Enantioselective reduction of ketones by polymethylhydrosiloxane in the presence of chiral zinc catalysts

Article abstract of DOI:10.1021/ja990522i

Enantioselective reduction of ketones, particularly acetophenones, by polymethylhydrosiloxane (PMHS) to the corresponding secondary alcohols can be achieved with high yields and enantiomeric excesses (ee's) up to 88% in the presence of chiral zinc catalysts (eq 1). Two catalytic systems have been developed giving similar ee's: (i) System A: ZnEt₂ + chiral diimine or diamine 1-10. (ii) System B: Zn(carboxylate)₂ + chiral diamine activated by Vitride. System B is inexpensive, stable, and ready to use in toluene, providing either (R) or (S) chiral secondary alcohols with 70-80% ee in the presence of (S,S)-or (R,R)-N,N′-ethylenebis-(1-phenylethylamine) (ebpe, 6). The reduction has been carried out at the 1 kg scale without scale-up problems. The ligand is cheap and is recovered at the end of reaction by simple distillation from residues of the organic phase. Both precursors ZnMe₂·(S,S)-ebpe (A) and Zn(dea)₂·(S,S)-ebpe (B) for systems A and B, respectively, have been isolated and characterized by X-ray structure and exhibit the same catalytic properties and the same ee's for the reduction of acetophenone as the in situ prepared catalytic system. The complex ZnEt₂·(S,S)-ebpe) (A′) reacts with benzaldehyde to give the seven-membered ring dimer complex La in which benzaldehyde inserts into the Zn-N bond of complex A′. Acetophenone also reacts with A′ to give a similar seven-membered ring dimer complex Lb. Both La and Lb are catalysts for the enantioselective reduction of acetophenone by PMHS and gave activities and ee's similar to those of A′. Synthetic and mechanistic aspects of this new economical method are discussed in this paper.

Full text of DOI:10.1021/ja990522i

6158
J. Am. Chem. Soc. 1999, 121, 6158-6166
Enantioselective Reduction of Ketones by Polymethylhydrosiloxane in
the Presence of Chiral Zinc Catalysts
Hubert Mimoun,*,† Jean Yves de Saint Laumer,† Luca Giannini,‡ Rosario Scopelliti,‡ and
Carlo Floriani‡
Contribution from Firmenich S.A., CH-1283 La Plaine-GeneVa, Switzerland, and Institut de Chimie
Mine´rale et Analytique, BCH, UniVersite´ de Lausanne, CH-1015 Lausanne, Switzerland
ReceiVed February 18, 1999
Abstract: Enantioselective reduction of ketones, particularly acetophenones, by polymethylhydrosiloxane
(PMHS) to the corresponding secondary alcohols can be achieved with high yields and enantiomeric excesses
(ee’s) up to 88% in the presence of chiral zinc catalysts (eq 1). Two catalytic systems have been developed
giving similar ee’s: (i) System A: ZnEt2 + chiral diimine or diamine 1-10. (ii) System B: Zn(carboxylate)2
+ chiral diamine activated by Vitride. System B is inexpensive, stable, and ready to use in toluene, providing
either (R) or (S) chiral secondary alcohols with 70-80% ee in the presence of (S,S)- or (R,R)-N,N′-ethylenebis-
(1-phenylethylamine) (ebpe, 6). The reduction has been carried out at the 1 kg scale without scale-up problems.
The ligand is cheap and is recovered at the end of reaction by simple distillation from residues of the organic
phase. Both precursors ZnMe2‚(S,S)-ebpe (A) and Zn(dea)2‚(S,S)-ebpe (B) for systems A and B, respectively,
have been isolated and characterized by X-ray structure and exhibit the same catalytic properties and the same
ee’s for the reduction of acetophenone as the in situ prepared catalytic system. The complex ZnEt2‚(S,S)-ebpe)
(A′) reacts with benzaldehyde to give the seven-membered ring dimer complex La in which benzaldehyde
inserts into the Zn-N bond of complex A′. Acetophenone also reacts with A′ to give a similar seven-membered
ring dimer complex Lb. Both La and Lb are catalysts for the enantioselective reduction of acetophenone by
PMHS and gave activities and ee’s similar to those of A′. Synthetic and mechanistic aspects of this new
economical method are discussed in this paper.
Introduction
developed using ruthenium catalysts coordinated by chiral
diamines9a-d or chiral amino alcohols.9eAsymmetric hydro-
silylation of prochiral ketones as a method for enantioselective
reduction has been known since the early 1970s, using rhodium
catalysts coordinated by chiral phosphines10 and later developed
with rhodium and chiral nitrogen ligands,11 titanium and chiral
diamines12 or binaphthol,13 hypervalent chiral trialkoxysilanes,14
and chiral ammonium fluoride.15
The search for economical methods of enantioselective
reduction of ketones to secondary alcohols is a rewarding goal,1
owing to the numerous applications in the fields of pharma-
ceuticals,2 agrochemicals,3 and flavor and fragrance.4 Known
industrial methods involve reduction by chiral hydride reagents
such as Corey’s oxazaborolidine,5 Yamaguchi-Mosher reagent
LiAlH4 coordinated by BINAL-H6 or Chirald,2 Mukaiyama’s
reduction of ketones by NaBH4 in the presence of chiral Co(II)
complexes,7 or Brown’s chiral boranes such as Alpine-Borane.8
Recently, asymmetric hydrogenation of ketones has been
Polymethylhydrosiloxane (PMHS) is a safe and inexpensive
polymer coproduct of the silicone industry, and its use as a
* Corresponding author. E-mail: hubert.mimoun@firmenich.com.
† Firmenich SA.
(8) Brown, H. C. Organic Synthesis Via Boranes; Wiley: New York,
1975 and references therein.
‡ Universite´ de Lausanne.
(9) (a) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; lkariya, T.; Noyori, R. J.
Am. Chem. Soc. 1995, 117, 2675. (b) Ohkuma, T.; Ooka, H.; Yamakawa,
M.; lkariya, T.; Noyori, R. J. Org. Chem. 1996, 61, 4872. (c) Ohkuma, T.;
Doucet, H.; Pham, T.; Mikami, K.; Korenaga, T.; Terada, M.; Noyori, R.
J. Am. Chem. Soc. 1998, 120, 1086. (d) Fujii, A.; Hashiguchi, S.; Uematsu,
N.; Ikariya, T.; Noyori, R. J. Am. Chem Soc. 1996, 118, 2521. (e) Alonso,
D. A.; Guijarro, D.; Pinho, P.; Temme, O.; Andersson, P. G. J. Org. Chem.
1998, 63, 2749.
(10) (a) Yamamoto, K.; Uramoto, Y.; Kumada, M. J. Organomet. Chem.
1971, 31, C9. (b) Ojima, I. In The Chemistry of Organic Silicon Compounds;
Patai, S., Ed.; Wiley: New York, 1989; Chapter 25, p 1479 and references
therein.
(11) Brunner, H.; Nishiyama, H.; Itoh, K. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH: New York, 1993; p 303 and references
therein.
(12) Buchwald, S. L.; Gutierrez, A.; Grossman, R. B. U.S. Patent
5,227,538 (July 13, 1993) to MIT.
(13) Imma, H.; Mori, M.; Nakai, T. Synlett 1996, 1229.
(14) Reduction by (RO)3SiH-Li(binaphthol): Shiffers, R.; Kagan, H.
B. Synlett 1997, 1175.
(15) Enantioselective reduction of acetophenones by PMHS in the
presence of cinchona alkaloids ammonium fluorides (up to 60% ee): Drew,
M. D.; Lawrence, N. J.; Watson, W.; Bowles, S. A. Tetrahedron Lett. 1997,
38, 5857.
(1) Reviews: (a) Itsuno, S. Organic Reactions; Paquette, A., et al., Eds.;
John Wiley & Sons: New York, 1998; Vol. 52, p 395. (b) Harada, K.;
Manegumi, T. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 8, p 139. (c) Nishizawa, M.;
Noyori, R. Ibid., p 159. (d) Singh, V. K. Synthesis 1992, 605. (e) Brunner,
H In Houben-Weyl Methoden der Organischen Chemie, 21st ed.; Helmchen,
G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Thieme Verlag:
Stuttgart, Germany, 1996; Vol. 7, pp 3945-4197.
(2) Astleford, B. A., Weigel, L. O. In Chirality in Industry II; Collins,
A. N., Ed.; Wiley: New York, 1997; p 99.
(3) Sheldon, R. A. Chirotechnology; Dekker: New York, 1993.
(4) (a) Rossiter, K. J. Chem. ReV. 1996, 96, 3201. (b) Boelens, M. Perfum.
FlaVor. 1993, 18, 2.
(5) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551. (b) Industrial applications: Caille, J. C.; Bulliard, M.; Laboue,
B. In Chirality in Industry II; Collins, A. N., Ed.; Wiley: New York, 1997;
p 391.
(6) (a) Noyori, R.; Tomino, I.; Tanimoto, Y. J. Am. Chem. Soc. 1979,
101, 3129. (b) Yamaguchi, S.; Mosher, S.; Pohland, A. J. Am. Chem. Soc.
1972, 94, 9254.
(7) (a) Nagata, T.; Yorozu, K.; Yamada, T.; Mukaiyama, T. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2145. (b) Nagata, T.; Sugi, K. D.; Yamada,
T.; Mukaiyama, T. Synlett. 1996, 1076.
10.1021/ja990522i CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/17/1999

EnantioselectiVe Reduction of Ketones
J. Am. Chem. Soc., Vol. 121, No. 26, 1999 6159
Figure 1. Representative ligands used in this study.
reducing silylating agent of ketones has been known since
1957.16 Chiral titanocene catalysts activated by n-butyllithium
have been used for the enantioselective reduction of acetophe-
nones by PMHS with enantiometric excesses (ee’s) up to 97%.17
In a previous paper,18 we have shown that zinc hydride
species, best generated from the reaction of zinc carboxylates
with hydride reducing agents such as NaBH4, are very effective
catalysts for the selective hydrosilylation-reduction of carbonyl
compounds, including esters, to the corresponding alcohols.
Among the various catalytic systems, dialkylzinc activated by
diamine ligands was found particularly effective for the hy-
drosilylation-reduction of carbonyl compounds. We thus
checked for possible chiral recognition of the substrate using
various bidentate optically active ligands and found that
diethylzinc coordinated by inexpensive chiral diimines or
diamines 1-10 catalyzes the enantioselective reduction of
ketones by PMHS with >90% isolated yields and up to 88%
ee (System A, eq 1). Further work allowed the design of
inexpensive, ready-to-use (R)- and (S)-carbinol forming catalytic
solutions made from soluble zinc carboxylates, chiral diamine
ligands, and Vitride in toluene (System B, eq 1), which have
been used on a 1 kg scale for the synthesis of various chiral
alcohols.
(16) (a) Nitzche, S.; Wick, M. Angew. Chem. 1957, 69, 96. (b) Grady,
G. L.; Kuivila, H. G. J. Org. Chem. 1969, 34, 2014. (c) Lipowitz, J.;
Bowman, S. A. Aldrichim. Acta 1973, 6, 1. (d) Corriu, R. J. P.; Perz, R.;
Re´ye´, C. Tetrahedron 1983, 39, 999. (e) Kobayashi, Y.; Takahisa, E.;
Nakano, M.; Watatani, K. Tetrahedron 1997, 53, 1627. (f) Drew, M. D.;
Lawrence, N. J.; Fontaine, D.; Sekhri, L.; Bowles, S. A.; Watson, W. Synlett
1997, 989.
(17) Carter, M. B.; Schiott, B.; Guttierez, A.; Buchwald, S. L. J. Am.
Chem. Soc. 1994, 116, 11667.
(18) Mimoun, H. J. Org. Chem. 1999, 64, 2582. Patent WO 96/12694
to Firmenich S.A.

6160 J. Am. Chem. Soc., Vol. 121, No. 26, 1999
Mimoun et al.
Table 1. Enantioselective Reduction of Acetophenone by PMHS
in the Presence of ZnEt2 (2 mol %) and a Chiral Ligand (2 mol %)
(toluene, 18 h, room temperature)
entry
ligands (see Figure 1)
Chiral Diimines
conversion (%) % ee
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
2a
2b
3
95
97
98
95
98
98
97
95
75 (S)
74 (S)
72 (S)
70 (S)
73 (S)
56 (S)
48 (S)
30 (S)
Chiral Primary Diamines
9
10
11
4a
5a
98
98
55
18 (S)
24 (S)
5 (R)
Results and Discussion
(R)-(+)-1,1′-bis(2-naphthylamine)
Chiral Secondary Diamines
The Catalytic Systems. Experiments were carried out using
acetophenone as the substrate, various metal precursors (par-
ticularly zinc) at 2 mol % concentration with various ligands
shown in Figure 1, and 1.1 mol equiv of PMHS in toluene at
room temperature for 18 h. The results are shown in Table 1.
Whereas ZnEt2 alone has no catalytic activity for reduction
using PMHS,18 it can be activated by ligands such as diamines
which transform the linear C-Zn-C backbone into monomeric
tetrahedral zinc complexes ZnEt2(diamine) in which the diamine
acts as a bidendate ligand.19 This reaction thus belongs to the
category of ligand-accelerated catalytic reactions,5a,20 where the
ligand can be used in a substoichiometric concentration with
respect to the metal. In our case, 0.04 mol % ligand is enough
to activate the 2 mol % ZnEt2 used.
Activation of ZnEt2 can be performed by chiral diimines
(Table 1, entries 1-8) which allowed up to 75% ee with the
bis(R-naphthyl)-(R,R)-cyclohexanediimine (1a). Chiral second-
ary diamines were found even more efficient than chiral
diimines, with the best ee’s (up to 88%) being reached so far
by N,N′-dibenzyl-1,2-diphenyl-1,2 ethanediamine (5c) (entry
18). Chiral primary diamines such as 4a, 5a, and binaphthyl-
amine (entries 9-11) were found to be inferior (24% ee max),
as well as chiral tertiary diamines (55% ee max). Chiral amino
alcohols prove ineffective as ligands, owing to the higher bond
strength of the Si-O vs the Zn-O bond, resulting in the
displacement of the ligand from zinc to PMHS.18 This reaction
is sensitive to steric effects, as shown by the low activity
observed with the encumbered ligands 5g and 7. So far, the
best ligands are those having a C2 symmetry. (S)-2-(Phenyl-
aminomethyl)pyrrolidine (8), cheaply made from glutamic acid,
aniline, and LiAlH4, gave only 8% ee.
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4b
4c
4d
4e
4f
5b
5c
5d
5e
5f
5g
6
99
95
98
97
98
95
98
98
98
97
15 (slow)
99
20 (slow)
98
70 (S)
52 (S)
62 (S)
63 (S)
62 (S)
47 (R)
88 (R)
83 (R)
84 (R)
83 (R)
58 (R)
75 (R)
8 (R)
7
8
8 (R)
Chiral Tertiary Diamines
26
27
28
9
96
60
98
17 (S)
19 (R)
55 (S)
sparteine
10
Amino Alcohols
29
30
31
32
11
67
6 (R)
8 (S)
13 (R)
1 (S)
12
13
14
100
60
9
Miscellaneous
32
33
34
16
17
18
88
10 (S)
32 (S)
5 (R)
100
10
Complexation of ZnMe2 by the diamine ligand (see eq 2) is
exemplified by the isolation and X-ray characterization of the
complex ZnMe2‚(S,S)-ebpe (A). The structure of the adduct A,
Our attention was concentrated on the use of N,N′-ethyl-
enebis(1-phenylethylamine) (ebpe, 6), which, although not the
most effective ligand, can be easily and inexpensively prepared
on a kilogram scale in the (R,R)- or (S,S)-configuration from
the reaction of 1,2-dichloroethane or 1,2-dibromoethane with 2
equiv of (R)- or (S)-R-phenylethylamine. This allowed the
preparation of (R)- or (S)-carbinols from (S,S)- or (R,R)-6,
respectively. The same general phenomenon was observed with
the other diimines or diamines with C2 symmetry, the (R,R)-
ligand giving the (S)-carbinol and the (S,S)-ligand giving the
(R)-carbinol.
prepared in near quantitative yield by mixing the two reactants,
is shown in Figure 2 with some significant bond lengths and
angles.21 The tetrahedral structure of this complex and its
structural parameters are similar to those of ZnMe2‚(-)-
sparteine19b and ZnMe2‚TMEDA19a [TMEDA ) tetramethyl-
ethylenediamine] complexes, which contain tertiary diamines
as ancillary ligands.
(19) (a) O’Brien, P.; Hursthouse, M. B.; Motevalli, M., Walsh, J. R.;
Jones, A. C. J. Organomet. Chem. 1993, 449, 1. (b) Motevalli, M.; O’Brien,
P.; Robinson, A. J.; Walsh, J. R.; Wyatt, P. B.; Jones, A. C. J. Organomet.
Chem. 1993, 461, 5.
(20) Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1059. See also ref 5a for an earlier example of ligand-
accelerated catalytic reaction.
The isolated complex ZnEt2‚(S,S)-ebpe behaves similarly to
the ZnEt2 + (S,S)-ebpe mixture, as shown in Table 2 (compare
(21) Details on crystallographic and structural parameters are reported
in the Supporting Information.

EnantioselectiVe Reduction of Ketones
J. Am. Chem. Soc., Vol. 121, No. 26, 1999 6161
Table 2. Enantioselective Reduction of Acetophenone by PMHS
in the Presence of Various Metal Derivatives (2 mol %), Ligands,
and Activators (toluene, 18 h, room temperature)
metal
entry
7
precursor
ligand
activator
conversion % ee
ZnEt2
35 ZnMe2
2b
2b
2b
2b
6
97
99
96
95
99
99
75
48 (S)
48 (S)
48 (S)
49 (S)
75 (R)
75 (R)
71 (R)
36 ZnH2
37 PhZnH‚Py
23 ZnEt2
38 ZnEt2‚ebpe A
39 Zn(dea)2
6 (included)
6
40 Zn(dea)2‚ebpe B 6 (included)
70 (60 °C) 71 (R)
41 Zn(dea)2
42 Zn(dea)2
43 Zn(dea)2
44 Zn(dea)2
45 Cd(dea)2
46 Cd(dea)2
48 Co(dea)2
49 Cu(dea)2
50 Sn(2-EH)2
6
6
6
6
6
5c
6
6
6
NaBH4 (2%) 100
LiAlH4 (1%) 100
Vitride (3%) 100
45 (R)
67 (R)
72 (R)
71 (R)
62 (R)
81 (R)
Figure 2. X-ray crystal structure of the complex ZnMe2‚(S,S)-ebpe
(A). Selected bond distances (Å) and angles (deg): Zn-N1 ) 2.230-
(3); Zn-N1′ ) 2.230(3); Zn-C1 ) 2.007(4); N1-C3 ) 1.475(5); N1-
C4 ) 1.472(5); C1-Zn-N1′ ) 108.0(2); C1-Zn-N1 ) 106.2(2);
N1-Zn-N1′ ) 80.3(2). Primes denote the following symmetry
operation: -x, y, -z.
LiH (4%)
100
100
100
90 (60 °C) 58 (R)
0
0
a
a 2-EH ) 2-ethylhexanoate.
entries 23 and 38). Other zinc precursors, such as ZnMe2, ZnH2,
or PhZnH‚Py, were found to be active as well for the
enantioselective reduction of acetophenone (entries 7 and 35-
37).
Soluble polymeric zinc carboxylates such as Zn(2-EH)2 [2-EH
) 2-ethylhexanoate] or Zn(dea)2 [dea ) diethyl acetate or
2-ethylbutyrate] are inactive as such, but form monomeric active
catalysts once coordinated by bidendate chiral secondary
diamines such as ebpe (6). Thus, the reaction of zinc diethyl
acetate with ebpe forms the adduct Zn(dea)2‚ebpe (B) in almost
quantitative yield (eq 3).
Figure 3. X-ray crystal structure of the complex Zn(dea)2‚(S,S)-ebpe‚
H2O (B) (hydrogens have been omitted for clarity). Selected bond
distances (Å) and angles (deg): Zn1-N1 ) 2.076(3); Zn1-N2 )
2.070(2); Zn1-O1 ) 1.964(2); Zn1-O2 ) 1.947(2); O2-Zn1-O1
) 99.21(9); N2-Zn1-N1 ) 87.4(1).
a carboxylato group is quite rare in Zn chemistry, except for
the recently reported structure of Zn(OAc)2Py2.23
The zinc carboxylate, converted into the monomeric form B
by the action of the bidentate amine, catalyzes the enantiose-
lective reduction (Table 2, entry 40) of ketones using PMHS
as a source of hydrido species. The activity of complex B can
be enhanced by the addition of hydride reducing agents such
as NaBH4, LiAlH4, LiH, or Vitride (entries 41-44).24 The
amount of Vitride necessary to activate the complex B was
optimized to 1.5 mol equiv of NaAlH2(OR)2 per zinc atom. This
allowed us to easily prepare homogeneous, ready-to-use,
inexpensive (R)- or (S)-carbinol forming catalytic solutions in
toluene containing Zn(dea)2 (1 equiv, ca. 20 wt %), (S,S)- or
(R,R)-ebpe (1 equiv), and Vitride (1.5 equiv), which can be
stored for months without deactivation. These catalytic solutions
were found more convenient to use than the diethylzinc catalyst,
which is expensive and hazardous. The experimental procedure
for the enantioselective reduction of ketones, which has been
carried out on a kilogram scale thus conveniently consists of
(i) adding PMHS (1.1 equiv) to the substrate containing the
catalytic solution (2 mol % Zn), (ii) stirring the mixture at room
temperature until completion of the reaction (ca. 12 h), (iii)
hydrolyzing the reaction mixture with concentrated aqueous
The structure of complex B [Zn(dea)2‚(S,S)-ebpe] has been
elucidated by X-ray crystal structure. The reaction occurs with
the depolymerization22 of the zinc carboxylate and the formation
of the monomeric species, B, where the carboxylato group
displays an η1-O monodentate bonding mode. The depolymer-
ization reaction can be monitored by the FT IR bands of the
[Zn(dea)2]n precursor [ν(CO2)as at 1630 (syn-syn), 1546 cm-1
(syn-anti), and ν(CO2)s at 1429 cm-1], changing into ν(CO2)as
at 1590 and ν(CO2)s at 1397 cm-1 bands of B.
The structure is shown in Figure 3 with some significant
structural parameters. The η1-O monodentate bonding mode of
(22) (a) Berkesi, O.; Dreveni, I.; Andor, J. A.; Mink, J. Inorg. Chim.
Acta 1992, 195, 169. (b) Goldschmied, E.; Rae, A. D.; Stephenson, N. C.
Acta Crystallogr. 1977, B33, 2117. (c) Clegg, W.; Little, I. R.; Straugham,
B. P. J. Chem. Soc., Dalton Trans. 1986, 1283. (d) Gordon, R. M.; Silver,
H. B. Can. J. Chem. 1983, 61, 1218.
(23) Singh, B.; Long, J. R.; Fabrizi de Biani, F.; Gatteschi, D.;
Stavropoulos, P. J. Am. Chem. Soc. 1997, 119, 7030.

6162 J. Am. Chem. Soc., Vol. 121, No. 26, 1999
Mimoun et al.
Table 3. Enantioselective Reduction of Various Ketones by PMHS
in the Presence of ZnEt2‚(R,R)-ebpe (System A) and
Zn(dea)2‚(R,R)-ebpe + Vitride (System B) (2 mol % Zn, 2 mol %
ebpe, 3 mol % Vitride, toluene, room temperature)
enantioselective hydrosilylation of ketones using PMHS, we
performed some model studies, looking at the reactivity of well-
characterized zinc complexes in the presence of silanes.
Alkyl and Hydride Zinc Complexes with (Dimethylami-
no)ethanol (DMAE). Chiral amino alcohols such as DAIB (14)
have been successfully used as auxiliary ligands for the
enantioselective alkylation of carbonyl compounds by alkyl zinc
species,26 but their use in the present study was only marginally
successful. Dimeric [EtZn(DMAE)]2 (C) and [HZn(DMAE)]2
(E) were prepared according to literature methods,27 and their
reactivity was briefly investigated (eqs 4 and 5). Complex C
does not react with benzaldehyde but reacts with (EtO)3SiH in
pentane to give a white solid, presumably EtZnH, which turns
gray at room temperature and evolves hydrogen in contact with
a protic source, together with the formation of (EtO)3Si(OCH2-
CH2NMe2) (D). This latter compound, which has been charac-
terized by 1H NMR, results from anion exchange between zinc
and silicon (eq 4).
The dimeric hydrido zinc complex E reacts with (EtO)3SiH
to give ZnH2 and (EtO)3Si(OCH2CH2NMe2) (D). It also reacts
with benzaldehyde to give a zinc alkoxy species with presumed
structure, F, which upon reaction with 1 equiv of (EtO)3SiH
1
gives a product exhibiting the same H NMR pattern as the
initial complex E (eq 5). Thus, the hydrido complex E appears
as a possible model for the hydrosilylation catalyst, although
the facile transfer of the alkoxo (dimethylamino)ethanol ligand
from Zn to Si severely limits the catalyst life and the use of
amino alcohols as ligands for the enantioselective hydrosilyla-
tion.
KOH or NaOH (1.2 equiv), and (iv) distilling the resulting chiral
alcohol in vacuo. The ligand can be recovered in pure form
and high yield by distillation from residues and reused for a
next run.
The possibility to use other metal carboxylates, reported to
be active in assisting the reduction with PMHS,18 in the
enantioselective reduction of acetophenone, has been explored
(Table 2). Mn(II), Fe(II), Sn(II), Ni(II), and Cu(II) carboxylates
or alkoxides,25 in conjunction with ebpe and in the presence or
absence of hydride activators, were found inactive and not
enantioselective. Other metals showing an interesting catalytic
activity were cadmium diethyl acetate (entries 45-46), which
was also active in the absence of any hydrido species, though
less enantioselective than [Zn(dea)2] (62 vs 75% ee with ebpe,
81 vs 88% ee with ligand 5c), and cobalt diethyl acetate (entry
48) in the presence of ebpe (58% ee at 60 °C).
Both zinc catalytic systems A [ZnEt2‚ebpe] and B [Zn(dea)2‚
ebpe + Vitride] were used for the enantioselective reduction
of various ketones, giving similar yields and ee’s, as shown in
Table 3. As for most systems allowing enantioselective reduction
of ketones,1 the present zinc catalytic species are particularly
well adapted for the reduction of acetophenones, acetonaph-
thones (entries 55 and 57), R-tetralone (entry 58), or acetyl-
thiophene (entry 59), where the two substituents adjacent to the
carbonyl moiety are well differentiated. Substrates such as
cyclohexyl methyl ketone (entry 59) or â-ionone (entry 60) are
reduced with much lower ee’s. (<20%).
Alkyl and Hydride Zinc Complexes with Diamines. Since
alkoxo ligands easily transfer from zinc to silicium, we
investigated the use of chelating amido-amino and bis-amino
ligands. The dimeric hydrido complex G28 reacts very slowly
with (EtO)3SiH to give insoluble ZnH2 and the silazane H (eq
(24) Vitride is the trademark of NaAlH2(OCH2CH2OCH3)2, conditioned
as a 70 wt % solution in toluene.
(25) The metal alkoxides were generated in situ from the reaction of
metal chlorides with potassium tert-pentylate in THF.
(26) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30,
49 and references therein.
(27) (a) Bell, N. A.; Kassyk, A. L. J. Organomet. Chem. 1988, 345,
245. (b) Bell, N. A.; Kassyk, A. L. Inorg. Chim. Acta 1996, 250, 345.
(28) Bell, N. A.; Moseley, P. T.; Shearer, H. M. M.; Spencer, C. B. J.
Chem. Soc., Chem. Commun. 1980, 359. Complex G has been characterized
by X-ray crystal structure, and recently shown to reduce ketones. (see ref
27b).
Mechanistic Studies. Is the Ancillary Ligand a Spectator
or an Actor? In an attempt to clarify the mechanism of the

EnantioselectiVe Reduction of Ketones
J. Am. Chem. Soc., Vol. 121, No. 26, 1999 6163
Scheme 1. Reduction of Carbonyl Compounds by
ZnEt2·ebpe and Evidence for a Metallacycle Intermediate
Figure 4. X-ray crystal structure of complex La (hydrogens have been
omitted for clarity). Selected bond distances (Å) and angles (deg):
Zn1-O1 ) 2.02(2); Zn1-O2 ) 1.96(2); Zn2-O1 ) 2.05(2); Zn2-
O2 ) 2.02(2); Zn1-N2 ) 2.17(2); Zn2-N4 ) 2.14(2).
with the carbonyl functionality. The conformation of the seven-
membered metallacycle is a slightly distorted boat. The absolute
configurations of the chiral carbon atoms are as follows: C3,
R; C10, S; C18, S; C28, S; C35, S; C43, S.21 The conformations
of C3, R and C28, S as from the structure of La reveal that we
fished out in the solid state the R,S form rather than the active
R,R or S,S species. It should be emphasized that the metal
complexation stabilizes a quite unusual and unstable form of a
gem-amino alcohol. The O2-C28 and N3-C28 bond lengths
(1.47 and 1.55 Å, respectively) are not far from a typical
O-C(sp3) and N-C(sp3). In addition, the sum of the dihedral
angles for C28 (331°) clearly shows that it is sp3 hybridized.
The same insertion of carbonyl group into the Zn-N bond
also occurs with acetophenone, and the resulting complex Lb
has similar NMR spectra and probably the same dimeric seven-
ring structure.
Both complexes La and Lb have catalytic activities similar
to that of ZnEt2‚ebpe complex A′ and gave similar ee’s (∼75%)
in the reduction of acetophenone under standard conditions.
Further, Lb reacts at room temperature with 1 equiv of PMHS
to give (R)-methylphenylcarbinol with 78% ee after hydrolysis
with aqueous NaOH. When Lb is used as catalyst (10 mol %)
for the PMHS (1.2 equiv) reduction of propiophenone (1 equiv)
in toluene, both (R)-ethylphenylcarbinol (100% yield, 80% ee)
and (R)-methylphenylcarbinol (10% yield, 78% ee) were
obtained after hydrolysis. This shows that both included and
external ketone substrates are reduced with similar ee’s30 and
suggests that an exchange may occur between the incorporated
ketone and the external one through a reverse equilibrium
between the amino alcoholate K and the zinc amide complex
K′ bearing the coordinated carbonyl substrate.31
6), thus confirming that N-donor ligands are less labile than
O-donor ligands and, therefore, more suitable for the hydro-
silylation.
We have further investigated the reactivity of ZnEt2‚(S,S)-
ebpe (A′) characterized by X-ray crystal structure (as the
dimethyl analogue A), toward carbonyl compounds and silanes.
Both A and A′ are quite thermally stable and do not easily
eliminate methane or ethane, respectively, at room temperature.
Complex A′ is conformationally fluxional, as shown by the fact
that a single set of signals is observed by 1H NMR, even when
either ZnEt2 or ebpe is used in excess. Concentrated solutions
of ZnEt2‚ebpe slowly react with benzaldehyde or acetophenone
to give products, La (R ) H) and Lb (R ) Me), respectively,
with release of ethane (see Scheme 1). Both are characterized
1
by rather complex H NMR spectra, and no further study was
undertaken to assign the signals. On the basis of the structure
determined for La, we suggest a pathway leading to the dimeric
structure and the seven-membered metallacycle (see Scheme
1). The coordination of the carbonyl functionality to A′ (see I)
is followed by the reaction of the amine with the carbonyl group,
resulting in the formation of an amino alcohol J,29 which is
readily deprotonated by ZnEt2 with loss of ethane and formation
of the metallacycle K. The latter contains a three-coordinated
zinc, which collapses to a dimer, in which zinc achieves the
stable tetracoordination. The structure of La is displayed in
Figure 4 with some relevant structural parameters.21 The two
zinc atoms are in a tetrahedral coordination environment, and
they are bridged in a dimeric structure via the oxygen of the
gem-aminoalkoxy group derived from the reaction of the ligand
This unprecedented mechanism is not only relevant to the
present enantioselective hydrosilylation but could, eventually,
be extended to nondeprotonable chiral diimines or tertiary
diamine ligands.32 Moreover, the proposed mechanism may shed
some light on the recently reported Noyori’s RuCl2(phosphine)n
+ diamine system, which efficiently acts as a selective achiral
and chiral ketone hydrogenation catalyst.9
(30) We thank a reviewer for this pertinent suggestion.
(31) Arvidsson, P. E.; Davidson, O.; Hilmersson, G. Tetrahedron:
Asymmetry 1999, 10, 527.
(32) Cozzi, P. G.; Veya, P.; Floriani, C.; Rotzinger, F. P.; Chiesi-Villa,
A.; Rizzoli, C. Organometallics 1995, 14, 4092 and references therein.
(29) Bergmann, E. D. Chem. ReV. 1953, 53, 309.

6164 J. Am. Chem. Soc., Vol. 121, No. 26, 1999
Mimoun et al.
Scheme 2. Mechanisms to Interpret the Enantioselective
Reduction of Ketones
Figure 5. Modelization by PM3 of the transition states M, N, and P
according to mechanisms A-C.
carbonyl moiety, giving the (R)-carbinol. Reduction of the
carbonyl substrate could then occur by Zn-H or Si-H
according to mechanism A or B.
Mechanistic Considerations. On the basis of the experi-
mental data so far available, we can suggest three different
mechanisms, the former two being very closely related (Scheme
2):
Mechanism A. Hydrogen transfers from Zn-H to the
carbonyl compound bonded to zinc in a fifth coordination site
(transition state M). This reaction has been shown to occur with
isolated zinc hydride complexes such as E and G28b and is
confirmed in this study (eq 5).
Mechanism B. Zinc hydride forms an adduct with the silane
in which SiH bonds are activated in a reactive pentavalent
hydridosilicate associated to the zinc Lewis acid center. As for
LiAlH4 and Zn(BH4)2, hydrogen is transferred in a concerted
way to the CdO coordinated to zinc in a six-membered ring
transition state N. This mechanism has previously been sug-
gested by us on the basis of steric effects of PMHS in
comparison with monomeric silanes and of ester reduction.18
Mechanism C. The coordinated carbonyl compound inserts
between zinc and a deprotonated coordinated secondary diamine
(intermediate P) according to Scheme 2. In the latter case, the
diamine, unlike in mechanisms A and B, not only is an ancillary
ligand but is presumably involved in the substrate activation.
Although speculative yet, the catalytic cycle shown in Scheme
2 may involve intramolecular displacement of an amido leaving
group by hydride with retention of configuration at the carbinol
carbon atom.30 Alternatively, the amino alcoholate P may revert
to the zinc amide O (see also K and K′ in Scheme 1) with
reformation of the carbonyl compound. In this case the reversible
formation of the amino alcoholate only serves to put the carbonyl
substrate in the right position to present the si face to the
The two hypothetical transition states M and N and the
intermediate P can be visualized using semiempirical PM3
calculations33 with constrained distances based on X-ray crystal
structures of the (S,S)-ebpe complexes A, B, and La shown in
Figures 2, 3, and 4, respectively. Acetophenone was chosen as
the substrate for the three models. The tetrahedral zinc
complexes A and B bearing (S,S)-ebpe ligand with a C2
symmetry have two stereochemically equivalent sites occupied
by alkyl or carboxylate groups. The two nitrogen atoms of the
ligand play a key role in transmitting the chirality of the adjacent
carbon atoms to the metal coordination sites. Chiral recognition
of the substrate is controlled by the nitrogen substituents which
create a classical asymmetric quadrant around the zinc atom.
All three models can be used to interpret the chiral recognition
of the substrate, with the (S,S)-ebpe ligand giving preferentially
the (R)-carbinol.
In intermediate M representing the reaction of ZnMeH‚(S,S)-
ebpe with acetophenone, hydrogen transfer occurs in the empty
quadrant (Figure 5). The two possible orientations of the ketone
are represented in models M1 and M2. Intermediate M1, which
gives the (R)-carbinol, is probably favored owing to a lower
steric constraint of the methyl group of acetophenone with the
ligand.
In intermediate N representing the reaction of ZnMeH‚(S,S)-
ebpe with SiH4 and acetophenone, hydrogen transfers from
pentavalent Si-H via a pseudo-chair conformation. Preference
for the si face of acetophenone can be explained by the
unfavorable pseudo-1,3-diaxial interaction of the substrate with

EnantioselectiVe Reduction of Ketones
J. Am. Chem. Soc., Vol. 121, No. 26, 1999 6165
Preparation of Ligands. Chiral cyclohexanediimines 1a-e were
easily prepared from the reaction of (R,R)-cyclohexanediamine tartrate34
with the corresponding aldehyde; diimines 2a,b and 3 were prepared
from 2,3-butanedione and glyoxal, respectively, with R-phenylethyl-
amine;33 chiral diamines 4b-f, 5a-g, and 7 were kindly provided as
samples by Prof. A. Alexakis (University Geneva);36 ligand 8 was
readily made from inexpensive glutamic acid and aniline, followed by
LiAlH4 reduction;37 chiral tertiary diamines 9 and 10 were prepared
according to the literature;38 chiral amino alcohols (11-15) are
commercial products, except (-)DAIB (14), which was kindly provided
by Prof. Kagan (University Orsay); ligands 16 and 17 were prepared
according to the literature.39
(R,R)-N,N′-Bis(1-naphthalenylmethylene)-1,2-cyclohexanedi-
amine (1a). (R,R)-Cyclohexanediamine tartrate (7 g, 26.0 mmol) and
solid K2CO3 (7.3 g) were dissolved in 35 mL of H2O and 130 mL of
ethanol. Then 1-naphthaldehyde (8.2 g, 52.0 mmol) was added, and
the mixture was stirred for 3 h at room temperature. A white-cream
solid precipitates, which is filtered, washed with EtOH-H2O mixture,
and then recrystallized in hot ethanol (75%).
the methyl group coordinated to zinc. As shown in Figure 5,
the model N1 gives the less unfavorable steric conformation
for the formation of the (R)-carbinol.
In intermediate P representing the reaction of ZnMe‚(S,S)-
ebpe (deprotonated) with acetophenone, the chirality of the
carbinol is determined by the attack of the deprotonated amido
nitrogen atom on the ketone coordinated to zinc. Four confor-
mations can be envisaged to model this transition state (Figure
5). The lowest energy transition state P4 allows the formation
of the (R)-isomer from the (S,S)-ligand. As shown in Figure 5,
P3 is probably disfavored by the highest steric constraint of the
phenyl group of acetophenone with the ligand, while P1 and P2
have relative energies superior to 3.5 kcal/mol.33
Thus, all three mechanisms A-C are compatible with the
observed enantioselectivity in the reduction of ketones by
PMHS.
Conclusion
Diimines 1b-g were prepared according to the same procedure in
good yields.40
We have extended the PMHS technology to the enantio-
selective reduction of ketones using zinc catalysts activated by
chiral diamines or diimines. The procedure is safe, inexpensive,
simple, and gives carbinols in either (R)- or (S)-configuration
with high yields and ee’s. The procedure has been carried out
on a 1 kg scale without scale-up problems. Moreover, the
inexpensive ebpe ligand is recovered at the end of the reaction
by simple distillation from residues and reused for a next
operation. Thus, in terms of cost, the present enantioselective
process is only slightly more expensive than the achiral one.18
Further work is being carried out to further increase the ee’s
over 90% and to extend the scope of the reaction.
(R,R)-N,N′-Ethylenebis(1-phenylethylamine) (ebpe, 6).41 1,2-Di-
bromoethane (170 g, 900 mmol) was added over 30 min with
temperature control to (R)-R-phenylethylamine (440 g, 3630 mmol)
heated to 130 °C. After cooling to 80 °C, the mixture was hydrolyzed
with 283 g of aqueous KOH 45% to remove KBr. The organic phase
was then distilled in vacuo to give first 9 g of recoverable starting
amine, then 192 g of (R,R)-ebpe with a 98% purity (bp ) 130 °C, 1
mbar, [R]D ) +65°) (77%). The (S,S)-ebpe ligand was prepared in the
same way from (S)-R-phenylethylamine.
(R,R)-2,2′-(1,2-Cyclohexylidene)diisoindole (10). This compound
was prepared in the same way as described for ligand 9.38 (R,R)-
Cyclohexanediamine (5 g, 43 mmol), dichloro-o-xylene (16 g, 90
mmol), and triethylamine (36 g) were mixed at 0 °C in CH2Cl2 (50
mL) over 1 h, then the mixture was refluxed at 60 °C for 7 h. After
being cooled to 5 °C, the mixture was washed 3 times with H2O (50
mL), then dried with Na2SO4. Addition of diethyl ether (20 mL) resulted
in the precipitation of a white solid which was crystallized in a CH2-
Cl2-Et2O mixture (60%).13C NMR (CDCl3, 25 °C): 20.91 (t), 24.63
Experimental Section
General Procedure. Chemicals described in this study were all
reagent grade purchased from Fluka or available in bulk quantities from
Firmenich S.A. PMHS used in this study (Mw ) 2200; specific gravity
at 25 °C ) 1; 1.55 wt % H) was obtained from Rhone Poulenc (trade
name Rhodorsil Hydrofugeant 68), but PMHS from other suppliers
(Aldrich, Hu¨ls, Bayer) was found suitable as well. The molecular weight
of PMHS was taken equal to 65 for stoichiometry calculation. Zinc,
iron, manganese, tin, and cobalt 2-ethylhexanoates (metallic soaps) were
commercially available from OMG-Vasset but can also easily be
prepared from the reaction of metal oxide, carbonate, or acetate with
2-ethylhexanoic acid in toluene at 120 °C, with azeotropic distillation
of water or acetic acid. Zinc diethyl acetate Zn(dea)2 was prepared from
the reaction of ZnO with diethylacetic acid (2 equiv) in toluene under
reflux with azeotropic distillation of water. All compounds were
(t), 57.05 (t), 62.60 (d), 122.30 (d), 126.60 (d), 140.08 (s). [R]D
-63.2°.
)
Preparation of Zinc Complexes. Zn(CH3)2[(S,S)-N,N′-ethyl-
enebis(1-phenylethylamine)] (A). A toluene solution of ZnMe2 (6.5
mL, 1.5 M, 9.7 mmol) was added to a solution of (S,S)-ebpe (6) (2.50
g, 9.33 mmol) in toluene (50 mL). A white precipitate forms before
the end of the addition. Volatiles were removed in vacuo, then pentane
(60 mL) was added to the residue. White complex A was collected
and dried in vacuo (2.9 g, 85%). Crystals suitable for X-ray structure
were grown in CH2Cl2/C6H6 at 9 °C. Anal. Calcd for C20H30N2Zn: C,
1
66.02; H, 8.31; N, 7.69. Found: C, 66.7; H, 8.21; N, 7.73. H NMR
1
characterized by GC-MS and H and 13C NMR. NMR spectra were
(CD2Cl2, 25 °C): δ 7.07 (m), 6.76 (m), 3.54 (m, 2H), 1.82 (m, 2H),
1.63 (m, 2H), 1.39 (d, 6H, J ) 6.8 Hz), 1.23 (m, 2H), -0.29 (s, 6H).
Zn(C2H5)2[(S,S)-N,N′-ethylenebis(1-phenylethylamine)] (A′). ZnEt2
(1.43 g, 11.3 mmol) and (S,S)-ebpe (6) (3.0 g, 11.3 mmol) were mixed
in toluene (80 mL). Volatiles were removed in vacuo, then pentane
(50 mL) was added to the residue. The resulting suspension was cooled
at -25 °C overnight, and finally A′ was collected and dried in vacuo
(3.16 g, 71%). Anal. Calcd for C22H34N2Zn: C, 67.42; H, 8.74; N,
recorded in CDCl3 at 360 MHz with a Bruker AMX spectrometer. All
1H NMR spectra are reported in δ units, parts per millions (ppm)
downfield from tetramethylsilane. All 13C NMR spectra are reported
in ppm referenced to CDCl3. Enantiomeric excesses (ee ) 100(R -
S)/(R + S)) were determined by chiral GC analysis using a Chrompack
CP-Chirasil-dex-CB 25 m capillary column.
(33) All calculations were carried out on a SGI R10000 computer using
the SPARTAN V5.0 program (Wavefunction, Inc., Irvine, CA, 1997). The
geometries of the structures were obtained by PM3 energy calculations
which incorporate parameters for Zn and Si. The lengths of the bonds
involved in the mechanism were controlled by hypothetical distance
constrains. The distances (in Å) were chosen as follows: Zn-O ) 2.1,
Zn-N ) 2.1, Zn-H ) 2.0, Si-H ) 1.8, C-O ) 1.4, C-N ) 1.8, C-H
) 1.8. Additional constraints were needed to control the geometries of M2,
N1, and N2. Thus, this method cannot be considered as a “true” transition
state calculation which is out of the scope of this paper. However, the
geometry of the complexes obtained by this method can be used to discuss
the three mechanisms. Energies of the complexes must be considered as
less significant. Only the energy differences superior to 3.5 kcal/mol were
considered in the discussion. PM3 energies (in kcal/mol) were as follows:
M1, 86.7; M2, 85.0; N1, 117.3; N2, 122.8; P1, 74.4; P2, 79.2; P3,72.2; P4,
70.8.
(34) Larrow, J. F.; Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp,
C. M. J. Org. Chem. 1994, 59, 1939.
(35) Tom Dieck, H.; Dietrich, J. Chem. Ber. 1984, 117, 695.
(36) Alexakis, A.; Mangeney, P. AdVanced Asymmetric Synthesis;
Stephenson, G. R., Ed.; Chapman & Hall: London, 1996, p 93 and
references therein.
(37) Iriochijima, S. Synthesis 1978, 684.
(38) Corey, E. J.; Sarshar, S.; Azimiora, M. D.; Newbold, R. C.; Noe,
M. C. J. Am. Chem. Soc. 1996, 118, 7851.
(39) Brunner, H.; Reiter, B.; Riepl, G. Chem. Ber. 1984, 117, 1330.
(40) NMR spectra are reported in the Supporting Information.
(41) This is a modified procedure from the original method using 1,2-
dichloroethane and R-phenylethylamine. Horner, L.; Dickerhof, K. Liebigs
Ann. Chem. 1984, 1240.

6166 J. Am. Chem. Soc., Vol. 121, No. 26, 1999
Mimoun et al.
1
7.15. Found: C, 67.51; H, 8.74; N, 7.06. H NMR (CD2Cl2, 25 °C):
spectra consisting of the superimposition of PhCHO and A′. After 1
day at room temperature, volatiles were removed in vacuo, pentane
was added to the residue, the resulting suspension was cooled at -25
°C overnight, and finally La was collected and dried in vacuo (2.6 g,
40%). Anal. Calcd for C27H35N2OZn: C, 69.15; H, 7.52; N, 5.97.
Found: C, 68.95; H, 7.64; N, 5.76. 1H NMR (C6D6, 25 °C): δ 9.64 (s,
PhCHO), 7.9-6.9 (m), 6.27 (b), 5.68 (s), 5.60 (s), 4.0 (m), 3.54 (m),
3.3-2.5 (m), 1.93 (m), 1.83 (m), 1.33 (d), 1.23 (d), 1.19 (d), 1.13 (d),
1.05 (d), 0.90 (m), 0.67 (m), 0.5 (m). Crystals suitable for X-ray analysis
were grown in pentane at -25 °C, which exhibited the same 1H NMR
spectra as the reaction mixture of A′ and PhCHO, after standing for
24 h. When the reaction was carried out in an NMR tube in C6D6,
evolution of ethane was observed (singlet at 0.80 ppm).
Reaction of ZnEt2‚(S,S)-ebpe A′ with Acetophenone. Synthesis
of the Dimeric Complex Lb. ZnEt2 (2.07 g, 16.7 mmol), (S,S)-ebpe
(4.49 g, 16.8 mmol), and acetophenone (2.0 g, 16.6 mmol) were mixed
in toluene to give a yellow solution. After 1 day at room temperature,
volatiles were removed in vacuo, pentane was added to the residue to
give a yellow oil which became a yellow powder after triturating with
cold pentane (2.68 g, 5.56 mmol). Anal. Calcd for C28H36N2OZn: C,
69.77; H, 7.53; N, 5.81. Found: C, 66.94; H, 6.74; N, 4.69. 1H NMR
(C6D6, 25 °C): δ 8.03 (m), 7.82 (m), 7.3-6.8 (m), 6.63 (m), 6.04 (s),
5.58 (m), 4-1.15 (b), 1.51 (J ) 8.3 Hz), 1.36 (d), 1.21 (d), 0.41 (q, J
) 8.3 Hz). When the reaction was carried out in an NMR tube in C6D6,
evolution of ethane was observed (singlet at 0.80 ppm).
Enantioselective Reduction of Acetophenone. Method A. In a
three-necked 1 L flask, ZnEt2 (33.2 mL, 1 M in toluene, 33 mmol) and
(S,S)-ebpe (6) (8.84 g, 33 mmol) were dissolved in 100 mL of toluene
for the formation of complex A′. Then 200 g of acetophenone (1.66
mol) was added, and 130 g of PMHS (2 mol) was added to the mixture
in 30 min, keeping the temperature between 25 and 30 °C. After 24 h
at room temperature, all the acetophenone was consumed (GC control
of an aliquot sample hydrolyzed by KOH 15%). The reaction mixture
was poured cautiously on 375 g of KOH (45%) (Caution: eVolution of
H2!) in ca. 30 min. The aqueous phase containing potassium polym-
ethylsiliconate was discarded, and the organic phase was concentrated
in vacuo, then methylphenylcarbinol was recovered by distillation in
vacuo (190 g, 94% yield, 99% purity, 75% ee (R)). The same results
were obtained using 4 times less (S,S)-ebpe (8.25 instead of 33 mmol).
Method B. In a three-necked 1 L flask, Zn(dea)2 (2.95 g, 10 mmol)
and (S,S)-ebpe (2.68 g, 10 mmol) were dissolved in toluene (100 mL)
to form complex B. Then, a 70% solution of Vitride (2 g) in toluene
was added. After the release of H2 stops, 120 g of acetophenone (1
mol) was introduced, followed by 70 g of PMHS (1.08 mol). The
reaction mixture was stirred 24 h at room temperature until complete
consumption of the substrate. Then the mixture was cautiously poured
on a 45% aqueous solution of KOH. After concentration of the solvent,
methylphenylcarbinol was recovered by distillation (116 g, 95% yield,
99% purity, 75% ee (R)).
7.07 (m), 6.76 (m), 3.54 (m, 2H), 1.82 (m, 2H), 1.63 (m, 2H), 1.39 (d,
6H, J ) 6,8 Hz), 1.23 (m,2H), -0.29 (s,6H). IR (Nujol, νmax cm-1):
1
3283 (m). H NMR (CD2Cl2, 25 °C, δ ppm): 7.36-7.23 (m, 10H),
3.75 (m, 2H), 2.45 (m, 2H), 2.23 (m, 2H), 1.85 (m, 2H), 1.50 (d, 6H,
J ) 6.8 Hz), 1.3 (t, 6H, J ) 8.1 Hz), -0,04 (m, 4H).
Zn(Et2CHCO2)2(S,S)-ebpe (B). To a solution of Zn(dea)2 (3 g, 10
mmol) in diisopropyl ether (50 mL) was added (S,S)-ebpe (6) (3.1 g,
10 mmol). A white solid precipitates which was filtered, washed with
pentane, and dried in vacuo (4.2 g, 73%). Crystals suitable for X-ray
structure were grown in cyclohexane. 1H NMR: δ 0.95 (tt, 12H, CH3-
CH2), 1.55 (d, 6H, CH3-CH), 1.6-1.7 (m, 8H, CH2-CH), 2.3 (m,
2H, CH-CdO), 2.55-2.8 (m, 4H, CH2-NH), 3.8 (m, 2H, CH-NH),
7.2-7.4 (m, 10H, arom). 13C NMR (δ (ppm)): 12.37, 12.42 (q, CH3),
23.36 (q, CH3), 25.99 (t, CH2), 46.42 (t, CH2-NH), 51.15 (d, CH),
58.91 (d, CH), 126-129 (d,d,d), 141.19 (s), 184.9 (s, CO2).
[ZnEt(OCH2CH2NMe2)]2 (C).31 ZnEt2 (18 mL, 1 M in hexane, 1.8
mmol) was added to a solution of 2-dimethylethanolamine (1.6 g, 1.8
mmol) in DME. Volatiles were removed in vacuo, and the residue was
taken up in n-hexane (40 mL). After keeping the flask 24 h at -25 °C,
C was collected as microcrystalline solid (1.7 g, 55%). Anal. Calcd
for C6H15NOZn: C, 39.47; H, 8.28; N, 7.67. Found: C, 40.0; H, 8.69;
N, 7.57. H NMR (C6D6, 25 °C): δ 4.01 (b), 3.78 (m), 3.65 (b), 2.7
(b), 2.20 (bm), 2.08 (s), 1.73 (m), 1.55 (m).
Reaction of C with (EtO)3SiH and Preparation of D. Complex C
(4.43 g, 24.3 mequiv) was reacted with (EtO)3SiH (4 g, 24.3 mmol) in
DME (100 mL). H NMR of the raw mixture (a sample was taken to
1
1
dryness in vacuo in a glovebox and dissolved in C6D6) showed that
1
the starting material had been consumed. H NMR (C6D6, 25 °C): δ
3.89 (m), 3.45 (b), 2.45 (m), 2.21(s), 2.13 (s), 1.67 (t, 3H, J ) 8.3 Hz),
1.87 (m), 0.48 (q, 2H, J ) 8.3 Hz). After standing overnight at room
temperature, some white solid formed; it was filtered off, volatiles were
removed in vacuo, and pentane was added to the resulting grayish solid
to give a white, sticky solid (D). H NMR (C6D6, 25 °C): δ 3.88 (m,
9H), 2.42 (m, 2H), 2.09 (m, 9H), 1.68 (t, 3H, J ) 8.3 Hz, 1.18 (m,
9H), 0.46 (q, 2H, J ) 7.8 Hz).
[ZnH(OCH2CH2NMe2)]2 (E). Dimethylethanolamine (1.98 g, 22.2
mmol) was added to a suspension of ZnH2 (1.5 g, 22.2 mmol) in THF,
prepared from the reaction of ZnEt2 with LiAlH4. Hydrogen evolution
was observed, and a white precipitate of E was collected and dried in
vacuo. Anal. Calcd for C4H11NOZn: C, 31.09; H, 7.17; N, 9.06.
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Found: C, 31.15; H, 7.29; N, 8.79. H NMR (C6D6, 25 °C): δ 4.28
(s), 3.88 (b), 2.13 (s), 0.49 (b).
Reaction of E with (EtO)3SiH. (EtO)3SiH (0.91 g, 5.5 mmol) was
added to a solution of E (0.86 g, 5.56 mequiv) in THF (100 mL). The
reaction mixture turned milky within minutes. H NMR of the raw
reaction mixture (a sample was taken to dryness and suspended in
C6D6): δ 4.01 (t, 2H, J ) 6.3 Hz), 3.89 (q, 6H, J ) 6.8 Hz), 2.49 (t,
2H, J ) 6.3 Hz), 2.13 (s, 6H, Me), 1.19 (t, 9H, J ) 6.8 Hz).
Reaction of E with Benzaldehyde, then (EtO)3SiH. PhCHO (0.66
g, 6.2 mmol) was added to a solution of E (0.95 g, 6.15 mequiv) in
DME (100 mL). H NMR of the raw reaction mixture (a sample was
taken to dryness and suspended in C6D6): δ 7.66 (b), 7.28 (b), 7.05
(b), 5.26 (b), 4.27 (b), 3.87 (b), 3.63 (b), 2.22 (b), 1.89 (b). (EtO)3SiH
(1 g, 6.1 mmol) was added to the reaction mixture. H NMR of the
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Acknowledgment. H.M. thanks MM Joe¨l Pastori and Daniel
Soares for their invaluable technical assistance. We thank also
Prof. A. Alexakis (Geneva University) for providing samples
of ligands 4b-f, 5a-g, and 7 and for helpful discussion.
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Supporting Information Available: X-ray crystallography
data, descriptions of the structures, tables of crystallographic
data for A, B, and La, and NMR spectra of ligands and
complexes. This material is available free of charge via the
Internet at http://pubs.acs.org.
raw reaction mixture (a sample was taken to dryness and suspended in
C6D6) δ 7.36 (m), 4.92 (s), 4.89 (s), 4.86 (s), 4.28 (bs), 3.87 (m), 2.13
(bs).
Reaction of ZnEt2‚(S,S)-ebpe A′ with Benzaldehyde. Synthesis
of the Dimeric Complex La. ZnEt2 (1.80 g, 14.6 mmol), (S,S)-ebpe
(3.77 g, 14 mmol), and benzaldehyde (1.66 g, 15.6 mmol) were mixed
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in toluene to give a yellow solution which exhibited in H NMR a
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