Synthesis of some cyclic and acyclic nucleoside analogues derived from 4-(trifluoromethyl)pyrimidines

Article abstract of DOI:10.1016/S0040-4020(01)00721-9

Cyclic nucleoside analogues 10, 11, 13b-d and 17 and acyclic derivatives 19 and 20b-d were prepared from 4-trifluoromethylpyrimidones 4a and 5b-d.

Full text of DOI:10.1016/S0040-4020(01)00721-9

TETRAHEDRON
Pergamon
Tetrahedron 57 62001) 7369±7375
Synthesis of some cyclic and acyclic nucleoside analogues derived
from 4-ꢀtri¯uoromethyl)pyrimidines
Hatice Berber,a Mustapha Soufyane,b Catherine Mirand,a,p Sylvie Schmidtc
and Anne-Marie Aubertinc
a
Á Â
Laboratoire de Transformations et Synthese de Substances Naturelles, UMR/CNRS 6013, Universite de Reims Champagne Ardenne,
Â
Faculte de Pharmacie, 51 rue Cognacq-Jay, 51096 Reims cedex, France
b
Â
Â
Departement de Chimie, Faculte des Sciences, 24000 El Jadida, Maroc
c
   Â
Institut de Virologie de la Faculte de Medecine, INSERM U74, Universite Louis Pasteur, 3rue Koeberle , 67000 Strasbourg, France
Received 16 March 2001; revised 25 May 2001; accepted 2 July 2001
AbstractÐCyclic nucleoside analogues 10, 11, 13b±d and 17 and acyclic derivatives 19 and 20b±d were prepared from 4-tri¯uoromethyl-
pyrimidones 4a and 5b±d. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Introduction of tri¯uoromethyl groups into bioactive
molecules is known to improve their therapeutic ef®cacy.
This result is related to an increased lipophilicity brought by
the substituent.1±3 The high electronegativity of ¯uorine and
the great strength of the C±F bond are also contributing
factors.
2.1. Synthesis of 4-tri¯uoromethylpyrimidones
ꢀScheme 1)
The benzoylpyrimidone 4a was obtained as previously
reported.5
In order to introduce other substituents at C-5 position of the
pyrimidine nucleus, we envisioned the preparation of new
enaminoketones by a classical enamine chemistry.6
A wide variety of methods for the synthesis of tri¯uoro-
methylated organic compounds has been developed and
efforts in this ®eld are in constant progress. Two general
approaches may be envisioned: the direct introduction of a
CF3 group into a prebuilt molecule1,2 or the use of tri¯uoro-
methylated building-blocks.2,3
Thus, 3-phenylpropionaldehyde,7 butyraldehyde and
3-methylbutyraldehyde, were converted into enamines
1b±d, respectively, by reacting with pyrrolidine or diethyl-
amine in the presence of a dehydrating reagent.6 Enamines
1b±d were not isolated 6their formation was monitored by
1H NMR). They were directly tri¯uoroacylated to enamino-
ketones 2b±d. With R1ˆCH2Ph, the pyrrolidinoenamine 2b
was obtained with 64% yield and was fully characterised.
Subsequent cyclocondensation of 2b with O-methylisourea
afforded the 2-methoxypyrimidine 3b in 74% yield. With
R1ˆEt or iPr, the cyclocondensation step of the pyrrolidino
derivatives failed, so diethylamine was preferred to pyrro-
lidine. Enaminoketones 2c and 2d proved to be very
unstable and were immediately treated by O-methylisourea
to give pyrimidines 3c and 3d in overall poor yields of 16
and 26%, respectively. Hydrolysis of 3b±d by hydrobromic
acid/acetic acid provided pyrimidones 5b±d or 4-methoxy-
dihydropyrimidones 6b±d depending on the method of
puri®cation 6column chromatography with CH2Cl2/MeOH
98:2 as eluent or recrystallisation from methanol). This
result agrees with a previous observation for 4a:5 the 3,4-
double bond easily undergoes addition of nucleophiles.
Along the second route, we previously studied the prepara-
tion of various tri¯uoromethylated heterocyclic compounds
starting from enaminodiketones.4,5
The present paper describes the further application of this
methodology to the synthesis of 4-tri¯uoromethylpyrimi-
dones and their coupling with modi®ed sugars toward
potential antiviral nucleosides.
Keywords: enaminones; pyrimidones; nucleosides; ¯uorine compounds.
Corresponding author. Tel.: 133-326-913587; fax: 133-326-918029;
e-mail: catherine.mirand@univ-reims.fr
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020601)00 721-9

7370
H. Berber et al. / Tetrahedron 57 ;2001) 7369±7375
Scheme 1.
Scheme 2. 6i) SnCl4, CH3CN, 2258C, 3 h; 6ii) NH3/MeOH, rt, 20h; 6iii) NH 4OH/MeOH 1:1, rt, 22 h; 6iv) Nal, dichloroethane, re¯ux, 4 h.

H. Berber et al. / Tetrahedron 57 ;2001) 7369±7375
7371
However whereas 6b±d were converted into 5b±d by heat-
ing, dehydration of 4a could not be achieved. Structural
distinction between 5b±d and 6b±d was deduced from
4a 6hydrated form), while nucleosides 12b±d, in the
absence of electrowithdrawing substituents at C-5, only
occured as aromatic, non hydrated forms.
1
the H and 13C NMR spectra which showed signi®cant
differences in the chemical shifts for H-6 and C-4.
In order to prepare 2-deoxyribonucleoside analogues,
condensation of 1-O-acetyl-3,5-di-O-benzoyl-2-deoxy-d-
erythro-pentafuranose 1413 with 7d was attempted. As
expected an a,b-mixture of 15 and 16 was obtained in a
28:72 ratio. After separation of the two anomers by column
chromatography, the b-anomer 16 was deprotected to 17.
Determination of the anomeric con®guration of 17 was
supported by NMR experiments, especially by observation
of 1H nuclear Overhauser effects 6nOe) between proton H-10
and proton H-20a and between proton H-30 and proton
H-20b.
2.2. Nucleoside analogues ꢀScheme 2)
Extensive studies on the synthesis and biological activity
of 5-tri¯uoromethylpyrimidine-nucleosides have been
reported.8,9,10
However 4-substituted derivatives are quite rare in the
literature. Therefore it seemed to be of interest to attempt
glycosylation and alkylation of pyrimidones 4a and 5b±d or
6b±d by several protected sugars or hydroxyalkylchlorides
in order to synthesize analogues of the heading antiviral
nucleosides AZT and HEPT.
The acyclic nucleoside analogues 19 and 20b±d were also
prepared starting from 2-methoxy-ethoxymethylchloride 18
6MEMCl) and silylated pyrimidines 7a±d, using sodium
iodide in order to favour the nucleophilic displacement.14
2.3. Biological assays
These nucleoside analogues, 10, 13b±d, 17, 19, 20b±d were
evaluated for their ability to inhibit HIV-1 multiplication in
human T4-lymphoblastoid cells, CEM-SS and MT4. Virus
released from CEM-SS in culture supernatant was quanti-
®ed by a measure of the reverse transcriptase activity
associated with the particles. None of the compounds
reduced virus production when present at concentrations
ranging from 100 mg/ml to 10 mg/ml. Under these con-
ditions, the IC50of AZT is 6 nM. To verify the lack of
antiviral activity a second type of assay was performed on
infected MT4 cells following virus multiplication by the
associated cytopathogenicity. The molecules were found
inactives. In parallel evaluations, the compounds used at
the same concentrations, did not reveal any cytotoxicity
for uninfected CEM-SS and MT4 cells.
Nucleosides were prepared according to the VorbruÈggen's
procedure 6Scheme 2).11 Activation of pyrimidones 4a and
5b±d or 6b±d was achieved with 1,1,1,3,3,3-hexamethyl-
disilazane 6HMDS) in the presence of a catalytic amount of
ammonium sulfate,12 leading to the monosilylated deriva-
tives 7b±d 6the C-4 signal deshielded to ,160ppm on the
13C NMR spectrum was in agreement with an aromatic
structure).
Couplings of the activated bases with protected sugars were
performed with tin6IV)chloride in acetonitrile at low
temperature.
3. Experimental
3.1. Antiviral assays
Thus, condensation of 7a with 1-O-acetyl-2,3,5-tri-O-
benzoyl-b-d-ribofuranose 8 gave the protected nucleoside
analogues 9e, f as a 1:1 diastereomeric mixture. As
generally observed for syntheses using that procedure, the
glycosylation reaction was regioselective and stereo-
selective and gave the N-1 substituted pyrimidine 6a three-
bond correlation was observed between the anomeric proton
H-10 and C-6 in HMBC NMR experiments) and b-nucleo-
side 6low coupling constant between H-10 and H-20).11b
Thus compounds 9e and 9f only differed by their con®gura-
tion at C-4. They were separated by repeated column
chromatographies. The available data did not allow us to
assign the de®nitive con®guration at C-4. Removal of the
benzoyl protecting groups of 9e, f was performed with
methanolic ammonia yielding 10. When the cleavage was
carried out with aqueous ammonia diluted with methanol
the 4-hydroxy derivative 11 was obtained.
The antiviral HIV-1 activity of a given compound was
measured in HIV-1 Lai infected CEM-SS cells by quanti-
®cation of the reverse transcriptase activity 6RT) associated
with virus particles released from the cells and in HIV-1 IIIb
infected MT4 cells by the inhibition of virus-induced
cytopathogenicity as already described.15
The CEM-SS cells were obtained from P. Nara through the
AIDS Research and Reference Reagent Program, Division
of AIDS, NIAID, NIH.
3.2. General techniques
Melting points were taken on a Reichert melting point
apparatus and are uncorrected. Optical rotations were deter-
mined with a Perkin-Elmer 241 polarimeter. 1H 6300 MHz)
and 13C 675 MHz) NMR spectra were recorded on a Bruker
AC 300 spectrometer. 19F NMR spectra 6235 MHz) were
recorded on a Bruker AC 250spectrometer. Chemical shifts
Similarly the ribonucleosides 13b±d were prepared from
7b±d and 8. Nucleosides 9e, f compare with the pyrimidone

7372
H. Berber et al. / Tetrahedron 57 ;2001) 7369±7375
3
are expressed in parts per million from TMS 61H and 13C) or
CFCl3 619F) as internal reference and coupling constants are
in Hz. Unless otherwise noted, NMR samples were
dissolved in CDCl3. IR spectra were recorded on a
BOMEM MB Series apparatus 6in cm21). Mass spectra
were recorded on a Fison VG Autospec spectrometer.
Elemental analyses were performed with a Perkin-Elmer
CHN 2400 apparatus. Solvents were dried before use.
1.31 6d, Jˆ6.9 Hz, 6H), 3.306sept, 3Jˆ6.9 Hz, 1H), 4.05
6s, 3H, CH3), 8.71 6s, 1H, H-6); dC 23.6, 23.7, 26.1, 55.2,
1
121.06q, JC±Fˆ275.0Hz, CF 3), 132.1 6C-5), 153.1 6q,
2JC±Fˆ34.0Hz, C-4), 161.2 6C-6), 163.5 6C-2); dF 265.7
6s, 3F, CF3).
3.4. Hydrolysis of pyrimidines 3b±d
A solution of pyrimidine and 33% HBr in acetic acid
620mL for 1.5 mmol) was left at rt for two days. The
reaction mixture was then concentrated under reduced
pressure. According to the cases, the residue was puri®ed
by recrystallisation or by ¯ash column chromatography.
3.3. General procedure for the synthesis of methoxy-
pyrimidines 3b±d
To a stirred suspension of K2CO3 61.2 equiv.) and Et2NH
61.01 equiv.) in CH2Cl2 was added dropwise aldehyde at
08C. After stirring for 3 h at rt, the precipitate was ®ltered
off. To the stirred solution of the resulting oil in CH2Cl2,
under N2, was added dropwise 6CF3CO)2O 61.2 equiv.) at
08C. The reaction mixture was gradually warmed to room
temperature over 3 h, then quenched by careful addition of
saturated aqueous Na2CO3 solution. The aqueous layer was
separated and extracted twice with CH2Cl2. The combined
organic phases were dried over MgSO4 and the solvent was
removed in vacuo. The resulting brown oil was added to a
stirred suspension of K2CO3 61.5 equiv.) and O-methyl-
isourea hemisulfate 61.5 equiv.) in CH3CN. After stirring
for 20h at rt or 60 8C, the precipitate was ®ltered off and
the solvent was evaporated under reduced pressure. The
residue was puri®ed by ¯ash column chromatography
6CH2Cl2/cyclohexane 1:1) to yield methoxypyrimidines
63b±d).
3.4.1. 5-Benzyl-4-methoxy-4-ꢀtri¯uoromethyl)-3,4-dihy-
dro-1H-pyrimidin-2-one ꢀ6b). The solid residue obtained
starting from 3b 6448 mg, 1.67 mmol) was recrystallised
from MeOH to give dihydropyrimidone 6b as a white
solid 6379 mg, 79%); nmax6KBr) 3450, 1707, 1684, 1179;
EIMS m/z 286 6M1, 42), 255 623), 217 6100); Anal. calcd for
C13H13F3N2O2: C, 54.55; H, 4.58; N, 9.79. Found: C, 54.27;
H, 4.55; N, 9.65; 6DMSO-d6) dH 3.106s, 3H, CH 3O), 3.29 6s,
2H, CH2), 5.89 6d, 3Jˆ4.7 Hz, 1H, H-6), 7.16±7.406m, 5H),
8.11 6br s, 1H), 9.00 6d, 3Jˆ4.7 Hz,1H, NH); dC 32.6, 48.7,
2
88.3 6q, JC±Fˆ31.3 Hz, C-4), 102.4 6C-5), 123.2 6q,
1JC±Fˆ288.6 Hz, CF3), 126.6, 128.7, 129.6, 130.6 6C-6),
138.5, 151.2 6C-2); dF 275.2 6s, 3F, CF3).
3.4.2. 5-Benzyl-4-ꢀtri¯uoromethyl)-1H-pyrimidin-2-one
ꢀ5b). 5b was characterized by NMR experiments starting
from 6b by heating at 608C in CDCl3. dH 3.95 6s, 2H,
CH2), 6.96±7.406m, 5H), 7.806s, 1H, H-6), 10.06br s,
1H); dC 33.0, 116.4 6C-5), 119.9 6q, 1JC±Fˆ278.6 Hz, CF3),
127.4, 128.9, 129.2, 136.8, 150.9 6C-6), 157.5 6C-2), 161.4
6q, 2JC±Fˆ31.3 Hz, C-4).
3.3.1. 3-Benzyl-1,1,1-tri¯uoro-4-pyrrolidin-1-yl-but-3-en-
2-one ꢀ2b). Yellow oil, 64%; EIMS m/z 283 6M1, 100),
3
214 665), 206 626), 186 631); dH 1.82 6t, Jˆ6.6 Hz, 4H),
3.506t, 3Jˆ6.6 Hz, 4H), 3.91 6s, 2H, CH2), 7.04±7.32 6m,
1
5H), 7.73 6s, 1H, CH); dC 26.0, 29.4, 47.3, 118.5 6q, JC±
3.4.3. 5-Ethyl-4-ꢀtri¯uoromethyl)-1H-pyrimidin-2-one
ꢀ5c). The residue obtained starting from 3c 6300 mg,
1.46 mmol) was puri®ed by ¯ash column chromatography
6CH2Cl2/MeOH 97:3) to give pyrimidone 5c as a white solid
6260mg, 93%); mp 138±140 8C; nmax6KBr) 3400, 1655,
1275, 1194, 1142; EIMS m/z 192 6M1, 55), 177 6100),
ˆ291.9 Hz, CF3), 125.6, 127.2, 128.4, 141.4, 151.9 6CH),
F
2
177.7 6q, JC±Fˆ30.6 Hz, CˆO).
3.3.2. 5-Benzyl-2-methoxy-4-ꢀtri¯uoromethyl)pyrimidine
ꢀ3b). Pale yellow oil, 74%; nmax6®lm) 1595, 1478, 1389,
1316, 1194, 1136, 1044; EIMS m/z 268 6M1, 100), 238
626), 183 617); HRMS calcd for C13H11F3N2O: 268.0819.
Found: 268.0823; dH 4.02 6s, 3H, CH3±O), 4.106s, 2H,
CH2), 7.08±7.38 6m, 5H), 8.46 6s, 1H, H-6); dC 33.4,
150624); HRMS calcd for C H7F3N2O: 192.0515. Found:
7
192.0510. dH 1.206t, 3Jˆ7.5 Hz, 3H, CH3), 2.68 6q,
3Jˆ7.5 Hz, 2H, CH2), 8.206s, 1H, H-6), 11.4 6br s, 1H);
dC 14.2, 20.4, 118.0 6C-5), 120.0 6q, 1JC±Fˆ278.6 Hz, CF3),
1
55.4, 119.1 6q, JC±Fˆ276.7 Hz, CF3), 126.06C-5), 126.9,
2
2
128.7, 128.9, 137.8, 154.3 6q, JC±Fˆ34.3 Hz, C-4), 164.0
149.5 6C-6), 157.6 6C-2),162.06q, JC±Fˆ34.5 Hz, C-4); dF
6C-2), 164.2 6C-6); dF 266.3 6s, 3F, CF3).
268.7 6s, 3F, CF3).
3.3.3. 5-Ethyl-2-methoxy-4-ꢀtri¯uoromethyl)pyrimidine
ꢀ3c). Oil, 16%; nmax6®lm) 1595, 1480, 1393, 1190, 1138;
EIMS m/z 206 6M1, 100), 191 660), 176 686); HRMS calcd
for C8H9F3N2O: 206.0689. Found: 206.0667; dH 1.24 6t,
3.4.4. 5-Ethyl-4-methoxy-4-ꢀtri¯uoromethyl)-3,4-dihydro-
1H-pyrimidin-2-one ꢀ6c). The solid residue obtained start-
ing from 3c 6300 mg, 1.46 mmol) was recrystallised from
MeOH to give 6c as a white solid 6235 mg, 72%); 6DMSO-
d6) dH 1.00 6t, 3Jˆ7.3 Hz, 3H, CH3), 1.98 6q, 3Jˆ7.3 Hz, 2H,
3
3Jˆ7.6 Hz, 3H, CH3), 2.79 6q, Jˆ7.6 Hz, 2H, CH2), 4.05
3
6s, 3H, CH3±O), 8.59 6s, 1H, H-6); dC 15.3, 21.3, 55.2,
CH2), 3.06 6s, 3H, CH3O), 6.38 6d, Jˆ5.1 Hz, 1H, H-6),
1
121.06q, JC±Fˆ276.5 Hz, CF3), 127.3 6C-5), 154.06q,
8.00 6br s, 1H), 9.08 6br s, 1H); dC 12.2, 18.9, 48.5, 88.3 6q,
2JC±Fˆ34.5 Hz, C-4), 163.3 6C-6), 163.8 6C-2); dF 266.8
6s, 3F, CF3).
2JC±Fˆ30.9 Hz, C-4), 103.1 6C-5), 123.0 6q, JC±
1
ˆ288.5 Hz, CF3), 128.06C-6), 151.1 6C-2).
F
3.3.4. 5-Isopropyl-2-methoxy-4-ꢀtri¯uoromethyl)pyrimi-
dine ꢀ3d). Oil, 26%; nmax6®lm) 1593, 1480, 1391, 1188,
1138, 1045; EIMS m/z 2206M 1, 40), 205 6100); HRMS
calcd for C9H11F3N2O: 220.0817. Found: 220.0823; dH
3.4.5. 5-Isopropyl-4-ꢀtri¯uoromethyl)-1H-pyrimidin-2-one
ꢀ5d). The solid residue obtained starting from 3d 6404 mg,
1.84 mmol) was recrystallised from 6CH2Cl2/cyclohexane
1:1) and the mother liquor was chromatographied

H. Berber et al. / Tetrahedron 57 ;2001) 7369±7375
7373
0
6CH2Cl2/MeOH 97:3) to give pyrimidone 5d all together as
a white solid 6354 mg, 93%); mp 168±1698C; nmax6KBr)
3437, 1643, 1190, 1142, 1049; EIMS m/z 206 6M1, 24),
7.28±8.03 6m, 22H); dC 64.06C-5 ), 71.1 6C-30), 73.1 6C-
2
20), 79.9 6C-40), 82.2 6q, JC±Fˆ34.6 Hz, C-4), 87.7 6C-10),
1
106.3 6C-5), 123.3 6q, JC±Fˆ290.0 Hz, CF3), 128.3±133.8
3
191 6100); dH 1.22 6d, Jˆ6.9 Hz, 6H, 2£CH3), 3.13 6m,
6CH-ar), 136.3, 141.7 6C-6), 148.2 6C-2), 165.2, 165.3,
165.9, 196.0; dF 287.1 6s, 3F, CF3).
1H, CH), 8.36 6s, 1H, H-6), 9.95 6br s, 1H); dC 23.4, 23.6,
1
25.7, 120.1 6q, JC±Fˆ276.7 Hz, CF3), 123.4 6C-5), 149.2
2
6C-6), 157.7 6C-2), 160.6 6q, JC±Fˆ34.0Hz, C-4); dF
3.5.2. 5-Benzyl-1-ꢀ2,3,5-tri-O-benzoyl-b-d-ribofurano-
syl)-4-ꢀtri¯uoromethyl)-1H-pyrimidin-2-one ꢀ12b). White
solid, 90%, mp 65±678C; nmax6KBr) 1730, 1686, 1269, 710;
EIMS m/z 698 6M1, 7), 445 6M1, 62), 201 652), 105 6100);
Anal. calcd for C38H29F3N2O8: C, 65.33; H, 4.18; N, 4.01.
Found: C, 65.64; H, 4.21; N, 3.72; dH 3.69 6d, 2Jˆ16.4 Hz,
267.6 6s, 3F, CF3).
3.4.6.
5-Isopropyl-4-methoxy-4-ꢀtri¯uoromethyl)-3,4-
dihydro-1H-pyrimidin-2-one ꢀ6d). The solid residue
obtained starting from 3d 6706 mg, 3.20 mmol) was recrys-
tallised from MeOH to give the product 6d as a white solid
6480mg, 63%); EIMS m/z 238 6M1, 5), 207 634), 191 613),
169 6100); HRMS calcd for C9H13F3N2O2: 238.0929.
2
1H, CHa-Ph), 3.83 6d, Jˆ16.4 Hz, 1H, CHb-Ph), 4.51 6m,
2H, H-50), 4.76 6m, 1H, H-40), 5.78 6m, 2H), 6.39 6d,
3Jˆ4.3 Hz, 1H, H-10), 7.00±7.60 6m, 14H), 7.64 6s, 1H,
H-6), 7.96 6m, 6H, Ho); dC 33.0, 63.9 6C-50), 71.5, 75.0,
81.3 6C-40), 90.2 6C-10), 114.1 6C-5), 119.7 6q,
1JC±Fˆ278.7 Hz, CF3), 127.3±136.5 6C-ar), 146.2 6C-6),
3
Found: 238.0929; 6DMSO-d6) dH 1.04 6d, Jˆ6.8 Hz, 3H),
3
1.106d, Jˆ6.8 Hz, 3H), 2.32 6sept, 3Jˆ6.8 Hz, 1H), 3.11 6s,
3H, CH3O), 6.506d, 3Jˆ5.4 Hz, 1H, H-6), 8.00 6br s, 1H),
3
2
9.106d, Jˆ3.9 Hz, 1H, NH); dC 24.1, 24.3, 25.7, 49.1, 88.5
153.3 6C-2), 161.7 6q, JC±Fˆ35.3 Hz, C-4), 165.2, 165.8;
2
1
6q, JC±Fˆ31.0Hz, C-4), 108.6 6C-5), 123.2 6q, JC±F
288.4 Hz, CF3), 128.6 6C-6), 151.1 6C-2).
ˆ
dF 268.6 6s, 3F, CF3).
3.5.3. 1-ꢀ2,3,5-Tri-O-benzoyl-b-d-ribofuranosyl)-5-ethyl-
4-ꢀtri¯uoromethyl)-1H-pyrimidin-2-one ꢀ12c). White
solid, 76%, mp 67±698C; nmax6KBr) 1728, 1683, 1269,
710; CIMS m/z 637 6M111, 13), 514 632), 445 6100), 201
624), 105 667); Anal. calcd for C33H27F3N2O8: C, 62.26; H,
4.27; N, 4.40. Found: C, 62.49; H, 3.94; N, 4.20; dH 0.95 6t,
3Jˆ7.5 Hz, 3H, CH3), 2.36 6m, 2H, CH2), 4.72 6dd,
3.5. General procedure for the preparation of nucleoside
analogues
Pyrimidone 4a or 5 vs 6 61.2 equiv./sugar) was re¯uxed with
an excess of HMDS 62±4 mL) and a catalytic amount of
6NH4)2SO4 until a clear solution was obtained 6for 3 h). The
excess of HMDS was removed by distillation in vacuo and
the silylated base was dissolved in CH3CN. A solution of the
protected sugar 8 or 14 in CH3CN was then added at rt under
N2. SnCl4 61.8±2 equiv./sugar) 61 M in CH2Cl2) was added
dropwise at 2258C. After stirring for 3 h at rt, the reaction
mixture was diluted with CH2Cl2, then quenched with
aqueous saturated NaHCO3 solution. The aqueous layer
was extracted twice with CH2Cl2 and the combined organic
phases were washed with water and dried over MgSO4. The
solvent was evaporated in vacuo and the residue was puri-
®ed by ¯ash column chromatography 6cyclohexane/AcOEt
80:20) to obtain nucleoside analogues.
2
3
0
0
0
0
0
J5 a-5 bˆ12.4 Hz, J5 a-4 ˆ4.0Hz, 1H, H-5 a), 4.83 6m, 1H,
2
3
H-40), 4.94 6dd, J5 b-5 aˆ12.4 Hz, J5 b-4 ˆ2.5 Hz, 1H, H-
0
0
0
0
3
3
50b), 5.79 6t, J2 -3 ˆ J2 -1 ˆ5.7 Hz, 1H, H-2 ), 5.95 6dd,
0
0
0
0
0
3
3
J3 -4 ˆ4.4 Hz, 1H, H-30), 6.56 6d,
0
0
0
0
J3 -2 ˆ5.7,
3
0
0
0
J1 -2 ˆ5.6 Hz, 1H, H-1 ), 7.30±7.69 6m, 9H), 7.88 6s, 1H,
H-6), 8.00 6m, 4H, Ho), 8.106m,02H, H o); dC 14.1, 20.5, 63.7
6C-50), 71.3 6C-30), 75.06C-2 ), 81.6 6C-40), 89.2 6C-10),
1
116.6 6C-5), 119.7 6q, JC±Fˆ279.2 Hz, CF3), 128.3±133.8
2
6C-ar), 144.4 6C-6), 153.5 6C-2), 162.06q, JC±Fˆ35.0Hz,
C-4), 165.3,165.4, 166.0; dF 268.7 6s, 3F, CF3).
3.5.4. 1-ꢀ2,3,5-Tri-O-benzoyl-b-d-ribofuranosyl)-5-iso-
propyl-4-ꢀtri¯uoromethyl)-1H-pyrimidin-2-one ꢀ12d).
White solid, 82%, mp 68±698C; nmax6KBr) 1728, 1682,
1269, 710; EIMS m/z 6506M 1, 9), 445 642), 105 6100);
Anal. calcd for C34H29F3N2O8: C, 62.77; H, 4.49; N, 4.31.
3.5.1. 5-Benzoyl-1-ꢀ2,3,5-tri-O-benzoyl-b-d-ribofurano-
syl)-4-hydroxy-4-ꢀtri¯uoromethyl)-3,4-dihydro-1H-pyri-
midin-2-one ꢀ9e,f). White solid, 85%, 2 diastereomers;
3
Found: C, 62.58; H, 4.32; N, 4.02; dH 0.90 6d, Jˆ6.8 Hz,
n
max6KBr) 3427, 3308, 2924, 1728, 1651, 1267; EIMS m/z
3H, CH3), 1.106d, 3Jˆ6.8 Hz, 3H, CH3), 3.02 6sept,
712 6M12H2O, 11), 687 621), 590 675), 445 699), 201 6100);
Anal. calcd for C38H29F3N2O10: C, 62.47; H, 4.00; N, 3.83.
Found: C, 62.37; H, 3.99; N, 3.68. 9e 6less polar): mp
2
3
3Jˆ6.8 Hz, 1H), 4.76 6dd, J5 a-5 bˆ12.1 Hz, J5 a-4
ˆ
ˆ
ˆ
0
0
0
0
2
4.2 Hz, 1H, H-50a), 4.82 6m, 1H, H-40), 4.91 6dd, J5 b-5 a
0
0
12.1 Hz, 3J5 b-4 ˆ2.4 Hz, 1H, H-5 b), 5.76 6t, J2 -3 ˆ J2 -1
3
3
90±928C; [a]26 ˆ2254.9 6c 1.00, CH2Cl2); dH 4.44 6dd,
0
0
0
0
0
0
0
D
3
3
2
2
3
0
0
0
0
0
0
0
0
0
5.9 Hz, 1H, H-20), 5.96 6dd, J3 -2 ˆ5.9 Hz, J3 -4 ˆ3.9 Hz,
J5 a-5 bˆ12.3 Hz, J5 a-4 ˆ2.1 Hz, 1H, H-5 a), 4.64 6dd,
3
3
0
0
0
0
0
0
0
0
1H, H-30), 6.57 6d, J1 -2 ˆ5.9 Hz, 1H, H-1 ), 7.30±7.68 6m,
9H), 8.00 6m, 5H), 8.11 6m, 2H); dC 23.4, 23.5, 25.6, 64.0
6C-50), 71.5 6C-30), 75.1 6C-20), 81.7 6C-40), 89.3 6C-10),
J5 b-5 aˆ12.3 Hz, J5 b-4 ˆ3.3 Hz, 1H, H-5 b), 4.68 6m, 1H,
3
3
H-40), 5.58 6t, J2 -3 ˆ J2 -1 ˆ6.3 Hz, 1H, H-2 ), 5.75 6dd,
0
0
0
0
0
3
3
J3 -4 ˆ2.7 Hz, J3 -2 ˆ5.7 Hz, 1H, H-30), 6.39 6d,
0
0
0
0
1
3
0
0
0
119.8 6q, JC±Fˆ278.0Hz, CF 3), 122.1 6C-5), 128.3±133.8
J1 -2 ˆ6.8 Hz, 1H, H-1 ), 7.13±8.03 6m, 22H); dC 64.9
2
6C-50), 71.8 6C-30), 73.6 6C-20), 80.7 6C-40), 82.3 6q,
6C-ar), 143.6 6C-6), 153.3 6C-2), 161.4 6q, JC±Fˆ34.0Hz,
2
0
C-4), 165.3,165.4, 166.1; dF 267.6 6s, 3F, CF3).
JC±Fˆ34.0Hz, C-4), 86.7 6C-1 ), 105.9 6C-5), 123.3 6q,
1JC±Fˆ287.8 Hz, CF3), 128.3±133.8 6CH-ar), 135.5, 140.5
6C-6), 147.8 6C-2), 165.36, 165.40, 165.45, 195.5; dF 286.4
3.5.5. 1-ꢀ3,5-Di-O-benzoyl-2-deoxy-a,b-d-erythro-pento-
furanosyl)-5-isopropyl-4-ꢀtri¯uoromethyl)-1H-pyrimi-
din-2-one ꢀ15 and 16). 67%. a anomer 615): white solid,
19%; dH 0.80 6d, 3Jˆ6.8 Hz, 3H), 1.16 6d, 3Jˆ6.8 Hz, 3H),
6s, 3F, CF3). 9f 6more polar): mp 70±728C; [a]23 ˆ223.7
D
3
0
0
0
6c 1.01, CH2Cl2); dH 4.506d, J5 -4 ˆ4.3 Hz, 2H, H-5 ), 4.65
3
3
3
0
0
0
0
0
0
0
6q, J4 -5 ˆ J4 -3 ˆ4.3 Hz, 1H, H-4 ), 5.69 6t, J2 -3
ˆ
ˆ
3
3
3
3
0
0
0
0
0
0
2.86±3.14 6m, 3H), 4.68 6d, Jˆ3.9 Hz, 2H, H-50), 4.92 6t,
00
J2 -1 ˆ5.7 Hz, 1H, H-2 ), 5.75 6dd, J3 -4 ˆ4.3, J3 -2
3
3
5.7 Hz, 1H, H-30), 6.16 6d, J1 -2 ˆ5.7 Hz, 1H, H-1 ),
0
0
3Jˆ3.9 Hz, 1H, H-40), 5.59 6d, Jˆ5.5 Hz, 1H, H-30), 6.30

7374
H. Berber et al. / Tetrahedron 57 ;2001) 7369±7375
6d, 3Jˆ5.9 Hz, 1H, H-10), 7.21±7.706m, 8H), 8.01±8.15 6m,
89.4 and 90.2 62£C-10), 105.8 and 106.0 62£C-5), 124.2 6q,
1
3H); dC 23.0, 24.3, 25.6, 38.2 6CH2, C-20), 63.8 6CH2, C-50),
1JC±Fˆ288.1 Hz, CF3), 124.3 6q, JC±Fˆ287.4 Hz, CF3),
1
74.9, 86.7, 90.7 6C-10), 120.0 6q, JC±Fˆ278.6, CF3), 121.0
128.1±140.3 6m, C-ar), 145.7 and 145.8 62£C-6), 151.9
and 152.062 £C-2), 193.7 and 193.9 62£CvO); dF 280.2
and 279.8 62£6s, 3F, CF3)).
6C-5), 128.4±133.9 6C-ar), 143.5 6C-6), 153.4 6C-2), 160.3
6q, 2JC±Fˆ34.3 Hz, C-4), 165.5, 165.9. b anomer 616): white
solid, 48%; nmax6KBr) 1723, 1678, 1512, 1453, 1271, 1196,
1105, 712; dH 0.90 6d, 3Jˆ6.9 Hz, 3H, CH3), 1.13 6d,
3Jˆ6.9 Hz, 3H, CH3), 2.31 6m, 1H, H-20a), 3.03 6m, 1H,
3.6.2. 5-Benzyl-1-ꢀb-d-ribofuranosyl)-4-ꢀtri¯uoromethyl)-
1H-pyrimidin-2-one ꢀ13b). White solid, 92%, mp 177±
1798C; nmax6KBr) 3440, 1665, 1287, 1202, 1144; EIMS
m/z 386 6M1, 26), 297 614), 255 6100), 133 616); Anal.
calcd for C17H17F3N2O5: C, 52.85; H, 4.43; N, 7.25.
Found: C, 52.66; H, 4.33; N, 7.28; 6CD3OD) dH 3.51 6dd,
2
3
0
0
0
0
CH), 3.32 6dd, J2 b-2 aˆ14.7 Hz, J2 b-1 ˆ5.6 Hz, 1H,
3
H-20b), 4.70±4.88 6m, 3H), 5.65 6d, Jˆ6.4 Hz, 1H, H-30),
3
3
6.32 6dd, J1 -2 aˆ8.1 Hz, J1 -2 bˆ5.6 Hz, 1H, H-10), 7.38±
7.706m, 6H), 7.906m, 2H), 8.09 6m, 2H), 8.21 6s, 1H, H-6);
dC 23.4, 23.6, 25.7, 39.5 6C-20), 64.4 6C-50), 75.3, 84.5, 88.9
0
0
0
0
2
2
3
0
0
0
0
0
J5 a-5 bˆ12.4 Hz, J5 a-4 ˆ2.7 Hz, 1H, H-5 a), 3.906dd,
6C-10), 119.9 6q, 1JC±Fˆ279.0Hz, CF 3), 121.5 6C-5), 128.3±
J5 b-5 aˆ12.4 Hz, J5 b-4 ˆ2.2 Hz, 1H, H-5 b), 3.95 6s, 2H,
3
0
0
0
0
0
2
133.7 6C-ar), 143.2 6C-6), 153.2 6C-2), 160.4 6q, JC±F
34.3 Hz, C-4), 165.9, 166.0.
3
0
0
ˆ
CH2), 4.04±4.14 6m, 2H), 4.18 6dd, J2 -3 ˆ4.5 Hz,
3
3
0
0
0
0
0
J2 -1 ˆ1.4 Hz, 1H, H-2 ), 5.87 6d, J1 -2 ˆ1.4 Hz, 1H,
H-10), 7.10±7.38 6m, 5H), 8.84 6s, 1H, H-6); dC 34.2, 60.9
6C-50), 69.5, 76.5 6C-20), 86.0, 94.1 6C-10), 115.4 6C-5),
3.5.6. 5-Benzoyl-4-hydroxy-1-ꢀb-d-ribofuranosyl)-4-ꢀtri-
¯uoromethyl)-3,4-dihydro-1H-pyrimidin-2-one ꢀ11). To
a solution of NH4OH 67 mL) in MeOH 67 mL) was added
9e, f 6220mg, 0.3 mmol) and the solution was stirred at rt
for 22 h. The reaction mixture was neutralized by diluted
HCl and the aqueous layer was separated and extracted with
AcOEt 63£15 mL). The combined organic layers were dried
over MgSO4 and the solvent was removed in vacuo. The
residue was puri®ed by ¯ash chromatography 6CH2Cl2/
MeOH 96:4) to give 11 as a white solid 663 mg, 2 dia-
stereomers, 50%); nmax6KBr) 3435, 1705, 1643, 1279,
1194; EIMS m/z 418 6M1, 0.5), 400 6M12H2O, 31), 349
613), 269 6100), 133 637); Anal. calcd. for C17H17F3N2O7: C,
48.81; H, 4.09; N, 6.70. Found: C, 48.45; H, 4.01; N, 6.51;
1
121.5 6q, JC±Fˆ278.1 Hz, CF3), 127.8, 129.5, 129.8,
2
139.7, 150.7 6C-6), 155.9 6C-2), 161.6 6q, JC±Fˆ34.3 Hz,
C-4); dF 265.2 6s, 3F, CF3).
3.6.3. 5-Ethyl-1-ꢀb-d-ribofuranosyl)-4-ꢀtri¯uoromethyl)-
1H-pyrimidin-2-one ꢀ13c). White solid, 94%, mp 180±
1828C; nmax6KBr) 3400, 1676, 1289, 1198, 1146; EIMS
m/z 324 6M1, 48), 193 6100), 133 628); Anal. calcd for
C12H15F3N2O5: C, 44.45; H, 4.66; N, 8.64. Found: C,
3
44.20; H, 4.24; N, 8.30; 6CD3OD) dH 1.21 6t, Jˆ7.5 Hz,
3
2
0
0
3H), 2.62 6q, Jˆ7.5 Hz, 2H), 3.83 6dd, J5 a-5 bˆ12.4 Hz,
3
2
0
0
0
0
0
J5 a-4 ˆ1.8 Hz, 1H, H-5 a), 4.04 6dd, J5 b-5 aˆ12.4 Hz,
3
0
0
0
J5 b-4 ˆ2.0Hz, 1H, H-5 b), 4.10±4.23 6m, 3H), 5.88 6s,
0
1H, H-10), 9.03 6s, 1H, H-6); dC 14.8, 21.7, 60.3 6C-50),
69.0, 76.5, 85.8, 94.0 6C-10), 118.1 6C-5), 121.6 6q,
1JC±Fˆ277.9 Hz, CF3), 149.4 6C-6), 156.06C-2), 161.4 6q,
2JC±Fˆ34.3 Hz, C-4); dF 265.7 6s, 3F, CF3).
6CD3OD) dH 3.25±3.606m, 2H, H-5 ), 3.85±4.106m, 3H,
3
H-20, H-30 and H-40), 5.806d, J1 -2 ˆ4.9 Hz, 0.5H, H-1 ),
0
0
0
5.89 6d, 3J1 -2 ˆ5.5 Hz, 0.5H, H-1 ), 7.50±7.90 6m, 7H, H-ar
and H-6); dC 62.5 and 62.7 62£C-50), 71.9 and 72.062 £CH),
75.4 and 75.7 62£CH), 76.0±76.3 6m, 2£C-4), 86.1 and 86.3
62£CH), 89.4 and 90.8 62£C-10), 107.5 and 107.7 62£C-5),
125.2 6q, 1JC±Fˆ288.8 Hz, CF3), 125.3 6q, 1JC±Fˆ289.6 Hz,
CF3), 128.1±140.3 6C-ar), 144.2 and 144.4 62£C-6), 150.8
and 150.9 62£C-2), 197.0and 197.3 62 £CvO); dF 283.3
and 282.8 62£6s, 3F, CF3)).
0
0
0
3.6.4.
5-Isopropyl-1-ꢀb-d-ribofuranosyl)-4-ꢀtri¯uoro-
methyl)-1H-pyrimidin-2-one ꢀ13d). White solid, 94%,
mp 186±1888C; nmax6KBr) 3410, 1659; EIMS m/z 338
6M1, 15), 191 627), 207 6100), 133 617); Anal. calcd for
C13H17F3N2O5: C, 46.16; H, 5.06; N, 8.28. Found: C,
46.43; H, 4.76; N, 8.17; 6CD3OD) dH 31.24 6m, 6H), 3.10
2
0
0
0
0
6m, 1H), 3.85 6dd, J5 a-5 bˆ12.2 Hz, J5 a-4 ˆ1.4 Hz, 1H,
3.6. General procedure for the deprotection of nucleo-
side analogues
2
3
H-50a), 4.06 6dd, J5 b-5 aˆ12.2 Hz, J5 b-4 ˆ1.7 Hz, 1H,
H-50b), 4.10±4.20 6m, 3H), 5.89 6s, 1H, H-1 0), 9.13 6s,
1H, H-6); dC 23.9, 24.1, 27.5, 60.0 6C-50), 68.7, 76.6,
0
0
0
0
The benzoylated nucleoside analogues were saponi®ed with
methanolic ammonia 620mL for 1 mmol). After stirring for
20h at rt, MeOH and NH 3 were evaporated in vacuo. The
residue was puri®ed by ¯ash chromatography 6CH2Cl2/
MeOH 96:4) to give nucleoside analogues.
1
85.6, 94.1 6C-10), 121.7 6q, JC±Fˆ277.8 Hz, CF3), 123.6
2
6C-5), 148.9 6C-6), 155.8 6C-2), 160.5 6q, JC±Fˆ33.9 Hz,
C-4); dF 264.7 6s, 3F, CF3).
3.6.5. 1-ꢀ2-Deoxy-b-d-erythro-pentofuranosyl)-5-isopropyl-
4-ꢀtri¯uoromethyl)-1H-pyrimidin-2-one ꢀ17). White
solid, 78%; nmax6KBr) 3450, 1653, 1281, 1198, 1144,
1096; EIMS m/z 322 6M1, 9), 141 677), 117 6100); HRMS
3.6.1. 5-Benzoyl-4-methoxy-1-ꢀb-d-ribofuranosyl)-4-ꢀtri-
¯uoromethyl)-3,4-dihydro-1H-pyrimidin-2-oneꢀ10).
White solid, 2 diastereomers, 77%; nmax6KBr) 3441, 1701,
1653, 1281, 1180, 1082; EIMS m/z 401 6M1-MeO, 10), 269
6100), 191 619), 133 624); Anal. calcd for C18H19F3N2O7: C,
50.01; H, 4.43; N, 6.48. Found: C, 50.02; H, 4.38; N, 6.27;
6CD3OD) dH 3.45 62£6s, 3H, CH3)), 3.46 and 3.55 6m, 2H,
2£H-50), 3.80and 4.05 6m, 3H, 2 £6H-20,30,40)), 5.84 6d,
H-10), 7.40±7.90 6m, 6H); dC 51.1 and 51.3 62£CH3),
62.5 and 62.8 62£C-50), 72.0and 72.1 62 £CH), 75.4 and
75.5 62£CH), 75.7±76.3 6m, 2£C-4), 86.3 and 86.7 62£CH),
calcd for C13H17F3N2O4: 322.1127. Found: 322.1140;
0
2
0
6CD3OD) dH 1.26 6m, 6H, 2£CH3), 2.27 6ddd, J2 b-2 a
ˆ
3
3
0
0
0
0
0
13.8 Hz, J2 b-3 ˆ6.3 Hz, J2 b-1 ˆ4.3 Hz, 1H, H-2 b), 2.60
2
3
3
0
0
0
0
0
0
6ddd, J2 a-2 bˆ13.8 Hz, J2 a-3 ˆ5.7 Hz, J2 a-1 ˆ6.2 Hz,
2
1H, H-20a), 3.11 6m, 1H, CH), 3.78 6dd, J5 a-5 bˆ12.1 Hz,
0
0
3
2
3
3
0
0
0
0
0
0
0
0
0
0
J5 a-4 ˆ2.6 Hz, 1H, H-5 a), 3.92 6dd, J5 b-5 aˆ12.1 Hz,
0 0
0 0
J1 -2 ˆ5.4 Hz, 0.5H, H-1 ), 5.906d, J1 -2 ˆ5.5 Hz, 0.5H,
3
J5 b-4 ˆ2.6 Hz, 1H, H-5 b), 4.05 6m, 1H, H-4 ), 4.39 6m,
3
3
1H, H-30), 6.19 6dd, J1 -2 aˆ6.2 Hz, J1 -2 bˆ4.3 Hz, 1H,
0
0
0
0
H-10), 9.106s, 1H, H-6); dC 23.9, 24.1, 27.5, 42.6 6C-20),

H. Berber et al. / Tetrahedron 57 ;2001) 7369±7375
7375
61.4 6C-50), 70.3 6C-30), 89.8 6C-40), 90.0 6C-10), 121.8 6q,
1JC±Fˆ277.9 Hz, CF3), 123.4 6C-5), 148.5 6C-6), 155.7
nmax6®lm) 1686, 1514, 1279, 1196, 1140; EIMS m/z 294
6M1, 11), 220 657), 207 6100), 191 629), 107 641); Anal.
calcd for C12H17F3N2O3: C, 48.98; H, 5.82; N, 9.52. Found:
2
6C-2), 160.4 6q, JC±Fˆ34.3 Hz, C-4).
3
C, 49.05; H, 5.95; N, 9.37; dH 1.21 6d, Jˆ6.9 Hz, 6H,
2£CH3), 3.12 6m, 1H, CH), 3.35 6s, 3H, CH3O), 3.55 6m,
2H, CH2), 3.81 6m, 2H, CH2), 5.406s, 2H, CH 2), 8.04 6s, 1H,
H-6); dC 23.6, 23.8, 25.6, 58.8, 70.2, 71.2, 79.4, 119.8 6q,
1JC±Fˆ279.0Hz, CF 3), 121.5 6C-5), 149.2 6C-6), 154.1
6C-2), 160.7 6q, 2JC±Fˆ34.3 Hz, C-4); dF 265.6 6s, 3F, CF3).
3.7. General procedure for the synthesis of acyclo-
nucleosides
Pyrimidone 4a or 5 vs 6 was re¯uxed with an excess of
HMDS 62±4 mL) and a catalytic amount of 6NH4)2SO4
until a clear solution was obtained 6for 3 h). The excess of
HMDS was removed by distillation in vacuo and 18 61.4±
2 equiv.) was added under N2 at rt. Then a suspension of NaI
61.1 equiv.) in 1,2-dichloroethane was added at rt. The
reaction mixture was re¯uxed for 4 h, then quenched with
aqueous Na2S2O3 solution at rt. After extraction with AcOEt
63£), the combined organic layers were dried over MgSO4
and the solvent was evaporated. The residue was puri®ed by
¯ash column chromatography 6CH2Cl2/MeOH 98:2) to give
acyclonucleosides.
Acknowledgements
Á
We thank the `Ministere de l'Education Nationale, de la
Recherche et de la Technologie' for ®nancial support and
for a fellowship 6H. B.), P. Sigaut 6MS), C. Petermann
6RMN), H. Baillia 6NOE) for spectroscopic recordings,
Â
S. Lanthony for microanalysis and Professor J. Levy for
fruitful advices.
References
3.7.1. 5-Benzoyl-4-hydroxy-1-ꢀ2-methoxy-ethoxymethyl)-
4-ꢀtri¯uoromethyl)-3,4-dihydro-1H-pyrimidin-2-one ꢀ19).
White solid, 36%; nmax6KBr) 3430, 1717, 1657, 1624, 1447,
1335, 1283, 1186, 1090; EIMS m/z 375 6M1 11, 17), 357
634), 305 6100), 139 652), 105 691); Anal. calcd for
C16H17F3N2O5: C, 51.34; H, 4.58; N, 7.48. Found: C,
1. Nucleophilic tri¯uoromethylation: Singh, R. P.; Shreeve, J. M.
Tetrahedron 2000, 56, 7613±7632.
2. Lin, P.; Jiang, J. Tetrahedron 2000, 56, 3635±3671.
3. Recent examples: 6a) Andrew, R. J.; Mellor, J. M.; Reid, G.
Tetrahedron 2000, 56, 7255±7260. 6b) Andrew, R. J.; Mellor,
J. M. Tetrahedron 2000, 56, 7261±7266. 6c) Andrew, R. J.;
Mellor, J. M. Tetrahedron 2000, 56, 7267±7272. 6d) Tyvorskii,
V. I.; Bobrov, D. N.; Kulinkovich, O. G.; Aelterman, W.; De
Kimpe, N. Tetrahedron 2000, 56, 7313±7318 and references
therein.
50.93; H, 4.45; N, 7.41; dH 3.32 6s, 3H, CH3O), 3.506m,
2
2H, CH2), 3.706m, 2H, CH ), 5.05 6d, Jˆ10.7 Hz, 1H,
2
2
CHa), 5.11 6d, Jˆ10.7 Hz, 1H, CHb), 6.00 6br s, 1H),
7.31 6s, 1H, H-6), 7.45±7.75 6m, 5H); dC 58.9, 68.6, 71.5,
2
76.7, 82.8 6q, JC±Fˆ34.2 Hz, C-4), 105.8 6C-5), 123.4 6q,
1JC±Fˆ289.7 Hz, CF3), 128.9, 129.3, 133.4, 136.5, 144.9
6C-6), 149.06C-2), 196.2; dF 286.9 6s, 3F, CF3).
Â
4. Soufyane, M.; Mirand, C.; Levy, J. Tetrahedron Lett. 1993,
34, 7737±7740.
5. Soufyane, M.; Van den Broek, S.; Khamliche, L.; Mirand, C.
Heterocycles 1999, 51, 2445±2451.
3.7.2. 5-Benzyl-1-ꢀ2-methoxy-ethoxymethyl)-4-ꢀtri¯uoro-
methyl)-1H-pyrimidin-2-one ꢀ20b). 80%, oil; nmax6®lm)
1680, 1510, 1198, 1142, 1107, 995; EIMS m/z 342 6M1,
19), 305 640), 268 651), 255 6100), 238 652); Anal. calcd
for C16H17F3N2O3: C, 56.14; H, 5.00; N, 8.18. Found: C,
6. Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.;
Terrell, R. J. Am. Chem. Soc. 1963, 85, 207±222.
7. The non commercial 3-phenylpropionaldehyde was prepared
by oxidation of 3-phenylpropan-1-ol using pyridinium
chlorochromate 6PCC): Kang, J.; Lim, G. J.; Yoon, S. K.;
Kim, M. Y. J. Org. Chem. 1995, 60, 564±577.
8. 5-Tri¯uoromethyl-20-deoxyuridine: Kobayashi, Y.; Yamamoto,
K.; Asai, T.; Nakano, M.; Kumadaki, I. J. Chem. Soc., Perkin
Trans. 1 1980, 2755±2761 and references therein.
56.06; H, 4.90; N, 8.12; dH 3.306s, 3H, CH ), 3.75 6m,
3
2H, CH2), 3.91 6s, 2H, CH2), 5.32 6s, 2H, CH2), 7.09±7.45
6m, 5H), 7.56 6s, 1H, H-6); dC 32.9, 57.8, 70.2, 71.2, 79.6,
1
106.6 6C-5), 120.3 6q, JC±Fˆ279.2 Hz, CF3), 127.3, 128.7,
2
128.9, 136.8, 149.1 6C-6), 154.2 6C-2), 161.4 6q, JC±F
35.2 Hz, C-4); dF 268.5 6s, 3F, CF3).
ˆ
9. Tri¯uoro AZT: Joshi, B. V.; Rao, T. S.; Reese, C. B. J. Chem.
Soc., Perkin Trans. 1 1992, 2537±2544 and references therein.
10. Acyclic nucleosides: Kelley, J. L.; Kelsey, J. E.; Hall, W. R.;
Krochmal, M. P.; Schaeffer, H. J. J. Med. Chem. 1981, 24,
753±756.
3.7.3. 5-Ethyl-1-ꢀ2-methoxy-ethoxymethyl)-4-ꢀtri¯uoro-
methyl)-1H-pyrimidin-2-one ꢀ20c). 63%, oil; nmax6®lm)
1
1678, 1514, 1279, 1196, 1140, 1003; EIMS m/z 2806M
9), 205 686), 193 6100); Anal. calcd for C11H15F3N2O3: C,
,
11. 6a) Niedballa, U.; VorbruÈggen, H. J. Org. Chem. 1974, 39,
47.14; H, 5.39; N, 10.00. Found: C, 46.74; H, 5.57; N, 9.87;
3
3
È
3654±3660. 6b) VorbruÈggen, H.; Ho¯e, G. Chem. Ber. 1981,
114, 1256±1268.
dH 1.24 6t, Jˆ7.5 Hz, 3H, CH3), 2.64 6q, Jˆ7.5 Hz, 2H,
CH2), 3.34 6s, 3H, CH3), 3.57 6m, 2H, CH2), 3.82 6m, 2H,
CH2), 5.42 6s, 2H, CH2), 8.01 6s, 1H, H-6); dC 11.8, 20.4,
12. Wittenburg, E. Chem. Ber. 1966, 99, 2380±2390.
13. Baud, M. V.; Chavis, C.; Lucas, M.; Imbach, J. L. Tetrahedron
Lett. 1990, 31, 4437±4440.
Â
14. Negron, G.; Molina, A. J.; Islas, G.; Cruz-Almanza, R. Synth.
Commun. 1999, 29, 435±445.
1
58.9, 70.2, 71.2, 79.4, 116.1 6C-5), 119.8 6q, JC±F
ˆ
2
279.0Hz, CF 3), 147.3 6C-6), 154.4 6C-2), 161.76q, JC±F
34.2 Hz, C-4); dF 268.7 6s, 3F, CF3).
ˆ
15. Moog, C.; Wick, A.; Le Ber, P.; Kirn, A.; Aubertin, A. M.
Antiviral Res. 1994, 24, 275±288.
3.7.4. 5-Isopropyl-1-ꢀ2-methoxy-ethoxymethyl)-4-ꢀtri-
¯uoromethyl)-1H-pyrimidin-2-one ꢀ20d). 63%, oil;