Journal of Fluorine Chemistry
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.
ester derivatives, the b-lactam derivatives 5 were obtained
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.