Enantioselective α-hydrazination of α-fluoro-β-ketoesters catalyzed by chiral nickel complexes

Article abstract of DOI:10.1016/j.jfluchem.2008.11.001

The catalytic enantioselective electrophilic α-hydrazination promoted by chiral nickel complexes is described. Treatment of α-fluoro-β-ketoesters with azodicarboxylates as electrophilic amination reagents under mild reaction conditions afforded the corres

Full text of DOI:10.1016/j.jfluchem.2008.11.001

Journal of Fluorine Chemistry 130 (2009) 259–262
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Journal of Fluorine Chemistry
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Short communication
Enantioselective
a
-hydrazination of
a
-fluoro-b-ketoesters catalyzed
by chiral nickel complexes
*
Joo Yang Mang, Dae Gil Kwon, Dae Young Kim
Department of Chemistry, Soonchunhyang University, Asan, Chungnam 336-745, Republic of Korea
A R T I C L E I N F O
A B S T R A C T
Article history:
The catalytic enantioselective electrophilic
a-hydrazination promoted by chiral nickel complexes is
Received 30 September 2008
Received in revised form 10 November 2008
Accepted 19 November 2008
Available online 27 November 2008
described. Treatment of -fluoro- -ketoesters with azodicarboxylates as electrophilic amination
a
b
reagents under mild reaction conditions afforded the corresponding
with high yields (80–96%) and enantioselectivities (up to 78% ee).
a-amino a-fluoro-b-ketoesters
ß 2008 Elsevier B.V. All rights reserved.
Keywords:
Nickel complexes
Hydrazination
Asymmetric reactions
a-Fluoro-b-ketoesters
1. Introduction
efficient asymmetric amination reactions using chiral Lewic acids
have been developed, a drawback is that most Lewis acids are
unstable in the presence of water and even sensitive to moisture.
Therefore, the development of amination reaction using moisture-
stable chiral Lewis acid is still in great demand.
Chiral organofluorine compounds containing a fluorine atom
bonded directly to a stereogenic center have been utilized in
studies of enzyme mechanisms and as intermediates in asym-
metric syntheses [1]. The development of effective methodologies
for the preparation of new selectively fluorinated, stereochemi-
cally defined compounds is critical to further advances of fluorine
chemistry [2]. Fluorinated amino acids are becoming increasingly
important in pharmaceuticals and other biological applications [3]
such as the development of anticancer drugs for the control of
tumor growth, drugs for control of blood pressure and allergies [4],
enzyme inhibitors [5]. The catalytic enantioselective electrophilic
2. Results and discussion
As part of research program related to the development of
synthetic methods for the enantioselective construction of
stereogenic carbon centers [12], we report the catalytic enantio-
selective amination of ester derivatives promoted by organocata-
lyst or chiral palladium complexes [7]. In this communications, we
amination of
the synthesis of chiral
a
-substituted esters seems to be alternate method for
-amino acid derivatives. The catalytic,
wish to report the direct a-hydrazination of a-fluoro-b-ketoesters
a
catalyzed by air- and moisture-stable chiral nickel complexes [13]
with azodicarboxylates as the electrophilic nitrogen source.
To determine optimum reaction conditions for the catalytic
enantioselective, direct C–N bond formation reaction of active
methine compounds represents an efficient and the simplest
procedures to generate stereogenic carbon center attached to a
nitrogen atom [6]. Several groups presented the direct enantio-
enantioselective electrophilic amination of
using air- and moisture-stable chiral nickel complexes 4 (Fig. 1),
we initially investigated the reaction of -fluoro benzoylacetate 1
a-fluoro-b-ketoesters
selective amination of active methine compounds such as
ketoester [7], -ketophosphonates [8], -cyanoacetates [9], and
-cyanoketones [10] in the presence of chiral metal complexes
or organocatalysts. Recently, Togni reported hydrazination of
-fluoro- -ketoesters using chiral Cu-bisoxazoline complexes
afforded -fluoro- -hydrazino- -ketoesters [11]. While several
b-
a
b
a
with azodicarboxylates 2 as the electrophilic aminating agent in
the presence of 5 mol% of catalyst in toluene at room temperature.
We first examined the nature of ester group of azodicarboxylates
on enantioselectivity (Table 1, entries 1–4). When employing t-
butyl azodicarboxylate (2d), the corresponding aminated adduct
3ad was isolated with high enantioselectivity of 69% ee (entry 4).
Concerning the solvent (entries 4–12), the use of toluene gave
the best results in the yield and the enantiomeric excess
(entry 4). We examined the impact of the structure of catalysts
a
a
b
a
a
b
* Corresponding author. Tel.: +82 41 530 1244; fax: +82 41 530 1247.
E-mail address: dyoung@sch.ac.kr (D.Y. Kim).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.11.001

260
J.Y. Mang et al. / Journal of Fluorine Chemistry 130 (2009) 259–262
on enantioselectivity (entries 4 and 13–21). The high selectivity
was obtained with catalysts 4i, which is prepared from 1,2-
diaminocyclohexane with p-fluorobenzaldehyde.
To examine the generality of the catalytic enantioselective
amination of
stable chiral nickel complex 4i, we studied the amination of
various -fluoro- -ketoesters 1a–f. As it can be seen by the results
summarized in Table 2, the corresponding -aminated
a-fluoro-b-ketoesters 1 using air- and moisture-
a
b
a
b-
ketoesters 3ad–fd were obtained in high yields (80–96%) and
enantioselectivities (61–74% ee).
To show substrate scope of the catalytic enantioselective
Fig. 1. Structure of chiral Ni(II) complexes.
amination of
b-ketoester derivatives 1g–j by using chiral nickel
Table 1
Optimization of the reaction conditions.
.
Entry
2, R
Cat.
Solvent
Time (h)
Yielda (%)
eeb (%)
1
2a, Et
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
Toluene
Toluene
Toluene
Toluene
Benzene
p-Xylene
Hexane
Pentane
THF
15
20
15
20
20
25
22
21
23
22
22
20
22
20
20
20
21
20
25
25
22
91
85
80
73
50
50
51
54
50
72
66
63
80
84
78
89
87
85
78
86
79
57
51
57
69
63
43
63
61
57
57
51
35
17
25
5
2
2b, i-Pr
2c, Bn
3
4
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
2d, t-Bu
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
1,4-Dioxane
Ether
EtOH
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
21
23
51
30
73
63
4g
4h
4i
4j
a
Yield of isolated product.
b
Enantiopurity of 3 was determined by HPLC analysis with Chiralpak AD column.
Table 2
Catalytic enantioselective amination of
a-fluoro-b-ketoesters 1.
.
Entry
1, R
Time (h)
Yield (%)
eea (%)
1
1a, H
20
28
26
14
28
34
3ad, 86
3bd, 84
3cd, 81
3dd, 84
3ed, 80
3fd, 80
73
73
74
65
65
61
2
1b, p-OMe
1c, p-CF3
1d, p-Me
1e, p-Br
1f, m-Br
3
4b
5b
6
a
Enantiopurity of 3 was determined by HPLC analysis with Chiralpak AD column.
Reaction carried out using catalyst 4a.
b

J.Y. Mang et al. / Journal of Fluorine Chemistry 130 (2009) 259–262
261
Scheme 1.
complex 4i, we studied the amination of aliphatic
ketoesters 1g–h and cyclic -ketoesters 1i–j. As it can be seen by
the results summarized in Scheme 1, the corresponding
aminated -ketoester derivatives 3g–j were obtained in excellent
a
-fluoro-
b
-
Technology Foundation (KOTEF) through the Human Resource
Training Project for Regional Innovation.
b
a
-
b
References
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a
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a
-hydrazination of
a-fluoro-b-ketoe-
sters 1: a mixture of -fluoro-
a
b
-ketoester 1 (0.2 mmol) and
catalyst 4i (8.79 mg, 0.01 mmol) in toluene (0.12 mL) was stirred
for 10 min. A solution of t-butyl azodicarboxylate (2, 46.05 mg,
0.4 mmol) in toluene (0.2 mL) was added dropwise over a period of
5 min. The reaction mixture was stirred for 14–34 h at room
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ꢀ
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