Nickel(0)-Catalyzed Enantio- and Diastereoselective Synthesis of Benzoxasiloles: Ligand-Controlled Switching from Inter- to Intramolecular Aryl-Transfer Process

Article abstract of DOI:10.1021/jacs.5b07827

A highly enantioselective synthesis of 3-aryl-, vinyl-, and alkynyl-2,1-benzoxasiloles (up to 99.9% ee and 99% yield) was achieved via the sequential activation of an aldehyde and a silane by nickel(0). This strategy was applied to a simultaneous generation of carbon- and silicon-stereogenic centers with excellent selectivity (dr = 99:1) via diastereotopic aryl transfer. Initial mechanistic studies revealed the complete switching of an aryl-transfer process from an intermolecular (racemic synthesis in the presence of IPr) to an intramolecular (enantioselective synthesis using chiral NHC, L5) fashion. A plausible rationale for the switching of the aryl-transfer process is given by a preliminary DFT calculation, which suggests that the coordination of 1 to the nickel(0)/L5 fragment in an ²-arene:²-aldehyde fashion would be a key to the intramolecular process, while the formation of the corresponding intermediate is not possible in the presence of IPr. Owing to the chemically labile nature of its C-Si and O-Si bonds, enantioenriched benzoxasiloles are utilized for the synthesis of chiral building blocks and antihistaminic and anticholinergic drug molecules such as (R)-orphenadrine and (S)-neobenodine with no erosion of the enantiomeric excess.

Full text of DOI:10.1021/jacs.5b07827

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Article
Nickel(0)-Catalyzed Enantio- and Diastereoselective
Synthesis of Benzoxasiloles: Ligand-Controlled Switching
from Inter- to Intramolecular Aryl-Transfer Process
Ravindra Kumar, Yoichi Hoshimoto, Hayato Yabuki, Masato Ohashi, and Sensuke Ogoshi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b07827 • Publication Date (Web): 24 Aug 2015
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Journal of the American Chemical Society
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Nickel(0)-Catalyzed Enantio- and Diastereoselective Synthesis of
Benzoxasiloles: Ligand-Controlled Switching from Inter- to Intramo-
lecular Aryl-Transfer Process
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Ravindra Kumar,† Yoichi Hoshimoto,†,‡ Hayato Yabuki,† Masato Ohashi,† and Sensuke Ogo-
shi*,†,§
†Department of Applied Chemistry, Faculty of Engineering and ‡Frontier Research Base for Global Young Researchers,
Graduate School of Engineering, Osaka University, Suita, Osaka 565ꢀ0871, Japan
§Advanced Catalytic Transformation program for Carbon utilization (ACTꢀC), JST, Suita, Osaka 565ꢀ0871, Japan
KEYWORDS. Ni(0)-Catalyzed, Enantioselective, Benzoxasiloles, Silicon-Stereogenic Center, Ligand-Controlled Switching
ABSTRACT: A highly enantioselective synthesis of 3ꢀarylꢀ, vinylꢀ and alkynylꢀ2,1ꢀbenzoxasiloles (up to 99.9% ee and 99% yield)
was achieved via the sequential activation of an aldehyde and a silane by nickel(0). This strategy was applied to a simultaneous
generation of carbonꢀ and siliconꢀstereogenic centers with excellent selectivity (dr = 99:1) via diastereotopic arylꢀtransfer. Initial
mechanistic studies revealed the complete switching of an arylꢀtransfer process from an intermolecular (racemic synthesis in the
presence of IPr) to an intramolecular (enantioselective synthesis using chiral NHC, L5) fashion. A plausible rationale for the
switching of the arylꢀtransfer process is given by a preliminary DFT calculation, which suggests that the coordination of 1 to the
nickel(0)/L5 fragment in an η2ꢀarene:η2ꢀaldehyde fashion would be a key to the intramolecular process while the formation of the
corresponding intermediate is energetically unfavorable in the presence of IPr. Owing to the chemically labile nature of its C−Si
and O−Si bonds, enantioenriched benzoxasiloles are utilized for the synthesis of chiral building blocks and antihistaminic and
anticholinergic drug molecules such as (R)ꢀorphenadrine and (S)ꢀneobenodine with no erosion of the enantiomeric excess.
INTRODUCTION
Scheme 1. Enantioꢀ and Diastereoselective Synthesis of
Benzoxasiloles via LigandꢀControlled Switching of Arꢀ
ylꢀTransfer Process
The transitionꢀmetalꢀcatalyzed enantioselective addition of
organometallic reagents to prochiral carbonyl groups is a venꢀ
erable area of fundamental research in organic chemistry.1
Indeed, various combinations of organometallic reagents and
transition metals have been developed to achieve correspondꢀ
ing chiral products with high enantioselectivities. These methꢀ
ods primarily follow the η1 coordination of a carbonyl group
to a metal, particularly Lewis acidic metals in their higher
oxidation states. In contrast, examples of catalytic enantioseꢀ
lective reactions via the η2 coordination of aldehydes towards
lowꢀvalent transition metals are limited,2−4 despite many conꢀ
tributions from the field of coordination chemistry.5 In addiꢀ
tion to its fundamental importance, the existing methodology
of an enantioselective addition to an aldehyde would be conꢀ
ceptually more appealing if the resultant chiral product could
serve as a versatile precursor for further transformations to
useful products. Benzoxasilole has privileged structural feaꢀ
tures that make it useful for further transformations due to
chemically labile C−Si and O−Si bonds. Several synthetic
methods and application of benzoxasiloles have been reportꢀ
ed,6 while their asymmetric version remains underdeveloped.7
Furthermore, such an asymmetric strategy would allow the
creation of a silicon stereogenic center. Very recently, Ryberg
and Hartwig et al. reported the first asymmetric synthesis of 3ꢀ
arylꢀ2,1ꢀbenzoxasiloles employing the Irꢀcatalyzed hydrosiꢀ
lylation of symmetrical diarylketone followed by Rhꢀcatalyzed
intramolecular enantioselective silylation of an arene C−H
bond through the desymmetrization of diarylmethanol silyl
ether.7 However, this strategy has not been utilized to generate
a silicon stereogenic center.
We recently reported the racemic synthesis of 3ꢀaryl, vinylꢀ,
and alkynylꢀ2,1ꢀbenzoxasiloles proceeded via an activation of
organosilanes with (η2ꢀaldehyde)Ni(IPr) complex, where IPr is
1,3ꢀbis(2,6ꢀdiisopropylphenyl)imidazolꢀ2ꢀylidene.8
Initial
mechanistic studies of this reaction revealed the involvement
of an intermolecular arylꢀtransfer from the silicon center to a
formyl carbon (Scheme 1). While the mild reaction conditions
suggest the development of a rational asymmetric version, the
mechanistic outcome offered further challenges to achieve
high enantioselectivity. Herein, we report the nickel(0)ꢀ
catalyzed enantioꢀ and diastereoselective synthesis of benzoxꢀ
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Page 2 of 8
asiloles with the simultaneous generation of carbonꢀ and siliꢀ
diisopropylnaphyl)ꢀsubstituted NHC L911 resulted in racemicꢀ
1
2
3
4
5
6
7
8
conꢀstereogenic centers by changing the ligand from IPr to a
chiral NHC L5 with a complete switching of the arylꢀtransfer
process from intermolecular to intramolecular (Scheme 1).
The results of a preliminary density functional theory (DFT)
calculation are also presented to rationalize the observed
change in mechanism.
2a, and the reactions were completed in 8 and 1 h, respectively.
Following 4 days at 60 °C, the reactions of 1a with Nꢀ(2ꢀ
biphenyl)ꢀsubstituted NHC L10 and Nꢀ(1ꢀmesitylpropyl) NHC
L11 resulted in 50 and 10% conversion, respectively. The
enantioselectivities (19 and 11% ee, respectively) were evaluꢀ
ated at these conversions. Kündig's NHC L1212 delivered 2a
with moderate enantioselectivity (40% ee). It is noteworthy
that benzoxasilole 2a was sensitive to silica column chromaꢀ
tography13 and HPLC. Hence, the enantiomeric composition of
2a was evaluated after converting it into 3a by Tamaoꢀ
Fleming oxidation6o (vide infra, Figure 2). The feasibility of
the reaction was also examined with other nickel source
Ni(acac)2 as well as in the absence of Ni(cod)2 (Table 1, enꢀ
tries 2 and 3, respectively). However, no reaction was obꢀ
served in either case. These results suggest that reactions are
neither catalyzed by NHCs nor do they appear to be promoted
by Lewis acidic Ni(II) species. The efficiency of the catalyst
using Ni(cod)2 was further examined by the lower catalyst
loading of 2 mol%, which delivered 2a with no erosion of the
enantiomeric excess (entry 4; 99% yield and ee). The reaction
produced high enantioselectivity even when 1 mol% of the
catalyst was used (entry 5; 97% ee), but a longer reaction time
was required (> 2 days, entry 5). (S,S)ꢀL5 was equally effecꢀ
tive to give (S)ꢀ2a (99% yield and ee, entry 6).
RESULTS AND DISCUSSION
9
Our study began with an evaluation of potential chiral ligꢀ
ands. A set of chiral phosphines9 and Nꢀheterocyclic carbenes
(NHCs) L1−L12 (10 mol%; generated in situ by treating corꢀ
responding imidazolinium salt with NaOtBu) were surveyed
using oꢀdimethylphenylsilylbenzaldehyde (1a) as a model
substrate (Scheme 2). Most of the NHCs (L1−L9) yielded
almost quantitative formation of benzoxasilole 2a, which
proved the robustness of this strategy. However, the enantioseꢀ
lectivity and reaction times varied with the structure of ligands
(Scheme 2). For example, reactions were completed within 2 h
in the presence of NHCs (L1−L9 except L8 and C1ꢀsymmetric
NHC L2) with a range of enantioselectivities. Excellent results
in both the yield and enantioselectivity (99% ee) were obꢀ
served with L5. This NHC was pioneered by Grubbs et al. and
employed for the Ruꢀcatalyzed enantioselective ringꢀclosing
metathesis reactions.10 Nꢀ(1ꢀNaphthyl)ꢀsubstituted NHC L8
gave 2a with good enantioselectivity (79% ee), while Nꢀ(2,7ꢀ
10
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Table 1. Further Optimization with L5·HBF4
Scheme 2. Survey of Chiral NHC Ligandsa
aYields were determined by GC using nꢀpentadecane as an
internal standard. bEnantioselectivity was determined by SFC
c
equipped with a chiral stationary phase. Ni(acac)2 was used
e
as a Ni(II) source. d(S,S)ꢀL5·HBF4 was employed. (S)ꢀ2a
was obtained as a major product.
The generality of the present catalytic enantioselective proꢀ
cess was evaluated for the synthesis of various chiral benzoxꢀ
asiloles using 2 mol% of the catalyst with (R,R)ꢀL5 (Table 2).
Enantioselectivities were determined either for the correspondꢀ
ing oxidation or for the desilylation products (3 or 4, respecꢀ
tively, vide infra, Figure 2). In the case of 2h, enantiomeric
composition of products were examined after both transforꢀ
mations (3h and 4h), resulted in the same enantioselectivity.9
The substituents on the silicon affected neither the yields nor
the enantioselectivities of the products (2a and 2b). When
either, or both, of the aryl groups were substituted with elecꢀ
tronꢀdonating groups (1c−e), the reaction was relatively slow
by comparison with the use of electronꢀwithdrawing groups
aReaction was examined at 0.2 mmol scale. Enantioꢀ
selectivity was determined by HPLC/SFC equipped with a
chiral stationary phase. bReaction was monitored at 60 °C and
ee was measured from aliquot collected at 50 and 10% converꢀ
sion in case of L10 and L11, respectively.
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Journal of the American Chemical Society
1
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Table 2. Catalytic Enantioꢀ and Diastereoselective
Synthesis of 3ꢀArylbenzoxasilolesa
3
4
5
6
7
8
2.2 mol% (R,R)ꢀL5—HBF4
R3
R3
2.0 mol% NaOtBu
R1
2.0 mol% Ni(cod)2
R
R2
Si
Si
toluene, rt
R1
O
R2
H
O
H
R
(R)ꢀ2a p
1a p
9
OMe
Et
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Si
O
Si
Si
Si
Et
O
H
O
O
H
H
H
OMe
2d
Figure 1. ORTEP representation with thermal ellipsoid at
50% probability level (a) (R)ꢀ2h (Flack parameter =
2a
2b
2c
1 h, 99%
(99% ee)
1 h, 99% (98% ee)b
1 h, 99%
(98% ee)
4 h, 97 %
(99% ee)
4 h, 97%
(98% ee)
0.02(3)) and (b) (C(R),Si(S))ꢀ2n (Flack parameter
=
0.03(15))
F
OMe
F
CF3
Si
enantioselectivity (2k and 2l). The absolute configuration of
2h was determined to be (R) by Xꢀray crystallography (Figure
1a) and other compounds were assigned either by analogy to
2h or by the elution order of enantiomers reported in the literaꢀ
ture. To demonstrate the practical nature of the present catalytꢀ
ic process, a gramꢀscale reaction of 1a (5.0 mmol, 1.22 g) was
conducted under identical conditions and gave 2a in 99% yield
and 98% ee (Table 2).
Si
Si
Si
O
H
O
H
O
O
H
H
OMe
2g
3 h, 93%
(99% ee)
2h
2f
2e
9 h, 98%c
(95% ee)
1 h, 99%
(97% ee)
2 h, 96%
(98% ee)
As the chirality of carbon is a key element for natural prodꢀ
ucts, the central chirality of silicon is an attractive and potenꢀ
tially useful attribute for unnatural chiral molecules due to the
unique chemical and physical properties of silicon.14 Therefore,
much recent attention has been paid to the asymmetric conꢀ
struction of silicon stereogenic centers,15 and catalytic asymꢀ
metric desymmetrization is one of the most promising apꢀ
proaches among them.15a,b In order to demonstrate our asymꢀ
metric approach to the diastereoselective activation of silicon,
which in turn leads to the generation of a silicon stereogenic
center, a prochiral silane (having two phenyl groups) was inꢀ
troduced. Diphenylmethylsilane derivative 1m gave 2m with a
moderate degree of diastereoselectivity (dr = 89:11) and high
enantioselectivity (98% ee). The diastereoselectivity was imꢀ
proved to almost one diastereomer by the introduction of a
tertꢀbutyldiphenylsilyl group (2n and 2o; dr = 99:1) with negꢀ
ligible erosion of the enantioselectivity (95 and 96% ee, reꢀ
spectively). A single diastereomer of 2n was isolated by reꢀ
Si
Si
Si
Si
O
O
H
O
H
O
H
H
F3C
F
2k
3 h, 99%
(99% ee)
2l
2i
2j
3 h, 97%
(99% ee)
1 h, 95%
(99% ee)
1 h, 95%
(99.9% ee)
F
Ph
Si
Ph
Si
Ph
Si
O
O
O
H
Si
H
H
O
H
2nd
8 h, 99%
(95% ee)
(99:1 dr)
2od
2pe
0%
2md
1 h, 99%
(98% ee)
(89:11 dr)
12 h, 99%
(96% ee)
(99:1 dr)
aReaction was examined at 0.2 to 2.0 mmol scale (0.2
M). Isolated yields are given. Enantioselectivity was deꢀ
termined by HPLC/SFC equipped with a chiral stationary
phase. bReaction was examined at 5.0 mmol scale.
cL5·HBF4/NaOtBu/Ni(cod)2 (4.4/4.0/4.0 mol%) was used.
dL5·HBF4/NaOtBu/Ni(cod)2 (2.2/2.2/2.0 mol%) was
used.16 eL5·HBF4/NaOtBu/Ni(cod)2 (11/10/10 mol%) was
employed and heated at 80 °C for 24 h.
o
crystallization (hexane at −20 C), and the absolute configuraꢀ
tions of both the carbon and the silicon centers were unambigꢀ
uously determined by Xꢀray crystallography to be C(R) and
Si(S) (Figure 1b). The overall catalytic process is comprised of
the first example of a synchronized generation of enantioenꢀ
riched carbon and silicon stereogenic centers at the 1, 3 posiꢀ
tions.15d
In order to check the feasibility of an alkyl group transfer
from silicon to carbonyl carbon to get 2p, oꢀ
trimethylsilylbenzaldehyde 1p was treated with 10 mol% of
catalyst. No reaction took place even at elevated temperatures
(80 °C, Table 2) but a dimeric ester was formed as a single
product via a nickelꢀcatalyzed Tishchenko reaction under
Ni(0)/IPr catalytic conditions.8,4d
(1f−1j). A fluorine atom at the paraꢀ position, with respect to
either a formyl (1f) or a dimethylphenylsilyl group (1g), reꢀ
sulted in almost the same results. The reactions of 1h and 1i,
which are equipped with an electronꢀwithdrawing CF3 group
at the metaꢀposition of either of the aryl groups was completed
in a relatively shorter time (1 h) with high enantioselectivity.
The reactions of 1, with either a metaꢀ or a paraꢀtolyl group on
the silicon, were completed in 3 h with excellent yields and
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We have also examined the enantioselective migration of
vinyl and alkynyl groups to form corresponding 3ꢀ substituted
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Scheme 3. Synthetic Utilities to Enantioenriched Diaꢀ
Table 3. Catalytic Enantioselective Synthesis of 3ꢀ
Vinylꢀ and Alkynylbenzoxasilolesa
1
2
rylmethanol and Antihistaminic Drug Moleculesa
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aIsolated yields are given. Enantioselectivity was deterꢀ
mined by SFC equipped with a chiral stationary phase.
benzoxasiloles (Table 3). We previously reported that the 1:2
mixture of Ni(cod)2 and IPr in THF was effective for the cataꢀ
lytic transformation of substrates with vinylꢀ and alkynylꢀsilyl
groups.8 Thus, we conducted the reaction of 1q and 1r with 5
mol% of Ni(cod)2 and 10 mol% of L5·HBF4 and NaOtBu each
in THF at 60 °C, which gave 2q (80% yield, 76% ee) and 2r
(78% yield, 73% ee), respectively. The enantioselective synꢀ
thesis of 3ꢀvinylꢀ2,1ꢀbenzoxasiloles required a much longer
time than that of the corresponding racemic reaction.8 The
reaction of 1q with a 1:1:1 mixture of L5·HBF4, NaOtBu, and
Ni(cod)2 (10 mol% each) failed to give the required product.
3ꢀAlkynylꢀ2,1ꢀ benzoxasilole (2s) was synthesized from diꢀ
ethyl(trimethylsilylethynyl)silyl benzaldehyde 1s in a 76%
yield with a high degree of enantioselectivity (93% ee),
whereas phenylethynyl variant 1t resulted in no reaction. The
enantiomeric compositions of 2q−s were determined for the
corresponding oxidation products (allylic and propargylic alꢀ
aIsolated yields are given. Enantioselectivity was deterꢀ
mined by SFC equipped with a chiral stationary phase.
After establishment of an efficient method for the synthesis of
enantioenriched diarylmethanols, which are important pharꢀ
macophores and found frequently in many biologically active
molecules,18 we further explored the synthesis of enantiomeriꢀ
cally pure antihistamic and anticholinergic drug molecules
such as (R)ꢀorphenadrine and (S)ꢀneobenodine.19 (R)ꢀ
Orphanadrine was synthesized in one step from 7, whereas
(S)ꢀneobenodine was achieved in a 75% overall yield via a
oneꢀpot procedure that started from 1l. The synthesis of (R)ꢀ
orphanadrine, however can be achieved directly from an oꢀ
tolylsilyl varient of 1, herein, we demonstrated the synthetic
utility of both C−Si and O−Si bonds of benzoxasilole 1a.
Another demonstration of the synthetic utility of enantioenꢀ
riched benzoxasilole as a useful product was accomplished
when designed benzoxasilole 2u was converted into 3ꢀ
phenylphthalides (S)−8 via a desilylationꢀoxidation reaction
sequence with an overall isolated yield of 65% (Scheme 4). In
medicinal chemistry, 3ꢀsubstituted phthalides are valuable
Scheme 4. Synthetic Utility to Enantioselective Synꢀ
thesis of 3ꢀPhenylphthalidea
Figure 2. Synthetic transformations of benzoxasiloles for the
determination of enantioselectivity.
cohols;8 Figure 2).
The synthetic utility of enantioenriched benzoxasiloles 2
was demonstrated by exploiting the chemically labile O−Si
and C−Si bonds (Schemes 3 and 4). Benzoxasilole (R)−2a was
converted into 2ꢀiododiarylmethanol (5) in a 61% yield in the
presence of AgF, which served as a chiral building block for
various coupling reactions and an asymmetric synthesis of
alkylidene phthalans17 that are known for fungal metabolites.
The aryl and alkyl groups were introduced using Hiyama couꢀ
pling reaction6o and anion relay chemistry6p to afford 6 and 7
in 74 and 78% yields, respectively. The enantioselectivity
remained consistent following all transformations (Scheme 3).
aIsolated yields are given. Enantioselectivity was deterꢀ
mined by SFC equipped with a chiral stationary phase.
pharmacological compounds.20 Benzoxasilole 2u was effiꢀ
ciently synthesized by modifying the reaction conditions that
were employed for 1q−1t using 2 mol% of Ni(cod)2 and 4
mol% of L5·HBF4 and NaOtBu each. The formation of benꢀ
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Journal of the American Chemical Society
ous η2 coordination of two formyl groups to the nickel center.
This is a rare example of direct isolation and confirmation of
the use of a transition metal with bisꢀη2ꢀaldehyde ligands.5k
( : ꢀ
η2 η2
1
2
3
Scheme 5. Isolation and Reaction of
dialdehyde)Ni ꢀcomplex (2u')a
In the case of a Ni(0)/IPr catalyst system (racemic synthesis
of benzoxasiloles), an intermolecular aryl transfer mechanism
was proposed based on the results of a crossover experiment.8
Since excellent enantioselectivities were observed in the preꢀ
sent optimized Ni(0)/L5 catalytic system, we reꢀexamined the
crossover experiment in order to confirm whether the reaction
proceeds via an interꢀ or an intramolecular arylꢀtransfer proꢀ
cess. When the crossover experiment was conducted with 1c
and 1d in the presence of 4 mol% of a chiral catalyst, the forꢀ
mation of crossover products was not observed, which indicatꢀ
ed a complete switching of the arylꢀmigration process from
intermolecular (Ni/IPr)8 to intramolecular (Ni/L5) fashion
(Table 4, entries 1 and 2). To exclude the influence of a base
(used for in situ generation of NHC L5) in this switching,
crossover experiment was conducted under similar conditions
using IPr·HCl/NaOtBu. Crossover products were obtained in
almost equal yields as produced in the case of the Ni(0)/IPr
system (entry 3), which showed that NaOtBu was not responꢀ
sible for the switching of an arylꢀtransfer process. The effect
of NaBF4 (generated from L5·HBF4 and NaOtBu) was also
ruled out after examining the reaction using NaBF4 (5 mol%)
as an additive to 5 mol% Ni/IPr experimental conditions (entry
4). A crossover experiment was also conducted with SIPr
(having backbone of sp3ꢀcarbons like L5) generated in situ
from SIPr·HBF4 and NaOtBu (entry 5), however crossover
products were obtained. This experiment also supported the
above result (entry 4) with in situ generation of NaBF4. These
sets of experiments clearly demonstrate that switching is absoꢀ
lutely controlled by ligands. In order to establish that the preꢀ
sent enantioselective pathway is completely intramolecular,
we sought to measure the enantioselectivities of crossover
products. However, the corresponding desilylation products
(4c and 4d) could not be isolated in pure form to evaluate their
enantiopurities due to their almost same polarity toward colꢀ
umn chromatography. Therefore, another set of crossover exꢀ
periments was carried out with 1c and 1k in the presence of 4
mol% of chiral catalyst (Table 5). As expected, no crossover
products were obtained, whereas, 37 and 39% of crossover
products (2v and 2a, respectively) were formed under similar
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aORTEP representation of 2u' with thermal ellipsoid at
50% probability level. H atoms are omitted for clarity. Seꢀ
lected bond lengths (Å): O1−C1 1.303(3), O2−C2 1.309(3),
O1−Ni 1.8922(15), C1−Ni 1.9653(19), O2−Ni 1.8923(15),
C2−Ni 1.9749(19), C3−Ni 1.9255(18).
zoxasilole (2u) was completely hampered when using a 1:1
mixture of Ni(cod)2 and IPr due to the formation of an unreacꢀ
tive (η2 η2ꢀdialdehyde)Ni complex (Scheme 5). That result
:
was confirmed by the stoichiometric reaction of 1u with an
equimolar mixture of Ni(cod)2 and IPr, which gave 2u' as the
sole product. The molecular structure of 2u' was confirmed by
NMR and Xꢀray analyses, which clearly shows the simultaneꢀ
Table 4. Crossover Experiments with 1c and 1da
Table 5. Crossover Experiments with 1c and 1ka
aReaction was monitored by GC analysis, and yields
aReaction was monitored by GC analysis, and yields
were determined with nꢀpentadecane as an internal standꢀ
ard.
were determined with nꢀpentadecane as an internal standꢀ
b
ard. Enantioselectivity was determined by SFC equipped
with a chiral stationary phase.
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η2
:
η2ꢀmanner, yielding (η2
:
η2ꢀ1a)Ni((R,R)ꢀL5) (Scheme 6a).
η2 intermediate
reaction conditions using IPr·HCl. The enantioselectivities
were measured for the corresponding benzoxasiloles 2c (99%
ee) and 2k (99% ee) after the crossover experiment, which
were compatible with the results obtained in each of the experꢀ
iments (Table 5, entry 2; cf Table 2). These results revealed
the involvement of a complete intramolecular arylꢀtransfer
process in the present catalytic asymmetric reaction.
Such intriguing behaviour of formation of η2
:
1
2
3
4
5
6
7
8
in the case of L5 would facilitate an intramolecular arylꢀ
transfer from the silicon to the formyl group giving (R)ꢀ2a. On
the other hand, an energy minima was not found for similar
η2 η2ꢀintermediate when IPr was used. It might be due to the
:
steric hindrance exerted by its two isopropyl groups attached
to each of the Nꢀaryl rings at the 2,6 positions (Scheme 6b). As
a result, in the transformation reaction from 1a to 2a, the use
of IPr as a ligand might be forced to undergo intermolecular
aryl transfer. Further theoretical studies on the full intramolecꢀ
ular reaction mechanism are ongoing by our group.
Comparing the diastereoselectivities observed during the
enantioselective and racemic versions of the reaction provides
further support for a change in reaction mechanism. A higher
degree of diastereoselectivities were observed for 2m−o the
present Ni(0)/L5 enantioselective catalytic system compared
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CONCLUSION
In summary, the nickel(0)ꢀcatalyzed enantioselective synꢀ
theses of 3ꢀarylꢀ, vinylꢀ, and alkynylꢀ2,1ꢀbenzoxasiloles was
achieved. The silicon stereogenic center was generated seꢀ
quentially with excellent selectivity through the desymmetriꢀ
zation of prochiral silane. Enantioenriched benzoxasiloles
were successfully utilized for the synthesis of diarylmethanols
including antihistaminic types of drug molecules such as (R)ꢀ
orphenadrine and (S)ꢀneobenodine. Crossover experiments
clearly demonstrate a complete switching of the arylꢀtransfer
process from an interꢀ to an intramolecular fashion by changꢀ
ing the ligand from IPr to L5, which could also account for the
excellent enantioꢀ and diasteoselectivity. This ligandꢀ
controlled switching mechanism was rationalized by the coorꢀ
Figure 3. Comparison of diastereoselectivity (L5 vs IPr)
with the racemic Ni(0)/IPr catalytic system (Figure 3).
We previously proposed the involvement of an η2ꢀaldehyde
nickel intermediate, which was directly observed by NMR
analyses at −50 °C. This η2ꢀaldehyde nickel complex was
converted into a benzoxasilole quantitatively by warming to
room temperature.8 Similarly, the coordination of aldehyde 1
to a Ni(0)/L5 moiety gives rise to the formation of an enantiꢀ
oenriched η2ꢀaldehyde nickel intermediate (η2ꢀ1)Ni(L5) which
undergo intramolecular arylꢀtransfer from the silicon to the
formyl carbon to yield benzoxasilole 2 in excellent enantioꢀ
and diastereoselectivity. A plausible rationale for the change
in reaction mechanism using IPr and the chiral NHC (R,R)ꢀL5,
respectively, is in the difference for Ni(NHC) complexes to
access coordination of substrate 1 through two η2 interactions
involving the formyl and phenyl moieties, respectively
(Scheme 6).21 A preliminary DFT calculation employing 1a as
a model substrate indicated that the chiral ligand L5 enabled
the coordination of substrate to the Ni(0)/L5 fragment in an
dination of 1 to the Ni(0)/L5 fragment in an η2ꢀarene:η2
ꢀ
aldehyde fashion, as found by DFT calculation. As far as we
could ascertain, this is the first example of ligandꢀcontrolled
switching from an interꢀ to an intramolecular arylꢀtransfer
process, and the asymmetric desymmetrization of silane with a
(
η2ꢀaldehyde)Ni complex could represent a novel tool for the
generation of an enantioenriched siliconꢀstereogenic center.
Detailed studies on the reaction mechanism and the utilization
of silicon stereogenic centers are ongoing in our laboratory.
ASSOCIATED CONTENT
Supporting Information
Experimental and computational details and spectral data. This
material is availꢀable free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Scheme 6. Plausible Rationale for Switching of Arylꢀ
Transfer Process
Corresponding Author
ogoshi@chem.eng.osakaꢀu.ac.jp
Notes
The authors declare no competing financial interest
ACKNOWLEDGMENT
This work was supported by GrantsꢀinꢀAid for Scientific Reꢀ
search (A) (21245028), for Young Scientists (A) (25708018),
Encouragement for Young Scientist (B) (15K17824), and Grantsꢀ
inꢀAid for Scientific Research on Innovative Area “Molecular
Activation Directed toward Straightforward Synthesis”
(23105546) and "Stimuliꢀresponsive Chemical Species"
(15H00943) from MEXT and by ACTꢀC from JST. Y.H.
acknowledges support from the Frontier Research Base for Global
Young Researchers, Osaka University, on the Program of MEXT.
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Journal of the American Chemical Society
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1
2
3
4
5
6
7
8
Switzerland for a generous gift of NHC salt (S,S)ꢀL12·I.
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up to 99.9% ee
dr = 99:1
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99% yield
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