Diastereoselective addition of some carbanions to an optically active trifluoromethyl imine derivative

Article abstract of DOI:10.1016/j.jfluchem.2013.03.019

Optically active trifluoromethyl 2-ethoxy-1-phenylethyl-1-imine can react with various carbanions diastereoselectively, and in hetero Diels-Alder addition and in Mannich reaction, it can be derived to the corresponding products with high optical purity.

Full text of DOI:10.1016/j.jfluchem.2013.03.019

Journal of Fluorine Chemistry 152 (2013) 77–80
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Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Diastereoselective addition of some carbanions to an optically active
trifluoromethyl imine derivative
*
Takumi Kagawa , Kana Fujita, Kosuke Kawada
Research Laboratory, TOSOH F-TECH, Inc., 4988 Kaisei-cho, Shunan, Yamaguchi 746-0006, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
Optically active trifluoromethyl 2-ethoxy-1-phenylethyl-1-imine can react with various carbanions
diastereoselectively, and in hetero Diels–Alder addition and in Mannich reaction, it can be derived to the
corresponding products with high optical purity.
Received 9 January 2013
Received in revised form 19 March 2013
Accepted 25 March 2013
Available online 9 April 2013
ß 2013 Elsevier B.V. All rights reserved.
Keywords:
Trifluoromethyl
2-Ethoxy-1-phenylethyl-1-imine
Trifluoroacetaldehyde
Hetero Diels–Alder addition
Mannich reaction
Diastereoselective synthesis
1. Introduction
2. Results and discussion
In recent years, various fluorinated compounds have been
studied and developed in the field of pharmaceuticals [1].
2.1. Hetero Diels–Alder addition of the trifluoromethyl imine (S)-1
Particularly, the interest for fluorinated
increased due to its importance for peptide synthesis [2,3].
Optically active trifluoromethylated -amino acids or its
a
- or
b
-amino acids has
The reaction of the optically active trifluoromethyl imine (S)-1
and 4-methoxy-2-trimethylsililoxy-1,3-butadiene (Danishefsky’s
diene) were reacted in the presence of Lewis acid, however in the
case of Yb(OTf)3 or BF3-OEt2 low diastereoselectivity was observed.
On the other hand, when ZnCl2, ZnBr2, or ZnI2 was used, the
reaction proceeded with high diastereoselectivity and with
moderate yield in non-polar solvents such as CH2Cl2, as shown
in Table 1. However, in those cases, the absolute configuration of
the 6-position on piperidine ring was reversed in the case of using
Yb(OTf)3.
Table 2 shows the influence of the reaction temperature and the
amount of Lewis acid for the case of ZnBr2. No improvement of
diastereoselectivity was observed in a temperature interval from
À40 8C to 40 8C. Moreover, when varying the amount of the Lewis
acid, yield and diastereoselectivity showed the best result at
50 mol% of ZnBr2.
b
derivatives were prepared by diastereoselective addition reac-
tions of optically active imide or imine compounds with various
carbanions. For example, the Mannich reaction of optically
active trifluoromethyl tert-butylsulphinimide [4] and the
Strecker reaction of optically active trifluoromethyl 2-meth-
oxy-1-phenylmethyl-1-imine derived from optically active 2-
methoxy-1-phenylethyl-1-amine (with optically active phenyl-
glycinol as an ingredient) and trifluoroacetaldehyde [5] have
been studied.
This paper presents a study on highly diastereoselective
hetero Diels–Alder reaction and Mannich reaction by using
optically active trifluoromethyl-2-ethoxy-1-phenylethyl-1-im-
ine that is prepared from trifluoroacetaldehyde hydrate (2,2,2-
trifluoroethanediol) and optically active phenyglycinol in high
yield (Fig. 1).
2.2. Mannich reaction of the trifluoromethyl imine (S)-1
As for the reaction of the optically active trifluoromethyl imine
(S)-1 with corresponding lithium enolates prepared from various
* Corresponding author. Tel.: +81 834 62 1300; fax: +81 834 62 1303.
E-mail address: kagawa@f-techinc.co.jp (T. Kagawa).
ester derivatives, the b-lactam derivatives 5 were obtained
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.03.019

78
T. Kagawa et al. / Journal of Fluorine Chemistry 152 (2013) 77–80
EtO
HO
EtO
N
CF
3
CF CH(OH)
3
NH
NH
2
EtI
2
2
up to 76%
(S)-1
Fig. 1. Preparation of the optically active trifluoromethyl imine derivative (S)-1.
Table 1
Hetero Diels–Alder addition of the optically active trifluoromethyl imine (S)-1.
OTMS
O
N
EtO
TMSO
+
Lewis acid
H
+
N
CF
3
Danishefsky's
diene(2.0mol),
solvent
MeO
EtO
N
CF
3
CF
3
EtO
OMe
(S)-1
2
3
.
Ent.
Lewis acid
Solventa
Condition
Yield (%)
Selectivity (de %)
1
2
Yb(OTf)3 (10 mol%)
Yb(OTf)3 (10 mol%)
Yb(OTf)3 (100 mol%)
BF3ÁOEt2 (100 mol%)
BF3ÁOEt2 (100 mol%)
BF3ÁOEt2 (100 mol%)
ZnCl2 (100 mol%)c
ZnCl2 (150 mol%)c
ZnCl2 (150 mol%)c
ZnCl2 (150 mol%)
ZnCl2 (150 mol%)
ZnBr2 (150 mol%)
ZnI2 (150 mol%)
CH3CN
THF
0 8C Â 24 h
60
49
41
8
11b
21b
21b
9b
À20 8C Â 24 h
À40 8C Â 16 h
À80 8C Â 16 h
À80 8C Â 16 h
À40 8C Â 16 h
À20 8C Â 16 h
0 8C Â 16 h
3
THF
4
CH2Cl2
Tol
5
Trace
62
8
–
6
THF
27b
22
50
31
87
96
94
94
7
THF
8
CH2Cl2
Tol
21
7
9
À20 8C Â 16 h
À40 8C Â 16 h
rt  16 h
10
11
12
13
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
22
39
39
41
rt  16 h
rt  16 h
a
The imene (S)-1 (1.30 mmol) in solvent(6 ml).
Anti-form comformation.
b
c
Used a solution of ZnCl2 in THF (0.5 M).
Table 2
Influence of the reaction temperature and of a Lewis acid’s amount.
OTMS
O
N
EtO
TMSO
Lewis acid
+
H
+
N
CF
3
Danishefsky's
diene(2.0mol),
solvent
MeO
EtO
N
CF
3
CF
3
EtO
OMe
(S)-1
2
3
.
Ent.
Lewis acid
Solvent
Condition
Yield (%)
Selectivity (de %)
14
15
ZnBr2 (150 mol%)
ZnBr2 (150 mol%)
ZnBr2 (150 mol%)
ZnBr2 (150 mol%)
ZnBr2 (150 mol%)
ZnBr2 (150 mol%)
ZnBr2 (100 mol%)
ZnBr2 (80 mol%)
ZnBr2 (50 mol%)
ZnBr2 (20 mol%)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
À10 8C Â 16 h
0 8C Â 16 h
rt  16 h
35
32
39
30
39
37
44
41
46
33
96
91
94
97
95
96
97
97
98
96
16
17
40 8C Â 16 h
rt  16 h
18a
19b
20
rt  16 h
rt  16 h
21
rt  16 h
22
rt  16 h
23
rt  16 h
a
2.0 volume of CH2Cl2 was used.
b
1.5 eq. of Danishefsky’s diene was used.

T. Kagawa et al. / Journal of Fluorine Chemistry 152 (2013) 77–80
79
Table 3
Mannich reaction of the optically active trifluoromethyl imine (S)-1.
EtO
EtO
EtO
CF
3
CF
OLi
3
3
CO R
3
1
2
R
R
N
N
H
+
N
CF
+
O
3
o
R
1
2
1
-78 C x 4hrs,
R
R
2
R
R
2
THF(6 ml)
O
(S)-1 (1.30 mmol)
4 (1.56 mmol)
1
2
3
t
1
2
5
6
a R = R = H, R = Bu
a R = R = H
1
2
3
i
1
2
b R = R = H, R = Pr
b R = Me, R = H
1
2
3
1
2
c R = H, R = Cl, R = Me
c R = OPh, R = H
.
Ent.
R1
R2
R3
Yield (%)
Selectivity (de %)
2S/2R
3S/3R
5
6
5
6
5
6
26
30
28
25
24
29
H
H
H
H
H
H
H
H
Cl
H
tBu
iPr
86
56
11
0
0
>99
98
>99
–
–
–
–
–
23
0
>99
–
–
Me
Me
Me
Et
87/13
–
57
68
72
95
–
–
–
–
Me
0
–
>99
>99
80/20
14/86
PhO
3
–
Br
O
Br
N
CF
OTf
3
Et
TfO
OTf
Zn
Et
Yb
CF
O
3
N
1
R
O
-
H
N
C
Li
3
R O
2
R
CF
EtO
3
Fig. 2. Transition state models in Hetero Diels–Alder addition.
Fig. 3. Transition state model for stereoselectivity in Mannich reaction.
diastereoselectively as main products when the ester part was a
derivatives as reactants, syn/anti (S/R) selectivity of the product is
methyl or an ethyl group (Table 3). In contrast, in case of tert-butyl
considered to originate from generation of E/Z mixture of the
ester, open chain
diastereoselectively. On the other hand, when the iso-propyl ester
was used as substrate, a mixture of -lactam derivatives 6 and
open chain -amino acid derivatives 5 was obtained. In the case of
the reaction of the lithium enolate prepared from methyl
propionate, the corresponding -lactam derivative 6 was obtained
b
-amino acid derivatives 5 were obtained
enolate anion (Fig. 3). But in the case of
configuration of 3-position on the -lactam ring was migrated to
stable conformation by the lithium amide of the product 6.
b-lactam derivative 6, the
b
b
b
Therefore, the trans-configuration of the 3- and 4-position on b-
lactam was mainly produced.
b
The progress of cyclization to the b
-lactam is depended on R2
with high diastereoselectivity in 68% yield, and the (3S, 4S)-
configurated product was formed mainly.
and R3 groups. For example, because the distance between anions
on the nitrogen and carbon atom in the carbonyl group increases
when both of R2 and R3 are bulky groups, the production of cyclic
compounds is prohibited.
3. Discussion
3.1. Hetero Diels–Alder addition of the trifluoromethyl imine (S)-1
4. Conclusions
In the case of the hetero Diels–Alder reaction using Yb(OTf)3 or
BF3-OEt2 as a Lewis acid, the low selectivity might be explained by
metal chelation only on a lone pair of the nitrogen, so the EtOCH2
In hetero Diels–Alder addition and in Mannich reaction,
optically active trifluoromethyl 2-ethoxy-1-phenylethyl-1-imine
can react with high diastereoselectively.
group does weakly shield the
a-face of the transition state.
On the other hand, when the zinc halide is used as the Lewis
acid, the reason of high selectivity is considered that zinc was
chelated on a lone pair of the nitrogen and a lone pare of oxygen as
a five-membered ring system, so the phenyl group was strongly
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.jfluchem.2013.03.019.
shielded at the
b-face of the transition state (Fig. 2).
3.2. Mannich reaction of the trifluoromethyl imine (S)-1
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