Application of a Heterogeneous Chiral Titanium Catalyst Derived from Silica-Supported 3-Aryl H8-BINOL to Enantioselective Alkylation and Arylation of Aldehydes

Article abstract of DOI:10.1021/acs.orglett.7b01625

A 3-aryl H₈-BINOL was grafted on the surface of silica gel using a hydrosilane derivative as a precursor, and the resulting silica-supported ligand (6 mol %) was employed in the enantioselective alkylation and arylation of aldehydes in the pres

Full text of DOI:10.1021/acs.orglett.7b01625

Letter
pubs.acs.org/OrgLett
Application of a Heterogeneous Chiral Titanium Catalyst Derived
from Silica-Supported 3‑Aryl H8‑BINOL to Enantioselective Alkylation
and Arylation of Aldehydes
Junichiro Akai, Satoshi Watanabe, Kumiko Michikawa, and Toshiro Harada*
Faculty of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
S
* Supporting Information
ABSTRACT: A 3-aryl H8-BINOL was grafted on the surface
of silica gel using a hydrosilane derivative as a precursor, and
the resulting silica-supported ligand (6 mol %) was employed
in the enantioselective alkylation and arylation of aldehydes in
the presence of Ti(OiPr)4. The reactions using Et2Zn, Et3B,
and aryl Grignard reagents all afforded the corresponding
adducts in high enantioselectivities and yields. The silica-
immobilized titanium catalyst could be reused up to 14 times without appreciable deterioration of the activity.
he catalytic enantioselective addition of organometallic
reagents to aldehydes is one of the most straightforward
enantioselective carbonyl addition reactions.10 Despite the
recent development of efficient polymer-supported catalysts,11
with very few exceptions,11e reported immobilized catalysts
have been developed and evaluated for the reaction of
diorganozincs, particularly Et2Zn. The high activity of the
chiral titanium catalysts derived from 3-aryl-H8-BINOLs 1a,b
prompted us to immobilize them on solid supports in
anticipation of developing a practical method for the
enantioselective alkylation and arylation using conventional
organometallic reagents other than diorganozincs. Herein, we
report a preliminary result of the study along these lines, which
demonstrates the potential of silica-supported 3-aryl-(SSA-)H8-
BINOL (R)-5 in practical use.
Silica was chosen as supports because of the high mechanical
strength, thermal stability, and chemical robustness.12,7c
Although the reaction of alkoxysilyl precursors is commonly
used to bind an organic moiety on the silica surface, purification
of the precursors is often hampered by the instability toward
hydrolysis. We adopted surface functionalization of silica by Si−
H activation through catalysis by B(C6F5)3, reported recently
by Shimada and co-workers,13 because the method is not only
rapid and efficient but also has an advantage that requisite
hydrosilyl precursors can be fully purified by silica gel column
chromatography.14
T
methods for the synthesis of enantioenriched chiral secondary
alcohols.1 Although relatively less reactive diorganozinc
reagents2 were previously used in the reaction, the scope of
the nucleophiles has been recently expanded to other
organometallic reagents,3 including more reactive, hence,
more difficult to be tamed, Grignard4 and organolithium5
reagents, by the development of highly active chiral catalyst
systems. Recent reports from this laboratory have revealed the
remarkably high activity of chiral titanium catalysts derived
from BINOLs, such as DPP-H8-BINOL 1a and DTBP-H8-
BINOL 1b, bearing a sterically demanding aryl group at the 3
position, enabling the use of a variety of organometallic
reagents (RM; M = MgX, Li, ZnX, BR′2, AlMe2) in the
enantioselective addition to aldehydes at less than 5 mol %
catalyst loadings (Scheme 1).
Immobilization of chiral molecular catalysts on solid supports
has been an active area of research to enhance the practicality
by simplifying separation and recycling process.7 Since the
pioneering work by Frec
́
het8 and Soai,9 a variety of chiral
ligands have been grafted on polymers and silicas for the
Scheme 1. Enantioselective Addition of Organometallic
Reagents Catalyzed by 3-Aryl-H8-BINOL-Derived Chiral
Titanium Catalysts
Thus, 3-aryl-H8-BINOL (R)-4 bearing a hydrosilyl group was
prepared starting from pinacol borate ester (R)-215 (Scheme
2). The palladium-catalyzed cross-coupling reaction with 1-
allyl-3-bromo-5-tert-butylbenzene followed by exchange of the
hydroxy protecting group gave bis-TMS ether derivative (R)-3
in 89% yield. Iridium-catalyzed hydrosilylation16 of (R)-3 with
HSiMe2Cl and subsequent reduction of the chorodimethylsilyl
group afforded (R)-4 in 77% yield after purification with silica
gel chromatography.13 Grafting of (R)-4 was performed by
Received: May 29, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01625
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
proceeded faster than those reported previously, which required
overnight or longer reaction time at 0 °C.10 In accord with the
previous reports of chiral titanium catalysts immobilized on
silica,18,14a,b the exclusion of free silanols on the surface of silica
by capping with a trialkylsilyl group was essential to achieve
high enantioselectivity. Thus, the use of SSA-H8-BINOL
without EtMe2Si capping resulted in significantly lower
conversion and selectivity.
Scheme 2. Preparation of SSA-H8-BINOL (R)-5
The possibility of recovery and reuse of the silica-
immobilized catalyst was examined in the reaction of 6a with
Et2Zn at 6 mol % catalyst loading (Table 1). In this experiment,
Table 1. Recycling Experiment for Enantioselective
a
Ethylation of Aldehyde 6a Using Et2Zn
b
cycle
conversion (%)
ee (%)
1st
91
96
90
94
86
91
87
86
84
85
96
96
95
95
94
94
92
92
90
90
2nd
3rd
4th
5th
6th
7th
8th
9th
10th
a
Reactions were carried out at 0 °C for 2 h under the conditions
shown in Scheme 2 with 6 mol % of SSA-H8-BINOL (R)-5 on a 0.5
mmol scale. Determined by H NMR (500 MHz) analysis.
treating with a suspension of amorphous silica (480 m2/g) in
dry CH2Cl2 in the presence of B(C6F5)3 (6 mol %) at room
temperature for 5 min. After filtration, washing, and drying, free
silanol groups present on the surface of the resulting grafted
silica were capped with Me2(Et)SiH under similar conditions to
furnish SSA-H8-BINOL (R)-5, which was estimated to contain
0.069−0.101 mmol/g (depending on the runs) of the (R)-H8-
BINOL unit by the elemental analysis of samples before and
after capping.
The catalytic activity and enantioselectivity of an immobi-
lized titanium catalyst derived from SSA-H8-BINOL (R)-5 was
evaluated first in the enantioselective ethylation of p-
chlorobenzaldehyde (6a) with Et2Zn (3 equiv) and Ti(OiPr)4
(1.4 equiv) in CH2Cl2 at 0 °C (Scheme 3). The reaction with 2
b
1
the supernatant solution was withdrawn with a syringe after
each run. The residual silica was washed with CH2Cl2 in a
similar manner and used in the next run. Following this
method, we managed successfully to run up to 10 cycles
keeping high conversion (84−96%) and enantioselectivity
(90−96% ee). The result demonstrates the robustness of the
present silica immobilized catalyst for multiple uses even at
relatively low catalyst loadings.
We have reported that Et3B can be used in the
enantioselective ethylation of aldehydes.6j It was revealed that
the present silica-immobilized titanium catalyst also exhibited
high performance in the reaction of Et3B (Table 2). Thus, in
the presence of (R)-5 (6 mol %), treatment of 1-
naphthaldehyde (6b) with Et3B (3 equiv) and Ti(OiPr)4 (3
equiv) in THF at 60 °C for 3 h gave the ethyl adduct (R)-7b
enantioselectively (96% ee) in 85% yield (entry A1). The
performance of the silica-immobilized catalyst paralleled with a
homogeneous catalyst derived from DTBP-H8-BINOL (R)-1b
(2 mol %) (entry B). The immobilized titanium catalyst
generated in entry A1 were reused in recycling experiments
(entries A2−A10), demonstrating that high product yields
(81−89%) and selectivities (93−98% ee) were entirely
maintained up to the tenth cycle. After the tenth cycle, SSA-
H8-BINOL 5 was recovered by filtration of the hydrolyzed
immobilized titanium catalyst. Thus, recovered ligand again
exhibited its original performance as shown by the 11−14th
cycles (entries A11−A14).
Scheme 3. Enantioselective Ethylation of Aldehyde 6a Using
Et2Zn
mol % of immobilized ligand (R)-5 attained 77% conversion
after 2 h to give the ethylation product (R)-7a (91% ee) as a
sole product. Although the conversion and enantioselectivity
were inferior to those observed in the reaction with the
corresponding soluble ligand, DTBP-H8-BINOL (R)-1b (2 mol
%),17 high conversion (91%) and enantioselectivity (96% ee)
were obtained in the reaction employing 6 mol % of the
immobilized ligand. It should be noted that the reaction
The high activity and durability of the immobilized chiral
titanium catalyst derived from (R)-5 was further exploited in
the enantioselective arylation of aldehydes using Grignard
reagents (Table 3). Addition of the mixed reagent of PhMgBr
(8a) (2 equiv) and Ti(OiPr)4 (3.3 equiv) to a CH2Cl2 solution
of aldehyde 6b and Ti(OiPr)4 (1.7 equiv) in the presence of
B
DOI: 10.1021/acs.orglett.7b01625
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Organic Letters
Letter
(R)-5 (6 mol %) at 0 °C for 3 h, and additional 1 h stirring
afforded the phenyl adduct (R)-9ba in 85% yield and 94% ee
(entry A1). The high enantioselectivity (88−95% ee) and yield
(85−99%) of 9ba were maintained up to the tenth cycle as
shown by a recycle experiment (entries A1−10).
Table 2. Enantioselective Ethylation of Aldehyde 6b Using
Et3B
a
The practicality of the present heterogeneous catalyst system
was further demonstrated by recycling experiments in which
the same immobilized catalyst was used in different
combinations of aldehydes and Grignard reagents. Thus, a
recycling experiment was conducted for the reaction of
benzaldehyde (6c) and p-ClC6H4MgBr (8b) (entries B1−B4)
and for the reaction of 6b and 8b (entries B5 and B6). These
six reactions were carried out in this order by using the same
immobilized titanium catalyst, prepared in entry B1, without
hydrolysis to the silica-supported ligand (R)-5, leading to the
enantioselective formation of the p-chlorophenyl adducts (S)-
9cb (85−90% ee) and (R)-9bb (88 and 89% ee) in high yields.
In a similar manner, enantioenriched diarylmethanols (S)-9cc
(90 and 91% ee), (R)-9da (91% ee), and (R)-9ea (91% ee)
were obtained in high yields by the reaction of the
corresponding aldehyde 6c−e and Grignard reagents 8a,c
through a recycling experiment in entries C1−C6.
In summary, we have developed a robust silica-supported 3-
aryl H8-BINOL ligand for the catalytic enantioselective
alkylation and arylation of aldehydes. The heterogeneous
titanium catalyst derived from the silica-supported ligand
exhibited high activity and enantioselectivity at 6 mol %
loading not only in the reaction using Et2Zn but also, for the
first time, in the reaction using Et3B and aryl Grignard reagents.
The synthetic potential of the catalyst was further indicated by
the fact that it could be reused up to 14 times without
appreciable deterioration of the activity.
entry
yield (%)
ee (%)
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
85
85
83
81
88
81
85
88
82
89
84
82
85
84
91
96
96
96
95
93
96
96
98
96
95
94
96
95
94
95
b
A11
A12
A13
A14
c
B
a
Unless otherwise noted, reactions were carried out with aldehyde 6
(0.5 mmol), Et3B (3 equiv), Ti(OiPr)4 (3 equiv), and (R)-5 (6 mol %)
b
in THF at 60 °C for 3 h. Ligand (R)-5, recovered in entry A10, was
c
employed. Et3B (1.5 equiv) and (R)-1b (2 mol %) were used.
Table 3. Enantioselective Arylation of Aldehydes Using Aryl
Grignard Reagents
a
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01625.
entry
aldehyde (R1)
ArMgBr (R2) product yield (%) ee (%)
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
B1
B2
B3
B4
B5
B6
C1
C2
C3
C4
C5
C6
6b (1-naphthyl)
8a (H)
9ba
9ba
9ba
9ba
9ba
9ba
9ba
9ba
9ba
9ba
9cb
9cb
9cb
9cb
9bb
9bb
9cc
9cc
9da
9da
9ea
9ea
85
91
99
93
83
86
91
99
96
99
90
99
90
92
92
90
91
92
86
85
88
94
94
95
89
89
93
95
92
92
90
88
90
89
89
85
88
89
91
90
91
91
91
91
6b
8a
Experimental procedures and characterization of prod-
ucts (PDF)
6b
8a
6b
8a
6b
8a
AUTHOR INFORMATION
■
6b
8a
Corresponding Author
*E-mail: harada-t@kit.ac.jp.
ORCID
6b
8a
6b
8a
6b
8a
6b
8a
Toshiro Harada: 0000-0002-9818-5386
Notes
6c (Ph)
8b (p-Cl)
8b
6c
6c
8b
The authors declare no competing financial interest.
6c
8b
6b (1-naphthyl)
8b (p-Cl)
8b
ACKNOWLEDGMENTS
■
6b
This work was supported by KAKENHI (No. 15K05500) from
the Ministry of Education, Culture, Sports, Science, and
Technology (MEXT), Japan.
6c (Ph)
8c (p-F)
8c
6c
6d (m-MeOC6H4)
8a (H)
8a
6d
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6e (p-CNC6H4)
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DOI: 10.1021/acs.orglett.7b01625
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