A novel approach to β-trifluoromethyl enaminones

Article abstract of DOI:10.1016/S0040-4039(02)01679-9

β-Trifluoromethyl enaminones 1 were prepared in good yields from the reaction of trifluoropropynyl lithium with N-methoxy-N-methylbenzamide, followed by quenching with H₂O in the presence of a variety of amines. The use of hydrazine or benzamid

Full text of DOI:10.1016/S0040-4039(02)01679-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7171–7174
A novel approach to b-trifluoromethyl enaminones
a,
a
b
b
In Howa Jeong, * Sung Lan Jeon, Yong Ki Min and Bum Tae Kim
a
Department of Chemistry, Yonsei University, Wonju 220-710, Republic of Korea
b
Korea Research Institute of Chemical Technology, Daejeon 305-606, Republic of Korea
Received 8 July 2002; revised 5 August 2002; accepted 9 August 2002
Abstract—b-Trifluoromethyl enaminones 1 were prepared in good yields from the reaction of trifluoropropynyl lithium with
N-methoxy-N-methylbenzamide, followed by quenching with H O in the presence of a variety of amines. The use of hydrazine
2
or benzamidine as an amine source in this reaction resulted in the formation of pyrazole 3 or pyrimidine 4. © 2002 Elsevier
Science Ltd. All rights reserved.
Considerable efforts have been made in the develop-
ment of trifluoromethylated building blocks because of
their potential to give new synthetic routes to a variety
of trifluoromethylated compounds, some of which
exhibit unique biological properties in the areas of
enaminones were prepared from the reaction of N-aryl
trifluoromethyl imidoyl chloride with methyl ketones in
13
the presence of LDA. All of the previous methods had
a lack of generality, low yield preparation and tedious
procedure. Therefore, we wish to describe a novel and
efficient method for the synthesis of b-trifluoromethyl
enaminones.
1,2
agrochemicals, pharmaceuticals and material science.
In the course of our studies on the synthesis of tri-
fluoromethylated compounds, we needed a facile and
convenient synthetic route to b-trifluoromethyl enam-
inones, which are quite useful synthetic intermediates
for the preparation of trifluoromethylated heterocyclic
compounds. Recently, several researchers showed b-
Originally, we attempted to prepare b-trifluoromethyl-
ated ynone, which is not easily prepared via previous
methods, from the reaction of trifluoropropynyl lithium
with
N-methoxy-N-methylbenzamide
(Weinreb
trifluoromethyl
exchange with nucleophiles to give a variety of hete-
enaminones
underwent
amine
14
benzamide ). When trifluoropropynyl lithium gener-
ated from the reaction of trifluoropropyne (1.1 equiv.)
3
–6
15
rocyclic compounds as b-halo-b-trifluoromethyl enones
with n-BuLi (1.1 equiv.) was reacted with N-methoxy-
N-methylbenzamide (1.0 equiv.) at −78°C followed by
7
–9
did. However, the previous methods for the prepara-
tion of b-trifluoromethyl enaminones have been quite
limited and cannot be easily utilized. Sosnovskikh pre-
pared b-trifluoromethyl enaminones from the reaction
of methyl ketones with trifluoroacetonitrile in the pres-
warming to 0°C and quenching with H O, however, an
2
E and Z isomeric mixture (E/Z=13/87) of b-tri-
fluoromethyl enaminone 1a was obtained in 64% yield
based on 60% conversion of N-methoxy-N-methylbenz-
amide. To consume N-methoxy-N-methylbenzamide
completely, the same reaction was performed at −78°C
followed by warming to room temperature and quench-
1
0
ence of N-ethylanilino magnesium bromide. The reac-
tions of trifluorinated b-diketones with ammonium
acetate and ammonium bicarbonate also afforded b-
trifluoromethyl enaminones in a mixture of isomeric
1
1
ing with H O. However, only N-methoxy-N-methyl-
2
aminoenones.
Huang also synthesized b-tri-
benzamide was recovered in 98% yield and no desired
product was observed. It seems likely that the reaction
was affected by temperature. Therefore, we decided to
examine influence of temperature on the reaction.
Treatment of trifluoropropynyl lithium (1.0 equiv.) with
N-methoxy-N-methylbenzamide (1.1 equiv.) at −78°C
followed by warming to −30°C and quenching with
fluoromethyl enaminones from the treatment of N-aryl
trifluoromethyl imidoyl iodides with methyl ketones in
3
the presence of sodium hydride. However, N-aryl tri-
1
2
fluoromethyl imidoyl iodide cannot be easily prepared
via previous methods. Similarly, b-trifluoromethyl
H O resulted in the formation of 1a in 62% yield based
2
Keywords: trifluoropropynyl lithium; N-methoxy-N-methylbenz-
amide; b-trifluorormethyl enaminones.
Corresponding author. Fax: 82-33-760-2182; e-mail: jeongih@
dragon.yonsei.ac.kr
on 27% conversion of N-methoxy-N-methylbenzamide.
These experimental results indicate that equilibrium
may occur in the reaction of trifluoropropynyl lithium
*
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01679-9

7
172
I. H. Jeong et al. / Tetrahedron Letters 43 (2002) 7171–7174
with N-methoxy-N-methylbenzamide to give addition
intermediate [I]. To prove this possibility, a large excess
of trifluoropropynyl lithium (4.0 equiv.) was used. Thus,
the reaction of trifluoropropynyl lithium (4.0 equiv.) with
N-methoxy-N-methylbenzamide (1.0 equiv.) at −78°C
Although an unusual arylamino group exchange of
enaminone with hydrazine or amidine to afford the
corresponding pyrazole or pyrimidine has been
3
reported in the previous literature, N-methoxy-N-
methylamino group exchange of 1a with other amines
has not been reported so far. When 1a was reacted with
piperidine at room temperature for 3 h in THF, only
the Z isomer of piperidine-substituted enaminone 1c
was obtained in 98% yield. However, the reaction of 1a
with aniline under the same reaction conditions
afforded only a trace amount of amine exchange
product. The possible formation of ynone intermediate
[II] and the result for the amine group exchange stimu-
lated us to perform the quenching of intermediate [I]
followed by warming to 0°C and quenching with H O,
2
only desired product 1a was obtained in 68% yield with
no observation of N-methoxy-N-methylbenzamide. The
use of N,N-dimethylbenzamide instead of N-methoxy-
N-methylbenzamide under the optimized reaction con-
ditions did not provide any desired product, but only
starting material was recovered. Therefore, the N-
methoxy group in Weinreb benzamide plays an impor-
tant role to give lithium complex in intermediate [I].
N-Methoxy-N-methylacetamide as well as N-methoxy-
N-methylbenzamide was also reacted with trifluoro-
propynyl lithium under the same reaction conditions to
give the corresponding b-trifluoromethylated enamione
with H O in the presence of other types of amines.
2
Therefore, treatment of intermediate [I] with H O in the
2
presence of the same equivalence of piperidine at 0°C
and then stirring at room temperature for 1 h resulted
in the formation of 1c (Z isomer only) in 85% yield.
The similar reactions of intermediate [I] with N,N-
dimethylamine, N-benzylmethylamine, benzylamine
and morpholine provided the only Z isomer of corre-
sponding enaminones 1d, 1e, 1f and 1g in 65–85%
1
b in 42% yield. A plausible mechanism for the forma-
tion of 1a seems likely that intermediate [I] was formed
from the reaction of trifluoropropynyl lithium with
Weinreb benzamide and then was reacted with H O to
2
give ynone intermediate [II] which was rapidly reacted
with N-methoxy-N-methylamine generated from the
reaction to give 1a. Trapping reaction of intermediate
yields. The reaction of intermediate [I] with H O in the
2
presence of aniline afforded the only Z isomer of the
corresponding enaminone 1h in 31% yield along with 1a
(E/Z=13/87, 50% yield). It is postulated that the for-
[
I] with trimethylsilyl chloride afforded the correspond-
16
ing siloxane derivative 2 in 80% yield.

I. H. Jeong et al. / Tetrahedron Letters 43 (2002) 7171–7174
7173
mation of 1a in this reaction could be due to the low
reactivity of aniline toward ynone intermediate [II] as
compare with N-methoxy-N-methylamine. The similar
results were obtained from the reaction of intermediate
Treatment of intermediate [I] with H O in the presence
2
of hydrazine or benzamidine also resulted in the forma-
18
3
tion of pyrazole 3 or pyrimidine 4 in 72 and 71%
yields, respectively. No other regioisomer was observed
in the formation of 3.
[
I] with H O in the presence of sterically hindered
2
amines such as diisopropyl amine, 2,6-dimethylpipe-
ridine, 2,2,6,6-tetramethylpiperidine, and hexamethyl-
disilazane. Especially, the reactions of intermediate [I]
with 2,2,6,6-tetramethylpiperidine and hexamethyldisi-
lazane did not provide any desired products 1k and 1l,
but only 1a was obtained in 60 and 61% yields, respec-
tively. The experimental results are summarized in
Table 1.
A typical reaction procedure for the preparation of 1c
is as follows. A 25 mL two-neck round-bottomed flask
equipped with a magnetic stirrer bar, septum and dry
ice condenser connected to an argon source was
charged with THF (10 mL) and then cooled to −78°C.
After a dry ice condenser was filled with slush of dry ice
and isopropyl alcohol, 3,3,3-trifluoropropyne (1.128 g,
1
2.0 mmol) was slowly added into flask by condensa-
tion via dry ice condenser. To a THF solution of
3,3,3-trifluoropropyne was added n-BuLi (12.0 mmol)
at −78°C and the reaction mixture was stirred at −78°C
for 0.5 h under argon atmosphere. N-Methoxy-N-
methylbenzamide (0.495 g, 3.0 mol) was added into a
mixture at −78°C and then warmed to 0°C. Piperidine
The assignment of E and Z isomers of 1a was made by
1
9
the comparison of chemical shift in F NMR spec-
1
9
troscopy. It has been well established that F NMR
signal in the Z isomer of CF -trisubstituted vinylic
3
compounds is more shielded than that in the E iso-
1
7
mer. Therefore, two singlet peaks at −65.97 and 61.84
(0.255 g, 3 mol) and H O (10 mL) were added into a
2
1
9
ppm in the F NMR spectrum are due to a CF group
mixture and then allowed to stir for 1 h at 0°C. The
reaction mixture was extracted with ether twice. The
3
in the Z and E isomers of 1a, respectively. Determina-
tion of the configuration of 1a was also supported by
NOE observation (1.2%) between N-methyl group and
the vinyl proton of (E)-1a, whereas no NOE observa-
tion was detected in (Z)-1a.
ether solution was dried and chromatographed on SiO
2
column. Elution with a mixture of hexane and ethyl
acetate (9:1) provided 0.722 g of 1c in 85% yield. 1c: oil;
1
H NMR (CDCl ) l 7.91–7.87 (m, 2H), 7.51–7.39 (m,
H), 6.22 (s, 1H), 3.24 (s, 4H), 1.68 (s, 6H); F NMR
3
1
9
3
(
2
CDCl ) l −64.46 (s, 3F); MS, m/z (relative intensity)
3
+
83 (M , 37), 266 (52), 131 (21), 105 (33), 103 (17), 91
(
1
1
11), 83 (100), 77 (25), 69 (11); IR (neat) 3062, 2941,
Table 1. Preparation of a variety of b-trifluoromethyl
enaminones
645, 1599, 1581, 1564, 1470, 1279, 1227, 1180, 1126,
−1
005, 1140, 771, 632 cm . Anal. calcd for
C H F NO: C, 63.60; H, 5.69. Found: C, 63.45; H, 5.
15
16 3
6
3%.
Acknowledgements
This work was supported by the Maeji Institute of
Academic Research (2002-2003), Yonsei University and
the Ministry of Science and Technology.
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