Catalytic enantioselective reformatsky reaction of alkyl iodoacetate with aldehydes catalyzed by chiral schiff base

Article abstract of DOI:10.1246/cl.2008.1298

The catalytic enantioselective Reformatsky reaction with aldehydes catalyzed by chiral Schiff base 1 in the presence of Me₂Zn under Ar-O₂ atmosphere was achieved (up to 72% ee). This process provides a potential method for the synthe

Full text of DOI:10.1246/cl.2008.1298

1298
Chemistry Letters Vol.37, No.12 (2008)
Catalytic Enantioselective Reformatsky Reaction of Alkyl Iodoacetate
with Aldehydes Catalyzed by Chiral Schiff Base
Takanori Tanaka and Masahiko HayashiÃ
Department of Chemistry, Graduate School of Science, Kobe University, Kobe 657-8501
(Received September 30, 2008; CL-080939; E-mail: mhayashi@kobe-u.ac.jp)
The catalytic enantioselective Reformatsky reaction with
Table 1. Enantioselective Reformatsky reaction in various sol-
ventsa
aldehydes catalyzed by chiral Schiff base 1 in the presence of
Me2Zn under Ar–O2 atmosphere was achieved (up to 72% ee).
This process provides a potential method for the synthesis of
chiral ꢀ-hydroxy esters in high enantiomeric excess.
20 mol%
chiral Schiff base 1
OH O
O
O
1 M HCl
+ I
OEt
Ph
OEt
Ph
H
Me2Zn (8 equiv)
Ar−O2
The first practical catalytic enantioselective Reformatsky re-
action with ketones was reported by Cozzi in 2006.1a He report-
ed the reaction of unsymmetric ketones with ethyl iodoacetate
using ClMn(salen) catalyst. After that report, Feringa and his
co-workers reported the catalytic enantioselective Reformatsky
reaction of ketones with ethyl iodoacetate using chiral binaph-
thol derivatives.1b In 2008, the same researchers also reported
the enantioselective Reformatsky reaction with aldehydes.2
Cozzi also reported the enantioselective imino-Reformatsky
reaction using N-methylephedrine as the chiral ligand.3,4 All of
these methods are mediated by Me2Zn (2–8 equiv) in an ethereal
solvent, such as Et2O, t-BuOMe, and Et2O/THF.
We have reported chiral Schiff base-catalyzed asymmetric
reactions, such as enantioselective trimethylsilylcyanation of
aldehydes,5 asymmetric alkylation of aldehydes,6 enantioselec-
tive addition of diketene to aldehydes,7 and enantioselective 1,4-
addition of enones.8 Chiral Schiff base ligands have the follow-
ing characteristic features. (i) They show high enantioselective
recognition. (ii) The introduction of substituents to a Schiff base
framework is easy, therefore, they have high tuning potential for
a variety of reactions and substrates. (iii) In the case of ketoimine
Schiff bases, handling is particularly easy and the ligand can be
recovered after hydrolysis. Herein, we report the catalytic enan-
tioselective Reformatsky reaction with aldehydes catalyzed by
chiral Schiff base 1 in the presence of Me2Zn under Ar–O2 atmo-
sphere (Scheme 1).9
Entry
Solvent
Temp/ꢀC
Time/h
Yield/%b
% eec
1
2
3
4
5
6
Et2O
Et2O
THF
t-BuOMe
CH2Cl2
Toluene
25
0
30
30
30
30
1
3
24
3
3
3
98
99
33
99
93
60
68 (S)
60 (S)
46 (S)
57 (S)
62 (S)
52 (S)
aAll reactions were carried out using 2 equiv of ethyl iodoacetate.
PhCHO was added slowly for 20 min. bIsolated yield after Kugelrohr dis-
tillation. cHPLC analysis (CHIRALCEL OD-H).
30 ꢀC). The reactions at 0 ꢀC did not increase the enantioselectiv-
ity or caused some decrease of the enantioselectivity.10
Then, we examined the enantioselective Reformatsky reac-
tion of various aldehydes with ethyl iodoacetate using chiral
Schiff base 1. All reactions were carried out in Et2O at room
temperature under Ar–O2 atmosphere using Me2Zn. The ob-
tained results are summarized in Table 2. Most aromatic alde-
hydes we examined were converted to corresponding chiral ꢀ-
hydroxy esters in high yield (83–94%) and enantiomeric excess
(61–72% ee). In the case of hetero aromatic and ꢁ,ꢀ-unsaturated
aldehydes, the enantioselectivities were moderate.
Table 2. Enantioselective Reformatsky reaction of various al-
dehydes with alkyl iodoacetatea
20 mol%
chiral Schiff base 1
OH O
O
O
Though Cozzi and Feringa carried out the reaction in ethe-
real solvent using 2 M Me2Zn toluene solution, we examined
the reaction using neat Me2Zn to investigate the solvent effect
strictly (Table 1). Using THF as a solvent, the reactivity decreas-
ed. These reactions were carried out at room temperature (25–
1 M HCl
I
+
OR2
R1
OR2
R1
H
Me2Zn (8 equiv)
Ar−O2, Et2O
Entry
R1
R2 Temp/ꢀC Time/h Yield/%b % eec,d
1
2
3
4
5
6
7
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
2-Thienyl
Et
Et
Et
Et
Et
27
23
23
26
25
25
30
1
1
1
1
8
87
94
83
86
83
88
99
72 (S)
61 (S)
68 (S)
68 (S)
58 (S)e
30 (S)
56 (S)
20 mol%
Ph
t-Bu
t-Bu
N
OH
(E)-C6H5CH=CH Et
Ph t-Bu
1
24
OH
OH O
O
O
1
1 M HCl
aAll reactions were carried out using 2 equiv of ethyl iodoacetate. bIsolated
yield after Kugelrohr distillation. cHPLC analysis (CHIRALCEL OD-H or
CHIRALPAK AS, see Supporting Information). dAll absolute configura-
tions were determined by the comparison of the optical rotation values with
those of reported ones unless otherwise noted. eAbsolute configuration was
estimated by the order of retention time of HPLC.
+
I
R
H
OEt
R
OEt
Me2Zn (8 equiv)
Ar−O2
Scheme 1. Catalytic enantioselective Reformatsky reaction
with aldehydes catalyzed by chiral Schiff base 1.
Copyright ꢀ 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.12 (2008)
1299
Minnaard, B. L. Feringa, Angew. Chem., Int. Ed. 2008, 47,
1317. b) P. G. Cozzi, F. Benfatti, M. G. Capdevila, A.
Mignogna, Chem. Commun. 2008, 3317.
For imines: P. G. Cozzi, Adv. Synth. Catal. 2006, 348, 2075.
For stoichiometric asymmetric Reformatsky reactions, see
references cited in 1a.
20 mol%
chiral Schiff base 1
O
O
O
HO Me
Ph
1 M HCl
+
I
Ph Me
OEt
OEt
Me2Zn (8 equiv)
Ar−O2
Et2O, 25 °C, 1 h
3
4
63% ee (S)
(30%)
Scheme 2. Catalytic enantioselective Reformatsky reaction
with acetophenone catalyzed by chiral Schiff base 1.
5
a) M. Hayashi, Y. Miyamoto, T. Inoue, N. Oguni, J. Chem.
Soc., Chem. Commun. 1991, 1752. b) M. Hayashi, Y.
Miyamoto, T. Inoue, N. Oguni, J. Org. Chem. 1993, 58,
1515.
a) T. Tanaka, Y. Yasuda, M. Hayashi, J. Org. Chem. 2006,
71, 7091. b) T. Tanaka, Y. Sano, M. Hayashi, Chem. Asian
J. 2008, 3, 1465.
a) M. Hayashi, T. Inoue, N. Oguni, J. Chem. Soc., Chem.
Commun. 1994, 341. b) M. Hayashi, T. Inoue, Y. Miyamoto,
N. Oguni, Tetrahedron 1994, 50, 4385. c) M. Hayashi, K.
Tanaka, N. Oguni, Tetrahedron: Asymmetry 1995, 6, 1833.
d) M. Hayashi, K. Yoshimoto, N. Hirata, K. Tanaka, N.
Oguni, K. Harada, A. Matsushita, Y. Kawachi, H. Sasaki,
Isr. J. Chem. 2001, 41, 241. e) C. Chu, K. Morishita, T.
Tanaka, M. Hayashi, Tetrahedron: Asymmetry 2006, 17,
2672.
The reaction of benzaldehyde with tert-butyl iodoacetate us-
ing the same chiral Schiff base 1 was performed under the same
reaction conditions (Table 2, Entry 7). The product was obtained
in 99% yield with 56% ee (S). In comparison with the reaction of
ethyl iodoacetate, it took longer to complete the reaction in the
case of the reaction of tert-butyl iodoacetate.
Next, we examined the reaction of acetophenone with ethyl
iodoacetate using chiral Schiff base 1 to give the product in 63%
ee (S) (30% yield) (Scheme 2). The reactions of other unsym-
metric ketones are now in progress.
As for the reaction mechanism, Cozzi and Feringa proposed
radical mechanisms. Actually, to obtain high yield, air (molecu-
lar oxygen) was used in Feringa’s system,1b,2a and 4-phenylpyr-
idine N-oxide, tert-butyl hydroperoxide and air were used in
Cozzi’s system.1a,2b,3 These authors suggested the generation
of methyl radical species by addition of the above oxidants, be-
cause without the oxidants the yield of the product was very low
(10–20% yield even for 24 h, rt). However, in our case, the prod-
uct was actually obtained in 40% yield and 64% ee (S) in the ab-
sence of oxygen (for 1 h, 25 ꢀC). We suppose that oxygen accel-
erates the reaction, but is not essential to promote the reaction,
and that a reaction pathway other than a radical mechanism ini-
tiated by oxygen may also exist.
6
7
8
9
K. Kawamura, H. Fukuzawa, M. Hayashi, Org. Lett. 2008,
10, 3509.
We examined a variety of chiral Schiff bases we reported in
ref. 5 and 6. Among those, chiral Schiff base 1 was the best
choice. Especially, the existence of a tert-butyl group at the
ortho position of a phenolic hydroxy group is essential to ob-
tain high ee. For example, the Schiff base only absent a tert-
butyl group at the ortho position of phenolic hydroxy group 1
(Other substituents are completely the same) gave only 22%
ee (S) in 95% yield.
In summary, the catalytic enantioselective Reformatsky re-
action of aldehydes catalyzed by chiral Schiff base 1 in the pres-
ence of Me2Zn under Ar–O2 atmosphere was reported (up to
72% ee). The chiral ꢀ-hydroxy esters were obtained directly
from carbonyl compounds with high enantiomeric excess.11
10 General procedure for catalytic enantioselective Refor-
matsky reaction: Dimethylzinc (0.28 mL, 4.0 mmol) was
added to a solution of chiral Schiff base 1 (35.4 mg,
0.1 mmol) and ethyl iodoacetate (118.4 mL, 1.0 mmol) in sol-
vent (6 mL) at room temperature under argon atmosphere.
After exchange of argon to oxygen diluted with argon, the
solution of aldehyde (0.5 mmol) in solvent (2 mL) was added
slowly. The reaction mixture was stirred under argon and
oxygen atmosphere. After confirmation of the completion
of the reaction by TLC analysis, the mixture was quenched
by addition of i-PrOH (5 mL) then 1 M HCl (20 mL). After
extraction with diethyl ether (20 mL Â 3) and evaporation,
the obtained residue was columned on silica gel (eluent; hex-
ane:ethyl acetate = 5:1), the following Kugelrohr distilla-
tion afforded the product. Enantiomeric excess (ee) was
determined by HPLC analysis (CHIRALCEL OD-H or
CHIRALPAK AS, see Supporting Information).
This work was supported by a Grant-in-Aid for Scientific
Research on Priority Areas ‘‘Advanced Molecular Transforma-
tions of Carbon Resources’’ and No. B17340020 from the Min-
istry of Education, Culture, Sports, Science and Technology,
Japan. T. T. is grateful to Grant-in-Aid for JSPS Fellows.
This paper is dedicated to Professor Ryoji Noyori on the oc-
casion of his 70th birthday.
References and Notes
1
2
For ketones: a) P. G. Cozzi, Angew. Chem., Int. Ed. 2006, 45,
´
´
´
´
2951. b) M. A. Fernandez-Iban˜ez, B. Macia, A. J. Minnaard,
B. L. Feringa, Chem. Commun. 2008, 2571.
11 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
´
´
´
´
For aldehydes: a) M. A. Fernandez-Iban˜ez, B. Macia, A. J.
Published on the web (Advance View) December 5, 2008; doi:10.1246/cl.2008.1298