), 1240 1140 (C F)
VIIIb 137 138 48 3295, 3180, 1580 sh. (NH), 3100 (C H stretch.), 1710 (CO2Et), 1670 (C=O amide.), 1560
(C=C conjug.), 1220 1130 (C F)
IXa
IXb
Xb
152 153 44 3235, 1600 (NH), 3100 (C H stretch.), 1710 (C=O ket.), 1675 (C=O amide.), 1660
(C=C=C), 1490(C=C conjug.), 1170 1100 (C F)
123 124 40 3150, 1590 (NH), 3090 (C H stretch.), 1665 (C=O ket.), 1650 (C=C), 1570 (C=C conjug.),
1210 1100 (C F)
218 220 42 2770, 2745, 2700 (N+ H), 1730 (CO2Et), 1660, 1500 (C=C, C=N conjug.), 1240 1140 (C F)
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872
BURGART et al.
Table 2. (Contd.)
Compd.
no.
1H NMR spectrum, , ppm, J, Hz
19F NMR spectrum, F, ppm, J, Hz
IIIa
IIIb
2.15
m
(2H, H5aH5e, AB-system,
18.28, J 13.7), 6.94 78.60 s (6F, 2CF3)
cis/trans 3/1
7.97 2s (4H, 2NH, 2OH)
cis/trans 3/1
cis: 2.21
m
(2H, H5aH5e, AB-system,
24.00,
J
13.9), cis: 79.56 s (6F, 2CF3)
trans: 80.52 s (6F, 2CF3)
7.32, 9.50 2s (4H, 2NH, 2OH)
trans: 2.38 s (2H, H5aH5e), 7.38, 9.24 2s (4H, 2NH, 2OH)
7.91 s (1H, H5), 13.74 br.s (1H, NH)
IVa
IVb
IVc
93.65 s (2CF3)
93.72 s (2CF3)
7.21 br.s (1H, SH), 8.48 s (1H,H5)
6.88 t.t [1H. H(CF2)2, JHF 51.8, JHF 5.6], 7.62 s (1H, H5), 7.54 24.37 d.t (2F, HCF2CF2, 2JFH 51.8, 3JFF 7.9),
2
3
3
3
8.21 m (5H, C6H5), 12.77 br.s (1H, NH)
42.36 m (2F, HCF2CF2, JFF 7.9, JFH 5.6)
IVda
Va
2.61 s (3H, CH3), 6.65 t.t [1H, H(CF2)2, JHF 51.6, JHF 6.0], 7.13 s
2
3
(1H, H5), 11.40 br.s (1H, SH)
0.87 t (3H, OCH2CH3, J 7.0), 2.92 d (1H, H5, J 11.6), 3.82 q (2H, 30.38 m (2F, HCF2, AB-system,
236.0,
OCH2CH3, J 7.0), 4.80 d (1H, H6, J 11.6), 5.88 t (1H, HCF2, JHF JFF 274.9, JFH 55.2)
2
2
55.2), 7.33 s (5H, C6H5), 6.67, 7.00, 7.15 3s (3H, 2NH, OH)
Vb
3.00 d (1H, H5, J 11.1), 3.27 s (3H, OCH3), 4.79 d (1H, H6, J 11.1), 27.57 m(2F, HCF2CF2, AB-system),
2
3
6.70 t.t [1H, H(CF2)2, HHF 51.4, JHF 5.1], 7.32 s (5H, C6H5), 35.14 m (2F, HCF2CF2, AB-system,
2
7.10 s (1H, OH), 7.20 s (2H, 2NH)
166.12, JFF 266.0)
Vc
Vd
3.04 d (1H, H5, J 11.0), 3.28 s (3H, OCH3), 4.81 d (1H, H6, J 11.0), 40.39 m (2F, CF2), 43.76 m (2F, CF2),
7.33 s (5H, C6H5), 7.17, 7.53, 7.61 3s (3H, 2NH, OH)
82.26 m (3F, CF3)
0.78 t (3H, OCH2CH3, J 7.1), 3.03 d (1H, H5, J 11.1), 3.74 q (2H, 37.25 m (2F, CF2), 44.66 43.51 m (4F,
OCH2CH3, J 7.1), 4.81 d (1H, H6, J 11.1), 7.33 s (5H, C6H5), 5.39, 2CF2), 82.42 m (3F, CF3)
7.11, 7.48 3s (3H, 2NH, OH)
Ve
3.09 d (1H, H5, J 11.7), 3.28 s (3H, OCH3), 4.81 d (1H, H6, J 11.7), 27.46 m (2F, HCF2CF2, AB-system),
2
3
6.79 t.t [1H, H(CF2)2, JHF 51.4, JHF 6.6], 7.33 c (5H, C6H5), 35.76 m (2F, HCF2CF2, AB-system)
7.73, 8.31, 9.19 3s (3H, 2NH, OH)
Vf
3.14 d (1H, H5, J 11.3), 3.30 s (3H, OCH3), 4.83 d (1H, H6, J 11.3), 40.38 m (2F, CF2), 44.05 m (2F, CF2),
7.34 s (5H, C6H5), 8.13, 9.35 2s (3H, 2NH, OH)
82.35 m (3F, CF3)
Vg
0.81 t (3H, OCH2CH3, J 7.1), 3.13 d (1H, H5, J 11.5), 3.78 q (2H, 37.08 m (2F, CF2), 43.73 m (2F, CF2),
OCH2CH3, J 7.1), 4.84 d (1H, H6, J 11.5), 7.35 s (5H, C6H5), 7.90, 44.86 m (2F, CF2), 82.33 m (3F, CF3)
7.98, 9.24 3s (3H, 2NH, OH)
Vh
0.81 t (3H, OCH2CH3, J 7.1), 3.02 d (1H, H5, J 11.8), 3.79 q (2H, 82.30 s (CF3)
OCH2CH3, J 7.1), 4.79 d (1H, H6, J 11.8), 7.34 s (5H, C6H5), 7.88,
8.89, 9.09 3s (3H, 2NH, OH)
VIa
4.65 m (2H, H5H6, AB-system,
47.45, J 11.0), 6.72 t.t [1H, 27.79 · (2F, HCF2CF2, AB-system,
2
3
H(CF2)2, JHF1,2 51.3, JHF3,4 6.7], 7.04 7.46 m (10H, 2C6H5), 7.54, 159.34, 2JF1
2
300.0, 2JF1,2
51.3,
F
H
7.62 2s (3H, 2NH, OH)
3JF1,2 3,4 7.6), 38.11 m (2F, HCF2CF2, AB-
F
system)
VIb
1.80 s (3H, CH3), 3.10 d (1H, H5, J 11.4), 4.82 d (1H, H6, J 11.4), 27.64 m (2F, HCF2CF2, AB-system),
2 3
6.71 t.t [1H, H(CF2)2, JHF1,2 51.5, JHF3,4 6.8], 7.21, 7.28 2s (3H, 36.69 m (2F, HCF2CF2, AB-system,
2
3
3
2NH, OH), 7.34 s (5H, C6H5)
116.83, JF3 4 267.0, JF3,4 6.8, JF3,4 1,2
F H F
7.6)
VIc
VId
VIe
1.88 s (3H, CH3), 3.11 d (1H, H5, J 11.6), 4.84 d (1H, H6, J 11.7), 82.04 s (CF3)
7.35 s (5H, C6H5), 7.19, 7.52, 7.61 3s (3H, 2NH, OH)
4.68 m (2H, H5H6, AB-system,
47.94, J 11.1), 7.10 7.40 m (10H, 82.71 s (CF3)
2C6H5), 7.60, 7.72 2s (3H, 2NH, OH)
4.72 m (2H, H5H6, AB-system,
41.79, J 11.5), 6.84 t.t [1H, 27.50 m (2F, HCF2CF2, AB-system),
2
3
H(CF2)2, JHF1,2 51.5, JHF3,4 6.0], 7.09 7.58 m (10H, 2C6H5), 7.66, 38.65 m (2F, HCF2CF2, AB-system,
80.22, 2JF3 4 264.4, 3JF3,4 6.0, JF3,4 1,2
3
8.30, 9.20 3s (3H, 2NH, OH)
F
H
F
7.3)
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 6 2001

FLUOROCONTAINING 1,3-DICARBONYL COMPOUNDS
873
Table 2. (Contd.)
Compd.
no.
1H NMR spectrum, , ppm, J, Hz
19F NMR spectrum, F, ppm, J, Hz
VIf
VIg
VIh
VIi
1.89 s (3H, CH3), 3.19 d (1H, H5, J 11.8), 4.86 d (1H, H6, J 11.8), 82.90 s (CF3)
7.35 s (5H, C6H5), 8.02, 8.96, 9.09 3s (3H, 2NH, OH)
4.75 m (2H, H5H6, AB-system,
38.80, J 11.5), 7.15 7.70 m 83.61 c (CF3)
(10H, 2C6H5), 7.75, 8.95, 9.09 3s (3H, 2NH, OH)
3.83 d (1H, H5, J 11.5), 4.88 d (1H, H6, J 11.5), 7.34 s (5H, C6H5), 81.17 q (3F, CF3, J 5.3), 84.03 q (3F,
7.44, 7.95, 8.09 3s (3H, 2NH, OH) CF3, J 5.3)
3.97 d (1H, H5, J 11.5), 4.89 d (1H, H6, J 11.5), 7.35 s (5H, C6H5), 82.59 q (3F, CF3, J 5.4), 84.59 q (3F,
8.38, 9.29, 9.46 3s (3H, 2NH, OH) CF3, J 5.4)
VIIIa 1.03 t (3H, OCH2CH3CH3, J 7.1), 4.00 q (2H, OCH2CH3, J 7.1), 36.92 m (2F, CF2), 42.85 m (2F, CF2),
5.25 br.s (1H, H4), 7.34 m (5H, C6H5), 7.96 br.s (1H, NH), 9.60 s 52.62 m (2F, CF2), 82.25 m (3F, CF3)
(1H, NH)
VIIIb 1.08 t (3H, OCH2CH3, J 7.1), 4.07 q (2H, OCH2CH3, J 7.1), 5.25 d 36.85 m (2F, CF2), 42.88 m (2F, CF2),
3
3
(1H, H4, J 3.1), 7.21 7.46 m (5H, C6H5), 9.20 d (1H, NH, J 3.1), 52.86 m (2F, CF2), 82.19 m (3F, CF3)
10.71 s (1H, NH)
2
3
IXa
5.13 br.s (1H, H4), 6.65 m [1H, H(CF2)2, JHF1,2 52.0, JHF3 7.4, 25.08 d.t (2F, HCF2CF2, 2JF1,2 52.0,
H
3JHF4 4.6], 7.18 7.65 m (10H, 2C6H5), 7.86, 9.43 2 br.s (2H, 2NH) 3JF1,2 3,4 7.9), 46.04 m (2F, HCF2CF2, AB-
F
2
3
system,
363.30, JF3 4 269.6, JF3,4 1,2
F F
7.9, 3JF3 7.4, 3JF4 4.6)
H
H
2
3
IXb
Xb
5.10 br.s (1H, H4), 6.76 t.t [1H, H(CF2)2, JHF 51.9, JHF 6.0], 24.75 m (2F, HCF2CF2, AB-system),
7.20 7.67 m (10H, 2C6H5), 9.70, 10.67 2 br.s (2H, 2NH)
1.11 t (3H, OCH3CH3, J 7.0), 3.71 m (2H, H2aH2e, J 6.5), 4.17 q
(2H, OCH2CH3, J 7.0), 4.58 m (2H, H3aH3e, J 6.5), 5.92 s (1H, H5),
7.50 m (5H, C6H5)
46.90 m (2F, HCF2CF2, AB-system)
a
1H NMR spectrum of compound IVd was recorded in acetone-d6.
1H NMR spectrum of compound X was recorded in CF3COOD.
b
ing the latter in toluene in the presence of p-toluene-
sulfonic acid while eliminating the arising water with
azeotrope (Scheme 1, Tables 1, 2).
compounds IVa d exist as one of the possible
tautomers. Analysis of the IR spectra of compounds
IVa, c where are present strong bands at 3440
1
3120 cm characteristic of amino group stretching
Fluoroalkyl-containing 2-mercaptopyrimidines, in
particular heterocycle IVd, were prepared before
from lithium salts of 1,3-diketones [5], and the
possibility to obtain the compounds from the free
ligands was deemed impossible.
vibrations, and also absorption bands at 1670
1
1660 cm corresponding to carbonyl group of amide
moiety suggest that the lactam structure of the
heterocycles is more favored.
Compounds IVa d may undergo lactam-lactim
tautomerism. These compounds can exist as dihydro-
pyrimidine-2-one(thione) (A) or as 2-hydroxy-
(mercapto)pyrimidine (B), or as a tautomers mixture.
Since in the IR spectra of compounds IVb, d
the vibration bands of amino groups in the high
frequency region are lacking and since the thio-
carbonyl compounds are known to be prone to tauto-
meric transformations [10] compounds IVb, d
apparently exist as pyrimidine B. We did not
succeed in more definite assignment of the pyrimidine
structure.
The study of Biginelli condensation in the series of
fluoroalkyl-containing 1,3-dicarbonyl compounds
revealed that in contrast to the nonfluorinated analogs
the fluoro-containing 3-oxoesters IIa e and 1,3-
diketones Ib e at boiling with urea or thiourea and
X = O, S.
However in the H and 19F NMR spectra appears
a single set of signals (Table 2) indicating that
1
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 6 2001

874
BURGART et al.
Scheme 1.
benzaldehyde in ethanol in the presence of catalytic
amounts of hydrochloric acid in 5 6 h give rise to
compounds Va h, VIa g (Scheme 2, Tables 1, 2).
These products may have either a structure of cyclic
hexahydropyrimidine (C) or open-chain derivative of
ureidopropionate (D). The elemental analyses of these
compounds are identical. The latter substance is
prone to keto-enol tautomerism and thus it may exists
enol (De), ketone (Dk), or as tautomers mixture.
absorption bands of hydroxy substituent at 3450
3315 cm in C structure.
1
1
The presence in the H NMR spectra of com-
pounds Va h, VIa g ot two doublets corresponding
to two methine protons (2.92 4.89 ppm) totally
excludes the enol structure De. The calculated
coupling constants (J 11 11.8 Hz) confirm the cyclic
structure of the products since the vicinal coupling
constants for open-chain saturated hydrocarbons are
commonly equal to 6 8 Hz [11].
The cyclic structure of compound Vh described
in [7] as ureidopropionate was finally proved by
13C NMR spectroscopy: In the spectrum was present
Scheme 2.
1
A single set of signals in the H and 19F NMR
spectra of compounds Va h, VIa g (Table 2)
evidences that the substances exist in a single struc-
tural form.
In [7] was described the formation of an open-
chain ureidopropionate (Dk, Rf=CF3, R=OEt) in
reaction of ethyl trifluoroacetylacetate, benzaldehyde,
and thiourea. Compound Vh that we isolated after
this reaction had a melting point and spectral char-
acteristics similar to those published in [7].
RF = HCF2, R = OEt (IIa) X = O (Va); RF =
H(CF2)2, R = OMe (IIb), X = O (Vb), S (Ve); RF =
C3F7, R = OMe (IIc), X = O (Vc), S (Vf); RF =
C4F9, R = OEt (IId), X = O (Vd, VIIIa), S (Vg,
VIIIb); RF = CF3, R = OEt (IIe), X= S (Vh); RF =
H(CF2)2, R = Ph (Ib), X = O (VIa, IXa), S (VIe,
IXb); RF = H(CF2)2, R = Me (Ic), X = O (VIb);
RF = CF3, R = Me (Id), X= O (VIc), S (VIf); RF =
CF3, R = Ph (Ie), X = O (VId), S (VIg).
In the IR spectra of compounds Va h, VIa g are
lacking two narrow absorption bands corresponding
to asymmetrical and symmetrical stretching vibrations
of NH2 belonging to Dk, De structures and a weak
band from enol hydroxy group of De form. At the
same time in the spectra appear strong broadened
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FLUOROCONTAINING 1,3-DICARBONYL COMPOUNDS
875
Table 3. 13C NMR spectra, C, ppm [J(13C 19F), Hz] of compounds Vh, VIc in DMSO-d6
Compd. no.
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
Vh
177.17 79.61 54.30 60.37 122.84 166.40 49.36 13.36 136.89 128.06 128.31 128.55
(31.13) (288)
164.22 80.69 53.21 57.21 123.21 203.89 30.58 153.72 127.97 128.52 138.04
(30.52) (288)
VIc
Table 4. Charges and Fukui indices on the reaction centers of 1,3-diketones (Ib e) and 3-oxoesters IIa e
Charges (Fukui indices for HOMO/Fukui indices for LUMO)
Compd.
no.
RF
R
C1
C2
C3
Ib
H(CF2)2
H(CF2)2
CF3
Ph
Me
+0.4023
(0.0000/0.1937)
+0.3503
(0.0004/0.1899)
+0.3501
0.3474
(0.0559/0.0639)
0.3474
(0.4799/0.1681)
0.3401
+0.1170
(0.0227/0.2147)
+0.1162
(0.1912/0.3830)
+0.1085
Ic
Id
Me
(0.0003/0.1892)
+0.4018
(0.4748/0.1770)
0.3389
(0.1937/0.3912)
+0.1095
Ie
CF3
Ph
(0.0000/0.1960)
+0.4418
(0.0004/0.1619)
+0.4362
(0.0003/0.1491)
+0.4354
(0.0002/0.1043)
+0.4405
(0.0124/0.0737)
0.3004
(0.4848/0.1979)
0.2891
(0.4791/0.2082)
0.2846
(0.4745/0.1896)
0.2822
(0.0052/0.2279)
+0.1015
(0.1960/0.4181)
+0.1036
(0.1985/0.4134)
+0.1003
(0.1938/0.3295)
+0.1054
IIa
IIb
IIc
IId
IIe
HCF2
H(CF2)2
C3F7
OEt
OMe
OMe
OEt
OEt
C4F9
(0.0001/0.1368)
+0.4411
(0.4724/0.2230)
0.2920
(0.1980/0.4124)
+0.1036
CF3
(0.0001/0.1440)
(0.4754/0.2161)
(0.1921/0.4220)
a quartet signal of carbon atom attached to the tri-
fluoromethyl group (2JC F 31.1 Hz) in the region
characteristic of quaternary carbons [12] (Table 3).
imidine for the products of the above reactions. The
hexahydropyrimidine structure of compounds Va h,
VIa g may be considered as unambiguously
determined, the more so as for the only earlier
obtained trifluoromethyl-substituted analog it was
solved by the X-ray diffraction analysis [6].
Thus the combined IR and NMR spectral data
confirm the cyclic C structure of hexahydropyr-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 6 2001

876
BURGART et al.
Scheme 3.
It should be noted that 2-methyl-substituted ethyl
the maximal value for C3 carbon bonded to the
fluorinated substituent. Therefore at the kinetic
control of the process the predominant place of
nucleophile attack should be C1 atom due to the
charge distribution; at the orbital control the reaction
should occur at C3.
trifluoroacetylacetate does not enter into condensation
with benzaldehyde and urea apparently due to steric
hindrances.
At the use in the Biginelli reaction of nonsymmetrical
1,3-diketones as 3-oxoester component the cyclization
The NMR spectra registered from compounds
VIa g contain a single set of signals. We chose for
the compounds E structure basing on the 13C NMR
spectrum of compound VIc: In this spectrum the
quartet signal from the carbon atom linked to the
trifluoromethyl group (2JC F 30.52 Hz) appeared in
the region characteristic of quaternary carbon and not
of carbonyl carbon [12] as should have been in F
structure (Table 3).
RF
= CF3, H(CF2)2; R = Me, Ph.
Thus the fluoroalkyl-containing 1,3-diketones in
the Biginelli reaction behave as fluorinated 3-oxo-
esters affording substituted hexahydropyrimidines,
and cyclocondensation occurs regioselectively at the
carbonyl group adjacent to the fluoroalkyl substituent
that corresponds to orbital and not charge control of
the reaction. Unlike the above described reactions of
into a pyrimidine ring may occur in two ways: The
condensation can either proceed at the carbonyl group
at the fluorinated substituent or at the carbonyl linked
to the nonfluorinated radical affording respectively
products E and F or their mixture.
The published data on condensation of nonsym-
metrical 1,3-diketones with one fluorinated substitu-
ent with amines (ammonia, primary amines, poly-
alkylenepolyamines show that the reaction is
predominantly directed on the carbonyl neighboring
3-oxoesters
IIa e
and
1,3-diketones
Ib e
hexafluoroacetylacetone (Ia) in Biginelli reaction with
benzaldehyde and urea at boiling in ethanol with
hydrochloric acid as catalyst yields substituted
hexahydropyrimidin-2-one IIIa (Scheme 3, Tables 1,
2). The structure of the latter compound results
apparently from reaction competing with Biginelli
condensation where hexafluoroacetylacetone reacts at
both carbonyl groups with amino groups of urea
without benzaldehyde participation.
to the nonfluorinated radical [3]. This fact is due to
+
induction of higher
on the remote carbonyl and
not on that near the fluorinated substituent. The latter
statement is supported by our quantum-chemical
calculations (Table 4) performed by MNDO proce-
dure [13]. According to calculations the highest
positive charge in fluoroalkyl-containing 1,3-di-
ketones I and 3-oxoesters II is located on C1 carbon
that in 1,3-diketones is linked to the nonfluorinated
substituent, and in 3-oxoesters belongs to the ester
moiety. Fukui indices for the lowest unoccupied
molecular orbital (LUMO) in all compounds have
A characteristic reaction of 1,3-diketones with two
fluorinated substituents is water or alcohol addition at
both carbonyl groups resulting in stable geminal
adducts (tetraols and bis-semiketals) [3]. Obviously
the hexafluoroacetylacetone under the reaction
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FLUOROCONTAINING 1,3-DICARBONYL COMPOUNDS
877
conditions (in alcohol water mixture) forms bis-
Scheme 4.
semiketal (or tetraol) (J) that no more contains an
activated methylene group and cannot react with
benzaldehyde, only with urea to afford heterocycle
IIIa (Scheme 3).
The assumed reaction path was indirectly sup-
ported by the behavior in Biginelli reaction of
2,2,4,4-tetrahydroxy-1,1,1,5,5,5-hexafluoropentane
(VII) that we studied. As expected, tetraol VII did
not react with benzaldehyde but condensed with urea
to furnish hexahydropyrimidine IIIa (Scheme 3).
X = O (VIh), S (VIi).
registered in DMSO-d6 is present a single set of
resonances (Table 2). In the IR spectrum of com-
pound VIc recorded from 0.1 M solution in chloro-
form also appears a single set of absorption bands
The assumed mechanism was also consistent with
the fact that in reaction of hexafluoroacetylacetone
(Ia) with urea and benzaldehyde under anhydrous
conditions in an aprotic solvent (tetrahydrofuran) in
the presence of catalytic amounts of p-toluenesulfonic
acid we separated product VIh (Scheme 4, Tables 1,
2) with hexahydropyrimidine structure of C type.
1
belonging to amide fragment (3220, 1660 cm ),
1
1
hydroxy (3400 cm ) and acetyl (1680 cm ) groups.
Presumably unlike the other hexahydropyrimidines
compound VIc exists as a mixture of two diastereo-
mers in the solid state and as one isomer in solution.
The experimental data obtained show that replace-
ment in the Biginelli condensation of the nonfluorin-
ated 3-oxoester component by 1,3-dicarbonyl com-
pounds with partially or fully fluorinated substituent
results in exclusive formation of derivatives of hexa-
hydropyrimidines Va h, VIa i. The formation of
stable hydrated heterocycles is characteristic of reac-
tions between fluorinated 2-substituted 1,3-dicarbonyl
compounds with dinucleophilic reagents [15], and it
is caused by the presence of a strong electron-acceptor
substituent.
The reaction of hexafluoroacetylacetone with
thiourea and benzaldehyde under classical conditions
of Biginelli condensation (ethanol, HCl) unlike that
with urea results in a traditional product VIi
(Scheme 4, Tables 1, 2). Apparently here the cyclo-
condensation by Biginelli occurs faster that the
concurrent reaction of thiourea addition to both
carbonyl groups of the 1,3-diketone. This fact may be
due to the higher basicity of thiourea (pKb 11.97) as
compared to that of urea (pKb 13.82) [14].
Since in the structure C of hexahydropyrimidine
are present three asymmetrical carbon atoms com-
pounds Va h, VIa i may exist as four possible
diastereomers (and additionally four enantiomeric
forms thereof). However the NMR spectra show that
in each case exists a single diastereomer (apparently
racemic one). The large conformational energies of
the phenyl and alkoxycarbonyl (acyl) groups ( GC F
On boiling compounds Vd, g and VIa, e in toluene
in the presence of p-toluenesulfonic acid at azeotrope
distillation of the forming water occurs the dehydra-
tion thereof to afford tetrahydropyrimidines VIIIa, b,
IXa, b (Scheme 2, Tables 1, 2).
We demonstrated the possibility to build up bi-
cyclic heterocyclic systems proceeding from the
fluorinated tetrahydropyrimidines. For instance,
tetrahydropyrimidine VIIIb on boiling in DMF with
6 5
12.1 kJ mol and GCO 43Et 5.2 kJ mol 1 respective-
ly) favor fixed conforma2tions where these groups take
equatorial orientation [9]. This is evidenced also by
the calculated value of the coupling constants (11.0
11.8 Hz) corresponding to the axial coupling of the
protons from these substituents. The comparison of
the conformational energies of substituents suggests
that the fluoroalkyl substituent is in equatorial posi-
1
dibromoethane furnished
a substituted thiazolo-
pyrimidine hydrobromide X (Scheme 5, Tables 1, 2).
Thus we proposed routes to derivatives of
pyrimidine molecular structures from fluoroalkyl-
containing 1,3-dicarbonyl compounds. The products
1
tion (for CF3 G 8.8 kJ mol ), and hydroxy group
1
( G 2.2 kJ mol ) in axial position (Fig. 3).
Interestingly in the IR spectrum of compound VIc
recorded from a mull in the mineral oil two sets of
bands from functional groups are observed apparently
corresponding to two diastereomers (see Table 2).
However in the NMR spectra of the product
Fig. 3. Conformational structure of hexahydropyr-
imidines Va h, VIa i.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 6 2001

878
BURGART et al.
4,6-Bis(hydroxy)-4,6-bis(trifluoromethyl)hexa-
Scheme 5.
hydropyrimidin-2-thione (IIIb). Along procedure a
from 1,3-diketone Ia (416 mg, 2 mmol) and thiourea
(152 mg, 2 mmol) after recrystallization from
dichloromethane was obtained 318 mg of reaction
product IIIb as a colorless powder.
2-Oxo-4, 6-bis(trifluoromethyl)-1,2-dihydro-
pyrimidine (IVa). To a solution of hexahydropyr-
imidine IIIa (536 mg, 2 mmol) in toluene (15 ml)
was added p-toluenesulfonic acid (344 mg, 2 mmol).
The mixture was boiled for 2 h, the forming water
was distilled off in azeotrope. The toluene was
evaporated, and the residue was sublimed. We
obtained 316 mg of compound IVa as colorless
crystals.
obtained besides their own importance can serve as
building blocks for various fused heterocyclic
systems.
EXPERIMENTAL
IR spectra were recorded on spectrophotometer
1
Specord 75 IR in 400 4000 cm range from mulls
2-Mercapto-4, 6-bis(trifluoromethyl)-1,2-di-
hydropyrimidine (IVb). In a similar way from
hexahydropyrimidine IIIb (568 mg, 2 mmol) and
p-toluenesulfonic acid (344 mg, 2 mmol) was
obtained 308 mg of colorless crystalline product IVb.
1
in mineral oil. H NMR spectra were registered on
spectrometer Tesla BS-567 A (80 MHz, reference
TMS), 19F and 13C NMR spectra were measured on
spectrometer Tesla BS-567 A at 75 and 20 MHz
respectively with C6F6 and TMS as references.
Elemental analysis was carried out on Carlo Erba
CHNS-O EA 1108 analyzer.
2-Oxo-4-phenyl-6-(1,1,2,2-tetrafluoroethyl)-1,2-
dihydropyrimidine (IVc). A mixture of 1,3-diketone
Ib (496 mg, 2 mmol) and urea (120 mg, 2 mmol) was
boiled in ethanol (8 ml) containing 2 drops of concn.
HCl for 20 h. Ethanol was evaporated, the residue
was dissolved in dichloromethane, the unreacted urea
was filtered off, and the product was precipitated
from dichloromethane with ethyl ether. As a result we
obtained 185 mg of compound IVc as a colorless
powder.
Quantum-chemical calculations for fluoroalkyl-
containing 1,3-dicarbonyl compounds I, II were
performed by MNDO procedure with the use of
MOPAC 6 software [13].
The yields and physical constants of compounds
synthesized are listed in Tables 1, 2.
4,6-Bis(hydroxy)-4,6-bis(trifluoromethyl)hexa-
hydropyrimidin-2-one (IIIa). (a) A mixture of
1,3-diketone Ia (416 mg, 2 mmol) and urea (120 mg,
2 mmol) was boiled in ethanol (8 ml) containing
2 drops of concn. HCl for 2 h. Ethanol was
evaporated, the residue was washed with chloroform
and a little water. As a result compound IIIa was
obtained in 386 mg amount as a colorless powder.
2-Mercapto-6-methyl-4-(1,1,2,2-tetrafluoro-
ethyl)pyrimidine (IVd). Along procedure a from
1,3-diketone Ic (372 mg, 2 mmol) and thiourea
(152 mg, 2 mmol) without hydrochloric acid additive
was obtained compound IVd that on recrystallization
from ethanol amounted to 145 mg (colorless powder).
Ethyl 4-hydroxy-4-difluoromethyl-2-oxo-6-
(b) A mixture of benzaldehyde (212 mg, 2 mmol),
1,3-diketone Ia (416 mg, 2 mmol), urea (180 mg,
3 mmol), and ethanol (8 ml) containing 2 drops of
concn. HCl was heated to reflux for 6 h. The product
was precipitated from ethanol with water, filtered off,
recrystallized from 50% ethanol, and dried in a
vacuum. We obtained 236 mg of compound IIIa.
phenylhexahydropyrimidine-5-carboxylate
(Va).
Along procedure b a mixture of benzaldehyde
(212 mg, 2 mmol), 3-oxoester IIa (332 mg, 2 mmol),
urea (180 mg, 3 mmol), and ethanol (8 ml) containing
two drops of concn. HCl was heated at reflux for 6 h
and left overnight at 4 C. The separated precipitate
was filtered off, recrystallized from ethanol, and
dried in a vacuum. We obtained 471 mg of compound
Va as a colorless powder.
(c) A mixture of tetraol VII (488 mg, 2 mmol),
benzaldehyde (212 mg, 2 mmol), and urea (120 mg,
2 mmol) was boiled in ethanol (8 ml) containing
2 drops of concn. HCl for 2 h. Ethanol was
evaporated, the residue was recrystallized from 50%
ethanol, and dried. We obtained 193 mg of product
IIIa.
Methyl 4-hydroxy-2-oxo-4-(1,1,2,2-tetrafluoro-
ethyl)-6-phenylhexahydropyrimidine-5-carboxylate
(Vb). In a similar way from benzaldehyde (212 mg,
2 mmol), 3-oxoester IIb (404 mg, 2 mmol), and urea
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 6 2001

FLUOROCONTAINING 1,3-DICARBONYL COMPOUNDS
879
(180 mg, 3 mmol) was obtained 553 mg of reaction
product Vb as a colorless powder.
5-Acetyl-4-hydroxy-4-trifluoromethyl-6-phenyl-
hexahydropyrimidin-2-one (VIc). In a similar way
from benzaldehyde (212 mg, 2 mmol), 1,3-diketone
Id (308 mg, 2 mmol), and urea (180 mg, 3 mmol)
was obtained 193 mg of compound VIc as a colorless
powder.
Methyl 4-heptafluoropropyl-4-hydroxy-2-oxo-6-
phenylhexahydropyrimidine-5-carboxylate (Vc). In
a similar way from benzaldehyde (212 mg, 2 mmol),
3-oxoester IIc (540 mg, 2 mmol), and urea (180 mg,
3 mmol) was obtained 610 mg of reaction product Vc
as a colorless powder.
5-Benzoyl-4-hydroxy-4-trifluoromethyl-6-phenyl-
hexahydropyrimidin-2-one (VId). In a similar way
from benzaldehyde (212 mg, 2 mmol), 1,3-diketone
Ie (432 mg, 2 mmol), and urea (180 mg, 3 mmol)
was obtained 306 mg of compound VId as a colorless
powder.
Ethyl 4-hydroxy-4-nonafluorobutyl-2-oxo-6-
phenylhexahydropyrimidine-5-carboxylate (Vd).
In a similar way from benzaldehyde (212 mg,
2 mmol), 3-oxoester IId (668 mg, 2 mmol), and urea
(180 mg, 3 mmol) was obtained 771 mg of reaction
product Vd as a colorless powder.
5-Acetyl-4-hydroxy-4-trifluoromethyl-6-phenyl-
hexahydropyrimidine-2-thione (VIe). In a similar
way from benzaldehyde (212 mg, 2 mmol), 1,3-di-
ketone Ia (308 mg, 2 mmol), and thiourea (228 mg,
3 mmol) was obtained 140 mg of compound VIe as
a colorless powder.
Methyl 4-hydroxy-4-(1,1,2,2-tetrafluoroethyl)-
2-thioxo-6-phenylhexahydropyrimidine-5-carb-
oxylate (Ve). In a similar way from benzaldehyde
(212 mg, 2 mmol), 3-oxoester IIb (404 mg, 2 mmol),
and thiourea (228 mg, 3 mmol) was obtained 336 mg
of reaction product Ve as a colorless powder.
5-Benzoyl-4-hydroxy-4-trifluoromethyl-6-phenyl-
hexahydropyrimidine-2-thione (VIf). In a similar
way from benzaldehyde (212 mg, 2 mmol), 1,3-di-
ketone Id (432 mg, 2 mmol), and thiourea (228 mg,
3 mmol) was obtained 228 mg of compound VIf as a
colorless powder.
Methyl 4-heptafluoropropyl-4-hydroxy-2-thioxo-
6-phenylhexahydropyrimidine-5-carboxylate (Vf).
In a similar way from benzaldehyde (212 mg,
2 mmol), 3-oxoester IIc (540 mg, 2 mmol), and
thiourea (228 mg, 3 mmol) was obtained 408 mg of
reaction product Vf as a colorless powder.
5-Benzoyl-4-hydroxy-4-(1,1,2,2-tetrafluoroeth-
yl)-6-phenylhexahydropyrimidin-2-thione (VIg). In
a similar way from benzaldehyde (212 mg, 2 mmol),
1,3-diketone Ie (496 mg, 2 mmol), and thiourea
(228 mg, 3 mmol) was obtained 297 mg of compound
VIg as a colorless powder.
Ethyl 4-hydroxy-4-nonafluorobutyl-2-thioxo-6-
phenylhexahydropyrimidine-5-carboxylate (Vg). In
a similar way from benzaldehyde (212 mg, 2 mmol),
3-oxoester IId (668 mg, 2 mmol), and thiourea
(228 mg, 3 mmol) was obtained 448 mg of reaction
product Vg as a colorless powder.
4-Hydroxy-5-trifluoroacetyl-4-trifluoromethyl-6-
phenylhexahydropyrimidin-2-one (VIh). A mixture
of benzaldehyde (212 mg, 2 mmol), 1,3-diketone Ia
(416 mg, 2 mmol), urea (180 mg, 3 mmol), p-toluene-
sulfonic acid (258 mg, 1.5 mmol), and tetrahydro-
furan (8 ml) was heated at reflux for 2 h. The product
was precipitated from tetrahydrofuran with water,
washed with dichloromethane, and dried in a vacuum.
We obtained 214 mg of compound VIh as a colorless
powder.
Ethyl 4-hydroxy-2-thioxo-4-trifluoromethyl-6-
phenylhexahydropyrimidine-5-carboxylate (Vh). In
a similar way from benzaldehyde (212 mg, 2 mmol),
3-oxoester IIe (368 mg, 2 mmol), and thiourea
(228 mg, 3 mmol) was obtained 300 mg of reaction
product Vh as a colorless powder.
5-Benzoyl-4-hydroxy-4-(1,1,2,2-tetrafluoro-
ethyl)-6-phenylhexahydropyrimidin-2-one (VIa).
In a similar way from benzaldehyde (212 mg,
2 mmol), 1,3-diketone Ib (496 mg, 2 mmol), and urea
(180 mg, 3 mmol) was obtained 301 mg of compound
VIa as a colorless powder.
4-Hydroxy-5-trifluoroacetyl-4-trifluoromethyl-6-
phenylhexahydropyrimidin-2-thione (VIh). Along
procedure b from benzaldehyde (212 mg, 2 mmol),
1,3-diketone Ia (416 mg, 2 mmol), and thiourea
(228 mg, 3 mmol) was prepared a product that after
separation was washed with water and dichloro-
methane. We obtained 114 mg of compound VIi as
colorless powder.
5-Acetyl-4-hydroxy-4-(1,1,2,2-tetrafluoroethyl)-
6-phenylhexahydropyrimidin-2-one (VIb). In a
similar way from benzaldehyde (212 mg, 2 mmol),
1,3-diketone Ic (372 mg, 2 mmol), and urea (180 mg,
3 mmol) was obtained 221 mg of compound VIb as a
colorless powder.
Ethyl 6-nonafluorobutyl-2-oxo-4-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (VIIIa). To a
solution of hexahydropyrimidine Vd (965 mg,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 6 2001

880
BURGART et al.
2 mmol) in toluene (15 ml) was added 100 mg of
p-toluenesulfonic acid, and the mixture was boiled for
6 h with azeotrope distillation of the forming water.
The solution was cooled to room temperature, and the
small portion of solids was filtered off. Then the
filtrate was partially evaporated, and the precipitate
formed was filtered off. As a result we obtained
520 mg of compound VIIIa as a colorless powder.
4. Kreutzberger, A. and Tesch, U.H., Chem. Ber.,
1976, vol. 109, no. 10, pp. 3255 3261; Dilli, S. and
Robards, K., Austral. J. Chem., 1978, vol. 31, no. 8,
pp. 1833 1837.
5. Filyakova, V.I., Karpenko, H.S., Kuznetsova, O.A.,
and Pashkevich K.I., Zh. Org. Khim., 1998, vol. 34,
no. 3, pp. 411 417.
6. Kappe, C.O., Falsone, S.F., Fabian, W.M.F., and
Belay, F., Heterocycles, 1999, vol. 51, no. 1,
pp. 77 84.
7. Akhtar, M.S., Seth, M., and Bhaduri, A.P., Indian
Journ. Chem., 1987, vol. 26B, no. 6, pp. 556 561.
8. Butler, A.R. and Leitch, E., J. Chem. Soc. Perkin
Trans. II, 1976, no. 7, pp. 832 835.
Ethyl 6-nonafluorobutyl-2-thioxo-4-phenyl-
1, 2, 3, 4-tetrahydropyrimidine-5-carboxylate
(VIIIb). In a similar way from hexahydropyrimidine
Vg (996 mg, 2 mmol) was obtained 462 mg of
compound VIIIb as colorless powder.
5-Benzoyl-2-oxo-6-(1,1,2,2-tetrafluoroethyl)-4-
phenyl-1,2,3,4-tetrahydropyrimidine (IXa). In a
similar way from hexahydropyrimidine VIa (793 mg,
2 mmol) was obtained 333 mg of compound IXa as a
colorless powder.
9. Potapov, V.M., Stereokhimiya (Stereochemistry),
Moscow: Khimiya, 1988, 464 p.
10. Comprehensive Organic Chemistry, Barton, D. and
Ollis, W.D., Eds., Pergamon Press, 1979. Translated
under the title Obshchaya organicheskaya khimiya,
Moscow: Khimiya, 1983, vol. 5.
5-Benzoyl-6-(1,1,2,2-tetrafluoroethyl)-2-thioxo-
4-phenyl-1,2,3,4-tetrahydropyrimidine (IXb). In a
similar way from hexahydropyrimidine VIe (825 mg,
2 mmol) was obtained 316 mg of compound IXb as a
colorless powder.
11. Ionin, B.I., Ershov, B.A., and Kol,tsov, A.I., YaMR-
spektroskopiya v organicheskoi khimii (NMR Spectro-
scopy in Organic Chemistry), Leningrad: Khimiya,
1983.
12. Levy, G.C., Lichter, R.L., and Nelson, G.L.,
Carbon-13 Nuclear Magnetic Resonance Spectro-
scopy, New York: Willey & Sons, 1980.
13. Koch, R. and Wiedel, B., QCMP 113, QCPE Bull.,
1992, vol. 12, p. 4.
14. Goronovskii, I.T., Hazarenko, Yu.P., and Hek-
ryach, E.F., Kratkii spravochnik po khimii (Brief
Handbook on Chemistry), Kiev: Naukova Dumka,
1987.
15. Pashkevich, K.I., Skryabina, Z.E., and Saloutin, V.I.,
Izv. Akad. Nauk SSSR, Ser. Khim., 1987, no. 11,
pp. 2527 2535; Skryabina, Z.E., Burgart, Ya.V., and
Saloutin, V.I., Zh. Org. Khim., 1997, vol. 33, no. 9,
pp. 442 444; Burgart, Ya.V., Kuzueva, O.G.,
Kodess, M.I., and Saloutin, V.I., Zh. Org. Khim.,
1998, vol. 34, no. 3, pp. 405 410; Kuzueva, O.G.,
Burgart, Ya.V., and Saloutin, V.I., Izv. Akad. Nauk,
Ser. Khim., 1998, no. 4, pp. 695 699; Burgart, Y.V.,
Fokin, A.S., Kuzueva, O.G., Chupakhin, O.N., and
Saloutin, V.I., J. Fluor. Chem., 1998, vol. 92, no. 2,
pp. 101 108.
Ethyl 7-nonafluorobutyl-5-phenyl-2,3-dihydro-
5H-thiazolo[3,2-a]pyrimidine-6-carboxylate hydro-
bromide (X). To a boiling solution of tetrahydro-
pyrimidine VIIIb (961 mg, 2 mmol) in DMF (5 ml)
was added dibromoethane (395 mg, 2.1 mmol), and
the mixture was boiled for 25 min. The precipitate
that separated on cooling was filtered off and re-
crystallized from ethanol. We obtained 493 mg of
product X as a colorless powder.
REFERENCES
1. Comprehensive Organic Chemistry, Barton, D. and
Ollis, W.D., Eds., Pergamon Press, 1979. Translated
under the title Obshchaya organicheskaya khimiya,
Moscow: Khimiya, 1961, vol. 6.
2. Kappe, S.O., Tetrahedron, 1993, vol. 49, no. 32,
pp. 6937 6963.
3. Pashkevich, K.I., Saloutin, V.I., and Postovskii, I.Ya.,
Usp. Khim., 1981, vol. 50, no. 2, pp. 325 354.
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