Enantioselective reduction of ketones with triethoxysilane catalyzed by chiral bis-oxazoline titanium complexes

Article abstract of DOI:10.1039/a807028h

Chiral bis-oxazoline titanium complexes [Ti(BOX)₂X₂] prepared from C₂ chiral bis-oxazolines, BuLi and titanium salts, catalyze the enantiosective reduction of ketones in the presence of triethoxysilane.

Full text of DOI:10.1039/a807028h

Enantioselective reduction of ketones with triethoxysilane catalyzed by chiral
bis-oxazoline titanium complexes
Marco Bandini, Pier Giorgio Cozzi,* Lucia Negro and Achille Umani-Ronchi*
Dipartimento Chimico ‘G. Ciamician’, Università di Bologna, Via Selmi 2, 40126 Bologna, Italy.
E-mail: umani@ciam.unibo.it; pgcozzi@ciam.unibo.it
Received (in Liverpool, UK) 7th September 1998, Accepted 17th November 1998
O
O
O
O
Chiral bis-oxazoline titanium complexes [Ti(BOX)
2 2
X ] pre-
pared from C chiral bis-oxazolines, BuLi and titanium salts,
2
N
N
N
N
catalyze the enantiosective reduction of ketones in the
presence of triethoxysilane.
Bn
Bn
Pri
Pri
1
2
Enantioselective reduction of ketones is an important and
widely utilized methodology for the preparation of key
intermediates for the synthesis of drugs and biologically active
O
O
O
O
Ph
1
Ph
compounds. Corey’s oxazaborolidine and related compounds
N
N
N
N
play a decisive role in these chirotechnologies.2 Recently,
Buchwald has demonstrated that chiral titanium metallocenes
are able to catalyze the enantioselective hydrosilylation of
ketones and imines with high ees.3 For these reactions
enantiomerically pure titanocene complexes should be availa-
Ph
Ph
Ph
Ph
3
4
ble. Although a new methodology to prepare the chiral C
2
O
O
O
O
metallocene complexes in high diastereomeric ratios was
Ph
Ph
Ph
N
N
Ph
N
N
4
recently reported, a resolution process is still needed to access
5
the enantiomerically pure metal complex. Based on a different
strategy, i.e. replacing chiral metallocene with more accessible,
easily prepared, chiral metal complexes, we have explored the
possibility of using chiral bis-oxazolines6 as ligands in
coordinating group 4 metals and to employ the corresponding
complexes in asymmetric catalysis (Fig. 1). To the best of our
OTBDMS
OTBDMS
OTIPS
OTIPS
6
5
O
O
N
N
knowledge, until now the use of early transition metals with C
2
chiral bis-oxazolines in asymmetric catalysis has never been
reported.7
Herein, we present a novel method for the enantioselective
titanium-catalyzed hydrosilylation of ketones and a-halo ke-
7
tones. The procedure involves the treatment of C
2
chiral bis-
4
commercially available TiF and oxazoline 4 as ligand. The
oxazolines (BOX 1–7) with BuLi followed by the addition of a
hydrosilylation proceeded at room temperature, affording in 48
8
h the (S)-1-phenylethan-1-ol3a in 86% yield and 61% ee. The ee
titanium salt. Since the titanium complex was prepared in situ
using a 2:1 molar ratio between the methylene bis-oxazoline
and a titanium salt, we suggest that the BOX–titanium complex
could have an octahedral structure (Fig. 1, M = Ti; X = Cl, F,
obtained in the asymmetric reaction seems to depend on the
steric hindrance of the BOX ligand (entries 4,9 and 10). THF
was the most suitable solvent with respect to both enantio-
selectivities and chemical yields. In the process of optimizing
catalytic conditions with a variety of titanium salts, we found
i
9
OPr ). These new BOX–titanium complexes were treated with
EtO) SiH leading to a catalytic system for the hydrosilylation
(
3
of ketones and a-halo ketones. It is noteworthy that no
that TiF
yellow BOX–titanium complexes. On the other hand,
TiCl (THF) gave insoluble complexes and we occasionally
observed a definite change in the color of the reaction to blue,
4
was more effective in preparing the soluble orange–
particular activation is necessary for the preparation of the
active catalytic species. Various silyl hydrides such as Cl
EtO) SiH, Ph SiH, PhSiH and poly(methylhydrosiloxane)
were tested for asymmetric reduction catalyzed by the BOX–
titanium complex. However, in general, (EtO) SiH gave better
results. Initially we investigated the reaction of acetophenone
with (EtO) SiH using various titanium salts and oxazolines
Scheme 1). As reported in Table 1 the best results were
3
SiH,
4
2
(
3
3
3
III
10
indicative of the presence of a Ti species.
Since TiF , bis(oxazoline) 4 and (EtO) SiH afforded the best
3
4
3
results,† the catalyst system reported in Scheme 2 was
successfully applied to the asymmetric reduction of branched
3
11
(
aromatic ketones and a-halo ketones. From the data in Table
obtained using 3–5 mol% of the catalyst prepared from
2, it is evident that the enantioselectivity is independent of the
R′
BOX
i,ii
R
X
R
2 2
Ti(BOX) X
R′
X
1–7
O
N
N
M
N
O
O
OH
*
R N
O
R
iii
R′
O
R′
+
(EtO)3SiH
M = Ti, Zr, Hf ; X = F, Cl, Br, OR, NR2
Scheme 1 Reagents and conditions: i, BuLi, THF; ii, TiX
4
, THF; iii,
Fig. 1 Hypothetic structure of M(BOX)
X
2 2
.
Ti(BOX) (3-8 mol%), room temp.
2 2
X
Chem. Commun., 1999, 39–40
39

Table 1 Enantioselective reduction of acetophenone catalyzed by Titanium-
BOX complex
of this reaction. In particular, we are unable to definitively
demonstrate that the reduction is due to the formation of an
a
3a,b
14
active titanium(III
)
or titanium(IV) species, or if other
b
Entry
1
BOX
TiX
4
(mol%)
Yield (%)
Ee (%)
15
mechanisms are involved. In conclusion, we have developed
a new methodology for the enantioselective reduction of
ketones based on chiral titanium bis(oxazoline) complexes.
We thank the MURST (Rome) (National Project ‘Stereo-
selezione in Sintesi Organica. Metodologie ed Applicazioni’)
and Bologna University (funds for selected research topics) for
the financial support of this research.
1
1
3
1
4
7
4
4
5
6
TiCl
TiCl
TiCl
TiCl
TiCl
TiCl
4
4
4
2
2
2
(THF)
(THF)
2
2
2
(4)
(3)
(4)
(15)
(4)
(3)
60
60
20
87
85
13
86
28
30
18
30 (R)
50 (R)
23 (R)
18 (S)
51 (S)
64 (S)
61 (S)
72 (S)
56 (S)
51 (S)
c
2
c
3
4
5
6
7
8
9
0
(THF)
i
(OPr )
2
2
2
i
(OPr )
i
(OPr )
TiF
TiF
TiF
TiF
4
4
4
4
(5)
(4)
(5)
(5)
d
Notes and references
†
Typical experimental procedure: A solution of 4 (0.044 g, 0.097 mmol) in
anhydrous THF (1.5 ml) was cooled to 278 °C and then BuLi (0.064 ml, 1.5
in hexane) was added under nitrogen. The resulting pale yellow solution
was stirred for 5 min at 278 °C and then warmed to 0 °C for 15 min. To this
yellow solution TiF was added (0.006 g, 0.048 mmol) all at once and the
1
a
Reaction conditions as in Scheme 1. All the reactions were performed
by employing 4 equiv. of (EtO) SiH as the reducing agent. The reactions
M
3
b
were stirred at room temperature for 2–3 d. The ee was evaluated by GC
analysis with a chiral cyclodextrin Megadex column. c The reaction was
4
mixture was vigorously stirred until complete dissolution of the salt. The
resulting solution was stirred for 60 min at room temperature and then
(EtO) SiH (0.240 ml, 1.2 mmol) and 8e (0.14 ml, 0.605 mmol) were added.
3
effected in the presence of molecular sieves 4 Å (1 g. for 1 mol of ketone).
d
The reaction was performed in Et
2
O.
The mixture was stirred for 96 h at room temperature. The reaction mixture
was diluted with AcOEt (5 ml) and then carefully made basic (pH 12) by the
addition of aq. NaOH (1 M). The solution was stirred at room temperature
O
OH
i
R1
R1
until a white precipitate was formed. The solid was separated by filtration
and the organic phase was collected. The aqueous phase was then extracted
with AcOEt (2 3 3 ml). The organic layers were combined, dried over
R2
+ (EtO) SiH
R2
3
2 4
anhydrous Na SO , then concentrated under reduced pressure to give a
1
0a–g
i
2
8
a R1 = Pr, R = H
yellow oil which was purified by column chromatography on silica gel
1
2
b R = Et, R = H
c R = Br, R = H
d R = Br, R = Me
e R = Br, R = OMe
= Br, R = Ph
g R = Br, R = Cl
(pentane–Et O, 9:1) (53%).
2
1
2
1
R. Hett, C. H. Senanayake and S. Wald, Tetrahedron Lett., 1998, 39,
705 and references cited therein.
1
2
1
1
2
2
Catalytic Asymmetric Synthesis, Ed. I. Ojima, VCH, New York, 1993;
R. Noyori, Asymmetric Catalysis In Organic Synthesis, Wiley, New
York, 1994; R. A. Sheldon, Chirotechnology, Marcel Dekker, New
York, 1993.
1
1
2
f
R
2
O
HO
3 (a) M. B. Carter, B. Schiøtt, A. Gutiérrez and S.L. Buchwald, J. Am.
Chem. Soc., 1994, 116, 11667; (b) X. Verdaguer, U. E. W. Lange, M. T.
Reding and S. L. Buchwald, J. Am. Chem. Soc., 1996, 118, 6784; X.
Verdaguer, U. E. W. Lange and S. L. Buchwald, Angew. Chem., 1998,
110, 1174; Angew. Chem., Int. Ed., 1998, 37, 1103. For the use of other
chiral ansa-titanocenes see also: S. Xin and J. F. Harrod, Can. J. Chem.,
1995, 73, 999; R. L. Halterman, T. M. Ramsey and Z. Chen,
J. Org. Chem., 1994, 59, 2642.
Br
Br
i
+
(EtO)3SiH
9
11
Scheme 2 Reagents and conditions: i, 4 (8 mol%), room temp., 80–120
4
G. M. Diamond, R. F. Jordan and J. L. Petersen, J. Am. Chem. Soc.,
996, 118, 8024.
B. Chin and S. L. Buchwald, J. Org. Chem., 1996, 61, 5650.
h.
1
5
Table 2 Enantioselective reduction of ketones and a-halo ketones catalyzed
by titanium–BOX complexes
a
6 For a recent and comprehensive review see: A. K. Ghosh, P. Mathivanan
and J. Cappiello, Tetrahedron: Asymmetry, 1998, 9, 1.
Alcohol Yield (%)b
Ee (%)c
7 Singh has reported the preparation of various titanium(IV)–bis(oxazo-
line) complexes, but not their use. The structures of the BOX–Ti
complexes, prepared in toluene with a 1:1 ligand to titanium reagent
ratio, have been proposed to adopt a trigonal bipyramidal geometry in
which two nitrogen atoms of the BOX ligand occupy equatorial sites.
The author described such complexes as not quite stable: R. P. Singh,
Synth. React. Inorg. Met.-Org. Chem. 1997, 27, 155.
Entry
Ligand
Ketone
1
2
3
4
5
6
7
8
4
4
4
4
4
4
4
4
8a
8c
8d
9
8e
8f
10a
10c
10d
11
10e
10f
10b
10g
61
60
61
64
53
50
58
50
85 (S)
84 (R)
83 (R)
84 (R)
80 (R)
8
M. Nakamura, M. Arai and E. Nakamura, J. Am. Chem. Soc., 1995, 117,
1179; M, Nakamura, A. Hirai and E. Nakamura, J. Am. Chem. Soc.,
78 (R)
75 (S)d
8b
8g
1
3
996, 118, 8489; S. Hanessian and R.-Y. Yang, Tetrahedron Lett., 1996,
7, 8997.
65 (R)
a
All the reactions were performed as reported in the experimental
procedure. Isolated yield after chromatographic purification. c The ee was
determined by GC analysis on Megadex cyclodextrin chiral column. The
D
configurations of 10a,c were assigned by comparison of the [a] values
reported in the literature. In the other cases, the absolute configuration was
assigned by analogy. The ee was determined on the silylated alcohol.
9
The crystal structures of octahedral titanium(III) and titanium(IV
)
b
hydroxyphenyloxazoline complexes have been reported: P. G. Cozzi, C.
Floriani, A. Chiesi-Villa and C. Rizzoli, Inorg. Chem. 1995, 34,
2
921.
1
0 In these cases, only racemic alcohol was obtained. Reduction of
titanium depending on the ligand is well known problem in metallocene
chemistry.
d
nature of the ketone, showing generality from aromatic
11 Aliphatic, non-branched aromatic and cyclic ketones were reduced with
our titanium catalyst in lower ees. For example, the reduction of octan-
12
substituted ketones to a-halo ketones. The excellent enantio-
selectivity and the satisfactory yields observed in these
reactions, accompanied by the simple protocol and the commer-
cial availability of the ligands and reagents, make this procedure
useful for the preparation of optically active epoxides and a-
amino alcohols.1
2
-one and indan-2-one afforded the corresponding alcohols in 65%
yield, 20% ee and 70% yield, 29% ee, respectively.
1
2 The absolute configurations of 10a [ref. 3(a)] and 10c (ref. 13) were
determined by comparison with the [a]
D
values reported in the
literature. The absolute configurations of 10b and the other halo ketones
were assigned by analogy.
Bis(oxazoline) ligands are able to replace Britzinger’s C
2
13 S. Itsuno, M. Nakano, K. Miyazaki, H. Masuda, K. Ito, A. Irao and S.
Nakahama, J. Chem. Soc., Perkin Trans. 1, 1985, 2039.
14 T. Nakai, M. Mori and H. Imma, Synlett., 1996, 1229.
metallocenes in these reductions, suggesting that other early
transition metal-mediated reactions can be successfully cata-
lyzed by early transition metals and appropriate BOX ligands.
At the present time we can only speculate about the mechanism
1
5 D. J. Parks and W. E. Piers, J. Am. Chem. Soc., 1996, 118, 9440.
Communication 8/07028H
40
Chem. Commun., 1999, 39–40