Catalytic hydrogenation of 3-amino-6-(trifluoromethyl)-5,6-dihydropyridin- 2(1 H)-ones and its use in the synthesis of trifluoromethyl-containing mimetics of ornithine and thalidomide

Article abstract of DOI:10.1055/s-0030-1258448

A series of 3-amino-6-(trifluoromethyl)-5,6-dihydropyridin-2(1H)-ones and 6-hydroxy-5,6-dihydropyridin-2(1H)-ones were hydrogenated to give the corresponding piperidinones. These lactams were used for the synthesis of novel trifluoromethyl-containing ornithine analogues and thalidomide mimetics. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258448

PAPER
1149
Catalytic Hydrogenation of 3-Amino-6-(trifluoromethyl)-5,6-dihydropyridin-
2(1H)-ones and Its Use in the Synthesis of Trifluoromethyl-Containing
Mimetics of Ornithine and Thalidomide
3
-Amino-6-(trifluo
a
romethyl)p
t
iperidi
a
n-2-ones liya A. Tolmachova,a Violetta G. Dolovanyuk,a Igor I. Gerus,a Ivan S. Kondratov,a Vitaliy V. Polovinko,b
Klaus Bergander,c Günter Haufe*c
a
Institute of Bioorganic Chemistry and Petrochemistry, National Ukrainian Academy of Science, Murmanska 1, Kiev 94 02660, Ukraine
Enamine Ltd., Alexandra Matrosova str. 23, 01103 Kiev, Ukraine
Organisch-Chemisches Institut der Universität Münster, Corrensstraße 40, 48149 Münster, Germany
b
c
Fax +49(251)8339772; E-mail: haufe@uni-muenster.de
Received 8 December 2010; revised 29 January 2011
R2
N
R2
N
Abstract: A series of 3-amino-6-(trifluoromethyl)-5,6-dihydropy-
ridin-2(1H)-ones and 6-hydroxy-5,6-dihydropyridin-2(1H)-ones
were hydrogenated to give the corresponding piperidinones. These
lactams were used for the synthesis of novel trifluoromethyl-con-
taining ornithine analogues and thalidomide mimetics.
R3
R3
F3C
N
R1
O
F3C
N
R1
O
Key words: amino acids, catalysis, halides, heterocycles, hydroge-
nation, piperidinones
2
1
R1 = H, alkyl
R2, R3 = H, acyl
Scheme 1 Retrosynthesis of piperidones 2 from pyridinones 1
The 3-aminopiperidin-2-one moiety is a relevant motif in
numerous biologically active compounds, including con-
formationally restricted peptidomimetics.1 Derivatives of
3-amino-6-(trifluoromethyl)piperidin-2-ones are there-
fore of interest, because the introduction of a trifluoro-
methyl group2 into biologically active compounds is
frequently an effective strategy for designing new drugs
and agrochemicals.3
We have previously described an effective method for the
preparation of benzoyl-containing 6-(trifluoromethyl)py-
ridinones 1a–d from pyrones 3 (Scheme 2, first two steps)
in one step (synthesis of compounds 1a–c) or two steps
(synthesis of compound 1d).8
We found the two-step method [via the 6-hydroxy-5,6-di-
hydropyridin-2(1H)-ones 4] was the most suitable for the
preparation of pyridinones 1e–g. Compound 1e has previ-
ously been synthesized in one step,8 but the two-step
method was more convenient for the gram-scale prepara-
tion of the compound (Scheme 2). The method was also
used to synthesize the pyridinones 4f and 4g, each bearing
an ester function. In these cases, the yield of the first step
was low, probably as a result of polycondensation pro-
cesses. When compound 1f was prepared, the side-prod-
uct 5 was also isolated in 17% yield (Figure 1). This
compound is formed as a result of intramolecular lacton-
ization with elimination of methanol. The search for suit-
able conditions for a selective synthesis of compound 5 is
in progress.
Among the various synthetic approaches to piperidin-2-
ones, the heterogeneous catalytic hydrogenation of the 2-
pyridinone ring is one of the most common methods.4
This method has been widely used in alkaloid synthesis5
and also for the preparation of several biologically active
piperidin-2-one derivatives,6 including some containing a
trifluoromethyl group.6d
We recently described the hydrogenation of 6-(polyfluo-
roalkyl)pyrones and the use of this reaction in the synthe-
sis of glutamic acid analogues.7 As part of our ongoing
program for the development of synthetic methods for the
preparation of new, potentially active, fluorine-containing
amino acids and their derivatives, we therefore attempted
the reduction of various 6-(trifluoromethyl)pyridin-
2(1H)-ones 1 with an amino or N-acylamino substituent in
the 3-position (Scheme 1).
NHBz
F3C
It is quite obvious that the target transformation will lead
to compounds 2, which contain an a-amino acid motif,
and might be useful for the synthesis of new fluorinated
amino acids and other potentially bioactive compounds.
N
O
O
O
5
Figure 1 Side-product 5 in the synthesis of compound 1f
Our attempts to apply the reaction of pyrone 3 with prima-
ry amines to the synthesis of pyridinones containing iso-
propylamino, (1-phenylethyl)amino, or a-alanine methyl
SYNTHESIS 2011, No. 7, pp 1149–1156
Advanced online publication: 01.03.2011
DOI: 10.1055/s-0030-1258448; Art ID: T52310SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
1

1150
N. A. Tolmachova et al.
PAPER
RNH2, 100–160 °C (R = H, Me, Bu)
60–80%
AcOH or
TsOH/toluene
reflux
RNH2
PhMe or DMF
80–90 °C
H
N
H
H
N
N
Bz
Bz
Bz
HO
60–79%
43–65%
F3C
N
R
O
F3C
N
R
O
F3C
O
O
4d–g
1a–g
3
30–60%
R = H, Me
30% HCl
100 °C
O
a,h: R = H
b,i: R = Me
c: R = n-Bu
phthalic anhydride
N
NH2
O
d: R = CH2CH2OMe
e: R = Bn
pyridine, reflux
O
f: R = CH2CO2Me
g: R = CH2CH2CO2Me
83%
R = Me
F3C
N
O
F3C
N
R
Me
1j
1h,i
Scheme 2 Synthesis of pyridinones 1a–j
ester groups failed for steric reasons. In all these cases, the 1a and 1b (Table 1, entries 1 and 2). Surprisingly, mix-
starting pyrone 3 was isolated.
tures of the corresponding cis- and trans-isomers were ob-
tained (as judged from the 19F NMR spectra of the crude
products). The formation of trans-isomers under the reac-
tion conditions can be explained in terms of partial
epimerization of the initially formed cis-2 isomer to the
thermodynamically more stable trans-2 isomer. This as-
sumption was confirmed by the fact that the proportion of
the minor diastereomer trans-2i increased from 5% to
20% (19F NMR) after standing for two days at room tem-
perature. However, compounds cis-2h and cis-2i and
trans-2 and -2i partially decomposed during column chro-
matography and on standing at room temperature for more
than one day. Only the diastereomers cis-2h and cis-2i
could be isolated in pure form from the reaction mixtures.
The pyridinones 1h–j were obtained from the correspond-
ing pyridinones 1a and 1b (Scheme 2, final two steps) by
acidic hydrolysis of the N-benzoyl group (1h and 1i), fol-
lowed by phthalimide ring formation (1j).
The pyridinones 1a–j were hydrogenated by using 5%
palladium-on-carbon as a catalyst. The rate and selectivity
of the pyridinone ring reduction depend markedly on the
substituents adjacent to both the endo- and the exocyclic
nitrogen atom (Scheme 3; Table 1). The reduction of the
N-unsubstituted pyridinone 1a required forcing condi-
tions and longer reaction times in comparison with the N-
substituted pyridinones 1b–g. In the case of pyridinones
1a and 1b, methanol was found to be the most convenient
solvent, whereas the less-soluble pyridinones 1c–g were
hydrogenated in tetrahydrofuran. The reaction proceeded
diastereoselectively, and the corresponding cis-lactams
1a–g were obtained in good-to-moderate yields
(Scheme 3; Table 1, entries 1–7). Note that in the case of
compound 1a, the phenyl ring of the N-benzoyl group was
hydrogenated to a form a cyclohexyl group under the re-
action conditions. On the other hand, in the case of com-
pound 1e, no hydrogenolysis of the benzyl group occurred
under the reaction conditions.
The reduction of N-methylpyridinone 1j bearing an
N-phthalimide protecting group gave the stable com-
pound cis-2j diastereoselectively (Table 1, entry 10).
Along with hydrogenation of the pyridinone ring, one of
the phthalimide carbonyl groups was reduced to a methyl-
ene group.
H
H
H
3
4
H
5
NHBz
6
1
N
H
H
2
Pyridinones 1h and 1i, bearing an unsubstituted NH2-
group (Table 1, entries 8 and 9), could be reduced under
more forcing conditions than required for the reduction of
F3C
O
R
1H {1H} NOE in cis-2c–e
H
5
H
5
H
H
3
H
H
4
3
4
H
H
X2
O
X2
O
X1
O
NHBz
NHBz
HO
H
H
H
H2, 5% Pd/C
(see Table 1)
2
2
6
F3C
6
N
N
1
+
1
F3C
O
O
R
F3C
N
R
F3C
N
R
F3C
N
R
OMe
cis-2c–e
1H {19F} NOE in cis-2c–e and 6e
6e
cis-2a–j
trans-2h,i
1a–j
Scheme 3 Hydrogenation of pyridinones 1a–i
Figure 2 NOE-interactions in compounds cis-2c–e and 6e
Synthesis 2011, No. 7, 1149–1156 © Thieme Stuttgart · New York

PAPER
3-Amino-6-(trifluoromethyl)piperidin-2-ones
1151
Table 1 Hydrogenation of Pyridinones 1a–i: Conditions, Products, and Yields
Entry
Pyridinone R
X1
X2
Conditions
Products (ratio)
cis-2a
Yield (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
H
NHBz
NHBz
NHBz
NHBz
NHBz
NHBz
NHBz
NH2
NHCOCy
NHBz
NHBz
NHBz
NHBz
NHBz
NHBz
NH2
MeOH, 60 °C, 60 atm, 4 d
MeOH, 25 °C, 25 atm, 6 h
THF, 25 °C, 40 atm, 8 h
THF, 25 °C, 40 atm, 8 h
THF, 25 °C, 40 atm, 16 h
THF, 25 °C, 40 atm, 8 h
THF, 25 °C, 40 atm, 8 h
80 °C, 60 atm, 7 d
75
Me
cis-2b
88
Bu
cis-2c
83
(CH2)2OMe
cis-2d
80
Bn
cis-2e
74
CH2CO2Me
cis-2f
72
1g
1h
1i
(CH2)2CO2Me
cis-2g
69
H
cis/trans-2h (85:15)
cis/trans-2i (95:5)
86 (65)a
92 (85)a
Me
NH2
NH2
80 °C, 60 atm, 3 d
O
N
O
10
1j
Me
r.t., 30 atm, 8 h
cis-2j
45
N
O
a Yields of isolated compounds cis-2h and cis-2i are given in parentheses.
The relative configurations of stereogenic centers of the of compounds cis-2a–i were additionally confirmed by
products cis-2a–j were determined by means of nuclear the results of 1H–1H COSY experiments.
Overhauser effect (NOE) experiments, which indicated a
relative cis-orientation of hydrogen atoms in the 3- and 6-
positions (Figure 2).
6-Hydroxydihydropyridinones 4d–f, which are stable in-
termediates in the synthesis of the corresponding pyridi-
nones 1d–f, were also hydrogenated by using 5%
On the other hand, a detailed analysis of the NMR data for palladium-on-carbon to give the corresponding 6-hydroxy-
compounds cis-2c–e indicated that the 3-H atom occupies piperidones 6d–f. Partial reduction of compounds 4 oc-
the axial position (J3-Ha/4-Ha = 11.3–12.0 Hz, J3-Ha/4-He
=
curred under 2–3 atm pressure. For example, the
6.6–6.7 Hz; 1,3-diaxial NOE between 3-Ha and 5-Ha), conversion of compound 4e under H2 at 3 atm was ~40%
whereas the 6-H atom occupies the equatorial position after two days, and this did not increase significantly with-
(J6-He/5-He = 0–2.4 Hz, J6-He/5-Ha = 5.9–7.0 Hz, NOE of 6-Ha in the next day, even when additional portions of the cat-
to both 5-Ha and 5-He). Additional confirmation was pro- alyst were added. Under more forcing conditions
vided by a hetero-NOE analysis, which showed the pres- (tetrahydrofuran, 25 °C, 40 atm, 8 h), the reduction was
ence of an interaction between the trifluoromethyl group complete and the 6-hydroxypiperidones 6d–f were ob-
and 5-He, as well as between the trifluoromethyl group tained in moderate-to-good yields (Scheme 4; Table 2)
and 4-Ha (Figure 2).
NHBz
NHBz
For compounds cis-2a and cis-2h the results of NMR ex-
H2, 5% Pd/C
HO
HO
periments are ambiguous. The structure of cis-2a was
therefore confirmed by X-ray crystal structure analysis
(Figure 3).9 The structure of compound cis-2h was con-
firmed by the identity with the products obtained by hy-
drolysis of cis-2a and cis-2h (see below). The structures
THF, 25 °C
40 atm, 8 h
F3C
N
R
O
N
R
O
F3C
4d–g
6d–g
Scheme 4 Hydrogenation of pyridinones 4d–g
Table 2 Hydrogenation of Pyridinones 4d–g
Entry
Pyridinone R
Product
Yield (%)
1
2
3
4
4d
4e
4f
(CH2)2OMe
6d
6e
6f
74
64
81
79
Bn
CH2CO2Me
(CH2)2CO2Me
4g
6g
Figure 3 Molecular structure of compound cis-2a as obtained by
X-ray crystal structure analysis
Synthesis 2011, No. 7, 1149–1156 © Thieme Stuttgart · New York

1152
N. A. Tolmachova et al.
PAPER
Compounds 6 generally exist as single epimers in chloro- hydrolytically stable selective inhibitors of cathepsin
form solution; only in the case of compound 6e was an K.10d,e Also, in the case of compound 2b (R = Me), hy-
equilibrium observed between the open form 7e and the drolysis under mild conditions gave the N-benzoyl amino
cyclic form 6e (ratio 1:17; 19F NMR) (Scheme 5). No oth- acid 9b in 95% yield.
er form was observed in the cases of compounds 6d, 6f,
and 6g in chloroform solutions. An intramolecular hydro-
gen bond between the hydroxy group and the oxygen
atom in the N-substituent could play an important role in
A detailed analysis of the NMR spectra of compounds 6
showed that the 3-H atom occupies an axial position
(J3-Ha/4-Ha = 11.9–12.1 Hz, J3-Ha/4-He = 5.8–6.4 Hz; 1,3-diaxial
NOE between 3-Ha and 5-Ha). The relative configuration
the configurational stability of these compounds.
of compound 6d was established by hetero-NOE analysis,
which showed the presence of an interaction between the
O
NHBz
O
trifluoromethyl group and 5-He, as well as between the tri-
fluoromethyl group and 4-Ha (Figure 2). The NMR data
for compounds 6e–g are very similar to those for 6d.
Therefore, the relative configuration of compounds 6e–g
is assumed to be the same as that of compound 6d.
NHBz
HO
F3C
N
F3C
O
N
H
Ph
Ph
6e
7e
The reaction of the cis/trans mixtures of 2a (85:15) or 2b
(95:5) (or of the diastereomerically pure cis-2b) with
phthalic anhydride led to corresponding diastereomeric
mixtures of cis/trans-10a or cis/trans-10b (Scheme 7).
Under the reaction conditions, partial epimerization oc-
curred to give a 55:45 ratio for cis/trans-10a and a 70:30
ratio for cis/trans-10b. We were unable to find any condi-
tions that caused the transformation to occur without
epimerization. The resulting mixtures were separated by
column chromatography to give the pure diastereomers
cis-10a and trans-10a and cis-10b and trans-10b.
According to Zanda’s principle,10 these compounds can
be considered as analogues of thalidomide, a well-known
sedative and hypnotic that was withdrawn from the mar-
ket in 1962 because of its teratogenicity. It is currently
used in the treatment of a number of diseases, and several
analogues have been developed based on thalidomide as a
lead structure [e.g., Actimid (CC-4047) and Revlimid
(lenalidomide)].11
Scheme 5 Equilibrium between compounds 6e and 7e in chloro-
form solution
The piperidones 2 prepared as described above can be
used for the synthesis of some potentially bioactive com-
pounds. Thus, hydrolysis of compounds cis-2a and -2b (or
cis-2h and -2i) under acidic conditions gave the diastereo-
merically pure amino acids 8a and 8b in 58–61% yield
after purification by ion-exchange chromatography.
These compounds are new d-trifluoromethyl group con-
taining analogues of ornithine (Scheme 6). They can also
be considered as analogues of glutamine, according to the
concept of bioisosteric replacement of a CONH group by
a CH(CF3)NH fragment, as proposed by Zanda.10a–c This
type of replacement has been used for the synthesis of new
NH2
CO2H
⋅2HCl
X
RHN
30% HCl, reflux
58–61%
F3C
N
R
O
CF3
8a,b
The relative configuration of the stereogenic centers of the
products cis-10a and -10b (as well as cis-2j) were deter-
mined by NOESY experiments, which showed a cis-ori-
entation of the hydrogen atoms in positions 3 and 6. In
case of compounds trans-10 and -10b, interactions be-
tween hydrogen atoms in positions 3, 4, 5, and 6 indicate
a trans-configuration (Figure 4, see also Scheme 7).
cis-2a,b,h,i
NHBz
CO2H
⋅HCl
10% HCl, r.t., 5 h
MeHN
95%,
from cis-2b
CF3
9b
The structures of compounds cis-10b, trans-10b and cis-
2j were further confirmed by 1H–1H COSY experiments,
and the structure of compound cis-10a was established
unambiguously by X-ray crystal structure analysis
(Figure 5).9
a: R = H, X = NHBz
b: R = Me, X = NHBz
h: R = H, X = NH2
i: R = Me, X = NH2
Scheme 6 Synthesis of amino acids 8a and 8b, and the a-N-benzoyl
amino acid 9b
O
O
O
NH2
phthalic anhydride
N
N
O
N
O
pyridine, reflux, 3 d
+
F3C
N
R
O
O
O
O
F3C
N
R
O
F3C
N
R
O
N
H
cis/trans-2a,b
thalidomide
cis-10a,b
trans-10a,b
a R = H
b R = Me
35–56%
23–33%
Scheme 7 Synthesis of compounds cis/trans-10a,b
Synthesis 2011, No. 7, 1149–1156 © Thieme Stuttgart · New York

PAPER
3-Amino-6-(trifluoromethyl)piperidin-2-ones
1153
raphy was performed on Amberlite IR-120 by standard tech-
niques.12 Elemental analyses were correct within 0.3% for C, H,
and N. Spectroscopic data are presented here for typical compounds
only; data for all other compounds can be found in the supporting
information.
H
4
H
H
H
H
X
H
4
5
X
3
2
5
6
3
2
H
6
H
N
O
N
R
O
F3C
F3C
All starting materials were of the highest commercial quality and
were used without further purification. The pyridinones 1a–d and
4d were prepared according to our earlier published procedures.8
The previously prepared pyridinone 1e was synthesized by an im-
proved procedure (see below).
R
cis-10a,b and cis-2j
trans-10a,b
Figure 4 NOESY experiments confirm the relative configurations
of compounds cis-10a, -10b, cis-2j, and trans-10a and -10b
N-[1-Benzyl-6-hydroxy-2-oxo-6-(trifluoromethyl)-1,2,5,6-tet-
rahydropyridin-3-yl]benzamide (4e)
Pyrone 3 (2.83 g, 10 mmol) and BzNH2 (1.60g, 15 mmol) were
heated in DMF at 80–90 °C for 8 h, while the progress of the reac-
tion was monitored by TLC. The reaction mixture was then cooled
to r.t., poured into H2O, and extracted with EtOAc (3 × 20 mL). The
organic layer was washed with water (3 × 10 mL) and brine (1 × 10
mL), dried (MgSO4), and concentrated. The 19F NMR spectrum of
the crude product showed ~80% conversion. The residue was puri-
fied by column chromatography [EtOAc–cyclohexane (1:2)] to give
a colorless oil; yield: 2.55 g (65%); Rf = 0.56.
Figure 5 Molecular structure of compound cis-10a obtained by X-
ray crystal structure analysis
IR (CH2Cl2): 1030, 1186, 1362, 1413, 1439, 1524, 1648, 1733,
2855, 2928, 3034, 3066, 3383, 3563 cm–1.
1H NMR (500 MHz, CDCl3): 2.93 (d, J = 18.8 Hz, 1 H, Ha of CH2),
3.11 (dd, J1 = 6.4 Hz, J2 = 18.8 Hz, 1 H, Hb of CH2), 4.69 (d,
J = 15.3 Hz, 1 H, Ha of CH2Ph), 4.98 (d, J = 15.3 Hz, 1 H, Hb of
CH2Ph), 5.42 (br s, OH), 7.13–7.55 (m, 9 H, Ph, CH), 7.76 (d,
J = 7.3 Hz, 2 H, 1 H, Ph), 8.85 (s, 1 H, NH).
13C NMR (126 MHz, CDCl3): d = 32.0, 45.2, 84.1 (q, J = 31.0 Hz),
112.6, 126.7, 127.0, 127.3, 127.4, 128.5, 128.8, 132.3, 133.7, 138.2,
162.0, 166.3. Peaks of the CF3-carbon signal were overlapped by
the signals of the aromatic carbon atoms.
Initial tests of the bioactivity of compounds 8b and 9b and
the thalidomide analogues 10 were carried out. Com-
pound 8b was found to be a defined stimulator of cellular
immunity and does not significantly influence the humor-
al immunity or nonspecific resistance of mice. In contrast,
compound 9b modulated all three types of immunity in
mice (see Supporting Information). Moreover, com-
pounds 10 showed antimicrobial activity against Staphy-
lococcus aureus (St. 209). Preliminary results showed that
compounds cis-10a and -10b and trans-10a possess visi-
ble activity in comparison to thalidomide, whereas com-
pound trans-10b does not have any activity at all (see
supporting information). Further investigations of com-
pounds 8a and 8b as mimetics of natural amino acids are
in progress.
19F NMR (470 MHz, CDCl3): d = –81.9 (s, CF3).
MS (ESI): m/z calcd for C20H17F3N2O3Na: 413.1089; found:
413.1086.
6-Hydroxydihydropyridinones (4f and 4g); General Procedure
A soln of the appropriate amino acid ester hydrochloride (35 mmol)
and Et3N (1.82 g, 18 mmol) in DMF was stirred at r.t. for 30 min.
Pyrone 3 (2.83 g, 10 mmol) was then added and the mixture was
stirred at 80–90 °C for 6 h while the progress of the reaction was
monitored by TLC. The mixture was then cooled to r.t., poured into
H2O, and extracted with EtOAc (3 × 20 mL). The organic layer was
washed with water (3 × 10 mL) and brine (1 × 10 mL), dried
(MgSO4), and concentrated. The residue was purified by column
chromatography.
In conclusion, the hydrogenation of 6-(trifluorometh-
yl)pyridinones 1 and the 6-hydroxydihydropyridinones 4
gave the corresponding piperidones 2a–j and 6d–g in
moderate-to-excellent yields. The new pyridinones 1e–j
and 6-hydroxydihydropyridinones 4e–j were also pre-
pared.
The products 2f, 2g, 6f, and 6g are of interest as building
blocks for conformationally restricted peptidomimetics
because of the presence of a dipeptide motif in their struc-
tures. The hydrogenation products were used in the syn-
thesis of amino acids 8a and 8b and the phthalimide
analogues cis/trans-10a and -10b.
Methyl [5-(Benzoylamino)-2-hydroxy-6-oxo-2-(trifluorometh-
yl)-3,6-dihydropyridin-1(2H)-yl]acetate (4f)
The product was obtained from methyl glycinate hydrochloride (4.4
g) and purified by column chromatography [EtOAc–cyclohexane
(1:2)]; yield: 1.71 g (46%); mp 143–145 °C; Rf = 0.24.
IR (CH2Cl2): 1039, 1188, 1398, 1430, 1525, 1654, 1741, 2958,
3062, 3391 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.01 (dd, J1 = 18.6 Hz, J2 = 4.2
Hz, 1 H, Ha of CH2), 3.15 (dd, J1 = 18.6 Hz, J2 = 5.3 Hz, 1 H, Hb of
CH2), 3.80 (s, 3 H, CH3), 4.16 (d, J1 = 17.6 Hz, 1 H, Ha of
CH2CO2Me), 4.79 (d, J1 = 17.6 Hz, 1 H, Hb of CH2CO2Me), 5.53
(br s, 1 H, OH), 7.43–7.58 (m, 4 H, Ar and CH), 7.80–7.85 (m, 2 H,
Ar), 8.75 (s, 1 H, NH).
13C NMR (126 MHz, CDCl3): d = 31.3, 43.9, 53.1, 84.2 (q, J = 30.9
Hz), 114.1, 123.4 (q, J = 290.0 Hz), 126.1, 127.0, 128.9, 132.2,
134.0, 162.2, 166.0, 172.3.
Melting points are uncorrected. NMR spectra were recorded on
Bruker Avance DRX and Varian INOVA spectrometers at 500
MHz (1H), 126 MHz (13C), or 470 MHz (19F), and on a Varian Unity
Plus spectrometer at 600 MHz (1H) at 25 °C. TMS (for 1H and 13
C
NMR) and CCl3F (for 19F NMR) were used as internal standards. IR
spectra were recorded on a Bruker Vertex 70 spectrometer. The
progress of reactions was monitored by TLC (silica gel 60 F254,
Merck). Column chromatography was carried out on silica gel 60
(Merck, particle size 0.040–0.063 mm). Ion-exchange chromatog-
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1154
N. A. Tolmachova et al.
PAPER
19F NMR (470 MHz, CDCl3): d = –81.8 (s, CF3).
3-Amino-6-(trifluoromethyl)pyridin-2(1H)-one (1h)
The product was obtained from 1a (282 mg).
MS (ESI): m/z calcd for C16H15F3N2O5Na: 395.0831; found:
395.0827.
Yield: 53 mg (30%), mp 110–111 °C; the hydrochloride could be
isolated in 55% yield (118 mg).
Pyridinones 1e–g; General Procedure
IR (KBr): 835, 953, 1091, 1128, 1178, 1195, 1285, 1320, 1605,
1639, 1864, 2749, 2838, 2903, 3078, 3165, 3308, 3425 cm–1.
1H NMR (500 MHz, CD3OD): d = 4.61 (s, 2 H, NH2), 6.52 (d,
J = 7.2 Hz, 1 H, CH), 6.56 (d, J = 7.2 Hz, 1 H, CH), 12.21 (s, 1 H,
NH).
13C NMR (126 MHz, CD3OD): d = 108.7 (q, J = 6.6 Hz), 109.7,
120.9 (q, J = 271.9 Hz), 120.6 (q, J = 31.8 Hz), 141.30, 157.1.
19F NMR (470 MHz, CD3OD): d = –67.0 (s, CF3).
A soln of corresponding dihydropyridinone 4e–g (1 mmol) and
TsOH in toluene (25 mL) was refluxed with simultaneous water/
toluene azeotrope removal while the progress of the reaction was
monitored by TLC. When conversion was complete, toluene was
evaporated off under low pressure, and the resulting crude product
was purified by crystallization or by column chromatography.
Methyl [3-(Benzoylamino)-2-oxo-6-(trifluoromethyl)pyridin-
1(2H)-yl]acetate (1f)
The product was obtained from compound 4f (372 mg) as a mixture
with compound 5 and isolated by column chromatography [EtOAc–
cyclohexane (1:2)]; yield: 216 mg (61%); mp 157–159 °C;
Rf = 0.24.
2-[1-Methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-3-
yl]-1H-isoindole-1,3(2H)-dione (1j)
A solution of amine 1i (192 mg, 1 mmol) and phthalic anhydride
(222 mg, 1.5 mmol) in pyridine (10 mL) was heated at 60 °C for 3
h, and then refluxed for 50–70 h while the progress of the reaction
was followed by 19F NMR spectroscopy. After completion of the re-
action, pyridine was evaporated at 30–40 °C (30–60 mmHg) and the
residue was purified by crystallization [hexane–toluene (4:1)];
yield: 267 mg (83%); mp 149–151 °C.
IR (CH2Cl2): 1130, 1192, 1225, 1306, 1378, 1522, 1621, 1660,
1761, 3375 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.81 (s, 3 H, Me), 4.93 (s, 2 H,
CH2), 6.89 (d, J = 7.7 Hz, 1 H, CH), 7.47–7.62 (m, 3 H, Ph), 7.90–
7.95 (m, 2 H, Ph), 7.58 (d, J = 7.7 Hz, 1 H, CH), 9.27 (br s, 1 H,
NH).
13C NMR (126 MHz, CDCl3): d = 47.0 (q, J = 2.7 Hz), 53.0, 108.8
(q, J = 6.4 Hz), 110.1, 118.9, 120.2 (q, J = 275.0 Hz), 126.8 (q,
J = 33.5 Hz), 127.4, 129.4, 132.7, 133.6, 157.9, 166.1, 167.1.
19F NMR (470 MHz, CDCl3): d = –63.16 (s, CF3).
IR (KBr): 691, 722, 820, 882, 944, 972, 1057, 1083, 1111, 1141,
1183, 1199, 1256, 1301, 1375, 1405, 1465, 1543, 1622, 1668, 1725,
1762, 1786, 1885 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.70 (s, 3 H, CH3), 6.81 (d, J = 7.5
Hz, 1 H, CH), 7.52 (d, J = 7.5 Hz, 1 H, CH) 7.79 (m, 2 H, phthal-
imide), 7.95 (m, 2 H, phthalimide).
13C NMR (126 MHz, CDCl3): d = 32.7, 105.1 (q, J = 6.5 Hz) 119.7
(q, J = 275.4 Hz), 124.0, 126.6, 132.0, 134.5, 136.1 (q, J = 33.7 Hz),
137.2, 158.6, 166.3.
19F NMR (470 MHz, CDCl3): d = –65.0 (s, CF3).
MS (ESI): m/z calcd for C16H13F3N2O4Na: 377.0725; found:
377.0722.
N-[2,5-Dioxo-8a-(trifluoromethyl)-2,3,8,8a-tetrahydro-5H-
[1,3]oxazolo[3,2-a]pyridin-6-yl]benzamide (5)
The product was obtained from compound 4f as a mixture with
compound 1f and isolated by column chromatography [EtOAc–cy-
clohexane (1:2)] as a colorless oil; yield 58 mg (17%); Rf = 0.64.
MS (ESI): m/z calcd for C15H9F3N2O3Na: 345.0463; found:
345.0457.
IR (CH2Cl2): 1200, 1426, 1525, 1672, 1836, 2926, 3055, 3401 cm–1.
Hydrogenation of Compounds 1a–j or 4d–f; General Procedure
A mixture of a pyridinone 1a–j or 4d–f (1 mmol) and 5% Pd/C (20–
60 mg) in an appropriate solvent (10 mL) was stirred in an autoclave
under appropriate conditions (for 1a–i: see Table 1; for 4d–f: THF,
25 °C, 40 atm, 8 h) while the progress was monitored by 19F NMR
spectroscopy and TLC. When hydrogenation was complete, the
mixture was filtered and the solvent was evaporated at 20–30 °C
(30–60 mmHg) to give a residue that was purified by crystallization
or column chromatography.
1H NMR (500 MHz, CDCl3): d = 3.10 (d, J = 18.7 Hz, 1 H, Ha of
CH2), 3.36 (dd, J1 = 18.7 Hz, J2 = 6.5 Hz, 1 H, Hb of CH2), 4.14 (d,
J = 17.5 Hz, 1 H, Ha of CH2N), 4.53 (d, J = 17.5 Hz, 1 H, Hb of
CH2N), 7.47–7.61 (m, 4 H, Ar and CH), 7.85–7.88 (m, 2 H, Ar),
8.56 (s, 1 H, NH).
13C NMR (126 MHz, CDCl3): d = 27.3, 43.5, 89.9 (q, J = 33.9 Hz),
112.1, 122.9 (q, J = 286.0 Hz), 126.7, 127.0, 128.9, 132.4, 133.8,
158.2, 165.8, 166.3.
19F NMR (470 MHz, CDCl3): d = –84.5 (s, CF3).
cis-N-[2-Oxo-6-(trifluoromethyl)piperidin-3-yl]cyclohexane-
carboxamide (cis-2a)
The product was obtained from 1a (281 mg) and purified by crys-
tallization [CHCl3–MeCN (2:1)]; yield: 219 mg (75%); mp 181–
182 °C.
MS (ESI): m/z calcd for C15H11F3N2O4Na: 363.0569; found:
363.0563.
Amines 1h and 1i: General Procedure
A soln of pyridinone 1a or 1b (1 mmol) in 30% aq HCl (15 mL) was
refluxed for 12 h while the progress of the reaction was monitored
by 19F NMR spectroscopy. After complete hydrolysis, the mixture
was cooled and the precipitated BzOH was filtered off. The filtrate
was evaporated at 30–40 °C (30–60 mmHg) to give the amine hy-
drochloride, which was purified by washing with MeCN. The salt
was dissolved in H2O (2 mL), and sat. aq KHCO3 was added drop-
wise until the pH was about 7. The soln was then extracted with
EtOAc (3 × 25 mL), and the organic layer was dried (MgSO4) and
concentrated at 20–30 °C (30–60 mmHg) to give a residue that was
crystallized (hexane).
IR (KBr): 1128, 1167, 1209, 1264, 1422, 1530, 1638, 1688, 3211,
3303 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 1.07–1.37 (m, 5 H, c-hex),
1.54–1.87 (m, 7 H, c-hex and CH2), 1.92–2.14 (m, 3 H, c-hex and
CH2), 4.02 (m, 1 H, CH), 4.21 (m, 1 H, CH), 7.94 (d, J = 8.5 Hz, 1
H, NH), 8.19 (s, 1 H, NH).
13C NMR (126 MHz, DMSO-d6): d = 19.6, 23.9, 25.4, 25.5, 25.6,
29.1, 29.3 44.8, 48.8, 52.1 (q, J = 31.3 Hz), 125.2 (q, J = 279.5 Hz),
171.8, 177.8.
19F NMR (470 MHz, DMSO-d6): d = –76.57 (d, J = 7.4 Hz, CF3).
MS (ESI): m/z calcd for C13H19F3N2O2Na: 315.1296; found:
315.1291.
Synthesis 2011, No. 7, 1149–1156 © Thieme Stuttgart · New York

PAPER
3-Amino-6-(trifluoromethyl)piperidin-2-ones
1155
trans-N-[6-Hydroxy-1-(2-methoxyethyl)-2-oxo-6-(trifluoro-
methyl)piperidin-3-yl]benzamide (trans-6d)
The product was obtained from 4d (358 mg) and purified by column
chromatography [EtOAc–cyclohexane (3:2)]; yield: 266 mg (74%);
mp 144–146 °C; Rf = 0.38.
cis/trans-10a and -10b; General Procedure
A soln of a mixture of diastereomers cis/trans-2a or cis/trans-2b (1
mmol) and phthalic anhydride (0.15 mmol) in pyridine (20 mL) was
heated at 60 °C for 3 h and then refluxed for 50–70 h while the
progress of the reaction was monitored by 19F NMR spectroscopy.
When the reaction was complete, pyridine was evaporated at 30–
40 °C (30–60 mmHg) and the residue was purified by column chro-
matography.
IR (KBr): 710, 1090, 1116, 1156, 1550, 1589, 1631, 2885, 2975,
3149, 3298 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.80–1.97 (m, 1 H, Ha of CH2),
2.00–2.16 (m, 1 H, Hb of CH2), 2.49–2.61 (m, 1 H, Ha of CH2),
2.61–2.71 (m, 1 H, Hb of CH2), 3.42 (s, 3 H, CH3), 3.45 (ddd,
J1 = 9.6 Hz, J2 = 3.6 Hz, J3 = 1.7 Hz, 1 H, Ha of CH2N), 3.51 (ddd,
J1 = 10.7 Hz, J2 = 9.6 Hz J3 = 1.8 Hz, 1 H, Ha of CH2N), 3.64 (ddd,
J1 = 14.4 Hz, J2 = 10.7 Hz, J3 = 3.6 Hz, 1 H, Ha of CH2O), 4.19 (dt,
J1 = 14.4 Hz, J2 = 1.7 Hz, 1 H, Hb of CH2O), 4.64 (dt, J1 = 11.9,
J2 = 6.0, 1 H, CHN), 5.81 (br s, 1 H, OH), 7.05 (d, J = 6.0 Hz, 1 H,
NH), 7.37–7.55 (m, 3 H, Ph), 7.77–7.84 (m, 2 H, Ph).
13C NMR (126 MHz, CDCl3): d = 23.9 (q, J = 2.3 Hz), 31.8, 42.1 (q,
J = 2.4 Hz), 51.5, 59.2, 69.2, 83.9 (q, J = 30.2 Hz), 124.2 (q,
J = 290.7 Hz), 127.1, 128.6, 131.8, 133.8, 167.9, 170.5.
19F NMR (470 MHz, CDCl3): d = –77.6 (s, CF3).
cis-2-[2-Oxo-6-(trifluoromethyl)piperidin-3-yl]-1H-isoindole-
1,3(2H)-dione (cis-10a)
The product was obtained from an 85:15 mixture of cis- and trans-
2a (182 mg) and purified by column chromatography [EtOAc–hex-
ane (1:4)]; yield: 109 mg (35%); mp > 200 °C (dec.); Rf = 0.3.
IR (KBr): 888, 1022, 1142, 1171, 1195, 1305, 1680, 1718, 1769,
1784, 2904, 3101, 3210 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 1.91 (m, 1 H, Ha of CH2), 2.11
(m, 1 H, Hb of CH2), 2.32 (m, 1 H, Ha of CH2), 2.51 (m, 1 H, Hb of
CH2), 4.13 (m, 1 H, CH), 4.74 (s, 1 H, CH), 7.84–7.92 (m, 4 H, Ar),
8.59 (s, 1 H, NH).
13C NMR (126 MHz, DMSO-d6): d = 20.3, 22.1, 49.1, 51.8 (q,
J = 29.5 Hz), 123.7, 126.0 (q, J = 268.5 Hz), 131.9, 135.2, 167.7,
168.1.
19F NMR (470 MHz, DMSO-d6): d = –80.3 (br s, CF3).
Amino Acids 8a and 8b; General Procedure
A soln of lactam cis-2a,b or cis-2h,i (1 mmol) in 30% aq HCl (25
mL) was stirred at 100 °C while the reaction was monitored by 19
F
NMR. When the reaction was complete (5–7 h), the soln was fil-
tered and the H2O was evaporated at 30–40 °C and 30–60 mmHg.
The residue was purified by ion-exchange chromatography to give
an ammonia soln that was concentrated. The residue was dissolved
in H2O and concentrated again in vacuo to remove traces of NH3.
Hydrochlorides of 8a and 8b were obtained by dissolving the free
diamino acids in 15% aq HCl and evaporating the resulting soln at
30–40 °C and 30–60 mmHg.
trans-2-[2-Oxo-6-(trifluoromethyl)piperidin-3-yl]-1H-iso-
indole-1,3(2H)-dione (trans-10a)
The product was obtained from an 85:15 mixture of cis- and trans-
2a (182 mg) and purified by column chromatography [EtOAc–
hexane (1:4)]; yield: 103 mg (33%); mp 179–181 °C; Rf = 0.2.
IR (KBr): 718, 1112, 1393, 1467, 1688, 1717, 1770, 2967 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.01 (m, 1 H, Ha of CH2), 2.20 (m,
1 H, Ha of CH2), 2.34 (m, 1 H, Hb of CH2), 2.54 (m, 1 H, Hb of CH2),
4.18 (m, 1 H, CH), 4.80 (m, 1 H, CH), 6.16 (s, 1 H, NH), 7.74 (m,
2 H, Ar), 7.86 (m, 2 H, Ar).
13C NMR (126 MHz, CDCl3): d = 21.1, 24.1, 48.6, 54.8 (q, J = 31.0
Hz), 123.6, 124.0 (q, J = 279.5 Hz), 132.0, 134.3, 167.6, 167.7.
(2R,5R/2S,5S)-2,5-Diamino-6,6,6-trifluorohexanoic Acid Dihy-
drochloride (8a)
The product was obtained as a white solid from cis-2a (292 mg) or
cis-2h (182 mg); yield: 167 mg (61%) or 123 mg (45%), respective-
ly; mp > 300 °C (dec.).
IR (KBr): 1126, 1269, 1415, 1504, 1600, 1664, 2968 cm–1.
19F NMR (470 MHz, CDCl3): d = –79.3 (br s, CF3).
1H NMR (500 MHz, D2O): d = 1.88 (m, 1 H, Ha of CH2), 2.06 (m,
2 H, CH2), 2.15 (m, 1 H, Hb of CH2), 3.95 (m, 1 H, CH), 4.12 (m, 1
H, CH).
13C NMR (126 MHz, D2O): d = 22.7, 25.0, 51.8 (q, J = 32.0 Hz),
52.5, 123.5 (q, J = 285.3 Hz), 171.5.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
19F NMR (470 MHz, D2O): d = –74.3 (d, J = 7.6 Hz, CF3).
This work was supported by the Deutsche Forschungsgemeinschaft
(Ha 2145/9-1; AOBJ: 560896). We thank Enamine Ltd (Kiev) for
technical and financial supports, and we wish to express our grati-
tude to Mrs. S. V. Shishkina and Dr O. V. Shishkin (STC ‘Institute
for Single Crystals’, Kharkov, Ukraine) for performing the X-ray
diffraction study and to Drs S. I. Vdovenko and L. A. Metelitsa
(Institute of Bioorganic Chemistry and Petrochemistry, National
Ukrainian Academy of Sciences, Kiev, Ukraine) for performing the
IR experiments and the biological tests, respectively.
(2R,5R/2S,5S)-2-(Benzoylamino)-6,6,6-trifluoro-5-(methyl-
amino)hexanoic Acid Hydrochloride (9b)
A soln of lactam cis-2b (300 mg, 1 mmol) was dissolved in 10% aq
HCl (10 mL). After 5 h, the soln was evaporated at r.t. and 30–60
mmHg to give a residue that was washed with Et2O and dried under
vacuum; yield: 305 mg (95%). mp 40 °C (dec.).
IR (KBr): 1040, 1096, 1132, 1168, 1192, 1264, 1312, 1336, 1408,
1488, 1534, 1638, 1666, 3007 cm–1.
1H NMR (500 MHz, acetone-d6): d = 1.96 (m, 1 H, Ha of CH2), 2.14
(m, 2 H, CH2), 2.28 (m, 1 H, Hb of CH2) (m, 2 H), 2.87 (s, 3 H, Me),
4.14 (m, 1 H, CH), 4.56 (m, 1 H, CH), 7.32 (m, 2 H, aryl), 7.38 (m,
1 H, aryl), 7.79 (m, 2 H, aryl).
13C NMR (126 MHz, acetone-d6): d = 21.4, 24.5, 36.5, 50.1, 59.1
(q, J = 28.3 Hz), 126.3 (q, J = 287.9 Hz), 127.8, 128.6, 131.7, 134.6,
166.5, 170.2.
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Synthesis 2011, No. 7, 1149–1156 © Thieme Stuttgart · New York

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Synthesis 2011, No. 7, 1149–1156 © Thieme Stuttgart · New York