Regiospecific O-alkylation of 4-polyfluoroalkyl-1H-pyrimidin-2-ones

Article abstract of DOI:10.1007/s11172-011-0141-8

The alkylation of 4-polyfluoroalkylpyrimidin-2-ones with iodomethane, 4-bromobutyl acetate, and epichlorhydrin occurs regiospecifically to form O-regioisomers.

Full text of DOI:10.1007/s11172-011-0141-8

Russian Chemical Bulletin, International Edition, Vol. 60, No. 5, pp. 901—905, May, 2011
901
Regiospecific Oꢀalkylation of 4ꢀpolyfluoroalkylꢀ1Hꢀpyrimidinꢀ2ꢀones*
O. G. Khudina, A. E. Ivanova, Ya. V. Burgart, M. I. Kodess, and V. I. Saloutin
I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22/20 ul. S. Kovalevskoi, 620990 Ekaterinburg, Russian Federation.
Fax: +7 (343) 374 5954. Eꢀmail: saloutin@ios.uran.ru
The alkylation of 4ꢀpolyfluoroalkylpyrimidinꢀ2ꢀones with iodomethane, 4ꢀbromobutyl
acetate, and epichlorhydrin occurs regiospecifically to form Oꢀregioisomers.
Key words: 4ꢀpolyfluoroalkylpyrimidinꢀ2ꢀones, alkylation, organofluorine compounds,
epichlorhydrin.
Guanine derivatives with the 2ꢀhydroxyethoxymethyl
fragment and its amino acylated analog, viz., acyclovir
and valacyclovir, are highly active against virus of simple
herpes.1 Another nonꢀsugar acyclic analog of nucleosides,
viz., 1ꢀ(2ꢀhydroxyethoxymethyl)ꢀ6ꢀ(phenylthio)thymine,
possesses activity against human immunodeficiency virus
(HIVꢀ1). This discovery marked the use in medicine of
nonꢀnucleoside inhibitors of reverse transcriptase, which
presently occupy a strong position in the treatment of HIVꢀ
1 infection.1,2
late the intermediate salts 2. The oneꢀstep method is most
convenient for the synthesis of compounds 3: stirring of
pyrimidinones 1 with iodomethane for ~5 h at room temꢀ
perature in DMF in the presence of sodium carbonate or
in DMSO with sodium hydride provided the formation of
the target products in 74—83% yield (Scheme 1).
Scheme 1
One of the convenient methods for the introduction
into the heterocyclic base of a residue containing the terꢀ
minal hydroxy group is the interaction of metal (Ag2+
,
Hg2+, Na+, K+) derivatives of heterocyclic systems with
Oꢀprotected haloalkanols.3
In the present work, we studied the alkylation of strucꢀ
tural analogs of uracil, namely, 4ꢀpolyfluoroalkylꢀ6ꢀRꢀ
pyrimidinꢀ2ꢀones 1 (R = Alk, Ar), with 4ꢀbromobutyl
acetate and epichlorhydrin.
Compounds 1 have three nonequivalent reaction cenꢀ
ters (two endocyclic nitrogen atoms (N(1) and N(3)) and
exocyclic oxygen atom) capable of undergoing alkylation
(Scheme 1). In order to reveal the most reactive reaction
center of pyrimidinones 1, we studied their reaction with
model iodomethane.
Compounds 1 were methylated in the presence of soꢀ
dium carbonate, sodium hydride, or sodium ethoxide. It
turned out that even manyꢀhour heating of pyrimidinones
1 with iodomethane in the presence of sodium ethoxide
did not provide their complete conversion. In the case of
sodium carbonate or hydride, methylation occurred sucꢀ
cessfully yielding the desired products 3. Intermediate soꢀ
dium salts 2 can be isolated and subjected to the further
treatment with iodomethane. It was not necessary to isoꢀ
i. DMF, 25 °C; ii. DMSO, 25 °C
RF = CF3 (1a, 2, 3a), HCF2CF2 (1b, 3b)
The structure of compound 3а and, in particular,
the position of the methyl group, was proved by the data of
13С NMR and 2D heteronuclear 1H—13C HSQC, 1H—13C
1
HMBC, and H—15N HMBC experiments. The value of
chemical shift of 55.44 ppm is characteristic of the subꢀ
stituent ОMe, whereas in the Nꢀmethylated products the
signals of the methyl group should resonate more than
20 ppm upfield compared to the Оꢀisomers.4
* Dedicated to Academician of the Russian Academy of Sciences
V. N. Charushin on his 60th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 881—885, May, 2011.
1066ꢀ5285/11/6005ꢀ901 © 2011 Springer Science+Business Media, Inc.

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Khudina et al.
H(5)
15N (δ, м.д.)
180
200
220
240
260
280
300
1
The 2D H—13C HMBC spectrum contains only one
crossꢀpeak between the protons of the CH3 group and the
C(2) carbon atom, which agrees with the structure of
Оꢀalkylated pyrimidinols, whereas in the case of Nꢀmethꢀ
ylꢀsubstituted pyrimidinꢀ2ꢀones (regioisomers A and B)
the HMBC spectrum should exhibit two crossꢀpeaks beꢀ
tween the protons of the N—CH3 group and the carbon
atoms С(2) and С(6) (see Ref. 4). Another evidence in
favor of the proposed structure are chemical shifts δN 239.7
and 254.4 of the nitrogen atoms N(1) and N(3) obtained
from the 2D 1H—15N HMBC experiment (Fig. 1), whose
values correspond to the shifts of the imine nitrogen atoms
(in regioisomeric structures A and B the signal of the subꢀ
stituted amide nitrogen atoms should be observed in
a substantially higher field). The IR spectra of compounds
3a,b contain no band in the region of absorption of the
carbonyl lactam group at 1660—1685 cm–1, unlike the
spectra of the starting pyrimidinones 1.
7.78
7.74 7.70 7.66
7.62 1H (δ)
Fig. 1. Fragment of the 2D H—15N HMBC spectrum of comꢀ
pound 3a (500 MHz, CDCl3).
1
room temperature. It was found that the following condiꢀ
tions are most appropriate for the synthesis of products 4:
either the stepwise addition of aqueous potassium carbonꢀ
ate for the formation of salt 2 followed by its heating in
DMF at 100 °C with 4ꢀbromobutyl acetate, or reflux of
pyrimidinone 1 in acetone with 4ꢀbromobutyl acetate in
the presence of potassium carbonate.
The position of the acetoxybutyl substituent in comꢀ
pounds 4 was established by spectral methods. It was found
1
that the 2D H—13C НМВС spectrum of compound 4а
contains one crossꢀpeak between the protons of the
C(1´)Н2 group of the acetoxybutyl substituent and the
carbon nucleus С(2) (Scheme 2), whereas in the 13С NMR
spectrum the signal at 67.81 ppm is characteristic of the
carbon atom of the О—СН2 fragment of the acetoxybutyl
Attempted introduction of the acetoxybutyl substituent
into pyrimidinones 1а—с (Scheme 2) with 4ꢀbromobutyl
acetate in the presence of K2CO3 in DMF did not occur at
Scheme 2
1, 4: RF = CF3, R = Ph (a); RF = HCF2CF2, R = Bu (b); RF = C4F9, R = Me (c)

2ꢀAlkoxyꢀ4ꢀpolyfluoroalkylpyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
903
substituent. The IR spectra of compounds 4а—с contain
no absorption bands characteristic of vibrations of the lacꢀ
tam carbonyl groups.
To assign products 6a,b and 7 to the Оꢀisomeric series,
we used the IR spectral data containing no absorption
band of the carbonyl group. In addition, in the 19F NMR
spectrum of derivative 6b, two СF3 groups appear as one
singlet signal because of their equivalence, which is possiꢀ
ble only in the case of symmetrical structure 6b.
Thus, we found that the alkylation of 4ꢀpolyfluoroꢀ
alkylpyrimidinꢀ2ꢀones with various alkylating agents proꢀ
ceeds regiospecifically to form Oꢀisomers.
Further we are planning to develop methods for the
introduction into pyrimidines 1 of other acyclic residues
modeling sugar fragments and methods for the synthesis
of glycosylꢀsubstituted pyrimidines. In addition, we asꢀ
sume to study the biological activity of the compounds
synthesized in this work.
The attempts to deacylate acetate 4а under basic conꢀ
ditions by the action of sodium methoxide gave methꢀ
oxylated derivative 3а due to transalkoxylation (see
Scheme 2). However, the deacylation proceeds smoothly
under acidic conditions when passing gaseous hydrogen
chloride through a solution of pyrimidine 4с in absolute
ethanol at room temperature to give 2ꢀ(4ꢀhydroxybutoxy)ꢀ
substituted pyrimidine 5 in high yield (see Scheme 2). The
IR spectrum of this compounds has no absorption band of
the acetoxy group at 1740 cm–1, as compared to acylated
precursor 4с, but the absorption band of stretching vibraꢀ
tions of the OH group is detected at 3375 cm–1
.
We studied the transformations of pyrimidinones 1 with
epichlorohydrin (Scheme 3). The successful occurrence of
these reactions needs heating of pyrimidinones 1a,d with
a small excess of epichlorhydrin in the presence of triethylꢀ
amine. It turned out that the main process in these reacꢀ
tions is the nucleophilic addition of the carbonyl oxygen
atom of pyrimidinones 1а,d to the С(3) atom of the epꢀ
oxide cycle followed by its opening5 leading to 2ꢀ(2ꢀhydrꢀ
oxyꢀ3ꢀchloropropoxy)ꢀcontaining pyrimidines 6a,b in
moderate yields. Apparently, the low yields of the prodꢀ
ucts are caused by side processes, for example, polymerꢀ
ization. In addition, these reactions are very sensitive to
the amount of the basic catalyst used, because even a slight
increase in the amount of triethylamine in the reaction of
pyrimidinone 1а resulted in the formation of 2ꢀglycidylꢀ
substituted pyrimidine 7 (see Scheme 3), most likely, due
to the dehydrochlorination of compound 6а under basic
conditions.
Experimental
NMR spectra were measured in CDCl3 on Bruker DRXꢀ400
(1Н: 400 MHz, relative to SiMe4; 19F: 376 MHz, relative to
С6F6) and Avance 500 (13C: 126 MHz, relative to the signal
from CDCl3 77 ppm; 15N: relative to external liquid ammonia)
1
spectrometers. The signals of Н and 13C were assigned on the
basis of 2D 1H—13C HSQC and HMBC experiments. IR spectra
were recorded on a Perkin Elmer Spectrum One FTꢀIR specꢀ
trometer in the range 4000—400 cm–1 using a diffuse reflectance
attachment (DRA) or frustrated total internal reflection (FTIR)
technique. Melting points were measured in open capillaries
on a Stuart SMP30 apparatus for melting point determination.
Column chromatography was carried out on silica gel 60
(0.063—0.02 mm, Merck). Mass spectra were recorded on an
Agilent GC 7890A MSD 5975C inert XL EI/CI GC/MS chromatoꢀ
graph with a quartz capillary column HP5ꢀMS (dimethylpolysilꢀ
oxane with 5% phenyl groups, 30 m×0.25 mm, film thickness
0.25 μm) and a quadrupole mass spectrometric detector in the
electron ionization mode (70 eV) using helium as a carrier gas
and chloroform as a solvent. Elemental analysis (С, Н, N) was
carried out on a Perkin—Elmer PE 2400 series II analyzer.
Starting pyrimidinones 1 were synthesized by the condensaꢀ
tion of fluoroalkylꢀcontaining 1,3ꢀdiketones with urea.6
Scheme 3
Alkylation of pyrimidinones 1а,b with iodomethane. А. A susꢀ
pension of pyrimidinone 1a (0.84 g, 3.5 mmol) in a 17% aqueous
solution of Na2СО3 (2.5 mL) was stirred at room temperature
for 30 min. Sodium salt 2 was filtered off, dried, and dissolved in
DMF (4 mL), iodomethane (0.57 g, 4 mmol) was added, and the
mixture was stirred at room temperature for 5 h. Water (30 mL)
was added, and the suspension was extracted with ethyl acetate.
The organic layer was separated and concentrated. The product
was purified by column chromatography using chloroform as
an eluent.
B. A suspension of 60% sodium hydride in mineral oil (0.14 g)
in DMSO (2 mL) was added to pyrimidinone 1а,b (3.5 mmol),
and the reaction mixture was stirred at room temperature for
30 min, then iodomethane (0.57 g, 4 mmol) was added dropwise,
and the mixture was stirred for more 10 h. The product was
precipitated from DMSO with water, filtered off, and dried.
2ꢀMethoxyꢀ6ꢀphenylꢀ4ꢀtrifluoromethylpyrimidine (3а). The
yield by method А was 83%, and the yield by method B was 75%,
m.p. 47—49 °С. IR (DRA), ν/cm–1: 1480, 1550, 1585, 1600
RF = CF3, R = Ph (1a, 6a); RF = R = CF3 (1d, 6b)

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Khudina et al.
1
(C=C, C=N); 1120—1255 (C—F). Н NMR, δ: 4.16 (s, 3 Н,
ОMe); 7.51—7.59 (m, 3 Н, Hm, Hp); 7.68 (s, 1 H, H(5)); 8.15
(dd, 2 H, Ho, J = 8.1 Hz, J = 1.5 Hz). 19F NMR (CDCl3), δ:
91.58 (s, CF3). 13С NMR, δ: 55.44 (OMe); 106.12 (q, С(5),
3JC,F = 2.8 Hz); 120.43 (q, СF3, 1JC,F = 275.1 Hz); 127.47 (Co);
2ꢀ(4ꢀAcetoxybutoxy)ꢀ6ꢀbutylꢀ4ꢀ(1,1,2,2ꢀtetrafluoroethyl)ꢀ
pyrimidine (4b). The yield was 69%, oil. IR (FTIR), ν/cm–1
:
1740 (С=O); 1565, 1595 (C=C, C=N); 1040—1245 (C—F).
3
1Н NMR, δ: 0.96 (t, 3 Н, Ме, JН,Н = 7.4 Hz), 1.40 (tq, 2 Н,
СН2, J = 7.4 Hz); 1.74 (m, 2 Н, СН2); 1.80—1.96 (m, 4 Н,
129.06 (Cm); 132.08 (Cp); 135.35 (Cipso); 158.24 (q, С(4), 2JC,F
=
2 СН2); 2.05 (s, 3 Н, MeСО); 2.79 (m, 2 Н, СН2); 4.14 (t, 2 Н,
= 35.8 Hz); 166.18 (С(2)); 169.23 (C(6)). 15N NMR, δ:
239.7, 254.4. Found (%): C, 56.74; H, 3.46; F, 22.2; N, 10.76.
С12Н9F3N2О. Calculated (%): C, 56.7; H, 3.57; F, 22.42;
N, 11.02.
OСН2, JН,Н = 6.2 Hz); 4.42 (t, 2 Н, OСН2, JН,Н = 6.2 Hz);
3
3
2
3
6.31 (tt, 1 Н, Н(СF2)2, JН,F = 53.1 Hz, JН,F = 5.3 Hz); 7.17
(s, 1 H, H(5)). MS, m/z (Irel (%)): 43 [C=OCH3]+ (21.7), 55
[C4H7]+ (14.9), 115 [C4H8OC=OCH3]+ (71.7), 210 [M – C3H6 –
– C4H7OC=OCH3]+ (99.9), 223 [M – C2H5 – C4H7OC=OCH3]+
(30.4), 237 [M – CH3 – C4H7OC=OCH3]+ (12.1), 253
[M – C4H7OC=OCH2]+ (46.3), 324 [M – C3H6]+ (33.1), 366
[M]+ (0.4). Found (%): C, 52.55; H, 5.89; F, 21.08; N, 7.68.
С16Н22F4N2О3. Calculated (%): C, 52.46; H, 6.05; F, 20.74;
N, 7.65.
Compound 3a was also obtained during attempted deacetylaꢀ
tion of derivative 4a. 2ꢀ(4ꢀAcetoxybutoxy)pyrimidine 4a (0.47 g,
1.3 mmol) was added to a solution of sodium methoxide
prepared from metallic sodium (32 mg, 1.4 mmol) and absoꢀ
lute methanol (10 mL). The reaction mixture was refluxed for
1 h, cooled, neutralized with acetic acid, and concentrated
in vacuo. Product 3a was isolated from the obtained residue by
column chromatography using chloroform as an eluent. The yield
was 76%.
2ꢀMethoxyꢀ6ꢀphenylꢀ4ꢀ(1,1,2,2ꢀtetrafluoroethyl)pyrimidine
(3b). The yield was 74%, m.p. 48—49 °С. IR (DRA), ν/cm–1
1555, 1580, 1600 (C=C, C=N); 1080—1150 (C—F). Н NMR
(DMSOꢀd6), δ: 4.08 (s, 3 Н, OMe); 6.98 (tt, 1 Н, Н(СF2)2, 2JН,F
= 51.7 Hz, JН,F = 5.5 Hz); 7.56—7.66 (m, 3 Н, Hm, Hp); 8.11
(s, 1 H, H(5)); 8.32 (dd, 2 H, Ho, J = 8.2 Hz, J = 1.5 Hz). 19F NMR
(DMSOꢀd6), δ: 24.12 (dt, 2 F, НCF2, JF,Н = 51.8 Hz, JF,F
= 8.1 Hz); 42.47 (td, 2 F, CF2, J = 8.1 Hz, J = 5.5 Hz).
Found (%): C, 54.7; H, 3.48; F, 26.26; N, 9.76. С13Н10F4N2О.
Calculated (%): C, 54.55; H, 3.52; F, 26.55; N, 9.79.
Alkylation of pyrimidinones 1а—с with 4ꢀbromobutyl acetate.
A. A suspension of pyrimidinone 1a (0.96 g, 4 mmol) in a 17%
aqueous solution of К2СО3 (3.5 mL) was stirred for 30 min at
room temperature. Potassium salt 2 was filtered off, dried and
dissolved in DMF (5 mL). 4ꢀBromobutyl acetate (0.78 g, 4 mmol)
was added to the reaction mixture, and the mixture was heated at
100 °С for 5 h. Water (30 mL) was added to the cooled reaction
mixture. The suspension was extracted with ethyl acetate. The
organic layer was separated and concentrated. The product
was purified with column chromatography using a dichloroꢀ
methane—hexane (2 : 1) mixture as an eluent.
B. A mixture of pyrimidinone 1а—с (2.5 mL), acetone
(10 mL), 4ꢀbromobutyl acetate (0.49 g, 2.5 mmol), and potassium
carbonate (0.3 g, 3.0 mmol) was refluxed for 8—10 h. The preꢀ
cipitate was filtered off, and the mother liquor was concentrated.
The product was purified with column chromatography using
a hexane—ethyl acetate (5 : 1) mixture as an eluent.
2ꢀ(4ꢀAcetoxybutoxy)ꢀ6ꢀmethylꢀ4ꢀnonafluorobutylpyrimidine
(4c). The yield was 70%, oil. IR (FTIR), ν/cm–1: 1740 (C=O);
1565, 1595 (C=C, C=N); 1135—1235 (C—F). 1Н NMR, δ:
1.80—1.95 (m, 4 Н, 2 СН2); 2.05 (s, 3 Н, MeСО); 2.58 (s, 3 Н,
3
:
Ме—C(6)); 4.13 (t, 2 Н, Н(4´), JН,Н = 6.2 Hz); 4.43 (t, 2 Н,
1
Н(1´), 3JН,Н = 6.2 Hz); 7.15 (s, 1 H, H(5)). 19F NMR, δ: 36.15
(m, 2 F, CF2); 39.10 (m, 2 F, CF2); 45.76 (tq, 2 F, CF2, J = 12.9 Hz,
J = 2.7 Hz); 80.86 (tt, 3 F, CF3, J = 9.8 Hz, J = 2.7 Hz). MS, m/z
(Irel (%)): 43 [C=OCH3]+ (21.6), 54 [C4H6]+ (9.3), 71 [C4H7O]+
(9.2), 312 [M – CH3 – C4H8OC=OCH3]+ (21.3), 313 [M –
– CH3 – C4H7OC=OCH3]+ (16.4), 329 [M – C4H7OC=OCH2]+
(99.9), 330 [M – СF3 – C=OCH3]+ (12.0), 355 [M –
– C2H4OC=OCH3]+ (15.4), 383 [M – OC=OCH3]+ (10.9),
442 [M]+ (2.7). Found (%): C, 40.91; H, 3.39; F, 38.51; N, 6.45.
С15Н15F9N2О3. Calculated (%): C, 40.74; H, 3.42; F, 38.66; N, 6.33.
2ꢀ(4ꢀHydroxybutoxy)ꢀ6ꢀmethylꢀ4ꢀnonafluorobutylpyrimidine
(5). Acetoxy derivative 4c (0.22 g, 0.5 mmol) was dissolved in
ethanol (5 mL), and then gaseous hydrogen chloride was bubꢀ
bled through the solution for 1 h. The reaction mixture was
stirred at room temperature for 30 min and neutralized with
NaHCO3. The product was extracted with chloroform and dried
over Na2SO4. The solvent was evaporated. Product 5 was puriꢀ
fied by column chromatography using chloroform as an eluent.
The yield was 84%, oil. IR (FTIR), ν/cm–1: 3375 (OH), 1570,
1595 (C=C, C=N); 1135—1235 (C—F). 1Н NMR, δ: 1.59—2.00
(m, 5 Н, 2 СН2, OH); 2.58 (s, 3 Н, Ме); 3.72 (t, 2 Н, Н(4´),
=
3
2
3
=
3
3JН,Н = 6.4 Hz); 4.44 (t, 2 Н, Н(1´), JН,Н = 6.4 Hz); 7.14
(s, 1 H, H(5)). 19F NMR, δ: 36.17 (m, 2 F, CF2); 39.10 (m, 2 F,
CF2); 45.76 (tq, 2 F, CF2, J = 12.8 Hz, J = 2.6 Hz); 80.86 (tt, 3 F,
CF3, J = 9.8 Hz, J = 2.6 Hz). MS, m/z (Irel (%)): 71 [C4H7O]+
(15.8), 312 [M – OC4H7OH]+ (11.4), 329 [M – C4H7O]+ (99.9),
330 [M – HСF3]+ (13.0), 400 [M]+ (1.9). Found (%): C, 38.85;
H, 3.2; F, 43.01; N, 7.12. С13Н13F9N2О2. Calculated (%):
C, 39.01; H, 3.27; F, 42.72; N, 7.0.
2ꢀ(4ꢀAcetoxybutoxy)ꢀ6ꢀphenylꢀ4ꢀtrifluoromethylpyrimidine
(4a). The yields were 73% (method А) and 82% (method B),
m.p. 48—49 °С. IR (DRA), ν/cm–1: 1735 (C=O); 1555, 1600
1
(C=C, C=N); 1120—1250 (C—F). Н NMR, δ: 1.88 (m, 2 Н,
СН2); 1.97 (m, 2 Н, СН2); 2.06 (s, 3 H, MeCO), 4.16 (t, 2 Н,
Alkylation of pyrimidinones 1а,d with epichlorohydrin. Epichloroꢀ
hydrin (0.175 g, 1.9 mmol) and triethylamine (0.16 g, 1.6 mmol)
(for compound 1a) or triethylamine (3 droplets) for compound
1d) were added dropwise to pyrimidinones 1а,d (1.6 mmol). The
mixture was heated at 60 °С for 8 h. The cooled melt was disꢀ
solved in chloroform (5 mL). The solution was placed on the top
of a chromatography column packed with silica gel. The prodꢀ
ucts were eluted with a chloroform—ethyl acetate (5 : 1) mixꢀ
ture. Two fractions were collected in the case of the reaction of
pyrimidine 1а with epichlorohydrin: the first fraction contained
compound 6a and the second one was product 7.
3
3
Н(4´), JН,Н = 6.3 Hz); 4.56 (t, 2 Н, Н(1´), JН,Н = 6.3 Hz);
7.51—7.60 (m, 3 Н, Hm, Hp); 7.67 (s, 1 H, H(5)); 8.13 (dd, 2 H,
Ho, J = 8.2 Hz, 1.5 Hz). 19F NMR, δ: 91.56 (s, CF3). 13С NMR
(CDCl3), δ: 20.88 (COMe); 25.23, 25.41 (C(2´), С(3´)); 63.95
3
(C(4´); 67.81 (C(1´)); 106.14 (q, С(5), JC,F = 2.8 Hz); 120.41
1
(q, СF3, JC,F = 275.1 Hz); 127.47 (Co); 129.05 (Cm); 132.06
2
(Cp); 135.38 (Cipso); 158.23 (q, С(4), JC,F = 35.8 Hz); 165.75
4
(q, С(2), JC,F = 0.8 Hz); 169.27 (C(6)); 171.08 (COMe).
Found (%): C, 57.36; H, 4.84; F, 16.08; N, 7.64. С17Н17F3N2О3.
Calculated (%): C, 57.63; H, 4.84; F, 16.09; N, 7.91.

2ꢀAlkoxyꢀ4ꢀpolyfluoroalkylpyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
905
2ꢀ(3ꢀChloroꢀ2ꢀhydroxypropoxy)ꢀ6ꢀphenylꢀ4ꢀtrifluoromethꢀ
ylpyrimidine (6а). The yield was 45%, m.p. 84—85 °С. IR (DRA),
ν/cm–1: 3415 (OH); 1560, 1590 (C=C, C=N); 1110—1195
(C—F). 1Н NMR, δ: 2.85 (br.s, 1 Н, ОН); 3.78 (dd, 1 Н, Н(3´b),
(15.3), 128 [M – NCOCH2CHOCH2 – CF3]+ (21.9), 197 [M –
NCOCH2CHOCH2]+ (13.8), 212 [M – CH2CHOCH2
–
– HCN]+ (19.5), 219 [M – C6H5]+ (17.5), 223 [M –
– OCH2CHOCH2]+ (13.1), 224 [M – OCHCHOCH2]+ (26.1),
227 [M – CF3]+ (20.1), 238 [M – CH3CHOCH2]+ (13.2), 239
[M – CH2CHOCH2]+ (45.9), 240 [M – CHCHOCH2]+ (24.3),
241 [M – OCH=C=CH2]+ (40.6), 253 [M – CHOCH2]+ (47.2),
254 [M – CHOCH]+ (16.5), 265 [M – CH2OH]+ (99.9), 266
[M – CH2O]+ (50.4), 267 [M – CHO]+ (20.3), 279 [M – OH]+
(19.1), 295 [M – H]+ (11.6), 296 [M]+ (9.5). Found (%):
C, 56.68; H, 3.75; F, 18.97; N, 9.51. С14Н11F3N2О2. Calculatꢀ
ed (%): C, 56.76; H, 3.74; F, 19.24; N, 9.46.
2JН,Н = 11.3 Hz, 3JН,Н = 5.5 Hz); 3.83 (dd, 1 Н, Н(3´a), 2JН,Н
=
= 11.3 Hz, 3JН,Н = 5.3 Hz); 4.34 (q, 1 Н, Н(2´), J = 5.3 Hz); 4.65
(dd, 1 Н, Н(1´b), 2JН,Н = 11.2 Hz, 3JН,Н = 5.0 Hz); 4.69 (dd, 1 Н,
Н(1´a), 2JН,Н = 11.2, 3JН,Н = 5.6 Hz); 7.52—7.61 (m, 3 Н, Hm,
Hp); 7.72 (s, 1 H, H(5)); 8.13 (dd, 2 H, Ho, J = 8.2 Hz, 1.5 Hz).
19F NMR, δ: 91.63 (s, CF3). MS, m/z (Irel (%)): 223 [M –
– OCH2CHOHCH2Cl]+ (10.0), 224 [M – OCHCHOHCH2Cl]+
(17.8), 241 [M – CH2COCH2Cl]+ (99.9), 242 [M –
– CHCOCH2Cl]+ (12.3), 253 [M – CHOHCH2Cl]+ (15.8),
254 [M – CHOCH2Cl]+ (10.3), 283 [M – CH2Cl]+ (26.6), 332
[M]+ (0.1). Found (%): C, 50.66; H, 3.71; F, 17.3; N, 8.48.
С14Н12ClF3N2О2. Calculated (%): C, 50.54; H, 3.64; F, 17.13;
N, 8.42.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 09ꢀ03ꢀ
00274a), the Ministry of Education and Science of the
Russian Federation (State Contract No. 02.740.11.0260),
the Ural Branch of the Russian Academy of Sciences
(Integration Project for Fundamental Research No. 09ꢀIꢀ
3ꢀ2004), and the Council on Grants at the President of the
Russian Federation (Program for State Support of Leadꢀ
ing Scientific Schools of the Russian Federation, Grant
NShꢀ65261.2010.3).
2ꢀ(3ꢀChloroꢀ2ꢀhydroxypropoxy)ꢀ4,6ꢀbis(trifluoromethyl)ꢀ
pyrimidine (6b). The yield was 51%, oil. IR (FTIR), ν/cm–1
:
3420 (OH); 1590 (C=C, C=N); 1120—1225 (C—F). 1Н NMR,
3
δ: 2.6 (br.d, 1 Н, ОН, JН,Н = 5.8 Hz); 3.77 (dd, 1 Н, Н(3´b),
2JН,Н = 11.4 Hz, 3JН,Н = 5.5 Hz); 3.81 (dd, 1 Н, Н(3´a), 2JН,Н
=
= 11.4 Hz, 3JН,Н = 5.3 Hz); 4.32 (m, 1 Н, Н(2´)); 4.62 (dd, 1 Н,
Н(1´b), 2JН,Н = 11.3 Hz, 3JН,Н = 4.9 Hz); 4.65 (dd, 1 Н, Н(1´a),
2JН,Н = 11.3 Hz, 3JН,Н = 5.6 Hz); 7.62 (s, 1 H, H(5)). 19F NMR, δ:
91.65 (s, CF3). MS, m/z (Irel (%)): 43 [HNCO]+ (12.8), 69 [CF3]+
(12.8), 79 [CHOHCH2Cl]+ (11.2), 147 [M – OCHCHOHCH2Cl –
– CF3]+ (11.1), 163 [M – CHCHOHCH2Cl – CF3]+ (13.7), 177
[M – CHOCH2Cl – CF3]+ (12.1), 196 [M – OCH2CHOHCH2Cl –
– F]+ (11.7), 216 [M – OCHCHOHCH2Cl]+ (60.5), 217 [M –
– OCH2COCH2Cl]+ (27.4), 218 [M – OCHCOCH2Cl]+ (23.2),
233 [M – CH2COCH2Cl]+ (66.6), 245 [M – CHOHCH2Cl]+
(12.3), 246 [M – CHOCH2Cl]+ (86.2), 249 [M – O=C=CCl]+
(13.7), 275 [M – CH2Cl]+ (99.9), 325 [M+H]+ (0.3). Found (%):
C, 33.16; H, 2.14; F, 35.36; N, 8.74. С9Н7ClF6N2О2. Calculatꢀ
ed (%): C, 33.3; H, 2.17; F, 35.12; N, 8.63.
References
1. E. De Clercq, J. Med. Chem., 2010, 53, 1438.
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er, J. Balzarini, E. De Clercq, J. Med. Chem., 1989, 32, 2507.
3. H. Vorbrüggen, C. RuhꢀPohlenz, Organic Reactions, Wiley,
New York, 2004, 55, 1.
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Flores, A. F. C. Flores, H. G. Bonacorso, M. A. P. Martins,
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khimiya [Organic Chemistry], Ed. V. M. Potapov, Khimiya,
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Savel´ev, A. A. Bredikhin, Zh. Org. Khim., 2002, 38, 233 [Russ.
J. Org. Chem., 2002, 38, 213].
2ꢀ(2,3ꢀEpoxypropoxy)ꢀ6ꢀphenylꢀ4ꢀtrifluoromethylpyrimidine
(7). The yield was 19%, m.p. 82—84 °С. IR (DRA), ν/cm–1
:
1555, 1585 (C=C, C=N); 1115—1200 (C—F). 1Н NMR, δ: 2.82
(dd, 1 Н, H(3´b), 2JН,Н = 4.9 Hz, 3JН,Н = 2.6 Hz); 2.93 (dd, 1 Н,
H(3´a), 2JН,Н = 4.9 Hz, 3JН,Н = 4.2 Hz); 3.47 (dtd, 1 Н, Н(2´),
J = 5.8 Hz, J = 4.0 Hz, J = 2.6 Hz); 4.52 (dd, 1 Н, Н(1´b), 2JН,Н
=
=
6. S. Dilli, K. Robards, Austral. J. Chem., 1978, 31, 1833.
3
2
= 11.8 Hz, JН,Н = 5.8 Hz); 4.72 (dd, 1 Н, Н(1´a), JН,Н
3
= 11.8 Hz, JН,Н = 3.9 Hz); 7.51—7.60 (m, 3 Н, Hm, Hp); 7.71
(s, 1 H, H(5)); 8.14 (dd, 2 H, Ho, J = 8.2 Hz, J = 1.5 Hz).
19F NMR, δ: 91.57 (s, CF3). MS, m/z (Irel (%)): 77 [C6H5]+
Received February 2, 2011;
in revised form February 25, 2011