Enantioselective Hydrosilylation of Ketones Catalyzed by a Readily Accessible N-Heterocyclic Carbene-Ir Complex at Room Temperature

Article abstract of DOI:10.1002/ejoc.201402279

A series of functionalized azolium compounds were synthesized from chiral α-amino acid derivatives such as β-amino alcohols. of hydroxy-amide-functionalized azolium salts thus obtained with Ag₂O afforded N-heterocyclic carbene-Ag (NHC-Ag) complexes. Subsequent treatment of the resulting silver compound with [IrCl(cod)]₂ yielded monodentate IrCl(cod)(NHC), which was stable in air. The NHC-Ir complex facilitated efficient asymmetric hydrosilylation of ketones using (EtO)₂MeSiH under ambient conditions. A chiral ligand containing an isobutyl stereodirecting group was found to be the best ligand for the functionalized NHC-Ir complexes that were examined. A linear relationship was found between the catalyst ee and the product ee. The hydroxy functional group on the NHC ligand side-arm not only induced stereocontrol but also enhanced the reaction rate.

Full text of DOI:10.1002/ejoc.201402279

FULL PAPER
DOI: 10.1002/ejoc.201402279
Enantioselective Hydrosilylation of Ketones Catalyzed by a Readily Accessible
N-Heterocyclic Carbene–Ir Complex at Room Temperature
Kanako Shinohara,[a] Shun Kawabata,[a] Hanako Nakamura,[a] Yoshiki Manabe,[a] and
Satoshi Sakaguchi*[a]
Keywords: Asymmetric catalysis / Ligand design / Carbenes / Nitrogen heterocycles / Hydrosilylation / Iridium
A series of functionalized azolium compounds were synthe-
sized from chiral α-amino acid derivatives such as β-amino
alcohols. Reaction of hydroxy-amide-functionalized azolium
salts thus obtained with Ag2O afforded N-heterocyclic carb-
ene-Ag (NHC–Ag) complexes. Subsequent treatment of the
ketones using (EtO)2MeSiH under ambient conditions. A chi-
ral ligand containing an isobutyl stereodirecting group was
found to be the best ligand for the functionalized NHC–Ir
complexes that were examined. A linear relationship was
found between the catalyst ee and the product ee. The
resulting silver compound with [IrCl(cod)]2 yielded mono- hydroxy functional group on the NHC ligand side-arm not
dentate IrCl(cod)(NHC), which was stable in air. The NHC–
Ir complex facilitated efficient asymmetric hydrosilylation of
only induced stereocontrol but also enhanced the reaction
rate.
The asymmetric hydrosilylation reaction of aceto-
phenone with diphenylsilane reported by Hermann in 1996
was the first catalytic application in which chiral induction
was achieved using a chiral NHC.[4] Many investigators
have been interested in the enantioselective hydrosilylation
of ketones and different classes of chiral NHCs have been
tested.[5] A breakthrough (giving 98% ee) was achieved
by Shi, who developed a bidentate axially chiral bis-
(NHC)-RhIII complex with a 1,1Ј-binaphthalenyl backbone
in 2003.[6] Gade and co-workers introduced a bidentate ox-
azoline/NHC–RhI complex for which a ligand precursor
was obtained through direct linkage of heterocycles.[7]
Andrus demonstrated Ru-catalyzed asymmetric hydro-
silylation using a monodentate chiral NHC ligand contain-
ing planar [2.2]paracyclophane.[8] More recently, Gawley
designed and synthesized a C2-symmetric monodentate
NHC ligand for Cu-catalyzed reactions (Scheme 1).[9]
We recently designed a chelating ligand with a carbene
unit and a second coordinating group, such as the hydroxy–
amide functional group on the side-arm of the NHC, and
synthesized it from natural α-amino acids. This combina-
tion of coordinating moieties generated a strongly coordi-
nating polydentate ligand that could lock stereodirecting
functional groups into a fixed conformation. Thus, highly
enantioselective Pd-catalyzed intermolecular Heck-type
couplings,[10a,10b] Pd-catalyzed asymmetric allylic substitu-
tions,[10d] and Cu-catalyzed asymmetric 1,4-additions[11]
were successfully achieved using this ligand. Other new
NHC–Ir and NHC–Ru complexes have been synthesized to
further explore the applications of this kind of chiral
hydroxy–amide-functionalized NHC ligand.[12] We briefly
described the enantioselective hydrosilane reduction of
ketones under mild conditions, catalyzed by the mono-
Introduction
Transition-metal-catalyzed asymmetric hydrosilylation
has attracted much attention for the reduction of a range
of functional groups containing ketone moieties.[1] This
process offers several advantages over hydrogenation, such
as the safe and mild reaction conditions employed, the re-
duced likelihood of over-reduction, the ease of handling the
materials, and the inexpensive nature of the hydrosilanes.
Therefore, the development of a highly efficient and readily
accessible metal catalyst to facilitate asymmetric hydro-
silylation under mild reaction conditions (at room tempera-
ture under open-air conditions) would be an important step
forward in the field of organic synthesis.[1]
N-Heterocyclic carbene (NHCs) are widely used as
homogeneous catalysts because of their strong M–NHC
bonds and electron-donating characteristics.[2] An equally
attractive feature is that NHC ligand precursors, such as
azolium salts, are easy to prepare. A wide range of function-
alized NHC ligands have, therefore, been reported in the
literature. Of particular interest are chiral NHC ligands pre-
pared from naturally occurring products such as amino
acids. Using natural products allows chiral NHC ligands to
be designed and produced easily, contributing to the con-
struction of NHC libraries that will advance asymmetric
catalysis.[3]
[a] Department of Chemistry and Materials Engineering, Faculty
of Chemistry, Materials and Bioengineering, Kansai University,
Suita, Osaka 564-8680, Japan
E-mail: satoshi@kansai-u.ac.jp
http://www2.itc.kansai-u.ac.jp/~satoshi/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402279.
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New Approach to Enantioselective Hydrosilylation of Ketones
CH2Cl2 to give silver NHC complexes. Subsequently, treat-
ing the silver compounds with [IrCl(cod)]2 in THF at room
temperature yielded desired IrCl(cod)(NHC) complexes 2a–
2f. Note that these iridium complexes were completely
stable in air and moist environments.
The reaction of propiophenone (3) with (EtO)2MeSiH in
the presence of a small amount of AgBF4 was selected as a
model reaction for evaluating the performance of NHC–
Ir catalysts 2a–2f (Table 1). The first promising result was
obtained for the reaction using 2b (R1 = Et) at room tem-
perature, which afforded (S)-1-phenylpropanol (4) with
good enantioselectivity (85% ee) (Table 1, Entry 2). Simi-
larly, iridium complex 2c (R1 = iBu) catalyzed the reduction
of 3 with silane under the same reaction conditions to yield
4 in an excellent yield (92%) and 88% ee (Table 1, Entry 3).
A high enantioselectivity (92% ee) was achieved when the
amount of solvent used was increased (Table 1, Entry 4).
Table 1. Screening of IrCl(cod)(NHC) complexes for optimal cata-
lyst.[a]
Scheme 1. Previously reported NHC ligand system for asymmetric
hydrosilylation.
dentate IrCl(cod)(NHC) complex, in a previous communi-
cation.[12b] Here, we present the entire set of results from
our study of the NHC–Ir-catalyzed asymmetric hydro-
silylation of ketones.
Entry
NHC–Ir
R1
Yield [%]
ee [%]
1
2
2a
Me
Et
iBu
iBu
tBu
sBu
Bn
63
81
92
87
78
73
67
93
86
75
85
88
92
2b
Results and Discussion
3
2c
4[b]
5
2c
The method for preparing IrCl(cod)(NHC) is shown in
Scheme 2. The catalyst was optimized by synthesizing a
series of NHC–Ir complexes 2a–2f by varying the stereo-
directing (R1) group on the hydroxy–amide-functionalized
NHC ligands. The functionalized azolium ligand precursors
1 could be readily prepared, in two steps, from commer-
cially available enantiopure β-amino alcohols. The obtained
azolium compounds 1a–1f were treated with Ag2O in
2d
18 (ent-4)
9 (ent-4)
86
90 (ent-4)
93 (ent-4)
6
7
2e
2f
8
ent-2c
ent-2c
iBu
iBu
9[b]
[a] Substrate 3 (0.5 mmol), (EtO)2MeSiH (2 mmol), IrCl(cod)-
(NHC) (5 mol-%), AgBF4 (5 mol-%), THF (0.5 mL), room temp.,
15 h. [b] THF (2 mL).
An unusual relationship between the steric properties of
the ligand and the enantioselectivity of the reaction was
identified. Increasing the bulkiness of the alkyl substituent,
e.g., tBu (2d) or sBu (2e), of the ligand led to poor enantio-
selectivity (Table 1, Entries 5 and 6 for 2d and 2e, respec-
tively). Similar observations have been reported for Cu-cat-
alyzed asymmetric conjugate addition reactions influenced
by chiral hydroxy–amide-functionalized azolium ligand pre-
cursor 1.[11b] Furthermore, 3 was reduced to 4 with 86% ee
using 2f (R1 = Bn) as a catalyst (Table 1, Entry 7). These
screening tests revealed that IrCl(cod)(NHC) complexes
containing a CH2R (R = H, alkyl, or phenyl) (Table 1, En-
tries 1–4, and 7) substituent at the asymmetric center were
more suitable catalysts than the complexes containing
CHR2 or CR3 substituents (Table 1, Entries 5 and 6, respec-
tively).
From a practical viewpoint, complex 2c is the most ef-
ficient catalyst because it can be prepared from a readily
available natural amino acid such as (S)-leucine. The corre-
Scheme 2. Facile route to IrCl(cod)(NHC) 2a–2f from enantiopure
β-amino alcohols.
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S. Sakaguchi et al.
FULL PAPER
sponding enantiomer, (R)-leucine, can also be easily ob- auxiliary is involved in the active catalyst species, although
tained from commercial sources. Therefore, we synthesized we have no experimental evidence to explain the reaction
IrCl(cod)(NHC) complex (ent-2c) from (R)-leucinol and in- mechanism at this stage.
vestigated the influence of the absolute configuration of the
The results of the asymmetric hydrosilylation of various
stereogenic center in the ligand on the enantiocontrol ketones, catalyzed by iridium complex 2c, are shown in
achieved in the catalytic hydrosilylation reaction. As ex- Table 2. From among the aryl methyl ketones, the best ee
pected, reduction of 3 in the presence of catalytic ent-2c value (90%) was found for the reduction of acetophenone
yielded the R-configured alcohol with excellent enantio- (5) (Table 2, Entry 1). Other ketones 6–9 were reduced to
selectivity (up to 93% ee) (Table 1, Entries 8 and 9). Besides their corresponding optically active alcohols with good
easy access to the air-stable NHC–Ir catalyst, the other ad- enantioselectivies at room temperature (Table 2, Entries 2–
vantages of this protocol include its operational simplicity 5). In our previous communication, we had investigated
and the mild reaction conditions (room temperature) re- NHC–Ir-catalyzed enantioselective hydrosilylation of aceto-
quired. Indeed, the reactions can be performed on the
bench top under open-air conditions (Schlenkware and in-
Table 2. Reduction of various ketones by IrCl(cod)(NHC) 2c cata-
lyst.[a]
ert gas are not required) and by using undistilled solvents.
Therefore, we believe that the catalytic system presented
here will be a useful alternative method for preparing chiral
alcohols in enantiopure fashion.
We were also interested in understanding the relationship
between catalyst ee (eecat) and product ee (eepro) in the
asymmetric reduction system presented here. Kagan
pointed out that a plot of eepro as a function of eecat is a
simple way of obtaining information on the enantio-
selectivity of a catalytic reaction.[13] Since we possessed
both enantiomers of the NHC–Ir catalyst, we carefully pre-
pared various mixtures of 2c and ent-2c (with S/R ratios of
100:0, 90:10, 80:20, 70:30, 60:40, and 50:50). The results of
the asymmetric catalytic reduction reactions are shown in
Figure 1. The clearly linear relationship between eepro and
eecat might indicate that only one molecule of the chiral
[a] Ketone (0.5 mmol), (EtO)2MeSiH (2 mmol), IrCl(cod)(NHC) 2c
(6 mol-%), AgBF4 (6 mol-%), THF (2 mL), room temp., 15 h.
[b] Isolated yield. [c] Determined by GC.
Figure 1. Relationship between the catalyst ee (eecat) and product
ee (eepro).
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New Approach to Enantioselective Hydrosilylation of Ketones
phenone derivatives 5–9 with (EtO)2MeSiH in 2-methyl- iBu). However, complexes 2d and 2e contained sterically
tetrahydrofuran.[12b] A comparison with previously re- hindered tBu and sBu groups, and were consequently, not
ported results revealed that these substrates, except for 5 effective, yielding ent-21 with poor enantioselectivity.
and 7, could be reduced efficiently in the reaction using
THF as solvent.
The previously reported NHC–Rh-catalyzed asymmetric
hydrosilylation of ketones using Ph2SiH2 was most suitable
for the reduction of methyl ketone derivatives.[6,7] In con-
trast, the IrCl(cod)(NHC) we studied here was found to be
a suitable catalyst for the enantioselective hydrosilane re-
duction of several alkyl aryl ketones using (EtO)2MeSiH.
Butyrophenone (10) was converted into (S)-1-phenyl-
butanol under these reaction conditions with excellent
enantioselectivity (96% ee) (Table 2, Entry 6). The re-
Scheme 3. Asymmetric hydrosilane reduction of ethyl 3-oxo-3-
phenylpropionate (20).
duction of butyl phenyl ketone (11) occurred smoothly, pro-
viding the desired alcohol product in 83% yield and with
92% ee (Table 2, Entry 7). Good stereoselectivity was
achieved for the reduction of cyclohexyl phenyl ketone (12),
but rather poor yield was achieved, probably because of
steric hindrance in the substrate (Table 2, Entry 8). The
enantioselective reduction of 2-acetylnaphthalene (13) was
successfully achieved using the catalytic system presented
here, but 1-acetylnaphthalene (14) was reduced to corre-
sponding alcohol with only moderate yield and enantio-
selectivity (Table 2, Entries 9 and 10).
Enantiomerically pure secondary alcohols that contain
heteroaromatic substituents are often employed as struc-
tural elements in the preparation of biologically active com-
pounds. In recent years, Adolfsson et al. have reported sys-
tematic studies on Ru-catalyzed asymmetric transfer hydro-
genation of heteroaromatic ketones.[14] Xiao and Gao devel-
oped the highly enantioselective Fe-catalyzed hydrogena-
tion of various aryl ketones.[15] The present catalytic system
was found to be successfully applied in enantioselective re-
duction of 2-acetylfuran (16) and 2-acetylthiophene (17)
(Table 2, Entries 12 and 13). These reactions produced cor-
responding alcohols with 84% ee and 89% ee, respectively.
Unfortunately, however, it was difficult to reduce dialkyl
ketones such as 2-octanone (18) and benzyl butyl ketone
(19) under these reaction conditions (Table 2, Entries 14
and 15).
As shown above, the NHC–Ir complex 2, having both
hydroxy and amide functionalities on the side-arm of the
NHC, facilitated asymmetric hydrosilane reduction of
ketones at room temperature with good to excellent
enantioselectivities. One significant benefit of this reaction
is that the ligand precursors, such as hydroxy–amide-func-
tionalized azolium salts, can be prepared easily from readily
available chiral β-amino alcohols. In this promising chiral
ligand system (using azolium ligand precursor 1), the
hydroxy functionality was found to be critical for the effi-
ciency of the enantioselective hydrosilylation of ketones
(Scheme 4).
Enantiopure β-hydroxy esters are important building
blocks for synthesizing biologically active compounds.[16]
To the best of our knowledge, there has only been one re-
port of highly enantioselective hydrosilylane reduction of β-
keto esters catalyzed by an axially chiral bidentate NHC–
RhIII complex.[6c] The reaction of ethyl 3-oxo-3-phenyl-
propionate (20) with (EtO)2MeSiH in the presence of irid-
ium catalyst 2c and AgBF4 in THF at room temperature
produced (S)-ethyl 3-hydroxy-3-phenylpropionate (21) in
quantitative yield and 86% ee (Scheme 3). Reversal of the
Scheme 4. Influence of the hydroxy functionality of the chiral NHC
ligand.
To investigate the role of the hydroxy functionality of the
stereoselectivity was achieved using ent-2c, affording ent- ligand, we first synthesized two azolium salts from commer-
21 with 86% ee (Scheme 3). A series of IrCl(cod)(NHC) cially available (S)-2-butanamine and (S)-1-methoxy-2-prop-
complexes 2a–2f were also examined (Table S1, Supporting ylamine. Monodentate NHC–Ir complexes 2g and 2h were
Information). In a manner similar to that of the reduction successfully synthesized from these azolium salts using a
of 3, the iBu-substituted NHC ligand proved to be promis- route similar to that used to synthesize 2a. NHC–Ir com-
ing. The ee values obtained using 2b (R1 = Et) and 2f (R1 plex 2a has the hydroxy–amide functionality, which pro-
= Bn) were comparable to those obtained using 2c (R1 = motes asymmetric hydrosilylation reactions (Table 1, Entry
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S. Sakaguchi et al.
FULL PAPER
1). However, newly designed iridium complexes 2g and 2h lecular nucleophilic addition of the hydroxy group to the
possess alkyl-amide and methoxy-amide functional groups, amide carbonyl moiety during the catalytic reaction. It
respectively, and were found to exhibit reduced catalytic ac- might be possible that a similar catalytically active species
tivities (Scheme 4). The reduction of 3 catalyzed by 2g pro- suggested by Wills is generated in the present asymmetric
vided a racemic mixture of the corresponding alcohol, and reduction catalyzed by NHC–Ir complex 2c. One possibility
the reduction of 3 catalyzed by 2h gave reversed enantio- is shown in Scheme 5. First, an anionic amidate iridium
selectivity, affording ent-4 with 19% ee. These results complex A might be formed.[10c] Then, intramolecular nu-
strongly suggest that the hydroxy functionality on the side- cleophilic addition of the hydroxy group to the amide carb-
arm of the NHC ligand not only induces stereoselectivity onyl moiety might give cyclic intermediate B, in which the
of the asymmetric reduction reaction but also enhances the stereodirecting group would be locked in a fixed conforma-
reaction rate.
tion. Further investigations into the catalytic active species
Mechanistically speaking, the catalytic cycle proposed by are currently ongoing.
Ojima et al. in 1975 is still generally accepted for RhI- (or
IrI-) catalyzed asymmetric hydrosilylations.[1] The oxidative
addition of the hydrosilane to a RhI species gives the silyl
Conclusions
metal hydride RhIII complex. Insertion of a ketone carbonyl
A monodentate iridium complex with a chiral NHC
functional group into the RhIII–Si bond forms the silyoxy-
alkyl-rhodium complex, and then reductive elimination lib-
erates the silyl ether and causes the RhI species to be reco-
vered. Recently, Gade and co-workers proposed a new path-
way for catalytic hydrosilylation with dihydrosilane
Ph2SiH2, involving the formation of a silylene intermedi-
ate.[7] The authors suggested that the catalytic hydro-
silylation of ketones occurs through mechanistic pathways
that depend on the nature of the silane. For a reaction with
a tertiary silane such as R3SiH, the reaction appears to pro-
ceed by the Ojima mechanism. In the previous report, we
showed the hydrosilylation of ketone 5 with Ph2SiH2 cata-
lyzed by IrCl(cod)(NHC) complex 2c furnished a racemic
mixture of the reduced product with low yield (36%).[12b]
Therefore, it is likely that the present hydrosilylation with
(EtO)2MeSiH proceeds through a reaction pathway similar
to that proposed by Ojima.
As mentioned above, the hydroxy moiety of the present
chiral ligand system plays a critical role in asymmetric
hydrosilylation (Scheme 4). In the literature, Wills et al. re-
ported the highly enantioselective catalytic transfer hydro-
genation of ketone under the influence of a RuII complex
bearing polydentate ligand.[17] Their chiral ligand system in-
volves the hydroxy–amide functionality derived from (S)-2-
phenylglycinol. They proposed that the hydroxy–amide
functionality is transformed into a cyclic form by intramo-
ligand containing a hydroxy–amide group on the side-arm
was easily synthesized from naturally occurring amino acids
such as leucine. The complex was stable in air and moisture.
The NHC–Ir complex catalyzed the asymmetric hydro-
silylation of aryl ketones by (EtO)2MeSiH at room tem-
perature, yielding the corresponding optically active
alcohols with moderate to good enantioselectivities. These
transformations could be performed under operationally
simple conditions, implying that the reactions can be car-
ried out on a bench under open-air conditions using sol-
vents that have not been distilled. The hydroxy–amide func-
tionality of the NHC ligand was found to be critical to the
asymmetric reduction reaction. We believe the catalytic sys-
tem presented here can be a useful alternative method for
achieving the asymmetric reduction of various aryl ketones
under mild conditions. The efficient enantioselective hydro-
silylation of ketones catalyzed by NHC–Ir catalysts gener-
ated in situ using highly tunable azolium NHC ligand pre-
cursors is the subject of ongoing research in our labora-
tory.[18]
Experimental Section
General: All chemicals were obtained from commercial sources and
were used as received. 1H- and 13C NMR spectra were recorded on
spectrometers at 400 and 100 MHz, respectively. Chemical shifts
were reported in ppm relative to TMS for 1H- and 13C NMR spec-
tra. (CD3)2SO or CDCl3 was used as the NMR solvent. Thin-layer
chromatography (TLC) analysis was performed with glass-backed
plates pre-coated with silica gel and examined under UV (254 nm)
irradiation. Flash column chromatography was executed on silica
gel 60 (230–400; particle size: 0.040–0.063 nm).
General Procedure for Preparation of Azolium Salt: To a flask were
added N-benzylbenzimidazole (3 mmol), 1,4-dioxane (12 mL) and
α-chloroacetoaminde derivative (3 mmol) derived from chloro-
acetyl chloride and β-amino alcohol. After stirring the reaction
mixture at 110 °C for 24 h, the solvent was removed under reduced
pressure. The residue was dissolved in methanol, and then activated
carbon (≈ 1 g) was added. After 16 h, the activated carbon was re-
moved by filtration. After removing methanol in vacuo from the
filtrate, the crude residue was purified by column chromatography
(SiO2, CH2Cl2/MeOH: 9:1) to yield the corresponding azolium salt.
Scheme 5. Locking of the stereocontrol element in a fixed confor-
mation.
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New Approach to Enantioselective Hydrosilylation of Ketones
1
Compounds 1a,[10d] 1c,[11b] 1d,[11b] 1f,[11b] 1g[10d] and 1h[10d] were
(2b): Yellow solid (yield 76%). H NMR (400 MHz, CDCl3): δ =
reported in the preceding papers.
7.50–6.98 (m, 9 H, CHbenzimid, CHPh), 6.86 (d, J = 9.6 Hz, 1 H,
NH), 6.30 (d, J = 15.6 Hz, 1 H, NCH2CO), 6.10 (d, J = 16.0 Hz,
1 H, CH2Ph), 5.99 (d, J = 16.0 Hz, 1 H, CH2Ph), 4.85 (d, J =
15.6 Hz, 1 H, NCH2CO), 4.87–4.77 (br., 2 H, CHcod), 3.88–3.38
(br., 3 H, CH2OH, NHCH), 3.04–2.89 (br., 3 H, CHcod, OH), 2.48–
2.19 (br., 2 H, CH2 cod), 2.07–1.55 (br., 6 H, CH2 cod), 1.28–1.17
(m, 2 H, CH2 Et), 0.47 (d, J = 7.6 Hz, 3 H, CH3 Et) ppm. 13C NMR
(100 Hz, CDCl3): δ = 191.9 (Ccarbene), 167.3 (CO), 135.3 (CHPh),
134.5 (Cbenzimid), 134.4 (Cbenzimid), 128.8 (CHPh), 127.9 (CHPh),
126.8 (CHPh), 123.4 (CHbenzimid), 123.3 (CHbenzimid), 111.3
(CHbenzimid), 110.2 (CHbenzimid), 88.8 (CHcod), 88.7 (CHcod), 67.8
(CHcod), 64.6 (CHcod), 53.9, 53.8, 53.6, 52.4, 33.7 (CH2 cod),
32.9 (CH2 cod), 30.2 (CH2 cod), 28.9 (CH2 cod), 25.5 (CH2 Et), 9.9
(CH3 Et) ppm. C28H35ClIrN3O2·0.5CH3CO2C2H5·0.5H2O: calcd. C
49.61, H 5.55, N 5.79; found C 49.25, H 5.31, N 5.58.
3-(2-{[(1S)-1-(Hydroxymethyl)propyl]amino}-2-oxoethyl)-1-phenyl-
methyl-1H-benzimidazolium Chloride (1b): White solid (yield 46%);
1
m.p. 191.9–192.4 °C. H NMR (400 MHz, [D6]DMSO): δ = 10.09
(s, 1 H, CHbenzimid), 8.75 (br., 1 H, NH), 8.01–7.98 (m, 2 H,
CHbenzimid), 7.67–7.30 (m, 7 H, CHbenzimid, CHPh), 5.87 (s, 2 H,
CH2Ph), 5.50–5.35 (m, 2 H, NCH2CO), 4.87 (br., 1 H, OH), 3.64–
3.61 (m, 1 H, NHCH), 3.38–3.36 (m, 2 H, CH2OH), 1.61–1.54 (m,
1 H, CH2 Et), 1.44–1.35 (m, 1 H, CH2 Et), 0.83 (t, J = 7.6 Hz, 3 H,
CH3 Et) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 164.3 (CO),
143.6, 134.0, 131.7, 130.5, 129.0, 128.7, 128.2, 124.1, 124.1, 113.9,
112.9, 62.6 (CH2OH), 53.1 (NHCH), 49.8, 48.7, 23.6 (CH2 Et), 10.5
(CH3 Et) ppm. C20H24ClN3O2·0.2H2O: calcd. C 63.64, H 6.52, N
11.13; found C 63.44, H 6.19, N 11.14.
3-(2-{[(1S)-1-(Hydroxymethyl)-2-methylbutyl]amino}-2-oxoethyl)-1-
phenylmethyl-1H-benzimidazolium Chloride (1e): White solid (yield
51%); m.p. 207.2–207.7 °C. 1H NMR (400 MHz, CDCl3): δ = 10.63
(s, 1 H, CHbenzimid), 9.04 (d, J = 8.2 Hz, 1 H, NH), 8.00–7.98 (m,
1 H, CHbenzimid), 7.58–7.33 (m, 8 H, CHbenzimid, CHPh), 5.85 (d, J
= 16.2 Hz, 1 H, CH2Ph), 5.77 (d, J = 16.2 Hz, 1 H, NCH2CO),
5.71 (d, J = 16.2 Hz, 1 H, NCH2CO), 5.59 (d, J = 16.2 Hz, 1 H,
CH2Ph), 4.65 (br., 1 H, OH), 3.75–3.65 (m, 3 H, NHCH, CH2OH),
1.69–1.67 (m, 1 H), 1.45–1.42 (m, 1 H), 1.16–1.11 (m, 1 H),
0.86 (d, J = 8.4 Hz, 3 H, CH3 sBu), 0.80 (t, J = 8.4 Hz, 3 H,
CH3 sBu) ppm. 13C NMR (100 Hz, CDCl3): δ = 164.8 (CO), 143.5,
132.8, 130.7, 128.4, 128.2, 128.0, 128.0, 127.3, 126.9, 114.3, 113.1,
61.8 (CH2OH), 57.1 (NHCH), 51.8, 48.9, 35.5 (CHsBu), 25.8
(CH2 sBu), 15.3 (CH3 sBu), 11.1 (CH3 sBu) ppm. C22H28ClN3O2·
0.1CHCl3: calcd. C 64.14, H 6.84, N 10.15; found C 64.33, H 6.61,
N 10.10.
Chloro(η4-1,5-cyclooctadiene)[3-(2-{[(1S)-1-(hydroxymethyl)-2,2-
dimethylpropyl]amino}-2-oxoethyl)-1-phenylmethylbenzimidazole-2-
ylidene]iridium(I) (2d): Yellow solid (yield 74 %). 1H NMR
(400 MHz, CDCl3): δ = 7.50–7.01 (m, 9 H, CHbenzimid, CHPh), 6.58
(d, J = 9.6 Hz, 1 H, NH), 6.41 (d, J = 15.6 Hz, 1 H, NCH2CO),
6.34 (d, J = 15.6 Hz, 1 H, CH2Ph), 5.78 (d, J = 15.6 Hz, 1 H,
CH2Ph), 4.88 (d, J = 15.6 Hz, 1 H, NCH2CO), 4.79 (br., 2 H,
CHcod), 3.88–3.63 (m, 3 H, CH2OH, NHCH), 3.02–2.98 (br., 2 H,
CHcod), 2.73 (t, J = 6.9 Hz, 1 H, OH), 2.28 (br., 2 H, CH2 cod),
1.82 (br., 2 H, CH2 cod), 0.55 (s, 9 H, CH3 tBu) ppm. 13C NMR
(100 Hz, CDCl3): δ = 191.9 (Ccarbene), 167.4 (CO), 135.4 (CHPh),
134.3 (Cbenzimid), 134.3 (Cbenzimid), 128.8 (CHPh), 128.0 (CHPh),
127.0 (CHPh), 123.5 (CHbenzimid), 123.3 (CHbenzimid), 111.3
(CHbenzimid), 110.3 (CHbenzimid), 88.8 (CHcod), 88.8 (CHcod), 67.8
(CHcod), 61.5 (CHcod), 59.5, 54.1, 53.5, 52.5, 33.7 (CH2 cod),
33.4 (CtBu), 32.9 (CH2 cod), 29.4 (CH2 cod), 28.8 (CH2 cod), 26.4
(CH3 tBu) ppm. C30H39ClIrN3O2 (701.33): calcd. C 51.38, H 5.61,
N 5.99; found C 51.30, H 5.47, N 5.80.
General Procedure for the Preparation of [IrCl(cod)(NHC)] Com-
plexes: A suspension of benzimidazolium salt 1 (0.1 mmol) and sil-
ver(I) oxide (0.05 mmol, 24 mg) in CH2Cl2 (5 mL) was stirred in
the dark for 1 h at room temperature under open air conditions.
After evaporation of the solvent, a solution of [IrCl(cod)]2 (34 mg,
0.05 mmol) in THF (5 mL) was added in the dark at room tempera-
ture. The resulting suspension was stirred for 16 h, filtered through
a membrane filter (pore size: 0.2 μm), and the solvents evaporated
to dryness in vacuo. The desired [IrCl(cod)(NHC)] complex was
purified by column chromatography on silica gel (CH2Cl2/CH3OH
= 9:1). Complexes 2c and 2f have been previously reported.[12b]
Chloro(η4-1,5-cyclooctadiene)[3-(2-{[(1S)-2-hydroxy-1-methylethyl]-
amino}-2-oxoethyl)-1-phenylmethylbenzimidazole-2-ylidene]iridium(I)
(2a): Yellow solid (yield 48%). 1H NMR (400 MHz, CDCl3): δ =
7.50–6.97 (m, 9 H, CHbenzimid, CHPh), 6.26 (d, J = 15.6 Hz, 1 H,
NCH2CO), 6.08 (d, J = 15.6 Hz, 1 H, CH2Ph), 6.01 (d, J = 15.6 Hz,
1 H, CH2Ph), 4.87 (d, J = 15.6 Hz, 1 H, NCH2CO), 4.82–4.79
(br., 2 H, CHcod), 4.07–4.02 (m, 1 H, CH2OH), 3.65–3.59 (m, 1 H,
Chloro(η4-1,5-cyclooctadiene)[3-(2-{[(1S)-1-(Hydroxymethyl)-2-
methylbutyl]amino}-2-oxoethyl)-1-phenylmethylbenzimidazole-2-yl-
idene]iridium(I) (2e): Yellow solid (yield 70%). 1H NMR (400 MHz,
CDCl3): δ = 7.52–6.98 (m, 9 H, CHbenzimid, CHPh), 6.78 (d, J =
8.7 Hz, 1 H, NH), 6.36 (d, J = 15.6 Hz, 1 H, NCH2CO), 6.19 (d,
J = 15.6 Hz, 1 H, CH2Ph), 5.90 (d, J = 15.6 Hz, 1 H, CH2Ph), 4.84
(d, J = 15.6 Hz, 1 H, NCH2CO), 4.80 (br., 2 H, CHcod), 3.80–3.48
(m, 3 H, CH2OH, NHCH), 3.03–2.97 (br., 2 H, CHcod), 2.71
(br., 1 H, OH), 2.31–1.62 (br., 9 H, CH2 cod, CHsBu), 1.40 (br., 1
H, CH2 sBu), 0.98–0.90 (m, 1 H, CH2 sBu), 0.62 (d, J = 6.9 Hz, 3 H,
CH3 sBu), 0.46 (t, J = 7.1 Hz, 3 H, CH3 sBu) ppm. 13C NMR
(100 Hz, CDCl3): δ = 191.9 (Ccarbene), 166.8 (CO), 135.2 (CHPh),
134.5 (Cbenzimid), 134.4 (Cbenzimid), 128.8 (CHPh), 128.0 (CHPh),
127.0 (CHPh), 123.5 (CHbenzimid), 123.3 (CHbenzimid), 111.3
(CHbenzimid), 110.3 (CHbenzimid), 88.9 (CHcod), 88.8 (CHcod), 62.7
(CHcod), 57.6 (CHcod), 56.1, 54.0, 53.5, 52.5, 34.9 (CH2 cod), 32.9
(CH2 cod), 30.2 (CH2 sBu), 29.3 (CH2 cod), 28.9 (CH2 cod), 25.0
(CHsBu), 15.2 (CH3sBu), 10.6 (CH3 sBu) ppm. C30H39ClIrN3O2·H2O:
calcd. C 50.09, H 5.74, N 5.84; found C 50.48, H 5.42, N 5.35.
NHCH), 3.51–3.42 (m, 1 H, CH2OH), 3.01–2.94 (br., 3 H, CHcod
,
OH), 2.35–2.20 (br., 3 H, CH2 cod, NH), 2.08–1.57 (br., 6 H,
CH2 cod), 0.83 (d, J = 6.9 Hz, 3 H, CH3 Me) ppm. 13C NMR
(100 Hz, CDCl3): δ = 192.0 (Ccarbene), 166.6 (CO), 135.4 (CHPh),
134.6 (Cbenzimid), 134.4 (Cbenzimid), 128.9 (CHPh), 127.9 (CHPh),
126.8 (CHPh), 123.4 (CHbenzimid), 123.4 (CHbenzimid), 111.3
(CHbenzimid), 110.2 (CHbenzimid), 88.8 (CHcod), 88.7 (CHcod), 66.5
(CHcod), 65.9 (CHcod), 53.9 (CH2OH), 53.8 (NHCH), 52.4
(CH2CO),48.5(CH2Ph),33.7(CH2cod),32.9(CH2cod),29.3(CH2cod),
29.0 (CH2 cod), 16.3 (CH3 Me) ppm. C27H33ClIrN3O2·0.5H2O: calcd.
C 48.53, H 5.13, N 6.29; found C 48.54, H 4.79, N 6.11.
Chloro(η4-1,5-cyclooctadiene)[3-(2-{[(S)-1-methylpropyl]amino}-2-
oxoethyl)-1-phenylmethylbenzimidazole-2-ylidene]iridium(I) (2g):
1
Yellow solid (yield 92%). H NMR (400 MHz, CDCl3): δ = 7.48–
6.98 (m, 9 H, CHbenzimid, CHPh), 6.24 (dd, J = 2.7, and 15.1 Hz, 2
H, CH2Ph), 6.08 (d, J = 15.6 Hz, 1 H, NCH2CO), 5.90 (d, J =
15.6 Hz, 1 H, NCH2CO), 4.82–4.76 (br., 2 H, CHcod), 3.87–3.78
(m, 1 H, NHCH), 2.98–2.94 (br., 2 H, CHcod), 2.32–1.79 (br., 9 H,
CH2 cod, NH), 1.45–1.24 (m, 2 H, CH2CH3), 1.14 (d, J = 6.9 Hz,
Chloro(η4-1,5-cyclooctadiene)[3-(2-{[(1S)-1-(hydroxymethyl)propyl]-
amino}-2-oxoethyl)-1-phenylmethylbenzimidazole-2-ylidene]iridium(I) 3 H, CH3 Me), 0.36 (t, J = 7.3 Hz, 3 H, CH2CH3) ppm. 13C NMR
Eur. J. Org. Chem. 2014, 5532–5539
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5537

S. Sakaguchi et al.
FULL PAPER
(100 Hz, CDCl3): δ = 166.0 (CO), 135.5, 134.6, 128.9, 128.0, 127.0,
CDCl3): δ = 143.0, 142.1, 128.4, 125.3, 70.2, 35.3, 33.6, 25.0, 22.3,
127.0, 123.3, 123.2, 111.1, 110.7, 88.5 (CHcod), 88.3 (CHcod), 77.2 13.9 ppm.
(CHcod), 53.7 (CHcod), 53.3 (NHCH), 52.5 (CH2CO), 47.3
1-Phenyl-1-butanol (Reduction Product from 10):[23] 1H NMR
(CH2Ph), 33.8 (CH2 cod), 33.3 (CH2 cod), 30.3 (CH2CH3), 29.4
(CH2 cod), 29.1 (CH2 cod), 20.1 (CHCH3), 10.6 (CH2CH3) ppm, the
carbene 13C NMR resonance was not observed. C28H35ClIrN3O
(657.28): calcd. C 51.17, H 5.37, N 6.39; found C 51.70, H 5.56, N
6.11.
(400 MHz, CDCl3): δ = 7.39–7.23 (m, 5 H), 4.67 (t, J = 6.6 Hz, 1
H), 1.85–1.63 (m, 3 H), 1.50–1.21 (m, 2 H), 0.93 (t, J = 7.3 Hz, 3
H) ppm. 13C NMR (100 Hz, CDCl3): δ = 144.9, 128.3, 127.4, 125.8,
74.4, 41.2, 19.0, 13.9 ppm.
1-Phenyl-1-pentanol (Reduction Product from 11):[23] 1H NMR
(400 MHz, CDCl3): δ = 7.38–7.25 (m, 5 H) 4.69–4.65 (m, 1 H),
1.84–1.67 (m, 3 H), 1.42–1.21 (m, 4 H), 0.89 (d, J = 7.3 Hz, 3
H) ppm. 13C NMR (100 Hz, CDCl3): δ = 144.9, 128.4, 127.5, 125.8,
74.7, 38.8, 27.9, 22.6, 14.0 ppm.
Chloro(η4-1,5-cyclooctadiene)[3-(2-{[(1S)-2-methoxy-1-methylethyl]-
amino}-2-oxoethyl)-1-phenylmethylbenzimidazole-2-ylidene]iridium(I)
1
(2h): Yellow solid (yield 42%). H NMR (400 MHz, CDCl3): δ =
7.48–6.97 (m, 9 H, CHbenzimid, CHPh), 6.16 (d, J = 15.1 Hz, 2 H,
CH2Ph), 5.92 (d, J = 15.1 Hz, 1 H, NCH2CO), 4.90 (d, J = 15.1 Hz,
1 H, NCH2CO), 4.82–4.76 (br., 2 H, CHcod), 4.18–3.98 (m, 1 H,
Cyclohexyl(phenyl)methanol (Reduction Product from 12):[24] 1H
NMR (400 MHz, CDCl3): δ = 7.35–7.24 (m, 5 H), 4.37 (d, J =
6.9 Hz, 1 H), 2.00–1.97 (m, 1 H), 1.86–1.74 (m, 2 H), 1.65–1.59 (m,
3 H), 1.39–1.35 (m, 1 H), 1.24–0.91 (m, 5 H) ppm. 13C NMR
(100 Hz, CDCl3): δ = 143.6, 128.2, 127.4, 126.6, 79.4, 45.0, 29.3,
28.8, 26.4, 26.1, 26.0 ppm.
NHCH), 3.76–3.73 (m,
2 H, CHcod), 3.05–2.81 (m, 2 H,
CH2OCH3), 2.81 (s, 3 H, OCH3), 2.30–1.79 (br., 9 H, CH2 cod
,
NH), 1.16 (d, J = 6.9 Hz, 3 H, CH3 Me) ppm. 13C NMR (100 Hz,
CDCl3): δ = 192.0 (Ccarbene), 166.1 (CO), 135.5, 134.6, 128.9, 128.0,
127.1, 127.0, 123.3, 123.1, 111.1, 110.9, 88.5 (CHcod), 88.3 (CHcod),
75.2 (CHcod), 58.8 (CH2OCH3), 53.7 (CHcod), 53.3 (NHCH), 52.5
(CH2CO), 45.5 (CH2Ph), 33.8 (CH2 cod), 33.0 (CH2 cod), 30.3
(OCH3), 29.5 (CH2 cod), 29.1 (CH2 cod), 16.8 (CHCH3) ppm.
C28H35ClIrN3O2 (673.28): calcd. C 49.95, H 5.24, N 6.24; found C
50.57, H 5.34, N 6.26.
1-(2-Naphthyl)ethanol (Reduction Product from 13):[25,26] 1H NMR
(400 MHz, CDCl3): δ = 8.13 (d, J = 8.2 Hz, 1 H), 7.88 (d, J =
7.8 Hz, 1 H), 7.79 (d, J = 8.2 Hz, 1 H), 7.69 (d, J = 7.8 Hz, 1 H),
7.55–7.47 (m, 3 H), 5.69 (q, J = 6.4 Hz, 1 H), 1.91 (d, J = 3.7 Hz,
1 H), 1.69 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 Hz, CDCl3):
δ = 141.3, 133.8, 130.3, 128.9, 127.9, 126.0, 125.5, 125.5, 123.2,
122.0, 67.1, 24.3 ppm.
General Procedure for the Hydrosilylation Reaction: A solution of
2c (21 mg, 0.03 mmol) in THF (2 mL) was added to AgBF4
(5.8 mg, 0.03 mmol). After the mixture was stirred for 1 h at room
temperature, ketone (0.5 mmol) and (EtO)2MeSiH (268 mg,
2.0 mmol) were added. The reaction mixture was stirred for 15 h
at room temperature under open-air conditions. K2CO3 (2 mg) and
MeOH (2 mL) were then added and the resulting mixture was
stirred for 2 h at room temperature. After evaporation of the sol-
vents, the residue obtained was purified by column chromatography
on silica gel (AcOEt/n-hexane = 1:10 to 1:4). The ee was measured
by chiral GLC or HPLC; see the Supporting Information for de-
tails.
1-Phenyl-1-propanol (4):[19] 1H NMR (400 MHz, CDCl3): δ = 7.37–
7.25 (m, 5 H), 4.60 (t, J = 6.4 Hz, 1 H), 1.95 (s, 1 H), 1.88–1.70 (m,
3 H), 0.92 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (100 Hz, CDCl3): δ
= 144.9, 128.4, 127.4, 125.9, 76.0, 31.8, 10.1 ppm.
1-(3-Methoxyphenyl)ethanol (Reduction Product from 6):[19] 1H
NMR (400 MHz, CDCl3): δ = 7.28–7.24 (m, 1 H), 6.95–6.93 (m, 2
H), 6.83–6.80 (m, 1 H), 4.87 (q, J = 6.4 Hz, 1 H), 3.81 (s, 3 H),
1.93 (s, 1 H), 1.49 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 Hz,
CDCl3): δ = 159.8, 147.5, 129.5, 117.6, 112.8, 110.8, 69.9, 55.3,
25.0 ppm.
1-(4-Methoxyphenyl)ethanol (Reduction Product from 7):[19] 1H
NMR (400 MHz, CDCl3): δ = 7.32–7.28 (m, 2 H), 6.91–6.87 (m, 2
H), 4.86 (q, J = 6.4 Hz, 1 H), 3.80 (s, 3 H), 1.77 (s, 1 H), 1.48 (d,
J = 6.4 Hz, 3 H) ppm. 13C NMR (100 Hz, CDCl3): δ = 159.0,
138.0, 126.7, 113.8, 70.0, 55.3, 25.0 ppm.
1-(4-Chlorophenyl)ethanol (Reduction Product from 8):[20,21] 1H
NMR (400 MHz, CDCl3): δ = 7.35–7.26 (m, 4 H), 4.89 (q, J =
6.4 Hz, 1 H), 1.82 (br., 1 H), 1.48 (d, J = 6.4 Hz, 3 H) ppm. 13C
NMR (100 Hz, CDCl3): δ = 144.2, 133.0, 128.5, 126.8, 69.7,
25.2 ppm.
1-(1-Naphthyl)ethanol (Reduction Product from 14):[25] 1H NMR
(400 MHz, CDCl3): δ = 7.80–7.75 (m, 4 H), 7.48–7.43 (m, 3 H),
5.00 (q, J = 6.4 Hz, 1 H), 2.20 (s, 1 H), 1.54 (d, J = 7.3 Hz, 3
H) ppm. 13C NMR (100 Hz, CDCl3): δ = 143.1, 133.2, 132.8, 128.2,
127.9, 127.6, 126.1, 125.7, 123.8, 123.7, 70.4, 25.1 ppm.
1-(4-Chlorophenyl)propanol (Reduction Product from 15):[26] 1H
NMR (400 MHz, CDCl3): δ = 7.33–7.24 (m, 4 H), 4.61–4.57 (m, 1
H), 1.83 (s, 1 H), 1.81–1.67 (m, 2 H), 0.90 (t, J = 7.3 Hz, 3 H) ppm.
13C NMR (100 Hz, CDCl3): δ = 142.9, 133.0, 128.5, 127.3, 75.2,
31.9, 9.9 ppm.
1-(2-Furanyl)ethanol (Reduction Product from 16):[19] 1H NMR
(400 MHz, CDCl3): δ = 7.39–7.37 (m, 1 H), 6.34–6.32 (m, 1 H),
6.24–6.23 (m, 1 H), 4.92–4.86 (m, 1 H), 1.94 (d, J = 3.2 Hz, 1 H),
1.55 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 Hz, CDCl3): δ =
157.5, 141.9, 110.1, 105.1, 63.6, 21.2 ppm.
1-(2-Thiophenyl)ethanol (Reduction Product from 17):[19] 1H NMR
(400 MHz, CDCl3): δ = 7.26–7.23 (m, 1 H), 6.99–6.95 (m, 2 H),
5.15 (q, J = 6.3 Hz, 1 H), 1.96 (s, 1 H), 1.61 (d, J = 6.9 Hz, 3
H) ppm. 13C NMR (100 Hz, CDCl3): δ = 149.8, 126.7, 124.4, 123.2,
66.3, 25.3 ppm.
Ethyl 3-Hydroxy-3-phenylpropionate (21):[6c] 1H NMR (400 MHz,
CDCl3): δ = 7.40–7.26 (m, 5 H), 5.16–5.12 (m, 1 H), 4.19 (q, J =
7.2 Hz, 2 H), 3.32 (br., 1 H), 2.79–2.68 (m, 2 H), 1.26 (t, J = 7.2 Hz,
3 H) ppm. 13C NMR (100 Hz, CDCl3): δ = 172.5, 142.5, 128.5,
127.7, 125.7, 118.2, 70.3, 60.9, 43.3, 14.1 ppm.
Supporting Information (see footnote on the first page of this arti-
cle): Table S1 giving asymmetric hydrosilylation of ethyl 3-oxo-3-
phenylpropionate (16) and chiral GC and LC traces.
1-(4-Butylphenyl)ethanol (Reduction Product from 9):[21,22] 1H NMR Acknowledgments
(400 MHz, CDCl3): δ = 7.29 (d, J = 7.8 Hz, 2 H), 7.17 (d, J =
7.8 Hz, 2 H), 4.88 (q, J = 6.4 Hz, 1 H), 2.60 (t, J = 7.6 Hz, 2 H),
This work was financially supported by the Japan Society for the
1.76 (s, 1 H), 1.63–1.55 (m, 2 H), 1.49 (d, J = 6.4 Hz, 3 H), 1.40– Promotion of Science (JSPS) through a Grant-in-Aid for Scientific
1.30 (m, 2 H), 0.92 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (100 Hz,
Research (C), grant number 23550128.
5538
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5532–5539

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Received: March 19, 2014
Published Online: July 22, 2014
Eur. J. Org. Chem. 2014, 5532–5539
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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