Synthesis of pyrimidine derivatives based on ethyl 2-ethoxymethylidene-3- polyfluoroalkyl-3-oxopropionates: And urea

Article abstract of DOI:10.1007/s11172-009-0164-6

Ethyl 2-ethoxymethylidene-3-polyfluoroalkyl-3-oxopropionates under mild conditions undergo regioselective condensation with urea at the ethoxymethylidene substituent giving rise to ethyl 3-polyfluoroalkyl-3-oxo-2- (ureidomethylidene)propionates. Under more drastic conditions, the latter cyclize at the fluoroacyl fragment to form ethyl 4-polyfluoroalkyl-4-hydroxy-2- oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates.

Full text of DOI:10.1007/s11172-009-0164-6

Russian Chemical Bulletin, International Edition, Vol. 58, No. 6, pp. 1259—1263, June, 2009
1259
Synthesis of pyrimidine derivatives based on
ethyl 2ꢀethoxymethylideneꢀ3ꢀpolyfluoroalkylꢀ3ꢀoxopropionates
and urea*
M. V. Goryaeva, Ya. V. Burgart, and V. I. Saloutin
I. Ya. Postovskii Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22/20 ul. S. Kovalevskoi, 620041 Ekaterinburg, Russian Federation.
Fax: +7 (343) 374 5954. Eꢀmail: saloutin@ios.uran.ru
Ethyl 2ꢀethoxymethylideneꢀ3ꢀpolyfluoroalkylꢀ3ꢀoxopropionates under mild conditions
undergo regioselective condensation with urea at the ethoxymethylidene substituent giving rise
to ethyl 3ꢀpolyfluoroalkylꢀ3ꢀoxoꢀ2ꢀ(ureidomethylidene)propionates. Under more drastic
conditions, the latter cyclize at the fluoroacyl fragment to form ethyl 4ꢀpolyfluoroalkylꢀ
4ꢀhydroxyꢀ2ꢀoxoꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀcarboxylates.
Key words: ethyl 2ꢀethoxymethylideneꢀ3ꢀpolyfluoroalkylꢀ3ꢀoxopropionates, urea, pyrimidines,
cyclization, isomerism.
Important role of pyrimidine derivatives1—3 in bioꢀ
chemical processes attracts attention of synthetic chemꢀ
ists and stimulates development of new representatives
of compounds of this class. A classic method for the conꢀ
struction of pyrimidine framework consists in cyclization
of a threeꢀcarbon biselectrophilic reagent with 1,1ꢀdiꢀ
nucleophiles.4 1,3ꢀDicarbonyl compounds are widely
used as the biselectrophilic reagents. For the preparaꢀ
tion of functionalized pyrimidines, it is reasonable to use
1,3ꢀdicarbonyl compounds containing various reactive
groups at position 2 (see Refs 5—9). Alternative ways
for the formation of pyrimidine skeleton are possible with
participation not only of a 1,3ꢀdicarbonyl fragment, but
also a functional group at position 2.
Such derivatives of 1,3ꢀdicarbonyl compounds as ethyl
2ꢀethoxymethylideneꢀ3ꢀoxoalkanoates are suitable buildꢀ
ing blocks for the preparation of pyrimidines. There is
described the reaction of 2ꢀethoxymethylideneꢀsubstituted
acetoacetic ester with thiourea leading initially to the
monocondensation product at the ethoxymethylidene
group, for which a further cyclization at the ester fragꢀ
ment is possible to yield 5ꢀacetylꢀ4ꢀhydroxypyrimidineꢀ
2ꢀthione.10 However, for ethyl 2ꢀethoxymethylideneꢀ
3ꢀoxoalkanoates the most common is cyclocondensation
with urea,11 morpholineꢀ4ꢀcarboxamide,12 4ꢀbenzylꢀ
1ꢀpiperazinecarboxamidine,13 and creatine14 at the alkoxyꢀ
methylideneacyl fragment to form 5ꢀethoxycarbonylꢀ
pyrimidine derivatives.
The use of analogous fluoroalkylꢀcontaining biselecꢀ
trophiles for the synthesis of pyrimidines is much less
known. There is described11 the reaction of ethyl
2ꢀethoxymethylideneꢀ4,4,4ꢀtrifluoroꢀ3ꢀoxobutanoates
with urea in the presence of sodium ethoxide leading to
ethyl 2ꢀhydroxyꢀ4ꢀ(trifluoromethyl)pyrimidineꢀ5ꢀcarboꢀ
xylate.
At the same time, trifluoromethylated pyrimidines
are promising objects for the study of their physiological
activity, since synthetic inhibitors of various enzymes
are found among them.11,15,16
In the present work, we studied the reaction of ethyl
2ꢀethoxymethylideneꢀ3ꢀpolyfluoroalkylꢀ3ꢀoxopropionꢀ
ates 1a—c with urea in order to obtain fluoroalkylated
pyrimidine derivatives containing ethoxycarbonyl subꢀ
stituent at position 5, available for subsequent transforꢀ
mations.
For the first time, we have experimentally shown that
the reaction of esters 1a—c with urea proceeds stepꢀwise
and, depending on conditions, can give either ethyl
4ꢀpolyfluoroalkylꢀ4ꢀhydroxyꢀ2ꢀoxoꢀ1,2,3,4ꢀtetrahydroꢀ
pyrimidineꢀ5ꢀcarboxylates 2a—c or ethyl 3ꢀpolyfluoroalkylꢀ
3ꢀoxoꢀ2ꢀ(ureidomethylidene)propionates 3a,c (Scheme 1).
It was found that prolonged heating in DMF at 80 °C
promotes cyclization of esters 1a—c with urea into
tetrahydropyrimidines 2a—c resulting from the cycloꢀ
addition of binucleophile at the ethoxymethylideneꢀ
fluoroacyl fragment, accompanied by elimination of the
ethanol molecule. However, products of monocondensaꢀ
tion at the ethoxymethylidene substituent, esters 3a,c,
were obtained from esters 1a,c and urea at room temperaꢀ
* Dedicated to Academician O. N. Chupakhin on the occasion
of his 75th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1224—1228, June, 2009.
1066ꢀ5285/09/5806ꢀ1259 © 2009 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 58, No. 6, June, 2009
Goryaeva et al.
Scheme 1
C(9)
C(8)
O(1)
O(2)
N(1)
F(2)
C(1)
C(2)
F(1)
F(6)
F(7)
C(4)
C(3)
N(2)
C(6)
F(5)
C(7)
C(5)
F(4)
C(10)
O(3)
O(4)
F(3)
Fig. 1. General view of the molecule of compound 3c. The
thermal ellipsoids of 50% probability are shown.
The structure of ester 3c in crystal was established
using Xꢀray diffraction analysis (Fig. 1).* According to
the Xꢀray data, the main 3ꢀoxoꢀ2ꢀureidomethylideneꢀ
propionate fragment of the 3c molecule has approximately
plane conformation (the largest deviation of atoms from
the plane O(1)C(1)C(2)C(7)N(1)C(10)N(2) is 0.075 Å),
whereas the heptafluorobutyryl substituent is the most
pulled out of this plane so as atoms C(3), O(4), C(4),
C(5), and C(6) deviate from it by 0.171, 0.301, 0.983,
1.645, and 2.742 Å, respectively. In crystal, ester 3c
exists as a sꢀcis,sꢀcisꢀconformer (Zꢀisomer). The conforꢀ
mation of the molecule is apparently determined by the
intramolecular hydrogen bond (IMHB) between atoms
O(2)...H(1) and the system of intermolecular hydrogen
bonds O(2)...H(2A), O(3)...H(2B), and O(3)...H(1)
(Table 1, Fig. 2), forming the molecular chains.
1—3: RF = CF3 (a), H(CF2)2 (b), C3F7 (c)
Reagents and conditions: i. DMF, 80 °C, 6—8 days; ii. DMF,
22 °C, 3 days; iii. EtOH, reflux, 30 min; iv. AcOH, reflux, 14 days.
ture in DMF (see Scheme 1). These products easily cyꢀ
clize on reflux in ethanol due to the nucleophilic addition
of the NH group of the aminocarbonyl fragment to
fluoroacyl residue, giving tetrahydropyrimidines 2a,c.
When the reaction of esters 1 with urea is performed
under classic conditions for obtaining pyrimidine derivaꢀ
tives in boiling acetic acid, a difficult to separate mixture
of products is formed.
Earlier, we have found that unlike compound 3c,
esters of 2ꢀalkyl(aryl, hetaryl)aminomethylideneꢀ3ꢀpolyꢀ
The data obtained by us testify that the first step of the
reaction of esters 1 with urea consists in condensation at
the ethoxymethylidene fragment, leading to the formaꢀ
tion of the openꢀchain products 3. Then, the formation of
pyrimidine framework takes place due to the intraꢀ
molecular cyclization proceeding without elimination
of the water molecule, in contrast to the described
earlier11 cyclocondensation of ethyl 2ꢀethoxymethylideneꢀ
4,4,4ꢀtrifluoroꢀ3ꢀoxobutanoate into pyrimidine.
Cyclic tetrahydropyrimidines 2a—c and openꢀchain
esters 3a,c are the structural isomers having the same
elemental analysis data and different spectral characꢀ
teristics.
For instance, the IR spectra of esters 3a,c are characꢀ
terized by the presence of three absorption bands at
1759—1740, 1709—1704, and 1664—1662 cm–1 correꢀ
sponding to the vibrations of three nonequivalent carꢀ
bonyl groups, as well as absorption bands in the ranges
3405—3402, 3310—3306, and 3226—3213 cm–1 related to
the stretching vibrations of the NH2 and NH groups.17
Table 1. Parameters of hydrogen bonds N—H...O in the crystal
packing of compound 3c
N—H...O
d(N—H) d(H...O)
ω/deg d(N...O)
/Å
Å
N(1)—H(1)...O(2)
0.796
2.131
2.025
1.929
2.417
127.55
159.73
163.30
144.92
2.691
2.855
2.808
3.102
N(2)—H(2А)...O(2)a 0.868
N(2)—H(2B)...O(3)b 0.905
N(1)—H(1)...O(3)c
0.796
Note. The following notations are used: d are the bond lengths or
interatomic distances, ω are the corresponding angles N—H...O.
The symmetry operations: a [–x + 1, y – 1/2, –z + 5/2];
b [–x + 1, y + 1/2, –z + 5/2]; c [–x + 1, y + 1/2, –z + 5/2].
* We are grateful to P. A. Slepukhin, a research fellow in the
I. Ya. Postovskii Institute of Organic Synthesis, Ural Branch of
the Russian Academy of Sciences, for the performing the Xꢀray
diffraction experiments.

Synthesis of pyrimidenes
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 6, June, 2009
1261
0
b
a
Fig. 2. The molecular packing of compound 3c along the c axis according to the Xꢀray diffraction data.
fluoroalkylꢀ3ꢀoxopropionic acid in solid state exist in form
of Eꢀisomer.18
In the 19F NMR spectra of compounds 3a,c, the sigꢀ
nals for the free CF3 groups and αꢀCF2 of the Zꢀisomer
A possibility of Z,Eꢀisomerism for esters 3a,c exists
due to the different positions of substituents with respect
to the C=C bond. In this case, in the Zꢀisomer the IMHB
is implemented involving the ethoxycarbonyl substiꢀ
tuent, whereas in the Eꢀisomer it involves the fluoroacyl
fragment.
(δCF ∼91.48, δα
∼49.77) are downfield shifted as
ꢀCF
3
com3pared to the corresponding signals for the IMHBꢀ
bound fluoroacyl group of the Eꢀisomer (δCF ∼90.19,
3
δα 2 ∼49.10).
ꢀCF
The existence of esters 3a,c in solution as a mixture
of Zꢀ and Eꢀisomers in contrast to the presence of only
Zꢀform in crystals is apparently explained by the fact that
partial isomeization of the ester molecules occurs on disꢀ
solution of the crystals. This is possible for compounds, in
the molecules of which there are functional groups neighꢀ
boring to the double bond, which cause polarization of
this bond or make it a part of a conjugated system,
resulting in significant reduction of a barrier to rotation
around the C=C bond.19,20 This is especially characterisꢀ
tic of enaminoketones, the soꢀcalled pushꢀpullꢀolefins,
which, from the one hand, contain electronegative
substituents and, from the other hand, electronꢀdonating.
In such compound, the formally double C=C bond
partially possesses character of a single bond due to the
delocalization of an electron. Earlier, we have found
that for ethyl 2ꢀalkyl(aryl, hetaryl)aminomethylideneꢀ
3ꢀpolyfluoroalkylꢀ3ꢀoxopropionates, the isomeization of
the Eꢀform into a mixture of Zꢀ and Eꢀisomers is characꢀ
teristic on dissolution.18
In the IR spectra of tetrahydropyrimidines 2a—c, there
are present two absorption bands (at 1716—1702 and
1688—1685 cm–1), related to the vibrations of the carboꢀ
nyl groups of the ester and ureide fragments, respectively.
The lowꢀfrequency shift of the absorption bands for the
carbonyl groups as compared to the values typical of such
groups17 is explained by the conjugation of the C=O bonds
with the C=C bond and their involvement into the IMHB
with the hydroxy group. The character of the highꢀ
1
The H and 19F NMR spectra of esters 3a,c contain
two sets of signals related to Zꢀ and Eꢀisomers. The
assignment of isomers was made using the rules found by
us for esters of 2ꢀalkyl(aryl, hetaryl)aminomethylideneꢀ
3ꢀpolyfluoroalkylꢀ3ꢀoxopropionic acids,18 according to
which the signals for the protons of the CH and NH
groups of the Eꢀisomer are observed more downfield
as compared to the signals for analogous protons of the
1
Zꢀform. In accordance with this, in the H NMR spectra
of compounds 3a,c the downfield doublet signals for the
CH and NH groups with the spinꢀspin coupling constants
14 Hz at δCH 8.56—8.69 and δNH 11.08—11.15 were
assigned to the Eꢀisomer, whereas the doublets at
δCH 8.37—8.47 and δNH 10.62—10.63, to the Zꢀform. The
ratio of Eꢀ and Zꢀisomers of compounds 3a,c, according
to the NMR spectra in DMSOꢀd6, is approximately 1 : 1
(see Experimental).

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Goryaeva et al.
reflections was 7061, measured on a XCalibur 3 diffractometer
at 293(2) K (ω/2θꢀscanning, MoꢀKαꢀirradiation, a graphite
monochromator, a CCD detector), the number of independent
reflections was 2732 (Rint = 0.0269), the number of reflections
with F0 > 4σ(F0) was 1810. The structure was solved by the direct
method and refined by the least squares method SHELXLꢀ97 21
to R = 0.0300, wR2 = 0.0610, and GOOF = 1.000.*
Ethyl 4ꢀfluoroalkylꢀ4ꢀhydroxyꢀ2ꢀoxoꢀ1,2,3,4ꢀtetrahydroꢀ
pyrimidineꢀ5ꢀcarboxylate (2) (general procedure). A. Ester 1a—c
(5 mmol) and urea (5 mmol) were heated (80 °C) with stirring in
DMF (15 mL) for 6—8 days. The reaction mixture was poured
into cold water, a precipitate formed was filtered off and
crystallized from EtOH to obtain the corresponding tetraꢀ
hydropyrimidine 2a—c.
frequency absorption bands related to the stretching
vibrations of the NH and OH groups (3237—3216,
3119—3108 cm–1) in the molecules of compounds 2a—c
also changes with respect to the spectral picture observed
for the stretching vibrations of the NH2 and NH groups
of esters 3a,c.
The 1H and 19F NMR spectra of tetrahydropyrimidines
2a—c considerably differ from the spectra of their openꢀ
chain isomers 3a,c. For instance, the signals for the proꢀ
tons of the CH2 group of the ethoxy substituent in the
1H NMR spectra of compounds 2a—c resonate as an
AВX3ꢀsystem due to the closeness of the asymmetric
center to this substituent.
B. Ester 1a,c (5 mmol) and urea (5 mmol) were stirred in
DMF (15 mL) for 3—4 days at 20 °C. The reaction mixture was
poured into cold water, a precipitate formed was filtered off
and washed with Et2O to obtain ester 3a,c. Further, ester 3a,c
(1 mmol) was refluxed for 30 min in EtOH (10 mL), the reacꢀ
tion mixture was concentrated, a precipitate formed was filtered
off to obtain the corresponding tetrahydropyrimidine 2a,c.
Ethyl 4ꢀhydroxyꢀ2ꢀoxoꢀ4ꢀ(trifluoromethyl)ꢀ1,2,3,4ꢀtetraꢀ
hydropyrimidineꢀ5ꢀcarboxylate (2a). Method A: the yield was
0.86 g (68%), method B: the yield was 1.23 g (97%), a white
powder, m.p. 203—205 °C. Found (%): C, 37.79; H, 3.65;
F, 22.38; N, 11.17. C8H9F3N2O4. Calculated (%): C, 37.80;
H, 3.57; F, 22.42; N, 11.02. IR, ν/cm–1: 3216, 3119 (NH, OH);
1702 (CO2Et); 1685 (C=O); 1665, 1560 (C=C, NH); 1236—1161
(C—O, C—F). 1H NMR, δ: 1.20 (t, 3 H, OCH2CH3, 3J = 7.1 Hz);
4.10 (m, 2 H, OCH2CH3, ABX3ꢀsystem, ΔAB = 0.05, JAB = 10.8 Hz,
3J = 7.1 Hz); 7.42 (s, 1 H, NH(3)); 7.49 (d, 1 H, H(6),
3JH(6)—NH(1) = 6.3 Hz); 8.46 (br.s, 1 H, OH); 9.89 (br.d, 1 H,
NH(1), 3JNH(1)—H(6) = 6.3 Hz). 19F NMR, δ: 79.63 (s, CF3).
Ethyl 4ꢀ(1,1,2,2ꢀtetrafluoroethyl)ꢀ4ꢀhydroxyꢀ2ꢀoxoꢀ1,2,3,4ꢀ
tetrahydropyrimidineꢀ5ꢀcarboxylate (2b). Method A: the
yield was 1.00 g (70%), a white powder, m.p. 166—167 °C.
Found (%): C, 37.65; H, 3.49; F, 26.32; N, 9.80. C9H10F4N2O4.
The 19F NMR spectra of tetrahydropyrimidines 2a,c
exhibit the upfield shift of the signals for the fluorine
atoms of the CF3 and αꢀCF2 groups (δCF ∼79.63,
3
δα
∼40.71) as compared to analogous signal in the
ꢀCF
spect3ra of esters 3a,c. In addition, the signals for the fluorꢀ
ine atoms of the αꢀCF2 and βꢀCF2 groups in the polyꢀ
fluoroalkyl substituents of compounds 2b,c resonate as
an AВꢀsystem, which is due to their closeness to the
asymmetric carbon atom.
Tetrahydropyrimidines 2 can undergo dehydration.
For instance, a prolonged reflux of ester 2c in acetic acid
leads to ethyl 4ꢀheptafluoroꢀ2ꢀoxopropylꢀ1,2ꢀdihydroꢀ
pyrimidineꢀ5ꢀcarboxylate 4, resembling the synthesized
earlier trifluoromethylꢀsubstituted pyrimidine.11
In conclusion, we have shown that the reaction of
2ꢀethoxymethylideneꢀ3ꢀpolyfluoroalkylpropionates 1 with
urea has a stepꢀwise character. Under mild conditions,
the reaction proceeds at the ethoxymethylidene substiꢀ
tuent, leading to 3ꢀpolyfluoroalkylꢀ2ꢀ(ureidomethylꢀ
idene)propionates 3, which under more drastic conditions
cyclize at the fluoroacyl fragment to yield ethyl 4ꢀpolyꢀ
fluoroalkylꢀ4ꢀhydroxyꢀ2ꢀoxoꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ
5ꢀcarboxylates 2.
Calculated (%): C, 37.77; H, 3.52; F, 26.55; N, 9.79. IR, ν/cm–1
:
3227, 3108 (NH, OH); 1713 (CO2Et); 1688 (C=O); 1629, 1500
(C=C, NH); 1233—1125 (C—O, C—F). 1H NMR, δ: 1.21
(t, 3 H, OCH2CH3, 3J = 7.2 Hz); 4.10 (m, 2 H, OCH2CH3,
AВX3ꢀsystem, Δ = 0.01, JAВ = 10.7 Hz, 3J = 7.2 Hz); 6.55
AB
Experimental
2
2
(dddd, 1 H, (CF2)2H, JH,F(2) = 52.0 Hz, JH,F(2) = 52.7 Hz,
A
B
3JH,F(1) = 7.4 Hz, JH,F(1) = 5.6 Hz); 7.41 (dd, 1 H, NH(3),
3
B
A
4JNH(3)—OH = 1.5 Hz, JNH(3)—NH(1) = 1.0 Hz); 7.47 (d, 1 H,
4
Melting points were measured in unsealed capillary tubes
on a Stuart SMP3 apparatus. IR spectra were recorded on a
Perkin—Elmer Spectrum One IR Fourier spectrometer in Nujol.
NMR spectra were recorded on a Bruker DRXꢀ400 spectrometer
(1H: 400 MHz, relatively to Me4Si; 19F: 376 MHz, relatively to
C6F6) in (CD3)2SO. Elemental analysis was performed using a
Perkin—Elmer PE 2400 Series II CHNSꢀO analyzer. The
reaction course was monitored by TLC on Sorbfil plates
PTLCꢀAFꢀVꢀUV.
H(6), JH(6)—NH(1) = 6.3 Hz); 8.16 (d, 1 H, OH, 3J = 1.5 Hz);
3
3
4
9.83 (dd, 1 H, NH(1), JNH(1)—H(6) = 6.3 Hz, JNH(1)—NH(3)
=
= 1.0 Hz). 19F NMR, δ: 28.23 (m, 2 F, HCF2, ABꢀsystem,
Δ
Δ
= 1.99, JAB = 295.7 Hz); 32.70 (m, 2 F, CF2, ABꢀsystem,
= 1.49, JAB = 259.2 Hz).
AB
AB
Ethyl 4ꢀ(1,1,2,2,3,3,3ꢀheptafluoropropyl)ꢀ4ꢀhydroxyꢀ2ꢀoxoꢀ
1,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀcarboxylate (2c). Method A: the
yield was 1.15 g (65%); method B: the yield was 0.35 g (98%),
a white powder, m.p. 198—200 °C. Found (%): C, 34.08;
H, 2.32; F, 37.40; N, 7.81. C10H9F7N2O4. Calculated (%):
C, 33.91; H, 2.56; F, 37.55; N, 7.91. IR, ν/cm–1: 3237, 3116
The starting ethyl 2ꢀethoxymethylideneꢀ3ꢀpolyfluoroalkylꢀ
3ꢀoxopropionates 1a—c were synthesized according to the
procedure described earlier.18
Monocrystals of compound 3c were obtained by crystalꢀ
lization from acetone. C10H9F7N2O4, M = 354.19, crystals
are monoclinic, space group is P2(1)/c, a = 15.5644(12) Å,
b = 9.2396(10) Å, c = 9.3890(10) Å, α = 90.00°, β = 95.084(7)°,
* A full set of crystallographic data was deposited with the
Cambridge Structural Database (CCDC 692523) and is availꢀ
able at www.ccdc.cam.ac.uk/conts/retrieving.html (or: CCDC,
12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033;
eꢀmail: deposit@ccdc.cam.ac.uk).
γ = 90.00°, V = 1344.9(2) Å3, Z = 4, dcalc = 1.749 g cm–3
,
μ(MoꢀKα) = 0.193 cm–1, F(000) = 712. The total number of

Synthesis of pyrimidenes
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 6, June, 2009
1263
(NH, OH); 1716 (CO2Et); 1684 (C=O); 1613, 1562 (C=C,
NH); 1230—1121 (C—O, C—F). 1H NMR, δ: 1.19 (t, 3 H,
OCH2CH3, 3J = 7.0 Hz); 4.11 (m, 2 H, OCH2CH3, AВX3ꢀ
References
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system, Δ
= 0.04, JAВ = 10.8 Hz, 3J = 7.0 Hz); 7.51 (s,
AB
1 H, NH(3)); 7.52 (s, 1 H, H(6)); 8.36 (br.s, 1 H, OH); 9.94
(br.s, 1 H, NH(1)). 19F NMR, δ: 37.41 (m, 2 F, βꢀCF2,
AВꢀsystem, ΔAB = 0.50, JAВ = 290.2 Hz); 40.71 (m, 2 F, αꢀCF2,
ABꢀsystem, Δ = 33.27, JAB = 275.0 Hz); 82.16 (t, 3 F, CF3,
AB
4J = 11.2 Hz).
Ethyl 4,4,4ꢀtrifluoroꢀ3ꢀoxoꢀ2ꢀ(ureidomethylidene)butanoate
(3a). Method B: the yield was 0.97 g (76%), white crystals,
m.p. 185—187 °C. Found (%): C, 37.79; H, 3.55; F, 22.26;
N, 11.07. C8H9F3N2O4. Calculated (%): C, 37.80; H, 3.57;
F, 22.42; N, 11.02. IR, ν/cm–1: 3402, 3306, 3213 (NH, NH2);
1759, 1704, 1664 (C=O); 1621, 1562 (C=C, NH, NH2);
1237—1162 (C—O, C—F). 1H NMR, δ: Eꢀisomer (53%): 1.24
(t, 3 H, OCH2CH3, 3J = 7.2 Hz); 4.20 (q, 2 H, OCH2CH3,
3J = 7.2 Hz); 7.66, 7.79 (both br.s, 1 H each, NH2); 8.63 (d,
1 H, CH, 3J = 13.5 Hz); 11.15 (d, 1 H, NH, 3J = 13.5 Hz);
Zꢀisomer (47%): 1.26 (t, 3 H, OCH2CH3, 3J = 7.2 Hz); 4.26 (q,
3
2 H, OCH2CH3, J = 7.2 Hz); 7.56, 7.72 (both br.s, 1 H each,
NH2); 8.47 (d, 1 H, CH, 3J = 13.0 Hz); 10.69 (d, 1 H, NH,
3J = 13.0 Hz). 19F NMR, δ: Eꢀisomer (53%): 90.19 (s, CF3);
Zꢀisomer (47%): 91.48 (s, CF3).
Ethyl 4,4,5,5,6,6,6ꢀheptafluoroꢀ3ꢀoxoꢀ2ꢀ(ureidomethylꢀ
idene)hexanoate (3c). Method B: the yield was 1.13 g (64%),
white crystals, m.p. 196—197 °C. Found (%): C, 34.08; H, 2.32;
F, 37.49; N, 7.81. C10H9F7N2O4. Calculated (%): C, 33.91;
H, 2.56; F, 37.55; N, 7.91. IR, ν/cm–1: 3405, 3310, 3226 (NH,
NH2); 1740, 1709, 1662 (C=O); 1622, 1571, 1554 (C=C, NH,
NH2); 1285—1191 (C—O, C—F). 1H NMR, δ: Eꢀisomer (44%):
1.23 (t, 3 H, OCH2CH3, 3J = 7.2 Hz); 4.20 (q, 2 H, OCH2CH3,
3J = 7.2 Hz); 7.66, 7.74 (both br.s, 1 H each, NH2); 8.56 (d,
1 H, CH, 3J = 13.2 Hz); 11.08 (d, 1 H, NH, 3J = 13.2 Hz);
Zꢀisomer (56%): 1.24 (t, 3 H, OCH2CH3, 3J = 7.1 Hz); 4.26 (q,
3
2 H, OCH2CH3, J = 7.1 Hz); 7.56, 7.67 (both br.s, 1 H each,
3
NH2); 8.37 (d, 1 H, CH, J = 13.0 Hz); 10.62 (br.d, 1 H, NH,
3J = 13.0 Hz). 19F NMR, δ: Eꢀisomer (44%): 38.39 (m, 2 F,
βꢀCF2); 49.10 (m, 2 F, αꢀCF2); 82.80 (t, 3 F, CF3, 4J = 9.5 Hz);
Zꢀisomer (56%): 39.35 (m, 2 F, βꢀCF2); 49.77 (m, 2 F, αꢀCF2);
82.87 (t, 3 F, CF3, 4J = 9.2 Hz).
Ethyl 4ꢀ(1,1,2,2,3,3,3ꢀheptfluoropropyl)ꢀ2ꢀoxoꢀ1,2ꢀdihydroꢀ
pyrimidineꢀ5ꢀcarboxylate (4). Solution of compound 2c (0.71 g,
2 mmol) in acetic acid (10 mL) was refluxed for 14 days. Then,
the reaction mixture was poured into water, the рH was made
neutral with aqueous soda. A precipitate formed was filtered off
and crystallized from hexane. The yield was 0.38 g (56%), a light
beige powder, m.p. 106—108 °C. Found (%): C, 35.39; H, 2.02;
F, 39.39; N, 8.12. C10H7F7N2O3. Calculated (%): C, 35.73;
H, 2.10; F, 39.56; N, 8.33. IR, ν/cm–1: 3237 (NH); 1750 (CO2Et);
1668 (C=O); 1627, 1534 (C=C, C=N, NH); 1237—1122
(C—O, C—F). 1H NMR, δ: 1.27 (t, 3 H, OCH2CH3, 3J = 7.1 Hz);
4.25 (q, 2 H, OCH2CH3, 3J = 7.1 Hz); 8.69 (s, 1 H, H(6)); 13.40
(br.s, 1 H, NH). 19F NMR, δ: 40.23 (m, 2 F, βꢀCF2); 53.27 (m,
2 F, αꢀCF2); 83.25 (t, 3 F, CF3, 4J = 9.5 Hz).
19. V. M. Potapov, Stereokhimiya [Stereochemistry], Khimiya,
Moscow, 1988, p. 262 (in Russian).
20. M. Oki, Applications of Dynamic NMR Spectroscopy to
Organic Chemistry, VCH Publishers, Inc, 1985, p. 76, 112.
21. G. M. Sheldrick, SHELXSꢀ97, A Software Package for
the Solutions and Refinement of Xꢀray Data, Göttingen
University, Germany, 1997.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 09ꢀ03ꢀ00274a)
and the Council on Grants of the President of the Russian
Federation (Program for the State Support of Leading
Scientific Schools, Grant NSh 3758.2008.3).
Received July 29, 2008;
in revised form February 20, 2009