New method of preparation of C2F5Li and its reactions with cyclic imines and lactims: Synthesis of α-pentafluoroethyl proline

Article abstract of DOI:10.1016/j.jfluchem.2008.01.013

Addition of pentafluoroethyllithium to cyclic imines leads to pentafluoroethyl substituted pyrrolidines, piperidines and azepanes while reaction of cyclic lactims gives rise to 2-pentafluoroethyl imines. Oxidative cleavage of 2-furyl-2-pentafluoroethyl pyrrolidine has been found to be an effective method for the preparation of a racemic α-pentafluoroethyl proline.

Full text of DOI:10.1016/j.jfluchem.2008.01.013

Available online at www.sciencedirect.com
Journal of Fluorine Chemistry 129 (2008) 390–396
www.elsevier.com/locate/fluor
New method of preparation of C2F5Li and its reactions with cyclic
imines and lactims: Synthesis of a-pentafluoroethyl proline
b
Nikolay E. Shevchenko a, Valentine G. Nenajdenko a, , Gerd-Volker Roschenthaler
*
¨
a Department of Chemistry, Moscow State University, Moscow 119899, Russia
b Institute for Inorganic and Physical Chemistry, The University of Bremen, Leobener Str., D-28334, Germany
Received 17 December 2007; received in revised form 23 January 2008; accepted 24 January 2008
Available online 6 February 2008
Abstract
Addition of pentafluoroethyllithium to cyclic imines leads to pentafluoroethyl substituted pyrrolidines, piperidines and azepanes while reaction
of cyclic lactims gives rise to 2-pentafluoroethyl imines. Oxidative cleavage of 2-furyl-2-pentafluoroethyl pyrrolidine has been found to be an
effective method for the preparation of a racemic a-pentafluoroethyl proline.
# 2008 Elsevier B.V. All rights reserved.
Keywords: Nucleophilic addition; Oxidative cleavage; Lewis acid; Cyclic imines; Pentafluoroethyl group; Azaheterocycles; a-Pentafluoroethyl proline
1. Introduction
potential importance for medicinal chemistry and material
science they may serve as potential fluorinated synthons for
further functionalization, for example, as useful precursors for
the synthesis of perfluoroalkyl containing analogues of natural
a-amino acids [3,8]. To the best of our knowledge, mainly there
are examples of trifluoromethylated derivatives described so
far. Pentafluoroethyl derivatives of aliphatic nitrogen hetero-
cycles are almost unexplored area despite the fact that in some
test pentafluoroethyl analogues of biological active compounds
show higher therapeutic affect compare with trifluoromethyl
ones [9].
Saturated nitrogen heterocycles are common feature of
many natural alkaloids, modern medications and potent drug
candidates [1]. Among them the most important are piperidine
and pyrrolidine rings which are the object of continuous and
numerous synthetic efforts [2].
On the other hand, it is well recognized that the introduction
of perfluoroalkyl groups into organic molecules leads to the
dramatic modification of their physico-chemical properties and
biological activities, may significantly improve metabolic
stability and is of powerful tool of modern drug design and drug
discovery [3]. Among large number of outstanding applications
of such organofluorine compounds in pharmaceutical field
Efavirenz [4] and Celecoxib [5] can be mentioned as two recent
prominent drugs used in the treatment of human diseases (HIV
and arthritis correspondingly).
In this article we describe the successful synthesis of 2-
pentafluoroethyl substituted cyclic amines and imines from
cyclic imines and lactims respectively by reaction with
pentafluoroethyllithium, easily generated from commercially
available pentafluoroethane. Another notable synthetic appli-
cation of this reaction is a key step in the synthesis of a
promising amino acid a-pentafluoroethylproline.
Organic molecules that combine in their structure piperidine
and pyrrolidine fragments with perfluoroalkyl moieties take an
important place in synthetic and medicinal chemistry for
reasons mentioned above [6,7]. Of these fluorinated com-
pounds, preparation of 2-perfluoroalkyl substituted aliphatic
nitrogen heterocycles is attractive target [7]. Besides of their
2. Results and discussion
Earlier we have developed a convenient strategy for the
generation of pentafluoroethyllithium based on the utilization
of easily available and inexpensive pentafluoroethane [10]. On
the other hand, we have a lot of experience in preparation of
different 2-substituted cyclic imines. The latter can be produced
* Corresponding author.
E-mail address: nen@acylium.chem.msu.ru (V.G. Nenajdenko).
0022-1139/$ – see front matter # 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.01.013

N.E. Shevchenko et al. / Journal of Fluorine Chemistry 129 (2008) 390–396
391
Scheme 2. Reaction of C2F5Li with cyclic imines.
Scheme 1. Synthesis of the starting imines 1: (i) Claisen condensation with
RCO2Alk, then deprotection; (ii) decarboxylation with HCl (aq.) or (iii)
reaction with RLi, then deprotection.
contrast to observation of Uno and coworkers [13], the order of
addition of the reagents has no influence on yields of the
products. Probably, this is due to different nature of the reagent
prepared by Li–Br exchange or by metalation of C2F5H with
BuLi. In case Uno’s method, 1 equiv. of LiBr or LiI salt was
present in the system to form complex with the lithium reagent.
Our technique permits to obtain a salt free lithium reagent
(Scheme 2).
by Claisen condensation of N-protected cyclic amides with
esters followed by simultaneous deprotection and decarbox-
ylation in acidic media. Alternatively, this type of imines can be
made by reaction of N-protected amides with readily available
organolithium reagents (Scheme 1) [11]. 2-Substituted cyclic
imines are very promising from the synthetic point of view and
some examples of their transformations have been published
recently [12].
It is notable that five-, six- and seven-membered cyclic
imines give very similar yields of the reaction products. The
reaction is general, there is no significant dependence of the
reaction yields on the nature of the substituent at the imine
double bond. Even the presence of a bulky tert-butyl group at
the imine function in case of 1a did not lead to a significantly
reduced yield.
We suggested that reaction of pentafluoroethyllithium with
these cyclic imines in the presence of a Lewis acid should
proceed as an addition to imine C N bond [13,14]. This
approach opens up opportunities for the synthesis of 2-
pentafluoroethyl substituted pyrrolidines, piperidines and
azepanes, which are very interesting building blocks for
potentially biologically active compounds.
An interesting result was obtained in the reaction of the 4-
pyridyl substituted imine 1h. Surprisingly, no addition to C N
imine bond was observed. Pentafluoroethyl reagent attacks 4-
position of the pyridine ring to form dihydropyridine derivative
3. Moreover, imine 3 is the only product of the reaction even if
2 equiv. of the organolithium reagent and boron trifluoride were
used, allowing both nitrogen atoms in imine 1h to coordinate
BF3. Although some details of the reaction deserve further
study, we suggest that pentafluoroethyllithium react on more
electrophilic and less sterically hindered position of the
complex between the Lewis acid and more electron-donating
pyrroline nitrogen atom. As well this direction for the attack of
pentafluoroethyl anion on the pyridinium ring may be due to the
stabilization of the transition state by delocalization of the
negative charge generated in the ring by the attack (Scheme 3).
Our interest in further investigation of cyclic imines in the
reaction with pentafluoroethyllithium led us to study lactim
ethers. Cyclic lactim ethers (cyclic lactims) are useful building
blocks for large variety of practically important organics [16].
The behavior of lactim ethers in reactions with various
organometallics is a topic described in a number of publications
[17]. It has been shown that lactims react easily with
organolithium and organomagnesium reagents to give the
corresponding imines or a,a-disubstituted amines depending
on the stoichiometry and reactivity of the organometallic
Searching of an appropriate Lewis acid to activate cyclic
imines was the first step of our investigation. We found that
boron trifluoride etherate is a simple and effective activator for
this reaction. Other tested Lewis acids such as TiCl4 and AlCl3
were essentially ineffective in promoting the addition of
pentafluoroethyllithium to the cyclic imine. This result coincide
with addition of perfluoroalkyllithium generated from the
halogen–metal exchange reaction of perfluoroalkyliodates to
acyclic imine bond early developed by Uno [15]. Addition of
the pentafluoroethyl group to the imine double bond of
compounds 1a–l proceed smoothly to afford the a-pentafluor-
oethylated heterocycles 2a–l in reasonable yields (Table 1). In
Table 1
Reactions of C2F5Li generated from C2F5H and BuLi with cyclic imines via
Scheme 2
Entry
Imine
Product
n
R
Yielda (%)
1
2
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
1
1
1
1
1
1
1
2
2
3
3
tert-Bu
Bu
65
58
52
49
59
55
43
48
59
55
43
3
Ph
4
3-CF3–C6H4
4-F–C6H4
4-MeO–C6H4
2-Furyl
tert-Bu
Ph
5
6
7
1g
1i
2g
2i
8
9
1j
2j
10
11
1k
1l
2k
2l
tert-Bu
Ph
a
The yields of 2-C2F5–2–R cyclic amines given after the purification by
column chromatography.
Scheme 3. Reaction of C2F5Li with 4-(3,4-dihydro-2H-pyrrol-5-yl)pyridine.

392
N.E. Shevchenko et al. / Journal of Fluorine Chemistry 129 (2008) 390–396
Table 2
Reactions of C2F5Li generated from C2F5H and BuLi with lactims via Scheme 4
Entry
Product
n
Yielda, %
19F NMR data)
Yieldb, %
(isolated)
(
1
2
3
5a
5b
5c
1
2
3
65
83
52
34
62
Scheme 5. Synthesis of a-pentafluoroethyl proline 6: (i) C2F5Li, Et2OBF3,
THF À78 8C, then H2O, K2CO3, 71%; (ii) O3, MeOH À78 8C 84% or NaIO4,
RuCl3, CH3CN/CCl4/H2O 41%.
a
The yields were determined with benzotrifluoride as internal standard.
The yields given after the vacuum recondensation.
b
The key step of our approach to the synthesis of a-
pentafluoroethylproline is the addition of C2F5Li in the
presence of boron trifluoride to furylimine 1g followed by
oxidative cleavage of furyl group to carboxylic moiety.
Chemoselective oxidative transformation of furyl ring of
amine 2g to the carboxylic group can be easily performed with
ozone or using NaIO4 with a catalytical amount of RuCl3 to
give target a-amino acid 5 in high yield. Thus, starting from
commercial available and inexpensive N-vinylpyrrolidone the
preparation of a-pentafluoroethylproline can be achieved in
three synthetic steps without using any expensive reagent.
species. Usually, both types of the products are produced at the
same time. In case of the most reactive organolithium and
Grignard reagents a,a-disubstituted amines are the main
products even with a large excess of lactim ether [18].
However, we found no reports of the addition of a
perfluoroalkyllithium reagent to the lactim carbon–nitrogen
double bond. As one would expect the pentafluoroethyllithium
itself did not react with a cyclic lactim unless the lactim moiety
is activated by a Lewis acid. We have tested several Lewis acids
and have found that TiCl4, SnCl4 and AlCl3 were essentially
ineffective in promoting the addition of pentafluoroethyllithium
to lactim. On the other hand, addition of pentafluoroethyl-
lithium to cyclic lactim ether in the presence of boron trifluoride
etherate occurred smoothly to afford the pentafluoroethyl
imines 5a–c in moderate yields (Table 2) (Scheme 4).
In contrast to reaction of the ordinary alkyllithium [17]
addition of pentafluoroethyllithium to the lactims led to the a-
pentafluoroethylimines 5 exclusively. Even if pentafluoroethyl-
lithium was present in large excess (3 equiv.) no formation of
a,a-disubstituted product was observed. Reasonable explana-
tion of this fact should be an extraordinaire stability of an
intermediate hemi-aminal arising from addition of C2F5Li to
lactim carbon–nitrogen double bond under reaction tempera-
ture. The stability of the initial tetrahedral adducts between the
organometallic reagent and carbonyl compounds at low
temperatures as a result of the presence of electron-with-
drawing perfluoroalkyl group are well documented [19].
Unfortunately, we have not succeeded to isolate seven-
membered pentafluoroethylimine 5c in pure form because of
its extreme instability under usual work-up conditions.
However, the compound 5c was characterized by NMR.
Having in our hands a number of cyclic amines bearing C2F5
group we have developed an efficient and practical synthesis of
a-pentafluoroethylproline. It is known, that substituted prolines
are conformationally constrained amino acids which influence
the conformation of the peptide backbone [20]. Among them the
less investigated are the analogues of proline with a fluorinated
group at a-position. In the literature only one synthesis of such
proline has been described just recently [21]: the authors used a
diastereoselective allylation reaction of ethyl trifluoropyruvate
and (R)-phenylglycinol-based oxazolidines or imine (Scheme 5).
3. Conclusion
In conclusion, we have shown that addition of pentafluor-
oethyllithium to cyclic imines leads to pentafluoroethyl
substituted pyrrolidines, piperidines and azepanes while the
reaction of lactims gives rise to new 2-pentafluoroethyl five-
and six-membered cyclic imines. We have developed a simple
and convenient pathway to a-pentafluroethylproline—a pro-
spective candidate for synthetic modification of biologically
active peptides [22].
4. Experimental
4.1. General experimental procedures
NMR spectra were obtained on a Bruker DPX-200
1
(200.1 MHz for H; 188.3 MHz for 19F; 50.32 MHz for 13C)
1
or a Bruker AM-360 (360.1 MHz for H; 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),
(CD3)2SO (39.5); chemical shifts for 19F NMR data are
referenced to CFCl3 (0.0) or PhCF3 (À63.90). High-resolution
mass spectra (HRMS) were recorded using a Varian MAT
CH7A instrument at 70 eV. Chemical ionization (CI) mass
spectra (MS) were obtained with ammonia or isobutane as the
reagent gas. Melting points are uncorrected. TLC was carried
out on precoated silica plates (Merck 60F254) with UV light
visualization. Flash chromatography was performed using MP
Silica 60 (320–630 mesh) with the indicated solvents. All
reactions were conducted in flame-dried or oven dried
glassware under nitrogen atmosphere. Tetrahydrofuran and
ether was distilled from sodium/benzophenone prior to use. All
reagents were purchased from Aldrich unless otherwise stated.
BuLi was a 2.5 M solution in hexane and was used without
verification of its titre. The starting imines 1a, 1h, 1i and 1k
were prepared by reaction of ethyl ester of the appropriate
Scheme 4. Reaction of C2F5Li with lactims.

N.E. Shevchenko et al. / Journal of Fluorine Chemistry 129 (2008) 390–396
393
2
1
carboxylic acids with N-vinylpyrrolidin-2-one, N-vinylcapro-
lactam or N-(diethoxymethyl)piperidin-2-one according to the
described procedure [23]. Cyclic imines 1b–g, 1j and 1l were
obtained by the reaction of correspondinglithium compounds
with N-vinylpyrrolidin-2-one, 1-(trimethylsilyl)caprolactam or
1-(trimethylsilyl)piperidin-2-one [24]. The lactim ethers were
prepared from the corresponding lactams by the reaction with
dimethyl sulfate [25].
(CH2NH), 69.9 (t, JCF = 21.7 Hz, C2F5C), 116.2 (qt, JCF
=
260.1 Hz, 2JCF = 34.3 Hz, CF3CF2), 120.0 (qt, 1JCF = 288.5 Hz,
2JCF = 37.9 Hz, CF3CF2), 127.3 (2C, s, Ar), 127.93 (Ar), 128.1
(2C, s, Ar), 139.2 (Ar). 19F NMR (188 MHz, CDCl3): d À122.2,
À120.8, À118.3, À116.8 (2F, AB-system, dA À122.63, dB
2
À115.89, JAB = 274.9 Hz), À78.8 (3F, s, CF3). EIMS 70 eV,
m/z (rel. int.): 264 [MÀH]+ (4), 236 [MÀ29]+ (18), 188
[MÀC6H5]+ (21), 146 [MÀC2F5]+ (100). CIMS NH3, m/z (rel.
int.): 266 [M+H]+ (100), 146 [MÀC2F5]+ (16). HRMS (EI):
calcd. for C12H11F5N (MÀH) 264.0812; found 264.0807.
2-(Pentafluoroethyl)-2-[3-(trifluoromethyl) phenyl]pyrroli-
4.2. General procedure for the reaction of cyclic imines
with pentafluoroethyllithium
1
dine (2d). Colourless liquid, H NMR (200 MHz, CDCl3): d
1.54–1.77 (1H, m), 1.84–2.00 (1H, m), 2.18–2.35 (2H, m, incl.
2.32 (1H, s, NH)), 2.58–2.74 (1H, m), 2.98–3.07 (1H, m), 3.17–
A pentafluoroethane (1.8 g, 15 mmol) was passed through
solution of BuLi (4.8 ml of 2.5 M in hexane, 12 mmol) in THF
(100 ml) at À85 to À80 8C. After 15 min a solution of the
corresponding imine (10 mmol) in THF (15 ml) and BF3
etherate (1.7 g, 12 mmol) was added subsequently. Then the
reaction mixture was stirred for 6 h at À78 8C, quenched with
water solution (50 ml) of K2CO3 (10 g). The organic phase was
separated and the aqueous phase was extracted with ether (2Â
20 ml). The combine extracts were dried over K2CO3, the
solvents and excess of pentafluoroethane were evaporated at
reduce pressure and the residue was purified by column
chromatography on silica gel eluting with 15/1 mixture hexane/
ethyl acetate afforded tagged amine.
3
3.29 (1H, m), 7.47 (1H, dd, JHH = 7.83 and 7.82 Hz, Ar-H),
3
7.58 (1H, m, JHH = 7.83 Hz, Ar-H), 7.75 (1H, d, JHH
3
=
7.82 Hz, Ar-H), 7.86 (1H, s, Ar-H). 13C NMR (50 MHz,
2
CDCl3): d 24.5, 35.6, 46.7 (CH2NH), 69.9 (t, JCF = 21.7 Hz,
1
2
C2F5C), 116.5 (qt, JCF = 260.1 Hz, JCF = 34.3 Hz, CF3CF2),
119.7 (qt, 1JCF = 288.2 Hz, 2JCF = 37.1 Hz, CF3CF2), 124.5 (t,
1JCF = 272.2 Hz, CF3Ar), 124.8 (bs, Ar), 125.3 (q,
3JCF = 4.1 Hz, Ar), 129.0 (Ar), 131.1 (q, JCF = 32.2 Hz, Ar),
2
131.4 (Ar), 141.2 (Ar). 19F NMR (188 MHz, CDCl3): d À122.2,
À120.2, À118.1, À116.6 (2F, AB-system, dA À122.26, dB,
À116.52, 2JAB = 274.9 Hz), À79.13 (3F, s, CF3). EIMS 70 eV,
m/z (rel. int.): 332 [MÀH]+ (2), 314 [MÀF]+ (5), 214
[MÀC2F5]+ (100). CIMS isobutan, m/z (rel. int.): 334
[M+H]+ (100), 314 [MÀF]+ (11), 214 [MÀC2F5]+ (100).
HRMS (EI): calcd. for C13H11F8N (MÀH) 332.0685; found
332.0695.
2-tert-Butyl-2-(pentafluoroethyl)pyrrolidine (2a). Colour-
less liquid, bp 67–79 8C (12 Torr), 1H NMR (200 MHz, CDCl3):
d 1.06 (9H, t, 5JHF = 1.7 Hz, (CH3)3C), 1.63–2.15 (4H, m), 2.98–
3.15 (2H, m, CH2N). 13C NMR (90 MHz, CDCl3): d 25.8, 27.1
(3C, (CH3)3C), 29.9, 39.7 (Cq, (CH3)3C), 48.1 (CH2NH), 72.9 (t,
1
2
2JCF = 19.7 Hz, C2F5C), 119.6 (qt, JCF = 263.0 Hz, JCF
=
2-(4-Fluorophenyl)-2-(pentafluoroethyl)pyrrolidine
(2e).
1
2
1
32.4 Hz, CF3CF2), 120.4 (tq, JCF = 287.7 Hz, JCF = 37.9 Hz,
CF3CF2). 19F NMR (188 MHz, CDCl3): d À116.1, À114.7,
À110.1, À108.6 (2F, AB-system, dA À118.25, dB À106.53,
2JAB = 274.1 Hz), À78.00 (3F, CF3). EIMS 70 eV, m/z (rel. int.):
230 [MÀCH3]+ (7), 188 [MÀC4H9]+ (100), 126 [MÀC2F5]+ (2),
111 [MÀCH3, –C2F5]+ (4). HRMS (EI): calcd. for C9H13F5N
(MÀCH3) 230.0968; found 230.0968.
Colourless liquid, H NMR (200 MHz, CDCl3): d 1.58–1.97
(2H, m), 2.18–2.31 (2H, m, incl. 2.28 (1H, s, NH)), 2.52–2.66
(1H, m), 2.94–3.25 (2H, m, CH2N), 6.96–7.08 (2H, m, Ar-H),
7.48–7.55 (2H, m, Ar-H). 13C NMR (50 MHz, CDCl3): d 24.6,
2
35.3, 46.6 (CH2NH), 69.6 (t, JCF = 21.2 Hz, C2F5C), 111.2
1
2
(2C, d, JCF = 22.6 Hz, m-CArom), 116.7 (qt, JCF = 263.5 Hz,
2JCF = 33.9 Hz, CF3CF2), 119.8 (qt, 1JCF = 288.2 Hz,
3
2-Butyl-2-(pentafluoroethyl)pyrrolidine (2b). Colourless
2JCF = 36.7 Hz, CF3CF2), 129.7 (2C, d, JCF = 8.5 Hz, o-
1
1
liquid, bp 68–70 8C (12 Torr), H NMR (200 MHz, CDCl3):
C
Arom), 135.4 (Ar), 162.9 (d, JCF = 247.2 Hz, Ar). 19F NMR
d 0.78–0.84 (3H, m), 1.20–1.35 (4H, m), 1.45–1.88 (6H, m,
incl. 1.52 (1H, bs, NH)), 1.97–2.10 (1H, m), 2.84–3.00 (2H, m,
CH2N). 13C NMR (50 MHz, CDCl3): d 13.6 (CH3), 23.1, 25.4,
(188 MHz, CDCl3): d À122.2, À120.8, À118.3, À116.8 (2F,
AB-system, dA À123.18, dB À115.89, 2JAB = 274.9 Hz), À78.8
(3F, s, CF3). EIMS 70 eV, m/z (rel. int.): 282 [MÀH]+ (1), 164
[MÀC2F5]+ (100). CIMS isobutane, m/z (rel. int.): 284 [M+H]+
(100), 188 [MÀC6H4F]+ (10), 164 [MÀC2F5]+ (100). HRMS
(EI): calcd. for C12H10F6N (MÀH) 282.0717; found 282.0726.
2-(4-Methoxyphenyl)-2-(pentafluoroethyl)pyrrolidine (2f).
2
26.0, 31.2, 35.5, 47.6 (CH2NH), 66.9 (t, JCF = 19.8 Hz,
1
2
C2F5C), 117.5 (qt, JCF = 257.7 Hz, JCF = 33.8 Hz, CF3CF2),
120.3 (tq, 1JCF = 288.2 Hz, 2JCF = 37.5 Hz, CF3CF2). 19F NMR
(188 MHz, CDCl3): d À122.0, À120.5, À120.3, À118.9 (2F,
AB-system, dA À121.18, dB À119.65, 2JAB = 274.1 Hz), À79.1
(3F, CF3). EIMS 70 eV, m/z (rel. int.): 245 [M]+ (21), 244
[MÀH]+ (16), 226 [MÀF]+ (13), 216 [MÀ29]+ (24), 188
[MÀC4H9]+ (100), 126 [MÀC2F5]+ (68). HRMS (EI): calcd. for
C10H16F5N 245.1203; found 245.1195.
1
Colourless liquid, H NMR (200 MHz, CDCl3): d 1.66–1.99
(2H, m), 2.23–2.36 (2H, m, incl. 2.34 (1H, s, NH)), 2.51–2.66
(1H, m), 3.01–3.26 (2H, m, CH2N), 3.82 (3H, s, OCH3), 6.86–
6.94 (2H, m, Ar-H), 7.43–7.47 (2H, m, Ar-H). 13C NMR
(50 MHz, CDCl3): d 24.6, 34.9, 46.5 (CH2NH), 55.2 (OCH3),
2
2-(Pentafluoroethyl)-2-phenylpyrrolidine (2c). Colourless
1
liquid, H NMR (200 MHz, CDCl3): d 1.62–2.02 (2H, m),
69.5 (t, JCF = 21.4 Hz, C2F5C), 113.5 (2C, s, Ar), 115.4 (qt,
1JCF = 260.7 Hz, 2JCF = 33.9 Hz, CF3CF2), 120.0 (qt,
2
2.26–2.40 (2H, m, incl. 2.30 (1H, s, NH)), 2.57–2.72 (1H, m),
2.98–3.27 (2H, m, CH2N), 7.31–7.42 (3H, m, Ar-H), 7.54–7.58
(2H, m, Ar-H). 13C NMR (50 MHz, CDCl3): d 24.5, 35.1, 46.5
1JCF = 287.8 Hz, JCF = 36.9 Hz, CF3CF2), 128.5 (2C, s, Ar),
130.9 (Ar), 159.3 (CArom-OCH3). 19F NMR (188 MHz,
CDCl3): d À122.0, À120.5, À118.4, À117.0 (2F, AB-system,

394
N.E. Shevchenko et al. / Journal of Fluorine Chemistry 129 (2008) 390–396
dA À122.70, dB À116.18, 2JAB = 271.2 Hz), À78.8 (3F, s, CF3).
EIMS 70 eV, m/z (rel. int.): 294 [MÀH]+ (2), 176 [MÀC2F5]+
(100), 133 [MÀ162]+ (12). CIMS isobutane, m/z (rel. int.): 296
[M+H]+ (100), 176 [MÀC2F5]+ (27). HRMS (EI): calcd. for
C12H11F5N (MÀH) 294.0917; found 294.0912.
EIMS 70 eV, m/z (rel. int.): 258 [MÀCH3]+ (72), 216
[MÀC4H9]+ (100), 154 [MÀC2F5]+ (15). HRMS (EI): calcd.
for C11H17F5N (MÀCH3) 258.1281; found 258.1273.
2-Pentafluoroethyl-2-phenylazapane (2l). Colourless liquid,
1H NMR (360 MHz, CDCl3): d 1.34–1.56 (4H, m), 1.64–1.80
(2H, m), 2.01 (1H, bs, NH), 2.32–2.39 (1H, m), 2.51–2.58 (1H,
m), 2.81–2.87 (1H, m), 3.10–3.17 (1H, m), 7.33–7.41 (3H, m,
Ar-H), 7.59–7.61 (2H, m, Ar-H). 13C NMR (90 MHz, CDCl3):
d 23.8, 30.7, 34.1, 34.8 (bs, CH2(Cq)C2F5), 44.5 (CH2NH), 66.8
2-(2-Furyl)-2-pentafluoroethylpyrrolidine (2g). Colourless
1
liquid, H NMR (200 MHz, CDCl3): d 1.69–2.04 (2H, m),
2.25–2.42 (2H, m), 2.51 (1H, s, NH), 2.96–3.19 (1H, m), 2.98–
3.27 (2H, m, CH2N), 6.34–6.38 (2H, m, Furyl), 7.40–7.41 (1H,
m, Furyl). 13C NMR (50 MHz, CDCl3): d 24.7, 32.5, 46.5
2
1
(t, JCF = 19.8 Hz, C2F5C), 117.6 (qt, JCF = 263.0 Hz,
2JCF = 33.8 Hz, CF3CF2), 120.6 (tq, 1JCF = 288.6 Hz,
2JCF = 37.2 Hz, CF3CF2). 19F NMR (188 MHz, CDCl3): d
À117.0, À118.5, À120.4, À121.9 (2F, AB-system, dA
2
(CH2NH), 66.9 (t, JCF = 22.9 Hz, C2F5C), 115.6 (qt,
1JCF = 259.6 Hz, 2JCF = 34.5 Hz, CF3CF2), 119.7 (qt,
2
1JCF = 287.6 Hz, JCF = 36.8 Hz, CF3CF2), 108.4 (Cq, Furyl),
110.6 (2C, s, Furyl), 142.8 (1C, s, Furyl). 19F NMR (188 MHz,
CDCl3): d À123.7, À122.3, À120.8, À119.4 (2F, AB-system,
dA À125.00, dB À120.34, 2JAB = 270.3 Hz), À80.6 (3F, s, CF3).
EIMS 70 eV, m/z (rel. int.): 255 [M]+ (4), 254 [MÀH]+ (17),
236 [MÀF]+ (12), 136 [MÀC2F5]+ (100). HRMS (EI): calcd.
for C12H11F5N (MÀH) 255.0812; found 255.0807.
À122.55, dB À116.36, JAB = 275.0 Hz), À77.6 (3F, CF3).
2
EIMS 70 eV, m/z (rel. int.): 293 [M]+ (4), 292 [MÀH]+ (12),
264 [MÀCH2NH]+ (11), 236 [MÀC3H6NH] (35), 174
[MÀC2F5]+ (100), 105 [MÀ188]+ (24). HRMS (EI): calcd.
for C14H16F5N 293.1203; found 293.1192.
4-(3,4-Dihydro-2H-pyrrol-5-yl)-4-(pentafluoroethyl)-1,4-
dihydropyridine (3). Yellow crystals, mp 117–119 8C, 1H NMR
(200 MHz, CDCl3): d 1.79–1.94 (2H, m), 2.56–2.64 (2H, m),
2-tert-Butyl-2-(pentafluoroethyl)piperidine (2i). Colourless
liquid, 1H NMR(360 MHz, CDCl3):d 1.03(9H, t, 5JHF = 1.3 Hz,
(CH3)3C), 1.46–1.73 (6H, m, incl. 1.70 (1H, bs, NH)), 1.87–1.91
(1H, m), 2.89–3.03(2H, m, CH2N). 13C NMR (90 MHz, CDCl3):
d 20.9, 23.8 (3C, (CH3)3C), 24.2, 26.3, 40.0 (Cq, (CH3)3C), 41.9
3
3.82–3.89 (2H, m, CH2N), 4.65 (2H, d, JHH = 7.5 Hz, C–
3
CHvinyl), 5.51 (1H, bs, NH), (2H, dd, JHH = 7.5 Hz,
3JHH = 4.9 Hz, HN-CHvinyl). 13C NMR (50 MHz, CDCl3): d
22.6, 33.8, 48.9 (t, 2JCF = 22.0 Hz, C2F5C), 60.5 (CH2N), 92,7
2
1
(CH2NH), 62.6 (t, JCF = 18.3 Hz, C2F5C), 121.6 (qt, JCF
=
266.7 Hz, 2JCF = 33.9 Hz, CF3CF2), 120.9 (tq, 1JCF = 288.6 Hz,
2JCF = 38.4 Hz, CF3CF2). 19F NMR (188 MHz, CDCl3): d
À111.0, À109.5, À108.7, À107.2 (2F, AB-system, dA À111.17,
dB À107.77, 2JAB = 286.2 Hz), À76.7 (3F, CF3). EIMS 70 eV, m/
z (rel. int.): 244 [MÀCH3]+ (37), 202 [MÀC4H9]+ (100), 174
[MÀ85]+ (10). HRMS (EI): calcd. for C10H15F5N (MÀCH3)
244.1125; found 244.1122.
(2C, CH-vinyl), 114.1 (qt, JCF = 260.2 Hz, JCF = 32.9 Hz,
CF3CF2), 119.6 (qt, 1JCF = 289.1 Hz, 2JCF = 37.2 Hz, CF3CF2),
127.8 (2C, HN-CH-vinyl), 177.3 (Cq N). 19F NMR (188 MHz,
CDCl3): d À121.0 (2F, CF2), À78.8 (3F, CF3). EIMS 70 eV, m/z
(rel. int.): 266 [M]+ (10), 198 [MÀC4H6N]+ (68), 147
[MÀC2F5]+ (100), 129 [MÀ137]+ (21). HRMS (EI): calcd.
for C11H11F5N2 266.08424; found 266.08344.
1
2
2-Phenyl-2-(pentafluoroethyl)piperidine (2j). Colourless
1
liquid, H NMR (200 MHz, CDCl3): d 1.25–1.53 (3H, m),
4.3. General procedure for the reaction of cyclic lactims
with pentafluoroethyllithium
1.68–1.74 (1H, m), 1.99–2.13 (1H, m, incl. 2.13 (1H, bs, NH)),
2.50–2.73 (2H, m), 2.88–2.95 (1H, m), 7.30–7.56 (5H, m, Ar-
H). 13C NMR (50 MHz, CDCl3): d 19.7, 26.0, 28.2 (bs,
A pentafluoroethane (1.8 g, 15 mmol) was passed through
solution of BuLi (4.8 ml of 2.5 M in hexane, 12 mmol) in THF
(100 ml) at À85 to À80 8C. After 15 min a solution of the
corresponding lactims (10 mmol) in THF (15 ml) and BF3
etherate (1.7 g, 12 mmol) was added subsequently. Then the
reaction mixture was stirred for 6 h at À78 8C, was quenched
by slow addition of 1N aqueous HCl (50 ml) and the organic
solvents were removed at reduce pressure. The residue was
quenched with water solution (50 ml) of K2CO3 (10 g). The
aqueous phase was extracted with ether (3Â 20 ml). The
combine extracts were dried over K2CO3, the ether was
evaporated at normal pressure. The residue was purified by
bulb-to-bulb recondensation under vacuum afforded corre-
sponding pentafluoroethylimines.
2
CH2(Cq)C2F5), 40.8 (CH2NH), 63.1 (t, JCF = 20.7 Hz,
1
2
C2F5C), 116.1 (qt, JCF = 260.5 Hz, JCF = 34.3 Hz, CF3CF2),
120.0 (tq, 1JCF = 288.4 Hz, 2JCF = 37.2 Hz, CF3CF2). 19F NMR
(188 MHz, CDCl3): d À121.8, À123.3, À123.5, À125.0 (2F,
AB-system, dA À124.12, dB À122.66, 2JAB = 277.6 Hz), À77.7
(3F, CF3). EIMS 70 eV, m/z (rel. int.): 278 [MÀH]+ (14), 260
[MÀF]+ (5), 160 [MÀC2F5]+ (100), 104 [MÀ175]+ (11).
HRMS (EI): calcd. for C13H13F5N (MÀH) 278.0968; found
278.0971.
2-tert-Butyl-2-(pentafluoroethyl)azapane (2k). Colourless
liquid, 1H NMR (360 MHz, CDCl3):
d 1.06 (9H, t,
5JHF = 1.7 Hz, (CH3)3C), 1.46–1.50 (4H, m), 1.71–1.74 (2H,
m), 1.82 (1H, bs, NH), 1.94–2.00 (2H, m), 2.90–2.93 (2H, m,
CH2N). 13C NMR (90 MHz, CDCl3): d 25.7, 27.7 (3C, t,
4JCF = 3.8 Hz, (CH3)3C), 30.4, 31.6, 33.7, 42.0 (Cq, (CH3)3C),
2-(Pentafluoroethyl)-3,4-dihydro-2H-pyrrole (4a). Colour-
less liquid, 1H NMR (200 MHz, CDCl3): d 1.94–2.10 (2H, m),
2.72–2.80 (2H, m), 4.02–4.14 (2H, m, CH2N). 13C NMR
(50 MHz, CDCl3): d 21.8, 34.0 (bs, CH2-Cq-C2F5), 62.4
(CH2N), 110.8 (qt, 1JCF = 252.6 Hz, 2JCF = 38.4 Hz, CF3CF2),
118.9 (tq, 1JCF = 286.2 Hz, 2JCF = 35.7 Hz, CF3CF2), 166.3 (t,
2JCF = 27.44 Hz, C2F5C). 19F NMR (188 MHz, CDCl3): d
2
45.8 (CH2NH), 69.3 (t, JCF = 17.4 Hz, C2F5C), 119.8 (qt,
2
1
1JCF = 267.9 Hz, JCF = 33.5 Hz, CF3CF2), 120.1 (tq, JCF
=
288.1 Hz, JCF = 38.0 Hz, CF3CF2). 19F NMR (188 MHz,
CDCl3): d À113.5, À112.0, À111.8, À110.3 (2F, AB-system,
2
2
dA À112.7, dB À111.2, JAB = 282.7 Hz), À76.7 (3F, CF3).

N.E. Shevchenko et al. / Journal of Fluorine Chemistry 129 (2008) 390–396
395
À118.2, (2F, CF2), À83.4 (3F, CF3). EIMS 70 eV, m/z (rel. int.):
References
201 [M]+ (71), 173 [MÀC2H4]+ (66), 132 [MÀCF3]+ (49), 82
[MÀC2F5]+ (50), 54 [C4H6]+ (100). CIMS NH3, m/z (rel. int.):
218 [M+NH3]+ (2), 216 [M+NH]+ (2), 202 [M+H]+ (100), 178
[MÀ23]+ (12). HRMS (EI): calcd. for C7H8F5N 201.0577;
found 201.0568.
[1] D. O’Hagan, Nat. Prod. Rep. 17 (2000) 435;
P.S. Watson, B. Jiang, B. Scott, Org. Lett. 2 (2000) 3679.
[2] For some review see:
P.D. Bailay, P.A. Millwood, P.D. Smith, J. Chem. Soc., Chem. Commun.
(1998) 633;
A. Mitchinson, A. Nadin, J. Chem. Soc., Perkin Trans. 1 (2000) 2862;
P.M. Weintraub, J.S. Sabol, J.M. Kane, D.R. Borcherding, Tetrahedron 59
(2003) 2953.
2-(Pentafluoroethyl)-2,3,4,5-tetrahydropyridine (4b). Col-
1
ourless liquid, H NMR (360 MHz, CDCl3): d 1.62–1.68 (2H,
m), 1.73–1.80 (2H, m), 2.30–2.33 (2H, m), 3.79–3.82 (2H, m,
CH2N). 13C NMR (50 MHz, CDCl3): d 18.3, 21.1, 24.1 (bs,
´ ´ ´
[3] J.P. Begue, D. Bonnet-Delpon, Chimie bioorganique et medicinale du
fluor, CNRS Editions, Paris, 2005;
1
CH2CqC2F5), 49.7 (CH2N), 110.6 (qt, JCF = 255.1 Hz,
P. Kirsch, Modern Fluoroorganic Chemistry, Wiley-VCH, Weinheim,
2004;
1
2
2JCF = 36.6 Hz, CF3CF2), 119.1 (tq, JCF = 286.4 Hz, JCF
=
2
3
F.M.D. Ismail, J. Fluorine Chem. 118 (2002) 27;
J.T. Welch, Tetrahedron 43 (1987) 3123.
36.4 Hz, CF3CF2), 160.2 (tq, JCF = 25.9 Hz, JCF = 0.8 Hz,
C2F5C). 19F NMR (188 MHz, CDCl3): d À120.5, (2F, CF2),
À82.7 (3F, CF3). EIMS 70 eV, m/z (rel. int.): 187 [M]+ (100),
159 [MÀCH2N]+ (76), 90 [MÀ97]+ (26), 68 [MÀC2F5]+ (16).
HRMS (EI): calcd. for C6H6F5N 187.04204; found 187.04158.
[4] O.S. Pedersen, E.B. Pedersen, Synthesis (2000) 479.
[5] M.L.P. Price, W.J. Jorgensen, J. Am. Chem. Soc. 122 (2000) 9455.
[6] P. Lin, J. Jiang, Tetrahedron 56 (2000) 3635.
[7] For representative examples of piperidines see:
A. Bariau, W.B. Jatoi, P. Calinaud, Y. Troin, J.-L. Canet, Eur. J. Org.
Chem. (2006) 3421;
4.4. 2-(Pentafluoroethyl)proline (5)
S. Gille, A. Ferry, T. Billard, B.R. Langlois, J. Org. Chem. 68 (2003)
8932;
4.4.1. Method A, ozonolysis
G. Margueur, J. Legros, F. Meyer, M. Ourevitch, B. Grousse, D. Bonnet-
Delpon, Eur. J. Org. Chem. (2006) 3421;
Ozone was passed through a solution of the amine 2 g
(1.28 g, 5 mmol) in methanol (75 ml) at À78 8C. When blur
color was appeared the reaction was stopped and excess of
ozone was removed by oxygen stream. Evaporation of the
solvent gave the crude product as yellowish solid which was
purified by washing with dichloromethane.
For representative examples of pyrrolidines see:
K. Itsumaro, J. Shuichi, S. Kazuyuki, O. Masaaki, A. Akira, Heterocyles
54 (2001) 589;
J. Legros, F. Meyer, M. Coliboeuf, B. Crousse, D. Bonnet-Delpon, J.-P.
Begue, J. Org. Chem. 68 (2003) 6444;
A. Hoffmann-Roeder, P. Seiler, F. Diederich, Org. Biomol. Chem. 2 (2004)
2267.
[8] G. Magueur, B. Crousse, D. Bonnet-Delpon, Tetrahedron Let. B6 (2005)
2219;
4.4.2. Method A, oxidation with RuCl3
To a solution of sodium periodate (8.5 g, 40 mmol) in a
mixed solvent carbon tetrachloride/acetonitrile/water (3/3/2,
60 ml) was added an aqueous solution of RuCl3ÁxH2O (0.05 g,
0.5 mmol). After stirring reaction mixture for 15 min at r.t. a
solution of the amine 2 g (1.28 g, 5 mmol) in carbon
tetrachloride (5 ml) was added in one portion. After a further
15 min, the reaction mixture was diluted with water (100 ml)
and extracted with ethyl acetate (3Â 30 ml). The combined
organic extracts were washed with brine, filtered through celite
and evaporated in vacuum. The crude product was purified by
precipitation from alkali water solution by adding of 1N
aqueous HCl to pH 5.5.
G.K.S. Prakash, M. Mandal, G.A. Olah, Synlett (2001) 77.
[9] M. Andrzejewska, L. Yepez-Mulia, R. Ceddilo-Rivera, A. Tapia, L. Vilpo,
J. Vilpo, Z. Kazimierczuk, Eur. J. Med. Chem. 37 (2002) 973;
A. Jihansson, A. Poliakov, E. Akerblom, K. Wiklund, G. Lindeberger, S.
Winiwarter, U.H. Danielson, B. Samuelsson, A. Hallberg, Bioorg. Med.
Chem. 11 (2003) 2551.
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Roeschenthaler, J. Barten, US Patent (2005) 6,872,861.
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K.L. Sorgi, A.C. Maryanoff, D.F. McComsey, B.E. Maryanoff, Org.
Synth. 75 (1998) 215.
[12] V.G. Nenajdenko, E.P. Zakurdaev, E.S. Balenkova, Tetrahedron Lett. 43
(2002) 8449;
White crystals, mp 168–169 8C, 1H NMR (200 MHz, D2O): d
1.64–1.98 (2H, m), 2.32–2.61 (2H, m), 3.23–3.37 and 3.75–3.85
V.G. Nenajdenko, A.M. Gololobov, E.P. Zakurdaev, E.S. Balenkova, Izv.
AN Ser. Khim. 52 (2003) 2473;
V.G. Nenajdenko, E.P. Zakurdaev, E.V. Prusov, E.S. Balenkova, Izv. AN
Ser. Khim. 53 (2004) 2866;
(2H, m, CH2N), 8.16 (1H, bs, NH). 13C NMR (90 MHz, D2O): d
2
22.1, 34.7, (bs, CH2CqC2F5), 47.2 (CH2N), 72.8 (t, JCF
=
V.G. Nenajdenko, E.P. Zakurdaev, E.S. Balenkova, Izv. AN Ser. Khim. 54
(2005) 220;
1
2
23.6 Hz, C2F5C), 115.6 (qt, JCF = 260.5 Hz, JCF = 34.7 Hz,
CF3CF2), 119.8 (tq, 1JCF = 287.8 Hz, 2JCF = 37.2 Hz, CF3CF2),
167.2 (CO2). 19F NMR (188 MHz, CDCl3): d À115.0, À113.5,
À113.3, À111.8 (2F, AB-system, dA À114.20, dB À112.60,
2JAB = 281.0 Hz), À78.7 (3F, CF3). EIMS 70 eV, m/z (rel. int.):
233 [M]+ (3), 216 [MÀF]+ (28), 188 [MÀCO2H]+ (100). HRMS
(EI): calcd. for C7H8F5NO2 233.0475; found 233.0471.
E.P. Zakurdaev, V.G. Nenajdenko, E.S. Balenkova, Izv. AN Ser. Khim. 54
(2005) 1219.
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[16] The Alkaloids, Special Periodic Report, The Chemistry Society of Lon-
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Acknowledgment
J.C. Jaen, V.E. Gregor, C. Lee, R. Davis, M. Emmerling, Bioorg. Med.
Chem. Lett. 6 (1996) 737.
The authors thank the Deutsche Forschungsgemeinschaft
(436 RUS 113/812/0-1) for financial support of this work.
[17] C.A. Zezza, M.B. Smith, B.A. Ross, A. Arhin, P.L.A. Cronin, J. Org.
Chem. 49 (1984) 4397 (and refernces therein).

396
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K.L. Sorgi, C.A. Maryanoff, D.F. McComsey, B.E. Maryanoff, Org.
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5922.
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A.B. Koldobsky, V.E. Vakhmistrov, E.V. Solodova, O.S. Sholova, V.N.
Kalinin, Doklady Akad. Nauk 387 (2002) 61 (Eng. Trans.);
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[22] For some examples see:
P.W.R. Harris, M.A. Brimble, V.J. Muir, M.Y.H. Lai, N.S. Trotter, D.J.
Callis, Tetrahedron 61 (2005) 10018;
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