Preparation of α,α-disubstituted trifluoromethyl ketones via Suzuki reaction of bromoenamines

Article abstract of DOI:10.1055/s-2000-6283

Palladium-catalyzed cross-coupling reaction of β-amino-β- trifluoromethylvinyl bromides 7 and 8 with boronic acids has been achieved to afford new stable β,β-disubstituted α-trifluoromethyl enamines 12 and 13, which can be used as masked ketones. The ketone function can be released in acidic medium.

Full text of DOI:10.1055/s-2000-6283

838
PAPER
Preparation of a,a-Disubstituted Trifluoromethyl Ketones via Suzuki
Reaction of Bromoenamines
Julien Legros, Denis Bouvet, Benoît Crousse, Danièle Bonnet-Delpon,* Jean-Pierre Bégué
Laboratoire BIOCIS associé au CNRS, Centre d’Etudes Pharmaceutiques, Rue J.B. Clément, F- 92296 Châtenay-Malabry, France
Fax +33(1)46835740, E-mail: daniele.bonnet-delpon@cep.u-psud.fr
Received 21 January 2000; revised 11 February 2000
Our previously described methods of preparation of triflu-
Abstract: Palladium-catalyzed cross-coupling reaction of b-amino-
oromethyl enamines by Wittig reaction5 and by the reac-
b-trifluoromethylvinyl bromides 7 and 8 with boronic acids has
tion of lithium amides with enol ethers6 cannot be applied
been achieved to afford new stable b,b-disubstituted a-trifluorome-
to the formation of b,b-dialkyl trifluoromethyl enamines.
Thus, we envisaged palladium-catalyzed cross-coupling
reaction performed on b-CF3 vinyl bromides. This reac-
tion is one of the most straightforward method for C-C
bond formation7 and has been applied to a-CF3 vinyl bro-
mides.8,9 Recently, we have successfully described the
Suzuki cross-coupling arylation, alkylation reaction of
b-ethoxy b-CF3 vinyl bromides.10 This prompted us to in-
vestigate this reaction with parent trifluoromethyl enam-
ines. To our knowledge, only one example of cross-
coupling reaction has been performed with enamines.11
We report here the preparation of b-amino-b-trifluorome-
thylvinyl bromides and their coupling with boronic acids.
thyl enamines 12 and 13, which can be used as masked ketones. The
ketone function can be released in acidic medium.
Key words: vinyl bromides, cross-coupling, boronic acids, enam-
ines, trifluoromethyl ketones, hydrolysis
Trifluoromethyl ketones are molecules of great interest as
synthetic intermediates in the preparation of more com-
plex molecules and because of their properties as enzyme
inhibitors.1 Among them, simple trifluoromethyl alkyl ke-
tones are selective inhibitors of esterases such as juvenile
hormone esterases.2 In recent years, great improvements
in the synthesis of fluoroalkyl ketones have been report-
ed.1,3 Most of these methods are not efficient for the prep-
aration of a,a-dialkyl trifluoromethyl ketones.
Furthermore a,a-disubstituted ketones, and particularly
a,a-diaryl ketones are very sensitive to traces of nucleo-
philic and basic agents.4 To overcome this problem, we
envisioned to prepare b,b-disubstituted trifluoromethyl
enamines as masked ketones (Figure).
Trifluoromethyl enamines 1-5 were prepared by Wittig
reaction with morpholinotrifluoroacetamide5 or by reac-
tion of lithium amides with enol ethers.6 Our previous
studies on the bromination/dehydrobromination of triflu-
oromethyl enamines showed that this classical method of
preparation of vinyl bromides was not straightforward in
the case of trifluoromethyl enamines.12 Problem arose
from the relative stabilities of intermediate iminium and
enammonium salts (Scheme).
Thus we reinvestigated this reaction in detail. It was per-
formed by reacting 1 with Br2 in THF at 0 °C. We noticed
that more than one equivalent of bromine was required.
With only one equivalent, the starting enamine was recov-
ered after neutralization with triethylamine. This suggests
that the first step of the reaction is a N-bromination lead-
Figure b,b-Disubstituted trifluoromethyl enamines as masked ke-
tones
Scheme
Synthesis 2000, No. 6, 838–842 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Preparation of a,a-Disubstituted Trifluoromethyl Ketones
839
Table 1 Bromination of Enamines 1−5
Table 2 Reaction of Aryl- or Alkenylboronic Acids 11a−d with Vi-
nyl Bromides 7−8
Sub-
strate
R1, R2
R
Prod- Yieldb Z/E
ucta
(%)
1
2
3
4
5
(CH2)2O(CH2)2
(CH2)2O(CH2)2
(CH2)2O(CH2)2
(CH2)5
(CH2)5CH3
Ph
(CH2)2Ph
Ph
Ph
6
7
8
9
10
95
90
89
51
82
75:25
70:30
90:10
70:30
90:10
Vinyl
Bromide
R
Boronic Acid
11 R’
Time Prod- Yielda
(h)
uct
(%)
Bn
7
7
7
7
8
8
8
8
Ph
Ph
Ph
Ph
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
a : 4-C6H4F
4
6
2.5
3
4
4.5
2.5
4
12a
12b
12c
12d
13a
13b
13c
13d
89
95
95
72
90
96
95
85
a No satisfactory microanalysis obtained.
b Yield of isolated products.
b : 4-C6H4OMe
c : a-naphthyl
d : CH=CHPh
a : 4-C6H4F
b : 4-C6H4OMe
c : a-naphthyl
d : CH=CHPh
ing to salt A and not a bromination of the double bond.
Furthermore, with 1.2 equivalent of Br2 a stable salt was
obtained, identified by NMR as the iminium salt B. This
salt cannot undergo dehydrobromination with triethy-
lamine. However, it could be totally isomerized into the
enamonium salt C by heating. Neutralization with trieth-
a Yield of isolated products.
ylamine could provide the expected vinyl bromides only ines 12 and 13 are very stable and can be stored for
at this stage. Under these conditions, enamines 1-5 could months at 0 °C.
be converted in high yields into 6-10 as a mixture of Z/E
isomers (Table 1).
Although the amino group has to be removed in view of
ketone preparation, we have checked the influence of the
The stereochemistry of 7 was unambiguously determined amino group in the cross-coupling reaction with 11c. Pre-
by 1H NMR experiments. For the minor isomer of 7, the liminary results showed that the coupling was also effi-
irradiation of CH2N entailed a NOE (8%) on the signal of cient from 9 when the amino substituent is a piperidine,
the ortho proton of the phenyl group, indicating their spa- leading to 14c (70:30), but failed in the case of the diben-
tial proximity. Thus, the major isomer has a Z-configura- zylamine parent compound 10.
tion. Stereochemistry of 6, 8-10 has been determined by
In order to liberate the ketone function, the hydrolysis of
19
comparison of their F NMR chemical shifts with those
enamines 12 and 13 has been investigated in acidic condi-
of 7.
tions. At room temperature, in acetonitrile with 2 equiva-
The Suzuki reaction was performed under the conditions lents of HCl (3 N), no reaction occurred after 24 hours. At
optimized for b-ethoxy vinyl bromides.10 b-Amino-b-tri- reflux of the solvent, enamines 12a-c and 13a-c could be
fluoromethylvinyl bromides 7 and 8 were treated in the hydrolyzed under these conditions, to provide the crude
presence of NaOH with boronic acids 11a-d under ketones 15a-c and 16a-c, respectively, in good yields.
Pd(PPh3)4 catalysis in benzene. In all cases compounds of However they could not be purified due to their instabili-
cross-coupling were obtained after 2-6 hours in very high ty.
yields (Table 2). Ratio of isomers is always the same as in
starting enamines. Due to the great number of aromatic
Table 3 Hydrolysis of Enamines 12, 13
protons, determination via 1H NMR spectroscopy was dif-
ficult. However, in 12b the presence of methoxy group
differentiated the ortho protons, and the above described
NOESY analysis confirmed the 70:30 mixture of Z/E-iso-
mers. Unfortunately in these series examination of 19F
NMR chemical shifts did not allow the determination of
Z/E ratio for other compounds. In the 1H NMR spectra of
13a-c, although signals of CH2O are well differentiated
in both isomers (0.4 ppm) assignment cannot be done un- 12a
ambiguously. Considering the stereospecificity of the Su-
zuki reaction, we assumed the Z/E values reported in the
Enamines
Time (min)
Producta
Yieldb (%)
15
15
15
60
60
60
15a
15b
15c
16a
16b
16c
87
80
78
90
87
91
12b
12c
13a
13b
experimental section for 12a, c-d, 13a-d. Thus, we have
shown that the Suzuki reaction is very efficient to intro-
duce a b-substitution to trifluoromethyl enamines. Enam-
13c
a Products 15, 16 obtained have less than 5% impurity.
b Yield of crude products.
Synthesis 2000, No. 6, 838–842 ISSN 0039-7881 © Thieme Stuttgart · New York

840
J. Legros et al.
PAPER
1
13C NMR: d = 35.3 (Z), 39.4, 49.7, 67.4, 122.9 (q, JC-F = 283 Hz,
In conclusion, we have developed a preparation of b-ami-
no-b-trifluoromethylvinyl bromides which could easily
undergo Suzuki cross-coupling reactions and provide
highly substituted-a-CF3-enamines. These stable enam-
ines are masked a,a-disubstituted trifluoromethyl ketones
whose access through classical routes is limited due to
their instability.
2
CF3), 126.5, 128.5, 135.5 (q, JC-F = 30 Hz, CCF3), 137.5 (q,
3JC-F = 3.8 Hz), 139.9.
(Z/E)-1-Bromo-1-phenyl-2-piperidino-3,3,3-trifluoroprop-1-
ene (9)
19F NMR: d = -57.1 (Z)/-61.8 (E) (70:30) (s, CF3).
1H NMR: d = 1.4 (Z)/1.7 (E) (m, 6 H, 3 CH2), 2.5 (E)/3.0 (Z) (t, 2
CH2N), 7.2-7.4 (m, 5 H).
13C NMR: d = 23.7 (E)/34.1 (Z), 26.3 (E)/26.5 (Z), 51.1 (Z)/53.2
19F NMR, 13C NMR, 1H NMR spectra were recorded on a 200 MHz
1
5
(E), 122.7 (q, JC-F = 287 Hz, CF3), 128.0, 128.2, 128.4 (q, JC-
2
F = 1.9 Hz), 129.2 (q, 3JC-F = 3.9 Hz, CF3C=C), 137.8 (q, JC-F = 29
multinuclear spectrometer. Chemichal shifts (d) are given in ppm
1
relative to CFCl3 for 19F NMR, and relative to TMS for H NMR
Hz, CF3C=C), 138.5.
and 13C NMR spectra. Coupling constants are given in Hz. In all
NMR measurements CDCl3 was used as a solvent. GC analyses
were performed using a SE 30 capillary column (12 m). Boronic ac-
ids 11a-c are commercially available. Enamines 1-3, 5,5,6 the bro-
moenamine 7,12 boronic acid 11d,13 Pd(PPh3)414 and ketones 15a,b15
were prepared according to the literature procedure. Petroleum
ether used had bp 40-65 °C.
(Z/E)-2-Dibenzylamino-1-bromo-1-phenyl-3,3,3-trifluoroprop-
1-ene (10)
19F NMR: d = -56.3 (Z)/-59.4 (E) (90:10) (s, CF3).
1H NMR: d = 3.7 (E)/4.2 (Z) (s, 4 H, 2 CH2), 6.9-7.4 (m, 15 H, 3
C6H5).
1
13C NMR: d = 56.2 (Z)/56.8 (E), 123.2 (q, JC-F = 283 Hz, CF3),
3
127.7, 128.1, 128.4, 128.5, 129.3, 129.5, 132.3 (q, JC-F = 3.4 Hz,
CF3C=C), 136.4 (q, 2JC-F = 29 Hz, CF3C=C), 138.0, 138.5.
(Z)-1-Phenyl-2-piperidino-3,3,3-trifluoroprop-1-ene (4)
2-Ethoxy-1-phenyl-3,3,3-trifluoroprop-1-ene5b (1 g, 4.6 mmol) was
added at -78 °C under argon to the N-lithiated amine prepared at
-30 °C from BuLi (9.2 mmol, 1.6 M in hexane) and piperidine
(861 mg, 10 mmol) in THF (15 mL). The colored solution was
stirred for 15 min at -78 °C and then was allowed to warm to 0 °C
over a period of 1 h. After 3 h, the brown solution was poured into
satd aq NH4Cl solution, the layers were separated and the aqueous
phase was extracted with Et2O (3 × 50 mL). The combined organic
phases were dried (MgSO4) and evaporated to afford after chroma-
tography on silica gel (pentane), pure (Z)-enamine 4 as a yellow oil;
yield: 1.05 g (90%).
(Z/E)-2-Morpholino-1-(4-fluorophenyl)-1-phenyl-3,3,3-trifluo-
roprop-1-ene (12a); Typical Procedure
A solution of vinyl bromide 7 (1 g, 2.7 mmol) and (Ph3P)4Pd
(162 mg, 0.14 mmol) in benzene (30 mL) was stirred for 15 min
under argon. A solution of 11a (546 mg, 3.5 mmol) in benzene
(10 mL) and 2 M aq NaOH (1.8 mL, 5.4 mmol) were added and the
mixture was refluxed for 4 h (the reaction was monitored by GC).
After washing with aq satd NH4Cl solution, the organic phase was
extracted with Et2O (3 × 20 mL). The combined organic phases
were dried (MgSO4) and concentrated to give, after chromatogra-
phy on silica gel (petroleum ether/EtOAc, 90:10), pure enamine 12a
as a white solid; yield: 939 mg (89%).
19F NMR: d = -58.7 (Z)/-58.9 (E) (70:30) (s, CF3), -113.8 (Z)/
-114.6 (E) (70:30) (m, C6H4F).
1H NMR: d = 2.6 (m, 4 H), 3.4 (m, 4 H), 6.8-7.3 (m, 9 H).
13C NMR: d = 53.5 (Z)/53.7, 68.3, 116.2 (d, 2JC-F = 22 Hz, CHCF),
123.0 (q, 1JC-F = 294 Hz, CF3), 128.7, 128.9, 129.3, 130.2, 130.9 (d,
3JC-F = 8 Hz), 135.1 (q, 2JC-F = 29 Hz, CF3C=C), 137.3 (d, 4J C-F = 4.5
Hz), 139.6, 140.2 (q, 3JC-F = 3 Hz, CF3C=C), 141.2, 162.5 (d,
1JC-F = 248 Hz, CF).
19F NMR: d = -63 (s, CF3).
1H NMR: d = 1.6 (m, 6 H, 3 CH2), 2.9 (m, 4 H, 2 CH2N), 6.5 (s, 1
H), 7.2-7.4 (m, 3 H), 7.7 (d, J = 7.9 Hz, 2 H).
3
13C NMR: d = 24.0, 26.3, 51.4, 121.5 (q, JC-F = 5 Hz, CF3C=C),
1
123.4 (q, JC-F = 281 Hz, CF3), 128.2, 129.7, 134.4, 137.5 (q,
2JC-F = 28 Hz, CF3C).
Anal. calcd for C14H16F3N (255.3): C, 65.87; H, 6.32; N, 5.49.
Found: C, 65.75; H, 6.28; N, 5.29.
(Z/E)-1-Bromo-2-morpholino-1-phenyl-3,3,3-trifluoroprop-1-
ene (7); Typical Procedure
Anal. calcd for C19H17F4NO (351.3): C, 64.95; H, 4.88; N, 3.99.
Found: C, 64.90; H, 4.87; N, 3.98.
To a solution of enamine 2 (400 mg, 1.55 mmol) in THF (20 mL)
at 0 °C was added Br2 (0.1 mL, 1.86 mmol). After 0.5 h at reflux of
the solvent, Et3N (0.3 mL, 3.1 mmol) was added at 0 °C, stirred for
a further 10 min and then poured into an aq satd NH4Cl solution
(20 mL). The layers were separated and the aqueous phase extracted
with Et2O (3 × 10mL). The combined organics phases were dried
(MgSO4) and evaporated to afford, after chromatography on silica
gel (petroleum ether/EtOAc, 90:10), pure vinyl bromide 7 as a yel-
low oil; yield: 479 mg (90%).
(Z/E)-2-Morpholino-1-(4-methoxyphenyl)-1-phenyl-3,3,3-trif-
luoroprop-1-ene (12b)
19F NMR: d = -58.8 (Z)/-59.0 (E) (70:30) (s, CF3).
1H NMR: d = 2.7 (m, 4 H), 3.58 (m, 4 H), 3.79/3.81 (Z) (s, OCH3),
6.85-7.3 (m, 9 H).
13C NMR: d = 52.7 (Z)/52.9, 55.1 (Z)/55.2, 67.4, 113.7/114.2 (Z),
123.7 (q, 1JC-F = 290 Hz, CF3), 127.4, 127.6, 129.0 (Z) (q, 5JC-F = 2
5
(Z/E)-3-Bromo-2-morpholino-1,1,1-trifluoronon-2-ene (6)
19F NMR: d = -56.9 (Z)/-58.1 (E) (75:25) (s, CF3).
1H NMR: d = 0.9 (m, 3 H), 1.2 (m, 8 H), 1.9 (m, 2 H), 2.6 (E)/2.9
(Z) (m, 4 H), 3.4 (E)/3.7 (Z) (m, 4 H).
Hz), 130.5/130.3 (E) (q, JC-F = 2 Hz), 133.5, 133.7, 134.3 (q,
3
2JC-F = 29 Hz, CF3C=C), 140.2, 140.9 (q, JC-F = 2.3 Hz, CF3C=C),
141.8, 159.2/159.3 (Z).
Anal. calcd for C20H20F3NO2 (363.4): C, 66.11; H, 5.55; N, 3.85.
Found: C, 66.21, H, 5.60; N, 3.83.
13C NMR: d = 13.7, 22.2, 27.9, 31.0, 36.9, 44.2, 49.5/50.5 (Z), 61.7
1
2
(Z)/67.2, 123.0 (q, JC-F = 283 Hz, CF3), 134.6 (q, JC-F = 29 Hz,
(Z/E)-2-Morpholino-1-naphthyl-1-phenyl-3,3,3-trifluoroprop-
1-ene (12c)
CCF3), 139.1 (q, 3JC-F = 3.8 Hz).
19F NMR: d = -58.8 (Z)/-58.9 (E) (70:30) (s, CF3).
(Z/E)-3-Bromo-2-morpholino-1,1,1-trifluoropent-2-ene (8)
19F NMR: d = -57.3 (Z)/-58.0 (E) (90:10) (s, CF3).
1H NMR: d = 2.6 (m, 4 H), 3.5 (m, 4 H), 7.0-7.7 (m, 12 H).
1H NMR: d = 2.8 (m, 8 H), 3.6 (m, 4 H), 7.1 (m, 7 H).
13C NMR: d = 52.8 (Z)/52.9, 67.4 (Z)/67.5, 123.5 (q, 1JC-F = 292 Hz,
CF3), 126.3-128.6, 129.4 (q, 5J C-F = 2 Hz), 132.8, 133.1, 135.4 (q,
Synthesis 2000, No. 6, 838–842 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Preparation of a,a-Disubstituted Trifluoromethyl Ketones
841
3
3
2JC-F = 29 Hz, CF3C=C), 138.9, 139.8, 141.1 (q, JC-F = 3 Hz,
(q, 2JC-F = 29 Hz, CF3C=C), 137.2, 137.5, 141.4 (q, JC-F = 3.6 Hz,
CF3C=C).
CF3C=C).
Anal. calcd for C23H20F3NO (383.4): C, 72.05; H, 5.26; N, 3.65.
Found: C, 71.67; H, 5.31; N, 3.61.
Anal. calcd for C23H24F3NO (387.4): C, 71.30; H, 6.24; N, 3.62.
Found: C, 71.90; H, 6.19; N, 3.55.
(E,E/Z,E)-4-Morpholino-1,3-diphenyl-5,5,5-trifluoropenta-1,3-
diene (12d)
(Z/E)-1-Naphthyl-1-phenyl-2-piperidino-3,3,3-trifluoroprop-1-
ene (14c)
19F NMR: d = -55.5 (s) (E,E)/-58.6 (s) (Z,E) (70:30).
19F NMR: d = -58.8 (Z)/-58.9 (E) (70:30) (s, CF3).
1H NMR: d = 2.6 (Z,E)/3.1 (E,E) (t, J = 4.3 Hz, 4 H), 3.4 (Z,E)/3.9
(E,E) (t, J = 4.6 Hz, 4 H), 6.1 (E,E)/6.2 (Z,E) (d, J = 16 Hz, 1 H),
7.1-7.5 (m, 10 H), 7.8 (d, J = 16 Hz, 1 H).
1H NMR: d = 1.5 (m, 6 H, 3 CH2), 2.8 (m, 4 H, 2 CH2), 7.0-8.1 (m,
12 H).
13C NMR: d = 24.0 (Z)/24.1(E), 26.5 (Z)/26.6 (E), 53.8 (Z)/53.9 (E),
13C NMR: d = 51.5 (E,E)/52.0 (Z,E), 67.2 (Z,E)/67.8 (E,E), 123.5
126.1-128.3, 129.5, 132.5, 132.9, 136.8 (q, JC-F = 29 Hz,
2
1
(q, JC-F = 280 Hz, CF3), 126.4, 127.9, 128.3, 128.5, 128.7, 128.8,
CF3C=C), 137.7, 140.2. CF3 (not observed)
129.1 (q, 5JC-F = 2.0 Hz), 134.0 (q, 2JC-F = 28 Hz, CF3C=C), 136.0,
136.9, 142.1 (q, 3JC-F = 3.6 Hz, CF3C=C).
3-(4-Fluorophenyl)-3-phenyl-1,1,1-trifluoropropan-2-one
(15a); Typical Procedure
Anal. calcd for C21H20F3NO (359.4): C, 70.18; H, 5.61, N, 3.90.
Found: C, 70.88, H, 5.40; N, 3.58.
To a solution of enamine 12a (200 mg, 0.57 mmol) in MeCN (5 mL)
was added 3 N HCl (0.38 mL, 1.1 mmol). After 15 min at reflux of
the solvent, the mixture was neutralized with aq 1 N NaHCO3 solu-
tion (1.1 mL). The organic phase was extracted with Et2O (3 × 10
mL). The combined organic phases were dried (MgSO4) and con-
centrated to give crude ketone 15a (140 mg, 87%).
(Z/E)-3-(4-Fluorophenyl)-2-morpholino-5-phenyl-1,1,1-tri-
fluoropent-2-ene (13a)
19F NMR: d = -54.8 (E)/-59.0 (Z) (10:90) (s, CF3), -114.5 (E)/
-116.0 (Z) (10/90) (m, C6H4F).
1H NMR: d = 2.5(Z)/2.9 (m, 4 H), 2.6 (m, 4 H), 3.4 (Z)/3.7 (m, 4 H),
6.9-7.3 (m, 9 H).
19F NMR: d = -77.3 (s, CF3), -114.0 (m, C6H4F).
1H NMR: d = 5.6 (s, 1 H), 6.9-7.5 (m, 10 H).
13C NMR: d = 33.3/34.7 (Z), 35.9 (Z)/37.1, 51.0/51.8 (Z), 67.2 (Z)/
2
1
13C NMR: d = 57.1, 116.0 (d, JC-F = 22 Hz), 116.1 (q, JC-F = 293
2
1
67.6, 115.4 (d, JC-F = 21.7 Hz, CHCF), 123.5 (q, JC-F = 281 Hz,
3
CF3), 126.2, 128.3, 128.4, 129.7 (d, 3JC-F = 7.3 Hz, CHCF), 135.3 (q,
HZ, CF3), 128.3, 128.8, 129.2, 130.5 (d, JC-F = 8.5 Hz), 131.5 (d,
4JC-F = 3.0 Hz), 135.4, 162.6 (d, 1JC-F = 247 Hz), 149.9 (q, 2JC-F = 34
Hz, CF3CO).
2JC-F = 29 Hz, CF3C=C), 136.4 (d, JC-F = 3.8 Hz, CCF), 141.1,
4
143.2 (q, 4JC-F = 2.2 Hz, CF3C=C), 162.5 (d, 1JC-F = 247 Hz, CHCF).
IR (CH2Cl2): nC=O = 1756 cm-1.
Anal. calcd for C21H21F4NO (379.4): C, 66.48; H, 5.58; N, 3.69.
Found: C, 66.46; H, 5.60; N, 3.58.
3-(4-Methoxyphenyl)-3-phenyl-1,1,1-trifluoropropan-2-one
(15b)
(Z/E)-3-(4-Methoxyphenyl)-2-morpholino-5-phenyl-1,1,1-tri-
fluoropent-2-ene (13b)
19F NMR: d = -77.3 (s, CF3).
19F NMR: d = -54.8 (E)/-59.4 (Z) (10:90) (s, CF3).
1H NMR: d = 3.8 (s, 3 H), 5.5 (s, 1 H), 6.8-7.5 (m, 9 H).
1H NMR: d = 2.5 (Z)/2.9 (m, 4 H), 2.65 (m, 4 H), 3.5 (Z)/3.75 (m, 4
H), 3.8 (s, OCH3), 6.7-7.4 (m, 9 H).
13C NMR: d = 55.2, 57.2, 114.6, 116.1 (q, JC-F = 293 Hz, CF3),
1
127.4, 128.1, 128.8, 129.0, 130.1, 136.1, 159.5, 190.2 (q, 2JC-F = 33
Hz, CF3CO).
13C NMR: d = 33.4/34.9 (Z), 36.2 (Z)/37.2, 51.1/52.6 (Z), 55.3, 67.3
1
IR (CH2Cl2): nC=O = 1729 cm-1.
(Z)/67.7, 113.5/113.7 (Z), 124.3 (q, JC-F = 281 Hz, CF3), 126.0,
2
128.3, 128.4, 129.3, 132.5, 134.5 (q, JC-F = 29 Hz, CF3-C=C),
3-Naphthyl-3-phenyl-1,1,1-trifluoropropan-2-one (15c)
141.5, 143.1 (q, 3JC-F = 1.8 Hz, CF3C=C), 159.1.
19F NMR: d = -77.4 (s, CF3).
Anal. calcd for C22H24F3NO2 (391.4): C, 67.51; H, 6.18; N, 3.58.
Found: C, 67.51; H, 6.26; N, 3.51.
1H NMR: d = 5.7 (s, 1 H), 7.2-8.2 (m, 12 H).
13C NMR: d = 58.0, 116.2 (q, 1JC-F = 293, CF3), 125.8-129.1, 132.9,
(Z/E)-2-Morpholino-3-naphthyl-5-phenyl-1,1,1-trifluoropent-
2-ene (13c)
133.0, 133.4, 138.5, 189.6 (q, 2JC-F = 34, CF3CO).
IR (CH2Cl2): nC=O = 1763 cm-1.
19F NMR: d = -54.8 (E)/-59.3 (Z) (10:90) (s, CF3).
1H NMR: d = 2.5 (Z)/3.0 (m, 4 H), 2.65 (m,4 H), 3.3 (Z)/3.7 (m, 4
3-(4-Fluorophenyl)-5-phenyl-1,1,1-trifluoropentan-2-one (16a)
19F NMR: d = -77.4 (s, CF3), -113.8 (m, C6H4F).
H), 6.9-7.8 (m,12 H).
1H NMR: d = 2.1 (m, 1 H), 2.5 (m, 3 H), 4.0 (t, J = 7.0 Hz, 1 H),
7.0-7.5 (m, 9 H).
13C NMR: d = 33.5/34.9 (Z), 36.0 (Z)/37.2, 51.1/51.9 (Z), 67.2 (Z)/
1
67.8, 123.9 (q, JC-F = 281 Hz, CF3), 125.8-128.6, 132.8, 133.2,
135.3 (q, 2JC-F = 29 Hz, CF3C=C), 138.1, 141.3, 143.8 (q, 3J C-F = 2.1
Hz, CF3C=C).
13C NMR: d = 32.9, 34.0, 51.3, 115.8 (q, 1JC-F = 293 Hz, CF3), 116.2
2
3
(d, JC-F = 22 Hz, CHCF), 126.4, 128.3, 128.6, 130.2 (d, JC-F = 8
4
1
Hz), 130.8 (d, JC-F = 4 Hz), 140.3, 162.5 (d, JC-F = 245 Hz, CF),
Anal. calcd for C25H24F3NO (411.5): C, 72.98; H, 5.88; N, 3.40.
Found: C, 72.82; H, 5.90; N, 3.30.
191.5 (q, 2JC-F = 31 Hz, CF3CO).
3-(4-Methoxyphenyl)-5-phenyl-1,1,1-trifluoropentan-2-one
(E,E/Z,E)-4-Morpholino-1-phenyl-3-(2-phenylethyl)-5,5,5-trif-
luoropenta-1,3-diene (13d)
(16b)
19F NMR: d = -76.9 (s, CF3).
19F NMR: d = -56.0 (Z,E)/-61.8 (E,E) (90:10) (s, CF3).
1H NMR: d = 2.1 (m, 1 H), 2.4 (m, 1 H), 2.5 (m, 2 H), 3.8 (s, 3 H,
OCH3), 3.95 (t, J = 7.0, 1 H), 6.9-7.5 (m, 9 H).
13C NMR: d = 33.0, 33.9, 51.4, 55.2, 114.7, 115.8 (q, 1JC-F = 293 Hz,
CF3), 126.3, 126.8, 128.4, 128.6, 129.8, 140.7, 159.6, 191. 5 (q,
2JC-F = 33 Hz, CF3CO).
1H NMR: d = 2.8 (m, 4 H, 2 CH2), 3.0 (m, 4 H, 2 CH2), 3.9 (t, J = 4.4
Hz, 4 H, 2 CH2), 6.9 (d, J = 16 Hz, 1 H), 7.1-7.6 (m, 10 H), 7.8 (d,
J = 16 Hz, 1 H).
13C NMR: d = 29.8 (Z,E)/30.8(E,E), 35.5(E,E)/36.4(Z,E),
50.9(E,E)/52.1(Z,E), 66.9(E,E)/67.8(Z,E), 124.7 (q, 1JC-F = 278 Hz,
CF3), 126.5, 127.0, 128.4, 128.7, 128.8, 129.0, 132.6, 132.9, 134.7
Synthesis 2000, No. 6, 838–842 ISSN 0039-7881 © Thieme Stuttgart · New York

842
J. Legros et al.
PAPER
3-Naphthyl-5-phenyl-1,1,1-trifluoropentan-2-one (16c)
(5) (a) Bégué, J. P.; Mesureur, D. Synthesis 1989, 309.
19F NMR: d = -77.0 (s, CF3).
(b) Bégué, J. P.; Bonnet-Delpon, D.; Mesureur, D.; Née, G.;
Wu, S. W. J. Org. Chem. 1992, 57, 3807.
(6) Bégué, J. P.; Bonnet-Delpon, D.; Bouvet, D.; Rock, H. M. J.
Chem.Soc., Perkin Trans. 1 1998, 1797.
(7) (a) Malleron, J. L.; Fiaud, J. C.; Legros, J. Y., Handbook of
palladium-catalyzed organic reactions. Synthetic aspects and
catalytic cycles, Academic Press: New York 1997.
(b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(8) Jiang, B.; Xu, Y. J. Org. Chem. 1991, 56, 7336.
Jiang, B.; Xu, Y. Tetrahedron Lett. 1992, 56, 7336.
Jin, F.; Xu, Y.; Jiang, B. J. Fluorine Chem. 1993, 65, 111.
Jin, F.; Xu, Y. J. Fluorine Chem. 1994, 67, 1.
1H NMR: d = 2.2 (m, 1 H), 2.5 (m, 3 H), 4.1 (t, J = 7 Hz, 1 H), 7.0-
7.8 (m, 12 H).
1
13C NMR: d = 33.0, 34.0, 52.3, 116.5 (q, JC-F = 293 Hz, CF3),
2
125.8-129.2, 132.4, 133.0, 133.6, 140.5, 192.0 (q, JC-F = 34 Hz,
CF3CO).
Acknowledgement
We thank Michèle Ourévitch for high-field NMR experiments.
Xu, Y.; Jin, F.; Huang, W. J. Org. Chem. 1994, 59, 2638.
(9) Shi, G.; Huang, X.; Hong, F. J. Org. Chem. 1996, 61, 3200.
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(10) Allain, L.; Bégué, J. P.; Bonnet-Delpon, D.; Bouvet D.
Synthesis 1998, 847.
(11) One successful example has been performed with non
fluorinated b-bromo enamide ester : Burk, M. J.; Allen, J. G.;
Kiesman, W. F.; Stoffan, K. M., Tetrahedron Lett. 1997, 38,
1309.
(12) Bégué, J. P.; Bonnet-Delpon, D.; Bouvet, D.; Rock, H. M. J.
Fluorine. Chem. 1996, 80, 17.
(13) Lane, C. F.; Kabalka, G. W., Tetrahedron 1976, 32, 981.
(14) Coulson, D. R. Inorg. Syn. 1972, 13, 21.
(15) Horniak, G.; Fetter, J.; Némek, G.; Poszavacz, L.; Simig, G. J.
Fluorine Chem. 1997, 84, 849.
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Article Identifier:
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Synthesis 2000, No. 6, 838–842 ISSN 0039-7881 © Thieme Stuttgart · New York