New approach to CF3-containing polysubstituted anilines: Reaction of β-trifluoroacetylvinyl ethers with enamines

Article abstract of DOI:10.1016/j.tet.2004.01.010

The reaction of β-trifluoroacetylvinyl ethers with 'push-pull' enamines having a methyl group at the α-position was investigated. As a result, a set of CF₃-containing dialkyl anilines and their covalent hydrates were obtained. A possible reaction mechanism and the stability of the covalent hydrates obtained are discussed.

Full text of DOI:10.1016/j.tet.2004.01.010

Tetrahedron 60 (2004) 2361–2371
New approach to CF3-containing polysubstituted anilines:
reaction of b-trifluoroacetylvinyl ethers with enamines
*
Dmitriy M. Volochnyuk, Alexander N. Kostyuk, Dmitriy A. Sibgatulin, Alexander N. Chernega,
Alexander M. Pinchuk and Andrei A. Tolmachev
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanskaya 5, Kiev 02094, Ukraine
Received 13 June 2003; revised 11 December 2003; accepted 8 January 2004
Abstract—The reaction of b-trifluoroacetylvinyl ethers with ‘push–pull’ enamines having a methyl group at the a-position was
investigated. As a result, a set of CF3-containing dialkyl anilines and their covalent hydrates were obtained. A possible reaction mechanism
and the stability of the covalent hydrates obtained are discussed.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
chosen as model compounds for investigation of this
reaction. These are depicted in Figures 1 and 2. Herein,
we report on the result of this investigation.
The introduction of a fluorine atom or perfluoroalkyl group
into organic molecules often confers significant and useful
changes in their chemical and physical properties. There-
fore, methods for the synthesis of fluorinated compounds,
for example, trifluoromethylated aromatic and hetero-
aromatic compounds have received considerable interest
in recent years.1 The main methods for the synthesis of
trifluoromethyl aromatic compounds are based on the direct
introduction of a trifluoromethyl group into the aromatic
nucleus, the transformation of other functional groups into
a trifluoromethyl group or the reaction of aromatic
compounds bearing trifluoromethyl substituents.2 Mean-
while one of the most satisfactory methods to introduce a
trifluoromethyl group into different heterocycles is via the
trifluoromethylated building block approach. Some of the
recently used trifluoromethylated building blocks are three
carbon 1,3-electrophilic agents: 1,3-trifluoromethyl-1,3-
diketones,3 b-alkoxyvinyl trifluoromethyl ketones,4 b-tri-
fluoromethylsulfones5 and others. To the best of our
knowledge, the synthesis of trifluoromethylbenzenes by
this method is unusual.6 Continuing our research on
electrophilic substitution in different systems having an
enamine moiety7 we decided to investigate the possibility
of using tertiary ‘push–pull’ enamines as three-carbon
binucleophilic building blocks8,9 for the synthesis of
CF3-containing benzenes. We chose highly electrophilic
b-trifluoroacetylvinyl ethers10 as the 1,3-electrophilic
agents. A set of ‘push–pull’ enamines 1–4 and three b-
tri-fluoroacetylvinyl ethers 5 of different reactivity were
Figure 1. The strucutre of the starting ‘push–pull’ enamines.
Figure 2. The structure of the starting b-trifluoroacetylvinyl ethers.
2. Results and discussion
2.1. Reaction of b-trifluoroacetylvinyl ethers with
b-dialkylaminocrotonitriles
Enamines 1, derivatives of b-aminocrotonitrile, reacted
with b-trifluoroacetylvinyl ethers 5 at the enamine b-pos-
ition giving the corresponding dienamines 6 (Scheme 1).
The reaction proved to be very sensitive to the structural
features of the enamine and enone. For example, under
analogous conditions a more active enone 5a (compared to
5b) reacted with enamine 1a, but did not react with enamine
1b. Enone 5b reacted with both enamines. This can be
rationalized by steric hindrance.
Keywords: b-Trifluoroacetylvinyl ethers; ‘Push–pull’ enamines; Trifluoro-
methyl; Arene hydrates.
*
Corresponding author. Tel./fax: þ380-44-2696794;
e-mail address: dov@fosfor.kiev.ua
The behavior of the trifluoroacylated dienamines 6 obtained
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.010

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Scheme 1. Reagents and conditions: (i) for 6aa,ab: toluene, rt, 24 h; for 6ac,bb: toluene, rt, 48 h; (ii) toluene, rt, spontaneously; (iii) Et3N, toluene, 60 8C, 2 h;
(iv) NaH, HMPA, Et2O, reflux, 10 h.
strongly depended on the substituent R at the d-position.
d,d-Bistrifluoroacetyldienamine 6aa (R¼COCF3) cyclized
spontaneously at rt affording ‘arene hydrate’ 7 (Scheme 1)
thus making purification to an analytically pure state
difficult. Unlike 6aa, dienamines 6ab and 6bb (R¼CO2Et)
were kinetically stable and could be separated as individual
compounds. They cyclized into the corresponding arene
hydrate 9 at 60 8C in the presence of catalytic amounts of
triethylamine. In the case of dienamine 6ac (R¼H) even the
use of a strong base such as NaH in the presence of HMPA
did not yield cyclic product.
influenced CH-acidity of the methyl group. Thus, in the
case of dienamine 6aa due to two trifluoroacetyl groups,
CH-acidity was sufficient for abstraction of proton by weak
bases, for example, such as the starting enamine 1a or the
dienamine 6aa, which were present in the reaction mixture.
With an ethoxycarbonyl group in dienamine 6ab, a stronger
base such as triethylamine was required for proton
abstraction. On the other hand, the substituent R influenced
the electrophilicity of the trifluoroacetyl group in carbanion
11. In resonance-stabilized anions 11 an electron-accepting
substituent increases electrophilicity of the neighboring
trifluoroacetyl group.
We suggest the following mechanism. First, abstraction of a
proton from the methyl group of dienamines afforded the
corresponding resonance-stabilized carbanions 11 which
underwent 6-exo-trig cyclization to give alkoxides 12.
Finally protonation yielded the corresponding arene hydrate
7 or 9 (Scheme 2). On the one hand, the substituent R
Figure 3. A perspective view and labeling scheme for the independent
molecule A of the compound 8.
Scheme 2.

D. M. Volochnyuk et al. / Tetrahedron 60 (2004) 2361–2371
2363
Scheme 3.
Table 1. Ratio of regioisomers, summary yields of cyclic products and reaction time of b-trifluoroacetylvinyl ether 5b with enamines 1–4
Enamine
Ratio of regioisomersa
Yield (%)
Time of reaction (h)b
A
B
1a
1b
2a
2b
3a
3b
4a
4b
100
100
67
84
86
57
59
72
0
0
79
42
83
—
—
24
72
24
120
48
33
16
14
43
41
28
75c
68c
35d
88c
34d
120
a
Data of 19F NMR spectra of reaction mixture.
At rt.
Refer to crude mixture of regioisomers.
Data of 19F NMR spectra and GC/MS of reaction mixture.
b
c
d
The structures of trifluoromethyl anilines were confirmed by
1H, 13C, 19F NMR spectroscopy, mass-spectrometry and
elemental analysis. Characteristic features for the aromatic
reactions made separation of the final products more
difficult. The reaction was also very sensitive to structural
features of the enone. For example, enone 5a having the
electrophilic center shielded by the bulky isobutyl group
only yielded a compound of type B (Scheme 4). Although
compound 25 was separated in a low yield, 19F NMR
spectra of the reaction mixture did not show formation of a
type A regioisomer.
1
ring in the H NMR spectra were two singlets at dH,7.0
and 8.0, in 19F NMR spectra presence of chemical shift
of CF3-group at dF,260 and in 13C NMR spectra signal of
CF3–C(sp2)-carbon at dC,130 with coupling constant
2JCF¼30 Hz (Tables 2, 5 and 6). Finally, the structure of 8
was confirmed by the X-ray diffraction study (Fig. 3).
2.2. Reaction of b-trifluoroacetylvinyl ethers with
b-dialkylaminocrotonoesters and a-methyl-b-
enaminones
The transition from the enamine 1 to the enamines 2–4
revealed that the latter could react with bielectrophilic
b-trifluoroacetylvinyl ethers affording two regioisomers.
For in-depth investigation of the reaction use of b-tri-
fluoroacetylvinyl ether 5b containing only one trifluoro-
methyl group facilitated monitoring of the reaction by 19F
NMR spectroscopy (Scheme 3). The ratio of regioisomers is
given in Table 1. Both the ratio of regioisomers and rate of
the reaction depended on the structure of the amine residue
and the nature of the electron-accepting group of the
enamine. Besides, use of morpholine enamines, less active
compared to pyrrolidine ones, revealed that many side
Scheme 4.
The structures of trifluoromethylanilines of types A0 and B0
were confirmed by H, 13C, 19F NMR spectroscopy, mass-
spectrometry and elemental analysis. Anilines of type A0
have similar spectral data to those of anilines 8 and 10.
Unlike anilines of A0 type, anilines of B0 type have two
doublets at dH,7.0 and 7.6 with coupling constant
1

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D. M. Volochnyuk et al. / Tetrahedron 60 (2004) 2361–2371
Table 2. Yields, melting points, Rf and 19F NMR data of compounds obtained
Compound
NAlk2
EWG
Yield (%)a
Mp (8C)b
Rf (eluent)
dF (solvent)
6abc
6acc
7
N(CH2)4
N(CH2)4
N(CH2)4
N(CH2)4
N(CH2)4
N(CH2)4O
N(CH2)4
N(CH2)4
N(CH2)4
N(CH2)4
N(CH2)4O
N(CH2)4
N(CH2)4
N(CH2)4O
N(CH2)4
N(CH2)4
N(CH2)4
N(CH2)4O
N(CH2)4
N(CH2)4O
CN
CN
CN
CN
52d
74d
27d
82d
92e
42d
55d
21d
38d
27d
12d
22d
91f
43d
90f
78f
88f
71f
84f
21a
108–110
66–69
113–115
134–135
95–97
60–62
101–102
126
125–128
103
74
150–152
83
Oil
67
72
Oil
Oil
Oil
113
—
—
272.3 (CHCl3)
278.4 (CHCl3)
270.0 (3F), 283.4 (3F) (CHCl3)
262.2 (3F), 271.8 (3F) (CHCl3)
259.4 (CH3CN)
259.1 (CH3CN)
283.8 (CHCl3)
283.5 (CHCl3)
282.3 (benzene)
284.6 (CHCl3)
284.4 (toluene)
283.1 (benzene)
258.7 (acetone)
261.0 (CHCl3)
259.0 (CHCl3)
259.1 (toluene)
253.1 (acetone)
254.5 (acetone)
251.0 (CHCl3)
270.0 (3F), 283.4 (3F) (CHCl3)
0.28 (EtOAc)
0.60 (EtOAc)
0.53 (EtOAc)
0.84 (EtOAc/cyclohexane 1:1)
0.70 (EtOAc/cyclohexane 1:1)
0.26 (EtOAc)
8
10a
10b
13a
14a
15a
16a
16b
18a
19a
19b
20a
21a
22a
22b
24a
25
CO2Et
CO2Et
CO2Et
COMe
COPh
CO2Et
CO2Et
COPh
CO2Et
CO2Et
COMe
COPh
CO2Et
CO2Et
COPh
CO2Et
0.39 (EtOAc)
0.88 (EtOAc/cyclohexane 1:1)
0.40 (EtOAc/cyclohexane 1:1)
0.72 (EtOAc)
0.65 (EtOAc)
0.59 (EtOAc/cyclohexane 1:1)
0.65 (EtOAc)
0.68 (EtOAc)
0.67 (EtOAc)
0.78 (EtOAc/cyclohexane 1:1)
0.71 (EtOAc/cyclohexane¼1:1)
0.57 (EtOAc)
a
Yields refer to pure isolated products.
Melting points are uncorrected.
These substances exist as a mixture of Z/E-isomers, herein and below spectral data refer to major isomer.
Yields refer to the reaction of the corresponding enamines with vinyl ethers.
Yield refers to the reaction of cyclization of dienamine 6ab.
b
c
d
e
f
Yields refer to the reaction of water elimination from the corresponding arene hydrate.
3JHH¼8.5 Hz in the aromatic region of their 1H NMR
when the EWG was CN, the attack at the methyl group
does not occur at all, but when EWG¼COR the attack at
the methyl group competes with classical attack at the
b-position. One can suppose that electrophilic attack at
the methyl group proceeds via participation of the carbo-
nyl group. We rationalized the formation of the type B
compounds by the sequence of reactions shown in (Scheme
5). The reaction proceeded through O-nucleophilic attack of
enaminone followed by [1,5]-sigmatropic rearrangement
spectra (Tables 2 and 5).
The formation of compounds of type A proceeded
analogously to compounds 7 and 9. The formation of
compounds of type B testified that electrophilic attack of
5b at the enamine occurred at the methyl group. Reactions
of this type are rare.11 Although nitrile, carbonyl and
alkoxycarbonyl groups are acceptors of the same order,
Scheme 5.

D. M. Volochnyuk et al. / Tetrahedron 60 (2004) 2361–2371
2365
(26–28), analogously to trichloroacylation,12 phosphoryl-
ation7d and silylation of previously lithiated enaminones.13
The intermediate 29 underwent enolization giving 30, which
was converted into the final product 31 via electrocyclic
cyclisation.14 The synchronous nature of the last stage was
responsible for the formation of the sole stereoisomer,
whose structure was determined by the single crystal X-ray
diffraction study of 25 (Fig. 4). Additional proof of the
proposed mechanism was obtained by 19F NMR spec-
troscopy. When the reaction of the enamine 1a with enone
5a was run, the signals of the starting enone in the 19F NMR
spectra gradually transformed into two equally intense
signals at d 275 and 272 assigned to the dienamine 6aa,
which, in their turn, were converted into two equally
intensive signals d 269 and 284 assigned to arene hydrate 7
and after 48 h were the dominant signals in the spectrum. In
the case of enamines 2–4 after few hours the 19F NMR
spectra of a reaction mixture showed a set of approximately
20 signals of different intensity at the region from d 267
through d 280, which gradually transformed into two main
signals at d282 and ,d284 assigned to arene hydrate of
type A and B correspondingly.
drawing CHal3 group destabilizes any carbocation character
in the E1-like mechanism of elimination of water. In our
case, both stabilizing factors could act a part. In both
structural types A and B resonance stabilization of the
‘push–pull’ dienamine fragment is present. X-ray analysis
and 19F NMR spectroscopy data evidence resonance
conjugation in the fragment. The chemical shift of the
CF3CO group for compounds 7 and 25 appears at d269,
which is a typical value for CF3CO group conjugated with a
strong p-donor substituent. At the same time, hydrates
prepared by us had prerequisites for kinetic stability as well.
Acid catalyzed E1cb-elimination of water should form a
carbocation, that would be destabilized by CF3 group, as in
the case of 5-CF3 pyrazoles. Apart from this, the hydrate
obtained can eliminate water by an E1cb-like mechanism at
the expense of electron-accepting substituents that explains
the basic catalysis of water elimination. That is the reason
why we failed to separate the hydrate 9.
2.3. Stability of arene hydrate obtained
Arene hydrate 7, 13–18 and 25 isolated as pure compounds
appeared to have interesting and unexpected properties.
Spectral methods and elemental analysis confirmed their
constituency. For both structural types the CF3-group
appeared at d 282 to 284 in 19F NMR spectra, and this is
typical for a CF3-group attached to an sp3 carbon. Also the
signals in the 13C NMR spectrum at d 73 and 75 with
2
coupling constant JCF¼30 Hz for CF3–C(sp3) carbons in
the type A and B structures, respectively, were character-
istic. Finally, the H NMR spectrum of type A compounds
1
displayed the CH2-protons as an AB-system (doublets at
dA,2.9 and dB,3.2 with a geminal coupling constant
2JHH,16 Hz) and the 1H NMR spectrum of type B
compounds showed two doublets at d,7.5 and 5.0 with
the coupling constant 3JHH,7 Hz, which corresponded with
observation for ‘push–pull’ dienamines (Tables 3 and 4).
Figure 4. A perspective view and labeling scheme for the molecule 25.
3. Conclusions
Arene hydrates 7, 13–18 and 25 are crystalline compounds
melting without decomposition. They are stable enough to
survive chromatographic separation on silica gel. They lost
a molecule of water irreversibly upon boiling in toluene in
the presence of acids such as p-Me–C6H4–SO3H or bases
such as Et3N, with hydrates B being far more kinetically
stable compared with hydrates A.
The reaction of b-trifluoroacetylvinyl ethers with ‘push–
pull’ enamines having a-methyl group was investigated. It
was shown that the reaction was very sensitive both to the
structure of the enamine and the b-trifluoroacetylvinyl
ether. The method for synthesis of trifluoromethylated
polysubstituted dialkylanilines, which are not accessible by
classical methods, was elaborated. A set of stable covalent
hydrates was obtained.
Our data do not match with data known for the simplest
representative of this type of compounds, which are stable at
215 8C in the absence of acids for a few weeks, while in
the presence of acids they violently loose water giving the
corresponding aromatic compounds.15 Relatively stable
covalent hydrates are described for electron-deficient
azine heterocycles, with their stability being rationalized
by formation of energy favorable conjugated groups.16 For
example, the hydrated form of the quinazolinium cation is
efficiently stabilized by amidinium type resonance. Besides,
stable hydrates for 5-CHal3 pyrazoles and isoxazoles are
also described,4,17 but their stability is determined not by
thermodynamic, but kinetic factors. The electron-with-
4. Experimental
4.1. General
All procedures with hydrolytically sensitive b-trifluoro-
acetylvinyl ethers were carried out under an atmosphere of
dry argon. All solvents were purified and dried by standard
methods. NMR spectra were recorded on a Varian VXR-300
spectrometer: 1H and 13C (300 and 75.4 MHz, respectively)
with TMS as an internal standard; 19F (282.2 MHz) with
CFCl3 as internal standard. IR spectra were recorded on a

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D. M. Volochnyuk et al. / Tetrahedron 60 (2004) 2361–2371
Nexus-470 spectrometer for samples in KBr discs. Mass
spectra were obtained on a ‘Hewlett–Packard’ HP GC/MS
5890/5972 instrument (EI, 70 eV) by GC inlet or on a
MX-1321 instrument (EI, 70 eV) by direct inlet for the
thermally labile dienamines and arene hydrates. Micro-
analyses were performed in the Microanalytical Laboratory
of the Institute of Organic Chemistry, National Academy
of Sciences of Ukraine. Column chromatography was
performed on silica gel (63–200 mesh, Merck). Silica
gel Merck 60F254 plates were used for TLC. Starting
enamines18 and b-trifluoroacetylvinyl ethers19 were pre-
pared according to the literature.
4.2. X-ray crystallography
Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with
the Cambridge Crystallographic Data Center as supplemen-
tary publication no. CCDC-206106 (8) and CCDC-206107
(25) and can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
(internat.) þ44-1223/336-033; e-mail: deposit@ccdc.cam.
ac.uk).
4.3. Synthesis of dienamines
4.3.1. Ethyl 4-cyano-5-pyrrolidin-1-yl-2-(trifluoroacetyl)-
hexa-2,4-dienoate (6ab). Enamine 1a (567 mg, 4.17 mmol)
was dissolved in toluene (20 mL) and to the solution formed
b-trifluoroacetylvinyl ether 5b (1 g, 4.17 mmol) was added.
The reaction mixture was maintained at rt overnight, cooled
to 4 8C and the precipitate formed was filtered affording 6ab
(715 mg, 52%) as a yellow solid. Mp 108–110 8C. 1H NMR
d
3
(CDCl3): d¼1.35 (3H, t, JHH¼6.9 Hz, CH3), 2.07 (4H, br
m, CH2), 2.42 (3H, s, CH3), 3.75 (2H, br m, NCH2), 3.97
(2H, br m, NCH2), 4.53 (2H, q, 3JHH¼6.9 Hz, OCH2), 7.82
(1H, s, CH). 13C NMR (DMSO-d6): d¼13.8 (CH3CH2O),
21.4 (C(6)H3), 23.8 (CH2), 25.7 (CH2), 53.7 (NCH2), 54.8
(NCH2), 60.2 (OCH2), 80.2 (C(4)), 110.7 (C(2)), 117.2
(CN), 117.6 (1JCF¼290.1 Hz, COCF3), 147.7 (C(3)), 165.5
(C(5)), 170.3 (C(1)O2Et), 177.3 (2JCF¼33.5 Hz, COCF3).
IR, nmax (cm21): 2989, 2868, 2197, 1716, 1642, 1551, 1522,
1306, 1235, 1193, 1141. MS, m/z (%): 330 (Mþ, 10), 312
(21), 284 (13), 267 (16), 261 (18), 215 (100), 147 (20), 69
(17), 55 (37), 43 (30). Anal. calcd for C15H17F3N2O3: C
54.54; H 5.19; N 8.48. Found C 54.32; H 4.86; N 8.40.
Note. The mother liquor remaining was evaporated to
dryness. The solid obtained was treated as described for
compound 10a given below to yield 210 mg (16%) of 10a.
4.3.2. 6,6,6-Trifluoro-5-oxo-2-(1-pyrrolidin-1-ylethyli-
dene)hex-3-enenitrile (6ac). A solution of enamine 1a
(405 mg, 2.9 mmol) and b-trifluoroacetylvinyl ether 5c
(500 mg, 2.9 mmol) in benzene (20 mL) was maintained at
rt for 4 days. Benzene was evaporated in vacuo. The residue
was dissolved in boiling cyclohexane (20 mL), after cooling
to rt the brown oil formed was maintained under cyclo-
hexane 24 h affording 6ac (570 mg, 74%) as a red-brown
solid. Mp 66–69 8C. 1H HMR (CDCl3): d¼2.05 (4H, br m,
CH2), 2.36 (3H, s, CH3), 3.70 (2H, br m, NCH2), 4.00 (2H,
3
br m, NCH2), 6.39 (1H, d, JHH¼14.1 Hz, CH), 8.09 (1H,
3JHH¼14.1 Hz, CH). 13C NMR (DMSO-d6): d¼20.3 (CH3),

D. M. Volochnyuk et al. / Tetrahedron 60 (2004) 2361–2371
2367
23.8 (CH2), 25.5 (CH2), 53.1 (NCH2), 53.2 (NCH2), 80.5
(C(2)), 102.0 (C(4)), 116.8 (1JCF¼290.1 Hz, COCF3), 118.3
(CN), 150.5 (C(3)), 166.6 (N–Cv), 176.0 (2JCF¼33.5 Hz,
COCF3). IR, nmax (cm21): 2982, 2197, 1654, 1578, 1509,
1412, 1185, 1133. MS, m/z (%): 258 (Mþ, 31), 189 (68), 161
(60), 147 (48), 119 (38), 69 (24), 65 (26), 55 (100), 42 (65).
Anal. calcd for C12H13F3N2O: C 55.81; H 5.07; N 10.85.
Found C 55.73; H 4.86; N 10.78.
4.4. Synthesis of arene hydrate and dialkylamino-
anilines
4.4.1. 4-Hydroxy-2-pyrrolidin-1-yl-5-(trifluoroacetyl)-4-
(trifluoromethyl) cyclohexa-1,5-diene-1-carbonitrile (7).
A solution of enamine 1a (234 mg, 1.72 mmol) and b-tri-
fluoroacetylvinyl ether 5a (500 mg, 1.72 mmol) in toluene
(20 mL) was maintained at rt for 40 h. Toluene was
evaporated in vacuo. The residue was triturated with
n-hexane and crystallized from mixture 2-propanol-cyclo-
hexane affording 7 (167 mg, 27%) as a yellow solid. Mp
113–115 8C. IR, nmax (cm21): 3530–3320 (br), 2953, 2875,
2223, 1708, 1617, 1544, 1477, 1197, 1144, 1021. MS, m/z
(%): 354 (Mþ, 7), 336 (Mþ2H2O, 27), 285 (48), 267 (100),
69 (24), 43 (49). Anal. calcd for C14H12F6N2O2: C 47.47; H
3.41; N 7.91. Found C 47.53; H 3.39; N 7.83.
4.4.2. 2-Pyrrolidin-1-yl-5-(trifluoroacetyl)-4-(trifluoro-
methyl)benzonitrile (8). A solution of 1a (468 mg,
3.47 mmol) and b-trifluoroacetylvinyl ether 5a (1 g,
3.47 mmol) in benzene (15 mL) was maintained at rt 3
days. To the reaction mixture few crystals of p-toluene-
sulfonic acid were added and it was refluxed for 1.5 h.
Benzene was evaporated in vacuo. The residue was
crystallized from cyclohexane affording 8 (946 mg, 82%)
as a white solid. Mp 134–135 8C. IR, nmax (cm21): 3144,
3078, 2950, 2982, 2223, 1708, 1545, 1477, 1363, 1288,
1193, 1144, 1021, 864, 734. MS, m/z (%): 336 (Mþ, 24), 267
(Mþ2CF3, 100), 225 (19). Anal. calcd for C14H10F6N2O: C
50.01; H 3.00; N 8.33. Found C 50.00; H 3.01; N 8.30.
d
4.4.3. Ethyl 5-cyano-4-pyrrolidin-1-yl-2-(trifluoro-
methyl)benzoate (10a). Dienamine 6ab (500 mg,
1.5 mmol) was dissolved in hot toluene (15 mL) and to
the solution formed Et3N (0.25 mL) was added. The
reaction mixture was maintained at 60 8C for 4 h. Toluene
was evaporated in vacuo. The residue was crystallized from
cyclohexane affording 10a (435 mg, 92%) as a white solid.
Mp 95–97 8C. IR, nmax (cm21): 2976, 2868, 2220, 1724,
1613, 1542, 1456, 1363, 1283, 1253, 1148, 1105, 1002. MS,
m/z (%): 312 (Mþ, 100), 311 (Mþ21, 77), 284 (Mþ2C2H4,
67), 267 (Mþ2C2H4–OH, 77), 256 (31), 239 (15), 225 (23).
Anal. calcd for C15H15F3N2O2: C 57.69; H 4.84; N 8.97.
Found C 57.81; H 4.93; N 8.91.
4.4.4. Ethyl 5-cyano-4-morpholin-4-yl-2-(trifluoro-
methyl)benzoate (10b). A solution of enamine 1b
(633 mg, 4.17 mmol) and b-trifluoroacetylvinyl ether 5b
(1 g, 4.17 mmol) in toluene (20 mL) was maintained at rt for
4 days. Then to the reaction mixture was added Et3N
(0.25 mL) and it was heated at 60 8C for 2 h. Toluene was
evaporated in vacuo. The residue was subjected to a column
chromatography over silica gel using EtOAc/cyclohexane
1:1 as eluent affording 10b (574 mg, 42%) as a white solid.

2368
D. M. Volochnyuk et al. / Tetrahedron 60 (2004) 2361–2371
Table 5. 1H NMR data of trifluoromethyl benzenesa
1H NMR, d (ppm), J (Hz)
NAlk2
EWG
EWG0
C(3 or 5)H
8.06 (1H, s)
C(6)H
7.09 (1H, s)
8b
2.12 (4H, m, CH2),
3.82 (4H, NCH2)
—
—
—
—
10ac
10bc
19ab
19bb
20ab
21ab
1.95 (4H, m, CH2),
3.62 (4H, m, NCH2)
3.35 (4H, t, 3JHH¼4.8),
3.76 (4H, t, 3JHH¼4.8)
2.00 (4H, m, CH2),
3.33 (4H, NCH2)
3.19 (4H, t, 3JHH¼4.8),
3.87 (4H, t, 3JHH¼4.8)
2.00 (4H, m, CH2),
3.20 (4H, m, NCH2)
1.95 (4H, m, CH2),
3.21 (4H, m, NCH2)
1.26 (3H, t, 3JHH¼7.2),
4.21 (2H, q, 3JHH¼7.2)
1.27 (3H, t, 3JHH¼7.2),
4.26 (2H, q, 3JHH¼7.2)
8.00 (1H, s)
8.06 (1H, s)
8.19 (1H, s)
8.25 (1H, s)
8.16 (1H, s)
7.89 (1H, s)
6.96 (1H, s)
7.32 (1H, s)
7.07 (1H, s)
7.28 (1H, s)
7.10 (1H, s)
7.13 (1H, s)
1.34–1.42 (6H, m, CH3),
4.31–4.41 (4H, m, CH2)
1.35–1.43 (6H, m),
4.33–4.43 (4H, m)
2.62 (3H, s)
1.37 (3H, t, 3JHH¼6.9),
4.34 (2H, q, 3JHH¼6.9)
1.31 (3H, t, 3JHH¼7.2),
4.28 (2H, q, 3JHH¼7.2)
7.50 (2H, t, 3JHH¼7.8),
7.62 (1H, t, 3JHH¼7.8),
7.92 (2H, d, 3JHH¼7.8)
1.32–1.41 (6H, m),
4.27–4.38 (4H, m)
1.32–1.41 (6H, m),
3
22ab
22bb
24ab
1.96 (4H, m, CH2),
7.69 (1H, d, 3JHH¼8.1)
7.57 (1H, d, 3JHH¼8.7)
7.65 (1H, d, 3JHH¼9.0)
7.39 (1H, d, JHH¼8.1)
3.32 (4H, m, NCH2)
3.00 (4H, t, 3JHH¼4.2),
3.78 (4H, t, 3JHH¼4.2)
1.60–1.80 (4H, m),
3
6.84 (1H, d, JHH¼8.7)
4.33–4.42 (4H, m)
7.44 (2H, t, 3JHH¼7.8),
7.57 (1H, t, 3JHH¼7.8),
7.82 (2H, d, 3JHH¼7.8)
1.32 (3H, t, 3JHH¼7.2),
4.28 (2H, q, 3JHH¼7.2)
6.94 (1H, d, JHH¼9.0)
3
3.04 (2H, m), 3.21 (2H, m)
a
Numbering of cycle is started from the carbon atom attached to dialkylamino group.
CDCl3.
CD3CN.
b
c
Table 6. 13C NMR data of arene hydrate and benzenesa
13C NMR, d (ppm), (JCF (Hz))
CF3 C1
NAlk2
EWG
EWG0
C2
C3
C4
C5
C6
36.7
7b
8b
24.3, 25.4,
52.3, 52.4
25.5, 50.6
118.6
118.7
116.6 (290.3),
177.5 (33.5)
116.4 (289.4),
176.7 (34.7)
125.6 (289.1) 161.4
122.3 (273.4) 151.0
77.0 152.6
94.8 140.9
108.3 73.0 (29.6)
118.6 134.6 (33.0) 115.2 (6.2)
10ac 25.2, 50.0
10bd 51.6, 67.2
119.1
118.7
13.9, 61.3, 163.6 122.8 (273.6) 150.0
14.2, 63.0, 166.1 122.8 (273.6) 146.5
126.4 (289.2) 161.2
94.4 140.0
94.8 138.7
95.1 146.3
114.9 132.1 (29.0) 113.6 (5.7)
118.0 131.8 (29.3) 117.8
13ab 25.3 (b), 51.5 (b), 14.4, 14.5, 59.9,
103.2 73.4 (29.0)
101.1 73.3 (27.2)
101.2 73.2 (28.7)
101.1 145.3
36.4
37.5
37.1
91.1
94.3
92.4
55.0 (b)
60.4, 164.8, 168.2
14ac 25.6 (b), 52.6 (b), 27.8, 189.4
56.5 (b)
14.8, 60.4, 167.7 127.0 (281.9) 162.8 106.1 146.7
15ac 24.9, 25.8,
52.4, 55.9
16ab 24.9, 48.3
129.0, 129.6, 132.1, 14.7, 60.3, 167.5 126.5 (288.5) 162.5 104.8 147.2
139.4, 189.5
14.0, 14.2, 60.0,
61.6, 166.5, 168.6
14.1, 14.2, 60.6,
61.7, 166.8, 168.1
126.1 (290.0) 150.4
49.2 74.9 (29.5)
48.0 74.9 (29.8)
46.9 76.1 (30.3)
16bb 46.9, 66.1
125.8 (289.2) 151.6
105.8 143.9
18ac 24.2 (b), 48.6 (b) 129.1, 129.4, 134.1, 14.8, 60.3, 168.8 126.4 (289.9) 154.0
96.6 146.7
138.4, 192.2
19ab 25.7, 50.9
19bb 51.7, 66.5
13.9, 14.1, 61.2,
61.4, 165.5, 167.4
13.9, 14.1, 61.6,
61.7, 165.4, 166.2
29.2, 199.1
123.0 (272.1) 148.5 115.5 135.5
117.7 132.2 (31.3) 112.5 (5.9)
121.9 132.4 (32.5) 116.4 (6.9)
122.8 (272.0) 153.4 124.4 135.1
20ab 25.7, 51.8
21ac 25.8, 51.3
14.0, 61.2, 165.5 123.1 (272.3) 148.1 126.0 133.9
115.1 131.9 (31.3) 112.9 (8.0)
115.1 131.9 (31.9) 112.6 (4.9)
128.6, 130.5, 133.4, 14.0, 61.2, 165.7 123.0 (272.1) 148.7 124.4 135.1
137.3, 195.1
22ab 25.9, 50.0
22bb 53.4, 66.5
24ab 25.6, 60.0
13.8, 14.0, 61.7,
62.4, 168.0, 168.4
13.9, 14.0, 62.4,
123.6 (274.2) 148.3 117.8 128.2 (30.6) 119.8 131.4
123.4 (274.2) 150.8 123.6 128.5 (30.3) 126.8 131.5
116.1
125.0
116.4
96.8
62.5, 166.2, 166.8
128.5, 129.3, 131.2, 13.9, 61.6, 168.0 123.4 (277.7) 149.2 124.4 128.4 (31.0) 120.9 133.4
137.9, 196.8
25b
48.7, 65.9
13.6, 61.7, 164.2
117.6 (289.6),
172.9 (32.5)
125.7 (290.6) 158.4
47.5 75.3 (30.0)
102.4 151.9 (3.4)
a
Numbering of cycle is started from the carbon atom attached to dialkylamino group.
CDCl3.
DMSO-d6.
CD3CN.
b
c
d

D. M. Volochnyuk et al. / Tetrahedron 60 (2004) 2361–2371
2369
Rf(EtOAc/cyclohexane 1:1)¼0.84. Mp 60–62 8C (MeOH).
IR, nmax (cm21): 3144, 3078, 2968, 2932, 2864, 2225, 1732,
1609, 1550, 1419, 1285, 1237, 1164, 1120, 1052, 983, 917,
885, 786. MS, m/z (%): 328 (Mþ, 85), 283 (Mþ2C2H4–OH,
36), 270 (Mþ2C2H4–CH2O, 61), 242 (Mþ2N(CH2CH2)2O,
54), 225 (Mþ2N(CH2CH2)2O–OH, 100), 215 (15). Anal.
calcd for C15H15F3N2O3: C 54.88; H 4.61; N 8.53. Found C
54.80; H 4.52; N 8.51.
(14). Anal. calcd for C17H20F3NO5: C 54.40; H 5.37; N
3.73. Found C 54.39; H 5.35; N 3.70.
4.4.7. Ethyl 3-acetyl-6-hydroxy-4-pyrrolidin-1-yl-6-(tri-
fluoromethyl)cyclohexa-1,3-diene-1-carboxylate (14a).
A solution of enamine 3a (637 mg, 4.17 mmol) and
b-trifluoroacetylvinyl ether 5b (1 g, 4.17 mmol) in toluene
(20 mL) was maintained at rt for 48 h and then heated at
40 8C for 0.5 h. Toluene was evaporated in vacuo. The
residue was triturated with n-hexane and crystallized from
ethanol affording 14a (295 mg, 21%) as a yellow solid. Mp
126 8C. Rf(EtOAc)¼0.26. IR, nmax (cm21): 3450–3350
(br), 2982, 2860, 1719, 1676, 1606, 1445, 1293, 1270, 1157,
1135. MS, m/z (%): 347 (Mþ, 13), 329 (10), 278 (9), 232
(100), 70 (20), 43 (21). Anal. calcd for C16H20F3NO4: C
55.33; H 5.80; N 4.03. Found C 55.62; H 5.61; N 4.00.
4.4.5. Diethyl 6-hydroxy-4-pyrrolidin-1-yl-6-(trifluoro-
methyl)cyclohexa-1,3-diene-1,3-dicarboxylate (13a) and
diethyl 2-hydroxy-6-pyrrolidin-1-yl-2-(trifluoromethyl)-
cyclohexa-3,5-diene-1,3-dicarboxylate (16a). A solution
of enamine 2a (763 mg, 4.17 mmol) and b-trifluoroacetyl-
vinyl ether 5b (1 g, 4.17 mmol) in toluene (20 mL) was
maintained at rt for 30 h. Toluene was evaporated in vacuo.
The residue was triturated with n-hexane and was subjected
to a column chromatography over silica gel using EtOAc/
cyclohexane 1:1 as eluent affording 13a (860 mg, 55%) and
16a (340 mg, 27%).
Note. The procedure given below allowed the separation of
438 mg (32%) of 20a. The mother liquor remaining from
crystallization of 14a and hexane washings were combined
and solvents were evaporated. The residue was taken up in
toluene (5 mL), a few crystals of p-toluenesulfonic acid
were added and the reaction mixture was refluxed for
15 min. Toluene was evaporated in vacuo, and the residue
was subjected to a column chromatography over silica gel
using EtOAc as eluent affording 20a.
Compound 13a. Yellow solid. Rf(EtOAc/cyclohexane
1:1)¼0.70. Mp 101–102 8C (n-hexane). IR, nmax (cm21):
3302, 2986, 2868, 1679, 1642, 1588, 1535, 1333, 1210,
1160, 1119, 1053, 760. MS, m/z (%): 377 (Mþ, 12), 332
(16), 330 (13), 308 (10), 262 (100), 234 (10). Anal. calcd for
C17H22F3NO5: C 54.11; H 5.88; N 3.71. Found C 54.03; H
6.00; N 3.70.
4.4.8. Ethyl 3-benzoyl-6-hydroxy-4-pyrrolidin-1-yl-6-
(trifluoromethyl)cyclohexa-1,3-diene-1-carboxylate
(15a) and ethyl 5-benzoyl-6-hydroxy-4-pyrrolidin-1-yl-
6-(trifluoromethyl)cyclohexa-1,3-diene-1-carboxylate
(18a). A solution of enamine 4a (896 mg, 4.17 mmol) and
b-trifluoroacetylvinyl ether 5b (1 g, 4.17 mmol) in toluene
(30 mL) was maintained at rt for 48 h and then heated at
50 8C for 2 h. Toluene was evaporated in vacuo, and the
residue was subjected to a column chromatography over
silica gel using EtOAc as eluent affording 15a (650 mg,
38%) and 18a (380 mg, 22%).
Compound 16a. Orange solid. Rf(EtOAc/cyclohexane
1:1)¼0.88. Mp 103 8C (n-hexane). IR, nmax (cm21): 3185,
2986, 2860, 1740, 1637, 1535, 1280, 1176, 1109, 1024, 761,
680. MS, m/z (%): 377 (Mþ, 11), 330 (13), 308 (11), 262
(100), 190 (29). Anal. calcd for C17H22F3NO5: C 54.11; H
5.88; N 3.71. Found C 54.06; H 6.02; N 3.71.
4.4.6. Diethyl 2-hydroxy-6-morpholin-4-yl-2-(trifluoro-
methyl)cyclohexa-3,5-diene-1,3-dicarboxylate (16b) and
diethyl 4-morpholin-4-yl-6-(trifluoromethyl)isophtha-
late (19b).
A
solution of enamine 2b (829 mg,
Compound 15a. Orange solid. Rf(EtOAc)¼0.26. Mp 125–
158 8C (n-hexane). IR, nmax (cm21): 3500–3400 (br), 2969,
2922, 2860, 1704, 1655, 1603, 1540, 1448, 1271, 1231,
1146, 1106, 1003. MS, m/z (%): 409 (Mþ, 18), 391 (23), 340
(9), 294 (100), 105 (30), 91 (9), 77 (19), 70 (22). Anal. calcd
for C21H22F3NO4: C 61.61; H 5.4; N 3.42. Found C 61.66; H
5.38; 3.38.
4.17 mmol) and b-trifluoroacetylvinyl ether 5b (1 g,
4.17 mmol) in toluene (20 mL) was maintained at rt for
30 h and then heated at 40 8C for 4 h. Toluene was
evaporated in vacuo. The residue was passed through a
short silica gel column using EtOAc as eluent to afford
a crude mixture of 16b and 19b, which was subjected to a
column chromatography over silica gel using EtOAc/
cyclohexane 1:1 as eluent affording 16b (670 mg, 43%)
and 19b (196 mg, 12%).
Compound 18a. Orange solid. Rf(EtOAc)¼0.72. Mp 150–
152 8C (n-hexane). IR, nmax (cm21): 3230–3180 (br), 2983,
2852, 1691, 1640, 1529, 1450, 1399, 1280, 1179, 1107, 759.
MS, m/z (%): 409 (Mþ, 8), 294 (30), 287 (10), 105 (100), 77
(23). Anal. calcd for C21H22F3NO4: C 61.61; H 5.4; N 3.42.
Found C 61.68; H 5.34; 3.38.
Compound 16b. Yellow solid. Rf(EtOAc/cyclohexane
1:1)¼0.40. Mp 74 8C (n-hexane). IR, nmax (cm21): 3500–
3250 (br), 2984, 2912, 2854, 1735, 1654, 1535, 1458, 1292,
1233, 1180, 1114. MS, m/z (%): 393 (Mþ, 16), 324 (21), 278
(100), 206 (27). Anal. calcd for C17H22F3NO6: C 51.91; H
5.64; N 3.56. Found C 52.13; H 5.81; N 3.63.
4.4.9. Ethyl 6-hydroxy-2-morpholin-4-yl-5-(trifluoro-
acetyl)-6-(trifluoromethyl)cyclohexa-2,4-diene-1-carb-
oxylate (25).
A solution of enamine 2b (684 mg,
Compound 19b. Colorless oil. Rf(EtOAc/cyclohexane
1:1)¼0.59. IR, nmax (cm21): 2983, 2852, 1727, 1609,
1510, 1370, 1302, 1233, 1148, 1052, 976, 919, 878, 780.
MS, m/z (%): 375 (Mþ, 22), 346 (36), 344 (27), 332 (46),
330 (Mþ2C2H4–OH, 54), 328 (22), 302 (Mþ2C2H4–
OH–CO, 100), 288 (46), 272 (28), 260 (13), 244 (20), 217
3.47 mmol) and b-trifluoroacetylvinyl ether 5a (1 g,
3.47 mmol) in cyclohexane (30 mL) was maintained at rt
for 24 h and then refluxed for 2 h. Cyclohexane was
evaporated in vacuo, and the residue was crystallized from
2-propanol affording 25 (293 mg, 21%) as an orange solid.
Mp 103 8C. IR, nmax (cm21): 3300–3100 (br), 3121, 2990,

2370
D. M. Volochnyuk et al. / Tetrahedron 60 (2004) 2361–2371
2927, 2849, 1736, 1598, 1513, 1412, 1332, 1176, 1026, 958,
925, 703, 642. MS, m/z (%): 417 (Mþ, 13), 348 (Mþ2CF3,
32), 276 (100), 206 (66), 148 (46), 69 (CFþ3 , 15). Anal. calcd
for C16H17F6NO5: C 46.05; H 4.11; N 3.36. Found C 46.17;
H 4.00; N 3.38.
4.5.4. Diethyl 4-pyrrolidin-1-yl-2-(trifluoromethyl)iso-
phthalate (22a). Procedure A was applied. Colorless oil.
IR, nmax (cm21): 2982, 2868, 1728, 1596, 1485, 1382, 1321,
1313, 1233, 1183, 1143, 1024, 991, 789. MS, m/z (%): 359
(Mþ, 47), 331 (Mþ2C2H4, 24), 330 (Mþ2C2H5, 100), 314
(Mþ2C2H4–OH, 42), 285 (16), 266 (19), 244 (18). Anal.
calcd for C17H20F3NO4: C 56.82; H 5.61; N 3.90. Found C
56.62; H 5.60; N 3.90.
4.5. General procedures for elimination of water from
arene hydrate
Procedure A. To a solution of arene hydrate (100 mg) in
toluene (2 mL) a few crystals of p-toluenesulfonic acid were
added and the reaction mixture was refluxed for 2–4 h
(reaction was monitored by TLC using EtOAc or mixture
EtOAc/cyclohexane 1:1 as eluent). Toluene was evaporated
in vacuo. The residue was extracted with boiling n-hexane
(2 mL) and n-hexane was evaporated in vacuo affording the
corresponding benzene.
4.5.5. Diethyl 4-morpholin-4-yl-2-(trifluoromethyl)iso-
phthalate (22b). Procedure C was applied. Pale yellow
oil. 2983, 2914, 2844, 1735, 1594, 1450, 1368, 1298, 1232,
1185, 1149, 1022, 964. MS, m/z (%): 375 (Mþ, 45), 344
(19), 332 (27), 330 (Mþ2C2H4–OH, 88), 302 (Mþ2C2H4–
OH–CO, 100), 262 (62), 240 (41), 224 (33), 204 (28), 176
(16), 144 (18), 59 (43). Anal. calcd for C17H20F3NO5: C
54.40; H 5.37; N 3.73. Found C 54.25; H 5.25; N 3.70.
Procedure B. To a solution of arene hydrate (100 mg) in
toluene (5 mL) Et3N (0.25 mL) was added and the reaction
mixture was refluxed for 2–4 h (Reaction was monitored by
TLC using EtOAc or mixture EtOAc/cyclohexane 1:1 as
eluent). Solvent was evaporated in vacuo. The residue was
extracted with boiling n-hexane (2 mL) and n-hexane was
evaporated in vacuo affording the corresponding benzene.
4.5.6. Ethyl 3-benzoyl-4-pyrrolidin-1-yl-2-(trifluoro-
methyl)benzoate (24a). Procedure A was applied. Pale
yellow oil. IR, nmax (cm21): 3054, 2977, 2868, 1723, 1675,
1593, 1449, 1369, 1300, 1143, 1027, 990, 881, 787, 710.
MS, m/z (%): 391 (Mþ, 100), 346 (Mþ2C2H4–OH, 26),
322 (16), 314 (16), 246 (21), 211 (11), 105 (PhCOþ, 25), 91
(10), 77 (Phþ, 32). Anal. calcd for C21H20F3NO3: C 64.44;
H 5.15; N 3.58. Found C 64.38; H 5.00; N 3.49.
Procedure C. To a solution of arene hydrate (50 mg) in
chloroform, (2 mL) a few drops of SOCl2 were added. The
reaction mixture was heated to boiling, allowed to cool and
maintained at rt overnight. Chloroform was evaporated in
vacuo. The residue was extracted with boiling n-hexane
(2 mL) and n-hexane was evaporated in vacuo affording the
corresponding benzene.
References and notes
1. (a) In Fluorine in bioorganic chemistry. Filler, R., Kobayasi,
Y., Yagupolskii, L. M., Eds.; Elsevier: Amsterdam, 1993.
(b) Filler, R. In Fluorine containing drugs in organofluorine
chemicals and their industrial application; Pergamon: New
York, 1979; Chapter 6. (c) Hudlicky, M. Chemistry of organic
fluorine compounds; Ellis Horwood: Chichester, 1992.
2. (a) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992,
48, 6555–6666. (b) Schiemann, G.; Cornils, B. Chemie und
Technolodie cyclischer Fluoroverbindungen; Enke: Stuttgart,
1969. (c) Yagupolskii, L. M. Aromatic and heterocyclic
compounds with fluorocontaining substituents; Naukova
Dumka: Kiev, 1988; Russian. (d) In Organofluorine
chemistry: principles and commercial applications; Banks,
R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum: New York,
1994.
4.5.1. Diethyl 4-pyrrolidin-1-yl-6-(trifluoromethyl)isoph-
thalate (19a). Procedure A was applied. White solid. Mp
83 8C. IR, nmax (cm21): 2980, 2875, 1706, 1606, 1540,
1451, 1368, 1271, 1251, 1222, 1151, 1088, 996, 858, 780.
MS, m/z (%): 359 (Mþ, 16), 331 (Mþ2C2H4, 25), 330
(Mþ2C2H5, 100), 314 (Mþ2C2H4–OH, 28), 302 (12), 275
(11). Anal. calcd for C17H20F3NO4: C 56.82; H 5.61; N
3.90. Found C 56.63; H 5.60; N 3.90.
4.5.2. Ethyl 5-acetyl-4-pyrrolidin-1-yl-2-(trifluoro-
methyl)benzoate (20a). Procedure A was applied. White
solid. Mp 67 8C. IR, nmax (cm21): 2977, 2860, 1725, 1072,
1605, 1533, 1445, 1365, 1292, 1267, 1246, 1148, 1071, 997,
955, 855, 779. MS, m/z (%): 329 (Mþ, 100), 315 (Mþ2CH3,
13), 312 (13), 301 (Mþ2C2H4, 21), 286 (53), 284
(Mþ2C2H4–OH, 58), 273 (53), 258 (20), 256 (21), 241
(17), 144 (16), 70 (N(CH2)þ4 , 56), 43 (CH3COþ, 46). Anal.
calcd for C16H18F3NO3: C 58.35; H 5.51; N 4.25. Found C
58.28; H 5.45; N 4.20.
3. (a) Denisova, A. B.; Sosnovskikh, V. Ya.; Dehaen, W.;
Toppet, S.; Meervelt, L. V.; Bakulev, V. A. J. Fluorine Chem.
2002, 115, 183–192. (b) Song, L. P.; Zhu, S. Z. J. Fluorine
Chem. 2001, 111, 201–205, and references cited therein.
(c) Volochnyuk, D. M.; Pushechnikov, A. O.; Krotko, D. G.;
Sibgatulin, D. A.; Kovaleva, S. A.; Tolmachev, A. A.
Synthesis 2003, 1531–1540.
4. (a) Bonacorso, H. G.; Wastowski, A. D.; Muniz, M. N.;
Zanatta, N.; Martins, M. A. P. Synthesis 2002, 1079–1083.
(b) Martins, M. A. P.; Sinhorin, A. P.; Da Rosa, A.; Flores,
A. F. C.; Wastowski, A. D.; Pereira, C. M. P.; Flores, D. S.;
Beck, P.; Freitag, R. A.; Brondani, S.; Cunico, W.; Bonacorso,
H. G. Synthesis 2002, 2353–2358.
4.5.3. Ethyl 5-benzoyl-4-pyrrolidin-1-yl-2-(trifluoro-
methyl)benzoate (21a). Procedure B was applied. White
solid. Mp 72 8C. IR, nmax (cm21): 2975, 2922, 2860, 1734,
1655, 1603, 1540, 1447, 1272, 1231, 1146, 1106, 1003, 955,
879, 724, 688. MS, m/z (%): 391 (Mþ, 100), 374 (11), 363
(Mþ2C2H4, 23), 362 (Mþ2C2H5, 33), 346 (Mþ2C2H4–
OH, 32), 334 (22), 105 (PhCOþ, 32), 91 (13), 77 (Phþ, 33),
70 (N(CH2)þ4 , 26). Anal. calcd for C21H20F3NO3: C 64.44;
H 5.15; N 3.58. Found C 64.41; H 5.01; N 3.51.
5. (a) Krasovsky, A. L.; Moiseev, A. M.; Nenajdenko, V. G.;
Balenkova, E. S. Synthesis 2002, 901–905. (b) Krasovsky,
A. L.; Hartulyari, A. S.; Nenajdenko, V. G.; Balenkova, E. S.
Synthesis 2002, 133–137.

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