Efficient and convenient entry to β-hydroxy-β-trifluoromethyl-β-substituted ketones and 2,6-disubstituted 4-trifluoromethylpyridines based on the reaction of trifluoromethyl ketones with enamines or imines

Article abstract of DOI:10.1039/b105636k

The reactions of trifluoromethyl ketones with enamines or imines are described. The reaction of trifluoroacetone with enamines or imines followed by hydrolysis gave the corresponding β-hydroxyβ-trifluoromethyl-β-methyl ketones in good yields. The reaction

Full text of DOI:10.1039/b105636k

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Efficient and convenient entry to ꢀ-hydroxy-ꢀ-trifluoromethyl-ꢀ-
substituted ketones and 2,6-disubstituted 4-trifluoromethylpyridines
based on the reaction of trifluoromethyl ketones with enamines or
imines
1
Kazumasa Funabiki,* Akie Isomura, Yoshihiro Yamaguchi, Wataru Hashimoto,
Kei Matsunaga, Katsuyoshi Shibata and Masaki Matsui*
Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193,
Japan. E-mail: kfunabik@apchem.gifu-u.ac.jp; Fax: ϩ81-58-230-1893
Received (in Cambridge, UK) 27th June 2001, Accepted 6th September 2001
First published as an Advance Article on the web 27th September 2001
The reactions of trifluoromethyl ketones with enamines or imines are described. The reaction of trifluoroacetone
with enamines or imines followed by hydrolysis gave the corresponding β-hydroxy-β-trifluoromethyl-β-methyl
ketones in good yields. The reaction of trifluoromethylated β-diketones with enamines in the presence of
ammonium acetate gave 4-trifluoromethylated pyridines exclusively in good yields, without any detectable
amount of regioisomers.
The trifluoromethyl group is one of the most attractive func-
tional groups in organic chemistry, since trifluoromethyl-1
containing organic molecules can serve as liquid crystals,
2
3
catalysts, and inhibitors, and these properties often confer
excellent physical and biological activities. Therefore, efficient
introduction of a trifluoromethyl group is a topic of growing
interest in organofluorine chemistry and many approaches to
Scheme 1 Reagents and conditions: i, rt, 1–3 h; ii, 10% HCl aq. rt,
0.5 h.
4
such compounds have been investigated recently. Among them,
α-trifluoromethylated carbonyl compounds are most useful and
applicable building blocks for the synthesis of organofluorine
compounds.
tion solvents (entries 4 and 5). Some enamines with p-tolyl,
p-chlorophenyl and thienyl groups participated well in the reac-
tion to give the corresponding β-hydroxy-β-methyl-β-trifluoro-
methyl ketones 2 in good to excellent yields (entries 6–8). The
reaction of trifluoroacetone with an enamine with a c-hexyl
group did not occur efficiently and gave only 32% of the
corresponding ketone 2e. This is probably owing to the lack of
stabilization of the iminium ion species by a π-system (entry 9).
Treatment of hexafluoroacetone trihydrate 3 with enamine,
prepared from acetophenone and morpholine, at room
temperature for 3 h, followed by hydrolysis with 10% HCl, gave
the corresponding β-hydroxy-β,β-bis(trifluoromethyl) ketone 4
in only 8% yield (Scheme 2). The yield was not improved even if
5
Recently, we have demonstrated that enamine- or imine-
assisted facile generation of trifluoroacetaldehyde from tri-
fluoroacetaldehyde ethyl hemiacetal or hydrate and sequential
carbon–carbon bond formation lead to β-hydroxy-β-trifluoro-
6
methyl ketone derivatives in the absence of additives. In this
paper we describe the reaction of trifluoromethyl ketones with
various enamines or imines followed by hydrolysis affording
β-hydroxy-β-trifluoromethyl-β-substituted ketones in good
yields as well as the application for the reaction of trifluoro-
methylated β-diketones with enamines in the presence of
ammonium acetate towards the regioselective synthesis of 4-
trifluoromethylated pyridines.
Results and discussion
Reaction of trifluoromethyl ketones with enamines leading to
ꢀ
-hydroxy-ꢀ-trifluoromethyl-ꢀ-substituted ketones
Scheme 2 Reagents and conditions: i, rt, 3 h; ii, 10% HCl aq. rt, 0.5 h.
The reactions of trifluoroacetone 1 with 1 equiv. of enamine,
prepared from acetophenone and morpholine, in hexane at
room temperature for 3 h, followed by hydrolysis with 10% HCl
solution, gave the corresponding β-hydroxy-β-methyl-β-tri-
fluoromethyl ketones 2a in 68% yield (Scheme 1, Table 1,
entry 1).
Elevated temperature gave only a small amount of ketone 2a
because of the low boiling point of the starting ketone (22 ЊC).
Employment of 3 equiv. of trifluoroacetone at ambient tem-
perature afforded the corresponding ketone 2a in 90% yield
reflux temperature or an excess amount of enamine was used.
Probably, the tetrahedral intermediate is too stable to generate
hexafluoroacetone effectively on account of the electron-
withdrawing properties of the two trifluoromethyl groups.
On the other hand, enamine reacted with hexafluoroacetone,
generated from hexafluoroacetone trihydrate 3 and conc.
H SO , followed by hydrolysis using 10% HCl, giving 4 in
2
4
31% yield.
It is significant that the reaction of acetone with enamine
under the same conditions did not proceed at all.
(
entry 3). Toluene and dichloromethane are also usable as reac-
2
578
J. Chem. Soc., Perkin Trans. 1, 2001, 2578–2582
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b105636k

View Online
Table 1 Reaction of trifluoromethyl ketones 1 with enamines
1
a
Entry
1 (equiv.)
R
Temp.
Time/h
Product
Yield (%)
b
1
2
3
4
5
6
7
8
9
1
1
3
3
3
3
3
3
3
Ph
Ph
Ph
Ph
Ph
4-MeC H
4-ClC H
rt
rt
rt
rt
rt
rt
rt
rt
rt
3
1
3
3
3
3
3
3
3
2a
2a
2a
2a
2a
2b
2c
2d
2e
68
16
b
90
80
79
77
94
89
32
c
d
6
4
6
4
2-Thienyl
c-Hex
a
b
19
c
d
Yields of isolated products. Yields were determined by F NMR. Toluene was used as reaction solvent. Dichloromethane was used as reaction
solvent.
Table 2 Reaction of trifluoromethyl ketones 1 with imines
1
b
b
Entry
R
Addition temp.
Time/h
Hydrolysis acid
Temp.
Time/h
Yield of 2 (%)
Yield of 5 (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
4-ClC H
c-Hex
t-Bu
rt
rt
rt
rt
3
3
3
24
1
24
24
24
A
A
B
B
B
B
B
B
rt
rt
rt
rt
rt
rt
rt
rt
0.5
24
24
24
24
24
24
24
2a (7)
5a (39)
2a (35)
2a (36)d
2a (55)
2a (7) d
2c (65)
2d (10)
2e (trace)
5a (22)
5a (trace)
5a (trace)
5a (trace)
5c (trace)
5d (trace)
5e (trace)
Reflux
rt
rt
rt
6
4
a
b
19
All the reactions were carried out with trifluoroacetone 1 (3 mmol) and imine (1 mmol) in hexane (4 ml). Yields were determined by F NMR.
c
d
A: 10% HCl (4 ml). B: conc. HCl (1 ml), SiO (1 g) and EtOH (2 ml). Yields of isolated products.
2
Reaction of trifluoroacetone with imines leading to ꢀ-hydroxy-ꢀ-
methyl-ꢀ-trifluoromethyl ketones 2
Regioselective synthesis of 4-trifluoromethyl-2,6-disubstituted
pyridines by the reaction of ꢀ-trifluoromethyl-ꢀ-diketones with
enamines in the presence of ammonium acetate
9
1
Treatment of imine (R = Ph) with 3 equiv. of trifluoroacetone 1
under the same conditions as the reaction of enamine, gave a
trace amount of the corresponding β-hydroxy-β-methyl-β-
trifluoromethyl ketone 2a together with 39% of β-hydroxy-β-
The reaction of enamine, prepared from acetophenone
and morpholine, with trifluoromethylated β-diketone 6a in
the presence of 2 equiv. of ammonium acetate for 0.5 h pro-
vided 4-trifluoromethyl-2,6-diphenylpyridine (7a) in 32% yield
7
methyl-β-trifluoromethyl imine 5a (Scheme 3, Table 2, entry 1).
(
Scheme 4, Table 3, entry 1). The other regioisomer of the
pyridine 7a was not detected in the reaction mixture.
Scheme 4 Reagents and conditions: i, NH OAc, solvent, reflux,
4
0
.5–3 h.
Among the solvents, such as hexane, acetonitrile, ethanol,
propan-1-ol, diglyme, triglyme and DMF, triglyme gave the
best result (entry 7). Prolonged reaction time (3 h) did not
improve the yield of 7a (entry 4). Use of 2 equiv. of enamine
in triglyme afforded 7a in 71% yield (entry 9). Other trifluoro-
methylated β-diketones 6 as well as other enamines participated
well in the reaction to afford 4-trifluoromethyl-2,6-disub-
stituted pyridine derivatives 7 in good yields (Scheme 5, Table 4,
entries 2–8).
Scheme 3 Reagents and conditions: i, 1–24 h; ii, hydrolysis.
Surprisingly, 10% HCl was not so effective for hydrolysis (24 h),
giving the mixture of ketone 2a and imine 5a in 35% and 22%
yields, respectively (entry 2). Hydrolysis using conc. HCl-
8
adsorbed silica gel and EtOH in place of 10% HCl occurred
smoothly to provide only ketone 2a in 36% yield (entry 3).
Longer time (24 h) for the reaction between 1 and enamine
resulted in good yield (55%) of 2a (entry 4).
At reflux temperature for 1 h the reaction did not proceed
smoothly giving only a trace amount of 2a (entry 5). A couple
of aromatic enamines reacted readily with trifluoroacetone 1 at
room temperature to provide the corresponding ketones 2a,c in
good yields (entries 4 and 6). However, aliphatic enamines
carrying c-hexyl or tert-butyl groups did not react well giving a
small or trace amount of products (entries 7 and 8).
Scheme 5 Reagents and conditions: i, NH OAc, triglyme, reflux, 0.5 h.
4
J. Chem. Soc., Perkin Trans. 1, 2001, 2578–2582
2579

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Table 3 Screening for the synthesis of 2,6-diphenyl-4-trifluoromethyl-
a
pyridine (7a)
b
Entry
Enamine (equiv.)
Solvent
Time/h
Yield (%)
1
2
3
4
5
6
7
8
9
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
2
Hexane
MeCN
EtOH
0.5
0.5
0.5
3
0.5
0.5
0.5
0.5
0.5
32
37
33
37
42
52
58
49
71
EtOH
n-PrOH
Diglyme
Triglyme
DMF
Triglyme
a
The reaction was carried out with diketone 4a, enamine and NH OAc
4
b
(
2 equiv.) in solvent at reflux. Yields of isolated products.
a
Table 4 Synthesis of 2,6-disubstituted 4-trifluoromethylpyridines (7)
1
2
b
Entry
R
R
Product
Yield (%)
1
2
3
4
5
6
7
8
Ph
4-ClC H4
4-MeOC H
2-Thienyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-ClC H
4-MeC H
7a
7b
7c
7d
7b
7e
7c
7d
71
75
73
72
75
74
70
71
6
6
4
6
4
6
4
4-MeOC H
2-Thienyl
6
4
a
The reaction was carried out with diketone 6 (1 mmol), enamine
(
2 mmol) and NH OAc (2 mmol) in triglyme (2 ml) at reflux for 0.5 h.
4
b
Yields of isolated products.
Scheme 6 Reagents and conditions: i, NH OAc, triglyme, reflux, 0.5 h.
4
To make a regiochemical assignment of 7, the reaction as
described in Scheme 6 was carried out under the same con-
ditions; the reaction of α,β-unsaturated trifluoromethyl ketone
Scheme 7 A plausible reaction mechanism for the formation of 7.
8
with 2 equiv. of enamine in the presence of 2 equiv. of
ammonium acetate in triglyme at reflux temperature gave
-trifluoromethylated pyridine 9 in 13% yield.
group accelerates the addition reaction of enamines or imines,
affording the first example for the convenient synthesis of β-
trifluoromethylated-β-methyl ketones. In addition, we have
described the reaction of trifluoromethylated β-diketones with
6
19
The chemical shift (Ϫ68.64 ppm) of 9 in F NMR appeared
at higher field than that of 7a (Ϫ63.04 ppm). This tendency is
entirely consistent with our previous report. Furthermore, the
9e
1
13
19
enamines in the presence of NH OAc which give the corre-
spectral data, H, C and F NMR, of 7c, which was produced
from the reaction between β-diketone 6c and an enamine with a
phenyl group, are identical with those of the product from the
reaction between β-diketone 6a and an enamine with a p-
methoxyphenyl group (entries 3 and 7). According to these
results, regiochemical assignment of pyridines 7 can be made as
4
sponding 4-trifluoromethylated 2,6-disubstituted pyridines
regioselectively in good yields.
Experimental
4
-trifluoromethylated compounds.
General
A plausible reaction mechanism for the formation of 7 is
described in Scheme 7. Trifluoromethylated β-diketones 6 exist
Melting points were obtained on a Shimadzu MM-2 micro
point determination apparatus and are uncorrected. Infrared
spectra (IR) were recorded on a Shimadzu IR-400 spec-
10
nearly exclusively as enols. The enol 6Ј and/or β-amino-α,β-
unsaturated ketones 10, which can be obtained from 6Ј and
11
1
ammonia, will react with an enamine via Michael addition,
trometer. H NMR spectra were measured with a JEOL α-400
followed by cyclisation to give the intermediate 12 or 13. These
intermediates 11, 11Ј, 12 and/or 13 would react with ammonia,
followed by elimination of NHR and XH leading to 4-tri-
(400 MHz) FT-NMR spectrometer in deuteriochloroform
(CDCl ) solutions with tetramethylsilane (Me Si) as the
internal standard. C NMR spectra were obtained on a JEOL
3
4
13
2
2
fluoromethylated pyridines 7.
α-400 (100 MHz) FT-NMR spectrometer in CDCl solutions
3
19
In summary, we have demonstrated that trifluoroacetone
reacts with enamines or imines, followed by hydrolysis, to
give the corresponding β-trifluoromethylated-β-methyl ketones
in good yields. We also show that one trifluoromethyl
relative to CDCl (77.0 ppm). F NMR spectra were recorded
3
on a JEOL α-400 (376 MHz) FT-NMR in CDCl solutions
3
using trifluoroacetic acid as the external standard and con-
verted to the CFCl standard by the calculation of δ(CFCl ) =
3
3
2
580
J. Chem. Soc., Perkin Trans. 1, 2001, 2578–2582

View Online
Ϫ[77.0 Ϫ δ(TFA)]. Mass spectra (MS) were taken on a Hitachi-
0B spectrometer operating at an ionization potential of 70
(100.0), 75 (60.1), 69 (15.1); Found: C, 49.55; H, 3.81.
C H ClF O requires C, 49.55; H, 3.78%.
8
11
10
3
2
eV. Elemental analyses were made on a Yanaco MT-5 CHN
corder. The isolation of pure products was carried out by
column chromatography using silica gel (Wakogel C-200,
4,4,4-Trifluoro-3-hydroxy-3-methyl-1-(2-thienyl)butan-1-one
Ϫ1
2d. νmax(film)/cm 1647.6 (C᎐O), 3422.4 (OH); δ (CDCl ) 1.50
H
3
1
00–200 mesh, Wako Pure Chemical Ind. Ltd.).
(3H, s, CH ), 3.05 (1H, d, J 16.59, CH CH ), 3.41 (1H, d,
3
A
B
J 16.59, CH CH ), 5.15 (1H, s, OH), 7.18–7.20 (1H, m, aryl H),
A
B
7
.76–7.78 (2H, m, aryl H); δ (CDCl ) 21.89 (s), 41.11 (s), 73.36
Typical procedure for the reaction of trifluoroacetone with
enamine
C 3
(
(
q, J 29.22), 125.55 (q, J 285.05), 128.55 (s), 135.87 (s), 143.43
s), 192.15 (s); δF (CDCl ) Ϫ81.81 (3F, s, CF ); MS (EI)
3
3
To a hexane (2 ml) solution of trifluoroacetone, 1 (0.336 g,
ϩ
m/z (rel intensity) 238 (M ; 63%), 126 (99), 111 (100.0), 97
3
mmol) was slowly added 4-(1-phenylethenyl)morpholine
(
21.7), 83 (42.2).
(
0.189 g, 1 mmol) at room temperature. After the reaction
mixture was stirred at room temperature for 3 h under an argon
atmosphere, 10% HCl solution (4 ml) was added, and left at this
temperature for 30 min. The resultant mixture was quenched
with brine (30 ml), extracted with diethyl ether (30 ml × 3),
1
-Cyclohexyl-4,4,4-trifluoro-3-hydroxy-3-methylbutan-1-one
Ϫ1
2
1
e. νmax(film)/cm 1696.0 (C᎐O), 3406.2 (OH); δ (CDCl )
.12–1.29 (6H, m, CH × 3), 1.31 (3H, s, CH ), 1.61–1.80 (4H,
2 3
m, CH × 2), 2.26–2.32 (1H, m, CH), 2.50 (1H, d, J 17.08,
CH CH ), 2.90 (1H, d, J 17.08, CH CH ), 5.33 (1H, s, OH);
δ (CDCl ) 22.04 (s), 25.30 (d, J 6.62), 25.56 (s), 27.71 (d,
J 8.72), 42.27 (s), 52.17 (s), 73.14 (q, J 28.67), 125.62 (q,
J 85.60), 214.97 (s); δ (CDCl ) Ϫ81.79 (3F, s, CF ); MS (EI)
H 3
2
dried over Na SO4 and concentrated under vacuum. The
2
A
B
A
B
residual oil was chromatographed on silica-gel and using
benzene as an eluent afforded analytically pure 2a (0.201 g,
C
3
8
6%) as a white solid.
F
3
3
ϩ
m/z (rel intensity) 238 (M ; 1.8%), 196 (1.7), 183 (8.0), 169 (2.8),
Typical procedure for the reaction of trifluoroacetone with imine
To a hexane (2 ml) solution of trifluoroacetone, 1 (0.336 g,
155 (3.3), 111 (21.7), 83 (100.0)
1
,1,1-Trifluoro-4-(cyclohexylimino)-2-methyl-4-phenylbutan-
Ϫ1
3
mmol) was slowly added N-(1-phenylethylidene)cyclohexyl-
2
-ol 5a. νmax(film)/cm 1649.2 (C᎐N), 3060.7 (OH); δ (CDCl )
H 3
amine (0.201 g, 1 mmol) at room temperature. After the
reaction mixture was stirred at room temperature for 3 h under
an argon atmosphere, conc. HCl (1 ml)-adsorbed silica gel (1 g)
and EtOH (2 ml) were added, and left at this temperature for
1
.12–1.70 (10H, m, CH × 5), 1.44 (3H, s, CH ), 2.66 (1H, d,
2 3
J 17.08, CH CH ), 2.88 (1H, d, J 17.08, CH CH ), 3.22–3.29
A
B
A
B
(
m, 1H, CH), 7.10–7.13 (2H, m, aryl H), 7.26–7.28 (1H, m, aryl
H), 7.37–7.45 (2H, m, aryl H); δ (CDCl ) 22.70 (s), 23.84 (s),
C
3
2
4 h. The resultant mixture was quenched with brine (30 ml),
2
(
5.45 (s), 33.44 (s), 41.69 (s), 59.64 (s), 73.77 (q, J 27.57), 126.44
q, J 286.16), 125.57 (s), 128.77 (s), 137.55 (s), 168.27 (s);
δF (CDCl ) Ϫ80.96 (3F, s, CF ); MS (CI) m/z (rel intensity)
extracted with diethyl ether (30 ml × 3), dried over Na SO and
2
4
concentrated under vacuum. The residual oil was chromato-
graphed on silica-gel and using benzene as an eluent afforded
analytically pure 2a (0.125 g, 54%) as a white solid.
3
3
2
44 (5.4), 202 (96.0), 186 (100.0), 172 (24.1), 158 (45.7), 146
(
44.6), 130 (25.5), 124 (15.2), 120 (70.9), 104 (69.7), 91 (15.7), 77
(
23.9); HRMS (CI) Found: 314.1713 (M ϩ H). C H F NO
17
23
3
4
,4,4-Trifluoro-3-hydroxy-3-methyl-1-phenylbutan-1-one 2a.
Ϫ1
requires 314.1733.
Mp 40.8–41.7 ЊC (hexane); νmax(KBr)/cm 1672.9 (C᎐O),
424.0 (OH); δH 1.51 (3H, s, CH ), 3.11 (1H, d, J 17.08,
CH CH ), 3.51 (1H, d, J 17.08, CH CH ), 5.27 (1H, s, OH),
3
3
Preparation of 4,4,4-trifluoro-3-hydroxy-3-methyl-1-phenyl-3-
trifluoromethylbutan-1-one (4)
A
B
A
B
7
.49–7.53 (2H, m, aryl H), 7.63–7.66 (1H, m, aryl H), 7.95–7.97
(
2H, m, aryl H); δ (CDCl ) 22.08 (s), 40.19 (s), 73.40 (q,
To a hexane (4 ml) solution of hexafluoroacetone trihydrate
(0.673 g, 3 mmol) was slowly added 4-(1-phenylethenyl)-
morpholine (0.189 g, 1 mmol) at room temperature. After
the reaction mixture was stirred at room temperature for 24 h
under an argon atmosphere, conc. 10% HCl solution (4 ml) was
added, and left at this temperature for 0.5 h. The resultant
mixture was quenched with brine (30 ml), extracted with diethyl
ether (30 ml × 3), dried over Na SO and concentrated under
C
3
J 28.67), 125.67 (q, J 285.05), 128.27 (s), 128.90 (s), 134.31 (s),
36.45 (s), 200.16 (s); δ (CDCl ) Ϫ81.97 (3F, s, CF ); MS (EI)
1
F
3
3
ϩ
m/z (rel intensity) 232 (M ; 45.7%), 214 (33.0), 163 (28.1),
1
requires C, 56.90; H, 4.77%.
45 (32.3), 77 (100.0); Found: C, 56.91; H, 4.79. C H F O
11 11 3 2
4
,4,4-Trifluoro-3-hydroxy-3-methyl-1-(4-methylphenyl)butan-
2
4
Ϫ1
vacuum. The residual oil was chromatographed on silica-gel
and using benzene as an eluent afforded analytically pure 4
1
-one 2b. Mp 53.0–53.6 ЊC (hexane); νmax(KBr)/cm 1681.0
(
C᎐O), 3486.7 (OH); δ (CDCl ) 1.49 (3H, s, CH ), 2.44 (3H, s,
᎐
H
3
3
(
0.022 g, 8%).
CH ), 3.07 (1H, d, J 16.84, CH CH ), 3.46 (1H, d, J 16.84,
3
A
B
CH CH ), 5.40 (1H, s, OH), 7.30 and 7.85 (4H, AB quartet,
A
B
4
,4,4-Trifluoro-3-hydroxy-3-methyl-1-phenyl-3-trifluoro-
J 8.29, aryl H); δ (CDCl ) 21.73 (s), 22.11 (s), 39.91 (s),
C
3
methylbutan-1-one 4. δ (CDCl ) 7.08 (1H, s, OH), 7.46–7.53
2H, m, CH ), 7.61–7.65 (1H, m, aryl H), 7.89–7.91 (2H, m,
2
aryl H); δ (CDCl ) Ϫ77.31 (6F, s); MS (EI) m/z (rel intensity)
F 3
ϩ
86 (M ; 1.5%), 267 (1.6), 249 (1.4), 217 (1.1), 201 (0.8), 105
7
3.40 (q, J 29.22), 125.68 (q, J 285.05), 128.44 (s), 129.59 (s),
H
3
(
1
34.00 (s), 145.50 (s), 199.80 (s); δF (CDCl ) Ϫ81.95 (3F,
3
ϩ
s, CF ); MS (EI) m/z (rel intensity) 246 (M ; 21.3%), 231
3
2
(
(
19.2), 134 (36.0), 119 (100.0), 91 (100.0), 77 (15.0), 65 (94.4);
100.0), 77 (100.0), 69 (33.9).
Found: C, 58.54; H, 5.34. C H F O requires C, 58.54; H,
12
13
3
2
5
.32%.
Typical procedure for the synthesis of 4-trifluoromethylpyridines
1
-(4-Chlorophenyl)-4,4,4-trifluoro-3-hydroxy-3-methylbutan-
After the triglyme (2 ml) solution of 4-(1-phenylethenyl)-
morpholine (2 mmol, 0.379 g), diketone 6a (1 mmol, 0.216 g)
and ammonium acetate (2 mmol, 0.154 g) was refluxed for
0.5 h, the resultant mixture was quenched with saturated
Ϫ1
1
(
-one 2c. Mp 40.0–40.6 ЊC (hexane); νmax(KBr)/cm 1686.5
C᎐O), 3485.9 (OH); δ (CDCl ) 1.51 (3H, s, CH ), 3.05 (1H,
᎐
H 3 3
d, J 17.08, CH CH ), 3.49 (1H, d, J 17.08, CH CH ), 5.06 (1H,
A
B
A
B
s, OH), 7.49 and 7.90 (4H, AB quartet, J 8.30, aryl H);
δ (CDCl ) 22.04 (s), 40.27 (s), 73.36 (q, J 28.67), 125.59 (q,
NaHCO solution, extracted with diethyl ether (30 ml × 3),
3
dried over Na SO4 and concentrated under vacuum. The
C
3
2
J 284.50), 129.26 (s), 129.69 (s), 134.74 (s), 140.97 (s), 198.74 (s);
δ (CDCl ) Ϫ81.88 (3F, s, CF ); MS (EI) m/z (rel intensity) 268
residue was purified by column chromatography on silica gel
eluting with hexane–benzene = 1 : 1, giving 7a (0.212 g, 71%) as
a white solid.
F
3
3
ϩ
(
M ϩ 2; 0.5%), 266 (M ; 1.3), 154 (26.1), 139 (100.0), 111
J. Chem. Soc., Perkin Trans. 1, 2001, 2578–2582
2581

View Online
4329; E. P. Kundig, C. M. Saudan and G. Bernardinelli, Angew.
Chem., Int. Ed., 1999, 38, 1220; T. Iwahama, S. Sakaguchi and
Y. Ishii, Chem. Commun., 1999, 727.
2
,6-Diphenyl-4-trifluoromethylpyridine 7a. Mp 85.1–85.9 ЊC
(
hexane); δ (CDCl ) 7.46–7.55 (6H, m, aryl H), 7.88 (2H, s, aryl
H), 8.16–8.18 (4H, m, aryl H); δ (CDCl ) 114.01 (q, J 3.31),
23.16 (q, J 272.92), 127.09 (s), 128.86 (s), 129.80 (s), 138.14 (s),
39.97 (q, J 33.08), 158.15 (s); δ (CDCl ) Ϫ63.04 (s, 3F); MS
EI) m/z (rel intensity) 298 (M ; 100.0%), 280 (36.7), 258 (20.2),
H
3
C
3
3
For recent examples, see: A. K. Holmeide and L. Skattebol, J. Chem.
Soc., Perkin Trans. 1, 2000, 2271; F. Benayoud, A. Abouabdellah,
C. Richard, D. Bonnet-Delpon, J.-P. Bégué, D. Levasseur,
O. Boutaud and F. Schuber, Tetrahedron Lett., 2000, 41, 6367.
1
1
(
F
3
ϩ
2
30 (100.0), 202 (54.5), 77 (71.0).
4 For recent reviews, see: R. P. Singh and J. M. Shreeve, Tetrahedron,
2
9
000, 56, 7613; G. K. S. Prakash and A. K. Yudin, Chem. Rev., 1997,
7, 757; T. Umemoto, Chem. Rev., 1996, 96, 1757; D. J. Burton
2
-(4-Chlorophenyl)-6-phenyl-4-trifluoromethylpyridine 7b. Mp
and Z.-Y. Yang, Tetrahedron, 1992, 48, 189; M. A. McClinton and
D. A. McClinton, Tetrahedron, 1992, 48, 6555.
5 For recent reviews on fluoromethyl ketones, see: V. G. Nenaidenko,
A. V. Sanin and E. S. Balenkova, Russ. Chem. Rev., 1999,
8
8
(
1
1
1
3
9.8–90.3 ЊC; δ (CDCl ) 7.47–7.56 (3H, m, aryl H), 7.50 and
.12 (4H, AB quartet, J 8.54, aryl H), 7.84 (1H, s, aryl H), 7.88
1H, s, aryl H), 8.10–8.16 (2H, m, aryl H); δ (CDCl ) 55.38 (s),
13.22 (s), 114.20 (s), 123.27 (q, J 273.75), 127.05 (s), 128.45 (s),
28.83 (s), 129.72 (s), 130.77 (s), 138.31 (s), 139.86 (q, J 33.08),
57.77 (s), 157.97 (s); δ (CDCl ) Ϫ63.88 (3F, s, CF ); m/z (EI)
H
3
C 3
4
37; J.-P. Bégué and D. Bonnet-Delpon, Tetrahedron, 1991, 47, 3207.
For recent examples, see Y. Kuroki, Y. Sakamaki and K. Iseki, Org.
Lett., 2001, 3, 457; I. Rodrigues, D. Bonnet-Delpon and J. P. Bégué,
J. Org. Chem., 2001, 66, 2098; W. Zhuang, N. Gathergood,
R. G. Hazell and K. A. Jørgensen, J. Org. Chem., 2001, 66, 1009;
R. V. Ramachandran, M. V. R. Reddy and M. T. Rudd, Chem.
Commun., 2001, 757; T. Matsuda, T. Harada, N. Nakajima, T. Itoh
and K. Nakamura, J. Org. Chem., 2000, 65, 157; Y. Kuroki,
D. Asada and K. Iseki, Tetrahedron Lett., 2000, 41, 9853;
J. M. Mellor, A. H. El-Sagheer and E. E.-D. M. Salem, Tetrahedron
Lett., 2000, 41, 7383; J. M. Mellor and A. H. El-Sagheer,
Tetrahedron Lett., 2000, 41, 7387; C. Pareja, E. Martín-Zamora,
R. Fernández and J. M. Lassaletta, J. Org. Chem., 1999, 64, 8846;
K. Uneyama, G. Mizutani, K. Maeda and T. Kato, J. Org. Chem.,
1999, 64, 6717; M.-A. Poupart, G. Fazal, S. Goulet and L. T. Mar,
J. Org. Chem., 1999, 64, 1356; H. Amii, T. Kobayashi, Y. Hatamoto
and K. Uneyama, Chem. Commun., 1999, 1323; M. E. Pierce,
R. L. Parsons, Jr., L. A. Radesca, Y. S. Lo, S. Silverman, J. R.
Moore, Q. Islam, A. Choudhury, J. M. D. Fortunak, D. Nguyen,
C. Luo, S. J. Morgan, W. P. Davis, P. N. Confalone, C.-Y. Chen,
R. D. Tillyer, L. Frey, L. Tan, F. Xu, D. Zhao, A. S. Thompson,
E. G. Corley, E. J. J. Grabowski, R. Reamer and P. J. Reider, J. Org.
Chem., 1998, 63, 8536.
F
3
3
ϩ
ϩ
35 (M ϩ2, 32%), 333 (M , 100).
2
-(4-Methoxyphenyl)-6-phenyl-4-trifluoromethylpyridine 7c.
Mp 81.5–82.0 ЊC; δ (CDCl ) 3.89 (3H, s, OCH ), 7.04 and 8.14
4H, AB quartet, J 8.78, aryl H), 7.45–7.55 (3H, m, aryl H),
.81 (2H, s, aryl H), 8.12–8.17 (2H, m, aryl H); δ (CDCl )
13.77 (q, J 3.30), 114.32 (q, J 3.31), 121.69 (q, J 273.74),
27.09 (s), 128.35 (s), 128.93 (s), 129.09 (s), 129.97 (s), 136.05
s), 136.56 (s), 137.96 (s), 140.17 (q, J 33.63), 156.95 (s), 158.35
s); δ (CDCl ) Ϫ63.88 (3F, s, CF ); m/z (EI) 329 (M , 100),
86 (25).
H
3
3
(
7
1
1
(
(
C 3
ϩ
F
3
3
2
2
-Phenyl-6-(2-thienyl)-4-trifluoromethylpyridine
7d.
Mp
1
7
7
1
1
10.5–111.0 ЊC; δ (CDCl ) 7.16 (1H, dd, J 5.1 and 3.7, aryl H),
.46–7.54 (3H, m, aryl H), 7.47 (1H, dd, J 5.1 and 0.98, aryl H),
.74 (1H, s, aryl H), 8.12–8.15 (2H, m, aryl H); δ (CDCl )
12.32 (q, J 3.30), 113.48 (q, J 3.31), 121.66 (q, J 273.17),
25.66 (s), 127.00 (s), 128.16 (s), 128.80 (s), 128.85 (s), 129.92
H
3
C
3
6
K. Funabiki, M. Nojiri, M. Matsui and K. Shibata, Chem.
Commun., 1998, 2051; K. Funabiki, K. Matsunaga, M. Matsui and
K. Shibata, Synlett, 1999, 1477.
7 The reaction of trifluoromethyl ketones with imines giving β-
substituted β-hydroxy-β-trifluoromethyl imines has been pre-
(
(
s), 137.60 (s), 139.90 (q, J 33.63), 143.99 (s), 153.43 (s), 158.02
s); δ (CDCl ) Ϫ64.04 (3F, s, CF ); m/z (EI) 305 (M , 100%).
ϩ
F
3
3
sented partly by another group and us independently, see:
2
-(4-Methylphenyl)-6-phenyl-4-trifluoromethylpyridine
7e.
th
(
a) J. Przyborowski and G.-V. Röschenthaler, 15 International
Mp 95.3–96.0 ЊC (hexane); δ (CDCl ) 7.33 and 8.07 (4 H, AB
quartet, J 8.30, aryl H), 7.46–7.55 (3H, m, aryl H), 7.85 (2H, s,
aryl H), 8.16–8.18 (2H, m, aryl H); δ (CDCl ) 21.34 (s), 113.71
s), 123.20 (q, J 274.58), 126.97 (s), 127.09 (s), 128.86 (s), 129.60
s), 129.75 (s), 135.43 (s), 138.29 (s), 139.90 (q, J 33.08), 140.00
s), 158.19 (s); δ Ϫ63.99 (3F, s, CF ); MS (EI) m/z (rel intensity)
H
3
Symposium on Fluorine Chemistry, Vancouver, August, 1997,
Abstract No. O(3) IL-10; (b) K. Funabiki, K. Matsunaga,
A. Isomura, M. Matsui and K. Shibata, the 78th Annual Meeting
of the Chemical Society of Japan, Funabashi, March, 2000,
Abstract No. 4F 203. The results will be reported elsewhere, see;
C
3
(
(
(
3
(
c) J. A. Barten, K. Funabiki and G.-V. Röschenthaler, J. Fluorine
F
3
Chem., accepted.
ϩ
12 (M ; 100.0), 244 (18.9), 91 (43.5); Anal. Calcd for: C, 72.83;
H, 4.50: N, 4.47. Found: C, 72.99; H, 4.61; N, 4.49%.
8
For our examples for silica-gel mediated synthesis of organofluorine
molecules, see: (a) K. Funabiki, H. Nakamura, M. Matsui and
K. Shibata, Synlett, 1999, 756; K. Funabiki, H. Nakamura,
M. Matsui and K. Shibata, Synlett, 1999, 1332; (b) I. Katsuyama,
S. Ogawa, H. Nakamura, Y. Yamaguchi, K. Funabiki, M. Matsui,
H. Muramatsu and K. Shibata, Heterocycles, 1998, 48, 779;
2
,4-Diphenyl-2-trifluoromethylpyridine 9. Mp 93.0–94.1 ЊC
(
hexane); δ (CDCl ) 7.45–7.57 (6H, m, aryl H), 7.69 (6H, m,
aryl H), 7.81 (1H, d, J 1.3, aryl H), 8.09 (1H, d, J 1.3, aryl H),
.10–8.13 (2H, m, aryl H); δ (CDCl ) Ϫ68.64 (s, 3F); MS (EI)
H
3
(
c) I. Katsuyama, K. Funabiki, M. Matsui, H. Muramatsu and
8
F
3
K. Shibata, Synlett, 1997, 591; (d ) I. Katsuyama, K. Funabiki,
M. Matsui, H. Muramatsu and K. Shibata, Tetrahedron Lett., 1996,
ϩ
m/z (rel intensity) 299 (M ; 100.0%), 230 (86.0).
3
7, 4177; (e) I. Katsuyama, K. Funabiki, M. Matsui, H. Muramatsu
and K. Shibata, Chem. Lett., 1996, 179.
Acknowledgements
9 For recent examples for the synthesis of ring-trifluoromethylated
pyridines, see: (a) A. M. Shestopalov, V. P. Kislti, E. Y. Kruglova,
K. G. Nikishin, V. V. Semenov, A. C. III, Buchanan and A. A. Gakh,
J. Comb. Chem., 2000, 2, 24; (b) T. Konakahara, M. Hojahmat and
S. Tamura, J. Chem. Soc., Perkin Trans. 1, 1999, 2803; (c) D. Dube,
C. Brideau, D. Deschenes, D. Deschenes, R. Fortin, R. W. Friesen,
R. Gordon, Y. Girard, D. Riendeau, C. Savoie and C.-C.
Chan, Bioorg. Med. Chem. Lett., 1999, 9, 1715; for our contribution
on ring-trifluoromethylated pyridines, see: Y. Yamaguchi,
I. Katsuyama, K. Funabiki, M. Matsui and K. Shibata,
J. Heterocycl. Chem., 1998, 35, 805; (e) I. Katsuyama, S. Ogawa,
Y. Yamaguchi, K. Funabiki, M. Matsui, H. Muramatsu and
K. Shibata, Synthesis, 1997, 1321.
We would like to thank Professors H. Yamanaka and
T. Ishihara as well as Dr T. Konno of the Kyoto Institute of
Technology for the HRMS measurements. We also thank the
Central Glass Co., Ltd., for the gift of trifluoroacetone.
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J. Chem. Soc., Perkin Trans. 1, 2001, 2578–2582