The reaction of cyclic imines with the Ruppert-Prakash reagent. Facile approach to α-trifluoromethylated nornicotine, anabazine, and homoanabazine

Article abstract of DOI:10.1016/j.tet.2010.11.032

We have demonstrated that the Ruppert-Prakash reagent is able to react with a number of cyclic imines under acidic condition to afford the corresponding α-trifluoromethyl derivatives of nitrogen heterocycles. 5-7-Membered cyclic imines bearing various alkyl, aryl or heterocyclic group were successfully involved in this transformation. Novel trifluoromethylated analogues of nicotine, anabasine, and homoanabasine alkaloids were synthesized.

Full text of DOI:10.1016/j.tet.2010.11.032

Tetrahedron 67 (2011) 69e74
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journal homepage: www.elsevier.com/locate/tet
The reaction of cyclic imines with the RuppertePrakash reagent.
Facile approach to
homoanabazine
a-trifluoromethylated nornicotine, anabazine, and
,
b,
*
Nikolay E. Shevchenko a, Katja Vlasov b, Valentine G. Nenajdenko a , Gerd-Volker Roschenthaler
*
€
a Department of Chemistry, Lomonosov Moscow State University, Moscow 119992, Russia
b School of Engineering and Science, Jacobs University Bremen gGmbH, Campus Ring 1, 28759 Bremen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 August 2010
Received in revised form 18 October 2010
Accepted 8 November 2010
Available online 13 November 2010
We have demonstrated that the RuppertePrakash reagent is able to react with a number of cyclic imines
under acidic condition to afford the corresponding -trifluoromethyl derivatives of nitrogen heterocycles.
5e7-Membered cyclic imines bearing various alkyl, aryl or heterocyclic group were successfully involved
in this transformation. Novel trifluoromethylated analogues of nicotine, anabasine, and homoanabasine
alkaloids were synthesized.
a
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
RuppertePrakash reagent
Nucleophilic trifluoromethylation
Cyclic imines
a
-trifluoromethylated alkaloids
1. Introduction
fluorinated analogues.7 In this paper, we have focused our interest
on direct trifluoromethylation of 5e7-membered cyclic imines. This
Piperidine and pyrrolidine moieties are common to many nat-
urally occurring and synthetic alkaloids, medications, and potent
drug candidates.1 The combination of these saturated heterocycles
with the pyridine ring gives rise to the well-known tobacco alka-
loids, such as nicotine, nornicotine, and anabasine. In the last two
decades much attention has been paid to the synthesis of novel
analogues of nicotine and anabasine and toward study of their bi-
ological activities.2 The goal of these investigations is to develop
drugs that have medical benefit for the effective treatment of
central nervous system (CNS) disorders without the unfavorable
side-effects of nicotine and anabasine.3 Many of these natural al-
kaloid analogues possess remarkable potential as therapeutic
agents for CNS neurodegenerative disorder due to their affinity to
neuronal acetylcholine receptors (nAChRs). In particular, they have
beneficial effects in the treatment of Alzheimer’s and Parkinson’s
disease, schizophrenia, Tourette’s syndrome, etc.4 (for example, the
anti-Parkinson’s drug SIB-1508Y5).
transformation can open an easy access to derivatives of
a-Tfm
pyrrolidines, -Tfm piperidines, and -Tfm azepanes, which are not
a
a
only valuable fluorinated building blocks that can be converted into
other nitrogen Tfm-containing heterocycles, but also are potential
bioactive substrates. Particularly, this approach gives a great op-
portunity to synthesize a-Tfm substituted nornicotine, anabazine,
and homoanabasine in one-step starting from the appropriate
cyclic imines with the pyridine moiety.
2. Results and discussion
According to available literature, cyclic imines can be synthe-
sized by several approaches.8 Our experience in this area has
demonstrated that the most convenient are the following two
methods: (a) Claisen condensation of N-protected cyclic amides
with esters followed by simultaneous deprotection and de-
carboxylation in acidic media; (b) reaction of N-protected amides
with readily available organolithium reagents followed by depro-
tection (Scheme 1).9 These approaches utilize cheap and easily
available starting compounds and allow the preparation of a broad
variety of 2-substituted cyclic imines. This is very promising from
a synthetic point of view.10 To investigate the possibility of direct
trifluoromethylation of cyclic imines, many 2-substituted
The synthesis of nicotine and anabasine derivatives bearing an
a
-trifluoromethyl (a-Tfm) group at the pyrroline or piperidine rings
has not yet been described so far,6 despite the possible interest in
* Corresponding authors. E-mail addresses: nen@acylium.chem.msu.ru (V.G.
€
Nenajdenko), g.roeschenthaler@jacobs-university.de (G.-V. Roschenthaler).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.032

70
N.E. Shevchenko et al. / Tetrahedron 67 (2011) 69e74
(CH2)n
(CH2)n
(CH2)n
1) RCO2Alk / NaH
1) RLi
O
O
N
PG
N
PG
R
N
2) HCl / H2O, reflux
2) HCl / H2O
47-98%
1a-q
2a-e
3a-e
(n = 1);
(n = 2);
(n = 3)
PG = vinyl, (EtO)2CH, TMS
R = Alk, Ar,Het
Scheme 1. Synthesis of cyclic imines.
pyrrolines 1aeq and their six- and seven-membered homologs
2aee and 3aee were synthesized (Scheme 1).
Table 1
Synthesis of 2-trifluoromethyl pyrrolidines with the RuppertePrakash reagent
Among the currently available reagents for nucleophilic tri-
fluoromethylation we have chosen TMSCF3, known as the Rup-
pertePrakash reagent, as the most efficient, general and widely
used.11 Under standard Ruppert’s reaction conditions, only acti-
vated imines, such as azirines,12 imines of perfluorinated ketones,13
N-sulfonylated aldimines,14 and nitrones15 react with TMSCF3. To
involve non-activated imines into this transformation several im-
provements have been reported. Namely, using up to one equi-
molar amount of highly lipophilic tetraalkylammonium fluoride,16
initial generation of an iminium boron complex,17 using highly
basic phosphines as initiators,18 addition of TMS-imidazole,19 and
carrying out the reaction under acidic conditions with KHF2 as
initiator.20 Only the last two approaches are applicable for non-
activated ketiminesdthe class of imines to which the 2-substituted
cyclic imines 1e3 belong.
Entry
Imine
Product
R
Yield (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
CH3e
n-C4H9e
cyclo-C6H11e
tert-C4H9e
1-Adamantyl
CH3SCH2e
4-CH3C6H4e
3,4-(CH3)2C6H3e
3,5-(CH3)2C6H3e
4-BrC6H4e
49
57
68
71
79
75
48
62
65
61
53
49
64
71
52
60
68
9
10
11
12
13
14
15
16
17
4-FC6H4e
4-CH3OC6H4e
3-CF3C6H4e
2-Thienyle
5-CH3e2-thienyl
2-Furyle
3-Pyridyle
We have chosen 2-methylpyrroline 1a as a model substrate and
examined its reaction with TMSCF3 in the presence of TMS-imid-
azole or with KHF2 as initiator. According to the 19F NMR data,
treatment of the imine 1a with TMSCF3, cesium fluoride, and TMS-
peptides due to the ability of proline to determine the conformation
of the peptide backbone.22
imidazole in THF did not lead to the desired
a-Tfm pyrrolidine,
Trifluoromethylation of the pyridine imine 1q leads selectively
despite the authors19 having reported the synthesis of Tfm amines
from acyclic imines under these conditions.
to target
a-Tfm-nornicotine 4q in 68% isolated yield. Earlier we
have shown that pentafluoroethylation of analogous imine 2-(4-
pyridine)pyrroline with C2F5Li was directed to the pyridine ring to
form the dihydropyridine derivative, and therefore cannot be ap-
plied for preparation of perfluoroalkyl derivatives of nicotine.21
To investigate the scope and limitation of the reaction several
tetrahydropyridines 2aee and dehydroazepanes 3aee were also
tested. Six- and seven-membered cyclic imines 2aee and 3aee
react with the TMSCF3 similarly to afford the 2-trifluoromethyl
substituted piperidines 5aee and azepanes 6aee in moderate to
It was rewarding to find that pyrroline 1a reacted with TMSCF3 in
the presence of an equimolar amount of trifluoroacetic acid and po-
tassium hydrofluoride in acetonitrile, giving rise to the 2-Tfm-2-
methylpyrrolidine 4a in 37% yield. It was also found that using DMF as
co-solvent not only accelerates the reaction, but increases the yield of
4a up to 49%. Under these conditions a variety of pyrrolines 1aeq were
introduced into the reaction to afford products of trifluoromethylation
4aeq in moderate to good yields (Scheme 2, Table 1).
good yields (Scheme 3, Table 2). In such way, the target
a-Tfm
CF3
anabasine 5e and -Tfm homoanabasine 6e were synthesized in
a
CF3TMS / KHF2 / TFA
67% and 56% isolated yield, respectively. It is also notable that the
reaction is general and the five-, six- and seven-membered cyclic
imines give similar results.
R
R
N
1a-q
MeCN / DMF
Table 1
N
H
R = Alk, Ar, Het (
)
4a-q
Scheme 2. Reaction of PuppertePrakash reagent with pyrrolines.
(CH2)n
CF3TMS / KHF2 / TFA
MeCN / DMF
(CH2)n
R
CF3
N
H
N
R
It is worthy to note that all pyrrolines studied give very similar
yields of the reaction products regardless of the nature of the
substituent at the pyrroline ring. The presence of a bulky tert-butyl
1d and adamantyl 1e group, the electron withdrawing pyridine ring
1q or electron releasing thienyl substituent 1n did not lead to re-
duced yield of the trifluoromethylated products. Moreover, this
approach was found to be applicable for acid sensitive furyl imine
1p giving rise to 2-furyl-2-Tfm-pyrrolidine 4p. The imine 4p can be
Table 2
R = Alk, Ar, Het (
2a-e (n = 1)
)
5a-e (n = 1)
3a-e (n = 2)
6a-e (n = 2)
Scheme 3. Reaction of the RuppertePrakash reagent with six- and seven-membered
cyclic imines.
Our interest in further investigations of cyclic imines toward the
reaction with the RuppertePrakash reagent led us to study
unsubstituted pyrroline and tetrahydropyridine, which are useful
building blocks for a large variety of biologically important organic
molecules.23 These highly reactive imines oligomerize easily form
mainly trimers 7a,b, which are not active under the basic condi-
tions usually required for the RuppertePrakash reaction. Carrying
conveniently transformed to a-Tfm-proline by oxidative cleavage of
the furyl group to the carboxylic moiety. Earlier we have performed
such oxidations with RuCl3/NaIO4 or ozone for the synthesis of
2-pentafluoroethyl-2-furyl pyrroline.21
a
-Tfm-proline is a pro-
spective candidate for synthetic modification of biologically active

N.E. Shevchenko et al. / Tetrahedron 67 (2011) 69e74
71
piperidin-2-one.25 Trimers of unsubstituted 3,4-dihydro-2H-pyrrole
(pyrroline) 7a and 2,3,4,5-tetrahydropyridine 7b were prepared
according to the procedure of Claxton et al.,26 starting from the N-
chloropyrrolidine and N-chloropiperidine, respectively, which were
synthesized from piperidine and pyrrolidine by chlorination with N-
chlorosuccinimide.27
Table 2
Synthesis of 2-trifluoromethyl piperidines and azepanes with the RuppertePrakash
reagent
Entry
Imine
Product
R
Yield (%)
1
2
3
4
5
6
7
8
9
10
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
5a
5b
5c
5d
5e
6a
6b
6c
6d
6e
tert-C4H9e
cyclo-C6H11e
C6H5e
56
53
49
65
67
56
71
44
56
56
2-Furyle
4.2. General procedure for the reaction of cyclic imines with
trifluoromethyltrimethylsilane
3-Pyridinyle
tert-C4H9e
4-CH3Bne
C6H5e
2-Furyle
3-Pyridinyle
Keeping the temperature at about 0 ꢀC, trifluoroacetic acid
(0.95 mL, 12.5 mmol), KHF2 (585 mg, 7.5 mmol), and tri-
fluoromethyltrimethylsilane (1.9 mL, 12.5 mmol) were successively
added to a solution of the corresponding imine 1, 2 or 3 (10 mmol)
in dry acetonitrile (50 mL). After stirring for 12 h at rt, the solvent
was gently evaporated under reduced pressure, the residue was
quenched with saturated aqueous NaHCO3 (50 mL) and extracted
with ether (3ꢁ10 mL). The combined extract was dried over
Na2SO4, the solvent was evaporated at reduced pressure and the
residue was purified by column chromatography on silica gel
eluting with a 20/1 mixture of hexane/ethyl acetate. This afforded
the tagged amine. In the case of volatile amines 4a, 4d, 5a, 6a, 8a,
and 8b the combined extract was mixed with hydrochloric acid
(1.5 mL), evaporated to dryness, and the residue was washed with
pentane. In this way the amines 4a, 4d, 5a, 6a were isolated as
hydrochloride. For comparison to the reported data, the hydro-
chloride of 2-Tfm-pyrrolidine 8a and 2-Tfm-piperidine 8b were
again treated with aqueous NaHCO3 and were analyzed as free
bases.
out such a reaction with KHF2/TFA gave us the opportunity to
synthesize 2-trifluoromethyl substituted pyrroline 8a and piperi-
dine 8b (Scheme 4).
(CH2)n
N
(CH2)n
CF3TMS / KHF2 / TFA
n(H2C)
N
N
CF3
N
H
n = 1,
MeCN / DMF
(CH2)n
8a
(47%)
n = 2, 8b (55%)
7a, b
Scheme 4. Reaction of the unsubstituted cyclic imines with RuppertePrakash reagent.
3. Conclusion
4.2.1. 2-Methyl-2-(trifluoromethyl)pyrrolidine hydrochloride (4a).
Colorless crystals (49%), mp 117e118 ꢀC; nmax (Nujol) 1157, 2897,
Thus we have found that the RuppertePrakash reagent is able to
react with a number of cyclic imines under acidic conditions to
3431 cmꢂ1
; d 1.75 (3H, s, CH3),
1H NMR (400 MHz, CDCl3):
afford the corresponding
a-trifluoromethylated nitrogen hetero-
1.93e2.01 (1H, m), 2.13e2.19 (1H, m), 2.34e2.39 (2H, m), 3.54e3.56
cycles. Cyclic imines bearing various alkyl, aryl or heterocyclic
groups can be successfully involved in these transformations. Novel
trifluoromethylated analogues of nicotine, anabasine, and homo-
anabasine alkaloids as well as simplest a-trifluoromethyl piperi-
dine and pyrrolidine alkaloids have been synthesized.
(2H, m), 10.43 and 10.78 (2H, br s, H2Nþ). 13C NMR (100 MHz,
2
CDCl3):
d
19.1, 23.2, 33.1, 46.8, 67.5 (q, JCF¼29.7 Hz, CeCF3), 124.9
(q, JCF¼282.8 Hz, CF3). 19F NMR (376 MHz, CDCl3):
d
ꢂ76.9 (CF3).
1
ESIMS m/z (rel int.): 154 [MþH]þ (100). HRMS (ESI): calcd for
C6H11F3N (MþH) 154.0838, found 154.0840.
4. Experimental
4.2.2. 2-Butyl-2-(trifluoromethyl)-pyrrolidine (4b). Colorless liquid
(57%); nmax (Nujol) 1144, 3444 cmꢂ1 1H NMR (400 MHz, CDCl3):
;
4.1. General information
d
0.91 (3H, t, J¼5.5 Hz, CH3), 1.28e1.35 (4H, m), 1.5e1.64 (3H, m),
1.68e1.76 (2H, m, incl. 1.74 (br s, NH)), 1.85e1.87 (1H, m), 1.97e2.02
NMR spectra were obtained on a Jeol ECX-400 (399.8 MHz for 1H;
376.2 MHzfor19F;100.5 MHzfor13C)oraBrukerAM-360(360.1 MHz
for 1H; 90.5 MHz for 13C) spectrometers, chemical shifts for 1H NMR
data are referenced internally to tetramethylsilane (0.0); chemical
shifts for 13C NMR data are referenced to corresponding CDCl3 (77.2);
chemical shifts for 19F NMR data are referenced to CFCl3 (0.0). High
resolution mass spectra (HRMS) were recorded using a Bruker Dal-
tonics (MicroTOF-Q). Electrospray ionization (ESI) mass spectra (MS)
were obtained from methanol solution. Melting points are un-
corrected. TLC was carried out on precoated silica plates (Merck
60F254) with UV light visualization. Flash chromatography was per-
formed using MP Silica 60 (320e630 mesh) with the indicated sol-
vents. All reactions were conducted in flame-dried or oven dried
glassware under a nitrogen atmosphere. Acetonitrile was distilled
from CaH2 prior to use. All reagents were purchased from Aldrich
unlessotherwisestated. The startingimines 1aej,1q, 2aec, 2e, 3a, 3c,
and 3ewere prepared by the reaction of ethyl esterof the appropriate
carboxylic acids with N-vinylpyrrolidin-2-one, N-vinylcaprolactam
or N-(diethoxymethyl)piperidin-2-one according to the described
procedure.9b,24 Cyclic imines 1kep, 2d, 3b, and 3d were obtained by
the reaction of corresponding lithium compounds with N-vinyl-
pyrrolidin-2-one, 1-(trimethylsilyl)caprolactam or 1-(trimethylsilyl)
(1H, m), 2.94e3.05 (2H, m, CH2eN). 13C NMR (100 MHz, CDCl3):
d
13.9 (CH3), 23.2, 25.6, 26.4, 31.2, 35.0, 47.7 (CH2eNH), 66.8 (q,
JCF¼24.9 Hz, CeCF3),128.6 (q, JCF¼283.7 Hz, CF3).19F NMR (376 MHz,
CDCl3):
d
ꢂ78.4 (CF3). ESIMS m/z (rel int.): 196 [MþH]þ (100). HRMS
(ESI): calcd for C9H17F3N (MþH) 196.1313, found 196.1306.
4.2.3. 2-Cyclohexyl-2-(trifluoromethyl)-pyrrolidine (4c). Colorless
liquid (68%); nmax (Nujol) 1139, 2931, 3391 cmꢂ1
;
1H NMR
(400 MHz, CDCl3):
d 1.05e1.25 (5H, m),1.47e1.53 (1H, m),1.64e1.68
(3H, m), 1.73e1.95 (7H, m), 2.94e3.00 (2H, m). 13C NMR (100 MHz,
CDCl3): d 26.2, 26.4, 26.8, 26.9, 27.9, 28.0, 30.0, 44.8, 47.6 (CH2eNH),
69.6 (q, JCF¼24.0 Hz, CeCF3), 129.0 (q, JCF¼286.6 Hz, CF3). 19F NMR
(376 MHz, CDCl3):
d
ꢂ73.1 (CF3). ESIMS m/z (rel int.): 222 [MþH]þ
(100). HRMS (ESI): calcd for C11H19F3N (MþH) 222.1464, found
222.1469.
4.2.4. 2-tert-Butyl-2-(trifluoromethyl)pyrrolidine
(4d). Colorless crystals (71%), mp 149e150 ꢀC; nmax (Nujol) 1158,
2977 cmꢂ1 1H NMR (400 MHz CDCl3):
1.27 (9H, br s, (CH3)3C),
2.00e2.04 (1H, m), 2.10e2.15 (1H, m), 2.19e2.26 (2H, m), 3.47e3.49
and 3.65e3.68 (2H, m, CH2eN), 9.58 and 11.02 (2H, br s, H2Nþ). 13
NMR (100 MHz, CDCl3): 24.4 (1C, (CH3)3C), 26.3 (3C, (CH3)3C),
hydrochloride
;
d
C
d

72
N.E. Shevchenko et al. / Tetrahedron 67 (2011) 69e74
30.2, 36.8, 48.4 (CH2eNH), 76.4 (q, JCF¼25.9 Hz, CF3eC), 125.8 (q,
(2H, m, CH2eN), 7.46 (2H, d, J¼8.7 Hz, AreH), 7.47 (2H, d, J¼8.7 Hz,
AreH). 13C NMR (100 MHz, CDCl3):
25.3, 34.6, 46.9 (CH2eN), 69.6
JCF¼287.5 Hz, CF3). 19F NMR (376 MHz, CDCl3):
d
ꢂ67.2 (CF3). HRMS
d
(ESI): calcd for C9H17F3N (MꢂCl) 196.1308, found 196.1292.
(q, JCF¼26.8 Hz, CeCF3), 122.3 (Cq, Ar), 127.2 (q, JCF¼284.7 Hz, CF3),
129.3 (2C, Ar), 131.3 (2C, Ar), 139.3 (Cq, Ar). 19F NMR (376 MHz,
4.2.5. 2-(1-Adamantyl)-2-(trifluoromethyl)pyrrolidine (4e). Yellow
CDCl3):
244.0132, found 244.0330.
d
ꢂ76.4 (CF3). HRMS (ESI): calcd for C10H12BrFN (MꢂCF2)
crystals (68%), mp 35 ꢀC; nmax (Nujol) 1160, 2929, 3274 cmꢂ1
;
1H
NMR (400 MHz, CDCl3):
1.92e1.99 (m, 4H), 2.91e2.95 (m, 1H), 3.00e3.04 (m, 1H). 13C NMR
(100 MHz, CDCl3): 26.3, 28.2, 28.6 (s, 3C, CAd), 36.9 (s, 6C, CAd),
d 1.61e1.72 (m, 14H), 1.76e1.83 (m, 2H),
4.2.11. 2-(4-Fluorophenyl)-2-(trifluoromethyl)-pyrrolidine
(4k). Colorless liquid (53%); nmax (Nujol) 1160, 2981, 3387 cmꢂ1; 1H
d
39.0 (1Cq, CAd), 47.9 (CH2eNH), 72.2 (q, JCF¼22.2 Hz, CF3eC), 129.7
NMR (400 MHz, CDCl3): d 1.75e1.86 (1H, m), 1.94e2.04 (1H, m),
2.16e2.21 (1H, m), 2.23 (1H, br s, NH), 2.50e2.57 (1H, m), 3.06e3.12
(1H, m), 3.18e3.24 (1H, m), 7.00e7.08 (2H, m, Ar), 7.49 (2H, dd,
(q, JCF¼289.0 Hz, CF3). 19F NMR (CDCl3):
d
ꢂ77.5 (CF3). MS (ESI) m/z
(%): 274 [MþH]þ (100). HRMS (ESI): calcd for C15H23F3N (MþH)
274.1777, found 274.1777.
J¼8.8 and 5.6 Hz. AreH). 13C NMR (100 MHz, CDCl3):
d 25.3, 34.7,
46.9 (CH2eN), 69.8 (q, JCF¼26.8 Hz, CeCF3), 115.1 (2C, d,
JCF¼22.0 Hz, Ar), 127.3 (q, JCF¼284.7 Hz, CF3), 129.3 (2C, d,
JCF¼7.7 Hz, Ar),137.1 (Cq, Ar),162.5 (Cq, d, JCF¼247.2 Hz, Ar). 19F NMR
4.2.6. 2-[(Methylthio)methyl]-2-(trifluoromethyl)-pyrrolidine
(4f). Colorless liquid (75%); nmax (Nujol) 1165, 2922, 3346 cmꢂ1; 1H
NMR (400 MHz, CDCl3):
d
1.80e1.94 (3H, m), 1.98e2.07 (2H, m, incl.
(376 MHz, CDCl3):
d
ꢂ76.6 (3F, s, CF3), ꢂ114.5 (1F, br s, AreF). ESIMS
2.00 (br s, NH)), 2.17 (3H, s, CH3eS), 2.82, 2.90 (2H, AB-system,
m/z (rel int.): 244 [MþH]þ (100). HRMS (ESI): calcd for C11H12F4N
(MþH) 234.0900, found 234.0889.
J¼13.3 Hz, CH2eSMe), 2.96e3.02 (1H, m), 3.11e3.14 (1H, m). 13C
NMR (100 MHz, CDCl3):
d 17.4, 26.4, 31.4, 40.2 (CH2eS), 48.0
(CH2eN), 67.0 (q, JCF¼25.9 Hz, CeCF3), 127.8 (q, JCF¼283.7 Hz, CF3).
4.2.12. 2-(4-Methoxyphenyl)-2-(trifluoromethyl)-pyrrolidine
19F NMR (376 MHz, CDCl3):
d
78.7 (CF3). ESIMS m/z (rel int.): 200
(4l). Reddish liquid (49%); nmax (Nujol) 1150, 2961, 3375 cmꢂ1 1H
;
[MþH]þ (100). HRMS (ESI): calcd for C7H13F3NS 200.0715 (MþH),
NMR (400 MHz, CDCl3): d 1.77e1.84 (1H, m), 1.96e2.02 (1H, m),
found 200.0726.
2.18e2.23 (1H, m), 2.25 (1H, br s, NH), 2.48e2.55 (1H, m), 3.06e3.12
(1H, m), 3.16e3.22 (1H, m), 3.80 (3H, s, CH3-OAr), 6.88 (2H, d,
J¼8.9 Hz, AreH), 7.42 (2H, d, J¼8.9 Hz, AreH). 13C NMR (100 MHz,
4.2.7. 2-(4-Methylphenyl)-2-(trifluoromethyl)-pyrrolidine
(4g). Colorless liquid (48%); nmax (Nujol) 1152, 2977, 3380 cmꢂ1; 1H
CDCl3):
d 25.4, 34.4, 47.0 (CH2eN), 55.2 (CH3O), 69.6 (q,
NMR (400 MHz, CDCl3):
d
1.77e1.86 (1H, m), 1.95e2.05 (1H, m),
2JCF¼26.8 Hz, CeCF3), 113.6 (2C, Ar), 127.6 (q, 1JCF¼284.7, CF3), 128.6
2.20e2.27 (2H, m), 2.35 (3H, s, CH3eAr), 2.51e2.58 (1H, m),
3.07e3.13 (1H, m), 3.17e3.22 (1H, m), 7.18 (2H, d, J¼7.8 Hz, AreH),
(2C, Ar), 132.0 (Cq, Ar),159.4 (Cq, Ar). 19F NMR (376 MHz, CDCl3):
d
ꢂ76.7 (CF3). ESIMS m/z (rel int.): 246 [MþH]þ (100). HRMS (ESI):
7.40 (2H, d, J¼7.8 Hz, AreH). 13C NMR (100 MHz, CDCl3):
d
21.1
calcd for C12H15F3NO (MþH) 246.1089, found 246.1100.
(CH3eAr), 25.4, 34.4, 47.0 (CH2eN), 69.7 (q, JCF¼25.9 Hz, CeCF3),
127.3 (2C, Ar), 127.6 (q, 1JCF¼283.7 Hz, CF3), 129.0 (2C, Ar), 137.1 (Cq,
4.2.13. 2-(Trifluoromethyl)-2-[3-(trifluoromethyl)phenyl]pyrrolidine
(4m). Colorless liquid (64%); nmax (Nujol) 1159, 2983, 3388 cmꢂ1; 1H
NMR (CDCl3): d 1.79e1.85 (1H, m),1.98e2.04 (1H, m), 2.19e2.26 (1H,
Ar), 137.9 (Cq, Ar). 19F NMR (376 MHz, CDCl3):
d
ꢂ76.6 (CF3). ESIMS
m/z (rel int.): 230 [MþH]þ (100). HRMS (ESI): calcd for C12H15F3N
(MþH) 230.1146, found 230.1151.
m), 2.32 (1H, br s, NH), 2.57e2.64 (1H, m), 3.09e3.15 (1H, m),
3.23e3.29 (1H, m), 7.49 (1H, t, J¼7.8 Hz, AreH), 7.60 (1H, d, J¼7.8 Hz,
AreH), 7.76 (1H, d, J¼7.8 Hz, AreH), 7.89 (1H, s, AreH). 13C NMR
4.2.8. 2-(3,4-Dimethylphenyl)-2-(trifluoromethyl)-pyrrolidine
(4h). Colorless liquid (62%); nmax (Nujol) 1151, 2972, 3381 cmꢂ1; 1H
(100 MHz, CDCl3):
d
25.2, 34.8, 46.9 (CH2eN), 69.8 (q, JCF¼26.9 Hz,
NMR (400 MHz, CDCl3):
d
1.79e1.85 (1H, m), 1.97e2.05 (1H, m),
CF3eC),124.1 (q, JCF¼273.2 Hz, CF3eAr),124.4 (q, JCF¼285.6 Hz, CF3),
124.4 (q, JCF¼2.8 Hz, Ar),124.9 (q, JCF¼3.8 Hz, Ar),128.7 (Ar),130.6 (q,
JCF¼31.6 Hz, Ar),131.0 (Ar),141.5 (Cq, Ar).19F NMR (376 MHz, CDCl3):
2.21e2.25 (1H, m), 2.24 (1H, br s, NH), 2.26 (3H, s, AreCH3), 2.30
(3H, s, AreCH3), 2.51e2.58 (1H, m), 3.10e3.17 (1H, m), 3.18e3.23
(1H, m), 7.13e7.15 (1H, m, AreH), 7.23e7.25 (1H, m, AreH), 7.29
d
ꢂ76.4 (3F, s, CF3eCq), ꢂ62.6 (3F, s, CF3eAr). HRMS (ESI): calcd for
(1H, br s, AreH). 13C NMR (100 MHz, CDCl3):
d
19.4 (AreCH3), 20.0
C12H12F6N (MþH) 284.0868, found 284.0874.
(AreCH3), 25.5, 34.4, 47.0 (CH2eN), 69.9 (q, JCF¼25.9 Hz, CeCF3),
124.8 (Ar), 127.6 (q, JCF¼284.7 Hz, CF3), 128.6 (Ar), 129.6 (Ar), 136.5
(Cq, Ar), 136.6 (Cq, Ar), 137.5 (Cq, Ar). 19F NMR (376 MHz, CDCl3):
4.2.14. 2-(2-Thienyl)-2-(trifluoromethyl)-pyrrolidine (4n). Colorless
liquid (71%); nmax (Nujol) 1161, 2980, 3377 cmꢂ1
;
1H NMR
d
ꢂ76.6 (CF3). ESIMS m/z (rel int.): 244 [MþH]þ (100). HRMS (ESI):
(400 MHz, CDCl3): d 1.85e1.92 (1H, m), 1.93e2.02 (1H, m),
calcd for C13H17F3N (MþH) 244.1285, found 244.1308.
2.21e2.28 (1H, m), 2.31 (1H, br s, NH), 2.47 (1H, dt, J¼13.2 and
8.1 Hz), 3.12e3.21 (2H, m), 7.01 (1H, dd, J¼3.7 and 5.1 Hz, AreH),
7.08 (1H, d, J¼3.7 Hz, AreH), 7.25 (1H, d, J¼5.1 Hz). 13C NMR
4.2.9. 2-(3,5-Dimethylphenyl)-2-(trifluoromethyl)-pyrrolidine
(4i). Colorless crystals (65%), mp 44e46 ꢀC; nmax (Nujol) 1161, 2976,
(100 MHz, CDCl3):
d
25.6, 36.1, 47.2 (CH2eN), 68.2 (q, JCF¼27.8 Hz,
3395 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
1.78e1.84 (1H, m),
CF3eC), 125.3 (2C, Ar), 126.9 (q, JCF¼283.7 Hz, CF3), 127.5 (Ar), 145.7
1.96e2.03 (1H, m), 2.17e2.27 (2H, m), 2.35 (6H, s, 2CH3eAr),
2.49e2.57 (1H, m), 3.07e3.13 (1H, m), 3.16e3.22 (1H, m), 6.96 (1H,
(Cq, Ar). 19F NMR (376 MHz, CDCl3):
d
ꢂ77.2 (CF3). ESIMS m/z (rel
int.): 222 [MþH]þ (100). HRMS (ESI): calcd for C9H11F3NS (MþH)
s, AreH), 7.11 (2H, s, AreH). 13C NMR (100 MHz, CDCl3):
d
21.5 (2C, s,
222.0559, found 222.0559.
2CH3eAr), 25.4, 34.4, 47.0 (CH2eN), 69.8 (q, JCF¼26.8 Hz, CeCF3),
125.2 (2C, s, Ar),127.5 (q, JCF¼284.7 Hz, CF3),129.8 (Ar),137.8 (2Cq, s,
4.2.15. 2-(5-Methylthien-2-yl)-2-(trifluoromethyl)-pyrrolidine
(4o). Colorless liquid (52%); nmax (Nujol) 1165, 2977, 3373 cmꢂ1; 1H
NMR (400 MHz, CDCl3): d 1.82e2.01 (2H, m), 2.23e2.28 (2H, m),
Ar), 140.0 (Cq, Ar). 19F NMR (376 MHz, CDCl3):
d
ꢂ76.5 (CF3). ESIMS
m/z (rel int.): 244 [MþH]þ (100). HRMS (ESI): calcd for C13H17F3N
(MþH) 244.1308, found 244.1301.
2.38e2.42 (1H, m), 2.43 (3H, s, CH3eAr), 3.14e3.17 (2H, m,
CH2eNH), 6.64 (1H, d, J¼3.7 Hz, AreH), 6.85 (1H, d, J¼3.7 Hz,
4.2.10. 2-(4-Bromophenyl)-2-(trifluoromethyl)-pyrrolidine
(4j). Colorless liquid (61%); nmax (Nujol) 1158, 2979, 3380 cmꢂ1; 1H
AreH). 13C NMR (100 MHz, CDCl3):
d 15.2, 25.6, 35.8, 47.2 (CH2eN),
68.3 (q, JCF¼27.8 Hz, CeCF3), 125.2 (Ar), 125.5 (Ar), 125.7 (q,
NMR (400 MHz, CDCl3):
d 1.72e1.80 (1H, m), 1.93e2.03 (1H, m),
1JCF¼283.7 Hz, CF3), 139.8 (Cq, Ar), 142.6 (Cq, Ar). 19F NMR (376 MHz,
2.13e2.18 (1H, m), 2.25 (br s, 1H, NH), 2.49e2.51 (1H, m), 3.08e3.21
CDCl3):
d
ꢂ77.2 (CF3). ESIMS m/z (rel int.): 236 [MþH]þ (100), 166

N.E. Shevchenko et al. / Tetrahedron 67 (2011) 69e74
73
[MꢂCF3] (80). HRMS (ESI): calcd for C10H13F3NS (MþH) 236.0715,
JCF¼26.8 Hz, CF3eC), 110.6 (Ar), 110.7 (Ar), 125.5 (q, JCF¼283.7 Hz,
found 236.0718.
CF3),142.9 (Ar),150.2 (Cq, Ar). 19F NMR (376 MHz, CDCl3):
d
ꢂ80.5 (s,
3F). ESIMS m/z (rel int.): 220 [MþH]þ (100). HRMS (ESI): calcd for
C10H13F3NO (MþH) 220.0944, found 220.0944.
4.2.16. 2-(2-Furanyl)-2-(trifluoromethyl)-pyrrolidine (4p). Colorless
liquid (60%); nmax (Nujol) 1168, 2977, 3386 cmꢂ1; 1H NMR (400 MHz,
CDCl3):
3.07e3.11 (2H, m, CH2eN), 6.33 (2H, br s, 2AreH), 7.38 (1H, br s,
AreH). 13C NMR (100 MHz, CDCl3):
25.4, 32.5, 47.0 (CH2eN), 66.6
(q, JCF¼28.8 Hz, CeCF3), 107.8 (Ar),110.6 (Ar),126.4 (q, JCF¼282.8 Hz,
d
1.80e1.86 (1H, m), 1.91e1.95 (1H, m), 2.24e2.30 (3H, m),
4.2.22. 2-(3-Pyridinyl)-2-(trifluoromethyl)-piperidine
methylanabasine) (5e). Colorless liquid (68%); nmax (Nujol) 1157,
2944, 3291 cmꢂ1 1H NMR (400 MHz, CDCl3):
1.31e1.36 (1H, m),
(a-trifluoro-
d
;
d
1.48e1.54 (2H, m), 1.76e1.81 (1H, m), 1.97e2.05 (2H, m), 2.47e2.60
(2H, m), 2.94e3.00 (1H, m), 7.38 (1H, dd, J¼8.7 and 5.1 Hz, AreH),
7.90 (1H, d, J¼8.7 Hz, AreH), 8.61 (1H, d, J¼5.1 Hz, AreH), 8.80 (s,
CF3), 142.5 (Ar), 152.6 (Cq, Ar). 19F NMR (376 MHz, CDCl3):
d
ꢂ77.5
(CF3). ESIMS m/z (rel int.): 206 [MþH]þ (100). HRMS (ESI): calcd for
C9H11F3NO (MþH) 206.0787, found 206.0786.
1H, AreH). 13C NMR (100 MHz, CDCl3):
d 19.63, 26.11, 28.06, 41.0
(CH2eN), 61.8 (q, JCF¼25.9 Hz, CF3eC), 123.5 (Ar), 125.5 (q,
4.2.17. 2-(3-Pyridinyl)-2-(trifluoromethyl)-pyrrolidine
methylnornicotine) (4q). Colorless liquid (68%); nmax (Nujol) 1161,
2979, 3297 cmꢂ1 1H NMR (400 MHz, CDCl3):
1.69e1.76 (1H, m),
(a-trifluoro-
JCF¼283.7 Hz, CF3), 130.9 (Cq, Ar), 136.8 (Ar), 149.4 (Ar), 150.4 (Ar).
19F NMR (376 MHz, CDCl3):
C11H14F3N2 (MþH) 231.1104, found 231.1104.
d
ꢂ80.0 (CF3). HRMS (ESI): calcd for
;
d
1.88e1.95 (1H, m), 2.09e2.16 (1H, m), 2.34 (1H, br s, NH), 2.46e2.53
(1H, m), 2.99e3.04 (1H, m), 3.12e3.18 (1H, m), 7.21 (1H, dd, J¼8.2
and 4.4 Hz, AreH), 7.79 (1H, d, J¼8.2 Hz, AreH), 8.47 (1H, d,
J¼4.4 Hz, AreH), 8.71 (s, 1H, AreH). 13C NMR (100 MHz, CDCl3):
4.2.23. 2-tert-Butyl-2-(trifluoromethyl)-azepane hydrochloride(6a).
Colorless crystals (55%), mp 157e159 ꢀC; nmax (Nujol) 1143, 2963,
3426 cmꢂ1 1H NMR (400 MHz, CDCl3):
; d 1.33 (9H, s, (CH3)3C),
d
25.0, 34.4, 46.7 (CH2eN), 68.7 (q, JCF¼25.9 Hz, CF3eC), 122.9 (Ar),
1.48e1.53 (1H, m), 1.73e2.12 (6H, m), 2.35e2.41(1H, m), 3.51e3.55
127.1 (q, JCF¼284.7 Hz, CF3), 135.2 (Ar), 135.8 (Cq, Ar), 149.0 (Ar),
(1H, m), 3.69e3.72 (1H, m), 9.15 and 10.31 (2H, br s, H2Nþ). 13C NMR
149.2 (Ar). 19F NMR (376 MHz, CDCl3):
d
ꢂ76.6 (CF3). ESIMS m/z (rel
(100 MHz, CDCl3): d 24.4 ((CH3)3C), 26.5, 27.5 (3C, (CH3)3C), 29.7,
int.): 217 [MþH]þ (100). HRMS (ESI): calcd for C10H12F3N2 (MþH)
30.1, 39.6, 48.5 (CH2eN), 71.7 (q, JCF¼23.0 Hz, CeCF3), 126.3 (q,
217.0948, found 217.0947.
JCF¼290.4 Hz, CF3). 19F NMR (376 MHz, CDCl3):
ꢂ65.7 (CF3). ESIMS
d
m/z (rel int.): 224 [MꢂCl]þ (100). HRMS (ESI): calcd for C11H21F3N
4.2.18. 2-tert-Butyl-2-(trifluoromethyl)piperidine hydrochloride (5a).
Colorless crystals (56%), mp 161e162 ꢀC; nmax (Nujol) 1152, 2921,
224.1628, found 224.1626.
3436 cmꢂ1; 1H NMR (400 MHz, CDCl3):
d
1.33 (s, 9H), 1.77e1.82 (2H,
4.2.24. 2-(4-Methylbenzyl)-2-(trifluoromethyl)azepane (6b). Color-
m), 1.90e1.99 (1H, m), 1.86 (br s, 1H), 2.03e2.11 (2H, m), 3.15e3.19
less liquid (71%); nmax (Nujol) 1144, 2957, 3431 cmꢂ1 1H NMR
;
(1H, m), 3.70e3.74 (1H, m), 8.72 and 10.33 (2H, br s, H2Nþ). 13C NMR
(400 MHz, CDCl3):
d 1.37e1.64 (3H, m), 1.64e1.80 (4H, m, incl. 2.23
(100 MHz, CDCl3):
d
24.4 (1C, (CH3)3C), 26.5, 27.5 (3C, ((CH3)3C)),
(br s, NH)), 1.87e1.95 (2H, m), 2.35 (3H, s, CH3eAr), 2.79e2.94 (4H,
29.7, 39.6, 48.5 (CH2eN), 71.7 (q, JCF¼23.0 Hz, CeCF3), 126.3 (q,
m, incl. 2.82 (s, (CH2eAr))), 7.10e7.15 (4H, m, AreH). 13C NMR
JCF¼290.4 Hz, CF3). 19F NMR (376 MHz, CDCl3):
d
ꢂ65.7 (CF3). ESIMS
(100 MHz, CDCl3): d 22.1, 23.0, 30.9, 32.7, 33.9, 41.4 (CH2eAr), 43.4
m/z (rel int.): 224 [MꢂCl]þ (100). HRMS (ESI): calcd for C10H19F3N
(CH2eN), 62.8 (q, JCF¼22.0 Hz, CeCF3), 128.8 (2C, Ar), 128.7 (q,
(MꢂCl) 209.1464, found 209.1466.
JCF¼290.4 Hz, CF3), 130.9 (2C, Ar), 132.8 (Cq, Ar), 136.4 (Cq, Ar). 19
F
NMR (376 MHz, CDCl3):
d
ꢂ76.3 (CF3). HRMS (ESI): calcd for
4.2.19. 2-Cyclohexyl-2-(trifluoromethyl)piperidine
liquid (53%); nmax (Nujol) 1157, 2933, 3386 cmꢂ1
(400 MHz, CDCl3): 1.10e1.23 (m, 5H), 1.50e1.54 (m, 3H), 1.63e1.74
(m, 6H), 1.76e1.81 (m, 4H), 2.76e2.80 (1H, m), 2.89e2.92 (1H, m).
13C NMR (100 MHz, CDCl3):
19.7, 25.1, 26.6 (2C, s), 26.8, 27.5, 27.6,
(5b). Colorless
C15H21F3N (MþH) 272.1626, found 272.1621.
;
1H NMR
d
4.2.25. 2-Phenyl-2-(trifluoromethyl)-azepane (6c). Yellowish liquid
(44%); nmax (Nujol) 1155, 2928, 3393 cmꢂ1 1H NMR (400 MHz,
CDCl3): 1.38e1.52 (2H, m), 1.53e1.57 (2H, m), 1.69e1.78 (2H, m),
;
d
d
27.7, 40.8, 42.5 (CH2eN), 59.6 (q, JCF¼23.0 Hz, CeCF3), 128.8 (q,
2.00 (1H, br s, NH), 2.27e2.43 (2H, m), 2.78e2.84 (1H, m),
3.07e3.13 (1H, m), 7.30e7.45 (3H, m, AreH), 7.60e7.66 (2H, m,
JCF¼290.4 Hz, CF3). 19F NMR (376 MHz, CDCl3):
ꢂ70.4 (CF3). ESIMS
d
m/z (rel int.): 236 [MþH]þ (100). HRMS (ESI): calcd for C12H21F3N
AreH). 13C NMR (100 MHz, CDCl3):
d 22.9, 30.1, 33.4, 34.0, 43.7
(MþH) 236.1621, found 236.1620.
(CH2eN), 65.7 (q, JCF¼24.0 Hz, CeCF3), 127.8 (q, JCF¼286.6 Hz, CF3),
127.9 (2C, Ar), 128.3 (Ar), 129.3 (2C, Ar), 140.1 (Cq, Ar). 19F NMR
4.2.20. 2-Phenyl-2-(trifluoromethyl)piperidine (5c). Colorless liquid
(376 MHz, CDCl3):
d
ꢂ77.2 (CF3). ESIMS m/z (rel int.): 244 [MþH]þ
(49%); nmax (Nujol) 1153, 2943, 3363 cmꢂ1
;
1H NMR (400 MHz,
(100). HRMS (ESI): calcd for C13H17F3N (MþH) 244.1301, found
CDCl3):
d
1.30e1.36 (1H, m), 1.46e1.52 (2H, m), 1.73 (1H, m), 1.98
244.1308.
(1H, dt, J¼13.3 and 3.7 Hz), 2.11 (1H, br s, NH), 2.50 (1H, dt, J¼13.7
and 3.2 Hz), 2.59e2.66 (1H, m), 2.90e2.97 (1H, m), 7.31e7.38 (1H,
m, AreH), 7.40e7.46 (m, 2H, AreH), 7.54 (2H, d, J¼7.8 Hz, AreH). 13C
4.2.26. 2-(2-Furanyl)-2-(trifluoromethyl)-azepane (6d). Yellow liq-
uid (56%); nmax (Nujol) 1146, 2929, 3415 cmꢂ1 1H NMR (400 MHz,
;
NMR (100 MHz, CDCl3):
d
19.8, 26.1, 28.3, 41.1 (CH2eN), 62.5 (q,
CDCl3): d 1.37e1.48 (3H, m), 1.60e1.65 (1H, m), 1.69e1.75 (1H, m),
JCF¼25.9 Hz, CF3eC), 126.3 (q, JCF¼282.7 Hz, CF3), 128.1 (Ar),128.8
1.77e1.82 (1H, m), 2.13e2.19 (1H, m), 2.23 (1H, br s, NH), 2.18e2.32
(1H, m), 2.82e2.88 (1H, m), 2.91e2.97 (1H, m), 6.32e6.39 (2H, m,
(2C, Ar), 129.1 (2C, Ar), 135.0 (Cq, Ar). 19F NMR (376 MHz, CDCl3):
d
ꢂ80.0 (s, 3F). ESIMS m/z (rel int.): 230 [MþH]þ (100). HRMS (ESI):
AreH), 7.41(1H, s, AreH).13CNMR(100 MHz,CDCl3):
d22.9, 30.1, 32.1,
calcd for C12H15F3N (MþH): 230.1163, found 230.1151.
33.3, 43.5 (CH2eN), 63.7 (q, JCF¼25.9 Hz, CeCF3),108.8 (Ar),110.4 (Ar),
126.9 (q, JCF¼287.5 Hz, CF3), 142.6 (Ar), 153.1 (Cq, Ar). 19F NMR
4.2.21. 2-(2-Furanyl)-2-(trifluoromethyl)-piperidine (5d). Colorless
(376 MHz,CDCl3):
HRMS (ESI): calcd for C11H15F3NO (MþH) 234.1100, found 234.1100.
d
78.3(CF3).ESIMSm/z(relint.):234[MþH]þ (100).
liquid (65%); nmax (Nujol) 1166, 2975, 3382 cmꢂ1
;
1H NMR
(400 MHz, CDCl3): d 1.33e1.40 (1H, m), 1.46e1.52 (2H, m),1.70e1.74
(1H, m), 1.89 (1H, dt, J¼12.8 and 4.1 Hz), 2.20e2.27 (1H, m), 2.36
(1H, br s, NH), 2.53e2.60 (1H, m), 2.90e2.96 (1H, m), 6.37e6.38
(1H, m), 6.40 (1H, dd, J¼3.2 and 1.8 Hz), 7.44e7.45 (1H, m). 13C NMR
4.2.27. 2-Pyridin-3-yl-2-(trifluoromethyl)azepane (
homoanabasine) (6e). Colorless liquid (56%); nmax (Nujol) 1160,
2929, 3274 cmꢂ1; 1H NMR (400 MHz, CDCl3):
1.24e1.34 (1H, m),
1.40e1.55 (3H, m), 1.60e1.78 (2H, m), 2.00 (1H, br s, NH),
a-trifluoromethyl-
d
(100 MHz, CDCl3):
d 19.9, 24.8, 26.9, 41.8 (CH2eN), 60.4 (q,

74
N.E. Shevchenko et al. / Tetrahedron 67 (2011) 69e74
6. Contrary to
tinamide with
a
-Tfm analogous of anabasine and nicotine, derivatives of nico-
-Tfm-group in pyridine ring are known and have outstanding
2.16e2.28 (1H, m, 1H), 2.30e2.40 (1H, m), 2.72e2.80 (1H, m),
3.05e3.14 (1H, m), 7.26 (1H, dd, J¼8.4 and 4.6 Hz, AreH), 7.90
(1H, d, J¼8.4 Hz, AreH), 8.52 (1H, d, J¼4.6 Hz, AreH), 8.84 (1H, br
a
application as modern agrochemicals. As an example, insecticide flonicamid
could be mentioned: U.S. Environ. Prot. Agency, Fed. Regist. 2002, 67, 49606.
7. (a) Fustero, S.; Sanz-Cervera, J. F.; Acena, J. L.; Sanchez-Roselloa, M. Synlett 2009,
525; (b) Mueller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
8. For FriedeleCrafts methods, see: (a) Koller, W.; Schlack, P. Chem. Ber. 1963, 96,
93; (b) Cheng, S.-S.; Piantadosi, C.; Irvin, J. L. J. Pharm. Sci. 1968, 57, 1910 For aza-
Wittig reactions, see: (c) Singh, P. N. D.; Klima, R. F.; Muthukrishnan, S.; Murthy,
R. S.; Sankaranarayanan, J.; Stahlecker, H. M.; Patel, B.; Gudmundsdorttir, A. D.
Tetrahedron Lett. 2005, 46, 4213; (d) Prabhu, K. R.; Sivanand, P. S.; Chandrse-
karan, S. Synlett 1998, 47; (e) Lambert, P. H.; Vaultier, M.; Carrie, R. J. Chem. Soc.,
s, AreH). 13C NMR (100 MHz, CDCl3):
d 22.4, 29.8, 33.0, 33.7, 43.4
(CH2eN), 64.7 (q, JCF¼24.9 Hz, CeCF3), 122.9 (Ar), 127.5 (q,
JCF¼287.5 Hz, CF3), 135.4 (Ar), 135.6 (Cq, Ar), 149.0 (Ar), 149.4 (Ar).
19F NMR (376 MHz, CDCl3):
d
ꢂ77.4 (CF3). ESIMS m/z (rel int.): 245
[MþH]þ (100). HRMS (ESI): calcd for C12H16F3N2 (MþH) 245.1262,
found 245.1266.
Chem. Commun. 1982, 1224 For syntheses with
u-bromonitriles, see: (f) Fry, D.
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4.2.28. 2-(Trifluoromethyl)pyrrolidine (8a). Compound 8a was
synthesized analogously to the General procedure for the reaction of
cyclic imines with trifluoromethyltrimethylsilane. Before the addition
of trifluoromethyltrimethylsilane the reaction mixture was stirred
for 20 min. Colorless liquid (47%); 1H, 13C, and 19F NMR data of free
base were identical with the reported ones.28,29
9. (a) Nenajdenko, V. G.; Zakurdaev, E. P.; Prusov, E. V.; Balenkova, E. S. Tetrahedron
2004, 60, 11719; (b) Sorgi, K. L.; Maryanoff, A. C.; McComsey, D. F.; Maryanoff, B.
E. Org. Synth. 1998, 75, 215.
4.2.29. 2-(Trifluoromethyl)piperidine (8b). Compound 8b was syn-
thesized analogously to the General procedure for the reaction of
cyclic imines with trifluoromethyltrimethylsilane. Before the addition
of trifluoromethyltrimethylsilane the reaction mixture was stirred
for 20 min. Colorless liquid (55%); 1H, 13C, and 19F NMR data of free
base were identical with the reported ones.30,29
€
10. (a) Gulevich, A. V.; Shevchenko, N. E.; Balenkova, E. S.; Roschenthaler, G.-V.;
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€
chenko, N. E.; Petrovskii, P. V.; Nenajdenko, V. G.; Roschenthaler, G.-V. Synthesis
2009, 577; (c) Nenajdenko, V. G.; Zakurdaev, E. P.; Balenkova, E. S. Tetrahedron
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The authors thank the Deutsche Forschungsgemeinschaft (RO 362/
42/1), RFBR (10-03-91333-NNIO_a) for financial support of this work.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.11.032.
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