Chiral N-heterocyclic carbene iridium catalyst for the enantioselective hydrosilane reduction of ketones

Article abstract of DOI:10.1016/j.molcata.2016.05.020

Enantioselective reduction of ketones with (EtO)₂MeSiH catalyzed by an in-situ generated N-heterocyclic carbene (NHC) Ir complex at room temperature has been developed. A series of benzimidazolium salts were synthesized and screened in the asymmetric hydrosilylation reaction. As a result, propiophenone was efficiently reduced by the combined catalytic system of [IrCl(cod)]₂ and NHC-Ag complex derived from N-(1-naphthalenylmethyl)-substituted benzimidazolium salt L12, affording the corresponding alcohol in 92% yield and with 92% ee. Moreover, the evaluation of an Ir catalyst precursor showed that cationic [Ir(cod)₂]BF₄ complex could be used. Furthermore, the introduction of a chiral hydroxyamide side arm into the benzimidazolium salt was critical for the successful design of the NHC ligand.

Full text of DOI:10.1016/j.molcata.2016.05.020

Accepted Manuscript
Title: Chiral N-heterocyclic carbene iridium catalyst for the
enantioselective hydrosilane reduction of ketones
Author: Yoshiki Manabe Kanako Shinohara Hanako
Nakamura Hiro Teramoto Satoshi Sakaguchi
PII:
S1381-1169(16)30191-1
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2016.05.020
MOLCAA 9895
To appear in:
Journal of Molecular Catalysis A: Chemical
Received date:
Revised date:
Accepted date:
4-3-2016
12-5-2016
18-5-2016
Please cite this article as: Yoshiki Manabe, Kanako Shinohara, Hanako Nakamura,
Hiro Teramoto, Satoshi Sakaguchi, Chiral N-heterocyclic carbene iridium catalyst for
the enantioselective hydrosilane reduction of ketones, Journal of Molecular Catalysis
A: Chemical http://dx.doi.org/10.1016/j.molcata.2016.05.020
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Chiral N-heterocyclic carbene iridium catalyst for the enantioselective
hydrosilane reduction of ketones
Yoshiki Manabe, Kanako Shinohara, Hanako Nakamura, Hiro Teramoto, Satoshi
Sakaguchi*
Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and
Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan
*
Corresponding author. Tel. +81 6 6368 0867; fax: +81 6 6339 4026.
E-mail address: satoshi@kansai-u.ac.jp
Keywords:
Asymmetric catalysis
Hydrosilylation
N-Heterocyclic carbene
Ligand design
Iridium
1

Graphical abstract
NHC ligand design
in-situ generated
IrCl(cod)(NHC) species
O
OH
R'
H
N
N
OH
Ar
R'
(EtO) MeSiH, AgBF
Ar
2
4
O
N
R
room temperature
open-air conditions 26 examples
up to 92% ee
highly tunable
2

Highlights
•
•
•
Enantioselective hydrosilylation of ketones catalyzed by an Ir complex is developed.
The in-situ generated N-heterocyclic carbene (NHC) Ir catalyst can be used .
The attachment of hydroxyamide side arm is critical for the NHC ligand design.
3

Abstract
Enantioselective reduction of ketones with (EtO) MeSiH catalyzed by an in-situ generated
2
N-heterocyclic carbene (NHC) Ir complex at room temperature has been developed. A series
of benzimidazolium salts were synthesized and screened in the asymmetric hydrosilylation
reaction. As a result, propiophenone was efficiently reduced by the combined catalytic
system of [IrCl(cod)] and NHC–Ag complex derived from N-(1-naphthalenylmethyl)-
2
substituted benzimidazolium salt L12, affording the corresponding alcohol in 92% yield and
with 92% ee. Moreover, the evaluation of an Ir catalyst precursor showed that cationic
[
Ir(cod) ]BF complex could be used. Furthermore, the introduction of a chiral
2 4
hydroxyamide side arm into the benzimidazolium salt was critical for the successful design
of the NHC ligand.
1
. Introduction
An important goal in homogeneous metal-mediated catalysis is the development of
inexpensive and easy-to-use chiral ligands [1]. The progress in N-heterocyclic carbene
NHC) ligands is one of the most important advances in catalytic asymmetric reactions in
(
the past decade [2,3]. The stereoselective hydrosilylation of ketones catalyzed by transition-
metal complexes is an important method for the synthesis of optically active alcohols [4].
Since Hermann reported the first catalytic asymmetric hydrosilylation reaction in which the
chiral induction was achieved using a chiral NHC [5], the enantioselective hydrosilylation
of ketones with different types of chiral NHCs has been widely investigated [6]. Among the
increasing number of the NHC–metal complexes, several NHC-containing well-defined Rh
4

complexes have been found to be efficient asymmetric catalysts for this transformation [7-
0].
1
The in-situ generated chiral metal complexes offer several distinct advantages over
the use of well-defined, preformed metal complexes as reported by Veige et al. [11]: (i)
facilitation of benchtop chemistry, (ii) rapid screening of diverse chiral NHC precursors,
(iii) avoiding additional catalyst synthetic steps. Despite the enormous progress of the
catalytic reaction using the well-defined metal complexes [7-10], the asymmetric
hydrosilylation with in-situ generated NHC–metal complexes has been rarely reported.
Previously, we developed a hydroxyamide-functionalized benzimidazolium salt as a
chiral NHC ligand precursor [12,13]. Fortunately, the well-defined, monodentate
IrCl(cod)(NHC) (cod = 1,5-cyclooctadiene) complex catalyzed the asymmetric
hydrosilylation of ketones efficiently under mild conditions [10]. An attractive feature of
this functionalized chiral NHC ligand is that an easy tuning of the N-functional groups of
the NHC ring helped to develop diverse NHC ligands. Indeed, the azolium ligand precursors
can be synthesized in two steps from enantiopure -amino alcohols (vide infra). Based on
these advantages, we now investigated the catalytic asymmetric hydrosilylation of ketones
using in-situ generated NHC–Ir species from readily available functionalized
benzimidazolium salts. This could be performed under operationally simple conditions
because the independent preparation and purification of the IrCl(cod)(NHC) complex were
not needed.
2
. Experimental
5

2
.1. General procedures
All of the reagents were purchased from Aldrich, Tokyo Chemical Industry Co., Ltd.
TCI), Wako Pure Chemical Industries, Ltd. and were used as received. All non-
commercially available compounds were prepared and characterized as described in Section
.2. Column chromatographies were performed with silica gel 60 (63-210 m) purchased
from Kanto Chemical Co., Inc. NMR spectra were recorded on JEOL ECA400 (400 MHz
(
2
1
13
for H NMR and 100 MHz for C NMR) spectrometer. Chemical shifts were reported
1
13
downfield from TMS (= 0 ppm) for H NMR. For C NMR, chemical shifts were reported
in the scale relative to the solvent used as an internal reference. Elemental analyses were
performed at Osaka University.
2
.2. Procedure for Synthesis of Azolium Salt L12
The reaction mixture of 1-(1-naphthalenyl)-1H-benzimidazole (373 mg, 1.44 mmol)
and -chloroacetamide (279 mg, 1.44 mmol), derived from chloroacetyl chloride and L-
luecinol, in 1,4-dioxane (4 mL) was heated to 110 °C and stirred for 24 h. After the reaction,
the solvent was removed under reduced pressure. The azolium salt L12 was purified by
reprecipitation using CH OH and CH CO C H affording white solid (yield: 472 mg, 72%).
3
3
2
2
5
Other azolium salts could be prepared by the similar reaction procedure. Compounds L1
12c], L6 [12c], L16 [13b], L17 [13b], L18 [12c], L19 [12a] and L20 [12a] were reported
in our previous publications (see also Appendix A. Supplementary data).
[
6

2
.2.1. Compound L12
1
H-NMR (CDCl ):  10.52 (s, 1H), 9.05 (d, J = 8.2 Hz, 1H), 8.00-7.76 (m, 4H), 7.59-7.47
3
(m, 3H), 7.38-7.22 (m, 4H), 6.24 (d, J = 16.0 Hz, 1H), 6.06 (d, J = 16.4 Hz, 1H), 5.81 (d, J
=
16.0 Hz, 1H), 5.62 (d, J = 16.4 Hz, 1H), 4.86 (br, 1H), 3.96-3.88 (m, 1H), 3.61-3.42 (m,
2
3
1
2
6
H), 1.55-1.42 (m, 2H), 1.21-1.17 (m, 1H), 0.78 (d, J = 6.4 Hz, 3H), 0.72 (d, J = 6.4 Hz,
1
3
H); C-NMR:  164.7, 144.1, 133.6, 132.1, 130.9, 130.3, 129.7, 129.0, 127.9, 127.5,
27.1, 126.8, 126.5, 126.1, 125.3, 122.2, 114.2, 113.1, 64.3, 51.0, 49.8, 49.0, 39.7, 24.7,
2.7, 22.2. Anal. Calc. for C H ClN O •0.2H O: C, 68.54; H, 6.73; N, 9.22. Found: C,
2
6
30
3
2
2
8.37; H, 6.72; N, 9.21%. M.p. 181.3-183.1 °C.
2
.2.2. Compound L2
1
H-NMR (CDCl ):  10.25 (s, 1H), 8.84 (d, J = 9.0 Hz, 1H), 7.95-7.92 (m, 1H), 7.67-7.64
3
(m, 1H), 7.58-7.53 (m, 2H), 5.71 (d, J = 16.2 Hz, 1H), 5.58 (d, J = 16.2 Hz, 1H), 4.57 (q, J
=
7.3 Hz, 2H), 4.00-3.96 (m, 1H), 3.63-3.61 (m, 1H), 3.54-3.50 (m, 1H), 3.96-3.50 (br, 1H),
1
.66 (t, J = 7.3 Hz, 3H), 1.62-1.53 (m, 1H), 1.50-1.45 (m, 1H), 1.28-1.22 (m, 1H), 0.85 (d, J
1
3
=
6.7 Hz, 3H), 0.81 (d, J = 6.7 Hz, 3H); C-NMR:  164.9, 142.8, 132.1, 130.7, 127.0,
1
26.7, 114.1, 112.4, 64.2, 50.9, 49.5, 42.9, 39.7, 24.8, 22.8, 22.2, 14.4. Anal. Calc. for
C H ClN O •2H O: C, 54.32; H, 8.04; N, 11.18. Found: C, 54.35; H, 7.69; N, 11.28%.
1
7
26
3
2
2
M.p. 136.2-136.6 °C.
2
.2.3. Compound L3
1
H-NMR (DMSO):  10.00 (s, 1H), 8.78 (d, J = 8.7 Hz, 1H), 8.13-8.09 (m, 1H), 7.99-7.95
(m, 1H), 7.69-7.64 (m, 2H), 5.40 (d, J = 16.0 Hz, 1H), 5.34 (d, J = 16.0 Hz, 1H), 4.89 (t, J =
7

6
2
3
1
.0 Hz, 1H), 4.56 (t, J = 7.1 Hz, 2H), 3.81-3.75 (m, 1H), 3.35-3.33 (m, 2H), 1.91-1.83 (m,
H), 1.63-1.56 (m, 1H), 1.39-1.26 (m, 4H), 0.90 (t, J = 7.3 Hz, 3H), 0.85 (d, J = 6.9 Hz,
1
3
H), 0.78 (d, J = 6.9 Hz, 3H); C-NMR:  164.1, 143.3, 131.5, 130.7, 126.6, 126.5, 113.7,
13.6, 63.4, 49.7, 48.6, 46.4, 39.7, 30.5, 24.2, 23.2, 21.8, 19.0, 13.3. Anal. Calc. for
C H ClN O •H O: C, 59.13; H, 8.36; N, 10.89. Found: C, 59.16; H, 8.35; N, 10.99%.
1
9
30
3
2
2
M.p. 161.8-162.4 °C.
2
.2.4. Compound L4
1
H-NMR (CDCl ):  10.34 (s, 1H), 8.95 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.66-
3
7
.55 (m, 3H), 5.77 (d, J = 16.2 Hz, 1H), 5.65 (d, J = 16.2 Hz, 1H), 4.35 (d, J = 7.6 Hz, 2H),
.00 (br, 2H), 3.67-3.64 (m, 1H), 3.55-3.51 (m, 1H), 2.39-2.29 (m, 1H), 1.67-1.55 (m, 1H),
.53-1.48 (m, 1H), 1.30-1.23 (m, 1H), 1.02 (d, J = 6.7 Hz, 3H), 1.00 (d, J = 6.7 Hz, 3H),
4
1
0
1
1
3
.86 (d, J = 6.7 Hz, 3H), 0.81 (d, J = 6.7 Hz, 3H); C-NMR:  164.7, 143.5, 132.0, 131.1,
27.2, 126.8, 114.3, 112.5, 64.3, 55.4, 51.0, 49.6, 39.7, 28.8, 24.8, 22.9, 22.3, 19.8, 19.8.
Anal. Calc. for C H ClN O •1.2H O: C, 58.58; H, 8.38; N, 10.79. Found: C, 58.55; H,
1
9
30
3
2
2
8
.35; N, 10.83%. M.p. 76.8-77.6 °C.
2
.2.5. Compound L5
1
H-NMR (DMSO):  9.94 (s, 1H), 8.76 (d, J = 8.7 Hz, 1H), 8.02-7.96 (m, 2H), 7.69-7.65
(m, 2H), 6.15-6.07 (m, 1H), 5.44-5.25 (m, 6H), 4.88 (t, J = 6.0 Hz, 1H), 3.81-3.75 (m, 1H),
3
.37-3.32 (m, 2H), 1.62-1.57 (m, 1H), 1.38-1.30 (m, 2H), 0.86 (d, J = 6.9 Hz, 3H), 0.79 (d,
1
3
J = 6.9 Hz, 3H); C-NMR:  164.0, 143.4, 131.6, 131.1, 131.0, 130.6, 126.7, 120.3, 113.8,
8

1
13.6, 63.4, 49.7, 48.7, 48.6, 39.7, 24.2, 23.2, 21.8. Anal. Calc. for C H ClN O •0.7H O:
18 26 3 2 2
C, 59.32; H, 7.58; N, 11.53. Found: C, 58.98; H, 7.34; N, 11.46%. M.p. 159.5-160.0 °C.
2
.2.6. Compound L7
1
H-NMR (CDCl ):  10.39 (s, 1H), 9.02 (d, J = 8.5 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.60-
3
7
.12 (m, 7H), 5.81 (d, J = 16.2 Hz, 1H), 5.74 (s, 2H), 5.57 (d, J = 16.2 Hz, 1H), 3.96 (br,
1
0
1
2
H), 3.66-3.50 (m, 2H), 2.37 (s, 3H), 2.37 (br, 1H), 1.63-1.46 (m, 2H), 1.29-1.22 (m, 1H),
1
3
.85 (d, J = 6.7 Hz, 3H), 0.81 (d, J = 6.7 Hz, 3H); C-NMR:  164.6, 143.7, 136.5, 132.3,
31.3, 130.9, 130.1, 129.4, 128.4, 127.4, 127.0, 126.9, 114.3, 113.1, 64.3, 51.1, 49.9, 39.7,
4.8, 22.8, 22.4, 19.4. Anal. Calc. for C H ClN O •0.5H O: C, 65.00; H, 7.35; N, 9.89.
2
3
30
3
2
2
Found: C, 64.66; H, 7.29; N, 9.95%. M.p. 172.0-172.6 °C.
2
.2.7. Compound L8
1
H-NMR (DMSO):  10.10 (s, 1H), 8.87 (d, J = 8.5 Hz, 1H), 7.99-7.96 (m, 2H), 7.67-7.61
(m, 2H), 7.34-7.16 (m, 4H), 5.81 (s, 2H), 5.43 (d, J = 16.2 Hz, 1H), 5.37 (d, J = 16.2 Hz,
1
H), 4.88 (t, J = 5.8 Hz, 1H), 3.83-3.75 (m, 1H), 3.35-3.34 (m, 2H), 2.27 (s, 3H), 1.65-1.55
1
3
(
m, 1H), 1.40-1.27 (m, 2H), 0.85 (d, J = 6.7 Hz, 3H), 0.79 (d, J = 6.7 Hz, 3H); C-NMR: 
1
1
6
64.1, 143.6, 138.3, 133.9, 131.7, 130.5, 129.4, 128.9, 128.8, 126.7, 126.7, 125.3, 113.9,
13.7, 63.5, 49.8, 49.7, 48.8, 39.7, 24.2, 23.2, 21.9, 20.9. Anal. Calc. for C H ClN O : C,
2
3
30
3
2
6.41; H, 7.27; N, 10.10. Found: C, 66.07; H, 7.30; N, 10.10%. M.p. 219.8-220.9 °C.
2
.2.8. Compound L9
9

1
H-NMR (CDCl ):  10.53 (s, 1H), 9.06 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.51-
3
7
1
2
1
5
6
.41 (m, 3H), 7.29 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 8.1 Hz, 2H), 5.83-5.64 (m, 4H), 4.80 (br,
H), 3.98-3.95 (m, 1H), 3.66-3.62 (m, 1H), 3.55-3.50 (m, 1H), 2.26 (s, 3H), 1.62-1.46 (m,
1
3
H), 1.27-1.20 (m, 1H), 0.82 (d, J = 6.3 Hz, 3H), 0.76 (d, J = 6.3 Hz, 3H); C-NMR: 
64.8, 143.5, 139.0, 132.2, 130.6, 129.9, 129.5, 128.0, 127.0, 126.7, 114.1, 113.2, 64.3,
1.3, 51.0, 49.7, 39.7, 24.8, 22.7, 22.2, 21.0. Anal. Calc. for C H ClN O •0.1H O: C,
2
3
30
3
2
2
6.13; H, 7.29; N, 10.06. Found: C, 66.07; H, 7.19; N, 10.20%. M.p. 225.5-226.7 °C.
2
.2.9. Compound L10
1
H-NMR (DMSO):  10.15 (s, 1H), 8.79 (d, J = 8.7 Hz, 1H), 8.04-7.98 (m, 3H), 7.81 (d, J =
7
.3 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.68-7.62 (m, 3H), 6.00 (s, 2H), 5.44 (d, J = 16.5 Hz,
H), 5.37 (d, J = 16.5 Hz, 1H), 4.90 (br, 1H), 3.82-3.77 (m, 1H), 3.38-3.35 (m, 2H), 1.63-
1
1
1
3
.55 (m, 1H), 1.39-1.26 (m, 2H), 0.85 (d, J = 6.4 Hz, 3H), 0.78 (d, J = 6.4 Hz, 3H); C-
NMR:  164.0, 143.9, 135.4, 132.4, 131.7, 130.4, 130.1, 126.8, 126.7, 125.5, 125.2, 125.1,
22.6, 113.8, 63.4, 49.7, 49.0, 48.8, 39.8, 24.2, 23.2, 21.8. Anal. Calc. for C H ClF N O :
1
2
3
27
3
3
2
C, 58.78; H, 5.79; N, 8.94. Found: C, 58.64; H, 5.74; N, 8.99%. M.p. 217.6-218.3 °C.
2
.2.10. Compound L11
1
H-NMR (DMSO):  10.15 (s, 1H), 8.76 (d, J = 8.7 Hz, 1H), 8.06-8.03 (m, 1H), 8.00-7.96
m, 1H), 7.71-7.60 (m, 8H), 7.60-7.35 (m, 3H), 5.92 (s, 2H), 5.44 (d, J = 16.0 Hz, 1H), 5.38
d, J = 16.0 Hz, 1H), 4.89 (t, J = 5.7 Hz, 1H), 3.83 (m, 1H), 3.37-3.30 (m, 2H), 1.65-1.58
(
(
(
1
3
m, 1H), 1.39-1.29 (m, 2H), 0.86 (d, J = 6.9 Hz, 3H), 0.79 (d, J = 6.9 Hz, 3H); C-NMR: 
64.0, 143.6, 140.5, 139.3, 133.1, 131.7, 130.5, 128.9, 128.9, 127.7, 127.2, 127.1, 126.7,
1
1
0

1
26.7, 113.9, 113.7, 63.5, 49.7, 49.4, 48.7, 39.8, 24.2, 23.2, 21.8. Anal. Calc. for
C H ClN O •1.2H O: C, 67.31; H, 6.94; N, 8.41. Found: C, 67.16; H, 6.73; N, 8.53%.
2
8
32
3
2
2
M.p. 167.8-168.6 °C.
2
.2.11. Compound ent-L12
1
H-NMR (CDCl ):  10.57 (s, 1H), 9.16 (d, J = 7.3 Hz, 1H), 8.02-7.77 (m, 4H), 7.57-7.37
3
(m, 3H), 7.34-7.22 (m, 4H), 6.27 (d, J = 16.0 Hz, 1H), 6.08 (d, J = 16.4 Hz, 1H), 5.86 (d, J
=
16.0 Hz, 1H), 5.66 (d, J = 16.4 Hz, 1H), 4.81 (br, 1H), 3.91 (br, 1H), 3.59-3.45 (m, 2H),
1
.56-1.44 (m, 2H), 1.22-1.18 (m, 1H), 0.78 (d, J = 6.4 Hz, 3H), 0.71 (d, J = 6.4 Hz, 3H);
C-NMR:  164.8, 144.1, 133.7, 132.2, 131.0, 130.4, 129.8, 129.1, 127.8, 127.6, 127.2,
26.9, 126.5, 126.3, 125.4, 122.2, 114.3, 113.2, 64.4, 51.1, 49.9, 49.1, 39.7, 24.8, 22.8, 22.2.
1
3
1
Anal. Calc. for C H ClN O : C, 69.09; H, 6.69; N, 9.30. Found: C, 68.61; H, 6.63; N,
2
6
30
3
2
9
.25%. M.p. 181.3-182.9 ºC.
2
.2.12. Compound L13
1
H-NMR (CDCl ):  10.49 (s, 1H), 9.02 (d, J = 8.5 Hz, 1H), 7.95 (t, J = 7.0 Hz, 2H), 7.82
3
(d, J = 8.1 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.55-7.43 (m, 3H), 7.34-7.28 (m, 2H), 7.26-
7
1
.18 (m, 2H), 6.25 (d, J = 16.2 Hz, 1H), 5.98 (d, J = 16.2 Hz, 1H), 5.81 (d, J = 16.2 Hz,
H), 5.63 (d, J = 16.2 Hz, 1H), 4.10 (br, 1H), 3.90 (br, 1H), 3.59-3.45 (m, 2H), 1.54-1.40
1
3
(
m, 2H), 1.19-1.12 (m, 1H), 0.76 (d, J = 6.3 Hz, 3H), 0.68 J = 6.3 Hz, 3H); C-NMR: 
1
1
64.7, 144.1, 133.6, 132.1, 130.9, 130.3, 129.6, 129.0, 128.0, 127.4, 127.1, 126.8, 126.4,
26.0, 125.2, 122.2, 114.2, 113.1, 64.3, 51.0, 49.8, 48.9, 39.7, 24.7, 22.7, 22.1. Anal. Calc.
1
1

for C H ClN O •0.1H O: C, 68.82; H, 6.71; N, 9.26. Found: C, 68.61; H, 6.64; N, 9.26%.
2
6
30
3
2
2
M.p. 170.6-171.0 °C.
2
.2.13. Compound L14
1
H-NMR (DMSO):  9.00 (s, 1H), 8.92 (s, 1H), 8.49 (d, J= 8.5 Hz, 1H), 8.40 (d, J = 8.1 Hz,
2
H) 8.35 (d, J = 8.1 Hz, 1H), 8.26 (d, J = 7.6 Hz, 2H), 7.89 (d, J = 8.1 Hz, 1H), 7.81-7.71
(m, 2H), 7.66-7.60 (m, 4H), 6.78 (s, 2H), 5.14 (d, J = 16.2 Hz, 1H), 5.07 (d, J = 16.2 Hz,
1
H), 4.77 (t, J = 5.4 Hz, 1H), 3.72-3.64 (m, 1H), 3.25 (br, 2H), 1.55-1.45 (m, 1H), 1.26-1.22
1
3
(
br, 2H), 0.80 (d, J = 6.3 Hz, 3H), 0.72 (d, J = 6.3 Hz, 3H); C-NMR:  163.9, 142.2,
1
1
31.8, 131.4, 131.2, 131.0, 130.5, 129.5, 127.9, 127.0, 126.7, 125.7, 123.4, 121.9, 114.3,
13.7, 63.4, 49.5, 48.6, 43.5, 39.7, 24.2, 23.2, 21.8. Anal. Calc. for C H ClN O •2.6H O:
3
0
32
3
2
2
C, 65.65; H, 6.83; N, 7.86. Found: C, 65.39; H, 6.49; N, 7.80%. M.p. 159.1-160.2 °C.
2
.2.14. Compound L15
1
H-NMR (CDCl ):  10.49 (s, 1H), 9.07 (d, J = 8.5 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.77
3
(d, J = 6.7 Hz, 2H), 7.66-7.59 (m, 6H), 5.97 (d, J = 16.2 Hz, 1H), 5.79 (d, J = 16.2 Hz, 1H),
4
1
.01-3.93 (m, 1H), 3.67-3.63 (m, 1H), 3.54-3.50 (m, 1H), 3.45 (br, 1H), 1.68-1.58 (m, 1H),
.56-1.48 (m, 1H), 1.29-1.22 (m, 1H), 0.86 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.7 Hz, 3H);
C-NMR:  164.7, 142.8, 133.0, 132.1, 131.0, 130.7, 130.5, 127.6, 127.4, 125.0, 114.5,
12.9, 64.2, 51.2, 49.9, 39.7, 24.8, 22.8, 22.3. Anal. Calc. for C H ClN O •1.1H O: C,
1
3
1
6
2
1
26
3
2
2
1.86; H, 6.97; N, 10.31. Found: C, 61.47; H, 6.48; N, 10.34%. M.p. 177.3-177.5 °C.
2
.3. Typical Procedure for Asymmetric Hydrosilane Reduction
1
2

2
.3.1. Procedure Using [IrCl(cod)] as an Ir Catalyst Precursor
2
A flask was charged with azolium salt L12 (0.02 mmol, 9.1 mg), Ag O (0.01 mmol, 2.4 mg)
2
and CH Cl (1 mL). After stirring the resulting mixture at room temperature for 2 h in the
2
2
dark, CH Cl was removed in vacuo. Then, a THF (1 mL) solution of [IrCl(cod)] (0.01
2
2
2
mmol, 6.9 mg) was added to the reaction vessel. The resulting mixture was stirred at room
temperature for an additional 4 h in the dark, filtered through a membrane filter, and
evaporated to dryness in vacuo. Subsequently, to the resulting flask containing yellow solid
of the unpurified IrCl(cod)(NHC) complex, a solution of AgBF (0.025 mmol, 4.9 mg) in
4
CPME (2 mL) was added, and then stirred at room temperature for 1 h. Finally,
propiophenone (0.5 mmol, 66 mg) and (EtO) MeSiH (2.25 mmol, 294 mg) were added to
2
the resulting CPME solution (see Appendix A. Supplementary data for details). After
stirring at room temperature for 20 h under open-air conditions, K CO (2 mg) and MeOH
2
3
(2 mL) were added. Then, the resulting mixture was stirred at room temperature for 2 h.
After evaporation of the solvents, the residue obtained was purified by column
chromatography on silica gel (Et O/n-hexane = 3:7) to give (S)-1-phenyl-1-propanol (61
2
mg, 91% isolated yield). The ee was measured by chiral GLC.
2
.3.2. Procedure Using [Ir(cod) ]BF as an Ir Catalyst Precursor
2 4
A flask was charged with azolium salt L12 (0.02 mmol, 9.1 mg), Ag O (0.01 mmol, 2.4 mg)
2
and CH Cl (1 mL). After stirring the resulting mixture at room temperature for 2 h in the
2
2
dark, CH Cl was removed in vacuo. Then, a CPME (1 mL) solution of [Ir(cod) ]BF (0.02
2
2
2
4
mmol, 9.9 mg) was added to the reaction vessel. The resulting mixture was stirred at room
temperature for an additional 4 h in the dark. Subsequently, propiophenone (0.49 mmol, 66
1
3

mg), (EtO) MeSiH (2.19 mmol, 294 mg) and CPME (1 mL) were added to the reaction
2
vessel. After stirring at room temperature for 20 h under open-air conditions, K CO (2 mg)
2
3
and MeOH (2 mL) were added. Then, the resulting mixture was stirred at room temperature
for 2 h.
3
. Results and discussion
3
.1. Establishment of an experimental procedure for the hydrosilylation by the in-situ
generated NHC–Ir catalyst
First, a series of azolium chlorides were synthesized from a commercially available
-amino alcohol (Scheme 1). The reaction of (S)-leucinol with chloroacetyl chloride

afforded the corresponding -chloroacetamide derivative 1 in an almost quantitative yield.
Then, compound 1 was coupled to a substituted benzimidazole. Thus, a small library of the
chiral NHC precursor L1–L15 was easily obtained via this synthetic route. Notably, these
newly synthesized azolium ligand precursors are completely air and moisture stable
products; thus, they can be handled under air atmosphere and stored as solids without any
special precaution.
(Scheme 1)
The aim of this study is the development of an asymmetric catalytic reaction using
the NHC–Ir species generated in situ. After several trials, a highly tunable chiral NHC Ir
1
4

catalyst could be generated in situ for the enantioselective hydrosilane reduction of ketones
Scheme 2).
(
(Scheme 2)
A representative reaction was carried out according to the following procedure. The
treatment of azolium chloride L12 with Ag O in CH Cl at room temperature afforded the
2
2
2
corresponding NHC–Ag complex. After the removal of the solvent, a THF solution of
IrCl(cod)] was added to the resulting Ag complex. The mixture was stirred at room
[
2
temperature, filtered through a membrane filter to remove the AgCl formed, and evaporated
to dryness under vacuum, affording the crude IrCl(cod)(NHC) complex. Next, the Ir
complex was treated with AgBF in cyclopentyl methyl ether (CPME) at room temperature
4
for 1 h. Finally, the reaction of propiophenone (2) with 4.5 equiv of (EtO) MeSiH was
2
carried out at room temperature for 20 h in a CPME solution containing the Ir species thus
obtained. Using this procedure, (S)-1-phenyl-1-propanol ((S)-3) was obtained in 92% yield
and with 92% ee (standard reaction conditions, see Appendix A. Supplementary data for
details).
The procedure has the advantage of operational simplicity, allowing easy ligand
screening without the purification of the NHC–Ir complex (vide infra). In addition, one
significant benefit of this procedure is that the isolation and spectroscopic characterization
of a pure NHC–Ir complex are not needed.
3
.2. Evaluation of NHC ligand
1
5

Based on the results of the reduction of 2 with (EtO) MeSiH using the in-situ
2
generated NHC–Ir catalyst, a series of benzimidazolium salts L1–L15 were screened in the
asymmetric hydrosilylation reaction (Table 1).
(Table 1)
The initial ligand screening showed that the introduction of a methyl substituent to
the azolium ring, far from the stereogenic center of the chiral ligand, significantly decreased
the catalytic activity of the Ir species. Thus, the Ir-catalyzed reaction of 2 with (EtO) MeSiH
2
under the influence of chiral NHC ligand derived from L1 afforded (S)-3 in a poor yield and
enantioselectivity (entry 1). Similarly, the chiral ligand bearing an ethyl substituent (azolium
L2) afforded a racemic mixture of the corresponding alcohol in 25% yield (entry 2). When
n
the linear alkyl substituent (N- Bu, azolium L3) was replaced with a branched alkyl
i
substituent (N- Bu, azolium L4) on the NHC ring, the catalytic activity of the Ir complex
remained unchanged (entries 3 and 4). Allyl-substituted azolium salt L5 was also
synthesized and evaluated. However, the reduction with L5 failed under the standard
reaction conditions (entry 5).
A promising result was obtained when L6 (R = benzyl) was used, affording (S)-3
with an excellent enantioselectivity (94% ee) (entry 6). This result may suggest that -
stacking between the benzylic moiety on the NHC ring and phenyl group of the substrate 2
is an important factor for the asymmetric hydrosilylation reaction. Another possibility is that
the NHC-Ir complex having a hemilabile benzylic moiety generated a vacant site in the
iridium coordination sphere during the reaction [14]. Therefore, the effect of a series of N-
benzyl analogs of the NHC ligand on the catalytic activity was next investigated. The
1
6

corresponding o-, m-, and p-toluylmethyl-substituted NHC ligand precursors (azolium
chlorides L7, L8, and L9) were synthesized. The reduction reaction using L7 occurred in a
similar manner as that using L6 (entry 7). A highly enantioselective hydrosilylation reaction
was also achieved when L8 or L9 was used (entries 8 and 9). The introduction of an
electron-withdrawing group such as a CF group at the meta position of the benzylic moiety
3
(azolium L10) improved the yield and enantioselectivity of the catalytic reaction. Thus, 2
could be reduced efficiently by the in-situ generated Ir species from ,,-trifluoro-m-
toluylmethyl-substituted azolium ligand precursor L10, affording (S)-3 in 84% yield and
with 92% ee (entry 10). An almost similar result was obtained when the reduction was
carried out using an Ir complex derived from benzimidazolium salt L11 bearing a 4-
biphenylbenzyl group (entry 11).
A further ligand screening showed that the use of azolium chloride bearing an N-
naphthalenylmethyl substituent increased the enantioselectivity of the hydrosilylation
reaction. 2 was reduced efficiently with the combined catalytic system of [IrCl(cod)] and
2
NHC–Ag complex derived from N-(1-naphthalenylmethyl)-substituted benzimidazolium
salt L12, affording (S)-3 in 92% yield and with 92% ee (entry 12). Similarly, the
enantioselective reaction using L13 bearing a 2-naphthalenylmethyl group afforded (S)-3
with 93% ee (entry 13). These results prompted us to prepare a ligand precursor bearing an
N-anthracenylmethyl substituent such as L14. However, the reaction using L14 afforded
(
S)-3 in a moderate yield (53%) and with a low ee (16%), probably because of steric effect
entry 14).
(
Furthermore, the benzyl moiety on the NHC ring was replaced with a phenyl moiety.
The synthesis of phenyl-substituted azolium chloride L15 illustrates the ease of ligand
1
7

variation via the synthetic route shown in Scheme 1. The hydrosilylation of 2 with
EtO) MeSiH was then carried out using the in-situ generated Ir-catalyst from L15 under the
(
2
standard reaction conditions. However, a poor catalytic activity was observed for the NHC–
Ir complex containing an N-phenyl group at the NHC ring (entry 15).
Finally, based on the high performance of L12, the synthesis of (R)-3 in the
asymmetric catalytic hydrosilylation of 2 was investigated using the chiral ligand with the
opposite configuration. (R)-Leucinol could be easily obtained from the commercial source,
allowing an effortless preparation of the chiral ligand precursor, ent-L12. As expected, the
reaction of 2 with (EtO) MeSiH in the presence of a catalytic amount of NHC–Ir complex
2
generated in situ from ent-L12 under the standard reaction conditions afforded (R)-3 in 95%
yield and with 91% ee (entry 16). Thus, this method that utilizes inexpensive and readily
available enantiomers of -amino acids has potential benefits.
3
.3. Evaluation of substrate
Scheme 3 summarizes the reactions of different substrates with the in-situ generated
NHC–Ir species under the standard reaction conditions.
(Scheme 3)
The reduction of butyrophenone (4) smoothly afforded (S)-1-phenyl-1-butanol ((S)-
) in an excellent yield (97%). Similarly, butyl phenyl ketone (6) was converted into (S)-1-
5
phenyl-1-pentanol ((S)-7) in a quantitative yield and with 90% ee. This in-situ generated
catalytic system was also suitable for the asymmetric hydrosilane reduction of alkyl aryl
1
8

ketones bearing a branched alkyl group. The reduction of isopropyl phenyl ketone (8) and
cyclohexyl phenyl ketone (10) yielded the corresponding optically active alcohols, (S)-9 and
(S)-11, with 92% ee and 93% ee, respectively. However, unfortunately, the reactions of 2,2-
dimethylpropiophenone under the standard reaction conditions using L6 and L12,
respectively, did not occur at all, probably due to the steric effect. On the other hand, the
reduction of aryl methyl ketones afforded the corresponding alcohols with slightly lower
stereoselectivities. Acetophenone (18) was transformed into (S)-1-phenylethanol ((S)-19) in
9
2% yield and with 86% ee, whereas 89% ee was achieved in the reduction of p-butylphenyl
methyl ketone (20).
The introduction of an electron-donating substituent such as methoxy group to
acetophenone in the hydrosilylation afforded the corresponding reduced alcohols in higher
yields. Thus, the reduction of p-methoxyacetophenone (22) and m-methoxyacetophenone
(24) smoothly afforded (S)-23 and (S)-25 in excellent yields and with 86% ee and 84% ee,
respectively. In contrast, the reduction of an aryl methyl ketone bearing an electron-
withdrawing group such as p-chloroacetophenone (26) with (EtO) MeSiH using this
2
catalytic system afforded (S)-27 in a slightly lower yield and enantioselectivity. Moreover,
the reduction of o-chloroacetophenone (28) proceeded slowly, affording the corresponding
alcohol in a moderate yield (63%) and stereoselectivity (47% ee), probably because of both
electronic and steric effects.
We also investigated the reactivity of alkyl aryl ketone bearing different arene
moieties using this catalytic system. Although the enantioselective reduction of 2-
acetylnaphthalene (32) was successful, the reduction of 1-acetylnaphthalene (34) afforded
the corresponding alcohol, (S)-35, in a moderate yield and enantioselectivity. The yields
obtained in the reactions of 34 and 28 were comparable. These results probably indicate that
1
9

the reactivity of the NHC–Ir catalyst is affected by the steric factor of the arene moiety on
the substance.
Enantiomerically pure secondary alcohols containing heteroaromatic substituents are
often used in the synthesis of biologically active compounds [15]. This catalytic system was
applied to the enantioselective reduction of 2-acetylthiophene (36) and 2-acetylfuran (38),
affording the corresponding alcohols, (S)-37 and (S)-39, with 86% ee and 80% ee,
respectively.
Finally, to evaluate the substrate scope and limitations of this method, the
asymmetric hydrosilylation of diverse ketones such as alkyl aryl ketones containing a
heteroatom-substituted alkyl moiety, cyclic ketone, dialkyl ketone, and diary ketone was
investigated. The reaction of ketones bearing chloro-substitutent afforded the corresponding
products with moderate enantioselectivity. When phenacyl chloride (40) was reacted with
(
EtO) MeSiH under the same reaction conditions, (R)-2-chloro-1-phenylethanol ((R)-41)
2
was obtained in 67% yield and with 50% ee. Based on this result, the reduction of -chloro-
substituted ketone such as 3-chloropropiophenone (42) was investigated. This reaction
afforded the corresponding optically active alcohol ((S)-43) in a slightly higher yield (82%)
and stereoselectivity (66%). Optically active halo alcohols are especially significant
structural elements for the formation of biologically active compounds, such as chiral
epoxides, diols, and amino alcohols. Recently, Cu-catalyzed asymmetric hydrosilylation of
- or -halo-substituted ketones was successfully achieved [16].
Moreover, the reduction of -hydroxy ketones such as phenacyl alcohol (44)
afforded phenylethylene glycol ((R)-45) in 59% yield and with 44% ee. The enantioselective
reduction of cyclic ketones such as 4-chromanone (46) was difficult under the standard
2
0

reaction conditions. The hydrosilylation of ,-unsaturated carbonyl compound such as
chalcone resulted in a complex mixture of several unidentified products.
The NHC–Ir complex was not a suitable catalyst for the hydrosilylation of dialkyl
ketones. For example, the reaction of 2-octanone (48) with (EtO) MeSiH in the presence of
2
a catalytic amount of chiral Ir complex at room temperature afforded a racemic mixture of
2
-octanol (49) in 31% yield. The reduction of benzyl butyl ketone (50) afforded 1-phenyl-2-
hexanol ((R)-51) in a poor yield. Again, it seems that - stacking between the benzylic
moiety on the NHC ring and phenyl group of the substrate is a critical factor for the
successful hydrosilylation reaction. In contrast, the present catalytic system facilitated the
enantioselective hydrosilylation of diaryl ketone. The reduction of 2,4'-
dichlorobenzophenone (52) afforded the corresponding diaryl methanol derivative, (R)-53,
in a moderate yield (55%) and enantioselectivity (59% ee). In recent years, highly
enantioselective Cu-catalyzed reduction of diaryl ketones with polymethylhydrosiloxane has
been successfully achieved using a chiral phosphine ligand [17]. The reduction products
such as optically active diarylmethanols have been used in the synthesis of many
physiologically and biologically active compounds.
3
.4. Performance of Ir catalyst precursor
Another advantage of the catalytic reaction using the in-situ generated catalyst is the
ability to screen diverse metal-ion precursors rapidly. Therefore, several Ir precursors were
evaluated in the asymmetric hydrosilylation of 2 with (EtO) MeSiH under the standard
2
reaction conditions (Table 2).
2
1

(Table 2)
4
The replacement of a neutral  -diene ligand such as 1,5-cyclooctadiene (cod) on the
2
Ir center with an  -diene ligand significantly decreased the catalytic activity. When the
reduction was carried out using an Ir catalyst precursor such as (IrClL ) (L = cyclooctene
2
2
(coe) or ethene), the reduction product was formed in a lower yield (entries 2 and 3). The ee
4
value of the product also slightly decreased. These results indicate that the bidentate  -cod
ligand plays an important role in the highly enantioselective transformation. Moreover, this
catalytic hydrosilylation reaction was carried out using a cationic Ir species, which was
formed by treating a neutral IrCl(cod)(NHC) complex with AgBF (entry 1). Therefore, the
4
performance of commercially available bis(1,5-cyclooctadiene)iridium(I) tetrafluoroborate
(
[Ir(cod) ]BF ) was evaluated as the catalyst precursor. After the treatment of azolium salt
2 4
L12 with Ag O, cationic [Ir(cod) ]BF was added to the reaction vessel containing the
2
2
4
resulting NHC–Ag species. Then, the reaction of 2 with (EtO) MeSiH was carried out using
2
the resulting NHC–Ir species (see Section 2.3.2). To our delight, this reaction afforded the
desired (S)-3 in an excellent yield and enantioselectivity (entry 4). This provides an
alternative, simplified reaction procedure for the in-situ generation of cationic NHC–Ir
species using [Ir(cod) ]BF as the Ir precatalyst.
2
4
3
.5. Performance of NHC ligand precursor
2
2

The results of the screening of chiral ligand precursor indicate that the catalytic
activity of the Ir species derived from m-toluylmethyl-substituted azolium precursor L8 may
be similar to that of the Ir species derived from azolium salt L10 bearing an ,,-trifluoro-
m-toluylmethyl substituent under the standard reaction conditions (Table 1, entry 8 vs. entry
1
0). It was assumed that through the choice of an appropriate ligand, a large range of
electronic effects could be imparted to the metal center. Therefore, any difference in the
activity of these catalyst systems in the initial stage of the asymmetric hydrosilylation would
be observed. Indeed, the reduction of 2 with (EtO) MeSiH using L8-based catalyst for 3 h
2
afforded (S)-3 in 19% yield, whereas the reaction catalyzed by the NHC–Ir species derived
from L10 bearing ad electron-withdrawing group such as a CF substituent afforded (S)-3 in
3
5
2% yield (Scheme 4). These results probably indicate that the catalytic activity of an Ir
complex increased with an increase in the Lewis acidic sites.
(Scheme 4)
The reduction of o-chloroacetophenone (28) with (EtO) MeSiH using the combined
2
catalytic system of [IrCl(cod)] and azolium salt L12 bearing a N-1-naphthalenylmethyl
2
substituent afforded (S)-29 with moderate enantioselectivity (47% ee) (Scheme 3). As
mentioned in the introduction, the development of an in-situ generated catalytic system
helped in the rapid screening of diverse NHC ligand precursors. To improve the
enantioselectivity of the reduction of 28, three sets of chiral azolium ligand precursors were
evaluated (Scheme 5). Fortunately, the reduction of 28 using the combined catalytic system
of [IrCl(cod)] and L6 afforded (S)-29 with a slightly increased stereoselectivity of 62% ee.
2
The reduction of 4-chromanone (46) by the use of several azolium salts was also
2
3

investigated. However, unfortunately, 46 was difficult to be reduced with high
stereoselectivity at this stage. Among the chiral ligands examined, azolium salt L12 gave
the corresponding optically active alcohol with 30% ee (Scheme 5).
(Scheme 5)
Adolfsson pointed out that high-throughput screening of the chiral ligand library is a
convenient way to find the optimum catalyst for a certain substrate or transformation [18].
We believe that the hydroxy-amide functionalized NHC ligands are highly tunable, thus
allowing the facile synthesis of ligand libraries and finding suitable catalysts for diverse
substrates.
In order to obtain further information, two functionalized azolium salts such as L16
and L17 were synthesized from commercially available L-alaninol and (S)-1-methoxy-2-
propanamine, respectively. The hydrosilylation of 2 catalyzed by in-situ generated NHC–Ir
catalyst derived from L16 afforded (S)-3 in 68% yield and with 88% ee. In contrast, when
the OH group (azolium L16) was replaced with an OCH group (azolium L17) in the chiral
3
ligand, the enantioselectivity significantly decreased (Scheme 6). These results strongly
indicate that the hydroxyl functionality on the NHC ligand induced a high stereoselectivity
in the hydrosilylation reaction.
(Scheme 6)
Our strategy for the design of NHC ligands was based on the introduction of a chiral
hydroxyamide side arm into the substituted benzimidazole derivative. In addition to these
2
4

ligand precursors, the corresponding imidazolium salt, L18, could be easily synthesized
from 3-benzylimidazole using the synthetic route shown in Scheme 2. However, the
asymmetric hydrosilane reduction of 2 using L18-based NHC–Ir catalyst afforded (S)-3 in
3
6% yield and with 81% ee (Scheme 6). This is probably because the -donating ability of
imidazol-2-ylidene NHC increased than that of benzimidazol-2-ylidene NHC [3k].
Moreover, for design of ligands, a methylene (CH ) linker was used between the
2
hydroxyamide group and NHC ring. To investigate the effect of different linkers of the
chiral ligand on the catalytic activity, two hydroxyamide-functionalized azolium salts
bearing a (CH ) linker (azolium L19) and C(CH ) linker (azolium L20) were synthesized
2
2
3 2
and evaluated. In both the cases, the asymmetric hydrosilylation with the in-situ generated
catalyst resulted in a poor yield and stereoselectivity (Scheme 6).
Wills et al. reported the enantioselective transfer hydrogenation of ketone catalyzed
by a Ru(II) complex bearing polydentate ligand involving a hydroxyamide functionality
[
19]. They proposed that the hydroxyamide functionality is transformed into a cyclic form
by intramolecular nucleophilic addition of hydroxy group to amide carbonyl moiety during
the catalytic reaction. As shown in Scheme 6, the hydroxy moiety and the methylene linker
of the chiral ligand system were critical in the present asymmetric hydrosilylation.
Therefore, we speculated that a similar catalytic active species suggested by Wills is
generated in the present asymmetric reduction catalyzed by NHC–Ir complex (Scheme 7).
First, an iridium complex B involving a carbene and an amidato group might be generated
from an cationic NHC–Ir catalyst precursor A [12d]. Because almost no reaction occurred
under the influence of L19 or L20 (Scheme 6), the formation of the six-membered amidato
iridium complex B might be important for successful catalytic reaction. Then,
intramolecular nucleophilic addition of hydroxy group to amide carbonyl moiety might give
2
5

a cyclic form C, in which the stereodirecting group would be locked in a fixed
conformation. The resulting C would act as an active catalyst of the asymmetric
hydrosilylation.
(Scheme 7)
4
. Conclusion
An enantioselective silane reduction of ketones catalyzed by an in-situ generated
NHC–Ir complex under operationally simple conditions was investigated. A small library
could be generated with ease via the modular synthesis of chiral NHC ligands by the use of
easily available leucine. The attachment of the hydroxyamide side arm to the
benzimidazolidene through a methylene (CH ) linker was important for achieving a high
2
enantioselectivity in the catalytic reaction. Further investigations on the asymmetric
reduction of various carbonyl compounds, especially diaryl ketones, by using [Ir(cod) ]BF
2
4
precatalyst are currently underway.
Acknowledgments
2
6

This work was financially supported by a Grant-in-Aid for Scientific Research (C)
26410254) from Japan Society for the Promotion of Science (JSPS).
(
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version,
at doi.
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