Catalytic Asymmetric Mannich-Type Reactions Using a Novel Chiral Iron Complex

Article abstract of DOI:10.1002/1615-4169(200210)344:9<929::AID-ADSC929>3.0.CO;2-Z

Catalytic asymmetric Mannich-type reactions using a novel chiral iron complex have been developed. The reactions proceeded smoothly in the presence of a catalyst prepared from iron(II) chloride, a BINOL derivative, and i-Pr₂NEt. The desired pro

Full text of DOI:10.1002/1615-4169(200210)344:9<929::AID-ADSC929>3.0.CO;2-Z

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Catalytic Asymmetric Mannich-Type Reactions Using a Novel
Chiral Iron Complex
Yasuhiro Yamashita, Masaharu Ueno, Yokusu Kuriyama, Shu≈ Kobayashi*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033 Japan
Fax: ( ‡ 81)-3-5684 0634; e-mail: skobayas@mol.f.u-tokyo.ac.jp
Received: May 2, 2002; Accepted: August 2, 2002
This paper is dedicated to Professor Roger Sheldon on the occasion of his 60th birthday.
Here, we report a novel chiral iron complex, which is
successfully used in asymmetric Mannich-type reac-
tions.
For realizinghigh asymmetric induction, the choice of
Abstract: Catalytic asymmetric Mannich-type reac-
tions usinga novel chiral iron complex have been
developed. The reactions proceeded smoothly in the
suitable chiral ligands and substrates is an important
presence of a catalyst prepared from iron(II)
factor. Imines prepared from aldehydes and o-amino-
chloride, a BINOL derivative, and i-Pr2NEt. The
phenol seemed to form effective bidentate chelation
desired products were obtained in good yield with
with a metal and provide an excellent asymmetric
good to high enantioselectivity, when 3,3'-I2BINOL
was employed as a chiral ligand. A protic additive
environment. We have already reported that chiral
zirconium complexes prepared from zirconium alkoxide
such as methanol facilitated the reactions effectively.
and 1,1'-binaphthalene-2,2'-diol (BINOL) derivatives
were effective for the activation of imines, and that high
reactivity and diastereo- and enantioselectivity were
observed in several zirconium-catalyzed asymmetric
reactions.[9,10] We decided to employ BINOL derivatives
Keywords: asymmetric catalysis; iron; Lewis acid;
Mannich reaction
as chiral ligands in this reaction. When FeCl2, a BINOL
derivative, and an alkylamine such as diisopropylethyl-
While iron is one of the most abundant elements in amine (i-Pr2NEt) were combined, significant chiral
nature, it is less harmful and readily accessible, and induction was observed (Table 1, run 1). For solvents,
environmentally benign processes using iron com- acetonitrile gave the best results. We then chose
pounds as catalysts or reagents are expected. Indeed, substituents at the 3,3'-positions of the BINOL deriva-
applications of iron compounds to organic synthesis tives which would give significant effects on the
have been investigated, and several useful synthetic asymmetric environment around Fe. Methyl groups
reactions usingiron compounds have already been
introduced at the 3,3'-positions worked well to improve
reported.[1] In the field of asymmetric synthesis, enantioselectivity; however, the yield was still not
although some chiral iron complexes have been em- satisfactory (run 2). Next we employed the BINOLs
ployed,[2] the use of chiral iron complexes as chiral Lewis containingelectron-withdrawingrgoups at the 3,3
'-
acids is limited. In 1991, Corey et al. reported an positions. It was interestingto find that the iodo group
À
enantioselective Diels Alder reaction usingan iron
gave the best result, and that the selectivity was
chloride/chiral bisoxazoline complex as a Lewis acid increased to 56% ee (run 5).[11] To improve the enantio-
catalyst.[3] Khiar et al., K¸ndiget al., and Kanemasa et al.
selectivity, we carried out further investigations and
also developed chiral iron catalyst systems in asymmet- found that a protic additive gave positive effects on both
[4,5,6]
À
ric Diels Alder reactions, independently.
On the reactivity and selectivity. It is noted that two equivalents
other hand, although activation of azomethine com- of water to the catalyst slightly improved the selectivity
pounds usinga catalytic amount of a chiral Lewis acid
and successive nucleophile addition provide an efficient
method for the preparation of optically active nitrogen-
MeO
OMe
NH
OSiMe3
containingcompounds, few examples of chiral iron
catalysts that activate azomethine compounds effec-
tively have been reported.[7] In the course of our study to
search for efficient chiral catalysts, it was revealed that
iron chlorides showed promisingcatalytic activity in
achiral Mannich-type reactions of imines with silicon
N
O
Catalyst (10 mol %)
CH2Cl2, 0 °C, 20 h
+
OMe
H
OMe
1a
2
FeCl3: 73% yield
FeCl2: 94% yield
Scheme 1. Catalytic Mannich-type reactions usingiron chlor-
enolates (ketene silyl acetals, for example, Scheme 1).[8] ides.
Adv. Synth. Catal. 2002, 344, No. 9
¹ 2002 WILEY-VCH VerlagGmbH & Co. KGaA, Weinheim 1615-4150/02/34409-929 931 $ 17.50+.50/0
929

Yasuhiro Yamashita et al.
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Table 1. Development of a chiral iron catalyst.
Table 2. Catalytic asymmetric Mannich-type reactions using the
chiral Fe catalyst.
FeCl2 (10 mol %)
FeCl2 (10 mol %)
HO
N
OH
NH
BINOL deriv. (11 mol %)
OH
NH
(R)-3,3'-I2BINOL (11 mol %)
HO
N
OSiMe3
OMe
i-Pr2NEt (25 mol %)
OSiMe3
i-Pr2NEt (25 mol %)
O
O
additive (mol %)
+
MeOH (100 mol %)
+
H
OMe
OMe
R
OMe
CH3CN, 0 °C, 16 h
R
H
CH3CN, 0 °C, 43 h
1b
2
1
2
BINOL deriv.
ee [%]
Run
additive [mol %]
Yield [%]
Yield [%]
ee [%]
66
Run
1
R
(R)-BINOL
1
2
25
23
46
50
(1b)
83
(R)-3,3'-Me2BINOL
(R)-3,3'-Cl2BINOL
(R)-3,3'-Br2BINOL
3
4
5
31
63
38
37
(1c)
2
76
84
(R)-3,3'-I2BINOL
(R)-3,3'-I2BINOL
(R)-3,3'-I2BINOL
62
68
69
56
3
6[a]
7
(1d)
(1e)
(1f)
3
4
5
6
74
76
82
76
82
62
65
46
Me
H2O (20)
61
(R)-3,3'-I2BINOL
MeOH (100)
8
73
68
[a] 2,6-Lutidine was used instead of i-Pr2NEt.
Me
Cl
(run 7), and that addition of an excess amount of
methanol enhanced the rate of the reaction dramati-
cally (run 8).[12]
(1g)
We then investigated reactions of other imines, and
the results are summarized in Table 2. In most cases, the
reactions proceeded smoothly to afford the desired
products in good yields with good to high enantioselec-
tivity. In particular, the imine 1c prepared from 1-
naphthaldehyde (run 2) and the imine 1d from o-
tolualdehyde gave high enantioselectivity, indicating
that the asymmetric environments created were affect-
ed by the substituents at the ortho-position of the
benzaldehyde moieties.
added, and the whole was stirred for additional 1 h. Then the
imine 1b (0.40 mmol) in acetonitrile (0.5 mL) and a ketene silyl
acetal 2 (0.48 mmol) in acetonitrile (0.5 mL) were successively
added. The mixture was stirred for the times indicated in the
Tables, and saturated aqueous NaHCO3 was added to quench
the reaction. After addition of dichloromethane, the organic
layer was separated and the aqueous layer was extracted twice
with dichloromethane. The organic layers were combined and
dried over anhydrous Na2SO4. After filtration and concen-
tration under reduced pressure, the residue was treated with
In conclusion, we have developed a novel chiral iron
catalyst system, which was effective for Mannich-type THF/1 N HCl (20:1) for 1 hat 0 8C. Then the solution was made
basic with saturated aqueous NaHCO3 solution. After usual
work-up, the crude product was purified by preparative thin
layer chromatography (benzene/ethyl acetate, 10:1) to afford
the desired Mannich adduct. The optical purity was deter-
mined by HPLC analysis usinga chiral column (Daicel
Chiralpak AD, hexane/i-PrOH ˆ 9/1).
reactions of imines with a ketene silyl acetal. Remark-
able rate enhancement was observed by addition of
protic additives such as methanol. Further investiga-
tions to survey the scope and limitation of this system as
well as to apply it to other reactions are in progress.
Acknowledgements
Experimental Section
This work was partially supported by CREST and SORST,
Japan Science Technology Corporation, and a Grant-in-Aid for
Scientific Research from Japan Society of the Promotion of
Sciences. M.U. thanks the Japan Society for the Promotion of
Science (JSPS) for the award of a postdoctoral research
fellowship.
Typical Procedure for the Reaction of the Imine
Derived from Benzaldehyde in the Presence of
Methanol
Dried acetonitrile was degassed by a freeze-thawing method
under reduced pressure before use. Under an argon atmos-
phere, to a suspension of anhydrous iron(II) chloride
(0.040 mmol) and (R)-3,3'-diiodo-1,1'-binaphthalene-2,2'-diol
(3,3'-I2BINOL, 0.044 mmol) in acetonitrile (0.4 mL) was added
i-Pr2NEt (0.10 mmol) in acetonitrile (0.3 mL) at 0 8C, and the
whole was stirred for 2 h at the same temperature. To this
mixture, MeOH (0.40 mmol) in acetonitrile (0.3 mL) was
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Catalytic Asymmetric Mannich-Type Reactions
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Adv. Synth. Catal. 2002, 344, 929 931
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