Enantioselective henry reactions catalyzed by chiral N-metal complexes containing R(+)/S(-)-α-ethylphenyl amines

Article abstract of DOI:10.1016/j.tetlet.2010.08.055

A series of novel N-metal complexes containing chiral α-ethylphenyl amines was synthesized and they catalyzed asymmetric Henry reactions affording products with high enantioselectivity.

Full text of DOI:10.1016/j.tetlet.2010.08.055

Tetrahedron Letters 51 (2010) 5577–5580
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Tetrahedron Letters
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Enantioselective henry reactions catalyzed by chiral N-metal complexes
containing R(+)/S(ꢀ)-
a-ethylphenyl amines
Mei Luo a, , Bing Yan b,c,
⇑
⇑
a Hefei University of Technology, Hefei, Anhui 230009, China
b St. Jude Children Research Hospital, Memphis, TN 38105, USA
c School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel N-metal complexes containing chiral a-ethylphenyl amines was synthesized and they
catalyzed asymmetric Henry reactions affording products with high enantioselectivity.
Received 26 July 2010
Revised 15 August 2010
Accepted 17 August 2010
Available online 21 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Organometallic complexes have been widely used in catalyzing
organic and polymer synthesis.1–17 Recently, it has been reported
that zinc and copper complexes can also catalyze Henry reac-
tion,18–28 as we all know, Henry reaction is a powerful synthetic
tool for the construction of complex molecules, and good results
have been reported in the literature.24,29–32 For example, Shibasaki
reported the first efficient method by making use of the two-center
catalysis29 and Trost revealed a novel family of dinuclear zinc com-
plexes30 catalyzing the reaction between nitromethane and alde-
hydes. Subsequently, Evans’s copper acetate–bis(oxazoline)
catalyst31 and Palomo’s zinc triflate–amino alcohol complex32
were both found to effectively catalyze the Henry reaction by con-
current activation. However, some of the catalysts still showed
limitations such as moisture or air sensitivity,33 requirement for
high catalyst loading,33 low temperature to ꢀ45 °C,34–36 uncertain
structure of the catalysts24,29,30,32 or multi-step procedures.26
These studies inspired us to develop novel chiral ligands and eval-
uate the catalytic utility of our catalysts–organometallic complexes
Using 15 mol % of catalysts 1a–c and 2a–c products 3 and 4
were produced in moderate conversion and excellent enantioselec-
tivity (Table 1) in product 3. In this reaction, the overall conversion
rate was high, but 3 was prone to dehydration and formed 4. Prod-
ucts 3 and 4 were all characterized by 1H NMR. The configuration
of 4a–l was identified as E-type by 1H NMR experiments. The re-
sults were confirmed by X-ray crystallography study of 4i.
In order to get the optimized conditions, we reduced the
amount of catalysts to 15 mol %, the scope of the reaction was fur-
ther explored at room temperature. Products generally showed
high conversion (>99%) and enantioselectivity (82–99%). Notably,
2- and 4-substituted benzaldehydes bearing electron-withdrawing
dry ethanol
reflux
containing chiral
a-phenylethylamine in Henry reaction and the
high enantioselectivity of Henry reaction products were achieved.
First, we synthesized novel complexes 1a, 2a or 1b, 2b
yield%:89.5%
yield%:74.5%
yield%:51.6%
(Scheme 1) by reacting R(+)/S(ꢀ)-
a-ethylphenyl amine with zinc
acetate dihydrate or copper acetate hydrate. The crystal structures
of complexes were determined after they were recrystallized from
hexane. Similarly, complexes 1c and 2c were synthesized by react-
ing R(+)/S(ꢀ)-
a-ethylphenyl amine with cupric chloride in abso-
dry ethanol
reflux
lute ethanol. Their crystal structures were determined after
sitting at room temperature for several days. In summary, we ob-
tained 1a–c and 2a–c in moderate to high yields and determined
their crystal structure. Then we compared their catalytic activities
in asymmetric Henry reactions (Table 1).
yield%:86.8%
yield%:80.1%
yield%:53.4%
⇑
Corresponding authors.
E-mail address: bing.yan@stjude.org (B. Yan).
Scheme 1. N-Metal complexes with chiral a-ethylphenyl amine
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.055

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M. Luo, B. Yan / Tetrahedron Letters 51 (2010) 5577–5580
Table 1
Catalysis of asymmetric Henry reactionsa
OH
O
H
NO2
H
NO2
15 mol% catalyst 1 or 2
-H2O
H
+
CH3NO2
CH3OH, 72h
3
4
b
½ ꢁ
a 2D5
Complex
Conv.%b (3)
Yield% (4)
eec (%)
Config.d
1a
1b
1c
2a
2b
2c
99
99
99
99
99
99
32
39
46
35
30
43
85
70
96
90
83
67
+38.8
+34.2
+43.8
+41.0
ꢀ36.40
+31.0
S
S
S
S
R
S
a
b
c
Reactions were carried out with 1 mmol PhCHO and 0.5 mL CH3NO2 in 5 mL CH3OH using 15 mol % of catalyst 1 or 2 at room temperature for 72 h.
Isolated yields after flash chromatography.
Determined by HPLC analysis using a Chiralcel OD-H column with a mobile phase of hexane/isopropanol 9:1.
d
The absolute configuration of the major product was assigned by comparing with the literature values.19,24–37,28a
Table 2
Catalysis of asymmetric Henry reactionsa,31,33–37
OH
O
H
NO2
H
NO2
15mol% catalyst 2b
-H2O
H
+
CH3NO2
CH3OH, 72h
R
R
R
3a-l
4a-l
ee%c (3)
Entry
Products
Conv.%
>99
Yield%b (4)
Config.d
OH
OH
NO2
NO2
3a
40
83
98
R
3b
3c
3d
3e
3f
>99
>99
>99
>99
>99
>99
47
28
30
29
29
34
S
S
CH3
OH
NO2
NO2
82
88
OCH3
OH
e
—
F
OH
NO2
OH
97
S
S
S
Br
NO2
>99
>99
H3C
OH
NO2
3g
H3CO

M. Luo, B. Yan / Tetrahedron Letters 51 (2010) 5577–5580
5579
Table 2 (continued)
Entry
Products
Conv.%
>99
Yield%b (4)
ee%c (3)
Config.d
OH
NO2
NO2
NO2
3h
3i
40
88
S
F
OH
>99
>99
55
40
82
86
S
Cl
OH
e
3j
—
Br
NO2
HO
3k
>99
>99
30
27
>99
60
S
OH
NO2
3l
R
a
Reactions were carried out with 1 mmol PhCHO and 0.5 mL CH3NO2 in 5 mL CH3OH using 15 mol % of catalyst 2b at room temperature for 72 h.
Isolated yields after flash column.
Determined by HPLC analysis using a Chiralcel OD-H column with a mobile phase of hexane/isopropanol 9:1.
The absolute configuration of the major product was S/R, as assigned by comparing HPLC with the literature.26–37,28a
The absolute configuration of the major product was not determined.
b
c
d
e
References and notes
H
R
R
CH NO
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.08.055.

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