An efficient synthesis of optically active trifluoromethyl aldimines via asymmetric biomimetic transamination

Article abstract of DOI:10.1039/c2cc37423d

This communication describes a chiral base-catalyzed asymmetric [1,3]-proton shift of trifluoromethyl ketimines, giving a wide variety of trifluoromethyl aldimines containing various functional groups with up to 94% ee.

Full text of DOI:10.1039/c2cc37423d

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An efficient synthesis of optically active trifluoromethyl
aldimines via asymmetric biomimetic transamination†
Mao Liu,a Jing Li,a Xiao Xiao,a Ying Xiea and Yian Shi*ab
Cite this: Chem. Commun., 2013,
49, 1404
Received 11th October 2012,
Accepted 17th December 2012
DOI: 10.1039/c2cc37423d
www.rsc.org/chemcomm
This communication describes a chiral base-catalyzed asymmetric a related study with high ee’s was reported by Deng and Wu.11
[1,3]-proton shift of trifluoromethyl ketimines, giving a wide Herein, we wish to report our own efforts on this subject.
variety of trifluoromethyl aldimines containing various functional
groups with up to 94% ee.
Several ketimines (5) derived from 1,1,1-trifluoro-4-phenyl-
butan-2-one and different benzylamines were initially examined
for the asymmetric [1,3]-proton shift using catalyst C1 (Fig. 1)
Optically active trifluoromethyl amines are very important (Table 1, entries 1–5). While little conversions were observed
functional moieties present in various biologically and medicinally with BnNH2 and 2-Cl(C6H4)CH2NH2 (Table 1, entries 1 and 2),
significant compounds.1,2 They are frequently prepared from high conversions (72–100%) were obtained with 4-NO2(C6H4)-
imines by asymmetric reduction and nucleophilic addition.3–7 CH2NH2, 4-CN(C6H4)CH2NH2, and 2-Cl–4-CN(C6H3)CH2NH2,
Chiral base-catalyzed asymmetric [1,3]-proton shift of trifluoro- giving the corresponding aldimines with 21–28% ee (Table 1,
methyl ketimines to aldimines provides another attractive entries 3–5) when the reactions were carried out at 55 1C
approach to enantiomerically enriched trifluoromethyl amines in benzene. It appears that electron-withdrawing groups on
and their derivatives.8,9 An early example of asymmetric syn- benzylamines enhance the acidity of the benzylic hydrogen and
thesis of trifluoromethyl-b-amino acids via such a process was facilitate the proton shift. To further improve the enantio-
reported by Soloshonok and co-workers in 1994.8a In later selectivity, various quinine NH derivatives at the 60 position
studies, Plaquevent and co-workers showed that as high as were subsequently investigated with 2-Cl–4-CN(C6H3)CH2NH2
71% ee was obtained.8d Recently, we reported an efficient chiral as an amine donor (Table 1, entries 6–14). Results show that the
base-catalyzed biomimetic transamination of a-keto esters to steric and electronic effects of the nitrogen substituent have a
a-amino esters with high ee’s.10 Along these lines, we have been significant impact on the enantioselectivity. In general, cata-
exploring if trifluoromethyl amines can also be obtained from lysts with nitrogen substituents (C2–C10) gave higher ee’s than
the corresponding ketones with high enantioselectivity via a those with the OH group (C1). A catalyst with benzenesulfon-
similar transamination process (Scheme 1). During our studies, amide (C6), which was shown to be highly enantioselective for
the transamination of a-keto ester,10c gave 76% ee in this case
(Table 1, entry 10). Lower ee’s were obtained for catalysts with
Scheme 1
a Beijing National Laboratory of Molecular Sciences, CAS Key Laboratory of
Molecular Recognition and Function, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100190, China
b Department of Chemistry, Colorado State University, Fort Collins,
Colorado 80523, USA.. E-mail: yian@lamar.colostate.edu; Fax: 001-970-4911801;
Tel: 001-970-4917424
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data, HPLC data for determination of enantiomeric
excesses, X-ray structure of ketimine 7a (CCDC 912043), and NMR spectra. See
DOI: 10.1039/c2cc37423d
Fig. 1 Selected examples of catalysts examined.
c
1404 Chem. Commun., 2013, 49, 1404--1406
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Table 1 Studies on benzylamines and catalystsa
Table 2 Catalytic asymmetric [1,3]-proton shift of trifluoromethyl iminesa
Conv.b (%)
eec (%)
Entry
Imine (8)b
Yieldc (%)
eed (%)
Entry
X
Cat.
T (1C)
1
2
3
4
5
6
7
8
H
2-Cl
4-NO2
4-CN
C1
C1
C1
C1
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C10
55
55
55
55
55
55
55
55
55
55
55
55
55
55
20
Trace
Trace
100
72
—
—
21
25
28
60
61
39
58
76
68
79
87
89
94
2-Cl–4-CN
2-Cl–4-CN
2-Cl–4-CN
2-Cl–4-CN
2-Cl–4-CN
2-Cl–4-CN
2-Cl–4-CN
2-Cl–4-CN
2-Cl–4-CN
2-Cl–4-CN
2-Cl–4-CN
100
100
100
100
100
100
100
100
100
100
100
1
2
3
4
5
6
8a, X = H
99
99
98
99
99
98
94
94
94
94
93
94
8b, X = o-Cl
8c, X = o-Br
8d, X = p-Me
8e, X = p-Cl
8f, X = p-OCH3
9
10
11
12
13
14
15
7
92
91
a
All reactions were carried out with imines 5 (0.50 mmol) and catalyst
b
(0.05 mmol) in benzene (0.50 mL) for 72 h. The conversion was
8
95
96
93
95
94
94
91
90
determined by 1H NMR of the crude reaction mixture based on
c
imines 5. The ee’s were determined by chiral HPLC (Chiralcel OD-H
for entry 3 and Chiralpak AD-H for entries 4–15).
9
amine (C2), acetylamine (C3), diphenylphosphinic amide (C4),
and thiourea (C5) (Table 1, entries 6–9). Catalysts with anilines
were also synthesized and examined for the reaction. A catalyst
with 4-NO2–2,6-diisopropylaniline (C10) gave the highest ee
(89%) (Table 1, entry 14). The ee was further increased to
94% when the reaction temperature was lowered to 20 1C
(Table 1, entry 15). The 2,6-diisopropyl and NO2 groups on
the aniline are beneficial for the enantioselectivity (Table 1,
entries 11–13).
10
11
As shown in Table 2, the asymmetric [1,3]-proton shift
catalyzed by C10 can be applied to a wide variety of trifluoro-
methyl ketimines generated from 2-Cl–4-CN(C6H3)CH2NH2 to
give the corresponding aldimines in 92–99% yield and with up
to 94% ee. Ketimines derived from various substituted 1,1,1-
trifluoro-4-phenylbutan-2-ones gave similarly high ee (Table 2,
entries 1–6), indicating that the substituent on the phenyl
group of the substrate had little effect on the enantioselectivity.
High yield and ee were also obtained for a substrate containing
thiophene (Table 2, entry 7). Trifluoromethyl ketimines with
non-aromatic groups were also found to be effective substrates,
giving the aldimines in 93–99% yield and with 86–94% ee
(Table 2, entries 8–14). The side chains can contain saturated
(Table 2, entries 8 and 9) or unsaturated aliphatic groups (Table 2,
entries 10 and 11) and heteroatoms like O and S (Table 2,
entries 12–14). It is particularly worth mentioning that high
yields were obtained in all these cases. However, lower ee was
obtained with ketimine derived from 2,2,2-trifluoroacetophenone
(Table 2, entry 15).
12
13
8l, X = O
8m, X = S
93
99
86
90
14
94
99
86
67
15
a
All reactions were carried out with imines 7 (0.50 mmol) and catalyst
C10 (0.05 mmol) in benzene (0.50 mL). For entries 1–6, 11 and 15, the
reactions were carried out at 20 1C for 72 h. For entries 7, 8, 10, and
12–14, the reactions were carried out at 35 1C for 72 h. For entry 9, the
reaction was carried out at 35 1C for 72 h and another 24 h at 50 1C.
b
For entries 1 and 15, the absolute configuration (R) was determined by
comparing the optical rotation with the reported ones of the corre-
sponding HCl salt after hydrolysis (ref. 7a). The absolute configurations
of remaining imines were tentatively proposed by analogy. The iso-
lated yield based on imines 7. The ee’s were determined by chiral
HPLC (Chiralpak AD-H column for entries 1, 4–6 and 15; Chiralcel
OD-H column for entries 2, 3 and 13; and Chiralpak AS-H column for
entries 7–12 and 14).
c
d
The resulting aldimines could be readily hydrolyzed to
optically active trifluoromethyl amines. Such an example is shown
in Scheme 2. Chiral trifluoromethyl amine 10 can be obtained
from ketone 9 in 81% overall yield. The Pd-catalyzed cyclization12
of 10 led to chiral 2-trifluoromethyl tetrahydroquinoline 11
Scheme 2
c
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group and consequently enhance the hydrogen bonding. The
(S)-trifluoromethyl aldimine is disfavored probably due to
the unfavorable interaction between the isopropyl group of
the catalyst and the trifluoromethyl group of the substrate in
transition state B.
In summary, we have developed an efficient quinine-derived
chiral base-catalyzed asymmetric [1,3]-proton shift process
for trifluoromethyl ketimines to produce a wide variety of
trifluoromethyl aldimines in 92–99% yield and with up to
94% ee. The resulting aldimine can be readily converted to
optically active trifluoromethyl amine. The current process
further demonstrates that organocatalytic biomimetic transa-
mination provides a useful approach to synthesize optically
active amine derivatives from carbonyl compounds. The develop-
ment of more effective catalytic systems and the expansion of
other carbonyl substrates are currently underway.
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The authors gratefully acknowledge the National Basic
Research Program of China (973 program, 2010CB833300)
and the Chinese Academy of Sciences for the financial support.
Notes and references
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c
1406 Chem. Commun., 2013, 49, 1404--1406
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