Optically active 4-amino-4-aryl-5,5,5-trifluoropentan-2-ones: Versatile reagents for synthesis of chiral 4-trifluoromethyl-3,4-dihydroazin-2-ones

Article abstract of DOI:10.1016/j.jfluchem.2008.09.003

A cyclocondensation of disubstituted (thio)ureas and isocyanates derived from enantiomerically enriched 4-amino-4-aryl-5,5,5-trifluoropentan-2-ones affords a novel synthetic access to chiral 4-trifluoromethyl-substituted 3,4-dihydropyrimidin-2(1H)-(thi)ones and 3,4-dihydro-1,3-oxazin-2-ones, respectively.

Full text of DOI:10.1016/j.jfluchem.2008.09.003

Journal of Fluorine Chemistry 129 (2008) 1180–1186
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Optically active 4-amino-4-aryl-5,5,5-trifluoropentan-2-ones: Versatile reagents
for synthesis of chiral 4-trifluoromethyl-3,4-dihydroazin-2-ones
*
Volodymyr A. Sukach, Nataliya M. Golovach, Nina V. Melnichenko, Ivan F. Tsymbal, Mykhaylo V. Vovk
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmans’ka 5, Kyiv 02094, Ukraine
A R T I C L E I N F O
A B S T R A C T
Article history:
A cyclocondensation of disubstituted (thio)ureas and isocyanates derived from enantiomerically
enriched 4-amino-4-aryl-5,5,5-trifluoropentan-2-ones affords a novel synthetic access to chiral 4-
trifluoromethyl-substituted 3,4-dihydropyrimidin-2(1H)-(thi)ones and 3,4-dihydro-1,3-oxazin-2-ones,
respectively.
Received 21 July 2008
Received in revised form 8 September 2008
Accepted 9 September 2008
Available online 20 September 2008
ß 2008 Elsevier B.V. All rights reserved.
Keywords:
Optically active compounds
b
b
-Aminoketones
-Isocyanatoketones
3,4-Dihydropyrimidin-2(1H)-(thi)ones
3,4-Dihydro-1,3-oxazin-2-ones
Cyclocondensation
1. Introduction
Structures I and II contain a quaternary endocyclic chiral centre
giving rise to optical isomerism. Much recent attention has been
Substituted 3,4-dihydropyrimidines I and 3,4-dihydro-1,3-oxa-
zines II are regarded as promising synthons in the design of new
bioactive compounds. For instance, structural scaffold I is repre-
sentedbypolyfunctional 3,4-dihydropyrimidines knownasBiginelli
compounds [1–3] which include a number of antiviral, antibacterial,
antihypertensive, and antiinflammatory agents [4]. Intensive high-
throughput screening has also revealed a number of compounds I
efficiently blocking calcium channels [5] and inhibiting KSP [6] and
FATP4 [7]. Great pharmacological promise is also shown by fused
3,4-dihydroazinones, e.g., 3,4-dihydroquinazolones bearing a tri-
fluoromethyl group and an alkynyl substituent at position 4 of the
heterocycle which exhibit anti-HIV activity [8].
paid to enantioselective preparation of 3,4-dihydroazinones,
because their bioactive derivatives in various enantiomeric forms
and racemic mixtures were shown to have very different and
sometimes opposite effects on the corresponding biological targets
[9]. However, it was not until very recently that the first
asymmetric syntheses of Biginelli compounds were reported
[10] and new methods to obtain highly optically pure 4-
trifluoromethyl-4-alkynyl-3,4-dihydroquinazolones (HIV RT inhi-
bitors) were found [11]. The synthesis of chiral 1,3-oxazin-4-one
derivatives can be exemplified by catalytic enantioselective
Mannich reactions [12] affording highly functionalized 3,4-
dihydrobenzoxazinones [12].
Lantzsch and Arlt were the first to use
b-aminoketones as
bifunctional reagents in the synthesis of dihydroazinones [14].
Starting from 4-methyl-4-aminopentan-2-one and phosgene, they
prepared 4-methyl-4-isocyanatopentan-2-one which was further
reacted with amines to give the corresponding ureas at room
temperature and 1-substituted 4,4,6-trimethyl-3,4-dihydropyri-
midin-2(1H)-ones on heating. As noted, heating the thus obtained
ureas in acetic acid provides the same dihydropyrimidones,
whereas the ketoisocyanate itself can thermally cyclize to 4,4,6-
trimethyl-3,4-dihydro-1,3-oxazin-2-one. An alternative approach,
though not studied systematically, was applied at one of the stages
in the conversion of chiral
b-alkoxycarbamoylketones to 1-benzyl-
* Corresponding author. Fax: +38044 5732643.
E-mail address: mvovk@i.com.ua (M.V. Vovk).
3,4-dihydropyrimidin-2(1H)-ones: it involves the initial reaction
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.09.003

V.A. Sukach et al. / Journal of Fluorine Chemistry 129 (2008) 1180–1186
1181
Scheme 1.
of
b
-aminoketones with isocyanates followed by heterocyclization
dihydropyrimidinethiones 4c,d are formed in high yields, evidently
as a result of aroyl group hydrolysis from the initially formed N-
aroyl-substituted products.
The optical purity of the heterocycles obtained has been
determined by 19F NMR spectroscopy using the chiral lanthanide
shift reagent, tris(3-heptafluorobutyryl-d-camphorato)europium
of intermediately formed ureas [10b].
With regard to the fact that fluorine atoms substantially affect
physical, chemical, and hence biological properties of compounds
[13], it is especially challenging to find a convenient pathway to
dihydroazinones I and II of high enantiopurity which would
contain a trifluoromethyl group at the chiral centre. Optically
active 4-amino-4-aryl-5,5,5-trifluoropentan-2-ones
described by us are easily accessible compounds; they are
conveniently obtained by the -proline-catalyzed asymmetric
1 formerly
Table 1
Analytical data of compounds 2 and 3.
L
Compound
Ar
R
Yield, (%)a
Mp, Cb
Ee (%)
reaction of aryl trifluoromethyl ketimines with acetone [15]. To
explore the potentialities of 1 as building blocks in the above-
mentioned synthetic schemes, we have studied their reactions
with various heterocumulenes and triphosgene which furnish
pharmacologically promising trifluoromethyl-substituted enan-
tiomerically enriched 3,4-dihydroazin-2-ones with a quaternary
endocyclic chiral centre.
2a
2b
2c
2d
2e
2f
Ph
4-FC6H4
60
75
80
81
62
75
70
88
88
81
79
71
78
75
91
90
77
168–170
178–180
165–167
149–151
145–147
166–168
95–97
76
76
75
77
76
80
78
75
77
76
76
74
70
71
77
78
75
Ph
4-ClC6H4
Ph
3,4-Cl2C6H3
3-CF3C6H4
4-CH3-3-ClC6H3
4-CH3-3-ClC6H3
4-tBuC6H4
4-FC6H4
Ph
Ph
4-FC6H4
4-FC6H4
Ph
2g
3a
3b
3c
3d
3e
3f
149–151
260–262
272–275
132–134
135–137
106–108
190–192
127–129
197–199
69–70
Ph
4-ClC6H4
2. Results and discussions
Ph
3,4-Cl2C6H3
3-CF3C6H4
4-CH3-3-ClC6H3
4-ClC6H4
Ph
Ph
2.1. Reaction of S(+)-4-amino-4-aryl-5,5,5-trifluoropentan-2-ones 1
with heterocumulenes
4-CH3C6H4
4-CH3C6H4
4-FC6H4
4-FC6H4
Ph
3g
3h
3i
3,4-Cl2C6H3
4-CH3-3-ClC6H3
4-tBuC6H4
n-Bu
When boiled with aryl isocyanates in dry benzene, S(+)-4-
amino-4-aryl-5,5,5-trifluoropentan-2-ones 1a–c provide, in high
yields, disubstituted ureas 2a–g (see Scheme 1 and Table 1). The
latter cyclize to S(À)-4-aryl-4-trifluoromethyl-3,4-dihydropyrimi-
din-2(1H)-ones 3a–e,h,i on boiling in glacial acetic acid. Hetero-
cyclic products 3f,g were isolated instead of the corresponding
ureas on long boiling of the reagents in dry benzene. Likewise,
compound 3j was formed by the reaction of aminoketone 1a with
n-butyl isocyanate.
3j
a
All compounds are white solids.
Melting points are not corrected.
b
Table 2
Analytical data of compounds 4 and 5.
Compound
Ar
R
X
Yield, (%)a
Mp, Cb
Ee (%)
1-Unsubstited dihydropyrimidones 4a,b were obtained by
heating aminoketones 1 with potassium cyanate in glacial acetic
acid. With potassium rhodanide, the reaction afforded 4-aryl-4-
trifluoromethyl-3,4-dihydropyrimidin-2(1H)-thiones 4c–e in
75%–96% yields (see Table 2).
Though aminoketones 1 are unreactive towards alkyl(aryl)
isothiocyanates, they readily react with more electrophilic aroyl
isothiocyanates in dry acetonitrile at room temperature to give
aroylthioureas 5a–c. By heating compounds 5 in glacial acetic acid,
4a
4b
4c
4d
4e
5a
5b
5c
Ph
–
O
O
S
73
71
75
91
96
83
75
74
–
–
75
70
74
71
76
76
72
70
4-CH3C6H4
Ph
–
–
202–204
154–156
192–194
121–123
155–157
174–176
4-CH3C6H4
4-FC6H4
Ph
–
S
–
S
Ph
–
Ph
4-ClC6H4
4-NO2C6H4
–
4-CH3C6H4
–-
a
All compounds are white solids excepting 4a,b which are colorless oiles.
b
Melting points are not corrected.

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V.A. Sukach et al. / Journal of Fluorine Chemistry 129 (2008) 1180–1186
Table 3
(III). The analytically pure samples of compounds 3 and 4 prepared
by us have much the same enantiomeric excess (ee) as starting
aminoketones 1 (75–90%), since the chiral centre is not involved in
the reactions.
Analytical data of compounds 7.
Compound
Ar
Yield (%)a
Ee (%)
7a
7b
7c
7d
Ph
48
63
69
62
80
75
79
75
4-CH3C6H4
4-FC6H4
4-CH3OC6H4
2.2. Reaction of 4-amino-4-aryl-5,5,5-trifluoropentan-2-ones 1 with
triphosgene
a
All compounds are colorless oiles.
To synthesize isocyanates 6 from the corresponding
b-
aminoketones 1, we studied their reactions with triphosgene
[16] in inert solvents in the presence of basic catalysts. It was
intramolecular cyclization of isocyanates 6 which is interme-
diated by isocyanato-substituted enolates A.
found that 85–90% conversion of compounds
1 afforded
products 6 in satisfactory yields when we used ethyl acetate
as a solvent and triethylamine as a catalyst (see Scheme 2). The
by-products of the reaction, symmetric bis-ureas and 3,4-
dihydro-1,3-oxazin-2-ones 7, were difficult to remove from
resulting isocyanates 6, so that the latter were further reacted as
obtained (70–80% pure). If conducted in butyl acetate, the
reaction leads to a mixture of difficult-to-separate products,
whereas acylation does not occur at all in toluene or
2.3. Reaction of isocyanates 6 with amines
Heating crude isocyanates 6 with primary aliphatic amines in
dry toluene furnishes mixtures of 1-alkyl-substituted dihydropyr-
imidones 3 and dihydrooxazinones 7 in the respective ratios 2:1 to
3:1 (see Scheme 3). Importantly, compounds 3 appear to result
from intramolecular cyclocondensation of intermediate ureas B
which, as mentioned in Section 2.1, are labile under the conditions
used. This conjecture about the conversion pathway is supported
by the formation of urea 8 and dihydrooxazinone 7a when
isocyanate 6a is reacted with a secondary amine (morpholine).
Dihydrooxazinones 7 are probably produced by a competing
chlorobenzene. At the same time, reacting
b-aminoketones 1
with triphosgene in ethyl acetate in the presence of a stronger
base, DBU, yields solely oxazines 7 which can thus be isolated in
a
pure state (Table 3). It is likely that DBU favours the
Scheme 2.
Scheme 3.

V.A. Sukach et al. / Journal of Fluorine Chemistry 129 (2008) 1180–1186
1183
reaction, the base-catalyzed cyclization of compounds 6 (see also
above in Section 2.2).
4.1.1. S(À)-N-(4-Fluorophenyl)-N’-[(3-oxo-1-phenyl-1-
trifluoromethyl)butyl]urea (2a)
1H NMR (CDCl3)
: 2.18 (s, 3H), 3.48 (d, 1H, J = 17.0 Hz), 3.81 (d,
d
2.4. Spectral properties of compounds 2–4 and 7
1H, J = 17.0 Hz), 6.23 (s, 1H), 6.87 (s, 1H), 6.87–6.98 (m, 2H), 7.18–
7.21 (m, 2H), 7.34–7.40 (m, 5H), 7.45 (d, 2H, J = 7.5 Hz). 19F NMR
The compounds synthesized have been structurally determined
by a combination of physicochemical techniques. The IR spectra of
solid-state ureas 2 show two types of bands in the C O group
absorption region, at 1660 and 1720 cmÀ1, and also the band of
associated NH groups at 3345 cmÀ1. These data suggest that ureas
2 form so-called ‘‘fork’’ hydrogen bonds in which the carboxamide
carbonyl oxygen atom of one molecule is bonded to two NH
protons of another [17]. On the contrary, the ketone carbonyl group
is not involved in hydrogen bonding. Pyrimidines 3 and 4, and
oxazines 7 in CDCl3 solutions give rise to the 1H NMR signals of the
CH and NH groups in the respective regions 4.9–5.3 and 5.8–
8.0 ppm; compounds 4 also exhibit the characteristic resonances
of the protons at position 1 of the heterocycle in the region 7.9–
8.1 ppm. The typical features of the 13C and 19F NMR spectra of the
products obtained provide firm evidence for their cyclic structure.
The signal from the carbon atom of the CF3 group appears in the
region 124.6–127.5 ppm as a quartet with a spin-spin coupling
constant J of 285.2–287.9 Hz, whereas the quaternary endocyclic
carbon atom also causes a quartet in the region 62.1–63.2 ppm
with J2C–F = 26.4–30.1 Hz. Likewise, the 19F NMR resonances of the
CF3 group observed in the region 79.2–79.9 ppm are characteristic
of the structural moieties N–C(CF3)(Ar)–NH and O–C(CF3)(Ar)–NH
[18].
(CDCl3)
(C O).
d
[
: À75.45 (s, 3F). IR (KBr):
y 3345, 3420 (N–H), 1660, 1720
a
]
D
20 = À7.54 (c = 0.66; MeOH). Anal. calculated for
C18H16F4N2O2: C, 58.70; H, 4.38; N, 7.61%. Found: C, 58.48; H,
4.24; N, 7.77%.
4.1.2. S(À)-N-(4-Chlorophenyl)-N’-[(3-oxo-1-phenyl-1-
trifluoromethyl)butyl]urea (2b)
1H NMR (CDCl3)
d
: 2.19 (s, 3H), 3.51 (d, 1H, J = 17.5 Hz), 3.76
(1H, J = 17.5 Hz), 6.38 (s, 1H), 7.18 (d, 1H, J = 8.5 Hz), 7.27–7.55 (m,
7H). 19F NMR (CDCl3)
H), 1660, 1715 (C O). [
d
: À75.43 (s, 3F). IR (KBr):
y 3340, 3440 (N–
a
]
D
20 = À37.69 (c = 0.26; MeOH). Anal.
calculated for C18H16ClF3N2O2: C, 56.19; H, 4.19; N, 7.28%. Found:
C, 56.47; H, 4.14; N, 7.57%.
4.1.3. S(À)-N-(4-Dichlorophenyl)-N’-[(3-oxo-1-phenyl-1-
trifluoromethyl)butyl]urea (2c)
1H NMR (CDCl3)
d
: 2.26 (s, 3H), 3.56 (d, 1H, J = 16.5 Hz), 3.78 (d,
1H, J = 16.5 Hz), 6.42 (s, 1H), 6.95 (d, 1H, J = 8.5 Hz), 7.18 (d, 1H,
J = 8.5 Hz), 7.38–7.49 (m, 6H), 7.55 (s, 1H). 19F NMR (CDCl3)
d
:
À75.43 (s, 3F). IR (KBr):
y
3330, 3440 (N–H), 1655, 1715 (C O).
[
C
a
]
20 = À47.55
(c = 1.2; MeOH). Anal. calculated for
D
18H15Cl2F3N2O2: C, 51.57; H, 3.61; N, 6.68%. Found: C, 51.77; H,
3.49; N, 6.57%.
4.1.4. S(À)-N-[(3-Oxo-1-phenyl-1-trifluoromethyl)butyl]-N’-[3-
(trifluoromethyl)phenyl]urea (2d)
3. Conclusion
1H NMR (CDCl3)
d
: 2.25 (s, 3H), 3.52 (d, 1H, J = 17.5 Hz), 3.78 (d,
In conclusion, we have shown experimentally that chiral
trifluoromethyl- -aminoketones 1 can be successfully applied in
the synthesis of optically active heterocycles containing
quaternary endocyclic chiral centre, e.g., trifluoromethyl-substi-
tuted 3,4-dihydropyrimidin-2(1H)-(thi)ones 3–5 and 3,4-dihydro-
1,3-oxazin-2-ones 7. As found, the most convenient synthetic
b-
1H, J = 16 Hz), 6.29 (s, 1H), 7.20–7.36 (m, 7H), 7.49 (s, 3H), 7.87 (s,
b
1H). 19F NMR (CDCl3)
3420, 3350 (N–H), 1665, 1720 (C O). [
MeOH). Anal. calculated for C19H16F6N2O2: C, 54.55; H, 3.85; N,
6.69%. Found: C, 54.78; H, 3.99; N, 6.58%.
d
: À61.77 (s, 3F), À75.45 (s, 3F). IR (KBr):
y
a
a
]
D
20 = À3.28 (c = 0.10;
route to pyrimidines 3–5 involves the reaction of b-aminoketones
4.1.5. S(À)-N-(3-Chloro-4-methylphenyl)-N’-[(3-oxo-1-phenyl-1-
trifluoromethyl)butyl]urea (2e)
1 with alkyl(aryl) isocyanates or potassium cyanate (rhodanide)
followed by cyclization of intermediate ureas 2. Depending on the
conditions used, the reaction of compounds 1 with triphosgene
results in isocyanates 6 or dihydrooxazinones 7. If reacted with
primary aliphatic amines, isocyanates 6 produce mixtures of
dihydropyrimidones 3 and dihydrooxazinones 7.
1H NMR (CDCl3)
d
: 2.20 (s, 3H), 2.24 (s, 3H), 3.53 (d, 1H,
J = 16.5 Hz), 3.80 (d, 1H, J = 16.5 Hz), 6.30 (s, 1H), 6.90–7.06 (m,
2H), 7.20 (s, 1H), 7.27–7.47 (m, 6H). 19F NMR (CDCl3)
: À75.18 (s,
d
3F). IR (KBr):
y 3340, 3360 (N–H), 1660, 1720 (C O).
[a
]
D
20 = À46.52 (c = 0.44; MeOH). Anal. calculated for
C19H18ClF3N2O2: C, 57.22; H, 4.55; N, 7.02%. Found: C, 57.57; H,
4. Experimental part
4.49; N, 7.09%.
IR spectra were measured with a UR-20 spectrometer in KBr. 1H
and 19F NMR spectra were recorded on
a
Varian-Gemini
4.1.6. S(À)-N-(3-Chloro-4-methylphenyl)-N’-[(1-(4-fluorophenyl)-
3-oxo-1-trifluoromethyl)butyl]urea (2f)
instrument at 299.94 and 188.14 MHz, respectively, with TMS
(1H) and CCl3F (19F) as internal standards. 13C NMR spectra were
recorded on a Bruker Arano DRX-500 spectrometer (125.75 MHz),
with TMS as internal standard. Elemental analysis was performed
in the Analytical Laboratory of the Institute of Organic Chemistry,
National Academy of Sciences of Ukraine.
1H NMR (DMSO-d6)
d
: 2.12 (s, 3H), 2.24 (s, 3H), 3.65 (d, 1H,
J = 16.0 Hz), 4.03 (d, 1H, J = 16.0 Hz), 6.93–7.00 (m, 2H), 7.12–7.21
(m, 3H), 7.56–7.61 (m, 3H), 8.84 (s, 1H). 19F NMR (DMSO-d6)
d
:
À75.87(s, 3F); À114.79 (s, 1F). IR (KBr):
y 3335, 3370 (N–H), 1660,
1720 (C O). [
a
]
D
20 = À18.98 (c = 0.43; MeOH). Anal. calculated for
C19H17ClF4N2O2. C, 54.75; H, 4.11; N, 6.72%. Found: C, 54.49; H,
4.1. General procedure for preparation of S(À)-N-aryl-N’-[(1-aryl-3-
oxo-1-trifluoromethyl)butyl]ureas (2a–g) and S(À)-1,4-diaryl-6-
methyl-4-trifluoromethyl-3,4-dihydropyrimidin-2(1H)-ones (3f,g,j)
4.19; N, 6.59%.
4.1.7. S(À)-N-(4-Tert-Butylphenyl)-N’-[(1-(4-fluorophenyl)-3-oxo-
1-trifluoromethyl)butyl]urea (2g)
To a solution of S(+)-4-amino-4-aryl-5,5,5-trifluoropentan-2-
one 1a–c (0.02 mol) in dry benzene or toluene (40 ml), aryl(alkyl)
isocyanate (0.02 mol) was added, followed by heating at 80 8C for
5 h. The resulting precipitate was filtered off and recrystallized
from a benzene:hexane mixture (1:2).
1H NMR (DMSO-d6)
d
: 1.25 (s, 3H), 2.12 (s, 3H), 3.65 (d, 1H,
J = 16.5 Hz), 4.06 (d, 1H, J = 16.5 Hz), 6.93–7.00 (m, 2H), 7.12–7.21
(m, 3H), 7.56–7.61 (m, 3H), 8.84 (s, 1H). 19F NMR (DMSO-d6)
d
:
À75.87 (s, 3F); À114.79 (s, 1F). IR (KBr):
y 3355, 3430 (N–H), 1663,
1723 (C = O). [
a
]
D
20 = À10.33 (c = 0.92; MeOH). Anal. calculated for

1184
V.A. Sukach et al. / Journal of Fluorine Chemistry 129 (2008) 1180–1186
C22H23F4N2O2: C, 62.55; H, 5.25; N, 6.63%. Found: C, 62.29; H, 5.13;
N, 6.51%.
3F). 13C NMR (CDCl3)
d: 20.45 (CH3), 63.18 (q, JCF = 28.9 Hz), 96.45
(C-5), 125.11 (q, JCF = 287.9 Hz), 125.92, 125.93, 128.80, 128.92,
129.40, 130.92, 134.38, 135.79 (Carom.), 137.99 (C-6), 152.39 (C-2).
4.1.8. S(À)-1-(4-Chlorophenyl)-6-methyl-4-(methylphenyl)-4-
trifluoromethyl-3,4-dihydropyrimidin-2(1H)-one (3f)
IR (KBr):
y
3095, 3210 (N–H), 1675, 1695 (C O). [
a
]
20 = À101.76
D
(c = 0.55, MeOH). Anal. calculated for C18H14F3ClN2O: C, 58.95; H,
3.85; N, 7.34%. Found: C, 59.24; H, 4.01; N, 7.51%.
1H NMR (DMSO-d6)
d
: 1.63 (s, 3H), 2.38 (s, 3H), 4.99 (s, 1H), 5.71
(s, 1H), 7.16 (d, 2H, J = 7.5 Hz), 7.26 (d, 2H, J = 7.5 Hz), 7.39 (d, 2H,
J = 8.0 Hz), 7.43 (d, 2H, J = 8.0 Hz). 19F NMR (CDCl3)
: À79.92 (s, 3F).
13C NMR (DMSO-d6)
: 19.74 (CH3), 20.49 (CH3), 62.18 (q,
d
4.2.3. S(À)-1-(3,4-Dichlorophenyl)-6-methyl-4-phenyl-4-
trifluoromethyl-3,4-dihydropyrimidin-2(1H)-one (3c)
d
JCF = 28.9 Hz), 95.25 (C-5), 126.24, 128.79, 128.97, 131.58, 132.41,
135.23, 136.44, 137.50 (Carom.), 127.50 (q, JCF = 285.4 Hz), 137.77 (C-
1H NMR (CDCl3)
d
: 1.67 (s, 3H), 5.03 (s, 1H), 5.85 (s, 1H), 7.03-
7.10 (m, 1H), 7.34–7.56 (m, 7H). 19F NMR (CDCl3)
: À79.65 (s, 3F).
13C NMR (DMSO-d6)
: 19.64 (CH3), 62.47 (q, JCF = 26.4 Hz), 125.01
d
6), 151.64 (C-2). IR (KBr):
y
3100, 3215 (N–H), 1674, 1697 (C O).
d
[
a D
]
20 = À124.17 (c = 1; MeOH). Anal. calculated for C19H16ClF3N2O:
(q, JCF = 271.6 Hz), 126.32, 128.37, 128.42, 130.22, 130.52, 130.80,
131.08, 131.85, 137.30, 137.43 (Carom.), 138.06 (C-6), 151.60 (C-2).
IR (KBr):
(c = 0.43; MeOH). Anal. calculated for C18H13F3Cl2N2O: C, 53.89; H,
3.27; N, 6.98%. Found: C, 54.14; H, 3.11; N, 6.71%.
C, 59.93; H, 4.24; N, 7.36%. Found: C, 60.16; H, 4.33; N, 7.54%.
y
3105, 3210 (N–H), 1675, 1700 (C O). [
a
]
20 = À158.76
D
4.1.9. S(À)-1-(3,4-Dichlorophenyl)-6-methyl-4-(methylphenyl)-4-
trifluoromethyl-3,4-dihydropyrimidin-2(1H)-one (3g)
1H NMR (DMSO-d6)
d: 1.62 (s, 3H), 2.32 (s, 3H), 5.30 (s, 1H),
7.20–7.27 (m, 3H), 7.55–7.68 (m, 4H), 8.73 (s, 1H). 19F NMR
4.2.4. S(À)-6-Methyl-4-phenyl-4-trifluoromethyl-1-(3-
(DMSO-d6)
d
: À77.86 (s, 3F). 13C NMR (DMSO-d6)
d
: 19.65 (CH3),
trifluoromethylphenyl)-3,4-dihydropyrimidin-2(1H)-one (3d)
20.49 (CH3), 62.21 (q, JCF = 28.9 Hz), 95.44 (C-5), 126.25, 128.95,
130.24, 130.52, 130.78, 131.02, 131.97, 135.13, 137.15, 137.46
(Carom.), 125.12 (q, JCF = 276.6 Hz), 137.78 (C-6), 151.64 (C-2). IR
1H NMR(CDCl3)
d: 1.64 (s, 3H), 5.05 (s, 1H), 5.82 (s, 1H), 7.41–
7.58 (m, 8H), 7.65 (d, 1H, J = 7.5 Hz). 19F NMR (CDCl3)
d
: À63.77 (s,
3F); À79.64 (s, 1F). 13C NMR (CDCl3)
d: 20.45 (CH3), 63.12 (q,
(KBr):
y
3105, 3220 (N–H), 1675, 1703 (C O). [
a
]
D
20 = À18.12
JCF = 28.9 Hz), 96.91 (C-5), 125.36, 125.88, 126.66, 128.88, 128.97,
129.73, 133.17, 137.66, 137.85, 137.89 (Carom.), 124.61 (q,
JCF = 245.2 Hz), 131.78 (q, J = 32.6 Hz), 125.41 (q, J = 272.8 Hz),
(c = 0.46; MeOH). Anal. calculated for C19H15Cl2F3N2O: C, 54.96; H,
3.64; N, 6.75%. Found: C, 55.19; H, 3.47; N, 6.54%.
137.89 (C-6), 152.11 (C-2). IR (KBr):
y 3100, 3220 (N–H), 1675,
4.1.10. S(À)-1-n-Butyl-6-methyl-4-phenyl-4-trifluoromethyl-3,4-
dihydropyrimidin-2(1H)-one (3j)
1700 (C O). [
a]
20 = À157.6 (c = 0.15; MeOH). Anal. calculated for
D
C18H13F3Cl2N2O: C, 53.89; H, 3.27; N, 7.00%. Found: C, 57.26; H,
3.43; N, 6.88%.
1H NMR (DMSO-d6)
d: 0.83 (t, 3H, J = 6.9 Hz), 1.30 (m, 4H), 1.97
(s, 3H), 2.81 (m, 2H), 3.48 (m, 2H), 5.04 (s, 1H), 7.34 (t, 1H,
J = 7.5 Hz), 7.38 (t, 2H, J = 7.5 Hz), 7.57 (d, 2H, J = 7.5 Hz). 19F NMR
4.2.5. S(À)-1-(3-Chloro-4-methylphenyl)-6-methyl-4-phenyl-4-
trifluoromethyl-3,4-dihydropyrimidin-2(1H)-one (3e)
(CDCl3)
d
: À79.93 (s, 3F). 13C NMR (DMSO-d6)
d: 14.00 (CH3), 18.90
(CH3), 31.93 (CH2), 32.69 (CH2), 41.75 (CH2), 62.18 (q,
JCF = 28.6 Hz), 94.97 (C-5), 125.05 (q, JCF = 276.6 Hz), 126.77,
128.63, 128.80, 138.28 (Carom.), 138.73 (C-6), 152.45 (C-2). IR
1H NMR (CDCl3)
d: 1.66 (s, 3H), 2.39 (s, 3H), 5.02 (s, 1H), 6.49 (s,
1H), 7.36 (s, 1H), 7.22–7.28 (m, 2H), 7.39–7.46 (m, 3H), 7.57 (d, 2H,
J = 7.5 Hz). 19F NMR (CDCl3)
19.75 (CH3), 20.75 (CH3), 63.20 (q, JCF = 28.9 Hz), 96.35 (C-5),
125.90, 127.82, 128.77, 128.91, 130.10, 131.19, 134.62, 135.79,
136.73, 138.01 (Carom.), 125.07 (q, JCF = 286.7 Hz), 138.06 (C-6),
d
: À79.75 (s, 3F). 13C NMR (CDCl3)
d:
(KBr):
y
3100, 3215 (N–H), 1675, 1700 (C O). [
a
]
20 = À138.76
D
(c = 0.9; MeOH). Anal. calculated for C16H19F3N2O: C, 61.53; H,
6.13; N, 8.97%. Found: C, 61.50; H, 6.06; N, 9.00%.
152.73(C-2). IR (KBr):
y 3090, 3220 (N–H), 1680, 1700 (C O).
4.2. General procedure for preparation of S(À)-1,4-diaryl-6-methyl-
4-trifluoromethyl-3,4-dihydropyrimidin-2(1H)-ones (3a–e,h,i)
[a
]
20 = À90.73 (c = 0.23; MeOH). Anal. calculated for
D
C19H15F4ClN2O: C, 57.23; H, 3.79; N, 7.03%. Found: C, 57.46; H,
3.53; N, 6.84%.
A solution of S(À)-N-aryl-N’-[(1-aryl-3-oxo-1-trifluoromethyl)-
butyl]urea 2a–g (0.001 mol) in acetic acid (10 ml) was refluxed for
4 h. After evaporating the solvent, water (5 ml) was added to the
residue. The solid product was filtered off, air-dried, and
recrystallized from a methanol:water mixture (2:1).
4.2.6. S(À)-1-(3-Chloro-4-methylphenyl)-4-(4-fluorophenyl)-6-
methyl-4-trifluoromethyl-3,4-dihydropyrimidin-2(1H)-one (3h)
1H NMR (CDCl3)
d
: 1.66 (s, 3H), 2.38 (s, 3H), 5.01 (s, 1H), 5.89 (s,
1H), 7.09 (d, 1H, J = 8.4 Hz), 7.26 (d, 3H, J = 7.5 Hz), 7.44 (d, 2H,
J = 7.5 Hz), 7.50 (d, 1H, J = 8.4 Hz). 19F NMR (CDCl3)
d
: À79.96 (s,
4.2.1. S(À)-1-(4-Fluorophenyl)-6-methyl-4-phenyl-4-
trifluoromethyl-3,4-dihydropyrimidin-2(1H)-one (3a)
3F), À114.10 (s, 3F). 13C NMR (CDCl3)
d: 19.68 (CH3), 20.39 (CH3),
62.84 (q, JCF = 28.9 Hz), 95.97 (C-5), 115.80, 127.80, 128.05, 130.07,
131.17, 134.01, 134.59, 135.74, 136.74 (Carom.), 124.98 (q,
JCF = 286.7 Hz), 138.30 (C-6), 152.48 (C-2), 162.73 (q,
1H NMR (CDCl3)
d: 1.63(s, 3H), 5.00(s, 1H), 5.85(s, 1H), 7.07–7.10
(m, 2H), 7.17 (s, 1H), 7.39–7.43 (m, 3H), 7.58 (d, 2H, J = 7.0 Hz). 19
F
:
NMR (CDCl3)
d
: À79.67 (s, 3F); À114.02 (s, 1F). 13C NMR (CDCl3)
d
J = 248.9 Hz). IR (KBr): y 3115, 3240 (N–H), 1675, 1698 (C O).
20.45 (CH3), 63.16 (q, JCF = 30.18 Hz), 96.28 (C-5), 116.01, 116.19,
125.93, 128.77, 128.90, 131.29, 133.17 (Carom.), 125.13 (q,
JCF = 286.7 Hz), 138.23 (C-6), 152.61 (C-2), 162.27 (d,
[
C
a
]
20 = À106.6 (c = 0.36; MeOH). Anal. calculated for
D
22H21F4N2O: C, 65.18; H, 5.22; N, 6.91%. Found: C, 65.39; H,
5.47; N, 6.74%.
J = 248.94 Hz). IR (KBr):
y 3090, 3210 (N–H), 1680, 1695 (C O).
[
a D
]
20 = À151.3 (c = 1.31; MeOH). Anal. calculated for C18H14F4N2O:
4.2.7. S(À)-1-(4-Tert-Buthylphenyl)-6-methyl-4-(4-methylphenyl)-
4-trifluoromethyl-3,4-dihydropyrimidin-2(1H)-one (3i)
C, 61.72; H, 4.03; N, 7.80%. Found: C, 61.95; H, 4.11; N, 7.59%.
1H NMR (CDCl3)
d: 1.32 c (s, 9H), 1.63 (s, 3H), 4.93 (s, 1H), 5.72
4.2.2. S(À)-1-(4-Chlorophenyl)-6-methyl-4-phenyl-4-
trifluoromethyl-3,4-dihydropyrimidin-2(1H)-one (3b)
(s, 1H), 7.09–7.15 (m, 4H), 7.40 (d, 2H, J = 8.1 Hz), 7.56 (d, 3H). 19
F
NMR(CDCl3)
d
: À79.91 (s, 3F); À114.24 (s, 1F). 13C NMR (CDCl3)
d:
1H NMR (CDCl3)
d
: 1.64 (s, 3H), 5.02 (s, 1H), 6.17 (s, 1H), 7.15 (s,
20.45 (CH3), 31.34 (3CH3), 34.69 (C(CH3)), 62.83 (q, JCF = 31.4 Hz),
95.48 (C-5), 115.64, 115.82, 126.09, 128.07, 128.84, 134.22, 134.40
2H), 7.40–7.43 (m, 5H), 7.57 (s, 2H). 19F NMR (CDCl3)
d
: -79.72 (s,

V.A. Sukach et al. / Journal of Fluorine Chemistry 129 (2008) 1180–1186
1185
(Carom.), 125.09 (q, JCF = 286.7 Hz), 138.99 (C-6), 151.36 (C-2),
JCF = 286.7 Hz), 135.62 (C-6), 137.44 (C-5), 174.80 (C S). IR (KBr):
y
162.69 (q, Carom, J = 248.9 Hz). IR (KBr):
y
3130, 3265 (N–H), 1680,
2995, 3200 (N–H) 1665 (C S). [
a
]
D
20 = À76.77 (c = 0.33; MeOH).
1695 (C O). [
a
]
D
20 = À103.3 (c = 0.32; MeOH). Anal. calculated for
Anal. calculated for C13H13F3N2S: C, 54.53; H, 4.58; N, 9.78%.
Found: C, 54.66; H, 4.54; N, 9.72%.
C19H15F4N2ClO: C, 57.23; H, 3.79; N, 7.02%. Found: C, 57.45; H,
3.67; N, 6.84%.
4.3.5. S(À)-4-(4-Fluorophenyl)-6-methyl-4-trifluoromethyl-3,4-
dihydropyrimidin-2(1H)-thione (4e)
4.3. General procedure for preparation of S(À)-4-aryl-6-methyl-4-
trifluoromethyl-3,4-dihydropyrimidin-2(1H)-(thi)ones (4a-e)
1H NMR (DMSO/CCl4, 2:1)
d: 1.81 (s, 3H), 4.97 (s, 1H), 7.16–7.33
(m, 2H), 7.56–7.59 (m, 2H), 9.58 (s, 1H), 10.22 (s, 1H). 19F NMR
To a solution of S(+)-4-amino-4-aryl-5,5,5-trifluoropentan-2-
one 1a–d (0.001 mol) in acetic acid (10 ml), potassium cyanate
or rhodanide (0.003 mol) was added and the reaction mixture
was boiled for 2 h. After evaporating the solvent, a 10% solution
of sodium hydrocarbonate (5 ml) was added to the residue,
followed by extracting with dichloromethane (2 Â 20 ml). The
organic layer was dried over sodium sulfate and evaporated.
(DMSO/CCl4, 2:1)
(DMSO-d6)
d
: À77.17 (s, 3F), À114.31 (s, 1F). 13C NMR
d
: 17.55 (CH3), 62.85 (q, JCF = 28.9 Hz), 93.76 (C-5),
115.06, 128.01, 128.54, 134.31 (Carom.), 124.4 (q, JCF = 287.9 Hz),
134.66 (C-6), 162.76 (C-5), 174.83 (C S). IR (KBr):
y 2998, 3210
(N–H) 1655 (C S).
[a
]
D
20 = À31.38 (c = 0.29; MeOH). Anal.
calculated for C12H10F4N2S: C, 49.65; H, 3.47; N, 9.65%. Found:
C, 49.64; H, 3.50; N, 9.65%.
Solid products were recrystallized from
a methanol:water
mixture (1:3) and oily products were chromatographed on a
silica gel column eluted with an ethyl acetate-hexane mixture
(2:1).
4.4. General procedure for preparation of S(À)-N-aroyl-N’-[(1-aryl-3-
oxo-1-trifluoromethyl)butyl]thioureas (5a–c)
To a solution of S(+)-4-amino-4-aryl-5,5,5-trifluoropentan-2-
one 1a–b (0.02 mol) in dry acetonitrile (40 ml), aroyl isothiocya-
nate (0.02 mol) was added, followed by stirring the mixture at
room temperature for 6 h. The resulting precipitate was filtered off,
washed with acetonitrile, and dried.
4.3.1. S(À)-6-Methyl-4-phenyl-4-trifluoromethyl-3,4-
dihydropyrimidin-2(1H)-one (4a)
1H NMR (CDCl3)
d
: 1.64 (s, 3H), 5.05 (s, 1H), 5.82 (s, 1H), 7.41–
7.58 (m, 8H), 7.65 (d, 1H, J = 7.5 Hz). 19F NMR (CDCl3)
: À79.64
(s, 3F). 13C NMR (CDCl3)
: 20.45 (CH3), 63.12 (q, JCF = 28.9 Hz),
d
d
96.91 (C-5), 125.36, 125.88, 126.66, 128.88, 128.97, 129.73,
133.17, 137.66, 137.85, 137.89 (Carom.), 124.61 (q, JCF = 245.2 Hz),
131.78 (q, J = 32.6 Hz), 125.41 (q, JCF = 272.8 Hz), 137.89 (C-6),
4.4.1. S(À)-N-Benzoyl-N’-[(3-oxo-1-phenyl-1-
trifluoromethyl)butyl]thiourea (5a)
1H NMR (CDCl3)
d
: 2.28 (s, 3H), 3.79 (d, 1H, J = 16.5 Hz), 4.50 (s,
1H, J = 16.5 Hz), 7.26–7.65 (m, 8H), 7.90 (d, 2H, J = 12 Hz), 9.07(s,
1H), 12.23 (s, 1H). 19F NMR (CDCl3) : -77.07 (s, 3F). 13C NMR
(CDCl3) : 31.30 (CH3), 41.76 (CH2), 65.65 (q, JCF = 27.6 Hz), 126.23
152.11 (C-2). IR (KBr):
y 2950, 3210 (N–H) 1700 (C = O).
[
a
]
20 = À108.93 (c = 0.5; MeOH). Anal. calculated for
d
D
C
12H11F3N2O: C, 56.25; H, 4.33; N, 10.93%. Found: C, 56.40; H,
d
4.26; N, 10.89%.
(q, JCF = 245.9 Hz), 127.13, 127.67, 128.57, 128.96, 129.16, 131.37,
133.81, 134.40 (Carom.), 167.33 (C O), 179.87 (C O), 201.50 (C O).
4.3.2. S(À)-6-Methyl-4-(4-methylphenyl)-4-trifluoromethyl-3,4-
dihydropyrimidin-2(1H)-one (4b)
IR (KBr): y 3400, 3010 (N–H) 1665, 1710 (C O), 1555 (C S).
[a
]
D
20 = À66.84 (c = 0.75; MeOH). Anal. calculated for
1H NMR (DMSO/CCl4, 2:1)
d
: 1.76 (s, 3H), 2.31 (s, 3H), 4.71 (s,
C19H17F3N2O2S: C, 57.86; H, 4.34; N, 7.10%. Found: C, 57.81; H,
1H), 7.18 (d, 2H, J = 7.5 Hz), 7.40 (d, 2H, J = 7.5 Hz), 7.96 (s, 1H), 8.70
4.32; N, 7.13%.
(s, 1H). 19F NMR (DMSO/CCl4, 2:1)
(DMSO-d6)
d
: À79.62 (s, 3F). 13C NMR
d
: 18.27 (CH3), 20.61 (CH3), 64.38 (q, JCF = 28.9 Hz),
4.4.2. S(À)-N-(4-Chlorobenzoyl)-N’-[(3-oxo-1-phenyl-1-
trifluoromethyl)butyl]thiourea (5b)
93.31 (C-5), 125.75, 128.25, 128.97, 129.44 (Carom.), 124.65 (q,
JCF = 247.7 Hz), 135.26 (C-6), 138.54 (C-5), 153.28 (C = S). IR (KBr):
1H NMR (DMSO-d6)
d: 2.21 (s, 3H), 3.96 (d, 1H, J = 17.4 Hz), 4.45
y
2950, 3200 (N–H) 1705 (C O). [
a
]
20 = À157.26 (c = 0.26;
(d, 1H, J = 17.4 Hz), 7.37–7.57 (m, 7H), 8.04 (d, 2H, J = 8.4 Hz), 11.60
D
MeOH). Anal. calculated for C13H13F3N2O: C, 57.78; H, 4.85; N,
10.37%. Found: C, 57.70; H, 4.87; N, 10.30%.
(s, 1H), 12.42 (s, 1H). 19F NMR (DMSO-d6)
NMR (DMSO-d6)
d
: À75.73 (s, 3F). 13C
d
: 30.71 (CH3), 41.52 (CH2), 64.67 (q, J = 27.2 Hz),
126.30 (JCF = 245.9 Hz), 127.15, 128.28, 128.49, 128.57, 128.62,
4.3.3. S(À)-6-Methyl-4-phenyl-4-trifluoromethyl-3,4-
dihydropyrimidin-2(1H)-thione (4c)
130.72, 134.54, 138.21 (Carom.), 168.29 (C O), 180.00 (C O),
201.91 (C O). IR (KBr):
y 3400, 3015 (N–H) 1665, 1705 (C O),
1H NMR (DMSO/CCl4, 2:1)
d
: 1.81 (s, 3H), 4.95 (s, 1H), 7.34–7.42
1565 (C S). [
a
]
D
20 = À49.76 (c = 0.15; MeOH). Anal. calculated for
(m, 4H), 7.52 (d, 2H, J = 8.0 Hz), 9.58 (s, 1H), 10.19 (s, 1H). 19F NMR
C19H16ClF3N2O2S: C, 53.21; H, 3.76; N, 6.53%. Found: C, 53.10; H,
(DMSO/CCl4, 2:1)
d
: À77.03 (s, 3F). 13C NMR (DMSO-d6)
d
: 17.47
3.75; N, 6.60%.
(CH3), 63.34 (q, JCF = 27.7 Hz), 94.16 (C-5), 125.63, 126.18, 128.30,
128.39 (Carom.), 129.2 (q, JCF = 285.4 Hz), 134.24 (C-6), 138.53 (C-5),
4.4.3. S(À)-N-(4-Nitrobenzoyl)-N’-[(1-(4-methylphenyl)-3-oxo-1-
trifluoromethyl)butyl]thiourea (5c)
175.00 (C S). IR (KBr):
y 2900, 3200 (N–H) 1655 (C S).
[a
]
D
20 = À23.33 (c = 0.40; MeOH). Anal. calculated for
1H NMR (DMSO-d6)
d: 2.21 (s, 3H), 2.34 (s, 3H), 3.95 (d, 1H,
C12H11F3N2S: C, 52.93; H, 4.07; N, 10.29%. Found: C, 52.83; H,
J = 17.0 Hz), 4.41 (d, 1H, J = 17.0 Hz), 7.19 (d, 2H, J = 9.0 Hz), 7.33 (d,
2H, J = 9.0 Hz), 8.23 (d, 2H, J = 8.8 Hz), 8.32 (d, 2H, J = 8.8 Hz), 11.89
4.01; N, 10.30%.
(s,1H), 12.24 (s, 1H). 19F NMR (DMSO-d6)
d
: À75.89 (s, 3F). 13C NMR
4.3.4. S(À)-6-Methyl-4-(4-methylphenyl)-4-trifluoromethyl-3,4-
dihydropyrimidin-2(1H)-thione (4d)
(CDCl3) d: 20.50 (CH3), 30.49 (CH3), 41.52
d
:
13C NMR (DMSO-d6)
(CH2), 64.57 (q, J = 27.2 Hz), 126.24 (JCF = 245.9 Hz), 123.08,
126.88, 128.68, 130.26, 131.39, 137.73, 149.80, 167.46 (Carom.),
1H NMR (DMSO/CCl4, 2:1)
d
: 1.80 (s, 3H), 2.31 (s, 3H), 4.91 (s,
1H), 7.20 (d, 2H, J = 7.5 Hz), 7.39 (d, 2H, J = 7.5 Hz), 9.51 (s, 1H),
174.80 (C O), 179.66 (C O), 201.34 (C O) IR (KBr): y 3400, 3010
10.16 (s, 1H). 19F NMR (DMSO/CCl4, 2:1)
(DMSO-d6)
d
: À77.04 (s, 3F). 13C NMR
(N–H) 1665, 1705 (C O), 1560 (C S). [
a
]
D
20 = À82.44 (c = 0.44;
d
: 17.47 (CH3), 20.37 (CH3), 63.10 (q, JCF = 28.9 Hz),
MeOH). Anal. calculated for C19H16F3N3O4S: C, 51.94; H, 3.67; N,
9.56%. Found: C, 52.13; H, 3.64; N, 9.49%.
94.18 (C-5), 125.94, 127.91, 128.61, 133.92 (Carom.), 126.7 (q,

1186
V.A. Sukach et al. / Journal of Fluorine Chemistry 129 (2008) 1180–1186
4.5. General procedure for preparation of 4-aryl-4-isocyanato-5,5,5-
calculated for C13H12F3NO3: C, 54.36; H, 4.21; N, 4.88%. Found:
C, 54.33; H, 4.18; N, 4.96%.
trifluoropentan-2-ones (6a–d)
To a solution of S(+)-4-amino-4-aryl-5,5,5-trifluoropentan-2-
one 1a–d (2.02 mmol) in dry ethyl acetate (10 ml), triphosgene
(2.78 g, 1.02 mmol), along with three drops of dry triethylamine,
was added. The reaction mixture was boiled for 15–20 h and the
solvent was evaporated. The dry residue of the product (yield 85–
90%) was converted further without additional purification.
4.7. Reaction of 4-aryl-4-isocyanato-5,5,5-trifluoropentan-2-ones
6a,b with amines
To a solution of 4-aryl-4-isocyanato-5,5,5-trifluoropentan-2-
one 6a,b (0.002 mol) in dry toluene (10 ml), an amine, e.g.,
butylamine, benzylamine, or morpholine (0.002 mol) was added.
The reaction mixture was boiled for 5 h and the solvent was
evaporated to obtain a mixture of dihydropyrimidone 3j,k and
dihydrooxazinone 7a,b. In the reaction with morpholine, the
residue was chromatographed on a silica gel column eluted with
an ethyl acetate-hexane mixture (2:1) to yield urea 8.
4.6. General procedure for preparation of S(À)-4-aryl-6-methyl-4-
trifluoromethyl-3,4-dihydro-1,3-oxazin-2-ones (7a–d)
To a solution of S(+)-4-amino-4-aryl-5,5,5-trifluoropentan-2-
one 1a–d (2.02 mmol) in dry ethyl acetate (10 ml), triphosgene
(2.78 g, 1.02 mmol), along with three drops of DBU, was added. The
reaction mixture was boiled for 8–10 h and the solvent was
evaporated. The residue was chromatographed on a silica gel
column eluted with an ethyl acetate-hexane mixture (1:1).
4.7.1. S(À)-N-[(3-Oxo-1-phenyl-1-
trifluoromethyl)butyl]morpholinecarboxamide (8)
1H NMR (CDCl3)
d: 2.22 c (s, 3H), 3.42–3.55 (m, 6H), 3.71 (m,
4H), 5.94 c (s, 1H), 7.06 (m, 2H), 7.43 (m, 2H). 19F NMR (CDCl3)
d:
À74.58 (s, 3F), À114.98 (s, 1F). 13C NMR (CDCl3)
d: 32.13 (CH3),
4.6.1. S(À)-6-Methyl-4-phenyl-4-trifluoromethyl-3,4-dihydro-1,3-
oxazin-2-one (7a)
44.16, 44.41 (CH2), 63.20 (q, JCF = 27.6 Hz), 66.51 (CH2), 115.38
(Carom), 125.42 (q, JCF = 286.7 Hz), 127.88, 132.85 (Carom.), 156.14
1H NMR (CDCl3)
7.41 (m, 5H). 19F NMR (CDCl3)
d
: 2.00 (s, 3H), 5.19 (s, 1H), 7.04 (s, 1H), 7.26–
(C O), 162.47 (q, J = 247.7 Hz), 205.68 (C O). [
(c = 0.95; MeOH).Anal. calculated for C16H19F3N2O3: C, 55.81; H,
a
]
D
20 = À33.65
d
: À79.25 (s, 3F). 13C NMR (CDCl3)
d
:
18.72 (CH3), 63.20 (q, J CF = 30.1 Hz), 95.25 (C-5), 124.33 (q, J
5.56; N, 8.14%. Found: C, 55.77; H, 5.58; N, 8.19%.
CF = 286.7 Hz), 125.90, 129.05, 129.19 (Carom.), 136.43 (C-6), 149.92
20 = À105.23 (c = 1.85; MeOH). Anal.
References
(Carom.), 150.62 (C-2). [
a
]
D
calculated for C12H10F3NO2: C, 56.04; H, 3.92; N, 5.45%. Found: C,
55.92; H, 3.88; N, 5.50%.
[1] C.O. Kappe, Tetrahedron 49 (1993) 6937–6963.
[2] C.O. Kappe, Acc. Chem. Res. 33 (2000) 879–888.
[3] C.O. Kappe, A. Stadler, Org. React. 63 (2004) 1–116.
[4] C.O. Kappe, Eur. J. Med. Chem. 35 (2000) 1043–1052.
[5] G.C. Rovnyak, S.D. Kimball, G. Cucinotta, J.D. Dimareo, J. Gougoutas, A. Hedberg, M.
Malley, J.P. McCarthy, R. Zhang, S. Moreland, J. Med. Chem. 38 (1995) 119–129.
[6] M. Gartner, N. Sunder-Plassmann, J. Seiler, M. Utz, I. Vernos, T. Surrey, A. Giannis,
ChemBioChem 6 (2005) 1173–1177.
[7] C. Blackburn, B. Guan, J. Brown, C. Cullis, S.M. Condon, T.J. Jenkins, S. Peluso, Y. Ye,
R.E. Gimeno, S. Punreddy, Y. Sun, H. Wu, B. Hubbard, V. Kaushik, P. Tummino, P.
Sanchetti, D.Y. Sun, T. Daniels, E. Tozzo, S.K. Balani, Bioorg. Med. Chem. Lett. 16
(2006) 3504–3509.
[8] J.W. Corbett, S.S. Ko, J.D. Rodgers, L.A. Gearhart, N.A. Magnus, L.T. Bacheler, S.
Diamond, S. Jeffrey, R.M. Klabe, B.C. Cordova, S. Garber, K. Logue, G.L. Trainor, P.S.
Anderson, S.K. Erickson-Viitanen, J. Med. Chem. 43 (2000) 2019–2030.
[9] (a) G.C. Rovnyak, S.D. Kimball, B. Beyer, G. Cucinotta, J.D. DiMarco, J. Gougoutas, A.
Hedberg, M. Malley, J.P. McCarthy, R. Zhang, S. Moreland, J. Med. Chem. 38 (1995)
119–129;
(b) D.J. Triggle, S. Padmanabhan, Chemtracts: Org. Chem. 8 (1995) 191–196;
(c) O.P. Kleiderningg, C.O. Kappe, Tetrahedron: Asymm. 8 (1997) 2057–2067.
[10] (a) Y. Huang, F. Yang, C. Zhu, J. Am. Chem. Soc. 127 (2005) 16386–16387;
(b) S. Lou, B.M. Taoka, A. Ting, S.E. Schaus, J. Am. Chem. Soc. 127 (2005) 11256–
11257;
4.6.2. S(À)-6-Methyl-4-(4-methylphenyl)-4-trifluoromethyl-3,4-
dihydro-1,3-oxazin-2-one (7b)
1H NMR (CDCl3)
d: 1.99 (s, 3H), 2.36 (s, 3H), 5.18 (s, 1H), 6.95 (s,
1H), 7.23 (d, 2H, J = 8.0 Hz), 7.38 (d, 2H, J = 8.0 Hz). 19F NMR (CDCl3)
d
: À79.27 (s, 3F). 13C NMR (CDCl3)
d: 18.68 (CH3), 20.99 (CH3),
63.10 (q, J = 30.2 Hz), 95.37 (C-5), 124.42 (q, J CF = 285.4 Hz),
125.80, 129.69, 133.54 (Carom.), 139.18 (C-6), 149.93 (Carom.),
150.47 (C-2). [
a
]
20 = À108.1 (c = 0.64; MeOH). Anal. calculated for
D
C
13H12F3NO2: C, 57.57; H, 4.46; N, 5.16%. Found: C, 57.58; H, 4.49;
N, 5.11%.
4.6.3. S(À)-4-(4-Fluorophenyl)-6-methyl-4-trifluoromethyl-3,4-
dihydro-1,3-oxazin-2-one (7c)
1H NMR (CDCl3)
d: 2.01(s, 3H), 5.20(s, 1H), 6.93(s, 1H), 7.08–7.15
(m, 2H), 7.50–7.56(m, 2H), 7.95(s, 1H).19FNMR(CDCl3)
d: 18.71 (CH3), 63.00 (q,
JCF = 30.1 Hz), 95.03 (C-5), 116.11 (Carom.), 124.40 (q, JCF = 285.6 Hz),
d
:À79.48(s,
3F), À113.31 (s, 1F). 13C NMR (CDCl3)
(c) X.-H. Chen, X.-Y. Xu, H. Liu, L.-F. Cun, L.-Z. Gong, J. Am. Chem. Soc. 128 (2006)
14802–14803;
(d) L.-Z. Gong, X.-H. Chen, X.-Y. Xu, Chem. Eur. J. 13 (2007) 8920–8926.
[11] N.A. Magnus, P.N. Confalone, L. Storace, M. Patel, C.C. Wood, W.P. Davis, R.L.
Parsons, J. Org. Chem. 68 (2003) 754–761.
128.12, 132.33, 149.90 (Carom.), 150.86 (C-6), 161.93 (C-2).
[
a D
]
20 = À112.766(c = 1.0;MeOH). Anal. calculated forC12H9F4NO2:
[12] (a) S. Saaby, K. Nakama, M.A. Lie, R.G. Hazell, K.A. Jorgensen, Chem. Eur. J. 9 (2003)
6145–6154;
C, 52.37; H, 3.30; N, 5.09. Found: C, 52.50; H, 3.26; N, 5.09%.
(b) W. Zhuang, S. Saaby, K.A. Jorgensen, Angew. Chem. Int. Ed. 43 (2004) 4476–
4478.
[13] Special issue on Fluorine in the Life Sciences, ChemBioChem 5 (2004) 559-562.
[14] R. Lantzsch, D. Arlt, Synthesis (1977) 756–757.
[15] V.A. Sukach, N.M. Golovach, V.V. Pirozhenko, E.B. Rusanov, M.V. Vovk, Tetrahe-
dron: Asymm. 19 (2008) 761–764.
[16] L. Cotarca, P. Delogu, A. Nardelli, V. Unji, Synthesis (1996) 553–576.
[17] L.N. Kuleshova, P.M. Zorkii, Acta Cryst. (B) 37 (1981) 1363–1366.
[18] (a) M.V. Vovk, P.S. Lebed, V.V. Pirozhenko, I.F. Tsymbal, Russ. J. Org. Chem. 40
(2004) 1669–1678;
4.6.4. S(À)-6-Methyl-4-(4-methoxylphenyl)-4-trifluoromethyl-3,4-
dihydro-1,3-oxazin-2-one (7d)
1H NMR (CDCl3)
d: 1.99 (s, 3H), 3.81 (s, 3H), 5.18 (s, 1H), 6.93 (s,
1H), 6.93 (d, 2H, J = 9.0 Hz), 7.35 (d, 2H, J = 9.0 Hz), 7.47 (s, 1H). 19
F
NMR (CDCl3)
d
: À79.45 (s, 3F). 13C NMR (CDCl3)
d: 18.61 (CH3),
55.31 (CH3), 62.97 (q, JCF = 28.92 Hz), 95.41 (C-5), 114.33 (Carom.),
124.44 (q, JCF = 285.5 Hz), 127.68, 128.47, 149.95 (Carom.), 150.42
(C-6), 160.03 (C-2).
[a
]
20 = À106.1 (c = 0.40; MeOH). Anal.
(b) M.V. Vovk, A.V. Bolbut, Russ. J. Org. Chem. 34 (1998) 593–594.
D