Catalytic enantioselective trifluoromethylation of azomethine imines with trimethyl(trifluoromethyl)silane

Full text of DOI:10.1002/anie.200902457

Communications
DOI: 10.1002/anie.200902457
Trifluoromethylation
Catalytic Enantioselective Trifluoromethylation of Azomethine Imines
with Trimethyl(trifluoromethyl)silane**
Hiroyuki Kawai, Akihiro Kusuda, Shuichi Nakamura, Motoo Shiro, and Norio Shibata*
Although the first report on the nucleophilic trifluoromethy-
lation of carbonyl compounds using tetrabutylammonium
fluoride by Prakash and Olah[1,2] was reported over 20 years
ago, the enantioselective nucleophilic trifluoromethylation
using trimethyl(trifluoromethyl)silane, Me3SiCF3, remains a
challenge in fluoroorganic chemistry. Although a variety of
methodologies for catalytic asymmetric reactions are now
available in modern organic synthesis, chiral auxiliary based
diastereoselective trifluoromethylation[3] is still the most
widely applied approach in the field of fluorine chemistry
with enantioselective catalysis remaining a big challenge.[4,5]
Scheme 1. Enantioselective trifluoromethylation of azomethine imines 1.
Our research group has recently devised such processes using
a catalyst system comprised of bromide salts of cinchona
alkaloids and tetramethylammonium fluoride (TMAF); aryl
alkyl ketones can be efficiently converted into the corre-
sponding trifluoromethylated alcohols in high yields and with
enantioselectivities up to 94% ee.[6] As for nucleophilic
trifluoromethylation of imines or their equivalents, however,
only classical diastereoselective approaches using chiral
auxiliaries have been reported,[7,8] and no examples of an
enantioselective variant has been reported, despite the
potential usefulness and wide applicability of enantiomeri-
cally pure trifluoromethylated amines in the syntheses of
pharmaceuticals and agrochemicals.[9] We disclose herein the
first enantioselective trifluoromethylation of imine equiva-
lents, azomethine imines 1, with Me3SiCF3 (Scheme 1).
Given our success with enantioselective trifluoromethy-
lation of carbonyl compounds,[6] we anticipated that imines
would perform with similar effectiveness as substrates in the
enantioselective trifluoromethylation reaction under our
catalytic protocol. We observed, however, that conventional
imines such as N-tosylimines were poor substrates from both
a reactivity and selectivity point of view under our reported
and modified reaction conditions. Work on the mechanistic
details of the present reaction led us to realize that the
observed insufficient selectivity may have resulted from the
size and flexibility in conformation of the N-tosylimines. Low
conversion might be attributed to the poor nucleophilicity of
the generated sulfonamide intermediates towards Me3SiCF3.
A substrate for trifluoromethylation is usually required to
generate a species which is sufficiently nucleophilic to attack
Me3SiCF3 in the autocatalytic process.[2a] These prerequisites
allowed us to employ azomethine imines 1 as a family of
sterically demanding imine equivalents with a constrained
conformation, which were expected to react with the CF3
anion stereoselectively to generate species having suitable
autocatalytic activity. The catalytic scenario in the presence of
a chiral phase transfer catalyst (PTC) is presented in
Scheme 2. Azomethine imines are well-known partners of
asymmetric 1,3-cycloaddition reaction with olefins or alkynes
for achieving heterocycle formation under mild reactions
conditions;[10] however, reports of simple nucleophilic addi-
tion to azomethine imines are not available.
We started our investigation with the reaction of an
azomethine imine 1a, derived from benzaldehyde, with
Me3SiCF3 in the presence of chiral ammonium bromide 3a,
and screened a broad range of additives (Table 1). First, our
original reaction conditions[6] for enantioselective trifluoro-
methylation of ketones were tested. A catalytic amount of
TMAF was added to a mixture of 1a and two equivalents of
Me3SiCF3 in CH2Cl2 in the presence of a catalytic amount of
N-3,5-bis(trifluoromethylbenzyl)cinchoninium bromide (3a)
at À408C; the product was obtained in a 12% yield with a
28% ee (Table 1, entry 1). The reaction was next attempted
using tBuOK at À408C, and trifluoromethylated adduct 2a
was formed in 70% ee, albeit in low yield (Table 1, entry 2).
This preliminary result encouraged us to investigate other
combinations in an attempt to improve enantioselectivity
(Table 1, entries 3–7). After screening several additives, the
enantioselectivity was increased to 77% ee by the use of
KOH, but the yield was still low at 11% (Table 1, entry 5). We
[*] H. Kawai, A. Kusuda, Dr. S. Nakamura, Prof. N. Shibata
Department of Frontier Materials, Graduate School of Engineering
Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
Fax: (+81)52-735-5442
E-mail: nozshiba@nitech.ac.jp
Dr. M. Shiro
Rigaku Corporation
3-9-12 Mastubara-cho, Akishima, Tokyo 196-8666 (Japan)
[**] Support was provided by KAKENHI by a Grant-in-Aid for Scientific
Research on Priority Areas “Advanced Molecular Transformations of
Carbon Resources” from the Ministry of Education, Culture, Sports,
Science, and Technology Japan. We also thank TOSOH F-TECH
INC. for a gift of Me3SiCF3.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902457.
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Chemie
CH2Cl2 (2:1), the ee value was slightly increased to
77% ee (Table 1, entry 10). Having established the
viability of enantioselective trifluoromethylation of
azomethine imine 1a under the chiral phase trans-
fer conditions, we next turned our attention to a
fine-tuning of the azomethine imine structure
(Table 1, entries 11 and 12). Steric hindrance
around the nitrogen atoms of 1b–c was found to
be necessary for achieving high enantiocontrol, and
ee values up to 89% were obtained when the 5,5-
dimethyl derivative 1c was used as a substrate
(Table 1, entry 12). Lowering the reaction temper-
ature to À508C allowed the enantioselectivity of
the CF3 adduct 2c to reach as high as 91% ee
(Table 1, entry 13). The amount of Me3SiCF3 could
be reduced to four equivalents without a significant
change to either the yield or enantioselectivity
Scheme 2. Autocatalytic scenario of chiral phase transfer catalyst (PTC) catalyzed
trifluoromethylation of azomethine imines 1 with Me3SiCF3.
Table 1: Optimization of additives for enantioselective trifluoromethyla-
(Table 1, entry 14); therefore, the optimum conditions
required the use of 5,5-dimethyl azomethine imine 1c,
10 mol% of the ammonium bromide 3a, four equivalents of
Me3SiCF3 with an excess of KOH in toluene/CH2Cl2 (Table 1,
entry 14). The sterically demanding tert-butyl ammonium
bromide 3b also proved to be an almost equally effective
catalyst, affording 2c in 82% yield with 87% ee (Table 1,
entry 15).
tion catalyzed by 3a.[a]
With optimized reaction conditions, several families of
azomethine imines differing in the nature of the R groups
were submitted to the action of our trifluoromethylation
system to explore the scope of the chiral ammonium bromide
3a or 3b/KOH catalyst. The best results of such reactions are
collected in Table 2. High chemical yields and high enantio-
selectivities, in the 90% range, were obtained in all cases, with
these being almost independent of the functional groups such
as alkyl, sterically demanding alkyl, halogen-containing, and
methoxy moieties, as well as the positions of the substituents
on the aromatic ring (Table 2, entries 1–12). For other
aromatic analogues bearing bulky naphthyl groups, we
obtained the CF3 products 2o–q in high yields with enantio-
selectivities ranging from 90 to 93% (Table 2, entries 13–15).
Cinnamyl- and alkyl-substituted azomethine imines 1r and 1 s
are also suitable substrates for 3b/KOH-catalyzed asymmet-
ric trifluoromethylation, although the enantioselectivities
were somewhat low at 79% and 71% ee, respectively
(Table 2, entries 16 and 17). To the best of our knowledge,
these are the first examples of enantioselective trifluorome-
thylation of imines or their equivalents. The absolute
stereochemistry of the newly generated stereocenter in 2n
was determined by X-ray crystallographic analysis and the
stereochemistry of other trifluoromethylated amines 2 was
tentatively assumed by analogy (Figure 1a).
Entry
1
Base (equiv)
Solvent
Yield [%] ee [%][b]
1[c]
2[c]
3[c]
4[c]
5
1a TMAF (0.2)
1a tBuOK (0.2)
1a NaOH (0.2)
1a PhOK (0.2)
1a KOH (0.2)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
12
15
7
28
70
71
74
77
75
75
75
75
77
85
89
91
90
87
18
11
14
7
6
7
1a CsOH·H2O (0.2) CH2Cl2
1a CsF (0.2)
1a KOH (1.5)
1a KOH (6.0)
1a KOH (6.0)
1b KOH (6.0)
1c KOH (6.0)
CH2Cl2
CH2Cl2
CH2Cl2
toluene/CH2Cl2 67
toluene/CH2Cl2 85
toluene/CH2Cl2 76
toluene/CH2Cl2 80
toluene/CH2Cl2 94
toluene/CH2Cl2 82
8[d]
9[d]
10[d]
11[d]
12[d]
57
73
13[d,e] 1c KOH (6.0)
14[e,f] 1c KOH (6.0)
15[d,g] 1c KOH (6.0)
[a] The reaction of 1 with Me3SiCF3 (2.0 equiv) was carried out in the
presence of 3a (10 mol%) and base in solvent (CH2Cl2 or toluene/
CH2Cl2 =2:1) at À408C, unless otherwise noted. [b] Determined by
HPLC methods using a Chiralcel OJ-H column. [c] The reaction mixture
was cooled to À408C and warmed to À208C over a 2 h time period.
[d] Me3SiCF3 (10 equiv) was used. [e] The reaction was carried out at
À508C. [f] Me3SiCF3 (4 equiv) was used. [g] Catalyst 3b (10 mol%) was
used instead of 3a.
believe that the low conversion is probably because of the
instability of Me3SiCF3 and poor solubility of KOH in the
reaction solution. We therefore used a large excess of
Me3SiCF3 (10 equiv) and KOH (1.5 equiv) to ensure high
conversion of azomethine imine, and the yield was improved
to 57% without any loss of enantioselectivity (Table 1,
entry 8). Additional improvement was observed in the
presence of six equivalents of KOH to give 2a in 73% with
75% ee (Table 1, entry 9). In a mixed solvent system, toluene/
To understand the high enantioselectivity observed for the
present reaction catalyzed by the bromide salts of cinchona
alkaloids 3, we postulated a transition-state structure for the
production of (S)-2c catalyzed by 3 generated from the results
of X-ray crystallographic analyses of 2n and 3a (Figure 1a–c).
The X-ray crystallographic analysis of 3a indicated that the
cinchona alkaloid exists in an open conformation.[11] The free
hydroxy group in 3 captures the substrate 1c, presumably by
intermolecular hydrogen-bond formation to the oxygen atom
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Table 2: Enantioselective trifluoromethylation of 1 with Me3SiCF3 cata-
lyzed by either 3a or 3b and KOH.[a]
in 1c. Sterically demanding dimethyl substituents on 1c
should be located in the space between the quinuclidine ring
and either the bulky CF3 or tBu group on the benzene ring of
3. The aromatic p–p interactions between 1c and 3 would
assist in the stabilization of the transition-state structure in
which the CF3 anion approaches from the Si face of 1c; the
Re face is effectively blocked by the bulky parts of the benzyl
substituent in 3 (Figure 1c).
Entry
1
R
3
t [h]
2
Yield [%] ee [%]
Final removal of the protective group of amines pro-
ceeded uneventfully even though there are no examples of
this type of amines which have been successfully deprotected.
Thus, treatment of the amine 2c with Raney-Ni in MeOH at
1808C and subsequent acid treatment led to the trifluorome-
thylated amine (S)-5 in high yield without any loss of
enantiopurity (Scheme 3).
1
1c
1d
1e
1 f
1g
Ph
3a 17
3a 20
2c
2d
2e
2 f
2g
94
86
72
87
73
90
88
94
90
92
95
96
98
88
89
86
83
93
90
90
79
71
2[b]
3
2-MeC6H4
3-MeC6H4
4-MeC6H4
3-MeOC6H4
3b
3b
3b
3b
3b
3b
3b
6
8
3
8
6
3
9
4
5
6
7
8
9
10
11[b]
12[b]
13[b]
14
15[c]
16[b]
17[d]
1h 4-MeOC6H4
2h 84
1i
1j
1k
4-iPrC6H4
4-tBuC6H4
3,4-Me2C6H3
2i
2j
2k
2 L 89
2m 81
2n 85
2o
2p 95
2q
2r
2 s 85
84
88
89
1 L 4-FC6H4
1m 4-ClC6H4
1n 4-BrC6H4
3b 12
3b
3b
9
9
1o
1-naphthyl
3b 18
74
1p 2-naphthyl
1q
1r
3b
4
8
9
7
6-MeO-2-naphthyl 3a
C6H4CH CH
90
78
=
3b
3b
Scheme 3. Removal of the protecting group of 2c to generate the
trifluoromethylated amine 5.
1 s cyclohexyl
[a] The reaction of 1 with Me3SiCF3 (4.0 equiv) was carried out in the
presence of 3 (10 mol%) and KOH (6.0 equiv) in toluene/CH2Cl2 (2:1) at
À508C unless otherwise noted. The ee values were determined by HPLC
methods using a Chiralcel OJ-H, AD-H, or OD-H column. [b] The
reaction mixture was cooled to À508C and warmed to À408C over a 2 h
time period. [c] Me3SiCF3 (6.0 equiv) and 30 mol% of 3a were used. The
reaction was carried out at À408C in CH2Cl2. [d] The reaction mixture
was cooled to À708C and warmed to À608C over a 2 h time period.
In summary, we have developed the first enantioselective
trifluoromethylation of imine equivalents with Me3SiCF3. The
use of azomethine imines 1 was key for the success in the
present reaction. By employing bromide salts of cinchona
alkaloids and KOH as chiral catalysts, we have efficiently
reacted a wide range of azomethine imines 1 and Me3SiCF3 to
provide pharmaceutically important trifluoromethylated
amines
2 in very good enantiomeric
excess. Asymmetric monofluoromethyla-
tion and difluoromethylation reactions, as
well as conventional cyanation and nitro-
aldol reactions of azomethine imines are
under investigation based on this strategy.
Received: May 8, 2009
Published online: July 15, 2009
Keywords: amines · autocatalysis · fluorine ·
.
organocatalysis · trifluoromethylation
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