Synthesis of α-trifluoromethyl-phenethylamines from α-trifluoromethyl β-aryl enamines and β-chloro-β- (trifluoromethyl)styrenes

Article abstract of DOI:10.1016/j.jfluchem.2011.06.030

A novel synthetic approach towards α-trifluoromethyl-phenethylamines was elaborated by reduction of the electron deficient β-aryl-α- trifluoromethyl enamines and imines with sodium cyanoborohydride in the presence of trifluoroacetic acid. The starting imines were prepared by the reaction of primary amines with β-aryl-α-trifluoromethyl enamines or β-chloro-β-(trifluoromethyl)styrenes.

Full text of DOI:10.1016/j.jfluchem.2011.06.030

Journal of Fluorine Chemistry 132 (2011) 1247–1253
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of
a
-trifluoromethyl-phenethylamines from
a-trifluoromethyl
b
-aryl enamines and
b
-chloro- -(trifluoromethyl)styrenes
b
Vasiliy M. Muzalevskiy a, Aleksey V. Shastin b, Elizabeth S. Balenkova a, Gu¨nter Haufe c,
Valentine G. Nenajdenko
*
,
a,**
a Moscow State University, Department of Chemistry, Leninskie Gory, Moscow 119992, Russia
b Institute of Problems of Chemical Physics, Chernogolovka, Moscow Region 142432, Russia
c
¨
¨
¨
¨
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster, D-48149 Munster, Germany
A R T I C L E I N F O
A B S T R A C T
Article history:
A novel synthetic approach towards a-trifluoromethyl-phenethylamines was elaborated by reduction of
Received 1 April 2011
the electron deficient
the presence of trifluoroacetic acid. The starting imines were prepared by the reaction of primary amines
with -aryl- -trifluoromethyl enamines or -chloro- -(trifluoromethyl)styrenes.
ß 2011 Elsevier B.V. All rights reserved.
b-aryl-a-trifluoromethyl enamines and imines with sodium cyanoborohydride in
Received in revised form 18 June 2011
Accepted 21 June 2011
Available online 6 July 2011
b
a
b
b
Dedicated to Dr. Alain Tressaud
awarded with the price for
creativity in fluorine chemistry.
Keywords:
b-Chloro-
b-(trifluoromethyl)styrenes
b
-Aryl- -trifluoromethyl enamines
a
Reduction
-Trifluoromethyl-phenethylamines
a
Primary amines
Transamination
Trifluoromethyl alcohols
1. Introduction
activities such as analgesic, antibacterial, antiviral, antimalarial,
antitumor, antileukemic, and anti-Parkinson’s. Also the very
well-known analgesic morphine can be considered as an
isoquinoline derivative.
On the other hand, the unique complex of physical and
biological properties provided by fluorine as a substituent [4–11]
resulted in numerous investigations of fluorinated compounds in
recent decades [12–15]. This led to remarkable results in the
design of new drugs [16–18].
The phenethylamine moiety is an important fragment present
in many biologically relevant compounds, e.g. in catecholamine
neurotransmitters. Phenethylamines have multiple neuronal
effects such as inhibition of neurotransmitter reuptake, increas-
ing of transmitter release and inhibition of monoamine oxidases
[1]. As a result, the phenethylamine moiety is a part of numerous
drugs and naturally occurring physiologically active compounds
(Fig. 1). For example amphetamine, mescaline and 3,4-methy-
lendioxy-N-methylamphetamine (MDMA) have the core of
phenethyl amine [2,3]. Moreover, phenethylamine is an impor-
tant structural unit of the large family of isoquinoline alkaloids.
These natural compounds exhibit a broad range of biological
A decade ago, a catalytic olefination reaction of aldehydes as
well as ketones was discovered by our research group [19]. Using
this reaction, various fluorinated alkenes were synthesized,
including
-bromo-
the vinylic halogen atom can be easily substituted by different
nucleophiles giving -fluoro- and -trifluoromethylacrylonitriles
[23], -fluoro- -arylvinyl sulfones [24], trifluoromethyl vinyl-
sulfides [25], alkoxy- -(trifluoromethyl)styrenes [26], CF3-
b
-bromo-
b-fluorostyrenes [20], b-chloro- [21] and
b
b-(trifluoromethyl)styrenes [22]. In such compounds,
a
a
a
b
* Corresponding author. Tel.: +49 251 83 33281; fax: +49 251 83 9772.
** Corresponding author. Tel.: +7 495 9392276; fax: +7 495 9328846.
E-mail addresses: haufe@uni-muenster.de (G. Haufe),
b
substituted imidazolidines [27],
[28] and enamines [29].
a-trifluoromethyl-b-aryl imines
nen@acylium.chem.msu.ru (V.G. Nenajdenko).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.06.030

1248
V.M. Muzalevskiy et al. / Journal of Fluorine Chemistry 132 (2011) 1247–1253
Scheme 2. Reduction of enamine–imine mixtures 5 and 6.
biological relevance of the final products 7), in case of electron rich
aryl compounds of type 3 an alternative reaction path, the
formation of vinylogous amidinium salts, was observed [28].
Fig. 1. Phenethylamine-based physiologically active compounds.
a
-CF3-
b
-aryl enamines are very interesting captodative
2.2. One-pot transamination – hydrogenation of
-aryl enamines
a-trifluoromethyl-
olefins, having an electron donating amino group and the
electron withdrawing CF3-group at the double bond in geminal
position. Its hydrogenation seems to be the shortest way to
b
The ability of trifluoromethylated carbonyl compounds to form
stable semiaminals frequently leads to difficulties in further
transformations. However, the secondary amino group of -CF3-
aryl enamines can be replaced in acidic media, which allowed the
application of -CF3- -aryl enamines as convenient synthetic
obtain
a-CF3-phenethylamines, which can be expected to
possess manifold physiological activities due to the presence
of two very well-known pharmocophores, namely the phenethy-
lamine moiety and the CF3-group. In this paper we present a new
a
b-
a
b
straightforward pathway towards a variety of substituted
phenethylamines.
a
-CF3-
equivalents of the parent carbonyl compounds. Thus, the above
mentioned enamines were successfully applied as synthetic
equivalents of the corresponding trifluoromethylbenzyl ketones
in both the Fischer indole synthesis and the Pictet–Spengler
reaction [31]. Consequently, it would be very promising to apply
this strategy for transamination reactions and subsequent reduc-
2. Results and discussion
2.1. Hydrogenation of
trifluoromethyl imines
a-trifluoromethyl-b-aryl enamines and
tion. Indeed, transamination of
a-CF3-b-aryl enamines 1 with
primary amines in acidic media gave trifluoromathylated imines
possibly in a mixture with the tautomeric enamines. These
products can be used for the synthesis of a-CF3-phenethylamines.
To the best of our knowledge, only one example of synthesis of
-CF3-phenethylamines by reduction of -CF3- -aryl enamines is
a
a
b
known. The method is based on catalytic hydrogenation with Pd/C
as a catalyst [30]. We decided to explore NaBH3CN as an alternative
reagent. The reduction of enamines 1 was carried out in THF at
room temperature in the presence of TFA. As a result, the
trifluoromethyl substituted amines 2 with a secondary amine
moiety were prepared in moderate to high yields (Scheme 1).
Initially, we investigated the influence of the solvent and the
acid on the reaction outcome. The enamine 1a bearing a nitro
group in the aryl part and benzylamine (4c) were used as a model
system. Since imines are not very stable [32] and can be easily
hydrolyzed to the corresponding ketones, the intermediate imine
5ac and its tautomer 6ac were not isolated but NaBH3CN was
added just after the transamination was completed. When HCl in
methanol or CH3SO3H in THF were applied as the reaction medium,
the enamine 1a was consumed within a few minutes, but after
reduction only the alcohol 8a was isolated in 65% yield. However,
suitable conditions were found to synthesize the desired amine
7ac. Thus, when the reaction of 1a with 4c was carried out in the
presence of TFA in THF at room temperature, the amine 7ac was
isolated in 78% yield. As a byproduct, the alcohol 8a (18%) was also
isolated (Scheme 3).
Previously, we reported that the reaction of
b-chloro-b-
(trifluoromethyl)styrenes with primary amines gave the
3
products of nucleophilic substitution, namely the enamine–imine
tautomers 5 and 6. We now investigated the reduction of these
enamine–imine mixtures with NaBH3CN (Scheme 2).
In case of methylamine, the intermediate mixtures of 5 and 6
were isolated (Table 1, entries 1 and 2). The reduction of 5 and 6
mixtures led directly to the amines 7aa and 7ca in high yields. The
iso-propyl substituted compounds 7ab and 7cb (Table 1, entries 3
and 4) were prepared in high yields by one pot reactions without
isolation of compounds 5 and 6. Unfortunately (with regard to the
The reactions of several enamines 1 with primary amines 4
were investigated. In most cases the corresponding amine 7 was
the major product, but always the formation of alcohols 8 was also
observed (Table 2).
Table 1
Synthesis of amines 7 from styrenes 3.
Entry
3
Ar
4
R
Yield of 5 + 6 [%]
Yield of 7 [%]
1
2
3
4
a
c
a
c
4-NO2C6H4
2-NO2C6H4
4-NO2C6H4
2-NO2C6H4
a
a
b
b
Me
Me
i-Pr
i-Pr
85 (1:3)
92
71
84
86
78 (1:2)
–
–
Scheme 1. Reduction of enamines 1.

V.M. Muzalevskiy et al. / Journal of Fluorine Chemistry 132 (2011) 1247–1253
1249
Scheme 3. One-pot synthesis of trifluoromethyl amines 7 from enamines 1.
The transformation was found to be very sensitive for both the
nature of the enamine 1 and the amine 4. The highest yields of the
desired amines 7 were obtained with the most nucleophilic
aliphatic amines 4 and enamines 1 with the strongly electron-
withdrawing nitro group. Also steric factors play a significant role,
leading to lower yields in case of ortho-nitro substituted enamine
1c in comparison with the para-nitro isomer 1a. 1-Aminoada-
mantane and 2-aminopyridine reacted slowly and about 5 days
were needed for the completion of the first step. The reduction step
gave only alcohol 8a (Table 2, entries 4 and 5). The enamine 1e
reacted very fast, but again the reaction led to the alcohol 8e
instead of the desired amine 7ec. Two explanations of alcohol 8
formation in the reaction mixture can be offered. The first
possibility is a hydrolysis of enamines 1, 5 and imines 6 into
ketones to give the alcohols 8 after reduction. It was reported, that
protonation of enamines 1 with TFA is accompanied by hydrolysis
to some extent [33]. However, the source of water remained
unclear. Another explanation includes the addition of TFA to the
enamine forming an O-trifluoroacetyl aminal, which by elimina-
tion of trifluoroacetamide forms the corresponding ketone, which
leads to the alcohols 8 on succeeding reduction. More detailed
investigations are in progress and will be published in due course.
NMR spectra were recorded on Bruker ARX 300 and Bruker AMX
400 spectrometers in CDCl3 with TMS, and CCl3F as internal
standards. IR spectra were obtained as films. Mass spectra were
measured on a MicroTof Bruker Daltonics (ESI-MS). The
a-CF3-b-
aryl enamines and -chloro- -trifluoromethylstyrenes 1 were
b
b
synthesized according to our previously reported procedures
[21,29]. 1H and 19F NMR spectra of compounds 8 are in agreement
with previously reported ones [34].
4.2. Synthesis of enamines 5 and azomethines 6 by the reaction of
chloro- -trifluoromethyl styrenes 1ac with primary amines
b-
b
The corresponding styrene 1ac (1 mmol) and an amine 4 (in the
case of methylamine 8 M solution in methanol was used)
(10 mmol) were stirred at room temperature for 1 day. The excess
of amine and the solvent were evaporated at reduced pressure and
the residue was purified by column chromatography in case of
methylamine derivatives (CH2Cl2/pentane 1:1) or used without
purification in case of iso-propylamine derivatives.
4.3. Mixture of enamine 5aa and imine 6aa
Yellow-orange solid. 3,3,3-Trifluoro-N-methyl-1-(4-nitrophenyl)-
prop-1-en-2-amine (5aa): 1H NMR (300 MHz, CDCl3): Z-isomer:
d
3. Conclusion
2.72 (d, J = 5.2 Hz, 3H, Me), 5.91 (s, 1H, CH55), 7.46 (d, J = 8.8 Hz, 2H,
Ar); E-isomer: 2.35 (d, J = 5.0 Hz, 3H, Me), 5.47 (s, 1H, CH55), 8.12
d
A new method was elaborated for the preparation of
phenethylamines by reduction of -CF3- -aryl enamine/imine
mixtures, obtained by the reaction of primary amines with -CF3-
-aryl enamines or -chloro- -(trifluoromethyl)styrenes. The
a-CF3-
(d, J = 8.3 Hz, 2H, Ar); 19F NMR (282 MHz, CDCl3): Z-isomer:
d
a
b
À68.7 (CF3); E-isomer:
isomer:
(C-2,6), 142.4 (C-1); E-isomer:
d
À63.2 (CF3); 13C NMR (75 MHz, CDCl3): Z-
a
d
30.3 (Me), 101.3 (q, J = 6.1 Hz, CH55); 123.6 (C-3,5), 129.0
b
b
b
d
33.7 (Me), 98.9 (q, J = 2.2 Hz,
transamination–reduction sequence was accompanied by the
formation of trifluoromethyl alcohols. The mechanisms of forma-
tion of these products will be studied in more detail in the future.
CH55); 123.3 (C-3,5), 128.9 (q, J = 2.6 Hz, C-2,6), 143.1 (C-1). N-
(1,1,1-Trifluoro-3-(4-nitrophenyl)propan-2-ylidene)methanamine
(6aa): 1H NMR (300 MHz, CDCl3):
d = 3.42 (s, 3H, Me), 3.96 (s, 2H,
CH2), 7.35 (d, J = 8.7 Hz, 2H, Ar), 8.21 (d, J = 8.7 Hz, 2H, Ar); 19F NMR
À72.6 (CF3); 13C NMR (75 MHz, CDCl3)
d 32.3
4. Experimental
(282 MHz, CDCl3):
d
(CH2), 39.6 (Me), 119.6 (q, J = 278.7 Hz, CF3), 124.2 (C-3,5), 129.1
(C-2,6), 141.2 (C-1), 147.1 (C-4), 157.2 (q, J = 32.9 Hz, C–CF3). Anal.
calcd. for C10H9F3N2O2: C, 48.79; H, 3.68; N, 10.38; found: C, 48.74;
H, 3.45; N, 10.33. ESI-MS (m/z): calcd. for C10H9F3N2O2Na [M]+
269.0508; found: 269.0508.
4.1. General
Column and TLC chromatography were performed using silica
gel Merck 60 or Merck 60F254 plates, respectively. 1H-, 13C- and 19
F
4.4. Mixture of 3,3,3-trifluoro-N-methyl-1-(2-nitrophenyl)prop-1-
en-2-amine (5ca) and N-(1,1,1-trifluoro-3-(2-nitrophenyl)propan-2-
ylidene)methanamine (6ca).
Table 2
Transamination of enamines 1 with primary amines 4, followed by reduction.
Entry
1
Ar
4
R
Yield 7 [%] Yield 8 [%]
Yellow-orange solid. 1H NMR (300 MHz, CDCl3):
d 2.55 (s, 3H,
1
a
a
a
a
a
c
c
c
c
c
c
b
d
e
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
2-NO2C6H4
2-NO2C6H4
2-NO2C6H4
2-NO2C6H4
2-NO2C6H4
2-NO2C6H4
2-BrC6H4
c
d
e
f
Bn
78
82
62
0
18
15
27
100
90
20
31
26
33
39
40
33
61
69
2
BnCH2
4-MeOC6H4
1-Ad
Me, Z-5ca), 2.84 (d, J = 4.6 Hz, 3H, Me, E-5ca), 3.40 (d, J = 1.8 Hz,
3H, Me, 6ca), 3.67 (br s, 1H, NH, Z-5ca), 3.93 (br s 1H, NH, E-5ca),
4.18 (s, 2H, CH2, 6ca), 5.81 (s, 1H, CH55, E-5ca), 6.15 (s, 1H, CH55,
Z-5ca), 7.21 (d, J = 8.8 Hz, 1H, Ar), 7.34–7.42 (m, 1H, Ar), 7.46–
7.54 (m, 1H, Ar), 7.56–7.65 (m, 1H, Ar), 8.00 (d, J = 8.8 Hz, 1H, Ar);
3
4
5
g
c
d
e
h
i
2-Py
0
6
Bn
37
35
19
41
7
BnCH2
4-MeOC6H4
n-Bu
8
E-isomer:
(dd, J = 8.2 Hz, J = 1.2 Hz, 1H, Ar), 8.10 (dd, J = 8.1 Hz, J = 1.4 Hz,
1H, Ar); 19F NMR (282 MHz, CDCl3):
d 2.35 (d, J = 5.0 Hz, 3H, Me), 5.47 (s, 1H, CH55), 8.00
9
10
11
12
13
14
4-MeOC6H4CH2 35
d
À68.9 (CF3, Z-5ca), À62.9
j
4-FC6H4CH2
Bn
39
53
23
0
(CF3, E-5ca), À72.3 (CF3, 6ca); 13C NMR (75 MHz, CDCl3): 30.4,
33.7, 39.4, 98.1 (q, J = 5.5 Hz), 119.4 (q, J = 278.9, CF3), 122.1 (q,
J = 275.4, CF3), 124.7, 125.6, 127.5, 128.6, 128.8, 130.4, 130.6,
c
d
c
4-MeO2CC6H4
4-ClC6H4
BnCH2
Bn

1250
V.M. Muzalevskiy et al. / Journal of Fluorine Chemistry 132 (2011) 1247–1253
131.6, 132.6, 132.4, 133.9, 136.5 (q, J = 30.3 Hz), 148.1, 157.0 (q,
J = 30.3 Hz). ESI-MS (m/z): calcd. for C10H9F3N2O2Na [M]+
269.0508; found: 269.0502.
J = 8.8 Hz, 2H, 4-NO2C6H4–); 19F NMR (282 MHz, CDCl3):
(d, J = 6.6 Hz, CF3); 13C NMR (75 MHz, CDCl3):
34.6 (q, J = 2.2 Hz,
CH2), 34.7 (Me), 61.9 (q, J = 27.1 Hz, C–CF3), 123.8, 126.5 (q,
J = 285.3 Hz, CF3), 130.1, 144.8, 147.0. ESI-MS (m/z): calcd. for
C
10H11F3N2O2H [M]+ 249.0845; found: 249.0819.
d
À74.14
d
4.5. Reduction of enamines 1 and mixtures of enamines 5 and imines 6
The corresponding enamine 1 or the mixture of enamines 5 and
imines 6 was dissolved in dry THF (2 mL) and then TFA (125 mg,
1.1 mmol) was added. The reaction mixture was cooled down to
0 8C and NaBH3CN (76 mg, 2 mmol) was added in three portions
during 30 min. Then the reaction mixture was allowed to warm up
to room temperature and kept at this temperature for 1 day. 0.1 M
NaOH (5 mL) was added, the organic layer was separated and the
aqueous phase was extracted with CH2Cl2 (3 Â 20 mL). The
combined extract was washed with brine (5 mL) and dried over
Na2SO4. The solvents were removed in vacuo and the residue was
purified by column chromatography (CH2Cl2/pentane, 1:1).
4.5.5. 1,1,1-Trifluoro-N-methyl-3-(2-nitrophenyl)propan-2-amine
(7ca)
Colorless oil. 1H NMR (300 MHz, CDCl3):
d 1.24 (br s, 1H, NH),
3.08 (dd, J = 14.6 Hz, J = 10.7 Hz, 1H, CH2), 3.24–3.35 (m, 2H, CH2,
CHCF3), 7.39–7.47 (m, 2H, 2-NO2C6H4–), 7.59 (td, J = 7.5 Hz,
J = 1.3 Hz, 1H, 2-NO2C6H4–), 8.20 (dd, J = 8.2 Hz, J = 1.3 Hz, 1H, 2-
NO2C6H4–); 19F NMR (282 MHz, CDCl3):
CF3); 13C NMR (75 MHz, CDCl3):
d
À74.39 (d, J = 6.9 Hz,
d
32.5 (CH2), 34.9 (Me), 61.7 (q,
J = 27.1 Hz, C–CF3), 125.0, 126.6 (q, J = 285.6 Hz, CF3), 128.1, 132.2,
133.0, 133.2, 149.7. Anal. calcd. for C10H11F3N2O2: C, 48.39; H, 4.47;
N, 11.29; found: C, 48.96; H, 4.39; N, 11.30; ESI-MS (m/z): calcd. for
C
10H11F3N2O2H [M]+ 249.0845; found: 249.0849.
4.5.1. 1-(1,1,1-Trifluoro-3-(4-nitrophenyl)propan-2-yl)pyrrolidine
(2a)
4.5.6. 1,1,1-Trifluoro-N-isopropyl-3-(4-nitrophenyl)propan-2-amine
Colorless oil. 1H NMR (300 MHz, CDCl3):
d
1.68–1.77 (m, 4H,
(7ab)
CH2CH2N), 2.68–2.80 (m, 2H, CH2CH2N), 2.90–3.08 (m, 4H,
CH2CH2N, CH2Ar), 3.51–3.65 (m, 1H, CHCF3), 7.39 (d, J = 8.8 Hz,
2H, 4-NO2C6H4–), 8.16 (d, J = 8.8 Hz, 2H, 4-NO2C6H4–); 19F NMR
(282 MHz, CDCl3):
(75 MHz, CDCl3):
Colorless oil. 1H NMR (300 MHz, CDCl3):
d 0.69 (d, J = 6.2 Hz, 3H,
Me), 0.98 (d, J = 6.2 Hz, 3H, Me), 1.00 (br s, 1H, NH), 2.72 (dd,
J = 13.8 Hz, J = 9.7 Hz, 1H, CH2), 2.81 (sept, J = 6.2 Hz, 1H, CH(Me)2),
3.16 (dd, J = 13.8 Hz, J = 3.8 Hz, 1H, CH2), 3.25–3.37 (m, 1H, CHCF3),
7.45 (d, J = 8.7 Hz, 2H, 4-NO2C6H4–), 8.20 (d, J = 8.7 Hz, 2H, 4-
d
À69.57 (d, J = 6.6 Hz, CF3); 13C NMR
d
24.1 (CH2CH2N), 32.3 (CH2Ar), 48.4
(CH2CH2N), 62.2 (q, J = 25.8 Hz, C–CF3), 123.5, 126.9 (q,
J = 291.1 Hz, CF3), 129.8, 146.2, 146.7. Anal. calcd. for
NO2C6H4–); 19F NMR (282 MHz, CDCl3):
CF3); 13C NMR (75 MHz, CDCl3):
22.2 (CH(CH3)2), 23.6 (CH(CH3)2),
d
À75.41 (d, J = 7.1 Hz,
d
C
13H15F3N2O2: C, 54.17; H, 5.24; N, 9.72; found: C, 54.82; H,
36.1 (CH2), 47.2 (CH(CH3)2), 58.2 (q, J = 27.1 Hz, C–CF3), 123.5,
126.5 (q, J = 284.2 Hz, CF3), 130.4, 145.0, 147.0. Anal. calcd. for
4.98; N, 9.63; ESI-MS (m/z): calcd. for C13H15F3N2O2H [M]+
289.1158; found: 289.1166.
C12H15F3N2O2: C, 52.17; H, 5.47; N, 10.14; found: C, 52.04; H, 5.26;
N, 10.13; ESI-MS (m/z): calcd. for C12H15F3N2O2H [M]+ 277.1158;
4.5.2. 1-(1,1,1-Trifluoro-3-(2-bromophenyl)propan-2-yl)pyrrolidine
found: 277.1155.
(2b)
Colorless oil. 1H NMR (300 MHz, CDCl3):
d
1.66–1.77 (m, 4H,
4.5.7. 1,1,1-Trifluoro-N-isopropyl-3-(2-nitrophenyl)propan-2-amine
CH2CH2N), 2.69–2.79 (m, 2H, CH2CH2N), 2.92–3.02 (m, 2H,
CH2CH2N), 3.04–3.10 (m, 2H, CH2Ar), 3.71–3.84 (m, 1H, CHCF3),
7.05–7.13 (m, 1H, 2-BrC6H4–), 7.19–7.26 (m, 2H, 2-BrC6H4–), 7.53
(7cb)
Colorless oil. 1H NMR (300 MHz, CDCl3):
d 0.55 (d, J = 6.2 Hz, 3H,
Me), 0.93 (d, J = 6.2 Hz, 3H, Me), 1.13 (br s, 1H, NH), 2.74 (sept,
J = 6.2 Hz, 1H, CH(Me)2), 3.05 (dd, J = 13.3 Hz, J = 10.3 Hz, 1H, CH2),
3.29 (dd, J = 13.3 Hz, J = 3.8 Hz, 1H, CH2), 3.31–3.42 (m, 1H, CHCF3),
7.39–7.46 (m, 2H, 2-NO2C6H4–), 7.57 (td, J = 7.5 Hz, J = 1.3 Hz, 1H,
2-NO2C6H4–), 7.96 (dd, J = 8.1 Hz, J = 1.2 Hz, 1H, 2-NO2C6H4–); 19
NMR (282 MHz, CDCl3):
(75 MHz, CDCl3):
(d, J = 7.7 Hz, 1H, 2-BrC6H4–); 19F NMR (282 MHz, CDCl3):
(d, J = 6.9 Hz, CF3); 13C NMR (75 MHz, CDCl3):
d
À69.53
d
24.2 (CH2CH2N),
32.4 (CH2Ar), 48.4 (CH2CH2N), 60.4 (q, J = 25.7 Hz, C–CF3), 124.4,
127.0 (q, J = 290.1 Hz, CF3), 127.2, 128.2, 131.7, 132.8, 137.4. Anal.
calcd. for C13H15BrF3N: C, 48.47; H, 4.69; N, 4.35; found: C, 48.37;
H, 4.73; N, 4.23; ESI-MS (m/z): calcd. for C13H15BrF3NH [M]+
322.0413; found: 322.0401.
F
d
À75.71 (d, J = 7.0 Hz, CF3); 13C NMR
d
21.8 (CH(CH3)2), 23.5 (CH(CH3)2), 33.5 (CH2),
47.3 (CH(CH3)2), 57.9 (q, J = 27.2 Hz, C–CF3), 124.8, 126.6 (q,
J = 284.4 Hz, CF3), 128.0, 132.4, 132.7, 133.5, 150.1. Anal. calcd. for
4.5.3. 1-(1,1,1-Trifluoro-3-(2-nitrophenyl)propan-2-yl)pyrrolidine
C12H15F3N2O2: C, 52.17; H, 5.47; N, 10.14; found: C, 52.18; H, 5.55;
(2c)
N, 10.18; ESI-MS (m/z): calcd. for C12H15F3N2O2H [M]+ 277.1158;
Yellowish oil. 1H NMR (300 MHz, CDCl3):
d
1.64–1.74 (m, 4H,
found: 277.1159.
CH2CH2N), 2.61–2.72 (m, 2H, CH2CH2N), 2.84–2.95 (m, 2H,
CH2CH2N), 3.16 (dd, J = 13.9 Hz, J = 4.7 Hz, 1H, CH2), 3.31 (dd,
J = 13.9 Hz, J = 9.3 Hz, 1H, CH2), 3.57–3.70 (m, 1H, CHCF3), 7.34–
7.43 (m, 2H, 2-NO2C6H4–), 7.54 (td, J = 7.6 Hz, J = 1.4 Hz, 1H, 2-
NO2C6H4–), 7.92 (dd, J = 8.2 Hz, J = 1.4 Hz, 1H, 2-NO2C6H4–); 19F
4.6. Synthesis of amines 7 and alcohols 8 by the reactions of
aryl enamines 1 with primary amines 4
a-CF3-b-
The enamine 1 (1 mmol), the primary amine 4 (1.2 mmol) and
dry THF (2 mL) were mixed in a 10 mL round-bottomed flask. TFA
(251 mg, 2.2 mmol) was added and the reaction mixture was
stirred for 2 days at room temperature. The reaction mixture was
cooled down to 0 8C and NaBH3CN (76 mg, 2 mmol) was added in
three portions during 30 min. Then the reaction mixture was
allowed to warm up to room temperature and kept at this
temperature for 1 day. 0.1 M NaOH (5 mL) was added, the organic
layer was separated, and the aqueous phase was extracted with
CH2Cl2 (3 Â 20 mL). The combined extract was washed with brine
(5 mL) and dried over Na2SO4. The solvents were removed in vacuo
and the residue was purified by column chromatography (CH2Cl2/
pentane, 1:1).
NMR (282 MHz, CDCl3):
(75 MHz, CDCl3):
d
À69.10 (d, J = 8.3 Hz, CF3); 13C NMR
d
24.0 (CH2CH2N), 29.8 (CH2Ar), 48.4 (CH2CH2N),
61.5 (q, J = 25.6 Hz, C–CF3), 124.7, 126.8 (q, J = 291.1 Hz, CF3), 127.7,
132.7, 133.2, 133.4, 149.7. ESI-MS (m/z): calcd. for C13H15F3N2O2H
[M]+ 289.1158; found: 289.1163.
4.5.4. 1,1,1-Trifluoro-N-methyl-3-(4-nitrophenyl)propan-2-amine
(7aa)
Colorless solid, m.p. 41–42 8C. 1H NMR (300 MHz, CDCl3):
d 1.35
(br s, 1H, NH), 2.46 (d, J = 1.1 Hz, 3H, Me), 2.85 (dd, J = 14.3 Hz,
J = 9.8 Hz, 1H, CH2), 3.11 (dd, J = 14.3 Hz, J = 3.9 Hz, 1H, CH2), 3.20–
3.32 (m, 1H, CHCF3), 7.44 (d, J = 8.8 Hz, 2H, 4-NO2C6H4–), 8.20 (d,

V.M. Muzalevskiy et al. / Journal of Fluorine Chemistry 132 (2011) 1247–1253
1251
4.6.1. N-Benzyl-1,1,1-trifluoro-3-(4-nitrophenyl)propan-2-amine
(m, 4H, Ph, 2-NO2C6H4–), 7.39 (td, J = 7.6 Hz, J = 1.6 Hz, 1H, 2-
NO2C6H4–), 7.47 (td, J = 7.6 Hz, J = 1.6 Hz, 1H, 2-NO2C6H4–), 7.93
(dd, J = 8.0 Hz, J = 1.6 Hz, 1H, 2-NO2C6H4–); 19F NMR (282 MHz,
(7ac)
Colorless oil. 1H NMR (300 MHz, CDCl3):
d 1.53 (br s, 1H, NH),
2.75 (dd, J = 14.1 Hz, J = 10.2 Hz, 1H, CH2), 3.11 (dd, J = 14.1 Hz,
J = 3.6 Hz, 1H, CH2), 3.24–3.36 (m, 1H, CHCF3), 3.70 (d, J = 13.4 Hz,
1H, Bn), 3.93 (d, J = 13.4 Hz, 1H, Bn), 6.98–7.05 (m, 2H, Ph), 7.13–
7.21 (m, 3H, Ph), 7.25 (d, J = 8.8 Hz, 2H, 4-NO2C6H4–), 8.10 (d,
CDCl3):
d
À74.91 (d, J = 7.0 Hz, CF3); 13C NMR (75 MHz, CDCl3):
d
32.7 (q, J = 2.4 Hz, CH2), 36.5, (CH2Bn), 49.5 (Bn), 60.4 (q,
J = 27.2 Hz, C–CF3), 125.0, 126.2, 126.7 (q, J = 285.2 Hz, CF3),
128.0, 128.4, 128.6, 132.1, 132.9, 133.3, 139.4, 149.7. Anal. calcd.
for C17H17F3N2O2: C, 60.35; H, 5.06; N, 8.28; found: C, 60.29; H,
4.94; N, 8.33; ESI-MS (m/z): calcd. for C17H17F3N2O2Na [M]+
361.11343; found: 361.11337.
J = 8.8 Hz, 2H, 4-NO2C6H4–); 19F NMR (282 MHz, CDCl3):
(d, J = 7.0 Hz, CF3); 13C NMR (75 MHz, CDCl3):
36.1 (CH2), 51.8
d
À74.34
d
(Bn), 59.0 (q, J = 27.4 Hz, C–CF3), 123.6, 126.6 (q, J = 285.3 Hz, CF3),
127.3, 128.2, 128.4, 130.2, 138.9, 144.7, 147.0. Anal. calcd. for
C
16H15F3N2O2: C, 59.26; H, 4.66; N, 8.64; found: C, 59.21; H, 4.48;
4.6.6. 4-Methoxy-N-(1,1,1-trifluoro-3-(2-nitrophenyl)propan-2-
N, 8.53; ESI-MS (m/z): calcd. for C10H11F3N2O2H [M]+ 325.1158;
yl)benzenamine (7ce)
found: 325.1175.
Yellow oil. 1H NMR (300 MHz, CDCl3):
d 3.20 (dd, J = 13.9 Hz,
J = 10.8 Hz, 1H, CH2), 3.44 (dd, J = 13.9 Hz, J = 3.9 Hz, 1H, CH2), 3.68
(s, 3H, OCH3), 4.17–4.29 (m, 1H, CHCF3), 6.42 (d, J = 9.0 Hz, 2H, 4-
CH3OC6H4–), 6.65 (d, J = 9.0 Hz, 2H, 4-CH3OC6H4–), 7.35–7.42 (m,
2H, 2-NO2C6H4–), 7.51 (td, J = 7.6 Hz, J = 1.5, 2H, 2-NO2C6H4–), 7.94
(dd, J = 7.6 Hz, J = 1.5, 2H, 2-NO2C6H4–); 19F NMR (282 MHz,
4.6.2. 1,1,1-Trifluoro-3-(4-nitrophenyl)-N-phenethylpropan-2-
amine (7ad)
Colorless oil. 1H NMR (300 MHz, CDCl3):
d 1.19 (br s, 1H, NH),
2.59–2.76 (m, 4H, CH2), 3.03–3.29 (m, 3H), 6.99–7.06 (m, 2H, Ph),
7.15–7.24 (m, 5H, Ph, 4-NO2C6H4–), 8.04 (d, J = 8.7 Hz, 2H, 4-
CDCl3):
d
À75.92 (d, J = 6.7 Hz, CF3); 13C NMR (75 MHz, CDCl3):
d
NO2C6H4–); 19F NMR (282 MHz, CDCl3):
d
À74.72 (d, J = 7.0 Hz,
33.0 (CH2), 55.6 (OCH3), 58.2 (q, J = 28.9 Hz, C–CF3), 114.7, 115.1,
125.2, 125.9 (q, J = 284.7 Hz, CF3), 128.4, 131.4, 133.0, 133.2, 140.1,
149.7, 153.0. Anal. calcd. for C16H15F3N2O3: C, 56.47; H, 4.44; N,
8.23; found: C, 56.25; H, 4.37; N, 8.28; ESI-MS (m/z): calcd. for
C16H15F3N2O3Na [M]+ 363.0927; found: 363.0918.
CF3); 13C NMR (75 MHz, CDCl3):
d 34.9 (q, J = 2.2 Hz, CH2), 36.3
(CH2Bn), 49.4 (Bn), 60.9 (q, J = 27.6 Hz, C–CF3), 123.7, 126.3, 126.4
(q, J = 285.0 Hz, CF3), 128.5, 128.6, 129.9, 139.1, 144.3, 146.9. Anal.
calcd. for C17H17F3N2O2: C, 60.35; H, 5.06; N, 8.28; found: C, 60.53;
H, 5.29; N, 8.13; ESI-MS (m/z): calcd. for C17H17F3N2O2H [M]+
339.1315; found: 339.1312.
4.6.7. N-(1,1,1-Trifluoro-3-(2-nitrophenyl)propan-2-yl)butan-1-
amine (7ch)
4.6.3. 4-Methoxy-N-(1,1,1-trifluoro-3-(4-nitrophenyl)propan-2-
Yellow oil. 1H NMR (300 MHz, CDCl3):
d 0.76 (t, J = 7.1 Hz, 3H,
yl)benzenamine (7ae)
CH3), 1.04–1.28 (m, 5H, NH, Bu), 2.33–2.43 (m, 1H, Bu), 2.69–2.80
(m, 1H, Bu), 3.07 (dd, J = 14.2 Hz, J = 10.8 Hz, 1H, CH2Ar), 3.25–3.38
(m, 2H, CH2Ar, CHCF3), 7.38–7.47 (m, 2H, 2-NO2C6H4–), 7.58 (td,
J = 7.6 Hz, J = 1.4, 2H, 2-NO2C6H4–), 7.98 (dd, J = 8.0 Hz, J = 1.3, 2H,
Yellow viscous oil. 1H NMR (300 MHz, CDCl3):
d 1.26 (br s, 1H,
NH), 2.96 (dd, J = 14.5 Hz, J = 9.4 Hz, 1H, CH2), 3.29 (dd, J = 14.5 Hz,
J = 4.0 Hz, 1H, CH2), 3.71 (s, 3H, OCH3), 4.02–4.13 (m, 1H, CHCF3),
6.51 (d, J = 9.0 Hz, 2H, 4-CH3OC6H4–), 6.71 (d, J = 9.0 Hz, 2H, 4-
CH3OC6H4–), 7.40 (d, J = 8.7 Hz, 2H, 4-NO2C6H4–), 8.14 (d,
2-NO2C6H4–); 19F NMR (282 MHz, CDCl3):
CF3); 13C NMR (75 MHz, CDCl3):
13.8 (Me), 19.8 (CH2), 32.3
d
À74.95 (d, J = 7.0 Hz,
d
J = 8.7 Hz, 2H, 4-NO2C6H4–); 19F NMR (282 MHz, CDCl3):
d
(CH2Ar), 32.9 (CH2), 48.0 (CH2NH), 60.4 (q, J = 27.1 Hz, C–CF3),
125.0, 126.6 (q, J = 290.4 Hz, CF3), 128.1, 132.5, 132.9, 133.4, 149.7.
Anal. calcd. for C13H17F3N2O2: C, 53.79; H, 5.90; N, 9.65; found: C,
54.31; H, 6.14; N, 9.16; ESI-MS (m/z): calcd. for C13H17F3N2O2H
[M]+ 291.1315; found: 291.1317.
À75.28 (d, J = 6.7 Hz, CF3); 13C NMR (75 MHz, CDCl3):
d 35.5
(CH2), 55.6 (OCH3), 58.2 (q, J = 28.7 Hz, C–CF3), 114.9, 115.4, 123.8,
125.8 (q, J = 283.5 Hz, CF3), 130.1, 139.6, 143.8, 147.1, 153.4. Anal.
calcd. for C16H15F3N2O3: C, 56.47; H, 4.44; N, 8.23; found: C, 56.84;
H, 4.29; N, 8.06; ESI-MS (m/z): calcd. for C16H15F3N2O3Na [M]+
363.0927; found: 363.0943.
4.6.8. 1,1,1-Trifluoro-N-(4-methoxybenzyl)-3-(2-
nitrophenyl)propan-2-amine (7ci)
4.6.4. N-Benzyl-1,1,1-trifluoro-3-(2-nitrophenyl)propan-2-amine
Colorless oil. 1H NMR (300 MHz, CDCl3):
d 1.54 (br s, 1H, NH),
(7cc)
3.02 (dd, J = 14.0 Hz, J = 11.0 Hz, 1H, CH2), 3.31 (dd, J = 14.0 Hz,
J = 3.6 Hz, 1H, CH2), 3.31–3.40 (m, 1H, CHCF3), 3.58 (d, J = 13.1 Hz,
1H, Bn), 3.63 (d, J = 13.1 Hz, 1H, Bn), 6.65 (d, J = 8.7 Hz, 2H, 4-
CH3OC6H4–), 6.85 (d, J = 8.7 Hz, 2H, 4-CH3OC6H4–), 7.29 (dd,
J = 7.8 Hz, J = 1.5 Hz, 1H, 2-NO2C6H4–), 7.43 (td, J = 7.8 Hz,
J = 1.5 Hz, 1H, 2-NO2C6H4–), 7.52 (td, J = 7.8 Hz, J = 1.5 Hz, 1H, 2-
NO2C6H4–), 7.96 (dd, J = 7.8 Hz, J = 1.5 Hz, 1H, 2-NO2C6H4–); 19F
Colorless oil. 1H NMR (300 MHz, CDCl3):
d 1.58 (br s, 1H, NH),
3.03 (dd, J = 13.4 Hz, J = 10.4 Hz, 1H, CH2), 3.31 (dd, J = 13.4 Hz,
J = 3.7 Hz, 1H, CH2), 3.31–3.42 (m, 1H, CHCF3), 3.64 (d, J = 13.3 Hz,
1H, Bn), 3.90 (d, J = 13.3 Hz, 1H, Bn), 6.90–6.96 (m, 2H, Ph), 7.09–
7.16 (m, 3H, Ph), 7.29 (dd, J = 7.7 Hz, J = 1.4 Hz, 1H, 2-NO2C6H4–),
7.42 (td, J = 7.7 Hz, J = 1.4 Hz, 1H, 2-NO2C6H4–), 7.51 (td, J = 7.7 Hz,
J = 1.4 Hz, 1H, 2-NO2C6H4–), 8.12 (dd, J = 7.7 Hz, J = 1.4 Hz, 1H, 2-
NO2C6H4–); 19F NMR (282 MHz, CDCl3):
CF3); 13C NMR (75 MHz, CDCl3):
32.9 (CH2), 51.9 (Bn), 58.6 (q,
J = 27.1 Hz, C–CF3), 125.0, 126.8 (q, J = 285.6 Hz, CF3), 127.1, 128.0,
128.1, 128.3, 128.8, 132.3, 132.9, 133.6, 149.7. Anal. calcd. for
NMR (282 MHz, CDCl3):
d
À74.67 (d, J = 7.0 Hz, CF3); 13C NMR
d
À74.62 (d, J = 6.9 Hz,
(75 MHz, CDCl3): d 33.0 (q, J = 2.4, CH2), 51.3 (Bn), 55.2 (OCH3), 58.2
d
(q, J = 27.1 Hz, C–CF3), 113.6, 125.0, 126.8 (q, J = 285.5 Hz, CF3),
128.0, 129.3, 131.0, 132.4, 132.9, 133.5, 149.9, 158.6. Anal. calcd.
for C17H17F3N2O3: C, 57.63; H, 4.84; N, 7.91; found: C, 57.24; H,
4.52; N, 7.79; ESI-MS (m/z): calcd. for C17H17F3N2O3Na [M]+
377.1083; found: 377.1077.
C
16H15F3N2O2: C, 59.26; H, 4.66; N, 8.64; found: C, 59.11; H, 4.59;
N, 8.60; ESI-MS (m/z): calcd. for C16H15F3N2O2Na [M]+ 347.09778;
found: 347.09780.
4.6.9. 1,1,1-Trifluoro-N-(4-fluorobenzyl)-3-(2-nitrophenyl)propan-
4.6.5. 1,1,1-Trifluoro-3-(2-nitrophenyl)-N-phenethylpropan-2-
2-amine (7cj)
amine (7cd)
Colorless oil. 1H NMR (300 MHz, CDCl3):
d 1.59 (br s, 1H, NH),
Colorless oil. 1H NMR (300 MHz, CDCl3):
d
1.19 (br s, 1H, NH),
3.06 (dd, J = 14.2 Hz, J = 11.2 Hz, 1H, CH2), 3.29 (dd, J = 14.2 Hz,
J = 3.5 Hz, 1H, CH2), 3.30–3.37 (m, 1H, CHCF3), 3.63 (d, J = 13.4 Hz,
1H, Bn), 3.87 (d, J = 13.4 Hz, 1H, Bn), 6.76–6.84 (m, 2H, 4-FC6H4–),
6.86–6.93 (m, 2H, 4-FC6H4–), 7.29 (dd, J = 7.8 Hz, J = 1.5 Hz, 1H, 2-
2.53–2.70 (m, 3H, CH2Bn), 2.99 (dd, J = 13.7 Hz, J = 10.3 Hz, 1H,
CH2), 3.00–3.10 (m, 1H, CH2Bn), 3.26 (dd, J = 13.7 Hz, J = 3.9 Hz, 1H,
CH2), 3.31–3.41 (m, 1H, CHCF3), 7.00–7.05 (m, 2H, Ph), 7.13–7.28

1252
V.M. Muzalevskiy et al. / Journal of Fluorine Chemistry 132 (2011) 1247–1253
NO2C6H4–), 7.45 (td, J = 7.8 Hz, J = 1.5 Hz, 1H, 2-NO2C6H4–), 7.53
(td, J = 7.8 Hz, J = 1.5 Hz, 1H, 2-NO2C6H4–), 7.97 (dd, J = 7.8 Hz,
4.6.15. Methyl 4-(3,3,3-trifluoro-2-hydroxypropyl)benzoate (8d)
Colorless solid, m.p. 94–95 8C. 1H NMR (300 MHz, CDCl3):
2.91
d
J = 1.5 Hz, 1H, 2-NO2C6H4–); 19F NMR (282 MHz, CDCl3):
d
À74.65
(dd, J = 14.2 Hz, J = 10.3 Hz, 1H, CH2), 2.93 (br s, 1H, OH), 3.08 (dd,
J = 14.2 Hz, J = 2.8 Hz, 1H, CH2), 3.88 (s, 3H, Me), 4.13–4.22 (m, 1H,
CHOH), 7.32 (d, J = 8.4 Hz, 2H, 4-CO2MeC6H4–), 7.95 (d, J = 8.4 Hz,
(d, J = 7.0 Hz, CF3), À115.69 (m, 4-FC6H4); 13C NMR (75 MHz,
CDCl3):
d 33.0 (q, J = 2.6, CH2), 51.0 (Bn), 55.2 (OCH3), 58.5 (q,
J = 27.3 Hz, C–CF3), 115.0 (d, J = 21.3 Hz), 125.0, 126.7 (q,
J = 285.8 Hz, CF3), 128.1, 129.7 (d, J = 8.2 Hz), 132.3, 132.9, 133.5,
134.7 (d, J = 3.0 Hz), 149.7, 161.9 (d, J = 245.1 Hz). Anal. calcd. for
2H, 4-CO2MeC6H4–); 19F NMR (282 MHz, CDCl3):
J = 6.6 Hz, CF3); 13C NMR (75 MHz, CDCl3):
d
À79.68 (d,
d
36.0, 52.2 (CO2Me),
71.1 (q, J = 31.1 Hz, C–CF3), 124.8 (q, J = 282.3 Hz, CF3), 128.8, 129.5,
129.9, 141.5, 167.2 (CO2Me). Anal. calcd. for C11H11F3O3: C, 53.23;
H, 4.47; found: C, 53.64; H, 4.50. ESI-MS (m/z): calcd. for
C
11H11F3O3Na [M]+ 271.0552; found: 271.0557.
C
16H14F4N2O2: C, 56.14; H, 4.12; N, 8.18; found: C, 55.62; H, 4.01;
N, 8.22; ESI-MS (m/z): calcd. for C16H14F4N2O2H [M]+ 343.1064;
found: 343.1061.
4.6.10. N-Benzyl-1,1,1-trifluoro-3-(2-bromophenyl)propan-2-amine
4.6.16. 3-(4-Chlorophenyl)-1,1,1-trifluoropropan-2-ol (8e)
(7bc)
Colorless crystals, m.p. 66–67 8C (lit.: 66–67 8C [34]). 1H NMR
Colorless oil. 1H NMR (300 MHz, CDCl3):
d
1.50 (br s, 1H, NH),
(300 MHz, EDCl3): d 2.16 (br s, 1H, OH), 2.84 (dd, J = 14.3 Hz,
2.78 (dd, J = 13.9 Hz, J = 10.8 Hz, 1H, CH2), 3.20 (dd, J = 13.9 Hz,
J = 3.7 Hz, 1H, CH2), 3.38–3.50 (m, 1H, CHCF3), 3.63 (d, J = 13.4 Hz,
1H, Bn), 3.86 (d, J = 13.4 Hz, 1H, Bn), 6.92–6.97 (m, 2H, Ph), 7.10–
7.20 (m, 4H, Ph, 2-BrC6H4–), 7.25 (td, J = 7.6 Hz, J = 1.2 Hz, 1H, 2-
BrC6H4–), 7.53 (dd, J = 7.9 Hz, J = 1.2 Hz, 1H, 2-BrC6H4–); 19F NMR
J = 10.0 Hz, 1H, CH2), 3.02 (dd, J = 14.3 Hz, J = 3.1 Hz, 1H, CH2),
3.98–4.11 (m, 1H, CHOH), 7.21 (d, J = 8.5 Hz, 2H, 40-ClC6H4–), 7.32
(d, J = 8.5 Hz, 2H, 4-ClC6H4–); 19F NMR (282 MHz, CDCl3):
(d, J = 6.5 Hz, CF3).
d
À79.61
(282 MHz, CDCl3):
CDCl3):
d
À75.07 (d, J = 7.1 Hz, CF3); 13C NMR (75 MHz,
Acknowledgements
d
35.8 (CH2), 52.2 (Bn), 57.7 (q, J = 27.3 Hz, C–CF3), 124.8,
126.9 (q, J = 284.5 Hz, CF3), 127.0, 127.4, 128.0, 128.3, 128.7, 132.0,
133.1, 136.2, 139.2. ESI-MS (m/z): calcd. for C16H15BrF3NH [M]+
358.0413; found: 358.0410.
This project was supported by the Deutsche Forschungsge-
meinschaft (DFG) (grant no. AOBJ 57877), the Russian Foundation
for Basic Research (grant no. 10-03-00897-a) and Federal Special
Program (grant no. P962).
4.6.11. Methyl 4-(3,3,3-trifluoro-2-
(phenethylamino)propyl)benzoate (7dd)
Colorless oil. 1H NMR (300 MHz, CDCl3):
d 1.06 (br s, 1H, NH),
References
2.54–2.72 (m, 4H, CH2), 3.01–3.10 (m, 2H), 3.17–3.29 (m, 1H), 3.94
(s, CO2CH3), 6.99–7.02 (m, 2H, Ph), 7.14–7.23 (m, 5H, Ph, 4-
CO2MeC6H4–), 7.91 (d, J = 8.7 Hz, 2H, 4-CO2MeC6H4–); 19F NMR
[1] T. Nogrady, D.F. Weaver, Medicinal Chemistry: A Molecular and Biochemical
Approach, Oxford University Press, New York, 2005.
[2] R. Laing, J.A. Siegel (Eds.), Hallucinogenes: A Forensic Drug Handbook, Academic
Press, London, 2003.
[3] M. Chrzanowska, M.D. Rozwadowska, Chem. Rev. 104 (2004) 3341–3370.
[4] J.T. Welch, S. Eswarakrishnan, Fluorine in Bioorganic Chemistry, Wiley & Sons,
Chichester, 1991.
[5] R. Filler, Y. Kobayashi, L.M. Yagupolskii (Eds.), Organofluorine Compounds in
Medicinal Chemistry and Biomedical Applications, Elsevier, Amsterdam,
1993 .
[6] I. Ojima, J.R. McCarthy, J.T. Welch (Eds.), Biomedical Frontiers of Fluorine Chem-
istry, ACS Symposium Series 639, American Chemical Society, Washington, 1996.
[7] Fluorine in the life sciences, Multiauthor Special Issue, Chem. Biochem. 5 (2004)
559–722.
[8] Fluorine in the life science industry, Multiauthor Special Issue, Chimia 58 (2004)
92–162.
(282 MHz, CDCl3):
CDCl3):
d
À75.04 (d, J = 7.1 Hz, CF3); 13C NMR (75 MHz,
d
35.1 (q, J = 2.3 Hz, CH2), 36.3 (CH2Bn), 49.7 (Bn), 52.1
(CH3), 61.0 (q, J = 27.6 Hz, C–CF3), 126.3, 126.7 (q, J = 284.0 Hz, CF3),
128.5, 128.6, 128.8, 129.1, 129.9, 139.1, 141.9, 166.8. Anal. calcd.
for C19H20F3NO2: C, 64.95; H, 5.74; N, 3.99; found: C, 64.57; H,
6.31; N, 3.85; ESI-MS (m/z): calcd. for C19H20F3NO2H [M]+
352.1519; found: 352.1511.
4.6.12. 3-(4-Nitrophenyl)-1,1,1-trifluoropropan-2-ol (8a)
Viscous oil. 1H NMR (300 MHz, CDCl3):
d 2.98 (dd, J = 14.2 Hz,
J = 10.0 Hz, 1H, CH2), 3.08–3.17 (m, 2H), 4.15–4.28 (m, 1H,
CHOH), 7.47 (d, J = 8.8 Hz, 2H, 4-NO2C6H4–), 8.15 (d, J = 8.8 Hz,
[9] G. Theodoridis, Fluorine-containing agrochemicals: an overview of recent devel-
opments, in: A. Tressaud (Ed.), Advances in Fluorine Science, Vol. 2, Elsevier,
Amsterdam, 2006, pp. 121–175.
2H, 4-NO2C6H4–); 19F NMR (282 MHz, CDCl3):
d
À79.69 (d,
´
´
[10] J.P. Begue, D. Bonnet-Delpon, Bioorganic and Medicinal Chemistry of Fluorine,
J = 6.5 Hz, CF3).
John Wiley & Sons, Hoboken, 2008.
[11] A. Tressaud, G. Haufe (Eds.), Fluorine and Health. Molecular Imaging, Biomedical
Materials and Pharmaceuticals, Elsevier, Amsterdam, 2008, pp. 553–778.
[12] M. Howe-Grant, Fluorine Chemistry: A Comprehensive Treatment, John Wiley &
Sons, New York, 1995.
4.6.13. 3-(2-Bromophenyl)-1,1,1-trifluoropropan-2-ol (8b)
Colorless solid, m.p. 56–57 8C (lit.: 56–57 8C [34]). 1H NMR
(300 MHz, CDCl3):
d
2.23 (br s, 1H, OH), 2.91 (dd, J = 14.2 Hz,
[13] R.D. Chambers, Fluorine in Organic Chemistry, Blackwell, Oxford, 2004.
[14] P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications,
Wiley-VCH, Weinheim, 2004.
[15] K. Uneyama, Organofluorine Chemistry, Blackwell, Oxford, 2006.
[16] M. Hudlicky, A.E. Pavlath, Chemistry of Organic Fluorine Compounds II, American
Chemical Society, Washington, DC, 1995.
J = 10.3 Hz, 1H, CH2), 3.28 (dd, J = 14.2 Hz, J = 2.9 Hz, 1H, CH2),
4.21–4.34 (m, 1H, CHOH), 7.15 (td, J = 6.5 Hz, J = 2.7 Hz, 1H, 2-
BrC6H4–), 7.24–7.31 (m, 2H, 2-BrC6H4–), 7.57 (dd, J = 8.0 Hz,
J = 1.0 Hz, 1H, 2-BrC6H4–); 19F NMR (282 MHz, CDCl3):
J = 6.5 Hz, CF3).
d
À79.78 (d,
[17] V.A. Soloshonok (Ed.), Fluorine-Containing Synthons, ACS Symposium Series 911,
American Chemical Society, Washington, 2005.
[18] V.A. Soloshonok, K. Mikami, T. Yamazaki, J.T. Welch, J.F. Honek (Eds.), Current
Fluoroorganic Chemistry. New Synthetic Directions, Technologies, Materials, and
Biological Applications, ACS Symposium Series 949, American Chemical Society,
Washington, 2006.
[19] A.V. Shastin, V.N. Korotchenko, V.G. Nenajdenko, E.S. Balenkova, Tetrahedron 56
(2000) 6557–6563.
[20] A.V. Shastin, V.M. Muzalevsky, E.S. Balenkova, V.G. Nenajdenko, Mendeleev
Commun. 16 (2006) 179–180.
[21] V.N. Korotchenko, A.V. Shastin, V.G. Nenajdenko, E.S. Balenkova, Tetrahedron 57
(2001) 7519–7527.
4.6.14. 3-(2-Nitrophenyl)-1,1,1-trifluoropropan-2-ol (8c)
Viscous oil. 1H NMR (300 MHz, CDCl3):
2.74 (br s, 1H, OH), 3.14
(dd, J = 13.8 Hz, J = 10.3 Hz, 1H, CH2), 3.38 (dd, J = 13.8 Hz,
J = 3.1 Hz, 1H, CH2), 4.27–4.42 (m, 1H, CHOH), 7.45–7.50 (m, 2H,
2-NO2C6H4–), 7.62 (td, J = 7.5 Hz, J = 1.4 Hz, 1H, 2-NO2C6H4–), 8.01
(dd, J = 8.2 Hz, J = 1.4 Hz, 1H, 2-NO2C6H4–); 19F NMR (282 MHz,
d
CDCl3):
d
À79.89 (d, J = 6.4 Hz, CF3); 13C NMR (75 MHz, CDCl3):
d
[22] V.G. Nenajdenko, G.N. Varseev, A.V. Shastin, E.S. Balenkova, J. Fluorine Chem. 126
(2005) 907–913.
[23] V.G. Nenajdenko, V.M. Muzalevskiy, A.V. Shastin, E.S. Balenkova, G. Haufe, J.
Fluorine Chem. 128 (2007) 818–826.
33.3, 70.6 (q, J = 31.4 Hz, C–CF3), 124.7 (q, J = 282.4 Hz, CF3), 125.1,
128.5, 131.0, 133.4, 133.7, 149.7. ESI-MS (m/z): calcd. for
C9H8F3NO3Na [M]+ 258.0348; found: 258.0342.

V.M. Muzalevskiy et al. / Journal of Fluorine Chemistry 132 (2011) 1247–1253
1253
[24] A.V. Shastin, V.M. Muzalevskiy, E.S. Balenkova, V.G. Nenajdenko, R. Fro¨hlich, G.
Haufe, Tetrahedron 64 (2008) 9725–9732.
[29] V.M. Muzalevskiy, V.G. Nenajdenko, A.V. Shastin, E.S. Balenkova, G. Haufe, Tetra-
hedron 65 (2009) 6991–7000.
[25] V.M. Muzalevskiy, A.V. Shastin, E.S. Balenkova, V.G. Nenajdenko, Russ. Chem. Bull.
56 (2007) 1526–1533.
[26] V.M. Muzalevskiy, V.G. Nenajdenko, A.V. Shastin, E.S. Balenkova, G. Haufe, Syn-
thesis (2009) 2249–2259.
[27] V.G. Nenajdenko, V.M. Muzalevskiy, A.V. Shastin, E.S. Balenkova, E.V. Kondrashov,
I.A. Ushakov, A.Y. Rulev, J. Org. Chem. 75 (2010) 5679–5688.
[28] A.Y. Rulev, V.M. Muzalevskiy, E.V. Kondrashov, I.A. Ushakov, A.V. Shastin, E.S.
Balenkova, G. Haufe, V.G. Nenajdenko, Eur. J. Org. Chem. (2010) 300–310.
[30] J.P. Be´gue´, D. Mesureur, Synthesis (1989) 309–312.
[31] V.M. Muzalevskiy, V.G. Nenajdenko, A.V. Shastin, E.S. Balenkova, G. Haufe, Tetra-
hedron 65 (2009) 7553–7561.
[32] A.V. Gulevich, N.E. Shevchenko, E.S. Balenkova, G.-V. Roschenthaler, V.G. Nenaj-
denko, Tetrahedron 64 (2008) 11706–11712.
[33] A. Yu Rulev, I.A. Ushakov, J. Fluorine Chem. 131 (2010) 53–58.
[34] V.M. Muzalevskiy, V.G. Nenajdenko, A.V. Shastin, E.S. Balenkova, G. Haufe, J.
Fluorine Chem. 129 (2008) 1052–1055.