New chiral Schiff base as a tridentate ligand for catalytic enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1021/jo060964u

We have developed new chiral Schiff base catalysts for the enantioselective addition of diethylzinc reagents to aldehydes. The reaction of benzaldehyde with diethylzinc in the presence of 1 mol % of the chiral Schiff base catalyst proceeded to afford 1-phenyl-1-propanol in 96% enantiomeric excess (ee).

Full text of DOI:10.1021/jo060964u

SCHEME 1. Synthesis of the Chiral Schiff Base
New Chiral Schiff Base as a Tridentate Ligand
for Catalytic Enantioselective Addition of
Diethylzinc to Aldehydes
Takanori Tanaka, Yorinobu Yasuda, and Masahiko Hayashi*
Department of Chemistry, Faculty of Science, Kobe UniVersity,
Kobe 657-8501, Japan
mhayashi@kobe-u.ac.jp
ReceiVed May 9, 2006
TABLE 1. Effect of Substituents in the Schiff Base on the
Asymmetric Addition to Benzaldehydea
entry
ligand
R1
% yieldb
% eec,d
1
2
3
4
5
6
7
8
9e
4a
5a
4b
5b
4c
5c
4d
4e
5e
H
H
Me
Me
Ph
Ph
36
53
84
90
95
94
90
93
92
18
21
88
94
90
96
86
87
95
We have developed new chiral Schiff base catalysts for the
enantioselective addition of diethylzinc reagents to aldehydes.
The reaction of benzaldehyde with diethylzinc in the presence
of 1 mol % of the chiral Schiff base catalyst proceeded to
afford 1-phenyl-1-propanol in 96% enantiomeric excess (ee).
4-tBu-C6H4
â-Np
â-Np
a Conditions: PhCHO/Et2Zn/Schiff base ) 1.0:2.0:0.05, 0 °C, 24 h.
b Determined by 1H NMR analysis after silica gel column chromatography.
c Determined by HPLC using a chiral OD-H column (DAICEL). d Absolute
configuration was determined as R by comparison of the optical rotation
values with those in the literature.9 e 1 mol % of Schiff base was used.
Since the first discovery by Oguni and Omi in 1984,1 there
have been many reports on enantioselective addition of dialkyl-
zinc to aldehydes. Most of them are catalyzed by bidentate
â-amino alcohol or its derivatives.2,3 To our knowledge, there
are only three reports using tridentate ligands;4 furthermore, all
of them afforded the alkylated products in lower enantiomeric
excess (ee). For example, Corey and Hannon reported enantio-
selective ethylation of benzaldehyde catalyzed by a tridentate
ligand derived from (+)-pseudoephedrine to give 1-phenyl-1-
propanol in 87% ee.4a In this paper, we report that our developed
tridentate chiral Schiff base catalyzed the alkylation of aldehydes
to give the alkylated products in high ee (up to 96% ee).5
The chiral Schiff bases used in our alkylation were prepared
according to the procedure shown in Scheme 1. The crucial
step was the oxidation of alcohol 2 to ketones 3; that is, the
conventional method using CrO3 afforded ketones only in low
yield (25-35%) because of oxidative decomposition of the
phenolic moiety. Fortunately, this oxidation problem was over-
come by a hydrogen transfer reaction using a Pd/C-ethylene
system.6 By the use of 30 wt % of 10% Pd/C under an ethylene
atmosphere, we obtained a high yield (83%) of ketone in the
case of R1 ) Ph. Thus, the obtained ketones 3 were condensed
with chiral â-amino alcohols that are now prepared by direct
reduction of R-amino acid as developed by Meyers7 and Abiko.8
We examined the reaction of benzaldehyde with diethylzinc
in the presence of 5 mol % of chiral Schiff bases in hexane.
Hexane or toluene was the choice for this reaction after
screening of the solvent effect. The obtained results are
summarized in Table 1. As shown in entry 6, the Schiff base
5c derived from L-tert-leucinol and 3-tert-butyl-2-hydroxyben-
zophenone afforded (R)-1-phenyl-1-propanol in 94% yield and
96% ee. When the amount of chiral Schiff base 5c was decreased
to 1 mol %, the same level of chemical yield and enantiomeric
excess were obtained (Table 2, entry 1).
* To whom correspondence should be addressed. Fax: +81-78-803-5688.
(1) Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823-2824.
(2) (a) Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M.; Oguni,
N.; Hayashi, M.; Kaneko, T.; Matsuda, Y. J. Organomet. Chem. 1990, 382,
19-37. (b) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991,
30, 49-69. (c) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833-856. (d) Pu,
L.; Yu, H.-B. Chem. ReV. 2001, 101, 757-824.
The effect of the tert-butyl group at the ortho position on the
phenolic hydroxy group should be mentioned. That is, in the
case of the use of 5 mol % of Schiff base without a tert-butyl
(3) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley
& Sons, Inc.: New York, 1994; Chapter 5.
(4) (a) Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1987, 28, 5237-
5240. (b) Cherng, Y.-J.; Fang, J.-M.; Lu, T.-J. J. Org. Chem. 1999, 64,
3207-3212. (c) Danilova, T. I.; Rozenberg, V. I.; Sergeeva, E. V.; Starikova,
Z. A.; Bra¨se, S. Tetrahedron: Asymmetry 2003, 14, 2013-2019.
(5) (a) Hayashi, M.; Tanaka, K.; Oguni, N. Tetrahedron: Asymmetry
1995, 6, 1833-1836. (b) Hayashi, M.; Yoshimoto, K.; Hirata, N.; Tanaka,
K.; Oguni, N.; Harada, K.; Matsushita, A.; Kawachi, Y.; Sasaki, H. Isr. J.
Chem. 2001, 41, 241-246.
(6) (a) Hayashi, M.; Yamada, K.; Nakayama, S. Synthesis 1999, 1869-
1871. (b) Hayashi, M.; Yamada, K.; Nakayama, S. J. Chem. Soc., Perkin
Trans. 1 2000, 1501-1503.
(7) (a) McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M. J. Org.
Chem. 1993, 58, 3568-3571. (b) Poindexter, G. S.; Meyers, A. I.
Tetrahedron Lett. 1977, 18, 3527-3528.
(8) Abiko, A.; Masamune, S. Tetrahedron Lett. 1992, 33, 5517-5518.
10.1021/jo060964u CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/05/2006
J. Org. Chem. 2006, 71, 7091-7093
7091

SCHEME 2. Effect of the tert-Butyl Group at the Ortho
Position on the Phenolic Hydroxy Group
TABLE 2. Asymmetric Addition to Various Aldehydesa
FIGURE 1. Nonlinear effect in the catalytic enantioselective ethylation
of benzaldehyde in the presence of 5c. Conditions: PhCHO/Et2Zn/
Schiff base ) 1.0:2.0:0.01, 0 °C, 24 h. The ee was determined by HPLC
using a chiral OD-H column (DAICEL).
entry
R
% yieldb
% eec,d
1
2
3
4
5
6
7
8
9
Ph
88 (86)
92
96 (90)
69 (55)
85
75 (81)
45
67
96 (95)
90
80 (84)
75 (76)
60
In the cases of DAIB and PDB reported by the Noyori11 and
Oguni12 groups, the difference in stability between the het-
erodimeric zinc complex and the homodimeric zinc complex
was explained; that is, the easiness of dissociation in the
presence of aldehydes caused a high nonlinear effect.
However, in our tridentate ligand case, the origin of the
observed nonlinear effect is unclear at present and is now under
investigation.
4-Cl-C6H4
4-MeO-C6H4
(E)-PhCHdCH
PhCtC
PhCH2CH2
n-C5H11
c-C6H11
2-furyl
2-thienyl
81 (83)
81e
94e
82
99
90e
10
95e
a Conditions: RCHO/Et2Zn/Schiff base ) 1.0:2.0:0.01, 0 °C, 24 h. The
values in parentheses indicated the one when toluene was used as a solvent.
b Isolated yield after Kugelrohr distillation. c Determined by HPLC analysis
using a chiral OD-H column (DAICEL). d All absolute configurations were
determined as R by comparison of the optical rotation values with those in
the literature.9 e Determined by HPLC analysis of the corresponding
benzoate using a chiral AD-H column (DAICEL).
As for the reaction mechanism, we carefully confirmed by
1H NMR analysis that two of the ethyl groups in diethylzinc
reacted with both hydroxy groups in Schiff base (phenolic and
amino alcohol) resulting in the disappearance of the ethyl groups
in diethylzinc. Therefore, the ethyl groups should add to
aldehyde activated by the chiral zinc Schiff base as an ethyl
transfer from diethylzinc.
group at the ortho position, the opposite enantiomer S was
obtained in 91% yield and 57% ee (Scheme 2). These results
mean that from the single stereogenic center of tert-leucine both
enantiomers were obtained in good to high ee in the case of
R1 ) Ph (when 10 mol % of Schiff base without a tert-butyl
group was used, 63% ee of the S-product was obtained in 90%
yield).
Experimental Section
Oxidation of Alcohol 2 by the Pd/C-Ethylene System. A dry
Schlenk tube under an ethylene atomosphere was charged with
alcohol 2 (R1 ) Ph, 3.9 g, 15.2 mmol) and acetonitrile (20 mL).
To this mixture was added 10% Pd/C (1.17 g). The mixture was
stirred vigorously at 80 °C for 7 h under an ethylene atmosphere
using a balloon (1 atm). After confirmation of completion of the
reaction by TLC, the palladium precipitate was filtered off. After
removal of the solvent, the residue was column chromatographed
on silica gel using hexane as an eluent to afford the corresponding
We then examined the reaction of a variety of aldehydes with
diethylzinc in the presence of 1 mol % of 5c in hexane at 0 °C
(Table 2). It should be noted that the present zinc-Schiff base
catalyst system is effective not only for aromatic aldehydes but
also for aliphatic aldehydes. For example, the reaction of
cyclohexanecarbaldehyde with diethylzinc aided by 1 mol
% of chiral Schiff base 5c gave the ethylated product in 94%
ee.10
ketone 3 (R1 ) Ph, 3.2 g, 12.6 mmol, 83%) as a yellow oil. H
1
NMR (400 MHz, CDCl3): δ 1.47 (s, 9H), 6.79 (t, J ) 7.8 Hz,
1H), 7.44 (dd, J ) 7.8 Hz, 1.6 Hz, 1H), 7.50 (m, 2H), 7.57 (s,
1H), 7.66 (d, J ) 6.8 Hz, 1H), 12.9 (brs, 1H). 13C NMR (100.6
MHz, CDCl3): δ 29.2, 34.9, 119.2, 120.6, 132.0, 134.1, 138.2,
161.2, 197.2.
We also examined the nonlinear effect (asymmetric ampli-
fication) in our zinc-Schiff base system. Actually, the nonlinear
effect was observed as shown in Figure 1. The degree of
amplification, however, is not so remarkable compared with the
case of DAIB11 and PDB.12 It is ascertained that aggregation
of the zinc species should participate in the catalytic cycle.
General Procedure for Asymmetric Ethylation (Table 2). To
a solution of chiral Schiff base (0.018 mmol) in solvent (4 mL) at
-40 °C was added diethylzinc (0.37 mL, 3.6 mmol). The solution
was warmed to 0 °C, stirred for 30 min, and then cooled to -40
°C again, when aldehyde (1.8 mmol) was added. The mixture was
stirred for 24 h at 0 °C and was then quenched by 1 N HCl aq (20
mL). After extraction with diethyl ether (20 mL × 3), silica gel
column chromatography [eluent, hexanes-ethyl acetate (10:1)], and
Kugelrohr distillation, a product was obtained. The ee was
determined by HPLC analysis using a chiral column.
(9) For determination of the absolute configuration of the products. See
Supporting Information.
(10) The reaction of dimethylzinc with benzaldehyde in the presence of
5 mol % of 5c in hexane afforded (R)-1-phenylethanol in 72% yield and in
64% ee (30 °C, 24 h).
(11) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc.
1989, 111, 4028-4036.
(12) Oguni, N.; Matsuda, Y.; Kaneko, T. J. Am. Chem. Soc. 1988, 110,
7877-7878.
7092 J. Org. Chem., Vol. 71, No. 18, 2006

Supporting Information Available: Experimental procedures
and compound characterization data. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. The authors thank Dr. Hideki Amii for
the helpful discussion. This research was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan (No. 17340020),
and the Hyogo COE program.
JO060964U
J. Org. Chem, Vol. 71, No. 18, 2006 7093