Zinc-catalyzed enantioselective hydrosilylation of imines

Article abstract of DOI:10.1002/adsc.200606149

The highly enantioselective reduction of imines is achieved by employing chiral Zn/diamine catalysts. This new catalytic protocol offers attractive features such as use of a non-precious metal and an inexpensive silane, easy modification of chiral diamine

Full text of DOI:10.1002/adsc.200606149

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DOI: 10.1002/adsc.200606149
Zinc-Catalyzed Enantioselective Hydrosilylation ofImines
Bu-Mahn Park,a Soungyun Mun,a and Jaesook Yuna,*
a
Department of Chemistry and Institute of Basic Science, Sungkyunkwan University, Suwon 440-746, Korea
Fax : (+82)-31-290-7075; e-mail: jaesook@skku.edu
Received: March 27, 2006; Accepted: April 6, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The highly enantioselective reduction of
imines is achieved by employing chiral Zn/diamine
catalysts. This new catalytic protocol offers attrac-
tive features such as use of a non-precious metal
and an inexpensive silane, easy modification of
chiral diamine ligands and provides ready access to
chiral amines in good yields and with excellent
enantioselectivities.
or ruthenium-chiral bisphosphine catalysts, and none
of these reactions afforded amines with high enantio-
selectivity. Highly enantioselective reduction systems
were developed with Ti, Cu, and Re, but either syn-
thesis of complex catalysts (ligand-metal) or use of
unusually modified substrates was necessary. There-
fore, the development of more general and simpler
catalyst systems for the reduction is required. Herein,
we describe a highly enantioselective hydrosilylation
of imines catalyzed by simple Zn-diamine catalysts.
Chiral diamine coordinated zinc catalysts for the
enantioselective hydrosilylation of aromatic ketones
first appeared in the literature in the late 1990s.[8]
However, asymmetric hydrosilylation of imines based
on zinc remains undeveloped. Recently, Carpentier
Keywords:
enantioselectivity;
hydrosilylation;
imine; ligands; zinc
The catalytic, enantioselective reduction of imines[1] et al. included a few reduction examples of imines in
to produce chiral amines is of great importance due their report on zinc-catalyzed hydrosilylation of ke-
to the prevalence of chiral amines in natural products tones,[9] but their system reduced imine substrates,
and pharmaceutical targets. Although greater atten- particularly aromatic imines in very low yields and
tion has been paid to the asymmetric hydrogena- with poor enantioselectivities (0–4% ee).
tion,[2] asymmetric hydrosilylation employing safe and
The major problem in developing a new reduction
inexpensive hydrosilanes such as polymethylhydrosi- methodology of imines based on zinc is that a strong
[10]
À
loxane (PMHS) provides an alternative and attractive zinc-nitrogen (Zn N) bond
formed by addition of
À
route to chiral amines. Catalysts derived from transi- Zn H to the imine substrate during the catalytic
tion metals such as Ti,[3] Rh,[4] Ru,[5] Cu,[6] and re- cycle (Scheme 1). For optimal reactivity, this particu-
cently Re[7] were employed for enantioselective hy- lar bond should be easily cleaved by an incoming hy-
drosilylation of imines: with regard to Rh and Ru, drosilane without disturbing the interaction between
only limited examples have been reported by rhodium the metal and the diamine ligand. Moreover, when a
Scheme 1. Presumed reaction pathway for Zn-catalyzed reduction of imines.
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Table 1. Asymmetric hydrosilylation of 1a under various conditions.
[a]
Determined by chiral HPLC.
[b] THF:MeOH = 20:80 (v/v), [1a] = 0.37M.
protic solvent is employed, the involvement of the were obtained (Table 1, entries 1–3). THF gave the
free amine product as a ligand should be minimized highest conversion among the solvents screened and,
for optimal enantioselectivity of each chiral ligand. thus, was chosen for further optimization.
Therefore, we thought that the choice of the substitu-
In order to improve the enantioselectivity of the
ent attached to the imine nitrogen was crucial. The di- product, we prepared a series of ligands, L2–L4
phenylphosphinyl moiety was chosen first as the sub- (Figure 1) from (R,R)-dpen (dpen=1,2-diphenyl-1,2-
stituent guided by the above requirements. The diphe- ethanediamine). Diphenylsilane was more effective
nylphosphinyl imine derivatives[11] are obtained as a than tetramethylsilyloxane (TMDS) and PMHS (en-
single isomer, tolerant to air and moisture, and can be tries 4–6), resulting in complete conversion and yield-
readily hydrolyzed to the desired amines.[12]
ing the desired amine product of >90% ee in THF
We initially examined the hydrosilylation of imine with L2 and L3 (entries 6 and 7). The reaction using
1a employing 6 mol% ZnEt2, N,N’-ethylenebis(1-phe- bulky ligand L4 did not go to completion, giving only
nylethylamine) (ebpe, L1) as the ligand, and PMHS as 88% conversion in 24 h (entry 8). We then focused on
the stoichiometric reducing agent in a range of sol- promoting rates of the reaction in which PMHS, a
vents. Although the reactions were not complete polymeric inexpensive silane, was employed. As re-
within 24 h, promising enantioselectivities (65–68% ee) ported in a few metal-catalyzed hydrosilylaitons by us
and others,[13a-c] alcohol additives greatly enhanced
reaction rates of the zinc-catalyzed reduction of
imines. The use of MeOH in combination with THF
drove the reduction employing L4 ligand and PMHS
to completion within the reaction time (entry 8 vs.
11). In general, all L2–L4 ligands offered good enan-
tioselectivity, and the best value (98% ee) was ob-
tained by employing L2 and PMHS in THF/MeOH;
these results are in contrast to the Zn-catalyzed
ketone hydrosilylation for which the addition of alco-
hol additives produced alcohol products with lowered
enantiomeric excess despite increased reaction
rates.[14] Particularly noteworthy is that unlike L2 and
L4, the L3 ligand having extra coordinating methoxy
groups provided the same level of enantioselectivity
Figure 1. (R,R)-Ebpe (L1) and chiral diamine ligands (L2–
L4) derived from (R,R)-dpen.
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Zinc-Catalyzed Enantioselective Hydrosilylation of Imines
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Table 2. Enantioselective hydrosilylation of N-diphenylphos-
the amine product in 86% ee and ketimine 1g derived
from isobutyrophenone was reduced with a low level
of enantioselectivity (55% ee). Heteroaromatic keti-
mine substrate 1h also reacted with excellent enantio-
selectivity (96% ee).
phinylimines.[a]
In conclusion, we have developed a highly enantio-
selective hydrosilylation of imines based on a chiral
Zn/diamine catalyst. This new catalytic process offers
attractive features such as use of a non-precious metal
and an inexpensive silane, easy modification of chiral
diamine ligands. Studies are underway to investigate
the full scope and the mechanism of this methodology
and to develop more efficient and enantioselective
catalyst systems.
Experimental Section
General Procedure for the Enantioselective
Hydrosilylation of N-Phosphinylimines (Table 2)
To a solution of ligand L2 (8.6 mg, 0.022 mmol) in freshly
distilled THF (0.4 mL), was added ZnEt2 (0.02 mL, 1.1M
solution in toluene, 0.022 mmol) under nitrogen. The reac-
tion mixture was stirred for 10 min, and a solution of phos-
phinylimine (0.44 mmol) in THF (0.4 mL), PMHS (0.08 mL,
1.32 mmol) and anhydrous MeOH (0.2 mL) was added suc-
cessively. The resulting solution was stirred for 12 h at room
temperature and the reaction was monitored by TLC. After
completion of the reaction, MeOH (10 mL) and 1 N NaOH
in MeOH (0.2 mL) were added. The mixture was stirred for
30 min, filtered through a pad of celite, and concentrated
under vacuum. Purification by silica gel chromatography
(10% acetone/CH2Cl2) gave the corresponding phosphinyl-
amines.
[a]
Reactions were all run by using 5 mol% ZnEt2, 5 mol%
L2, and 3 equivs. PMHS in THF/MeOH (1 mL, 80:20
(v/v), [Imine] = 0.44m) at room temperature for 12 h.
Reaction time was not optimized.
[b] Determined by chiral HPLC.
Acknowledgements
This work was supported by Korea Research Foundation
grant funded by the Korean Government (R08–2004–000–
10429–0). LC and GC equipment was supported by the Fac-
ulty Research Fund 2005, Sungkyunkwan University.
under the reaction conditions with or without MeOH
(entries 7 and 10).
Having chosen L2 as the best chiral ligand, various
N-phosphinylimines were reduced by using 5 mol%
catalyst, 3 equivs. of PMHS, and in MeOH/THF
[20:80 (v/v)].[15] The results are summarized in
Table 2. Reduction of phenyl methyl ketimine 1a af-
forded amine 2a with good ee (97% ee).[16] The re-
duction of phenyl methyl ketimine derivatives bearing
electron-withdrawing (entry 2) and electron-donating
groups (entry 3) on the aromatic ring yielded amines
with high enantioselectivities. Ketimines derived from
propiophenone and indanone were efficiently re-
duced, affording the corresponding amine products in
high enantiomeric excess as well (entries 4 and 5).
However, a further increase of the steric bulk of the
alkyl side chain adversely affected the ee values (en-
tries 6 and 7). Six-membered ring ketimine 1f gave
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À
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C
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À
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