Practical synthesis of 4,4,4-trifluorocrotonaldehyde: A versatile precursor for the enantioselective formation of trifluoromethylated stereogenic centers via organocatalytic 1,4-additions

Article abstract of DOI:10.1039/c2cc32757k

The practical synthesis of 4,4,4-trifluorocrotonaldehyde (1) and its application to enantioselective 1,4-additions are described. The organocatalytic 1,4-addition of 1 with several nucleophiles such as heteroaromatics, alkylthiols and aldoximes afforded t

Full text of DOI:10.1039/c2cc32757k

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COMMUNICATION
Practical synthesis of 4,4,4-trifluorocrotonaldehyde: a versatile precursor
for the enantioselective formation of trifluoromethylated stereogenic
centers via organocatalytic 1,4-additionsw
Kazutaka Shibatomi,* Akira Narayama, Yoshiyuki Abe and Seiji Iwasa
Received 18th April 2012, Accepted 1st June 2012
DOI: 10.1039/c2cc32757k
The practical synthesis of 4,4,4-trifluorocrotonaldehyde (1) and
its application to enantioselective 1,4-additions are described.
The organocatalytic 1,4-addition of 1 with several nucleophiles
such as heteroaromatics, alkylthiols and aldoximes afforded the
corresponding products, each bearing a trifluoromethylated
stereogenic center with high optical purity. A resulting product
was converted into an MAO-A inhibitor, befloxatone.
Scheme 1 Synthetic strategy.
Incorporation of perfluoroalkyl substituents into organic
there are only four reports on the synthesis of 1,5 but no report on
molecules is a highly valuable process in pharmaceutical,
agrochemical and material sciences. In particular, introduction
the isolation of this compound or its use in enantioselective
of a trifluoromethyl (CF3) group into biologically active com-
cursors in numerous organocatalytic asymmetric transformations.6
pounds often modifies their physical and/or biological properties
transformations, although a,b-enals have been widely used as pre-
such as lipophilicity, metabolic stability, and bioavailability.1
One possible reason for this is the high volatility of 1 and the
Although a large number of pharmaceuticals contain the CF3
consequent difficulty in its purification. In the present research, we
group(s), developing flexible methods for the highly enantio-
successfully isolated 1 for the first time and applied it to enantio-
selective construction of trifluoromethylated stereogenic centers
selective 1,4-addition with several nucleophiles in the presence of
the Jørgensen–Hayashi-type prolinol ether catalyst 2.7
remains a challenging task. Trifluoromethylated chiral carbon
centers are mostly constructed by either of these approaches:
We first focused on the development of an efficient method
(i) asymmetric direct trifluoromethylation of a prochiral carbon;
for the synthesis of 1. Since 1 is highly volatile, we decided to
(ii) asymmetric functionalization of a trifluoromethylated
avoid the use of liquid–liquid extraction and column chromato-
prochiral carbon. Although the former approach is simpler
graphy for the isolation and purification of this compound.
and straightforward, only a few catalytic methods that provide
Thus, we planned to synthesize 1 by the oxidation of 4,4,4-
high enantioselectivity are known.2 Therefore, the latter approach,
trifluoro-2-butenol (4) with manganese dioxide, which can be
the so-called building block approach, has often been adopted to
removed from the reaction system by a simple filtration
obtain a chiral center bearing a CF3 moiety, mainly by using
process. First, 4 was synthesized in 61% yield by the reduction
trifluoromethyl ketones, trifluoroacetaldehyde, trifluoropyruvates
of ethyl 4,4,4-trifluorocrotonate (3) with lithium aluminum
or their derivatives as precursors.3 Intrigued by the fact that 4,4,4-
trifluorocrotonates are simple building blocks of various trifluoro-
methyl compounds, some research groups, including our group,
have applied them to asymmetric transformations.4 During the
course of our continuous research in this direction, we envisaged
that 4,4,4-trifluorocrotonaldehyde (1) would be a versatile
precursor for the construction of trifluoromethylated stereo-
genic centers (Scheme 1). However, to the best of our knowledge,
hydride and aluminum trichloride.8 Fortunately, the manganese
dioxide oxidation of 4 proceeded smoothly to afford the
desired product with high conversion (85%, determined by
1H NMR analysis using an internal standard). After the
removal of manganese dioxide by filtration, the filtrate was
distilled to afford nearly pure 1 (98% purity) in 47% yield on a
5 g scale (Scheme 2).
Department of Environmental and Life Sciences, Toyohashi University
of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi 441-8580,
Japan. E-mail: shiba@ens.tut.ac.jp; Fax: +81 532 48 5833;
Tel: +81 532 44 6810
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization of all new compounds. See DOI:
10.1039/c2cc32757k
Scheme 2 Synthesis of 4,4,4-trifluorocrotonaldehyde.
c
7380 Chem. Commun., 2012, 48, 7380–7382
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Table 2 Enantioselective Michael addition of heteroatom nucleophilesa
Table 1 Enantioselective Friedel–Crafts arylation of 1a
Yieldb eec
Entry Nucleophile
Product
(%)
(%)
1
9a: R = Ph
9a
9b: R = CH2Ph 98
9c: R = c-Hex 99
9d: R = n-Bu
9e: R =
CH2CO2Et
10a: X = N
Y = CH
97
92
94
90
95
96
93
92
2d
3
Pyrrole or
Entry indole
Time/ Yieldb eec
R1 R2
Product
h
(%)
(%)
4
5
6
RSH
1
10
4
12
16
11
92
92
96
85
61
96
93
97
99
80
H
H
5a
93
87
2d
3
Me
Bn
H
H
H
Me
5b
5c
5d
4
5e
7e
8e
1,2,4-Triazole
1,2,3-Triazole
77
74
86
83
10b: X = CH
Y = N
6
7
8
H
Me
H
H
H
6a
6b
12
14
13
98
83
71
90
97
93
OMe 6c
9f,g
PhCH=N–OH
11
73
95
a
All reactions were carried out using 1.5 equiv. pyrrole or indole in the
b
presence of 10 mol% of 2. Isolated yield. Determined by chiral
c
d
HPLC analysis. a,a-Diphenyl-2-pyrrolidinemethanol trimethylsilyl
ether was used instead of 2. The product was obtained as a mixture
of 2,4- and 2,3-disubstituted forms.
a
All reactions were carried out using 1.5 equiv. of 1 (based on the
nucleophile) in the presence of 10 mol% 2 and benzoic acid, unless
e
b
otherwise noted. Isolated yield. Determined by chiral HPLC analysis.
d
c
a,a-Diphenyl-2-pyrrolidinemethanol trimethylsilyl ether was used
e
instead of 2. Reaction was carried out at À20 1C for 40 h with
With the method for the practical synthesis of 1 in hand, we
attempted the enantioselective transformation of 1. First,
organocatalytic Friedel–Crafts arylation of 1 was carried out
with pyrroles and indoles as the nucleophiles.9 The reaction of
an unprotected pyrrole with 1 in the presence of 10 mol% 2
afforded the corresponding 2-substituted pyrrole 5a in 96% ee
(Table 1, entry 1).10 High enantioselectivity was also observed
when N-substituted pyrroles were used (97% and 99% ee,
entries 3 and 4). The reaction of 3-methylpyrrole with 1 afforded
the corresponding 2,4-disubstituted product 5d in 61% yield with
good enantioselectivity, along with a 2,3-disubstituted product in
25% yield (entry 5). When indoles were employed, the corre-
sponding 3-substituted indoles 6 were obtained with high
enantioselectivities, irrespective of the substituent on the indole
ring (entries 6–8). We also examined the use of other electron-
rich aromatic compounds. The reaction with 3-methoxy-N,N-
dimethylaniline11 afforded the desired compound 7 with 99% ee.
On the other hand, the reaction with 2-methoxyfuran afforded
the corresponding product 8 with 70% ee (Scheme 3).
f
g
20 mol% of 2 and benzoic acid. ent-2 was used instead of 2. Reaction
was carried out using 3 equiv. of aldoxime (based on 1).
1 was allowed to react with several nucleophiles in the presence
of 10–20 mol% 2 and benzoic acid (Table 2). The reaction of 1
with alkylthiols proceeded smoothly to yield the corre-
sponding adducts, which were subsequently reduced to the
primary alcohols 9 in good yields. The optical purity of 9 was
found to be 92–96% ee (entries 1, 3–6). The reactions of 1 with
triazoles also afforded the corresponding adducts with good
enantioselectivities (entries 7 and 8). Unfortunately, the reac-
tions with succinimide and N-methoxycarbamates were not
productive. Furthermore, the oxa-Michael reaction of 1 was
carried out using benzaldehyde oxime as the nucleophile
(entry 9). The reaction yielded the corresponding b-oxime
ether with good conversion, which was isolated after reduction
to 11 (73% yield, 95% ee).
Finally, we demonstrated the asymmetric synthesis of
a reversible monoamine oxidase A (MAO-A) inhibitor,
befloxatone,13 using a literature procedure (Scheme 4).13e
First, 4,4,4-trifluorobutane-1,3-diol 12 was synthesized by
palladium-catalyzed hydrogenolysis of 11.14,15 Selective tosylation
of the primary alcohol in 12 afforded tosylate 13 in 53% yield.
Next, oxazolidinone 17 was synthesized. Carbamate 14 was
prepared by the treatment of 4-benzyloxyaniline with methyl
chloroformate. Subsequent condensation with commercially
available (S)-4-methoxymethyl-1,3-dioxolane-2-one (15) in the
presence of K2CO3 afforded 16 in 83% yield.16 Then, depro-
tection of 16 by palladium-catalyzed hydrogenolysis yielded
oxazolidinone 17. Finally, etherification of 17 with 13 yielded
befloxatone in 84% yield with 95% de, as shown in Scheme 4.
In conclusion, we developed a practical synthetic route to
4,4,4-trifluorocrotonaldehyde (1), which is a versatile precursor
for organocatalytic enantioselective 1,4-additions. Reactions with
We next attempted the enantioselective Michael addition of 1
with heteroatom nucleophiles. As per the reported procedure,12
Scheme 3 Enantioselective Friedel–Crafts arylation of 1 with electron-
rich aromatic compounds.
c
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Chem. Commun., 2012, 48, 7380–7382 7381

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2011, 47, 632; (b) A. Cordova, Catalytic Asymmetric Conjugate
Reactions, Wiley-VCH, Weinheim, 2010; (c) S. Bertelsen and
K. A. Jørgensen, Chem. Soc. Rev., 2009, 38, 2178.
7 For early reports, see: (a) M. Marigo, T. C. Wabnitz,
D. Fielenbach and K. A. Jørgensen, Angew. Chem., Int. Ed.,
2005, 44, 794; (b) Y. Hayashi, H. Gotoh, T. Hayashi and
M. Shoji, Angew. Chem., Int. Ed., 2005, 44, 4212.
8 N. Ishikawa, M. G. Koh, T. Kitazume and S. K. Choi, J. Fluorine
Chem., 1984, 24, 419.
9 For early reports on the enantioselective Friedel–Crafts alkylation
of pyrroles and indoles with MacMillan catalyst, see:
(a) J. F. Austin and D. W. C. MacMillan, J. Am. Chem. Soc.,
2002, 124, 1172; (b) N. A. Paras and D. W. C. MacMillan, J. Am.
Chem. Soc., 2001, 123, 4370; For the report with Jørgensen–Hayashi
catalyst, see: (c) L. Hong, L. Wang, C. Chen, B. Zhang and
R. Wang, Adv. Synth. Catal., 2009, 351, 772.
10 Recently, Soloshonok revealed that compounds containing a
trifluoromethyl group directly bonded to a stereogenic carbon
center are prone to an enantiomer self-disproportionation effect
on achiral silica gel. We therefore confirmed that the optical purity
of selected products, 6a, 9b and 11, do not change even after
chromatographic purification using achiral silica gel. For the self-
disproportionation effect of the enanatiomers, see: (a) H. Ueki,
M. Yasumoto and V. A. Soloshonok, Tetrahedron: Asymmetry,
2010, 21, 1396; (b) V. A. Soloshonok, H. Ueki, M. Yasumoto,
S. Mekala, J. S. Hirschi and D. A. Singleton, J. Am. Chem. Soc.,
2007, 129, 12112; (c) V. A. Soloshonok and D. O. Berbasov,
J. Fluorine Chem., 2006, 127, 597; (d) V. A. Soloshonok, Angew.
Chem., Int. Ed., 2006, 45, 766.
Scheme 4 Asymmetric synthesis of befloxatone. Reaction conditions:
(a) Pd(OH)2 (20 mol% Pd), MeOH, H2, rt, 3 h; (b) TsCl (1.5 equiv.),
pyridine, rt, 24 h; (c) K2CO3 (3 equiv.), DMF, reflux, 3 h; (d) Pd/C
(10 mol% Pd), MeOH, H2 (1 atm), rt, 3 h; (e) K2CO3 (2 equiv.), DMF,
85 1C, 6 h.
various nucleophiles such as alkylthiols, pyrroles, indoles,
triazoles, and aldoximes afforded a variety of trifluoromethylated
chiral stereogenic centers in a highly enantioselective manner.
We also demonstrated the application of this method to the
asymmetric synthesis of an MAO-A inhibitor, befloxatone.
This study was supported by the Takeda Science Foundation
and a Grant-in-Aid for Young Scientists (B) (23750111) from
MEXT. The partial support from the Asahi Glass Foundation
is also acknowledged.
11 N. A. Paras and D. W. C. MacMillan, J. Am. Chem. Soc., 2002,
124, 7894.
12 For the addition of alkylthiols, see: (a) S. Brandau, E. Maerten and
K. A. Jørgensen, J. Am. Chem. Soc., 2006, 128, 14986;
(b) M. Marigo, T. Schulte, J. Franzen and K. A. Jørgensen,
J. Am. Chem. Soc., 2005, 127, 15710; For the addition of triazoles,
see: (c) P. Diner, M. Nielsen, M. Marigo and K. Anker Jørgensen,
Angew. Chem., Int. Ed., 2007, 46, 1983; For the addition of
succinimide and N-methoxycarbamates, see: (d) H. Jiang,
J. B. Nielsen, M. Nielsen and K. A. Jørgensen, Chem.–Eur. J.,
2007, 13, 9068; (e) J. Vesely, I. Ibrahem, R. Rios, G.-L. Zhao,
Y. Xu and A. Cordova, Tetrahedron Lett., 2007, 48, 2193; (f) For
the addition of aldoximes, see: (g) S. Bertelsen, P. Diner,
R. L. Johansen and K. A. Jørgensen, J. Am. Chem. Soc., 2007,
129, 1536.
Notes and references
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D. Bonnet-Delphon, Bioorganic and Medicinal Chemistry of Fluorine,
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13 For selected papers on the pharmacology of befloxatone or
11C]befloxatone, see: (a) M. Bottlaender, H. Valette, J. Delforge,
[
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4 For the catalytic asymmetric reaction with 4,4,4-trifluorocrotonates,
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2011, 47, 11110; For the reactions with 4,4,4-trifluorocrotonoyl
amide or oxazolidinone, see: (d) Y. Huang, E. Tokunaga,
S. Suzuki, N. Shibata and M. Shiro, Org. Lett., 2010, 12, 1136;
(e) T. Konno, T. Tanaka, T. Miyabe, A. Morigaki and T. Ishihara,
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5 There are four reports describing the synthesis of 1. All of them
mentioned the difficulty involved in the isolation of 1:
(a) D. M. Pearson, N. R. Conley and R. M. Waymouth, Organo-
metallics, 2011, 30, 1445; (b) L. Dumitrescu, D. T. M. Huong,
N. V. Hung, B. Crousse and D. Bonnet-Delpon, Eur. J. Med.
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ref. 13e.
15 The absolute configuration of 12 was determined to be R by
comparing the optical rotation with a value described in ref. 14a.
16 S. Jegham, A. Nedelec, Ph. Burnier, Y. Guminski, F. Puech,
J. J. Koenig and P. George, Tetrahedron Lett., 1998, 39, 4453.
c
7382 Chem. Commun., 2012, 48, 7380–7382
This journal is The Royal Society of Chemistry 2012