Asymmetric reduction of ketones with sodium aluminum hydride modified with chiral amino alcohols

Article abstract of DOI:10.1023/A:1011307125755

Asymmetric reduction of ketones with hydride complexes, which were prepared by in situ modification of NaAlH₄, with various chiral amino alcohols or diamines, was studied. The highest enantioselectivity (up to 93% ee) was achieved using 2-(hydroxydiphenyl-methyl)pyrrolidine as a chiral inducing agent.

Full text of DOI:10.1023/A:1011307125755

Russian Chemical Bulletin, International Edition, Vol. 50, No. 5, pp. 843—845, May, 2001
843
Asymmetric reduction of ketones with sodium aluminum hydride modified
with chiral amino alcohols
M. G. Vinogradov,a« O. V. Mikhalev,a V. A. Pavlov,a V. A. Ferapontov,a O. R. Malyshev,a and G. L. Heise b
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. E-mail: ving@cacr.ioc.ac.ru
bCambrex Corporation, One Meadowlands Plaza, East Rutherford, NJ 07073, USA
Asymmetric reduction of ketones with hydride complexes, which were prepared by in situ
modification of NaAlH4, with various chiral amino alcohols or diamines, was studied. The
highest enantioselectivity (up to 93% ee) was achieved using 2-(hydroxydiphenyl-
methyl)pyrrolidine as a chiral inducing agent.
Key words: ketones, sodium aluminum hydride, chiral alcohols, amino alcohols, di-
amines, asymmetric reduction.
Scheme 1
Catalytic methods for asymmetric hydrogenation have
been developed intensively in recent years.1,2 Simulta-
neously, reduction with chiral aluminum-hydride re-
agents, which proceeds under mild conditions and does
not require special chemical apparatus for operations
with hydrogen under pressure, have attracted attention
of researchers.3,4
–
*
*
N
H
X
Na+
2 H2
+
NaAlH4
N
H
X
+
Al
H
H
L
Recently, we have demonstrated5 that asymmetric
reduction of ketones by some hydride reagents, which
were prepared by modification of NaAlH4 with chiral
diols, proceeds with higher enantioselectivity than re-
duction by analogous LiAlH4 derivatives. This fact gave
impetus to studies of the stereochemistry of reduction of
ketones by hydride complexes based on NaAlH4 which
contain chiral 1,2-N,O- or 1,2-N,N-bidentate ligands.
These complexes have not been used previously as chiral
reducing agents. The results of this investigation are
discussed in the present work.
1
X = O or NR
Ph
Ph ;
OH
Ph
Ph
L:
N
H
;
;
N
H
N
H
OH
HO
2
3
4
Ph
Results and Discussion
;
N
H
;
Ph
NH
Me2N
OH
We prepared chiral dihydride reagents with the as-
sumed structures 1 by the in situ reactions of NaAlH4
with equimolar amounts of bidentate amino alcohols
2—4 or 7 or diamines 5 or 8. In all cases, two moles of
hydrogen were eliminated (Scheme 1). For comparison,
tridentate ligand 9 and amino alcohol 6 containing the
tertiary amino group were tested as chiral inducing
agents.
5
6
O
;
NH
OH
7
The IR spectrum of dihydride 1, which was prepared
from NaAlH4 and amino alcohol 2 in THF, has an
–1
absorption band at 1675 cm (εmax = 85) characteristic
;
Ph
Ph
NH
HN
Ph
of vibrations of the Al—H bonds in sodium or lithium
aluminum dihydride complexes.5 At the same time, the
IR spectrum does not have bands characteristic of Al—H
bonds in monohydride complexes (1760—1770 cm–1) or
NH HN
Ph
OH
8
9
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 806—808, May, 2001.
1066-5285/01/5005-843 $25.00 © 2001 Plenum Publishing Corporation

844
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 5, May, 2001
Vinogradov et al.
AlH3 derivatives (1800—1900 cm–1), which could be
formed by disproportionation or dissociation of dihydride
1.5 These data indicate that it is the complex of general
formula 1 that performs reduction of ketones 10
(Scheme 2), thus determining the stereochemistry of the
reaction under study.
is far lower (see Table 1, runs 9—12). In the case of
reagent 1 containing ligand 4, the pronounced depen-
dence of the enantioselectivity of reduction on the
temperature was observed (see Table 1, runs 9—11;
cf. Ref. 5).
Aluminum-hydride reagents prepared by modifica-
tion of NaAlH4 with ligands 6—9 proved to be ineffi-
cient or poorly efficient in the reaction under study (see
Table 1, runs 12—17).
Scheme 2
Apparently, the stereochemistry of hydrogenation of
aromatic ketones with reagents 1 is determined by the
configuration of the chiral ligand. Thus in the case of
NaAlH4 modified with ligands possessing the (S) con-
figuration, the corresponding (R) enantiomers of 11
were obtained as the major products of asymmetric
reduction.
Therefore, of all amino alcohols and diamines under
study, amino alcohols 2 and 3 containing the 2-hydroxy-
diphenylmethyl-substituted pyrrolidine or piperidine ring
are the most efficient chiral reagents for modification
of NaAlH4.
O
OH
*
1
Ar
A k
l
Ar
l
A k
10a—e
11a—e
a
b
c
d
2-naphthyl
Me
e
2-fluorenyl
Me
Ar
Ph
Me
Ph
Et
1-naphthyl
Alk
Me
The highest enantioselectivity of reduction (up to
93% åå) was achieved using amino alcohol 2 as an
inducing agent (Table 1, runs 1—6). It should be noted
that the reactivity of 1-acetonaphthone in the reaction
with the above-mentioned reagent appeared to be more
than an order of magnitude lower than that with 2-aceto-
naphthone (cf. the degrees of conversion of ketones 10c
and 10d in runs 4 and 5, respectively). The reaction
involving NaAlH4 modified with ligand 3, which is
structurally similar to ligand 2, proceeded with moder-
ate enantioselectivity (55—70% åå) (see Table 1, runs 7
and 8). The enantioselectivity of the reaction using
ligands 4 or 5, which are structural analogs of ligand 2
but contain less bulky substituents at position 2 of the
pyrrolidine ring (CH2OH and CH2NHPh, respectively),
Experimental
Polarimetric measurements were carried out on a Jasco
1
DIP-360 instrument (1-cm cell). The H NMR spectra were
recorded on a Bruker AC-200 instrument. Commercial NaAlH4
and (S)-α-phenylethylamine (Zeeland Chemicals, USA) were
used. Ligands 2 and 4—7 and THF were purchased from Fluka.
Ligands 3 and 8 were synthesized according to known proce-
dures.6,7 The compositions of hydrogenation products of ke-
tones 10a,b and 10c—e were determined by capillary GLC and
HPLC, respectively, as described previously.5
Table 1. Reduction of ketones 10 with chiral complexes 1, prepared in situ from NaAlH4 and ligands 2—9 in THF
Run
LigandLigand
configuration
[Ligand]
Ketone
Reaction conditions
Conversion*
Product
ee (%)*
[NaAlH4]
10→11 (%)
T/°C
τ/h
1
2
2
2
2
2
2
2
3
3
4
4
4
5
6
6
7
8
9
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S,S)
(S,S)
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
2 : 1
2 : 1
1 : 1
1 : 1
1 : 1
10a
10a
10b
10c
10d
10e
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
–70
–20
–70
–70
–70
–70
0***
20
–70
0
20
–70
–20
0
–20
–20
–20
3
3
3
3
3
85
92
87
0.6
26
70
72
82
32
57
60
15
36
46
8
11a
11a
11b
11c
11d
11e
11a
11a
11a
11a
11a
11a
11a
11a
11a
11a
11a
92 (R)
68 (R)
67 (R)
—**
64 (R)
93 (R)
69 (R)
54 (R)
47 (R)
10 (R)
0
23 (R)
19 (R)
19 (R)
0
5 (R)
0
3
4
5
6
3
7
8
24
24
5
2
2
9
10
11
12
13
14
15
16
17
3
24
24
24
48
48
61
60
* The results averaged over several runs are given.
** We failed to determine the ee value for 11c due to the low conversion of ketone 10c.
*** At temperatures below 0 °C, the results were not reproducible.

Asymmetric reduction of ketones
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 5, May, 2001
845
Asymmetric hydrogenation of ketones 10 (general proce-
dure). A 0.5 Ì solution of the chiral ligand in THF was added
with stirring to a 0.3 Ì solution of NaAlH4 in THF cooled to
–20 °C. The reaction mixture was stirred at this temperature,
then warmed to ∼20 °C during 1 h, and kept at this temperature
for 3 h. The resulting solution of reagent 1 was cooled to the
required temperature (see Table 1) and added dropwise with
stirring to a 1 Ì solution of ketone in THF (the molar ratio
1/10 = 3). After completion of the reaction, the mixture was
treated with aqueous MeOH (MeOH—H2O, 9 : 1 v/v) and then
with a 1 N HCl solution until the mixture became weakly acidic
and extracted with ether. The solvent was evaporated and the
residue was analyzed by GLC or HPLC.
dryness in vacuo. Pure ligand 9 was obtained as an oil in a yield
of 0.95 g (96%). The ligand was used for modification of
NaAlH4 without additional purification.
This work was financially supported by the Cambrex
Corporation (USA).
References
1. T. Naota, H. Takaya, and S.-I. Murahashi, Chem. Rev.,
1998, 98, 2599.
(S,S)-N,N´-Bis(1-phenylethyl)-1,3-diaminopropan-2-ol (9).
A solution of (S)-α-phenylethylamine (2.57 mL, 20 mmol) and
freshly distilled epichlorohydrin (0.39 mL, 5 mmol) in MeOH
(20 mL) was refluxed for 30 min. Then the reaction mixture
was concentrated in vacuo. The residue was dissolved in PriOH
and treated with HCl. The precipitate that formed was filtered
off and pure diamino alcohol 9 was obtained as dihydrochloride
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22
in a yield of 1.22 g (66%). T.decomp. 255 °C, [α]D –36
(c 2, MeOH). Found (%): C, 61.42; H, 7.58; Cl, 19.22;
N, 7.65. C19H28Cl2N2O. Calculated (%): C, 61.45; H, 7.60;
Cl, 19.09; N, 7.54. 1H NMR (CDCl3—CCl4, 1 : 1), δ: 1.50 (d,
6 H, 2 Me); 2.30—2.80 (m, 4 H, 2 CH2N); 3.20 (br.s, 3 H,
2 NH and OH); 3.70—4.00 (m, 3 H, 2 CHN and CHO);
7.10—7.60 (m, 10 H, arom.). 13C NMR (CDCl3—CCl4, 1 : 1),
δ: 24.2 (2 Me); 51.3, 57.8 (2 CH2N); 58.1, 58.7 (2 CHN); 68.6
(CHO); 126.5, 127.0, 128.5, 144.7 (arom.).
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Diamino alcohol dihydrochloride 9 was treated with Et3N
(3 mL) in 95% EtOH (5 mL). Then a 1 : 1 ether—hexane
mixture (15 mL) was added, the precipitate of Et3N•HCl that
formed was filtered off, and the filtrate was concentrated to
Received August 18, 2000;
in revised form November 4, 2000