Practical synthesis of α-perfluoroalkyl cyclic imines and amines

Article abstract of DOI:10.1055/s-0029-1217104

A convenient and simple approach for the preparation of -CF₃and C₂F₅ substituted pyrrolines, tetrahydropyridines, tetrahydroazepine is described. Claisen condensation of N-protected cyclic amides with esters of perfluorocarboxylic acids followed by deprotection and decarboxylation in acidic media leads to the desired products. Reduction of these imines permits to obtain 5-, 6-, and 7-membered cyclic amines with - CF₃and C₂F₅ group in good to moderate overall yields. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1217104

120
PAPER
Practical Synthesis of a-Perfluoroalkyl Cyclic Imines and Amines
S
ynthesis of
a-Per
i
fluoroa
k
lkyl Cyclic
I
o
mines and
A
l
mines ay E. Shevchenko,a Elisabeth S. Balenkova,a Gerd-Volker Röschenthaler,*b Valentine G. Nenajdenko*a
a
Department of Chemistry, Moscow State University, Moscow 119991, Russian Federation
Fax +7(495)9322286; E-mail: nen@acylium.chem.msu.ru
Institute for Inorganic and Physical Chemistry, The University of Bremen, Leobener Str., 28334 Bremen, Germany
Fax +38(421)2184267; E-mail: gvr@chemie.uni-bremen.de
b
Received 20 August 2009; revised 3 September 2009
try. Much attention has been devoted to the development
of synthetic routes to various classes of fluorinated com-
pounds. Very often fluorinated compounds demonstrate
unusual, unpredictable chemical properties due to the in-
Abstract: A convenient and simple approach for the preparation of
a-CF3 and a-C2F5 substituted pyrrolines, tetrahydropyridines, tet-
rahydroazepine is described. Claisen condensation of N-protected
cyclic amides with esters of perfluorocarboxylic acids followed by
deprotection and decarboxylation in acidic media leads to the de- fluence of perfluorinated fragment.
sired products. Reduction of these imines permits to obtain 5-, 6-,
and 7-membered cyclic amines with a-CF3 or a-C2F5 group in good
to moderate overall yields.
C(O)R
n
n
(ii)
(i)
n
Key words: fluorine, nitrogen heterocycles, a-polyfluoroalkyl
imines, reductions
N
O
N
O
N
R
PG
PG
n = 0, 1, 2
Scheme 1 Claisen approach to the nonfluorinated cyclic imines,
Reagents and conditions: (i) RCO2Alk, base (usually NaH or AlkO-
Na); (ii) H3O+, reflux – deprotection, hydrolysis, and simultaneous
decarboxylation.
From different viewpoints, the a-substituted cyclic imines
are of important class of nitrogen heterocycles. Besides
the fact that some of them are present in natural products,1
they are also very versatile and useful building blocks to
construct a large variety of biologically interesting hetero-
cyclic compounds, especially pyrrolidine, piperidine, or
azepane cycles.2 Since these azacycles are the structural
feature of many alkaloids, the a-substituted cyclic imines
can be also a starting point in alkaloid synthesis.3 As an
evidence of their outstanding importance it may be noted
that by the end of the year 2000 there were over 12 000
compounds with piperidine and pyrrolidine entities men-
tioned in clinical or preclinical studies.4
Concerning the organometallic approach, we have recent-
ly been able to demonstrate that a-pentafluoroethylpyrro-
line and -tetrahydropyridine are accessible by the reaction
of pentafluoroethyllithium with lactim esters in the pres-
ence of boron trifluoride.9 Unfortunately, on account of
the instability of trifluoromethyllithium and low reactivity
of other nucleophilic trifluoromethylating reagents10 this
method does not permit the synthesis of the a-CF3 hetero-
cycles. This restriction promoted us to study Claisen
strategy, especially because the starting fluorinated com-
pounds (esters of perfluorinated carboxylic acids) in this
approach are readily available.
Despite the possible interest in fluorinated analogues of
these imines, the preparation of cyclic imines bearing an
a-fluoroalkyl group has almost not been studied so far.5 In
this paper, we have focused our interest on an easy access
to a-trifluoromethylated and a-pentafluoroethylated pyr-
rolines, tetrahydropyridines, and tetrahydroazepines not
only for potential bioactivity of their derivatives but also
as prospective valuable fluorinated building blocks that
can be converted into a variety of nitrogen heterocycles
and other functionalized acyclic compounds.
Our attempt to synthesize the a-CF3 pyrroline starting
from N-vinylpyrrolidinone and ethyl trifluoroacetate
(model substrates) under literature conditions for non-
fluorinated aromatic and aliphatic esters7 was unsuccess-
ful. Therefore, we decided to study each steps separately
and more carefully.11
At first, we carried out the condensation of N-protected
cyclic amides with esters of aliphatic perfluorinated acids
(Scheme 2). As one would expect, the polyfluorinated
esters easily react with amides in Claisen condensation
manner and after deprotection, the corresponding per-
fluorinated acyllactams 2 were synthesized in very good
yields. It is not unusual that initially these substances were
isolated from aqueous media as hydrate as the correspond-
ing 1,1-diols 1; the ability of electron-withdrawing CF3
and C2F5 group to stabilize the tetrahedral adducts of such
type are well documented.12
Among the known syntheses of the nonfluorinated a-sub-
stituted cyclic imines,6 the most common and useful is the
Claisen condensation of N-protected lactams with esters
followed by simultaneous deprotection and decarboxyla-
tion in acidic media (Scheme 1)7 or the reaction of N-pro-
tected amides with organolithium reagents.8 It seems to be
a challenging synthetic task to extend the field of applica-
tion of these two methods to the organofluorine chemis-
SYNTHESIS 2010, No. 1, pp 0120–0126
x
x
.
x
x
.2
0
0
9
Advanced online publication: 06.11.2009
DOI: 10.1055/s-0029-1217104; Art ID: Z17609SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of a-Perfluoroalkyl Cyclic Imines and Amines
121
RF
RF
RF
a: RF = CF3; n = 0
OH
OH
(ii)
b: RF = C2F5; n = 0
c: RF = CF3; n = 1
d: RF = C2F5; n = 1
e: RF = CF3; n = 2
f: RF = C2F5; n = 2
OH
(i)
n
n
O
or
n
quantitative
N
O
67–84%
N
N
O
O
H
N
O
H
PG
H
(iii)
for n = 0,1
for n = 2
1a–f
2a–f
Scheme 2 Synthesis of perfluoroacyllactams, Reagents and conditions: (i) RFCO2Et (1.05 equiv), NaH, THF reflux 1 h, then aq 3 M HCl,
reflux, 0.5 h; (ii) azeotropic drying with toluene; (iii) dissolving in hot H2O with a drop of concd HCl and leaving for 12 h.
After elimination of water from the gem-diols 1a–f by
azeotropic drying with toluene, the corresponding per-
fluoroacyllactams 2a–f were isolated in quantitative
yields. Like the nonfluorinated derivatives,13 the acyl-
caprolactams 2e and 2f exist exclusively in the keto form,
whereas the perfluoroacycllactams 2a–d with five- and
six-membered rings were isolated as enols (accordingly to
the NMR data, the content of keto form in chloroform so-
lution of 2a–d is less than 2%). Earlier,13 it has been
shown that 2-acyl derivatives of piperidin-2-one are ami-
doketones, but in the corresponding pyrrolidin-2-ones, the
keto form is the major tautomer. As an example, N-meth-
yl-3-trifluoroacylpyrrolidin-2-one consists of 20% of enol
form.14
Table 1 Progress of Hydrolysis and Decarboxylation of Perfluoro-
acyllactams 1a
Reaction time (h)
Conversion (%)
1
10
24
45
60
4.5
35
60
90
97
Unfortunately, the water-stable salt 3a easily loses a mol-
ecule of water when we attempted to isolate it in pure
form. Nevertheless, more stable pentafluoroethyl deriva-
tive 3b was isolated successfully and fully characterized
by NMR data and chemical analysis.
We have then investigated the hydrolysis and decarboxy-
lation of perfluoroacyllactams 1a–f under aqueous acidic
condition. In a typical experiment, trifluoroacylated
amide 1a was dissolved in aqueous 6 M HCl and heated
under reflux and the reaction was monitored by spectra.
After one hour, besides the signal at –83.9 ppm, the sin-
glet at –87.7 ppm appeared, which corresponds to the
structure 3a and no other signals were detected in 19F
NMR spectra during the progress of hydrolysis. Conse-
quently, decarboxylation of a-trifluoroacylated g-amino
acid A – intermediate that initially formed in the course of
hydrolysis of amide bond of 1a – proceeds very fast and
the rate-determining step seems to be the hydrolysis
(Scheme 3). Progress of the reaction is shown in Table 1.
Quite a prolonged time (60 h) is necessary to complete the
reaction. It dramatically differs from the reaction time
necessary for decarboxylation of the nonfluorinated acyl-
lactams for which four hours are quite enough to finish the
transformation.7
When decarboxylation was completed, the reaction mix-
ture was carefully made alkaline with potassium hydrox-
ide under cooling, and the hemiaminal formed was
extracted with diethyl ether. Removal of solvent under at-
mospheric pressure yields aminal 4a admixed with imine
5a. To prepare pure imine 5a, this mixture was dissolved
in chloroform and refluxed using a Dean–Stark adapter
and after careful removal of solvents, the residue was dis-
tilled under atmospheric pressure. Alternately, the crude
cyclic hemiaminals can be distilled at atmospheric pres-
sure to the receiving flask charged with anhydrous sodium
sulfate. Removal of the drying agent afforded the imine 5a
in pure form.
With an aim to determine the scope and limitations of this
procedure, we carried out decarboxylation under analo-
gous conditions with substrates 1b–f. In all instances, the
RF
RF
OH
OH
OH
OH
OH
(i)
(i)
H3N+
RF
n
n
n
– CO2
OH
3a–e
N
H
O
H3+N
O
OH
1a–f
A
a: RF = CF3; n = 0 b: RF = C2F5; n = 0
c: RF = CF3; n = 1 d: RF = C2F5; n = 1
e: RF = CF3; n = 2 f: RF = C2F5; n = 2
n
n
RF
(iii)
(ii)
N
H
OH
N
RF
4a–e
5a–e
Scheme 3 Hydrolysis and decarboxylation of perfluoroacyllactams 1a–f, Reagents and conditions: (i) aq 6 M HCl, reflux 60 h; (ii) aq 50%
KOH; (iii) azeotropic drying with CHCl3 or distillation under atmospheric pressure.
Synthesis 2010, No. 1, 120–126 © Thieme Stuttgart · New York

122
N. E. Shevchenko et al.
PAPER
a-pentafluoroethyl- or a-trifluoromethylimines 5b–d with catalyst as reducing agents. The isolated yields and reac-
five- and six-membered rings were obtained in excellent tion times for reduction are summarized in Table 3. The
to good yields (Table 2) after a reaction time of 60 hours. best yields were achieved in the reduction of 5a,b with hy-
Hemiaminals 4b and 4d were found to be stable so that drogen and palladium under atmospheric pressure. Unfor-
they could be isolated and characterized in pure form.
tunately, this method does not work in the case of six- and
seven-membered imines 5c–e due to very low rate of the
reactions. Probably, hydrogenation under higher pressure
permits to overcome this problem. Zinc in acetic acid gave
low yield and the problem of separation of reaction mix-
ture from inorganic materials. The most convenient and
practical reduction of imines 5a–e for laboratory use was
found to be with the in situ generated sodium triacetoxy-
borohydride in methanol. It is applicable for all substrate
5a–e under investigation; the reaction proceeds in reason-
able time and leads to good yields of the desired products
6a–e (Scheme 4).
Table 2 Synthesis of Hemiaminals 4b–d and Imines 5a–e
Ring size RF
Yield (%)
4
5 (from 1) 5 (one-pot)
5
5
6
6
7
CF3
–
83
79
86
79
21
79
74
82
75
19
C2F5
CF3
82
89
83
–
C2F5
CF3
[Red]
Red:
n
n
NaBH(OAc)3;
Zn/AcOH;
H2, Pd/C
Notable results were obtained when we studied the hy-
drolysis and decarboxylation of perfluoroacylcaprolac-
tams 1e,f. Accord to 19F NMR spectra, starting
acyllactams were consumed in 40 hours and the main
fluoro-containing products were the corresponding tri-
fluoroacetic and pentafluoropropionic acids. Therefore,
we were unable to prepare imine 5f, which was only de-
tected by 19F NMR spectroscopy. Another tetrahydro-
azepine product 5e was isolated in low yield. Although
some details of the reaction deserve further study, we sug-
gest that retro-Claisen reaction takes place in these cases.
Reasonable explanation of dramatic difference between
five- and six-membered acyllactams 1a–d contrary to
seven-membered acyllactams 1e,f seems to be connected
with the fact that 1a–d can exist in water as a mixture of
gem-diols and enols whereas 1e,f as a mixture of gem-
diols and ketones (Scheme 2).
N
RF
N
RF
H
5a–e
6a–e
a: RF = CF3; n = 0 b: RF = C2F5; n = 0
c: RF = CF3; n = 1 d: RF = C2F5; n = 1
e: RF = CF3; n = 2
Scheme 4 Reduction of fluorinated cyclic imines
Table 3 Reduction of a-CF3 and a-C2F5 Substituted Cyclic Imines 5
Amines 6
Yields (%)
H2, Pd/C
NaBH(OAc)3
Zn/AcOH
a
b
c
99
94
–
67
75
71
75
82
42
40
–
d
e
–
–
We have simplified further the preparation of imines
5a–e by carrying out the acylation of N-protected amides
followed by deprotection and simultaneous decarboxyla-
tion without isolation of 1a–e (one-pot). In all cases for
one-pot procedure yields are better than the corresponding
overall yields obtained in two-step approach (Table 2).
Therefore, starting from cheap and available starting ma-
terials the cyclic amines bearing a-CF3 or a-C2F5 group
can be easily synthesized in a two-step one-pot procedure.
This sequence can be easily scaled up to produce these
imines in large quantities. For instance, 100 g of 5a have
been produced in one batch.
–
–
In conclusion, we have shown that syntheses of the a-CF3
and a-C2F5 substituted pyrrolines, tetrahydropyridines,
and tetrahydroazepine can be achieved through classic
Claisen condensation of N-protected cyclic amides with
esters of perfluorocarboxylic acids followed by deprotec-
tion and decarboxylation. This practical and easily scal-
able method utilizes available and cheap fluorinated
starting materials and can be realized in two-step one-pot
technique. Together with subsequent reduction this opens
a general and practical way to new synthesis of simplest
trifluoro and pentafluoro analogues of monosubstituted
pyrrolidine, piperidine, and azepane alkaloids. The reduc-
ing reagent of choice was found to be the sodium triacet-
oxyborohydride.
Having in our hands a number of cyclic imines bearing
CF3 and C2F5 group, we decided to investigate the reduc-
tion of them. This reaction opens a general and practical
way to a new synthesis of simplest trifluoro and penta-
fluoro analogues of monosubstituted pyrrolidine, piperi-
dine, and azepane alkaloids. As far as we know, the
syntheses of only a-trifluromethyl pyrrolidine and piperi-
dine have been reported in literature.15
NMR spectra were obtained on a Bruker DPX-200 (200.1 MHz for
1H; 188.3 MHz for 19F; 50.32 MHz for 13C) or a Bruker AM-360
1
(360.1 MHz for H; 90.5 MHz for 13C) spectrometer. Chemical
We chose zinc in acetic acid, NaBH4/AcOH system in
methanol, and catalytic hydrogenation using Pd/C as a
1
shifts for H NMR data are referenced internally to TMS (0.0);
Synthesis 2010, No. 1, 120–126 © Thieme Stuttgart · New York

PAPER
Synthesis of a-Perfluoroalkyl Cyclic Imines and Amines
123
chemical shifts for 13C NMR data are referenced to corresponding
CDCl3 (77.2), DMSO-d6 (39.5); and chemical shifts for 19F NMR
data are referenced to CFCl3 (0.0) or PhCF3 (–63.90). High-resolu-
tion mass spectra (HRMS) were recorded using a Varian MAT
CH7A instrument at 70 eV. Melting points are uncorrected. TLC
was carried out on precoated silica gel plates (Merck 60F254) with
UV light visualization. Flash chromatography was performed using
MP Silica 60 (320–630 mesh) with the indicated solvents. All reac-
tions were conducted under N2. THF was distilled from sodium/
benzophenone prior to use. All reagents were purchased from
Aldrich, unless otherwise stated. The starting N-(diethoxymeth-
yl)piperidin-2-one was prepared by the reaction of piperidin-2-one
with triethyl orthoformate according to the described procedure.16
N-Vinylpyrrolidin-2-one and N-vinylcaprolactams were distilled
prior to use.
HRMS (EI): m/z calcd for C7H6F5NO2 (M – H2O): 231.0319; found:
231.0317.
3-(2,2,2-Trifluoro-1,1-dihydroxyethyl)piperidin-2-one (1c)
Yield: 35.4 g (83%); white crystals; mp 95–96 °C (dec.).
1H NMR (200 MHz, DMSO-d6): d = 1.55–1.90 (m, 4 H), 2.60–2.68
(m, 1 H), 3.08–3.22 (m, 2 H), 7.34 (s, 1 H, NH), 8.39 (s, 1 H, OH),
9.02 (s, 1 H, OH).
13C NMR (50 MHz, DMSO-d6): d = 21.00, 21.94, 40.91, 43.70,
94.30 [t, J = 30.4 Hz, C(OH)2], 123.29 (t, J = 289.7 Hz, CF3),
172.42 (CONH).
19F NMR (188 MHz, DMSO-d6): d = –80.74.
HRMS (EI): m/z calcd for C7H8F3NO2 (M – H2O): 195.0507; found:
195.0509.
Trifluoroacetyl and Pentafluoropropanoyl Lactams 2a–f and
Their Hydrated Forms (gem-Diols) 1a–c; General Procedure
To a stirred and heated at reflux suspension of NaH (60% in mineral
oil, 10.4 g, 0.26 mol) in anhyd THF (300 mL) was added a mixture
of the N-protected lactam [0.20 mol, N-vinylpyrrolidin-2-one (22
g), N-(diethoxymethyl)piperidin-2-one (40 g), or N-vinylcaprolac-
tam (28 g)] and the ester of the corresponding perfluorocarboxylic
acid [0.21 mol, ethyl trifluoroacetate (30 g) or ethyl pentafluoropro-
pionate (40 g)] at a such rate that the evolution of H2 and boiling of
the mixture was not very intensive. After heating for an additional
hour, the reaction mixture was cooled down to r.t. and the resultant
clear solution was carefully diluted with a mixture of H2O (50 mL)
and AcOH (15.6 g). The layers were separated and the aqueous lay-
er was extracted again with THF (100 mL). The combined organic
extracts (solution of the crude N-protected ketolactam in THF) were
slowly added (over 1 h) to aq 3 M HCl (400 mL) under stirring and
heating at reflux. THF was collected during the addition by use of a
short-path distilling head. After heating for an additional 0.5 h, the
mixture was cooled to r.t., filtered through a Celite plug, extracted
with cold pentane (2 × 100 mL) and the aqueous solution was evap-
orated carefully under reduced pressure at r.t. To obtain the pure
gem-diols 1a–c, the residues were crystallized from H2O with a
drop of concd HCl. To isolate the pure acyllactams 2a–f, the resi-
dues were dissolved in CHCl3 (250 mL), and the solutions were
dried under Dean–Stark condition; the CHCl3 was removed in vac-
uo and residues were crystallized from hexane–CH2Cl2 mixture.
(3Z)-3-(2,2,2-Trifluoro-1-hydroxyethylidene)pyrrolidin-2-one
(2a)
Yield: 30.4 g (84%); white crystals; mp 117–121 °C.
1H NMR (200 MHz, CDCl3): d = 2.90–3.02 (m, 2 H), 3.49–3.56 (m,
2 H), 6.80 (br s, 1 H, NH), 11.88 (br s, 1 H, OH).
13C NMR (50 MHz, DMSO-d6): d = 22.12, 40.70, 104.65, 119.50
(q, J = 274.6 Hz, CF3), 148.66 [q, J = 37.2 Hz, C(OH)CF3], 175.60
(CONH).
19F NMR (188 MHz, DMSO-d6): d = –71.60.
HRMS (EI): m/z calcd for C6H6F3NO2: 181.0351; found: 181.0351.
(3Z)-3-(2,2,3,3,3-Pentafluoro-1-hydroxypropylidene)pyrroli-
din-2-one (2b)
Yield: 37.4 g (81%), white crystals; mp 110–114 °C.
1H NMR (200 MHz, CDCl3): d = 2.81–2.87 (m, 2 H), 3.35–3.42 (m,
2 H), 6.80 (br s, 1 H, NH).
13C NMR (50 MHz, CDCl3): d = 22.32, 41.09, 110.03, 110.71 (tq,
J = 254.8, 38.8 Hz, CF2CF3), 119.21 (qt, J = 287.4, 37.1 Hz,
CF2CF3), 146.84 [t, J = 27.3 Hz, C(OH)CF3], 175.34 (CONH).
19F NMR (188 MHz, CDCl3): d = –121.58 (2 F, CF2CF3), –83.70 (3
F, CF2CF3).
HRMS (EI): m/z calcd for C7H6F5NO2: 231.0315; found: 231.0319.
(3Z)-3-(2,2,2-Trifluoro-1-hydroxyethylidene)piperidin-2-one
(2c)
Yield: 32.3 g (83%); white crystals; mp 88–90 °C.
1H NMR (200 MHz, CDCl3): d = 1.78–1.91 (m, 2 H), 2.49–2.63 (m,
2 H), 3.27–3.41 (m, 2 H), 6.84 (br s, 1 H, NH), 15.26 (s, 1 H, OH).
13C NMR (50 MHz, CDCl3): d = 21.55, 21.66, 41.43, 99.85, 119.75
(q, J = 277.4 Hz, CF3), 155.77 [q, J = 34.4 Hz, C(OH)CF3], 171.64
(CONH).
19F NMR (188 MHz, CDCl3): d = –68.35.
3-(2,2,2-Trifluoro-1,1-dihydroxyethyl)pyrrolidin-2-one (1a)
Yield: 33.4 g (84%); white crystals; mp 91–92 °C (dec.).
1H NMR (200 MHz, DMSO-d6): d = 2.01–2.14 (m, 2 H), 2.73 (dd,
J = 9.7, 9.9 Hz, 1 H), 3.14–3.22 (m, 2 H), 7.22 (s, 1 H, NH), 8.14 (s,
1 H, OH), 8.45 (s, 1 H, OH).
13C NMR (50 MHz, DMSO-d6): d = 22.51, 39.54, 93.11 [q, J = 31.3
Hz, C(OH)2], 122.95 (q, J = 288.2 Hz, CF3), 177.53 (CONH).
19F NMR (188 MHz, DMSO-d6): d = –83.87.
HRMS (EI): m/z calcd for C6H6F3NO2 (M – H2O): 181.0351; found:
181.0351.
HRMS (EI): m/z calcd for C7H8F3NO2: 195.0507; found: 195.0510.
(3Z)-3-(2,2,3,3,3-Pentafluoro-1-hydroxypropylidene)piperidin-
2-one (2d)
Yield: 38.7 g (79%); white crystals; mp 117–118 °C.
1H NMR (200 MHz, DMSO-d6): d = 1.63–1.75 (m, 2 H), 2.43–2.49
(m, 2 H), 3.15–3.22 (m, 2 H), 3.52 (br s, 1 H, OH), 8.80 (br s, 1 H,
NH).
13C NMR (50 MHz, DMSO-d6): d = 20.97, 21.18, 40.14, 101.61,
109.84 (tq, J = 257.3, 38.3 Hz, CF2CF3), 118.39 (qt, J = 287.3, 36.6
Hz, CF2CF3), 154.93 [t, J = 24.2 Hz, C(OH)C2F5], 170.87 (CONH).
3-(2,2,3,3,3-Pentafluoro-1,1-dihydroxypropyl)pyrrolidin-2-one
(1b)
Yield: 41.8 g (81%); white crystals; mp 82–84 °C (dec.).
1H NMR (200 MHz, DMSO-d6): d = 2.04–2.13 (m, 2 H), 2.81 (dd,
J = 9.8, 9.3 Hz, 1 H), 3.16–3.23 (m, 2 H), 7.19 (s, 1 H, NH), 8.39 (s,
1 H, OH), 8.51 (s, 1 H, OH).
13C NMR (50 MHz, DMSO-d6): d = 22.71, 39.85, 42.43, 94.15 [t,
J = 25.4 Hz, C(OH)2], 111.20 (tq, J = 260.7, 34.1 Hz, CF2CF3),
118.39 (qt, J = 287.7, 36.0 Hz, CF2CF3), 177.27 (CONH).
19F NMR (188 MHz, DMSO-d6): d = –116.64 (2 F, CF2CF3), –83.10
(3 F, CF2CF3).
19F NMR (188 MHz, DMSO-d6): d = –127.89, –126.43, –123.60,
–122.14 (2 F, AB system, JAB = 275.9 Hz, CF2), –78.70 (3 F, CF3).
Synthesis 2010, No. 1, 120–126 © Thieme Stuttgart · New York

124
N. E. Shevchenko et al.
PAPER
HRMS (EI): m/z calcd for C8H8F5NO2: 245.0479; found: 245.0475.
to the receiving flask charged with anhyd Na2SO4 (20 g). The drying
agent was removed by filtration to afford the imine as a clear, col-
orless liquid with characteristic odor.
3-(Trifluoroacetyl)azepan-2-one (2e)
Yield: 29.7 g (71%); white crystals; mp 78–80 °C.
Method B (Without Isolation of Acyllactams): To a stirred and heat-
ed at reflux suspension of NaH (60% in mineral oil, 10.4 g, 0.26
mol) in anhyd THF (300 mL) was added a mixture of the N-protect-
ed lactam [0.20 mol, N-vinylpyrrolidin-2-one (22 g), N-(di-
ethoxymethyl)piperidin-2-one (40 g) or N-vinylcaprolactam (28 g)]
and the ester of the corresponding perfluorocarbonic acid [0.21 mol,
ethyl trifluoroacetate (30 g) or ethyl pentafluoropropionate (40 g)]
at such rate that the evolution of H2 and boiling of the mixture was
not very intensive. After heating for an additional hour, the reaction
mixture was cooled to r.t. and the resultant clear solution was care-
fully diluted with a mixture of H2O (50 mL) and AcOH (15.6 g).
The layers were separated and the aqueous layer was extracted with
THF (100 mL). The combined organic extracts (solution of the
crude N-protected ketolactam in THF) was slowly added (over 1 h)
to aq 6 M HCl (400 mL) under stirring and heating at reflux. THF
was collected during the addition using a short-path distilling head.
After heating for an additional 60 h, the mixture was cooled to r.t.,
and the product was isolated as described above in Method A.
1H NMR (200 MHz, CDCl3): d = 1.43–1.61 (m, 2 H), 1.80–1.94 (m,
2 H), 2.08–2.16 (m, 2 H), 3.22–3.38 (m, 2 H), 3.95 (d, J = 11.3 Hz,
1 H), 6.57 (br s, 1 H, NH).
13C NMR (50 MHz, CDCl3): d = 21.55, 21.66, 41.43, 99.85, 119.75
(q, J = 277.4 Hz, CF3), 171.64 (CONH), 190.7 [q, J = 34.4 Hz,
C(O)CF3].
19F NMR (188 MHz, CDCl3): d = –78.13.
HRMS (EI): m/z calcd for C8H10F3NO2: 209.0662; found:
209.0664.
3-(2,2,3,3,3-Pentafluoropropanoyl)azepan-2-one (2f)
Yield: 34.7 g (67%); white crystals; mp 75–77 °C.
1H NMR (200 MHz, CDCl3): d = 1.40–1.57 (m, 2 H), 1.75–1.87 (m,
2 H), 2.01–2.15 (m, 2 H), 3.22–3.32 (m, 2 H), 3.97 (d, J = 10.7 Hz,
1 H), 7.18 (br s, 1 H, NH).
13C NMR (50 MHz, CDCl3): d = 24.32, 28.68, 28.79, 42.52, 53.27,
106.60 (tq, J = 265.7, 61.8 Hz, CF2CF3), 117.93 (qt, J = 286.8, 64.7
Hz, CF2CF3), 173.93 (CONH), 191.20 [dd, J = 25.4, 29.7 Hz,
C(O)C2F5].
19F NMR (188 MHz, CDCl3): d = –125.67, –124.15, –122.52,
–121.00 (2 F, AB system, JAB = 287.9 Hz, CF2), –82.22 (3 F,
CF2CF3).
2-(Pentafluoroethyl)pyrrolidin-2-ol (4b)
Yield: 82% (Method A); colorless crystals; mp 52–54 °C (dec.).
1H NMR (200 MHz, CDCl3): d = 1.88–2.16 (m, 4 H), 2.67 (br s, 2
H, NH and OH), 3.09–3.16 (m, 2 H).
19F NMR (188 MHz, CDCl3): d = –128.55, –127.11, –123.77,
–122.34 (2 F, AB system, JAB = 269.0 Hz, CF2), –79.78 (3 F, CF3).
HRMS (EI): m/z calcd for C9H10F5NO2: 259.0643; found:
259.0632.
HRMS (EI): m/z calcd for C6H6F5N (M – H2O): 187.0420; found:
187.0420.
6-Amino-1,1,1,2,2-pentafluorohexane-3,3-diol Hydrochloride
(3b)
2-(Trifluoromethyl)piperidin-2-ol (4c)
Yield: 89% (Method A); colorless crystals; mp 91–92 °C (dec.).
1H NMR (200 MHz, DMSO-d6): d = 1.39–1.66 (m, 6 H), 1.67 (br s,
1 H, NH or OH), 2.67–3.13 (m, 2 H), 5.80 (br s, 1 H, NH or OH).
13C NMR (50 MHz, DMSO-d6): d = 18.64, 24.36, 28.49, 39.16,
81.37 [t, J = 28.5 Hz, C(OH)NH], 125.16 (q, J = 286.1 Hz, CF3).
19F NMR (188 MHz, DMSO-d6): d = –78.65.
The gem-diol 1b (2.5 g, 10 mmol) was dissolved under heating in
aq 6 M HCl (50 mL) and the clear solution was heated at reflux for
60 h. After cooling, the solvent was carefully removed in vacuo at
r.t. and the residue was triturated with cold hexane, filtered, and
dried in vacuo to give the hydrochloride 3b as a brownish solid;
yield: 1.9 g (87%); mp 127–129 °C (H2O).
1H NMR (200 MHz, D2O): d = 1.85–1.94 (m, 4 H), 3.03 (t, J = 6.0
Hz, 2 H), 3.16–3.23 (m, 2 H), 4.75 (br s, 3 H, NH3), 8.55 (br s, 2 H,
OH).
Anal. Calcd for C6H13ClF3NO2: C, 42.6; H, 6.0. Found: C, 42.1; H,
6.1.
13C NMR (50 MHz, D2O): d = 19.91, 31.64, 39.65, 94.60 [t, J = 25.4
Hz, C(OH)2], 112.90 (tq, J = 262.8, 33.9 Hz, CF2CF3), 119.18 (qt,
J = 286.9, 35.3 Hz, CF2CF3).
19F NMR (188 MHz, D2O): d = –127.34 (2 F, CF2), –79.84 (3 F,
CF3).
2-(Pentafluoroethyl)piperidin-2-ol (4d)
Yield: 83% (Method A); colorless crystals; mp 59–61 °C (dec.).
1H NMR (200 MHz, CDCl3): d = 1.53–1.75 (m, 6 H), 2.04 (br s, 1
H, NH or OH), 2.58 (br s, 1 H, NH or OH), 2.86–3.13 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 18.79, 24.55, 29.04, 39.85, 82.36
[t, J = 29.7 Hz, C(OH)NH], 110.24 (tq, J = 258.1, 35.6 Hz,
CF2CF3), 118.12 (qt, J = 287.4, 36.2 Hz, CF2CF3).
Anal. Calcd for C6H13ClF5NO2·H2O: C, 26.0; H, 4.7. Found: C,
26.4; H, 4.8.
19F NMR (188 MHz, CDCl3): d = –128.65, –127.21, –123.87,
–122.44 (2 F, AB system, JAB = 269.0 Hz, CF2), –80.88 (3 F, CF3).
Trifluoromethyl- and Pentafluoroethylimines 5a–e and Hemi-
aminals 4a–c; General Procedure
Method A (Stepwise): The cyclic acyllactams 2a–e (0.10 mol) or
gem-diols 1a–c (0.10 mol) were dissolved under heating in aq 6 M
HCl (200 mL) and the clear solutions were heated at reflux for 60 h.
After that, the reaction mixture was cooled to r.t., filtered through a
Celite plug, extracted with cold pentane (2 × 100 mL), carefully
made alkaline with aq 50% KOH to pH 12–13 under cooling (ice-
bath) and then extracted with Et2O (4 × 75 mL). The combined or-
ganic layers were dried (K2CO3) and concentrated under atmospher-
ic pressure to give a liquid residue consisting of a mixture of crude
cyclic hemiaminal and the corresponding imine. The hemiaminal
products usually are unstable at r.t., but in several cases (4b, c, and
d) they can be isolated in pure form as a solid. To remove the H2O,
the crude cyclic hemiaminals were distilled at atmospheric pressure
HRMS (EI): m/z calcd for C7H8F5N (M – H2O): 201.0571; found:
201.0579.
5-(Trifluoromethyl)-3,4-dihydro-2H-pyrrole (5a)
Yield: 83% (Method A); colorless liquid; bp 78–81 °C/760 Torr.
1H NMR (200 MHz, CDCl3): d = 2.01–2.12 (m, 2 H), 2.70–2.78 (m,
2 H), 3.98–4.08 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 22.60, 33.67, 62.19, 120.15 (q,
J = 274.5 Hz, CF3), 165.17 (q, J = 35.4 Hz, C=N).
19F NMR (188 MHz, CDCl3): d = –71.14.
HRMS (EI): m/z calcd for C5H6F3N: 137.0452; found: 137.0456.
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PAPER
Synthesis of a-Perfluoroalkyl Cyclic Imines and Amines
125
5-(Pentafluoroethyl)-3,4-dihydro-2H-pyrrole (5b)
Yield: 79% (Method A); colorless liquid; bp 99–102 °C/760 Torr.
1H NMR (200 MHz, CDCl3): d = 1.94–2.10 (m, 2 H), 2.72–2.80 (m,
2 H), 4.03–4.14 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 21.81, 34.01, 62.42, 110.78 (tq,
J = 252.6, 38.4 Hz, CF2CF3), 118.91 (qt, J = 286.2, 35.7 Hz,
CF2CF3), 165.90 (t, J = 27.4 Hz, C=N).
19F NMR (188 MHz, CDCl3): d = –118.15 (2 F, CF2), –83.43 (3 F,
CF3).
ic extracts were dried (K2CO3). Evaporation of the solvent under at-
mospheric pressure followed by distillation of the residue gave the
target amine as a colorless liquid.
Method C: To neat 5a or 5b (0.2 mol) was added 10% Pd/C (500
mg) and H2 was purged through the reaction mixture with simulta-
neous stirring for 15 h at r.t. The mixture was thoroughly filtered
through a Celite plug to afford the corresponding amines in almost
quantitative yields as a colorless liquid.
2-(Trifluoromethyl)pyrrolidine (6a)
Prepared by Method A (67%), Method B (42%), and Method C
(99%); colorless liquid; bp 89–90 °C/760 Torr.
HRMS (EI): m/z calcd for C6H6F5N: 187.0420; found: 187.0416.
1H and 19F NMR data were identical with the reported data.17
13C NMR (50 MHz, CDCl3): d = 25.53, 25.76, 47.07, 58.54 [q,
J = 29.7 Hz, C(CF3)NH], 126.90 (q, J = 279.8 Hz, CF3).
6-(Trifluoromethyl)-2,3,4,5-tetrahydropyridine (5c)
Yield: 86% (Method A); colorless liquid; bp 100–103 °C/760 Torr.
1H NMR (200 MHz, CDCl3): d = 1.55–1.79 (m, 4 H), 2.23–2.31 (m,
2 H), 3.71–3.77 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 18.47, 21.48, 23.95, 49.61, 120.05
(q, J = 278.4 Hz, CF3), 159.21 (q, J = 32.5 Hz, C=N).
19F NMR (188 MHz, CDCl3): d = –75.64.
2-(Pentafluoroethyl)pyrrolidine (6b)
Prepared by Method A (73%), Method B (40%), and Method C
(94%); colorless liquid; bp 109–111 °C/760 Torr.
1H NMR (200 MHz, CDCl3): d = 1.69–2.03 [m, 5 H, incl. 1.94 (br
s, 1 H, NH)], 2.96–3.02 (m, 2 H), 3.57–3.75 (m, 1 H).
HRMS (EI): m/z calcd for C6H8F3N: 151.0609; found: 151.0610.
13C NMR (50 MHz, CDCl3): d = 25.33, 25.61, 47.10, 57.15 [dd,
J = 24.0, 21.2 Hz, C(C2F5)NH], 109.57–127.91 (m, 2 C, CF2CF3).
6-(Pentafluoroethyl)-2,3,4,5-tetrahydropyridine (5d)
Yield: 79% (Method A); colorless liquid; bp 125–128 °C/760 Torr.
19F NMR (188 MHz, CDCl3): d = –128.23, –128.15, –126.80,
–126.72, –125.67, –125.61, –124.24, –124.18 (2 F, AB part of ABX
system, JAB = 268.9 Hz, JAX = 12.1 Hz, JBX = 15.5 Hz, CF2), –82.87
(3 F, CF3).
1H NMR (200 MHz, CDCl3): d = 1.62–1.68 (m, 2 H), 1.73–1.80 (m,
2 H), 2.30–2.33 (m, 2 H), 3.78–3.83 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 18.23, 21.08, 24.06, 49.69, 110.64
(tq, J = 255.1, 36.6 Hz, CF2CF3), 119.12 (qt, J = 286.4, 36.4 Hz,
CF2CF3), 159.75 (t, J = 25.9 Hz, C=N).
HRMS (EI): m/z calcd for C6H7F5N: 188.0500; found: 188.0492.
19F NMR (188 MHz, CDCl3): d = –120.51 (2 F, CF2), –82.68 (3 F,
CF3).
2-(Trifluoromethyl)piperidine (6c)
Yield: 71% (Method A); colorless liquid; bp 118–120 °C/760 Torr.
HRMS (EI): m/z calcd for C7H8F5N: 201.0571; found: 201.0579.
1H and 19F NMR data were identical with the reported data.18
13C NMR (50 MHz, CDCl3): d = 23.09, 24.88, 25.42, 45.94, 57.96
[q, J = 28.2 Hz, C(CF3)NH], 125.78 (q, J = 279.8 Hz, CF3).
7-(Trifluoromethyl)-3,4,5,6-tetrahydro-2H-azepine (5e)
Yield: 21% (Method A); colorless liquid; bp 148–151 °C/760 Torr.
1H NMR (200 MHz, CDCl3): d = 1.44–1.62 (m, 4 H), 1.77–1.85 (m,
2-(Pentafluoroethyl)piperidine (6d)
Yield: 75% (Method A); colorless liquid; bp 136–138 °C/760 Torr.
1H NMR: d = 1.34–1.62 [m, 5 H, incl. 1.38 (br s, 1 H, NH)], 1.80–
1.92 (m, 2 H), 2.56–2.69 (m, 1 H), 3.07–3.23 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 23.57, 24.69, 25.87, 46.45, 57.07
[dd, J = 22.6, 21.2 Hz, C(C2F5)NH], 109.15–127.79 (m, 2 C,
CF2CF3).
2 H), 2.48–2.54 (m, 2 H), 3.74–3.78 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 23.04, 25.14, 28.40, 31.12, 52.26,
120.23 (q, J = 278.4 Hz, CF3), 163.64 (q, J = 32.5 Hz, C=N).
19F NMR (188 MHz, CDCl3): d = –76.08.
HRMS (EI): m/z calcd for C7H10F3N: 165.0765; found: 165.0760.
Reduction of Imines 5 to 6
19F NMR (188 MHz, CDCl3): d = –128.01, –127.93, –126.54,
–126.48, –125.53, –125.47, –124.07, –124.01 (2 F, AB part of
ABX system, JAB = 274.1 Hz, JAX = 12.1 Hz, JBX = 13.8 Hz, CF2),
–81.97 (3 F, CF3).
Method A: To a solution of imine 5 (50 mmol) in MeOH (100 mL)
was added AcOH (12 mL) dropwise at 0 °C. The reaction mixture
was cooled to –20 °C and kept at this temperature while NaBH4 (4
g, 0.1 mol) was added portionwise over a period of 1 h. After stir-
ring at r.t. for 12 h, the mixture was quenched with aq 6 M HCl (15
mL). The solvent was evaporated under reduced pressure and the
residue was dissolved in H2O (50 mL), made alkaline with aq am-
monia (10 mL) and extracted with Et2O (3 × 20 mL). The combined
organic extracts were dried (K2CO3), concentrated under atmo-
spheric pressure, and the residue was distilled to yield the desired
amine as a colorless liquid.
HRMS (EI): m/z calcd for C7H10F5N: 203.0733; found: 203.0730.
2-(Trifluoromethyl)azepane (6e)
Prepared by Method A and was isolated as the hydrochloride; yield:
82%; white solid; mp 163–164 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.61–2.20 (m, 8 H), 3.32–3.36
and 3.51–3.54 (m, 2 H, CH2N), 3.92–3.96 [m, 1 H, CH(CF3)N],
+
10.35 (br s, 1 H, NH2 ).
Method B: To a stirred suspension of Zn powder (13 g, 0.2 mol) in
AcOH (50 mL) with an additive ZnCl2 (0.5 g) as an activator was
added a solution of cyclic imine 5 (70 mmol) in AcOH (20 mL)
dropwise at such a rate that the temperature of the reaction mixture
did not exceed 40 °C. After stirring for 12 h, the mixture was fil-
tered, quenched with aq 6 M HCl (15 mL) and the solvents were re-
moved in vacuo. The residue was made alkaline with aq ammonia
(50 mL), extracted with Et2O (3 × 20 mL), and the combined organ-
13C NMR (50 MHz, DMSO-d6): d = 24.15, 24.81, 25.19, 27.32,
46.13, 57.95 [q, J = 30.7 Hz, C(CF3)NH], 123.70 (q, J = 281.7 Hz,
CF3).
19F NMR (188 MHz, DMSO-d6): d = –77.80 (d, J = 8.7 Hz), 2.65
(m, 1 H), 2.99–3.13 (m, 2 H).
Anal. Calcd for C7H13ClF3N: C, 41.3; H, 6.4. Found: C, 41.4; H, 6.5.
Synthesis 2010, No. 1, 120–126 © Thieme Stuttgart · New York

126
N. E. Shevchenko et al.
PAPER
(7) (a) Nenajdenko, V. G.; Zakurdaev, E. P.; Prusov, E. V.;
Acknowledgment
Balenkova, E. S. Tetrahedron 2004, 60, 11719. (b) Sorgi,
K. L.; Maryanoff, C. A.; McComsey, D. F.; Maryanoff, B. E.
Org. Synth. 1998, 75, 215.
The authors thank the Deutsche Forschungsgemeinschaft (436 RUS
113/812/0-1) and Grant P1471 Federal Special Program for finan-
cial support of this work.
(8) (a) Feringa, B. L.; Jansen, F. G. A. Tetrahedron Lett. 1986,
27, 507. (b) Koldobskij, A. B.; Vakhmistrov, V. E.;
Solodova, E. V.; Sholova, O. S.; Kalinin, V. N. Dokl. Acad.
Nauk 2002, 387, 61; Dokl. Chem. (Engl. Transl.) 2002, 387,
289.
(9) Shevchenko, N. E.; Nenajdenko, V. G.; Röschenthaler, G.-
V. J. Fluorine Chem. 2008, 129, 390.
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Synthesis 2010, No. 1, 120–126 © Thieme Stuttgart · New York