Enantioselective addition of diethylzinc to aromatic aldehydes catalyzed by new chiral oxazolidine ligand

Article abstract of DOI:10.1081/SCC-200063964

The chiral oxazolidine ligand can catalyze the enantioselective addition of diethylzinc to aromatic aldehydes at room temperature with high enantioselectivity (98-99% ee). The conditions for this catalytic process are both mild and simple as compared with the same kind catalyst. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200063964

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Synthetic Communications , 35: 1819–1823, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200063964
Enantioselective Addition of Diethylzinc to
Aromatic Aldehydes Catalyzed by New
Chiral Oxazolidine Ligand
Yong-feng Kang and Lei Liu
Department of Biochemistry & Molecular Biology, School of Life
Sciences, Lanzhou University, Lanzhou, China
Rui Wang
Department of Biochemistry & Molecular Biology, School of Life
Sciences, Lanzhou University, Lanzhou, China and State Key Laboratory
for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of
Chemical Physics, Chinese Academy of Sciences, Lanzhou, China
Ming Ni and Zhi-jian Han
Department of Biochemistry & Molecular Biology, School of Life
Sciences, Lanzhou University, Lanzhou, China
Abstract: The chiral oxazolidine ligand can catalyze the enantioselective addition of
diethylzinc to aromatic aldehydes at room temperature with high enantioselectivity
(98–99% ee). The conditions for this catalytic process are both mild and simple as
compared with the same kind catalyst.
Keywords: Oxazolidine, addition, diethylzinc, aldehydes, enantioselectivity
[1–3]
Enantioselective additions of organozinc reagents to carbonyl compounds
allow the synthesis of chiral alcohols that are ubiquitous in the structures of
natural products and drug compounds. They are also important precursors to
many other functional organic molecules. The chiral ligands play a key role
Received in Japan January 11, 2005
Address correspondence to Rui Wang, Department of Biochemistry & Molecular
Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
Tel.: þ86-931-891-2567; Fax: þ86-931-891-2561; E-mail: wangrui@lzu.edu.cn
1
819

1820
Y.-f. Kang et al.
in this asymmetric catalytic reaction. Although there has been much interest in
the design of new ligands, there has been a trend of using the same ligand in
different asymmetric catalytic reactions at present. Since the initial report of
[4]
the reaction of diethylzinc with benzaldehyde in 1984, numerous elegant
and efficient catalysts have been developed for this purpose. Among these
[
5]
catalysts, only BINOL has resulted in an exciting result for the asymmetric
addition of terminal alkyne to aldehydes and ketones and the asymmetric
addition of diethylzinc to aldehydes. In this article we report another
example of chiral ligand catalyzing these three kinds of reactions.
In our previous work, we conveniently synthesize a new chiral oxazolidine
ligand 1 from natural amino acid and high ee was obtained in the addition of
[6]
terminal alkyne to aldehydes and ketones (Scheme 1). Now we communicate
that the oxazolidine 1 promotes the asymmetric addition of diethylzinc to
aromatic aldehydes with good yields and high enantioselectivity (Tables 1
and 2). We found that the catalytic activity of oxazolidine 1 in the addition
of diethylzinc with aldehydes was the highest among the three kinds reactions.
Some examples of the direct use of the chiral oxazolidine ligands or chiral
[
7]
oxazolidinyl alcohols in combination with metal salts in asymmetric
addition of the diethylzinc to aldehydes have already been reported, but
chiral oxazolidine ligand 1 has more excellent properties as compared with
them. We have found a) to our surprise, the coordination of oxazolidine
ligand with diethylzinc in this reaction completes under room temperature
[7c]
as distinguished from the high temperatures in the literature,
and this
will simplify the working processes of the asymmetric reaction of diethylzinc
to aldehydes; b) for most aldehydes, 99% ee values were obtained when the
amount of ligand was only 3% equiv. and the amount of diethylzinc was
only 140% equiv.; c) and the mild conditions and the wide-ranging category
of solvent of the asymmetric reaction will be useful in industry.
The catalytic properties of ligand 1 in asymmetric addition of diethylzinc
to benzaldehyde were explored (Table 1). (General addition procedures: Under
argon, to a solution of the ligand 1 (0.0075 mmol, 2.6 mg) in ether (2 ml), was
added a solution of Et Zn (0.35 mmol, 1.0 M in toluene, 0.35 mL) at room
2
temperature. After the mixture was stirred at room temperature for 2 h,
Scheme 1.

Addition of Diethylzinc to Aromatic Aldehydes
1821
Table 1. Addition diethylzinc to benzaldehyde using 1 as ligand
Ligand 1
(mol%)
ZnEt2
(mol%)
Solvent
(0.35 mL/2 mL)
Ee
(%)
a
Entry
Temp (8C)
b
1
2
3
4
5
6
7
8
9
10%
10%
10%
10%
10%
10%
10%
10%
10%
2%
200
200
200
200
200
300
140
120
140
140
140
Tol
0
0
0
0
0
0
0
0
84
63
96
89
89
87
97
91
99
45
99
2 2
Tol–CH Cl
Tol–ether
Tol–THF
Tol–hexane
Tol–ether
Tol–ether
Tol–ether
Tol–ether
Tol–ether
Tol–ether
c
rt
1
1
0
1
rt
rt
3%
a
The enantiomeric excess was determined by HPLC analysis of the corresponding
products on a Chiralcel OD column.
b
Tol ¼ toluene.
c
rt ¼ room temperature.
the solution was cooled to 08C and treated with aldehyde (0.25 mmol, 25 mL),
and then the resultant mixture was stirred for 48–72 h at room temperature.
After the reaction was complete as checked by TLC, it was cooled to 08C
and quenched by 2% aqueous HCl. The mixture was extracted with ether.
The organic layer was washed with brine, dried over Na SO , and concentrated
2
4
under vacuum. The residue was purified by flash column chromatography
(
silica gel, 12.5% EtOAc in hexane) to give the product.)
We varied the category of solvent on this reaction in the first place and
found that this reaction was slightly influenced by the solvent (entries 1–5).
Moderate ee values were obtained in toluene CH Cl (63% ee, entry 2),
2
2
high ee values were obtained in toluene–ether (96% ee, entry 3), and the
others were between 84% and 89% ee, so toluene–ether was the best
solvent. We then examined the effect of amount of ZnEt on this reaction,
2
and found decreasing the amount of ZnEt from 300 mol% to 140 mol%
2
gave higher ee, but further decreasing the amount of ZnEt to 120 mol% led
2
to a decrease in ee values. So, the appropriate amount of ZnEt2 was
1
40 mol% (entries 3, 6–8). We examined the effect of temperature on this
reaction, but found decreasing the reaction temperature from room tempera-
ture to 08C led to decreased ee values (entries 7, 9). Increaseing the amount
of ligand led to higher enantioselectivity (entries 9–11).
Under such optimized reaction conditions, ligand 1 was employed to
induce the enantioselective addition of diethylzinc to a family of aromatic

1822
Y.-f. Kang et al.
Table 2. Asymmetric addition diethylzinc to aromatic aldehydes promoted by
a,b
ligand 1
Isolated
yield (%)
c
Ee (%)
d
Entry
Aldehydes
benzaldehyde
3-anisaldehyde
Time (h)
Config.
1
2
3
4
5
6
7
8
9
72
48
72
48
72
72
72
72
72
80
75
82
76
80
71
75
84
87
99
98
S
S
S
S
S
S
S
S
S
e
4-anisaldehyde
99
99
e
3-bromobenzaldehyde
4-bromobenzaldehyde
4-chlorobenzaldehyde
4-fluorohenzaldehyde
a-naphthaldehyde
b-naphthaldehyde
98
99
f
98
99
f
99
a
In all of the entries: Et Zn–aldehyde–1 ¼ 1.4: 1.0:0.03.
2
b
c
All the reactions were processed under argon and at rt.
The ee values were determined by chiral HPLC with Chiracel OD column.
d
Assigned by the retention time of the major peak of the isomers and the direction of
[
1c,1d]
optical rotation with the literature.
e
Ligand 1 (10 mol%) was used.
Ligand 1 (5 mol%) was used.
f
aldehydes. All the aldehydes afforded high enantioselectivity and the ee value
was up to 99% (Table 2).
Although the mechanism of the reaction is still not clear, but the experi-
mental outcome from the ligand 1 shows that the product is in the S configura-
tion (Table 2); this is consistent with the behavior speculated by us. An
empirical model is shown in Figure 1; it may be helpful to explain the
influence of structure of the ligand on the transition state and the configuration
of the product.
In conclusion, we have successfully described the second ligand catalyz-
ing three kinds reaction of organozinc with carbonyl compounds. The oxazo-
lidine 1 has excellent catalytic activity for the asymmetric addition
of diethylzinc to aromatic aldehydes under very mild condition with 98–
99% ee. As compared with the same kind catalysts, the coordination of
oxazolidine ligand 1 with diethylzinc in this reaction does not require
Figure 1. Possible mechanism of addition of diethylzinc to aldehydes.

Addition of Diethylzinc to Aromatic Aldehydes
1823
heating, the amount of ligand 1 is only 3% equiv., and the amount of diethyl-
zinc was only 140% equiv.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China (Nos.
2
0372028, 20472026), the Ministry of Science and Technology of China,
the Teaching and Research Award Program for Outstanding Young
Teachers, and the Specialized Research Fund for the Doctoral Program in
Higher Education Institutions of the Ministry of Education of China.
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