CF3-substituted 1,3-dicarbonyl compounds in the Biginelli reaction promoted by chlorotrimethylsilane

Article abstract of DOI:10.1016/j.jfluchem.2008.05.004

Trifluoromethyl-1,3-diones were investigated as reactants in the Biginelli reaction promoted by Me₃SiCl. The dependence of the reaction pathway on the nature of substituent at the α-position to the carbonyl group was established. A set of new CF₃-containing dihydropyrimidine(thi)one derivatives was obtained. A number of novel 5-CF₃CO dihydropyrimidine(thi)ones were synthesized.

Full text of DOI:10.1016/j.jfluchem.2008.05.004

Journal of Fluorine Chemistry 129 (2008) 625–631
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
CF3-substituted 1,3-dicarbonyl compounds in the Biginelli reaction
promoted by chlorotrimethylsilane
Sergey V. Ryabukhin a,b, , Andrey S. Plaskon a,b, Eugeniy N. Ostapchuk a, Dmitriy M. Volochnyuk a,c
*
,
Oleg V. Shishkin d, Andrey A. Tolmachev b
a ‘‘Enamine Ltd.’’, 23 A. Matrosova Street, 01103 Kyiv, Ukraine
b National Taras Shevchenko University, 62 Volodymyrska Street, 01033 Kyiv, Ukraine
c Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska, 02094 Kyiv, Ukraine
d Institute for Scintillation Materials, National Academy of Science of Ukraine, 60 Lenina Avenue, 61001 Kharkiv, Ukraine
A R T I C L E I N F O
A B S T R A C T
Article history:
Trifluoromethyl-1,3-diones were investigated as reactants in the Biginelli reaction promoted by Me3SiCl.
The dependence of the reaction pathway on the nature of substituent at the -position to the carbonyl
Received 15 February 2008
Received in revised form 5 May 2008
Accepted 5 May 2008
a
group was established. A set of new CF3-containing dihydropyrimidine(thi)one derivatives was obtained.
A number of novel 5-CF3CO dihydropyrimidine(thi)ones were synthesized.
ß 2008 Elsevier B.V. All rights reserved.
Available online 13 May 2008
Keywords:
Biginelli reaction
Ureas
Thioureas
Chlorotrimethylsilane
4-Trifluorometyl-1,3-diones
1. Introduction
2. Results and discussion
Recently, we became interested in derivatives of dihydropyr-
imidones (DHPMs), which have diverse pharmacological activities.
They are classified as one of the most important groups of drug-like
scaffolds [1a]. The Biginelli reaction is a powerful tool for the facile
synthesis of these scaffolds [1b,c]. It was shown that the use of
TMSCl in this reaction allowed extending its scope [2]. Continuing
our research on DMF/TMSCl condensing system we wished to use
CF3-substituted 1,3-dicarbonyl compounds as the reactants in the
First, we subjected the unsubstituted urea 5a and thiourea 5e,
to the Biginelli reaction. These building-blocks reacted accordingly
to the established procedure, taking 1:1:1:4 molar ratio of
(thio)urea, aldehyde, CF3-b-diketones and Me3SiCl in DMF
solution (Scheme 1) [2a]. The reactions came to completion in
24–48 h at room temperature afford compounds 7–10a, 7–10e,
which is in agreement with the literature data [3]. In our case,
stereoselectivity observed leading to exclusive formation of the
diastereoisomers shown in Scheme 2. The spectroscopic data for
products 7a and 8a are similar to compounds, which structure has
been previously determined by X-ray diffraction [3b,h].
mentioned reaction. Before the trifluoromethyl-b-diketones and
ethyl 4,4,4-trifluoro-3-oxobutanoate were subjected to Biginelli
reaction with unsubstituted (thio)urea [3,4], guanidine [5a],
aminotetrazole and amino-1,2,4-triazole [5b]. In this paper we
compare the procedure employing DMF/TMSCl with the literature
data on unsubstituted urea 5a and thiourea 5e, and report the
results of extending the mentioned reaction to their substituted
analogues 5b–d and 5f–h (Fig. 1). Benzaldehyde 6 was chosen as
model aldehyde for this investigation.
With the substituted ureas and thioureas, which have never
been subjected to Biginelli reaction with trifluoromethyl-b-
diketones, an interesting dependence of chemical behavior of
diketones 1–4 on the substituent R was disclosed. For R = Ph, OEt,
CF3 and R2 = H the formation of expected products 7, 9, 10 (b,f,h)
was observed (Scheme 2). As for compounds 7–10a, the same
relative configuration of the stereocenters was observed, which
was confirmed by NOESY experiments for the compounds 9b, 9f
and 8a (Fig. 2). The most convincing evidence of this is the
observation of NOE correlation between H4 and (C6)-OH group
marked in red.
* Corresponding author at: ‘‘Enamine Ltd.’’, 23 A. Matrosova Street, 01103 Kyiv,
Ukraine. Tel.: +38 44 2289652; fax: +38 44 5373253.
E-mail address: Ryabukhin@mail.enamine.net (S.V. Ryabukhin).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.05.004

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S.V. Ryabukhin et al. / Journal of Fluorine Chemistry 129 (2008) 625–631
Fig. 1. The structures of model starting compounds for Biginelli reaction.
Scheme 1. Reagents and conditions: i, 4 eq. Me3SiCl, DMF, rt, 24–48 h.
Scheme 2. Reagents and conditions: i, 4 eq. Me3SiCl, DMF, rt, 48–72 h.
In the case of N,N0-dimethyl(thio)urea 5c,g and diketones 1, 3, 4
ortho-protons of (C5)-COPh groups is an additional evidence for the
relative configuration. Finally the structure of compound 9c was
unambiguously determined by single crystal X-ray diffraction
study (Fig. 4).
At the same time, for the diketone 2 (R = Me), the cyclization
leads to compounds 11. These data are in agreement with the
results obtained previously for the Friedla¨nder reaction [6] and can
be explained by the bulkiness of TMSCl. Some parallels with
formation of diastereomers 7, 9, 10(c,g), possessing other relative
configuration of the stereocenters, occurred. The stereochemistry
of the products was also confirmed by NOE-experiments for
compounds 9c and 9g (Fig. 3). In this case, instead of correlation
between H4 and (C6)-OH group, correlation between H5 and (C6)-
OH group was observed. Correlation between (C6)-OH group and
reaction of trifluoromethyl-b-diketones with hydrazines can be
outlined [7] (Scheme 3).
To the best of our knowledge, compounds 11 are the first
examples of DHPMs with the CF3CO groups at the 5th positions [8].
The formation of structures 11 is fully confirmed by analysis of
the corresponding spectral data, e.g. the signal of CF3 group in 19
F
Fig. 2. Significant NOE-correlations for compounds 8a, 9b and 9f. (For interpretation
of the references to colour in the text regarding this figure, the reader is referred to
the web version of the article.)
Fig. 3. Significant NOE-correlations for compounds 9c and 9g.

S.V. Ryabukhin et al. / Journal of Fluorine Chemistry 129 (2008) 625–631
627
Scheme 3. Reagents and conditions: i, 4 eq. Me3SiCl, DMF, rt, 48–72 h.
Fig. 5. Some 1H NMR data for compounds 11d and 11g.
Fig. 4. Single crystal X-ray structure of 9c.
2
quartet in 13C spectra of CF3-ketones 11 at ꢀ81 ppm with JCF
ꢀ31 Hz which is characteristic for C-4 of tetrahydropyrimidine
cycle of compounds 8a and 8e; the presence of a wide singlet of
two protons in the spectrum of compound 11d at 7.03 ppm with
Dn1/2 = 42 Hz which corresponds to two benzene core ortho-
protons; NOE is observed for the compound 11g (Fig. 5).
spectra of ketones 11 is shifted to the lower field in comparison to
compounds 8a and 8e (ꢀꢁ72 ppm for 11, ꢀꢁ80 ppm for 8); the
presence of a doublet (or a singlet in the case of 11g) in 1H spectra
at ꢀ5.3 ppm with 3JHH ꢀ5 Hz which corresponds to the proton at C-
4, unlike the compounds 7–10 where two doublets are observed;
We suggest that the reaction proceeds by the mechanism which
is generally accepted for the Biginelli-type reactions in the
presence of Me3SiCl [2]. The first key step is the formation of
iminium intermediate 13 (Scheme 4) [9]. The next step is addition
the presence of a quartet in 13E spectra at ꢀ177 ppm with JCF
2
ꢀ33 Hz which corresponds to the carbon of C O group, unlike the
singlet at ꢀ204 ppm in the compounds 8a and 8e; the absence of a
Scheme 4. Proposed mechanism for the formation of compounds 7–11 promoted by chlorotrimethylsilane.

628
S.V. Ryabukhin et al. / Journal of Fluorine Chemistry 129 (2008) 625–631
of silylated ketones 14 [10] to the imine 13 affording intermediate
15. There are two possible positions for silylation of the
intermediate product 15. In the case of methyl, which is less
hindered than the CF3 group, silylation of carbonyl group adjacent
to methyl leads to compounds 18. Intermediates 18 undergo 6-exo-
trig cyclization followed by elimination of TMS2O giving 19. In the
case of the substituents more hindered than the methyl group,
silylation of COCF3 groups afford intermediates 16 which cyclized
to intermediate 17. The hydrolysis of 17 gives final products 7–10.
Meanwhile, intermediates 19 converts into compounds 11.
4.3. General procedures
Trifluoromethyl-1,3-dione 1–4 (2 mmol), an appropriate urea
5a–d or thiourea 5e–h (2 mmol) and benzaldehyde 6 (2 mmol)
were placed in 15 mL pressure tube and dissolved in DMF
(10 mL). Chlorotrimethylsilane (869 mg, 8 mmol) was added
dropwise to the solution. The tube was thoroughly sealed and
allowed to stand at 20 8C in ultrasonic bath for 1 h and then
allowed to stand at 20 8C for 24–72 h (by TLC). The reaction
mixture was poured into water (15–20 mL) and allowed to stand
at 20 8C in ultrasonic bath for 1 h. The precipitate formed was
filtered and washed with small amount of i-PrOH or diethyl
ether. First filtrate was evaporated under reduced pressure and
the residue was treated with small amount of i-PrOH or diethyl
ether. Recrystallization of both parts from an appropriate solvent
yielded target compounds.
3. Conclusions
The chemical behavior of various trifluoromethyl-1,3-diones
such as 1,1,1-trifluoropentane-2,4-dione, 4,4,4-trifluoro-1-phenyl-
butane-1,3-dione, ethyl 4,4,4-trifluoro-3-oxobutanoate and
1,1,1,5,5,5-hexafluoropentane-2,4-dione in classical Biginelli reac-
tion using DMF/TMSCl was investigated. We demonstrated the
possibility to use CF3-b-diketones and substituted (thio)ureas in
this reaction. We established that regioselectivity of the conver-
sion is controlled by sterical factors and depends on the nature of
4.3.1. Ethyl rel-(4S,5R,6S)-4-hydroxy-2-oxo-6-phenyl-4-
(trifluoromethyl)hexahydropyrimidine-5-carboxylate (7a)
White solid (498 mg, 75%); mp 163 8C (Et2O-i-PrOH), (Lit.:
162 8C [3b]). 19F NNR (470 MHz, DMSO-d6):
d
= ꢁ81.9. APSI MS:
substituent at
a
-position to carbonyl group of trifluoromethyl-1,3-
M+ + 1 = 333. 1H NMR, 13C NMR, and IR spectroscopic data agree
with published ones [3b].
diones. In the case of 1,1,1-trifluoropentane-2,4-dione and
substituted (thio)ureas unexpected cyclization route was dis-
closed. The derivatives of dihydropyrimid(thi)ones containing
COCF3 group at 5-position were obtained for the first time.
4.3.2. Ethyl rel-(4S,5R,6S)-6-hydroxy-1-methyl-2-oxo-4-phenyl-6-
(trifluoromethyl)hexahydropyrimidine-5-carboxylate (7b)
White solid (506 mg, 73%); mp 190 8C (hexane-i-PrOH). 1H
4. Experimental
NMR (500 MHz, DMSO-d6): d
= 0.74 (t, 3JHH = 7.1 Hz, 3H, CH2CH3),
3
2.86 (s, 3H, NCH3), 3.11 (d, JHH = 11.5 Hz, 1H, 5-HTHPM), 3.73 (m,
3
4.1. General
2H, CH2CH3), 4.66 (d, JHH = 11.5 Hz, 1H, 4-HTHPM), 7.32 (m, 5H,
H
Ph), 7.43 (s, 1H, NH), 7.75 (s, 1H, OH). 13C NMR (125 MHz, DMSO-
All chemicals were obtained from commercially available
sources and used without further purification (Aldrich, Fluka,
‘‘Enamine LTD’’). DMF for the reactions was freshly distilled and
dried by standard methods, monitoring of water content in
solvents (all solvents have <0.05%, usually 0.02% of water) was
performed using Mettler Toledo DL31 KF Titrator. All solvents for
the crystallizations were used without additional purification.
Melting points were measured with a Buchi melting points
apparatus and are uncorrected. The 1H spectra (400 and 500 MHz)
were recorded on a Varian Mercury-400 spectrometer and Bruker
Avance DRX 500 spectrometer with TMS as an internal standard.
13C spectra (125 MHz) were recorded on a Bruker Avance DRX 500
spectrometer with TMS as an internal standard. 19F NMR
(470 MHz) were recorded on a Bruker Avance DRX 500 spectro-
meter with CFCl3 as an internal standard. NMR experiments (NOE,
NOESY) were recorded on a Bruker Avance drx 500 spectrometer.
LC/MS spectra were recorded using chromatography/mass spec-
trometric system that consists of high-performance liquid
chromatograph ‘‘Agilent 1100 Series’’ equipped with diode-matrix
and mass-selective detector ‘‘Agilent LC\MSD SL’’. According to
HPLC MS and 1H NMR data all the synthesized compounds have
purity 95%. IR spectra were recorded on a Nexus-470 spectrometer
for samples in KBr discs. Microanalyses were performed in the
Microanalytical Laboratory of the Institute of Organic Chemistry,
National Academy of Sciences of Ukraine.
d6): d
= 13.9, 29.0, 53.2, 54.7, 60.6, 84.1 (q, 2JCF = 29.5 Hz), 124.1 (q,
1JCF = 291.3 Hz), 128.5, 128.8, 129.0, 138.0, 155.8, 167.1. 19F NMR
(470 MHz, DMSO-d6):
d
= ꢁ76.8. IR (KBr), nmax (cmꢁ1): 3280 (br,
NH), 3201 (br, OH), 3053, 3003, 2987, 2929, 2904, 1740 (C Oester),
1641 (C O), 1504, 1402, 1348, 1255 (C–F), 1192, 1049, 949, 769,
704, 661. APSI MS: M+ + 1 = 347. Analysis calc. for C15H17F3N2O4: C,
52.03; H, 4.95; F, 16.46; N, 8.09; O, 18.48. Found: C, 52.09; H, 4.88;
N, 8.12.
4.3.3. Ethyl rel-(4R,5R,6S)-4-hydroxy-1,3-dimethyl-2-oxo-6-phenyl-
4-(trifluoromethyl)hexahydropyrimidine-5-carboxylate (7c)
Colourless crystals (375 mg, 52%); mp 188 8C (Et2O). 1H NMR
3
(500 MHz, DMSO-d6):
d
= 0.98 (t, JHH = 7.1 Hz, 3H, CH2CH3), 2.47
3
(s, 3H, NCH3), 2.88 (s, 3H, NCH3), 3.33 (d, JHH = 12.0 Hz, 1H, 5-
H
THPM), 3.95 (m, 2H, CH2CH3), 4.63 (d, 3JHH = 12.0 Hz, 1H, 4-HTHPM),
7.23 (d, 3JHH = 7.6 Hz, 2H, 2,6-HPh), 7.32 (t, 3JHH = 7.6 Hz, 1H, 4-HPh),
7.38 (t, JHH = 7.6 Hz, 2H, 3,5-HPh), 8.04 (s, 1H, OH). 13C NMR
3
(125 MHz, DMSO-d6):
2JCF = 30.5 Hz), 124.3 (q, 1JCF = 292.2 Hz), 128.0, 129.0, 129.3, 139.5,
154.4, 166.9. 19F NMR (470 MHz, DMSO-d6):
d = 14.1, 28.7, 33.7, 55.9, 59.0, 61.5, 82.4 (q,
d
= ꢁ76.6. IR (KBr),
nmax (cmꢁ1): 3157 (br, OH), 3032, 2991, 2947, 2922, 1734
(C Oester), 1626 (C O), 1606 (OH), 1498, 1400, 1323, 1252 (C–
F), 1234, 1186, 1090, 1030, 727, 700. APSI MS: M+ + 1 = 361.
Analysis calc. for C16H19F3N2O4: C, 53.33; H, 5.31; F, 15.82; N, 7.77;
O, 17.76. Found: C, 53.39; H, 5.23; N, 7.84.
4.2. X-ray crystallography
4.3.4. Ethyl rel-(4S,5R,6S)-4-hydroxy-6-phenyl-2-thioxo-4-
(trifluoromethyl)hexahydropyrimidine-5-carboxylate (7e)
White solid (550 mg, 79%); mp 195 8C (i-PrOH-hexane), (Lit.:
Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Center as supplementary pub-
lication no. CCDC 686176 and can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax:
(international)+441223/336033;E-mail:deposit@ccdc.cam.ac.uk).
191–192 8C [3c,d]). 13C NMR (125 MHz, DMSO-d6):
d = 14.0, 49.9,
2
1
54.8, 60.9, 80.1 (q, JCF = 31.3 Hz), 123.3 (q, JCF = 286.9 Hz),
128.7, 128.9, 129.1, 137.4, 167.0, 177.6. APSI MS: M+ + 1 = 349. 1H
NMR, 19F NMR and IR spectroscopic data agree with published
ones [3c].

S.V. Ryabukhin et al. / Journal of Fluorine Chemistry 129 (2008) 625–631
629
4.3.5. Ethyl rel-(4S,5R,6S)-6-hydroxy-1-methyl-4-phenyl-2-thioxo-
4.3.10. rel-(4S,5R,6S)-5-Benzoyl-4-hydroxy-6-phenyl-4-
6-(trifluoromethyl)hexahydropyrimidine-5-carboxylate (7f)
(trifluoromethyl)tetrahydropyrimidin-2(1H)-one (9a)
Colourless crystals (435 mg, 60%); mp 195 8C (hexane-Et2O). 1H
White solid (619 mg, 85%); mp 206 8C (EtOH), (Lit.: 204–205 8C
[3c,d]). 13C NMR (125 MHz, DMSO-d6):
= 48.6, 55.2, 81.9 (q,
NMR (500 MHz, DMSO-d6):
d
= 0.76 (t, 3JHH = 7.1 Hz, 3H, CH2CH3),
d
3
3.26 (s, 3H, NCH3), 3.32 (d, JHH = 11.2 Hz, 1H, 5-HTHPM), 3.77 (m,
2JCF = 31.3 Hz), 123.7 (q, 1JCF = 286.9 Hz), 128.2, 128.5, 128.6, 128.7,
128.9, 133.7, 137.8, 138.8, 154.3, 196.3. APSI MS: M+ + 1 = 365. 1H
NMR, 19F NMR and IR spectroscopic data agree with published ones
[3c].
3
2H, CH2CH3), 4.64 (d, JHH = 11.2 Hz, 1H, 4-HTHPM), 7.34 (m, 5H,
H
Ph), 8.34 (s, 1H, OH), 9.25 (s, 1H, NH). 13C NMR (125 MHz, DMSO-
d6):
1JCF = 291.7 Hz), 128.8, 129.07, 129.14, 136.5, 166.6, 182.5. 19F
NMR (470 MHz, DMSO-d6):
max (cmꢁ1): 3213
d
= 13.9, 35.5, 54.1, 54.9, 60.8, 84.2 (q, 2JCF = 30.5 Hz), 123.8 (q,
d
= ꢁ76.5. IR (KBr),
n
4.3.11. rel-(4S,5R,6S)-5-Benzoyl-6-hydroxy-1-methyl-4-phenyl-6-
(trifluoromethyl)tetrahydropyrimidin-2(1H)-one (9b)
(br, NH, OH), 3045, 3003, 2983, 2954, 2908, 1736 (C Oester), 1537,
1489, 1373, 1344, 1279 (C–F), 1242, 1188, 1119, 1043, 1016, 970,
766, 729, 702. APSI MS: M+ + 1 = 363. Analysis calc. for
White solid (560 mg, 74%); mp 225 8C (EtOH). 1H NMR
(400 MHz, DMSO-d6):
1H, 5-HTHPM), 4.84 (d, JHH = 11.1 Hz, 1H, 4-HTHPM), 7.08 (t,
3JHH = 7.8 Hz, 1H, 4-HPh), 7.14 (t, JHH = 7.8 Hz, 2H, 3,5-HPh),
d
= 2.91 (s, 3H, NCH3), 4.50 (d, 3JHH = 11.1 Hz,
3
C15H17F3N2O3S: C, 49.72; H, 4.73; F, 15.73; N, 7.73; O, 13.25; S,
3
8.85. Found: C, 49.79; H, 4.69; N, 7.75; S, 8.81.
7.29–7.36 (m, 4H, 2,6-HPh + 3,5-HPh’), 7.46 (m, 2H, 4-HPh’ + NH),
3
4.3.6. Ethyl rel-(4R,5R,6S)-4-hydroxy-1,3-dimethyl-6-phenyl-2-
7.64 (d, JHH = 7.4 Hz, 2H, 2,6-HPh’), 7.65 (s, 1H, OH). 13C NMR
2
thioxo-4-(trifluoromethyl)hexahydropyrimidine-5-carboxylate (7g)
(125 MHz, DMSO-d6):
d
= 29.0, 51.2, 54.4, 85.2 (q, JCF = 30.0 Hz),
1
Colourless crystals (361 mg, 48%); mp 147 8C (Et2O). 1H NMR
124.2 (q, JCF = 291.8 Hz), 128.2, 128.56, 128.59, 128.77, 128.83,
133.5, 137.7, 138.0, 155.7, 195.7. 19F NMR (470 MHz, DMSO-d6):
3
(500 MHz, DMSO-d6):
d
= 1.02 (t, JHH = 7.1 Hz, 3H, CH2CH3), 2.91
3
(s, 3H, NCH3), 3.34 (s, 3H, NCH3), 3.43 (d, JHH = 12.3 Hz, 1H, 5-
THPM), 4.01 (q, 3JHH = 7.1 Hz, 2H, CH2CH3), 4.88 (d, 3JHH = 12.3 Hz,
d
= ꢁ76.0. IR (KBr),
n
max (cmꢁ1): 3280 (br, NH), 3190 (br, OH), 3059,
H
3003, 2972, 2927, 2900, 1682 (C OCOPh), 1643 (C O), 1599 (OH,
NH), 1497, 1448, 1404, 1344, 1252 (C–F), 1194, 1149, 1043, 955,
768, 700, 685, 631. APSI MS: M+ + 1 = 379. Analysis calc. for
3
1H, 4-HTHPM), 7.17 (d, JHH = 7.6 Hz, 2H, 2,6-HPh), 7.35 (t,
3
3JHH = 7.6 Hz, 1H, 4-HPh), 7.40 (t, JHH = 7.6 Hz, 2H, 3,5-HPh), 8.49
(s, 1H, OH). 13C NMR (125 MHz, DMSO-d6):
d
= 13.7, 35.0, 41.7,
1
C19H17F3N2O3: C, 60.32; H, 4.53; F, 15.06; N, 7.40; O, 12.69. Found:
C, 60.39; H, 4.45; N, 7.46.
2
55.1, 61.2, 61.4, 81.9 (q, JCF = 30.6 Hz), 123.3 (q, JCF = 291.3 Hz),
127.2, 128.7, 129.1, 138.7, 166.2, 180.6. 19F NMR (470 MHz, DMSO-
d6):
d
= ꢁ76.4. IR (KBr), nmax (cmꢁ1): 3157 (br, OH), 3032, 2989,
4.3.12. rel-(4R,5R,6S)-5-Benzoyl-4-hydroxy-1,3-dimethyl-6-phenyl-
4-(trifluoromethyl)tetrahydropyrimidin-2(1H)-one (9c)
2943, 1738 (C Oester), 1498, 1454, 1396, 1329, 1252 (C–F), 1225,
1190, 1082, 1003, 762, 698. APSI MS: M+ + 1 = 377. Analysis calc.
for C16H19F3N2O3S: C, 51.06; H, 5.09; F, 15.14; N, 7.44; O, 12.75; S,
8.52. Found: C, 51.15; H, 5.01; N, 7.48; S, 8.49.
White solid (439 mg, 56%); mp 215 8C (i-PrOH-hexane). 1H
NMR (400 MHz, DMSO-d6):
d = 2.58 (s, 3H, NCH3), 2.93 (s, 3H,
NCH3), 4.33 (d, 3JHH = 11.7 Hz, 1H, 5-HTHPM), 4.84 (d, 3JHH = 11.7 Hz,
1H, 4-HTHPM), 7.14 (m, 1H, 4-HPh), 7.23 (m, 4H, 2,3,5,6-HPh), 7.32 (t,
3JHH = 8.0 Hz, 2H, 3,5-HPh), 7.45 (t, 3JHH = 8.0 Hz, 1H, 4-HPh), 7.52 (s,
4.3.7. Ethyl rel-(4S,5R,6S)-6-hydroxy-1,4-diphenyl-2-thioxo-6-
3
(trifluoromethyl)hexahydropyrimidine-5-carboxylate (7h)
1H, OH), 7.68 (d, JHH = 8.0 Hz, 1H, 2,6-HPh). 13C NMR (125 MHz,
DMSO-d6):
White solid (475 mg, 56%); mp 180 8C (EtOH). 1H NMR
d
= 29.1, 33.7, 55.4, 59.6, 83.1 (q, JCF = 30.1 Hz), 124.4
2
3
1
(500 MHz, DMSO-d6):
d
= 0.74 (t, JHH = 7.1 Hz, 3H, CH2CH3),
(q, JCF = 292.7 Hz), 128.1, 128.7, 128.85, 128.88, 129.3, 133.9,
138.4, 139.6, 154.5, 196.0. 19F NMR (470 MHz, DMSO-d6):
3
3.50 (d, JHH = 11.8 Hz, 1H, 5-HTHPM), 3.76 (m, 2H, CH2CH3), 4.99
(d, 3JHH = 11.8 Hz, 1H, 4-HTHPM), 7.19 (m, 1H, 4-HPh), 7.27–7.42 (m,
9H, 2,3,5,6-HPh + 2,3,4,5,6-HPh), 8.37 (s, 1H, OH), 9.46 (s, 1H, NH).
d
= ꢁ75.0. IR (KBr), nmax (cmꢁ1): 3111 (br, OH), 2987, 2964,
2924, 1682 (C OCOPh), 1620 (C O), 1597 (OH), 1491, 1448, 1396,
1354, 1286, 1250 (C–F), 1200, 1147, 1086, 1036, 771, 725, 702, 660.
APSI MS: M+ + 1 = 393. Analysis calc. for C20H19F3N2O3: C, 61.22; H,
4.88; F, 14.53, N, 7.14; O, 12.23. Found: C, 61.30; H, 4.78; N, 7.19.
13C NMR (125 MHz, DMSO-d6):
d = 13.9, 52.1, 54.6, 60.8, 84.0 (q,
2JCF = 30.5 Hz), 124.1 (q, JCF = 286.8 Hz), 127.4, 127.9, 128.2,
1
128.7, 129.0, 132.4, 137.3, 141.3, 166.6, 181.2. 19F NMR (470 MHz,
DMSO-d6):
d
= ꢁ77.2. IR (KBr), nmax (cmꢁ1): 3385 (br, NH), 3180
(br, OH), 3061, 2981, 2939, 1738 (C Oester), 1535, 1462, 1342,
1257 (C–F), 1217, 1173, 1103, 1011, 754, 723, 696. APSI MS:
M+ + 1 = 425. Analysis calc. for C20H19F3N2O3S: C, 56.60; H, 4.51; F,
13.43; N, 6.60; O, 11.31; S, 7.55. Found: C, 56.71; H, 4.42; N, 6.67; S,
7.61.
4.3.13. [rel-(4S,5R,6S)-4-Hydroxy-6-phenyl-2-thioxo-4-
(trifluoromethyl)hexahydropyrimidin-5-yl](phenyl)methanone (9e)
White solid (624 mg, 82%); mp 230 8C (EtOH), (Lit.: 229–230 8C
[3c,d]). 13C NMR (125 MHz, DMSO-d6):
d = 47.0, 56.2, 81.1 (q,
2JCF = 31.0 Hz), 123.3 (q, JCF = 288.8 Hz), 128.3, 128.7, 128.8,
128.98, 129.01, 133.8, 137.5, 137.7, 177.4, 195.4. APSI MS:
M+ + 1 = 381. 1H NMR, 19F NMR and IR spectroscopic data agree
with published ones [3c].
1
4.3.8. rel-(4S,5R,6S)-5-Acetyl-4-hydroxy-6-phenyl-4-
(trifluoromethyl)tetrahydropyrimidin-2(1H)-one (8a)
White solid (417 mg, 69%); mp 172 8C (Et2O-i-PrOH), (Lit.: 180–
182 8C [3c,d]). 13C NMR (125 MHz, DMSO-d6):
81.2 (q, JCF = 31.3 Hz), 123.7 (q, JCF = 287.7 Hz), 128.5, 128.95,
129.02, 138.6, 154.1, 204.4. APSI MS: M+ + 1 = 303. 1H NMR, 19F
NMR and IR spectroscopic data agree with published ones [3c].
d
= 31.1, 53.7, 57.8,
4.3.14. [rel-(4S,5R,6S)-4-Hydroxy-6-phenyl-2-thioxo-4-
2
1
(trifluoromethyl)hexahydropyrimidin-5-yl](phenyl)methanone (9f)
White solid (450 mg, 57%); mp 200 8C (i-PrOH-hexane). 1H NMR
(500 MHz, DMSO-d6):
1H, 5-HTHPM), 4.81 (d, JHH = 10.5 Hz, 1H, 4-HTHPM), 7.11 (t,
3JHH = 7.4 Hz, 1H, 4-HPh), 7.16 (t, JHH = 7.4 Hz, 2H, 3,5-HPh),
d
= 3.30 (s, 3H, NCH3), 4.70 (d, 3JHH = 10.5 Hz,
3
3
4.3.9. 1-[rel-(4S,5R,6S)-4-Hydroxy-6-phenyl-2-thioxo-4-
(trifluoromethyl)hexahydropyrimidin-5-yl]ethanone (8e)
White solid (433 mg, 68%); mp 210 8C (Et2O-i-PrOH), (Lit.: 211–
3
7.32–7.39 (m, 4H, 2,6-HPh + 3,5-HPh’), 7.49 (t, JHH = 7.5 Hz, 1H,
4-HPh’), 7.73 (d, 3JHH = 7.5 Hz, 2H, 2,6-HPh’), 8.17 (s, 1H, OH), 9.27 (s,
212 8C [3c,d]). 13C NMR (125 MHz, DMSO-d6):
80.3 (q, JCF = 31.3 Hz), 123.4 (q, JCF = 287.6 Hz), 128.7, 129.0,
129.1, 137.2, 177.3, 203.7. APSI MS: M+ + 1 = 319. 1H NMR, 19F NMR
and IR spectroscopic data agree with published ones [3c].
d
= 31.1, 54.7, 56.0,
1H, NH). 13C NMR (125 MHz, DMSO-d6):
d = 35.6, 51.2, 55.2, 85.2
2
1
2
1
(q, JCF = 30.1), 123.8 (q, JCF = 291.8), 128.5, 128.6, 128.7, 128.9,
129.0, 133.7, 136.7, 137.6, 181.9, 195.0. 19F NMR (470 MHz, DMSO-
d6):
d
= ꢁ74.7. IR (KBr),
n
max (cmꢁ1): 3650–3300 (br, NH), 3205 (br,

630
S.V. Ryabukhin et al. / Journal of Fluorine Chemistry 129 (2008) 625–631
OH), 3043, 3007, 2960, 2920, 1682 (C O), 1541, 1493, 1448, 1342,
1240 (C–F), 1196, 1117, 1030, 957, 764, 685. APSI MS: M+ + 1 = 395.
Analysis calc. for C19H17F3N2O2S C, 57.86; H, 4.34; F, 14.45; N, 7.10;
O, 8.11; S, 8.13. Found: C, 57.80; H, 4.25; N, 7.17; S, 8.12.
4.3.19. 2,2,2-Trifluoro-1-[rel-(4R,5S,6R)-4-hydroxy-6-phenyl-2-
thioxo-4-(trifluoromethyl)hexahydropyrimidin-5-yl]ethanone (10e)
White solid (484 mg, 65%); mp 211 8C (hexane-i-PrOH), (Lit.:
215–216 8C [3c,d]). 13C NMR (125 MHz, DMSO-d6):
d = 49.2, 55.8,
2
1
80.8 (q, JCF = 32.8 Hz), 114.2 (q, JCF = 293.0 Hz), 123.0 (q,
1JCF = 286.1 Hz), 128.9, 129.1, 129.5, 136.2, 177.5, 187.6 (q,
2JCF = 33.9 Hz). APSI MS: M+ + 1 = 373. 1H NMR, 19F NMR and IR
spectroscopic data agree with published ones [3c].
4.3.15. [rel-(4R,5R,6S)-4-Hydroxy-1,3-dimethyl-6-phenyl-2-thioxo-
4-(trifluoromethyl)hexahydropyrimidin-5-yl](phenyl)methanone
(9g)
White solid (417 mg, 51%); mp 182 8C (hexane-i-PrOH). 1H NMR
(500 MHz, DMSO-d6):
(d, JHH = 10.0 Hz, 1H, 5-HTHPM), 5.05 (d, JHH = 10.0 Hz, 1H, 4-
d
= 3.03 (s, 3H, NCH3), 3.31 (s, 3H, NCH3), 4.97
4.3.20. 6-Methyl-1-(4-methylphenyl)-4-phenyl-5-(trifluoroacetyl)-
3,4-dihydropyrimidin-2(1H)-one (11d)
3
3
3
3
H
THPM), 7.18 (t, JHH = 7.6 Hz, 1H, 4-HPh), 7.24 (t, JHH = 7.6 Hz, 2H,
White solid (442 mg, 59%); mp 180 8C (i-PrOH-hexane). 1H NMR
3,5-HPh), 7.38(d,3JHH = 7.6 Hz, 2H,2,6-HPh), 7.42(t, 3JHH = 7.6 Hz, 2H,
3,5-HPh), 7.55 (t, 3JHH = 7.6 Hz, 1H, 4-HPh), 7.86 (d, 3JHH = 7.6 Hz, 1H,
2,6-HPh),8.19(br.s,1H,OH). 13CNMR(125 MHz,DMSO-d6):
d = 36.9,
(400 MHz, DMSO-d6): d = 2.16 (s, 3H, CH3), 2.33 (s, 3H, CH3), 5.28 (d,
3JHH = 4.7 Hz, 1H, 4-HDHPM), 7.03 (br. s, Dn1/2 ꢀ42 Hz, 2H, 2,6-HAr),
7.25 (d, 3JHH = 8.0 Hz, 2H, 3,5-HAr), 7.34 (t, 3JHH = 7.2 Hz, 1H, 4-HPh),
2
1
3
41.6, 50.3, 61.2, 84.7 (q, JCF = 30.7 Hz), 123.8 (q, JCF = 292.5 Hz),
7.37–7.46 (m, 4H, 2,3,5,6-HPh), 8.75 (d, JHH = 4.7 Hz, 1H, NH). 13C
128.8, 128.9, 128.97, 129.02, 129.2, 133.8, 136.6, 137.6, 183.3, 195.2.
NMR (125 MHz, DMSO-d6): d = 20.5, 21.2, 51.4, 105.0, 117.1 (q,
19F NMR (470 MHz, DMSO-d6):
d
= ꢁ74.6. IR (KBr), nmax (cmꢁ1):
1JCF = 293.0 Hz), 118.6, 126.6, 128.5, 129.4, 130.1, 134.7, 138.7,
2
3196 (br, OH), 3003, 2924, 1682 (C O), 1497, 1451, 1241 (C–F),
1198, 765. APSIMS: M+ + 1 = 409. Analysiscalc. for C20H19F3N2O2S C,
58.81; H, 4.69; F, 13.95; N, 6.86; O, 7.83; S, 7.85. Found: C, 58.89; H,
4.61; N, 6.90; S, 7.81.
142.6, 151.6, 160.6, 176.9 (q, JCF = 32.8 Hz). 19F NMR (470 MHz,
DMSO-d6):
d
= ꢁ71.9. IR (KBr), nmax (cmꢁ1): 3242 (br, NH), 3126,
3032, 2927, 1716 (C OCOCF3), 1684 (C O), 1568 (NH), 1512, 1448,
1394, 1242 (C–F), 1201, 1171, 1138, 1101, 1022, 935, 721, 696. APSI
MS: M+ + 1 = 375. Analysis calc. for C20H17F3N2O2: C, 64.17; H, 4.58;
F, 15.22; N, 7.48; O, 8.55. Found: C, 64.23; H, 4.51; N, 7.52.
4.3.16. rel-(4R,5S,6R)-4-Hydroxy-6-phenyl-5-(trifluoroacetyl)-4-
(trifluoromethyl)tetrahydropyrimidin-2(1H)-one (10a)
White solid (506 mg, 71%); mp 196 8C (hexane-i-PrOH), (Lit.:
4.3.21. 2,2,2-Trifluoro-1-(1,3,6-trimethyl-4-phenyl-2-thioxo-1,2,3,4-
tetrahydropyrimidin-5-yl)ethanone (11g)
200–201 8C [3d]). 13C NMR (125 MHz, DMSO-d6):
d = 50.9, 54.9,
2
1
81.7 (q, JCF = 31.4 Hz), 114.2 (q, JCF = 292.9 Hz), 123.3 (q,
1JCF = 286.1 Hz), 128.7, 129.1, 129.4, 137.5, 153.8, 187.6 (q,
2JCF = 36.0 Hz). APSI MS: M+ + 1 = 357. 1H NMR, 19F NMR and IR
spectroscopic data agree with published ones [3d].
Colourless crystals (315 mg, 48%); mp 171 8C (hexane-Et2O). 1H
NMR (500 MHz, DMSO-d6): d = 2.53 (s, 3H, CH3), 3.51 (s, 3H, NCH3),
3.56 (s, 3H, NCH3), 5.55 (s, 1H, 4-HDHPM), 7.07 (d, 3JHH = 7.4 Hz, 2H,
2,6-HPh), 7.24–7.36 (m, 3H, 3,4,5-HPh). 13C NMR (125 MHz, DMSO-
d6):
128.9, 129.4, 138.7, 156.9, 177.2 (q, 2JCF = 33.2 Hz), 178.2. 19F NMR
(470 MHz, DMSO-d6):
max (cmꢁ1): 3035, 2926,
d
= 18.5, 38.7, 43.7, 59.7, 106.4, 117.0 (1JCF = 292.3 Hz), 126.5,
4.3.17. rel-(4R,5S,6R)-6-Hydroxy-1-methyl-4-phenyl-5-
(trifluoroacetyl)-6-(trifluoromethyl)tetrahydropyrimidin-2(1H)-one
(10b)
d
= ꢁ71.5. IR (KBr),
n
1698 (C O), 1489, 1389, 1218 (C–F), 1150, 960, 696. APSI MS:
M+ + 1 = 329. Analysis calc. for C15H15F3N2OS: C, 54.87; H, 4.60; F,
17.36; N, 8.53; O, 4.87; S, 9.76. Found: C, 54.92; H, 4.55; N, 8.56; S,
9.71.
White solid (422 mg, 57%); mp 190 8C (hexane-i-PrOH). 1H
NMR (500 MHz, DMSO-d6):
d = 2.90 (s, 3H, NCH3), 4.04 (d,
3JHH = 10.8 Hz, 1H, 5-HTHPM), 4.78 (d, 3JHH = 10.8 Hz, 1H, 4-HTHPM),
7.34 (m, 4H, HPh), 7.66 (s, 1H, NH), 8.28 (s, 1H, OH). 13C NMR
(125 MHz, DMSO-d6):
115.3 (q, JCF = 291.7 Hz), 123.7 (q, JCF = 286.1 Hz), 128.0, 128.6,
129.2, 136.9, 154.7, 187.3 (2JCF = 36.0 Hz). 19F NMR (470 MHz,
d
= 28.9, 53.8, 56.0, 84.1 (2JCF = 31.0 Hz),
4.3.22. 2,2,2-Trifluoro-1-(6-methyl-1,4-diphenyl-2-thioxo-1,2,3,4-
tetrahydropyrimidin-5-yl)ethanone (11h)
1
1
White solid (452 mg, 60%); mp 188 8C (i-PrOH-hexane). 1H NMR
DMSO-d6):
d
= ꢁ76.4, ꢁ78.2. IR (KBr),
n
max (cmꢁ1): 3277 (br, NH),
(500 MHz, DMSO-d6):
4-HDHPM), 7.28–7.48 (m, 10H, HPh), 10.56 (d, 3JHH = 5.4 Hz, 1H, NH).
d
= 2.16 (s, 3H, CH3), 5.35 (d, 3JHH = 5.4 Hz, 1H,
3197 (br, OH), 3051, 2985, 2929, 2897, 1759 (C OCOCF3), 1637
(C O), 1504, 1406, 1352, 1292, 1246 (C–F), 1213, 1165, 1147,
1047, 769, 702, 652. APSI MS: M+ + 1 = 371. Analysis calc. for
13C NMR (125 MHz, DMSO-d6):
d = 20.4, 51.8, 106.5, 116.9 (q,
1JCF = 293.2 Hz), 123.5, 126.7, 128.8, 129.1, 129.3, 129.5, 140.1,
2
C
14H12F6N2O3: C, 45.42; H, 3.27; F, 30.79; N, 7.57; O, 12.96. Found:
C, 45.49; H, 3.22; N, 7.60.
141.4, 155.9, 177.5, 177.9 (q, JCF = 33.9 Hz). 19F NMR (470 MHz,
DMSO-d6):
d
= ꢁ72.0. IR (KBr), nmax (cmꢁ1): 3650–3320 (br, NH),
3169, 3037, 2926, 1689 (C O), 1578 (NH), 1493, 1387, 1252, 1213
(C–F), 1151, 1113, 962, 696. APSI MS: M+ + 1 = 377. Analysis calc. for
4.3.18. rel-(4S,5S,6R)-4-Hydroxy-1,3-dimethyl-6-phenyl-5-
(trifluoroacetyl)-4-(trifluoromethyl)tetrahydropyrimidin-2(1H)-one
(10c)
C19H15F3N2OS: C, 60.63; H, 4.02; F, 15.14; N, 7.44; O, 4.25; S, 8.52.
Found: C, 60.64; H, 3.98; N, 7.45; S, 8.49.
Colourless crystals (315 mg, 41%); mp 179 8C (hexane-Et2O). 1H
NMR (500 MHz, DMSO-d6):
d = 2.52 (s, 3H, NCH3), 2.93 (s, 3H,
Acknowledgements
NCH3), 4.19 (d, 3JHH = 11.9 Hz, 1H, 5-HTHPM), 4.75 (d, 3JHH = 11.9 Hz,
3
1H, 4-HTHPM), 7.23 (d, JHH = 8.1 Hz, 2H, 2,6-HPh), 7.36 (t,
The authors acknowledge V.V. Polovinko (‘‘Enamine Ltd.’’) and
Dr. S.A. Alekseev (Department of Chemistry of Kyiv National Taras
ShevchenkoUniversity)forspectralmeasurements,andD.Dontsova
for helpful discussions upon preparation of the manuscript.
3JHH = 8.1 Hz, 1H, 4-HPh), 7.41 (t, JHH = 8.1 Hz, 2H, 3,5-HPh), 8.60
3
(s, 1H, OH). 13C NMR (125 MHz, DMSO-d6):
d = 28.9, 33.6, 56.4,
2
1
58.5, 82.9 (q, JCF = 31.0 Hz), 114.5 (q, JCF = 291.7 Hz), 123.9 (q,
1JCF = 292.7 Hz), 128.0, 129.5, 129.6, 138.0, 154.1, 188.5 (q,
2JCF = 37.0 Hz). 19F NMR (470 MHz, DMSO-d6):
d
= ꢁ75.6, ꢁ78.1.
max (cmꢁ1): 3152 (br, OH), 2988, 2927, 1759 (C OCOCF3),
References
IR (KBr),
n
1625 (C O), 1502, 1403, 1241 (C–F), 1196, 1145, 766, 703. APSI
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3.67; F, 29.66; N, 7.29; O, 12.49. Found: C, 46.95; H, 3.60; N, 7.23.
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