Concise stereoselective synthesis of 1-perfluoroalkyl enamines via the addition of N-lithiated amines to enol ethers and their subsequent metalation to form new functionalized enamines

Article abstract of DOI:10.1039/a801243a

Addition of lithium amides derived from a range of cyclic, sterically demanding, and chiral amines, to trifluoromethyl (Z)-enol ethers 1 and 4, provides stereoselectively the corresponding (Z)-enamines 3a-e and 7 in good yields. This reaction has been ext

Full text of DOI:10.1039/a801243a

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Concise stereoselective synthesis of 1-perfluoroalkyl enamines via the
addition of N-lithiated amines to enol ethers and their subsequent
metalation to form new functionalized enamines
Jean-Pierre Bégué, Danièle Bonnet-Delpon,* Denis Bouvet and
Michael H. Rock
BioCIS-CNRS, Centre d’Etudes Pharmaceutiques, Rue J.B. Clément F-92296
Châtenay-Malabry, France
Addition of lithium amides derived from a range of cyclic, sterically demanding, and chiral amines, to
trifluoromethyl (Z)-enol ethers 1 and 4, provides stereoselectively the corresponding (Z)-enamines 3a–e
and 7 in good yields. This reaction has been extended to the perfluoroalkyl and chlorofluoroalkyl enol
ethers (CF2Cl, C2F5). The enamines can react with ButLi to give vinylic anions and, after quenching with
aldehydes and ethyl chloroformate, provide new functionalized enamines 12–16.
organolithium reagent to the double bond giving the intermedi-
ate A followed by a trans-elimination of LiOEt.
Introduction
Organofluorine compounds have found increasing use in the
areas of agrochemicals, pharmaceuticals, polymers and new
materials.1 The fluorine atom brings specific chemical and
physical properties to molecules. In the pharmaceutical field,
molecules containing CF2 or CF3 can offer a significant change
in biological activity, compared to their non fluorinated
analogs. For example, the enzyme inhibitory activity of tri-
fluoromethyl ketones has been widely proved.2 The interest in
molecules containing the CF3 group entailed the development
of new and efficient synthetic methodologies. Direct trifluoro-
methylation3 and synthesis using fluorine-containing building
blocks4 are two major approaches which have gained consider-
able improvement in recent years. For the latter approach, the
elaboration of new versatile building blocks is required. Per-
fluoroalkylated enamines are precursors of ketones and amines,
and are versatile building blocks for the synthesis of complex
fluorinated compounds. For their preparation, we have previ-
ously developed a Wittig reaction with amides, which was
limited to trifluoroacetamides.5 Other described preparations
are the amination of fluoroalkyl ketones6 and in particular
examples, the addition of an amine to fluoroalkynes,7 the
nucleophilic displacement of a vinylic fluoride by a lithium
amide,8 and a direct trifluoromethylation of pyrrolidinones.9
Most of these preparations are not stereoselective. We report
here a new and stereoselective access to functionalized per-
fluoroalkyl enamines from the corresponding enol ethers.
Those results prompted us to investigate the reactivity of
CF3 enol ether 1 towards lithium amides. The treatment of
enol ether 1 with one equivalent of lithium dibenzyl amide
at Ϫ78 ЊC in THF, and stirring for 3 h at 0 ЊC, resulted
in the stereoselective formation of the (Z)-trifluoromethyl-
substituted enamine 3a accompanied by starting material.
Two equivalents of lithium amide were required to drive the
reaction to completion and to obtain the enamine in high yield
(Scheme 2, Table 1). This unusual reaction of addition of
lithium amides to a double bond occurs at the opposite site of
that expected in Michael-type reactions, and is quite different
to reaction with CF3 substituted terminal olefins.12 The reaction
has been successfully extended to N-lithiated species derived
from a cyclic amine and the sterically demanding diiso-
propylamine. The reaction occurred in high yield with complete
stereoselectivity. The configuration of double bonds has been
3
determined using an established empirical rule based on JCF
coupling constants in the 13C NMR spectra.14 Their values,
higher than 4 Hz, demonstrate the Z-configuration of the
double bonds which was confirmed by NOE experiments per-
formed on the enamine 3a. After complete assignments of the
protons by COSY heteronuclear multiple-quantum coherence
(HMQC), and heteronuclear multiple bond coherence
(HMBC), irradiation of the benzylic protons resulted in a 6%
signal enhancement of the ortho-aromatic protons, indicating
their spatial proximity.
The reaction most likely occurs under kinetic control since
the enamines 3 possess the same configuration as the starting
material whatever the bulkiness of substituents of the double
bond, and since, when an isomerisation can occur, a Z/E
mixture was obtained as in the case of enamine 3d (Table 1,
Entry 4).
We then studied the addition of chiral amines and first chose
the (S)-phenethyl amine (Table 1, entry 4). However, although
the reaction was successful with this monoalkyl lithium amide,
it was not stereoselective, leading to a 55:45 mixture of Z:E
isomers. A facile prototropy is probably responsible for the
isomerisation of the Z-enamine to the less hindered E-isomer.
When performed with a chiral dialkyl lithium amide, the
reaction provided stereoselectively the chiral Z-enamine 3e
(Table 1, entry 5).
Results and discussion
We have previously reported the synthetic utility of CF3 enol
ethers which can be involved in electrophilic reactions such as
epoxidation and bromination, to give the corresponding epoxy
ethers10 and vinyl bromides.11 We then exploited their electro-
philicity in reactions involving organolithium reagents. CF3
Enol ethers 1 can undergo addition of alkyllithium reagents but
with a regioselectivity opposite to that of CF3-substituted ter-
minal olefins,12 giving stereoselective access to trifluoromethyl
alkenes 2 (Scheme 1).13
We proposed that this formal substitution of the ethoxy
group by the alkyl group occurs through a syn-addition of the
F3C
EtO
F3C
R
Li
F3C
R
As in the carbolithiation reaction of enol ethers, the limit-
ation of this reaction is the presence of a conjugated β-
substituent which can stabilize an intermediate anionic species.
With the enol ether 4, the reaction still occurs in high yield,
although the p-methoxyphenyl substituent renders the double
RLi
–LiOEt
Ph
EtO
Ph
Ph
(Z)-1
A
(E)-2
Scheme 1
J. Chem. Soc., Perkin Trans. 1, 1998
1797

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Table 1 Addition of N-lithiated amines to enol ether 1
Table 2 Addition of N-lithiated amines to enol ethers 4–7
Entry
R1R2NLi
Products 3a–e
Yield (%)
Entry Enol ethers 4–7 R1R2NLi Enamines 8–11
Yield (%)
73
F3C
F3C
F3C
NLi
Ph
1
84
1
NLi
N
Ph
EtO
Ph
N
Ph
Ph
Ph
Ph
Ph
(Z)-3a
Ph
OMe
OMe
Ph
(Z)-4
(Z)-5
(Z)-8
F3C
F3C
EtO
NLi
2
78
80
85
87
2
3
4
0
70
75
71
NLi
No reaction
N
Ph
(Z)-3b
CF3CF2
N
CF3CF2
EtO
NLi
F3C
N
Ph
Ph
Ph
NLi
Ph
Ph
Ph
Ph
Ph
3
4
Ph
(Z)-6
(Z)-9
CF3CF2
N
(Z)-3c
F3C
CF3CF2
EtO
NLi
H
NLi
*
NH
(S)
Ph
Ph
(S)
*
Ph
Ph
(Z,E)-3d
(Z)-6
(Z)-10
ClCF2
F3C
ClCF2
EtO
NLi
NLi
*
Ph
N
Ph
5
5
(S)
N
*
Ph
Ph
(S)
Ph
Ph
(Z)-7
(Z)-11
(Z)-3e
1) 2 equiv. R1R2NLi
THF, –78 °C
Table 3
F3C
EtO
F3C
N
t/mina
Yield of 12 (%)
Yield of 3a (%)
2) 0 °C, 3 h
3) NH4Cl
Ph
R1
Ph
R2
(Z)-3
7
10
15
20
42
50
77
43
58
50
23
57
(Z)-1
Scheme 2
bond less electrophilic. In contrast, the enol ether 5, substi-
tuted with an alkyl group, was completely unreactive towards
lithium diisopropylamide (LDA) (Table 2).
a t = time between ButLi and aldehyde additions.
time before introduction of the aldehyde. The former had no
significant influence on the results. Conversely, the proportion
of allylic alcohols and starting enamines was highly dependent
on the time (t) between addition of ButLi and the aldehyde
(Table 3). Experiments performed with 3a showed that 15 min
was required for the optimal formation of the vinylic anion.
This anion then rapidly underwent protonation in the reaction
medium. Under these conditions, the proportion of allylic
alcohols 12 and 13 could be improved and after separation from
starting material, they could be isolated in 65% yield (Table 4).
With benzaldehyde the reaction occurred in a lower yield
(55%). Vinylic anions generated from 3a and 3f have also been
quenched with ethyl chloroformate leading to the correspond-
ing enamino esters 15 (58%) and 16 (55%) but without stereo-
selectivity (E:Z ~ 30:70). Since no isomerisation of the vinyl
anions is observed in reactions with aldehydes, the lack of stereo-
selectivity is explained by mesomeric forms of enamino esters.
The E-configuration of the trisubstituted enamine 14 was
demonstrated by a hetero NOE experiment. Irradiation of the
fluorine atoms resulted in a 9% enhancement of the signal of
the proton geminal to the hydroxy group. The spatial proximity
The generality of this reaction was investigated by studying
the reactivity of other fluoroalkyl enol ethers. C2F5- and ClCF2-
Substituted enol ethers 6 and 715 reacted under the same
conditions with lithium amides to provide the corresponding
enamines 9, 10 and 11. The reaction between the enol ether 6
and LDA to provide 10 in good yield confirms the insensitivity
of the reaction to steric hindrance and is a good alternative
to the Wittig reaction.5
In these experiments, we have checked, by performing the
reaction in the presence of trimethylsilyl chloride, that the
excess of LDA does not allow a vinylic metalation to occur.
In order to generate these vinyllithium reagents, we thus used
the more basic tert-butyllithium reagent (ButLi) under the
conditions which have been successful for the metalation of
CF3-substituted olefins.13 Enamines 3c and 3f15 reacted at
room temperature with 1.3 equiv. of ButLi in hexane in the pres-
ence of tetramethylethylenediamine (TMEDA), and, after a few
minutes, trapping by one equivalent of propanal, followed by
hydrolysis, provided the allylic alcohols 12 and 13 respectively
(E-isomers), accompanied with about 60% of starting enamines
(Scheme 3). These results confirm that, in the absence of
4
between these atoms is confirmed by a through space JCF
coupling constant of 3.5 Hz, observed for the 13C NMR signal
4
F3C
F3C
E
F3C
of the hydroxy-substituted carbon. Similar JCF were observed
1) 1.3 equiv. ButLi
for enamines 12 and 13.
hexane, TMEDA (1 equiv.)
R1
N
Ph
R1
N
Ph
R1
N
Ph
2) E+
R2
(Z)-3a,f
R2
12–16
R2
(Z)-3a,f
Conclusions
We have developed a method for the preparation of CF3-
substituted enamino alcohols and enamino esters in two steps
from enol ethers. The first step involves addition of lithium
amides to CF3-substituted enol ethers, giving stereoselective
access to the corresponding enamines in high yields. Lithium
amides derived from a range of amines, including chiral ones,
were all reactive towards enol ethers. This good alternative to
Scheme 3
a leaving group, the addition of organolithium reagents of
CF3-substituted double bonds does not occur.13 Since partial
recovering of the enamine could be the result of an incomplete
formation of the vinylic anions, we investigated the influence of
two parameters, the number of equivalents of ButLi, and the
1798
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
as an oil (0.30 g, 84%); ν(neat)/cmϪ1 1631 (C᎐C); δ Ϫ62.6;
Table 4 Preparation of enamines 12–16 from enamine 3a and 3f
᎐
F
δH 3.9 (4H, s), 6.5 (1H, s), 6.8 (2H, m), 7.2 (13H, m); δC 54.7,
Entry
Electrophile Products 12–16
Yield (%)
3
1
118.5 (q, JCF 4.6), 122.5 (q, JCF 279), 126.9, 128.1, 128.7,
134.3, 134.5 (q, 2JCF 29), 137.3, 139.7 (Found: C, 75.29; H, 5.58;
N, 3.90. C23H20F3N requires C, 75.18; H, 5.50; N, 3.81%).
(Z)-1-Phenyl-2-pyrrolidinyl-3,3,3-trifluoropropene 3b. From
enol ether 1 (0.22 g, 1 mmol) and N-lithiated pyrrolidine
(n-butyllithium 1.32 cm3, 1.5  in hexane; pyrrolidine 0.14 g,
2 mmol), after purification, compound 3b was obtained in 96%
purity (0.19 g, 78%); ν(neat)/cmϪ1 1634 (C᎐C); δ Ϫ64.7; δH 1.7
OH
F3C
C2H5CHO
1
N
Ph
65
Ph
Ph
(E)-12
OH
F3C
N
᎐
F
2
3
C2H5CHO
65
57
(4H, m), 3.05 (4H, m), 6.15 (1H, s), 7.3 (m, 5H); δC 25.6, 50.3,
Ph
1
110.2 (q, 3JCF 5), 122.6 (q, JCF 279), 126.6, 127.9, 129.3, 133.7
O
(q, 2JCF 28), 135.9.
(E)-13
OH
Ph
(Z)-2-Diisopropylamino-1-phenyl-3,3,3-trifluoropropene 3c.
From enol ether 1 (0.22 g, 1 mmol) and LDA (n-butyllithium
1.32 cm3, 1.5  in hexane; diisopropylamine 0.2 g, 2 mmol),
after purification, compound 3c was obtained in 98% purity
(0.23 g, 80%); ν(neat)/cmϪ1 1665 (C᎐C); δ Ϫ62.3; δH 1.1 (12H,
F3C
PhCHO
N
Ph
O
(E)-14
᎐
F
F3C
CO2Et
Ph
d, J 6.6), 3.54 (2H, m), 6.9 (1H, s), 7.3 (3H, m), 7.95 (2H, m);
1
N
δC 20.47 (CH3), 48.2 (CH), 124.0 (q, JCF 285), 128.0, 129.0,
4
5
ClCO2Et
ClCO2Et
58
55
130.5, 134.5, 132.5 (q, 2JCF 28.2).
O
15 E:Z = 33:77
2-[(1S)-1-phenylethylamino]-1-phenyl-3,3,3-trifluoropropene
3d. From enol ether 1 (0.22 g, 1 mmol) and N-lithiated (S)-(Ϫ)-
α-methylbenzylamine [n-butyllithium 1.32 cm3, 1.5  in hexane;
(S)-(Ϫ)-α-methylbenzylamine 0.24 g, 2 mmol], after purifi-
cation, compound 3d was obtained as an oil (0.25 g, 85%);
ν(neat)/cmϪ1 3452 (N᎐H), 1650 (C᎐C); δ Ϫ62.9, Ϫ68.5 (55:45);
F3C
CO2Et
N
Ph
Ph
Ph
16 E:Z = 30:70
᎐
F
δH 1.35 (3H, d, J 6), 1.5 (3H, d, J 6), 3.9 (1H), 4.35 (1H, q, J 6),
5.4 and 6.0 (2H, s), 7.2 (2 × 5H, m); δC 23.1/24.9, 53.6/53.9,
105.6 (q, JCF 2.3)/108.7 (q, JCF 4), 122.4/122.5 (q, JCF 275),
126.2, 128.9, 131.9/132.0 (q, 2JCF 30), 135.1/135.7, 143.5/143.9.
(Z)-2-{N-Benzyl-N-[(1S)-1-phenylethyl]amino}-1-phenyl-
the Wittig reaction performed on trifluoroacetamide, can be
applied to other fluoroalkyl enol ethers. The second reaction
is metalation of the (Z)-enamine in the presence of tert-
butyllithium, and subsequent condensation with electrophiles.
These new functionalized enamines can be useful precursors of
γ amino alcohols and amino acids.
3
3
1
3,3,3-trifluoropropene 3e. From enol ether 1 (0.22 g, 1 mmol)
and N-lithiated (S)-(Ϫ)-α-methyldibenzylamine [n-butyllithium
1.32 cm3, 1.5  in hexane; (S)-(Ϫ)-α-methyldibenzylamine
0.42 g, 2 mmol], after purification compound 3e was obtained
Experimental
19F NMR chemical shifts (δF) are reported in ppm, negative
upfield relative to internal CFCl3, 1H NMR and 13NMR chem-
ical shifts (δH, δC) are reported in ppm, positive downfield
relative to internal Me4Si; spectra were recorded in CDCl3 at
200 MHz (Bruker AC200) and 400 MHz (Bruker ARX 400).
J Values are in Hz. Infrared spectra (ν/cmϪ1; neat) were
recorded on a Perkin-Elmer 841 spectrophotometer. Elemental
analyses were performed by the Service de Microanalyses of
the Centre d’Etudes Pharmaceutiques, Châtenay-Malabry. All
reactions were performed in an oven-dried apparatus under an
inert atmosphere of argon. THF and diethyl ether were distilled
from sodium benzophenone ketyl, and amines were distilled
from calcium hydride prior to use. All other reagents were used
without further purification. Column chromatography was per-
formed on SiO2 (70–230 or 230–400 Mesh Merck).
(0.25 g, 87%); ν(neat)/cmϪ1 1631 (C᎐C); δ Ϫ60.5; δ 1.6 (3H, d,
᎐
F
H
J 6.7), 3.75 (1H, d, J 14.4) and 4.1 (1H, d, J 14.4), 4.7 (1H, q,
J 6.6), 6.6 (1H), 7.1 (m, 15H); δC 20.3 (CH3), 51.7 (CH2N), 61.5
1
3
(CHN), 123.0 (q, JCF 282), 126.5 (q, JCF 3.62), 127.7, 128.8,
128.9, 129.7, 133.6 (q, 2JCF 27.5), 134.3, 138.4, 143.2 (Found: C,
75.34; H, 5.82; N, 3.49. C24H22F3N requires C, 75.56; H, 5.82;
N, 3.49%).
(Z)-2-Dibenzylamino-1-p-methoxyphenyl-3,3,3-trifluoro-
propene 8. From enol ether 4 (0.25 g, 1 mmol) and N-lithiated
dibenzylamine (n-butyllithium 1.32 cm3, 1.5  in hexane;
dibenzylamine 0.4 g, 2 mmol), after purification, compound 8
was obtained as an oil (0.29 g, 73%); ν(neat)/cmϪ1 1632 (C᎐C);
᎐
δF Ϫ62; δH 3.9 (3H, s), 4.1 (4H, s), 6.6 (s, 1H), 6.8 (2H, d, J 9),
7.0 (2H, d, J 9), 7.4 (10H, m); δC 55.0 (CH2Ph), 55.3 (CH3O),
3
1
113.5, 114.1, 120.0 (q, JCF 4.5), 122.5 (q, JCF 279), 126.9,
2
127.5, 128.5, 129.1, 130.6, 131.1, 133.5 (q, JCF 28.2), 137.8,
General procedure for the synthesis of the enamines 3a–e, 8–11
An enol ether (1 mmol) was added at Ϫ78 ЊC under argon to an
N-lithiated amine prepared at Ϫ30 ЊC from n-butyllithium (2
equiv., 1.5  in hexane) and the appropriate amine (2 equiv.) in
THF (25 cm3). The colored solution was stirred for 15 min at
Ϫ78 ЊC and then was allowed to warm to 0 ЊC over a period of
1 h. After 1 to 3 h, the brown solution was poured into satur-
ated aq. ammonium chloride, the layers were separated and the
aqueous phase was extracted with diethyl ether (3 × 50 cm3).
The combined organics were dried (MgSO4) and evaporated to
afford a brown oil. The final enamine was purified by chrom-
atography on SiO2 (eluent pentane). Enamines prepared from
dialkyl amines were obtained with traces of starting material
which could not be separated.
159.3 (Found: C, 72.35; H, 5.68; N, 3.45. C24H22F3O requires C,
72.52; H, 5.59; N, 3.52%).
(Z)-2-Dibenzylamino-3,3,4,4,4-pentafluoro-1-phenylbut-1-ene
9. From enol ether 6 (0.27 g, 1 mmol) and N-lithiated dibenzyl-
amine (n-butyllithium 1.32 cm3, 1.5  in hexane; dibenzylamine
0.4 g, 2 mmol), after purification, compound 9 was obtained
as an oil (0.29 g, 70%); ν(neat)/cmϪ1 1621 (C᎐C); δ Ϫ83 (CF ),
᎐
F
3
Ϫ107.6 (CF2); δH 3.7 (4H, m), 6.5 (1H, s), 7.2 (15H, m); δC 55.3
2
(CH2Ph), 122.7 (CHPh), 127.1, 128.6, 129.5, 134.7 (t, JCF 21,
CCF2), 134.8, 137.2 (C5F5 not observed) (Found: C, 69.19; H,
4.96; N, 3.43. C24H20F5N requires C, 69.05; H, 4.84; N, 3.43%).
(Z)-2-Diisopropylamino-3,3,4,4,4-pentafluoro-1-phenylbut-1-
ene 10. From enol ether 6 (0.27 g, 1 mmol) and LDA (n-
butyllithium 1.32 cm3, 1.5  in hexane; diisopropylamine 0.2 g,
2 mmol), after purification, compound 10 was obtained in 97%
purity (0.23 g, 75%); ν(neat)/cmϪ1 1641 (C᎐C); δ Ϫ81 (CF3),
(Z)-2-Dibenzylamino-1-phenyl-3,3,3-trifluoropropene
3a.
From enol ether 1 (0.22 g, 1 mmol) and N-lithiated dibenzyl-
amine (n-butyllithium 1.32 cm3, 1.5  in hexane; dibenzylamine
0.4 g, 2 mmol), after purification, compound 3a was obtained
᎐
F
Ϫ107.4 (CF2); δH 1.1 (12H, d, J 6.4), 3.6 (2H, septet, J 6.4), 6.8,
1
2
7.3, 7.9 (5H); δC 20.9, 48.9, 113.9 (tq, JCF 220, JCF 37, CF2),
J. Chem. Soc., Perkin Trans. 1, 1998
1799

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1
2
119.5 (qt, JCF 288, JCF 40, CF3), 128.0, 129.2, 130.2, 132.3
1.1 (Z)/1.2 (3H, t, J 7.1), 3.7 (Z)/4.1 (4H, s), 4.15 (2H, q, J 7.1),
(t, 2JCF 23.2), 134.5, 136.0.
6.7–7.2 (15H, m); δC 14.0 (Z)/14.2, 55.6, 56.9, 61.7, 123.0 (q,
(Z)-3-Chloro-3,3-difluoro-2-dimethylamino-1-phenylpropene
11. From enol ether 7 (0.27 g, 1 mmol) and N-lithiated diethyl-
amine (n-butyllithium 1.32 cm3, 1.5  in hexane; diethylamine
0.14 g, 2 mmol), after purification, compound 11 was obtained
in 98% purity (0.17 g, 71%); ν(neat)/cmϪ1 1628 (C᎐C); δ Ϫ48.2;
1JCF 280.4), 128.4, 128.6, 128.9, 129.1, 134.0 (Z)/134.4, 135.0
2
(q, JCF 30.5), 136.9 (Z)/137.6, 167.2/167.8 (Found: C, 70.91;
H, 5.59; N, 3.16. C26H24F3NO2 requires C, 71.07; H, 5.47;
N, 3.18%).
᎐
F
Acknowledgements
δH 1.0 (6H, t, J 6), 2.9 (4H, q, J 6), 6.5 (s, 1H), 7.2, 7.5 (5H);
δC 13.5, 46.5, 121.0 (q, JCF 4.5), 126.9 (t, JCF 297.5), 128.0,
129.0, 134.7, 139.5 (t, 2JCF 22.1).
3
1
This work was supported by CNRS and the European
Community Network on Synthesis and Molecular Recognition
of Selectively Fluorinated Bioactive Molecules (ERBCHRXCT-
930279). We thank Michèle Ourévitch for her invaluable high-
field NMR experiments.
General procedure for preparation of enamines 12–16
tert-Butyllithium (1.5  in hexane, 1.3 equiv.) was added at
room temperature under argon to a solution of enamine 3a or
3f (1 mmol) in hexane (15 cm3) in the presence of TMEDA
(1.3 equiv.). A red color appeared. The mixture was stirred 15
min at room temperature before the addition of the electrophile
(1 equiv.). The solution was then treated with saturated aq.
ammonium chloride. The layers were separated and the
aqueous phase was extracted with diethyl ether (3 × 20 cm3).
The combined organics were dried (MgSO4) and evaporated to
afford a brown oil. The final enamine was separated by chrom-
atography (eluent pentane–diethyl ether, 9:1).
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3 M. A. McClinton and D. A. McClinton, Tetrahedron, 1992, 48, 6555;
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4 D. J. Burton, Z. Y. Yang and W. Qiu, Chem. Rev., 1996, 96, 1641;
K. J. Uneyama, Synth. Org. Chem. Jpn, 1991, 49, 612; J. M. Percy,
Contemp. Org. Synth., 1995, 251.
5 (a) J. P. Bégué and D. Mesureur, Synthesis, 1989, 309; (b) J. P. Bégué,
D. Bonnet-Delpon, D. Mesureur, G. Née and S. W. Wu, J. Org.
Chem., 1992, 57, 3807.
6 V. A. Soloshonok and T. Ono, Synlett, 1996, 919; P. Bravo,
M. Crucianelli and M. Zanda, Tetrahedron Lett., 1995, 36, 3043.
7 R. D. Chambers, S. Partington and D. B. Speight, J. Chem. Soc.,
Perkin Trans. 1, 1974, 2673; W. Cen, Y. Ni and Y. Shen, J. Fluorine
Chem., 1995, 73, 161.
8 W. Dmowski, J. Fluorine Chem., 1984, 26, 379; C. Portella and
M. Iznaden, J. Fluorine Chem., 1991, 51, 1; W. Y. Huang, Y. S. Liu
and L. Lu, J. Fluorine Chem., 1994, 66, 209; L. F. Jalander and
J. E. Lönnqvist, Synth. Commun., 1996, 26, 3549.
9 H. Bürger, T. Dittmar and G. Pawelke, J. Fluorine Chem., 1995, 70,
89.
(E)-2-Dibenzylamino-4-hydroxy-3-phenyl-1,1,1-trifluorohex-
2-ene 12. From enamine 3a (0.37 g, 1 mmol) and tert-butyl-
lithium (0.86 cm3, 1.5  in hexane, 1.3 equiv.), after addition of
propanal (0.06 g, 1 mmol) and purification, compound 12 was
obtained (0.27 g, 65%); δF Ϫ53.6; δH 0.7 (3H, t, J 6), 0.8 (m,
OH), 1.2 (2H, m), 3.7 (4H, s), 4.6 (1H, m), 7.0 (15H, m); δC 9.9,
4
1
27.6, 55.6, 71.0 (q, JCF 3.2), 124.0 (q, JCF 276), 127.1, 128.0,
2
3
129.1, 129.2, 133.2 (q, JCF 32.7), 135.6, 137.7, 148.3 (q, JCF
28.2) (Found: C, 71.62; H, 6.55; N, 2.94. C26H26F3NO requires
C, 73.41; H, 6.11; N, 3.29%).
(E)-4-Hydroxy-2-morpholino-3-phenyl-1,1,1-trifluorohex-2-
ene 13. From enamine 3f (0.26 g, 1 mmol) and tert-butyllithium
(0.86 cm3, 1.5  in hexane, 1.3 equiv.) after addition of pro-
panaldehyde (0.06 g, 1 mmol) compound 13 was obtained after
purification (0.2 g, 65%); ν(neat)/cmϪ1 3442 (OH), 1687 (C᎐C);
᎐
δF Ϫ56.7; δH 0.9 (3H, t, J 7.4), 1.4 (2H, q, J 7.4), 1.7 (s, OH),
2.45 (4H, m), 3.3 (4H, m), 4.7 (1H, td, J 6.4, J 1.47), 7.1–7.3
1
(5H, m); δC 9.44, 28.6, 51.3, 67.0, 70.8, 123.0 (q, JCF 282),
127.0, 128.0, 129.0, 135.0, 137.0 (q, 2JCF 29.4), 144.0 (Found: C,
60.83; H, 6.47; N, 4.29. C16H20O2F3N requires C, 60.76; H, 6.35;
N, 4.44%).
(E)-4-Hydroxy-2-morpholino-3,4-diphenyl-1,1,1-trifluorobut-
2-ene 14. From enamine 3f (0.26 g, 1 mmol) and tert-butyl-
lithium (0.86 cm3, 1.5  in hexane, 1.3 equiv.) after addition of
benzaldehyde (0.11 g, 1 mmol), and purification, compound 14
was obtained (0.21 g, 57%); ν(neat)/cmϪ1 3426 (OH), 1620
(C᎐C); δ Ϫ56.3; δH 2.5 (4H, m), 3.3 (4H, m), 6.1 (1H, s), 6.7–
᎐
F
1
7.2 (10H, m); δC 51.5, 67.1, 70.4, 123.5 (q, JCF 282), 126.0,
127.0, 128.0, 129.0, 135.0, 136.5 (q, JCF 29.4), 140.8, 143.1
2
(Found: C, 66.16; H, 5.65; N, 3.74. C20H20F3NO2 requires C,
66.12; H, 5.51; N, 3.86%).
Ethyl 3-morpholino-2-phenyl-4,4,4-trifluorobut-2-enoate 15.
From enamine 3f (0.26 g, 1 mmol) and tert-butyllithium (0.86
cm3, 1.5  in hexane, 1.3 equiv.) after addition of ethyl chloro-
formate (0.11 g, 1 mmol) and purification, compound 15 was
obtained (0.19 g, 58%); ν(neat)/cmϪ1 1729 (OH), 1619 (C᎐C); δ
10 J. P. Bégué, F. Benayoud and D. Bonnet-Delpon, J. Org. Chem.,
1995, 60, 5029; J. P. Bégué, D. Bonnet-Delpon, N. Fischer-Durand,
A. Amour and M. Reboud-Ravaux, Tetrahedron: Asymmetry, 1994,
5, 1094; J. P. Bégué, D. Bonnet-Delpon and A. Kornilov, Synthesis,
1996, 4, 529.
11 D. Bonnet-Delpon, D. Bouvet, M. Ourévitch and M. H. Rock,
Synthesis, 1998, 288.
12 J. P. Bégué, D. Bonnet-Delpon and M. H. Rock, J. Chem. Soc.,
Perkin Trans. 1, 1996, 1409.
13 J. P. Bégué, D. Bonnet-Delpon, D. Bouvet and M. H. Rock, J. Org.
Chem., 1996, 61, 9111.
᎐
F
Ϫ57.8/Ϫ62.3 (E:Z = 33:77); δH 1.2/1.25 (3H, t, J 6.6), 2.95 (Z)/
2.62 (4H, m), 3.6 (Z)/3.4 (4H, m), 4.1/4.2 (2H, q, J 7.1), 7.25
(5H, m); δC 13.9, 51.1 (Z)/51.0, 61.8 (Z)/61.7, 67.0 (Z)/67.5,
1
122.0 (Z)/123.0 (q, JCF 280), 128.7, 129.0, 132.4, 135.6, 136.2
2
(Z)/137.2 (q, JCF 31), 167.1, 167.2 (Found: C, 58.20; H, 5.55;
14 J. P. Bégué, D. Bonnet-Delpon, D. Mesureur and M. Ourévitch,
Magn. Reson. Chem., 1991, 29, 675.
15 For preparation of enol ethers and enamine 3f see ref. 5(b).
N, 4.11. C16H18F3NO2 requires C, 58.36; H, 5.47; N, 4.25%).
Ethyl 3-dibenzylamino-2-phenyl-4,4,4-trifluorobut-2-enoate
16. From enamine 3a (0.37 g, 1 mmol) and tert-butyllithium
(0.86 cm3, 1.5  in hexane, 1.3 equiv.), after addition of ethyl
chloroformate (0.11 g, 1 mmol) and purification, compound 16
was obtained (0.24 g, 55%); δF Ϫ59.4/Ϫ57.6 (E:Z = 30:70); δH
Paper 8/01243A
Received 12th February 1998
Accepted 25th March 1998
1800
J. Chem. Soc., Perkin Trans. 1, 1998