Synthesis and characterization of new trifluoromethyl substituted 3-ethoxycarbonyl- and 3-pyrimidin-2-yl-(1,2,3)-oxathiazinane-S-oxides

Article abstract of DOI:10.1002/jhet.5570450207

(Chemical Equation Presented) This paper describes the synthesis and characterization of a new series of 4-substituted-3-ethoxycarbonyl-6- trifluoromethyl-(1,2,3)-oxathiazinane-S-oxides and 3-(4,6-diphenyl-pyrimidin-2- yl)-6-trifluoromethyl-(1,2,3)oxathiazinane-S-oxides from the cyclization reaction of 4,4,4-trifluoro-3-hydroxybutylcarbamates and 4-(4,6-diphenyl- pyrimidin-2-ylamino)-1,1,1-trifluoro-butan-2-ols with thionyl chloride. The analysis of the NMR data allowed us to define important features of the molecular structure. Significant chemical and structural differences were observed between the trifluoromethylated oxathiazinanes obtained in this work from other analogue compounds reported in the literature.

Full text of DOI:10.1002/jhet.5570450207

Mar-Apr 2008
335
Synthesis and Characterization of New Trifluoromethyl Substituted
3-Ethoxycarbonyl- and 3-Pyrimidin-2-yl)-(1,2,3)-Oxathiazinane-S-
Oxides
Nilo Zanatta,* Deise M. Borchhardt, Darlene C. Flores, Helena S. Coelho, Tiago M.
Marchi, Alex F. C. Flores, Helio G. Bonacorso, and Marcos A. P. Martins
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de
Santa Maria, 97.105-900, Santa Maria, RS, Brazil
Received February 27, 2002
H
R
O
NHR1
R
R1
OH
R
O
OR1
N
O
H
H
CF3
O
NHR1
F3C
F3C
F3C
R
S
H
This paper describes the synthesis and characterization of a new series of 4-substituted-3-
ethoxycarbonyl-6-trifluoromethyl-(1,2,3)-oxathiazinane-S-oxides and 3-(4,6-diphenyl-pyrimidin-2-yl)-6-
trifluoromethyl-(1,2,3)oxathiazinane-S-oxides from the cyclization reaction of 4,4,4-trifluoro-3-
hydroxybutylcarbamates and 4-(4,6-diphenyl-pyrimidin-2-ylamino)-1,1,1-trifluoro-butan-2-ols with
thionyl chloride. The analysis of the NMR data allowed us to define important features of the molecular
structure. Significant chemical and structural differences were observed between the trifluoromethylated
oxathiazinanes obtained in this work from other analogue compounds reported in the literature.
J. Heterocyclic Chem., 45, 335 (2008).
Due to its modest steric requirements, high lipophilicity
and electron-withdrawing effect and difficult
metabolization, fluorine compounds have been
extensively utilized in medicinal chemistry [12]. In this
context, trifluoromethyl substituted heterocycles have
been receiving special attention due to their broad scope
of biological activity [13]. However, to the best of our
knowledge, no example of oxathiazinanes bearing a
trifluoromethyl group has been submitted to biological
evaluation prior to our study.
In this context, we were primarily interested in the
synthesis of (1,2,3)-oxathiazinane-S-oxides containing a
trifluoromethyl group at the α-position of the endocyclic
oxygen atom. The trifluoromethyl group has a strong
electron-withdrawing effect and we were interested to
know how this group could affect the reactivity and the
structure of the title compounds. As an extension of our
study we are proposing the synthesis of N-substituted
6-trifluoromethyl-(1,2,3)-oxathiazinane-S-oxides with
groups such as ethyl ester and pyrimidines. The influence
of an α-substituent at the endocyclic nitrogen atom on the
reactivity of the cyclization reaction and configuration of
the oxathiazinane ring system is also the subject of this
study. The (1,2,3)-oxathiazinane-S-oxides obtained in this
study could be used as the starting material to synthesize
acyclic compounds functionalized at the –CF3 α-position,
which are difficult to achieve by other methods.
INTRODUCTION
A
wide variety of chemically and biologically
important molecules has been prepared from 2-oxo-
[1,2,3]-oxathiazinanes and 2,2-dioxo-[1,2,3]oxathia-
zinanes, also known as cyclic sulfamidites and
sulfamidates, respectively [1]. For example, cyclic
sulfamidate has been used as a chiral educt for the
synthesis of enantiopure γ-substituted α-amino acids [2],
for the enantioselective synthesis of the bromopyrrole
alkaloid manzacidin A and C [3], for the generation of a
variety of unnatural α,α-dissubstituted amino acid
derivatives [4] and optical active hydroxy amino acids [5],
and for the synthesis of a variety of aliphatic compounds
through the opening of the cyclic sulfamidates with
azides,
cyanide,
amines,
phenol,
thiophenol,
thioisocyanides, and potassium acetate [6]. In addition,
cyclic sulfamidites have been used as starting material for
the preparation of enantiomerically enriched sulfinamides
and sulfoximides [7,8].
Only a single method has been reported to synthesize
six-membered sulfamidites, which is through the reaction
of a γ-amino alcohols with thionyl chloride [9]. Curiously,
most six-membered sulfamidites bear bulky substituents
at the nitrogen as well as at the α-endocyclic nitrogen
position. In addition, it has been shown that carbamoyl-
ation of the NH improves the electrophilic reactivity of
these compounds [10]. However, it is relatively rare to
find such compounds bearing substituents at the α-oxygen
position and, to our knowledge, oxathiazinanes containing
a trifluoromethyl group at the α-oxygen position have not
yet been reported.
RESULTS AND DISCUSSION
The strategy utilized to synthesize the 1,2,3-
oxathiazinanes 3a-e is shown in Scheme 1. In this

336
N. Zanatta, D. M. Borchhardt, D. C. Flores, H. S. Coelho, T. M. Marchi,
A. F. C. Flores, H. G. Bonacorso, and M. A. P. Martins
Vol 45
Scheme, the synthesis starts with the reaction of the
readily available 4-alkoxy-1,1,1-trifluoro-alk-3-en-2-ones
[14], with ethyl carbamate in dichloromethane or
chloroform in the presence of a catalytic amount of p-
toluene sulfonic acid, to give (4,4,4-trifluoro-3-oxo-but-1-
enyl)-carbamic acid ethyl esters 1a-f [15]. Compounds
1a-f were reduced with sodium borohydrade in ethanol to
give the ethyl 4,4,4-trifluoro-3-hydroxybutylcarbamates
2a-f [15].
of the amino alcohols 2a-e (Scheme 1) and 6a-c (Scheme
2) with thionyl chloride in toluene and in the presence of
pyridine, the use of imidazole was not required to obtain
the 1,2,3-oxathiazinane-S-oxides 3a-e and 7a-c.
Scheme 2
R1
R1
Scheme 1
i
ii
N
N
OH
R
30 - 70%
NH2
O
NHCO2Et
R
26 -85%
i
Ph
N
4a-c
R1
Ph
N
N
H
F3C
NHCO2Et
F3C
38-82%
CF3
2a -f
1a-f
O
5a-c
ii
30 - 70%
R1
e
Compd
R
a
b
c
d
f
H
4-Me-Ph
Ph
Me n-Pr n-Bu
CF3
iii
i) NaBH4, EtOH, rt-70 C, 5-24 h (Ref. 15)
ii) SOCl2, Py, Toluene, r.t., 9-24 h.
41 - 57%
O
S
N
OH
N
O
R
N
O
S
CO2Et
Ph
Ph
N
NH
CF3
N
N
O
3a-e
CF3
6a-c
7a-c
Although, the synthesis of 1a-d and 2a-d has been
recently reported [15], in this paper we are extending
these reactions to include two new substituents to obtain
1e-f and 2e-f. The 4-substituted-3-ethoxycarbonyl-6-
trifluoromethyl-(1,2,3)-oxathiazinane-S-oxides 3a-e were
obtained through the cyclization reaction of the ethyl
Compd
R1
a
b
c
H
Cl
OMe
i) 4-Ethoxy-1,1,1-trifluoro-but-3-en-2-one, EtOH, reflux, 18 h
ii) NaBH4, EtOH, rt-70 oC, 5-24 h (Ref. 15).
iii) SOCl2, py, toluene, r.t., 24 h.
4,4,4-trifluoro-3-hydroxybutylcarbamates
2a-e
with
thionyl chloride, in toluene, and in the presence of
pyridine. It was necessary to use an excess of the thionyl
chloride to improve yields. When an equivalent of thionyl
chloride was used, unreacted starting material 2 (Scheme
1) and 6 (Scheme 2) was obtained, especially with
compounds with bulky groups at the 4-position. The best
reaction condition was achieved when a 1.5 equivalent of
thionyl chloride was used. The cyclic products 3 (Scheme
1) or 7 (Scheme 2) were not obtained when the reactions
were carried out under reflux, using triethylamine instead
of pyridine, or other solvents such as CHCl3 or CH2Cl2.
When the reaction was carried in THF for 24 h, the
products were obtained but some starting material
remained unreacted. Longer reaction times as well as
larger amounts of thionyl chloride did not improve the
yields of the cyclization products. It has been reported
that the cyclization of homoserine by using a similar
protocol required the addition of a large excess of
imidazole to obtain the corresponding 1,2,3-
oxathiazinane-S-oxides, and when the imidazole was
omitted from the reaction mixture, the major isolated
product was a symmetrical sulfite [2a]. For the reaction
The strategy used for the synthesis of compounds 7a-c
is shown in Scheme 2. This strategy starts with the
reaction of pyrimidin-2-amines 4a-c, which synthesis has
been reported elsewhere [16]. The reactions of the
pyrimidin-2-amines 4a-c with 4-ethoxy-1,1,1-trifluoro-
but-3-en-2-one were carried out in ethanol under reflux
for 18 hours to obtain the desired 1,1,1-trifluoro-4-
(pyrimidin-2-ylamino)but-3-en-2-ones 5a-c. Although the
Michael addition reaction of amines to 4-alkoxy-1,1,1-
trihalo-alk-3-en-2-ones (enones), followed by the
elimination of the 4-alkoxy group, leading to the
corresponding enamino ketones has been widely reported
[17], the reaction of weak nitrogen nucleophiles such as
pyrimidin-2-amines with these enones was not yet
reported. It was observed that the substitution on the β-
carbon of the enones makes the attack of the pyrimidin-2-
amines to this carbon more difficult. For the reaction of
the 4-substituted enones with pyrimidin-2-amines 4, other
reaction conditions such as changing solvents and the use
of acid catalysis was tested, but no positive result for
these reactions was found.

Mar-Apr 2008
Synthesis and Characterization of New Trifluoromethyl Substituted 3-Ethoxycarbonyl-
337
The reduction of compounds 5a-c, using the same
procedure described above for compounds 1a-f, furnished
the corresponding 4-(pyrimidin-2-ylamino)-1,1,1-tri-
fluoro-butan-2-ol 6a-c (Scheme 2), in moderate to good
yields. The cyclization of compounds 6a-c with thionyl
chloride to give a series of 3-(4,6-diphenyl-pyrimidin-2-
yl)-6-trifluoromethyl-(1,2,3)oxathiazinane-S-oxides 7a-c
was carried out using the same procedure as described for
the synthesis of compounds 3a-e.
however, was stereoselective because the minor
diastereoisomer was formed at 10% of the major isomer.
This result confirms the data observed on the NMR
spectroscopy and GC-MS.
The 1,2,3-oxathiazinane-S-oxides 3 and 7 show both
1H- and 13C-NMR spectra similar to the corresponding
amino alcohol precursors. The formation of compounds 3
and 7 was evidenced by the multiplicity of H-4 of the
cyclic products, showing a signal with well defined
coupling constants, as well as by the molecular ion on the
mass spectra, which showed that the 1,2,3-oxathiazinane-
S-oxides had 46 mass units more than the corresponding
amino alcohols 2.
The structure of the enamino ketones 1 and 5, amino
alcohols 2 and 6 and oxathiazinanes 3 and 7 were
1
analyzed by GC-MS, elemental analysis, H, 13C, and 19F
NMR spectroscopy, and 2-D NMR COSY to confirm the
hydrogen assignments. These data are reported in the
experimental part. The atom numbering used for the
NMR assignment of compounds 1, 3, 5, and 7 is presented
in Figure 1. Compounds 2 and 6 follow the same
numbering of the compounds 1 and 5, respectively.
The interpretation of the coupling constants of H-4 and
H-5 furnished important information about the spatial
position of the substituents attached to the oxathiazinane
six-membered ring. It was observed that the H-4 of
compound 3b shows a coupling constant with one of the
H-5 with 13.0 Hz and with the other with 6.0 Hz. These
coupling constants are consistent with the position of the
phenyl group in a pseudo-equatorial position. The
coupling constant of one of the H-5 (axial) shows a
geminal coupling constant with the other H-5 (equatorial)
and vicinal coupling constants with H-4 and with H-6
with about 13.0 Hz for all of these nuclei (Figure 2). This
indicates that the CF3 group is in equatorial position and
confirms the pseudo-equatorial position of the 4-phenyl
group. The same analysis done for the other sulfamidites
3 and 7 shows the same trend as presented for 3b. It is
interesting to note that in a recent study with analogues of
1,2,3-oxathiazinane-S-oxides derived from homoserine
[2a], the 4-t-butyl carboxyl group was reported in axial
position. Figure 2 shows the structure of the oxathia-
5-7
NHCO2Et
R
O
7
O
2
4
3
N
5
8
O
9
4
F3C
1
R
S
2
3
6
F3C
O
1
O
1
3
R1
18
R1
16
17
16
15
14
15
13
6
8
9
N
7
7
O
2
N
5
4
3
N
9-12
Ph
5
10
N
9-12
F3C
1
N
H
N Ph
8
4
S
2
3
6
F3C
O
1
O
7
5
1
zinane 3b drawn according to the interpretation of the H
Figure 1. atom numbering for the NMR assignment of compounds 1, 3,
5, and 7.
NMR coupling constants and the structure of analogue
oxathiazinanes reported in the literature [2a].
Structural Considerations. For the reduced
compounds 2b-c that presented more than one stereogenic
center, as well as for 1,2,3-oxathiazinanes 3b-c, only a
H
Ph
O
H
H
PhFN
EtO2CN
O
PhFN
O
H
H
CF3
O
1
single set of signals was observed in both H and 13C-
O
S
S
S
H
NMR spectra. In addition, a single peak was observed in
the total ion chromatogram registered on a GC-MS
CO2t-Bu
O
CO2t-Bu
3b
II
I
equipped with
a non-chiral capillary column. For
JH4-H5ax = 13.2 Hz
JH4-H5eq = 6.0 Hz
JH5eq-H5ax = 14.0 Hz
JH5eq-H6 = 3.0 Hz
J5ax-H6 = 13.2 Hz
compound 3c, a gas-chromatogram registered on a chiral
column showed two peaks of about the same intensity for
the oxathiazinanes containing two asymmetric carbons
and a sulfoxide group. This indicates that only a pair of
enantiomers was formed and that the reduction and
cyclization reactions were stereoselective. However, for
compounds 3d-e, two peaks were observed in the total ion
chromatogram and for compound 3d, a gas-chromatogram
registered using a chiral column showed four peaks,
which is an indication that a pair of diastereoisomers and
two pairs of enantiomers were formed. The reaction,
I = (2S)-3-(4-Fluoro-phenyl)-2-oxo-[1,2,3]oxathiazi-
nane-4-carboxylic acid tert-butyl ester
II = (2R)-3-(4-Fluoro-phenyl)-2-oxo-[1,2,3]oxathiazi-
nane-4-carboxylic acid tert-butyl ester
Figure 2. Structure and 1H NMR coupling constants of compound 3b
and structure of oxathiazinanes from Reference 2a.
Oxidation of ethyl 2-oxo-6-trifluoromethyl-(1,2,3)-
oxathiazinane-3-carbamate (3a) to ethyl 2-dioxo-6-
trifluoromethyl-(1,2,3)-oxathiazinane-3-carbamate (8a)
was performed using two methods: m-chloroperbenzoic

338
N. Zanatta, D. M. Borchhardt, D. C. Flores, H. S. Coelho, T. M. Marchi,
A. F. C. Flores, H. G. Bonacorso, and M. A. P. Martins
Vol 45
acid and potassium periodate catalized by ruthenium
trichloride. The reaction with the first oxidant was not
effective and the starting compound 3a was recovered.
The oxidation carried out with potassium periodate
catalyzed by ruthenium trichloride [2a] (Scheme 3)
furnished the desired product 8a (in a small amount) and a
ruthenium dichloride-sulfamidate complex 9a (as the
major product) that was analyzed by GC-MS. For 9a, a
typical molecular ion of m/z 447 with several
characteristic peaks due to natural isotopes of ruthenium
was observed [18]. We were not able to completely
hydrolyze the ruthenium-sulfamidate complex 9a
following procedures from the literature [2a]. Compound
8a was isolated, as a pure compound, only after column
chromatography in silica gel in a 50% yield. In addition,
it has been reported that the reaction of γ-amino alcohols
derived from homoserine with thionyl chloride furnished
a mixture of 2R and 2S sulfamidites and that only the 2R
(equatorial oxygen) could be oxidized to the
correspondent sulfamidate [2a]. For the oxathiazinane 3a
obtained in this work, it seems that only the equatorial
oxygen-sulfoxide was obtained and this conclusion rises
from the following evidences: (i) Only one set of signals
observed between the trifluoromethylated oxathiazinanes
obtained in this work and other analogue compounds
reported in the literature, as discussed in the text. The
oxathiazinanes were assessed against
a panel of
microorganisms including yeast like fungi, bacteria and
algae, but no activity was observed.
EXPERIMENTAL
The solvents were purified and dried before use and the 4-
alkoxy-1,1,1-trifluoro-alk-3-en-2-ones were prepared according
to procedures from the literature [14]. Column chromatography
was carried out in silica gel Aldrich 60A (230-400 mesh), using
mixtures of adequate solvents as eluants. Melting points were
determined on
a Reichert Thermovar apparatus and are
uncorrected. 1H and 13C NMR spectra were acquired on a Bruker
DPX 200 spectrometer (1H at 200.13 MHz and 13C at 50.32
MHz) or on a Bruker DPX 400 (1H at 400.13 MHz and 13C at
100.62 MHz) in CDCl3 or DMSO-d6 and using TMS as internal
reference. 19F NMR spectra were registered on a Bruker DPX
400 at 376.6 MHz in CDCl3 or DMSO-d6 and using
fluorobenzene as the external reference. Mass spectra were
registered on a HP 5973 MSD connected to a HP 6890 GC and
interfaced by a pentium PC. The GC was equipped with a split-
splitless injector, autosampler, cross-linked HP 5MS capillary
column (30 m of length, 0.32 mm of internal diameter, and 0.25
µm of film thickness), and helium was used as the carrier gas.
The chiral cromatography was registered on a Varian 3800 GC
equipped with a split-splitless injector, FID detector, and a home
made capillary column of 2,3-di-O-pentyl-6-O-iso-butyril (25 m
of length, 0.25 mm of internal diameter, and 0.25 µm of film
thickness) and/or lipodex E (25 m of length, 0.25 mm of internal
diameter, and 0.25 µm of film thickness). The following
conditions were used: initial temperature 40 °C, final
temperature 180 °C, rate of heat of 3 °C/min, pressure of the
hydrogen carrier gas 7 Psi, temperature of the injector 220 °C,
and temperature of the detector 280 °C. Compounds 1a-d and
2a-d were prepared according to reference [15] and compounds
1e-f, 2e-f and 6a-c are new and were synthesized using the same
methods [15]. Compounds 1e-f and 2e-f were purified by silica
gel column chromatography Aldrich 60A (230-400 Mesh) using
hexane/dichloromethane 2:1 as the eluant. Compounds 6a-c
were purified by recrystallization from ethanol.
1
in both H and 13C NMR was observed, (ii) a single peak
was observed in the total ion chromatogram registered on
a GC-MS equipped with a non chiral capillary column,
and (iii) oxathiazinane 3a was completely oxidized to 2-
dioxo-(1,2,3)oxathiazinane 8a (Scheme 3).
Scheme 3
CF3
CF3
CF3
CF3
ii
O
O
O
O
i
O
O
O
50%
S
+
S
S
RuCl2
S
N
O
N
N
N
O
O
O
CO2Et
CO2Et
CO2Et
CO2Et
3a
8a
9a
8a
minor comp.
major comp.
i) RuCl3.2H2O, KIO4, CH3CN, 0 °C, 15 min.
ii) Column chromatography 60A (230-400 mesh)
General procedure for the preparation of 1,1,1-trifluoro-
4-(4,6-diphenyl-pyrimidin-2-ylamino)-but-3-en-2-one (5a-c).
To a solution of pyrimidin-2-amine 4 (5.0 mmol) in ethyl
alcohol (15.0 mL) the 4-ethoxy-1,1,1-trifluoro-alk-3-en-2-one
(0.84 g, 5.0 mmol) was added at room temperature. The mixture
was stirred under reflux for 18 h. The solid obtained was filtered
and compounds 5a-c were purified by recrystallization from
ethanol.
In conclusion, this paper showed the synthesis and
characterization of a new series of 4-substituted-3-
ethoxycarbonyl-6-trifluoromethyl-(1,2,3)-oxathiazinane-
S-oxides and 3-(4,6-diphenyl-pyrimidin-2-yl)-6-trifluoro-
methyl-(1,2,3)oxathiazinane-S-oxides. The structure of
the oxathiazinanes was studied by GC-MS, GC-chiral
1
chromatography, and H, 13C, and 19F NMR spectroscopy
4-(4,6-Diphenyl-pyrimidin-2-ylamino)-1,1,1-trifluoro-but-
3-en-2-one (5a). This compound was obtained as a colorless
solid, yield 30 %; mp. 154 °C (ethanol); MS, EI (70ev): m/z (%)
decomposed in the GC-column. 1H NMR (200.13 MHz, DMSO-
d6) δ: 6.24 (d, JH3-H4=12.1 Hz, 1H, H-3), 7.60 (m, 7H, H-7, H-11,
H-12), 8.31 (m, 4H, H-10), 9.03 (t, 1H, JH4-H3-NH=12.1 Hz, 1H,
H-4), 11.79 (d, 1H, JNH-H4=12.1 Hz, NH); 13C NMR (100.6 MHz,
as well as 2-D NMR experiments. The interpretation of
the 1H NMR coupling constants showed conclusive
information about the spatial positions of the substituents
bonded to the oxathiazinane ring. GC-chiral
chromatography showed the nature of the enantiomeric/
diastereomeric composition of the obtained products.
Significant chemical and structural differences were
1
DMSO-d6) δ: 95.4 (C-3), 108.0 (C-7), 117.0 (q, JC-F=289.9 Hz,
CF3), 127.4 (C-10, C-14), 129.0 (C-12, C-16), 131.5 (C-11, C-

Mar-Apr 2008
Synthesis and Characterization of New Trifluoromethyl Substituted 3-Ethoxycarbonyl-
339
15), 135.9 (C-9, C-13), 148.0 (C-5), 157.5 (C-4), 165.8 (C-6, C-
8), 178.0 (q, 2JC-F = 33.1 Hz, C-2). Anal. Calcd. for C20H14F3N3O.
Found: C, 65.04; H, 3.82; N, 11.38.
MHz, CDCl3) δ: 14.4 (C-9), 30.3 (C-5), 36.5 (C-4), 61.4 (C-8),
2
1
67.8 (q, JC-F=31.0 Hz, C-6), 125.1 (q, JC-F=279.5 Hz, CF3),
157.9 (C-7); 19F NMR (376.5 MHz, CDCl3, fluorobenzene) δ: -
79.42. Anal. Calcd. for C7H10F3NO4S: C, 32.19; H, 3.86; N,
5.36. Found: C, 32.29; H, 3.86; N, 5.30.
4-[4-(4-Chloro-phenyl)-6-phenyl-pyrimidin-2-ylamino]-
1,1,1-trifluoro-but-3-en-2-one (5b). This compound was
obtained as an orange solid, yield 60 %; mp. 117°C (ethanol);
MS, EI (70ev): m/z (%) decomposed in the GC-column; 1H
NMR (200.13 MHz, CDCl3) δ: 5.79 (d, JH3-H4=8.2 Hz, 1H, H-3),
7.40–7.55 (m, 5H, H-11, H-12, H-15), 7.77 (s, 1H, H-7), 8.05–
8.14 (m, 4H, H-10, H-14), 8.51 (dd, JH4-NH=12.4 Hz, JH4-H3=8.2
Hz, 1H, H-4) 11.50 (d, JH4-NH=12.4 Hz, 1H, H-3); 13C NMR
2-Oxo-4-phenyl-6-trifluoromethyl-2λ4-[1,2,3]oxathiazinane-
3-carboxylic acid ethyl ester (3b). This compound was
obtained as a colorless oil, yield 42 %; MS, EI (70ev): m/z (%)
337 (M+, 2), 272 (14), 244 (25), 200 (49), 185 (12), 104 (100),
1
77 (38); H NMR (400.13 MHz, CDCl3) δ: 1.15 (t, JH9-H8=7.0
Hz, 3H, H-9), 2.36–2.42 (ddd, JH5eq-H5ax=14.0 Hz, JH5eq-H4ax=6.0
Hz, JH5eq-H6=3.0 Hz, 1H, H-5), 3.20–3.30 (dt, JH5ax-H5eq=14.0 Hz,
JH5ax-H6=13.2 Hz, JH5ax-H4ax=13.2 Hz, 1H, H-5), 4.14 (q, JH8-H9=7.0
Hz, 2H, H-8), 4.64–4.70 (m, 1H, H-6), 5.06–5.11 (dd, JH4ax-
H5ax=13.2 Hz, JH4ax-H5eq=6.0 Hz, 1H, H-4), 7.25–7.43 (m, 5H, Ph);
13C NMR (100.6 MHz, CDCl3) δ: 14.0 (C-9), 27.0 (C-5), 57.1
1
(100.6 MHz, CDCl3): δ 92.2 (C-3), 107.9 (C-7), 116.5 (q, JC-
F=286.9 Hz, CF3), 127.2 (C-10), 128.4 (C-14), 129.0 (C-11),
129.2 (C-15), 131.5 (C-12), 134.6 (C-16), 136.0 (C-13), 137.7
(C-9), 147.5 (C-4), 157.2 (C-8), 165.0 (C-6), 166.5 (C-5), 180.8
2
(q, JC-F=34.4 Hz, C-2). Anal. Calcd. for C20H13ClF3N3O: C,
2
1
59.49; H, 3.25; N, 10.41. Found: C, 59.72; H, 3.29; N, 10.26.
4-[4-(4-Methoxy-phenyl)-6-phenyl-pyrimidin-2-ylamino]-
1,1,1-trifluoro-but-3-en-2-one (5c). This compound was obtained
as an orange solid, yield 70 %; mp. 111 °C (ethanol); MS, EI
(70ev): m/z (%) decomposed in the GC-column; 1H NMR (200.13
MHz, CDCl3) δ: 5.77 (d, JH3-H4=8.0 Hz, 1H, H-3), 7.00–7.04 (m,
2H, H-15), 7.47–7.54 (m, 3H, H-11, H-12), 7.74 (s, 1H, H-7),
8.00–8.13 (m, 4H, H-10, H-14), 8.53 (dd, JH4-NH=12.6 Hz, JH4-
H3=8.0 Hz, 1H, H-4) 11.50 (d, JH4-NH=12.6 Hz, 1H, N-H); 13C
NMR (100.6 MHz, CDCl3) δ: 55.2 (OCH3), 101.0 (C-3), 107.0
(C-7), 114.1 (C-15), 116.8 (q, 1JC-F=290.0 Hz, CF3), 127.1 (C-10),
128.0 (C-13), 128.7 (C-14), 128.9 (C-12), 131.1 (C-11), 135.9 (C-
9), 148.2 (C-4), 161.9 (C-16, C-8), 165.0 (C-5, C-6), 178.0 (q, 2JC-
F=33.1 Hz, C-2). Anal. Calcd. for C21H16F3N3O2: C, 63.16; H,
4.04; N, 10.52. Found: C, 63.54; H, 4.12; N, 10.59.
(C-4), 63.3 (C-8), 73.8 (q, JC-F=35.3 Hz, C-6), 122.4 (q, JC-
F=278.7 Hz, CF3), 126.7, 128.1, 128.9, 140.0 (Ph), 152.3 (C-7).
Anal. Calcd. for C13H14F3NO4S: C, 46.29; H, 4.18; N, 4.15.
Found: C, 46.37; H, 4.26; N, 4.09.
4-(4-Methyl-phenyl)-2-oxo-6-trifluoromethyl-2λ4-[1,2,3]-
oxathiazinane-3-carboxylic acid ethyl ester (3c). This
compound was obtained as a colorless oil, yield 30 %; MS, EI
(70ev): m/z (%) 351 (M+, 3), 258 (12), 214 (15), 200 (41), 118
1
(100), 91 (33), 65 (12); H NMR (200.13 MHz, CDCl3) δ: 1.18
(t, JH9-H8=7.2 Hz, 3H, H-9), 2.33 (s, 3H, H-14), 2.39–2.43 (ddd,
JH5eq-H5ax=15.0 Hz, JH5eq-H4ax=5.8 Hz, JH5eq-H6=3.2 Hz, 1H, H-5),
3.14–3.34 (ddd, JH5ax-H5eq=15.0 Hz, JH5ax-H6=13.0 Hz, JH5ax-
H4ax=13.2 Hz, 1H, H-5), 4.14 (q, JH8-H9=7.2 Hz, 2H, H-8), 4.61–
4.72 (m, 1H, H-6), 5.01–5.10 (dd, JH4ax-H5ax=13.2 Hz, JH4ax-
H5eq=5.8 Hz, 1H, H-4), 7.17 (d, J=8.0 Hz, 2H, Ph), 7.32 (d, J=8.0
Hz, 2H, Ph). 13C NMR (100.6 MHz, CDCl3): δ 14.0 (C-9), 21.0
General procedure for the preparation of 3- and 4-
substituted 6-trifluoromethyl-(1,2,3)-oxathiazinane-S-oxides
(3a-e, 7a-c). The γ-amino alcohols 2 and 6 (1.0 mmol) in toluene
(8.0 mL) were stirred at 110 °C in Dean-Stark under argon for 1
h. The reaction was allowed to cool to room temperature, then
pyridine (0.16 mL, 2.0 mmol) was added and after five minutes
the mixture was cooled at 0°C. Thionyl chloride (0.1 mL, 1.5
mmol) was added, the ice bath was removed, and the stirring
was continued for 9 to 24 h at room temperature. A solid
(pyridine hydrochloride) was observed at the end of the reaction
and was filtered off. The solvent was removed by rotatory
evaporator, CH2Cl2 (15.0 mL) was added and the solution was
washed with water (3 × 10.0 mL). The aqueous layer was
extracted with CH2Cl2 (2 × 10.0 mL). The organic layers were
combined, dried (MgSO4), and the solvent was removed by
rotatory evaporator. Compounds 3a-e were purified by silica gel
column chromatography, Aldrich 60A (230-400 Mesh) using
hexane/methyl chloride 1:1 as the eluant. The compounds 7a-c
were purified by recrystallization from ethanol.
2
(CH3), 27.1 (C-5), 56.8 (C-4), 63.3 (C-8), 73.8 (q, JC-F = 34.6
1
Hz, C-6), 122.4 (q, JC-F=278.7 Hz, CF3), 126.7, 129.5, 137.0,
137.9 (Ph), 152.3 (C-7); 19F NMR (376.6 MHz, CDCl3,
fluorobenzene) δ: -78.70. Anal. Calcd. for C14H16F3NO4S: C,
47.86; H, 4.59; N, 3.99. Found: C, 48.47; H, 4.88; N, 3.64.
4-Methyl-2-oxo-6-trifluoromethyl-2λ4-[1,2,3]oxathiazinane
-3-carboxylic acid ethyl ester (3d). This compound was
obtained as an orange oil, yield 64 %. Data for the major isomer:
MS, EI (70ev): m/z (%) 260 (M+-15, 53), 230 (5), 188 (89), 56
1
(100); H NMR (200.13 MHz, CDCl3) δ: 1.33 (t, JH9-H8=7.0 Hz,
3H, H-9), 1.50 (d, JH10-H4 = 6.2 Hz, 3H, CH3), 2.26–2.38 (ddd,
JH5eq-H5ax=14.6 Hz, JH5eq-H4ax=6.9 Hz, JH5eq-H6=2.8 Hz, 1H, H-5),
2.92–3.12 (ddd, JH5ax-H5eq=14.6 Hz, JH5ax-H6=12.6 Hz, JH5ax-
H4ax=12.4 Hz, 1H, H-5), 4.24–4.37 (m, 1H, H-4), 4.29 (q, JH8-
H9=7.0 Hz, 2H, H-8), 4.42–4.58 (m, 1H, H-6); 13C NMR (100.6
MHz, CDCl3) δ: 14.2 (C-9), 22.6 (CH3), 26.0 (C-5), 48.4 (C-4),
2
1
63.3 (C-7), 73.7 (q, JC-F=34.4 Hz, C-6), 122.5 (q, JC-F=278.6
Hz, CF3), 152.27 (C-7); 19F NMR (376.5 MHz, CDCl3,
fluorobenzene) δ: -79.00. Anal. Calcd. for C8H12F3NO4S: C,
34.91; H, 4.39; N, 5.09. Found: C, 35.26; H, 4.77; N, 5.18.
2-Oxo-4-propyl-6-trifluoromethyl-2λ4-[1,2,3]oxathiazin-
ane-3-carboxylic acid ethyl ester (3e). This compound was
obtained as a yellow oil, yield 30 %; MS, EI (70ev): m/z (%) 260
(M+-43, 80), 188 (100), 124 (44); 1H NMR (200.13 MHz,
CDCl3) δ: 0.94 (t, J=7.2 Hz, 3H, CH3), 1.32 (t, JH8-H9=7.2 Hz,
3H, H-9), 1.25–1.35 (m, 2H, CH2), 1.72–2.04 (m, 2H, CH2),
2.28–2.40 (ddd, JH5eq-H5ax=14.4 Hz, JH5eq-H4ax=7.4 Hz, J H5eq-H6=2.8
Hz, 1H, H-5), 2.81–3.00 (ddd, JH5ax-H5eq=14.4 Hz, JH5ax-H6=12.5
Hz, JH5ax-H4ax=11.8 Hz, 1H, H-5), 4.23–4.34 (m, 1H, H-4), 4.29
(q, JH8-H9=7.2 Hz, 2H, H-8), 4.42–4.52 (m, 2H, H-6); 13C NMR
6-trifluoromethyl-2λ4-[1,2,3]oxathiazinane-3-carboxylic
acid ethyl ester (3a). This compound was obtained as a yellow
oil, yield 70%; MS, EI (70ev): m/z (%) 261 (M+, 6), 233 (20),
1
217 (12), 189 (10), 172 (36), 152 (14), 109 (32), 56 (100); H
NMR (200.13 MHz, CDCl3) δ: 1.33 (t, JH9-H8=7.0 Hz, 3H, H-9),
1.93–2.03 (dddd, JH5eq-H5ax=13.8 Hz, JH5eq-H4eq=3.8 Hz, JH5eq-
H4ax=3.2 Hz, JH5eq-H6=3.0 Hz, 1H, H-5), 2.07–2.29 (dtd, JH5ax-
H5eq=13.8 Hz, JH5ax-H6=12.0 Hz, JH5ax-H4ax=12.0 Hz, JH5ax-H4eq=4.4
Hz, 1H, H-5), 3.82–3.96 (ddd, JH4ax-H4eq=13.4 Hz, JH4ax-H5ax=12.0
Hz, JH4ax-H5eq=3.2 Hz, 1H, H-4), 4.02–4.13 (ddd, JH4eq-H4ax=13.4
Hz, JH4eq-H5ax=4.4 Hz, JH4eq-H5eq=3.8 Hz, 1H, H-4), 4.30 (q, JH8-
H9=7.0 Hz, 3H, H-8), 5.05–5.20 (m, 1H, H-6); 13C NMR (100.6

340
N. Zanatta, D. M. Borchhardt, D. C. Flores, H. S. Coelho, T. M. Marchi,
A. F. C. Flores, H. G. Bonacorso, and M. A. P. Martins
Vol 45
(100.6 MHz, CDCl3): δ 13.7 (C-12), 13.9 (C-9), 14.4 (C-11),
2
18.8 (C-10), 37.3 (C-5), 48.7 (C-4), 61.1 (C-8), 69.0 (q, JC-
Procedure for the preparation of 2-Dioxo-6-trifluoro-
methyl-2λ4-[1,2,3]oxathiazinane-3-carboxylic acid ethyl ester
(8a). To a solution of 3a (0.26 g, 1.0 mmol) in CH3CN (12.0
mL) stirred in an ice bath and under argon atmosphere,
ruthenium chloride (RuCl3.2H2O) in catalytic amount (5.0 mg)
and KIO4 (0.23 g, 2.0 mmol) was added. After 15 min water
(10.0 mL) was added and stirring was continued for 6 h at 0 °C.
The reaction mixture was extracted with ethyl ether (3 × 10.0
mL) and the organic layer were combined and washed with
saturated sodium bicarbonate solution (10.0 mL) and with 50%
sodium chloride solution. The organic phase was dried (MgSO4)
and the solvent was removed by rotatory evaporator. Compound
8a was purified by silica gel column chromatography, Aldrich
60A (230-400 Mesh) using hexane/methyl chloride 2:1 as the
eluant. Yield 50 %; oil; MS EI (70ev): m/z (%) 277 (M, 1), 232
(14), 205 (42), 109 (100), 56 (26). 1H NMR (200 MHz, CDCl3):
δ 1.37 (t, J = 7.0 Hz, 3H, CH3), 2.16–2.27 (m, 2H, H-5), 3.83–
3.97 (m, 1H, H-4), 4.35 (q, J = 7.0 Hz, 2H, CH2), 4.43–4.50 (m,
1
F=31.6 Hz, C-6), 125.0 (q, JC-F=280.2 Hz, CF3), 157.0 (C-7).
Anal. Calcd. for C10H16F3NO4S: C, 39.60; H, 5.32; N, 4.62.
Found: C, 39.86; H, 5.46; N, 4.32.
2-(2-Oxo-6-trifluoromethyl-2λ4-[1,2]oxathian-3-yl)-4,6-di-
phenyl-pyrimidine (7a). This compound was obtained as a
colorless solid, yield 42 %; mp. 130–135 °C (ethanol); MS, EI
(70ev): m/z (%) 419 (M+, 22), 328 (79), 273 (43), 232 (8), 129
(50), 77 (53); 1H NMR (200.13 MHz, DMSO-d6) δ: 1.78–2.07
(m, 1H, H-5), 2.07–2.12 (m, 1H, H-5), 3.97–4.20 (m, 1H, H-4),
4.71–4.80 (ddd, JH4eq-H4ax=13.8 Hz, JH4eq-H5ax=3.4 Hz, JH4eq-
H5eq=3.8 Hz, 1H, H-4), 5.44–5.58 (m, 1H, H-6), 7.53–7.62 (m,
6H, H-13, H-14, H-17, H-18), 7.76 (s, 1H, H-9), 8.29–8.38 (m,
4H, H-12, H-16); 13C NMR (50.6 MHz, DMSO-d6): δ 29.4 (C-
2
5), 37.1 (C-4), 66.7 (q, JC-F=29.5 Hz, C-6), 101.7 (C-9), 127.0
(C-12, C-16), 128.6 (C-13, C-17), 130.7 (C-14, C-18), 137.0 (C-
11, C-15), 162.2 (C-7), 164.5 (C-8, C-10). Anal. Calcd. for
C20H16F3N3O2S: C, 57.27; H, 3.85; N, 10.02. Found: C, 57.38; H,
4.21; N, 9.63.
1H, H-4), 5.00–5.16 (m, 1H, H-6). 13C NMR (100 MHz, CDCl3):
2
δ 14.0 (CH3), 22.7 (C-5), 44.7 (C-4), 64.9 (C-8), 79.0 (q, JC-F
35.5 Hz, C-6), 121.5 (q, 1JC-F = 277.2 Hz, CF3), 151.1 (C=O).
=
4-(4-Chloro-phenyl)-2-(2-oxo-6-trifluoromethyl-2λ4-[1,2]-
oxathian-3-yl)-6-phenyl-pyrimidine (7b). This compound was
obtained as a yellow solid, yield 57 %; mp. 151 °C (ethanol);
MS, EI (70ev): m/z (%) 453 (M+, 9), 362 (47), 307 (38), 293
(100), 266 (64), 231 (53), 189 (10), 163 (27), 77 (76); 1H NMR
(400.13 MHz, CDCl3) δ: 2.09–2.18 (dddd, JH5eq-H5ax=14.0 Hz,
JH5eq-H4eq=3.4 Hz, JH5eq-H4ax=3.1 Hz, JH5eq-H6=3.2 Hz, 1H, H-5),
2.32–2.39 (dtd, JH5ax-H5eq=14.0 Hz, JH5ax-H6=12.0 Hz, JH5ax-
H4ax=12.0 Hz, JH5ax-H4eq=4.1 Hz, 1H, H-5), 4.07–4.22 (ddd, JH4ax-
H4eq=14.0 Hz, JH4ax-H5ax=12.0 Hz, JH4ax-H5eq=3.1 Hz, 1H, H-4),
4.73–4.80 (ddd, JH4eq-H4ax=14.0 Hz, JH4eq-H5ax=4.1 Hz, JH4eq-
H5eq=3.4 Hz, 1H, H-4), 5.18–5.27 (m, 1H, H-6), 7.46–7.54 (m,
5H, H-13, H-17, H-18); 7.70 (s, 1H, H-9); 8.04–8.12 (m, 4H, H-
12, H-16); 13C NMR (100.6 MHz, CDCl3): δ 23.0 (C-5), 34.5
Acknowledgement. The authors thank the financial support
from the CNPq-Conselho Nacional de Desenvolvimento
Científico e Tecnológico (Universal grant No. 477682/01-4) and
fellowships (D. M. Borchhardt, H. S. Coelho, and T. M.
Marchi).
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1
(C-4), 64.6 (q, JC-F=34.3 Hz, C-6), 106.2 (C-9), 123.3 (q, JC-
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H4eq=3.4 Hz, JH5eq-H4ax=3.1 Hz, JH5eq-H6=3.2 Hz, 1H, H-5), 2.30–
2.41 (dtd, JH5ax-H5eq=14.0 Hz, JH5ax-H6=12.0 Hz, JH5ax-H4ax=12.0 Hz,
JH5ax-H4eq=4.1 Hz, 1H, H-5), 4.10–4.18 (ddd, JH4ax-H4eq=14.0 Hz,
JH4ax-H5ax=12.0 Hz, JH4ax-H5eq=3.1 Hz, 1H, H-4), 4.74–4.79 (ddd,
JH4eq-H4ax=14.0 Hz, JH4eq-H5ax=4.1 Hz, JH4eq-H5eq=3.4 Hz, 1H, H-4),
5.18–5.26 (m, 1H, H-6), 7.01 (d, JH17-H16=8.8 Hz, 2H, H-17),
7.50–7.52 (m, 3H, Ph), 7.67 (s, 1H, H-9), 8.08–8.11 (m, 4H, Ph).
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2
(OCH3), 64.7 (q, JC-F=34.30 Hz, C-6), 105.7 (C-9), 114.3 (C-
1
17), 123.4 (q, JC-F=277.2 Hz, CF3), 127.2 (C-16), 128.8 (C-12),
128.9 (C-13), 129.1 (C-14), 131.0 (C-15), 136.8 (C-11), 159.9
(C-7), 162.4 (C-18), 165.4 (C-8), 165.6 (C-10); 19F NMR (376.5
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C21H18F3N3O3S: C, 56.12; H, 4.04; N, 9.35. Found: C, 56.02; H,
4.04; N, 9.25.

Mar-Apr 2008
Synthesis and Characterization of New Trifluoromethyl Substituted 3-Ethoxycarbonyl-
341
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