Silica-Supported Catalyst for Enantioselective Arylation of Aldehydes under Batch and Continuous-Flow Conditions

Article abstract of DOI:10.1021/acs.orglett.8b00945

A silica-supported 3-aryl H₈-BINOL-derived titanium catalyst exhibited high performance in the enantioselective arylation of aromatic aldehydes using Grignard and organolithium reagents not only under batch conditions but also under continuous-

Full text of DOI:10.1021/acs.orglett.8b00945

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Silica-Supported Catalyst for Enantioselective Arylation of Aldehydes
under Batch and Continuous-Flow Conditions
Satoshi Watanabe, Naoyuki Nakaya, Junichiro Akai, Kenji Kanaori, 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 silica-supported 3-aryl H8−BINOL-derived titanium catalyst exhibited high performance in the enantioselective
arylation of aromatic aldehydes using Grignard and organolithium reagents not only under batch conditions but also under
continuous-flow conditions. Even with a simple pipet reactor packed with the heterogeneous catalyst, the enantioselective
production of chiral diarylmethanols could be achieved through a continuous introduction of aldehydes and mixed titanium
reagents generated from the organometallic precursors. The pipet reactor could be used repeatedly in different reactions without
appreciable deterioration of the activity.
Scheme 1. Enantioselective Carbonyl Addition by a Silica-
Supported Heterogeneous Catalyst
mmobilization of chiral molecular catalysts on solid supports
1
Ihas been an active area of research to enhance practicality.
The resulting heterogeneous catalysts would not only simplify
separation and the recycling process when used in a batch system
but also enable continuous production of enantiopure products
when used in a flow system.2 In spite of these potential
advantages, immobilization often results in lower activities and
enantioselectivities as compared to those observed for their
homogeneous counterparts due to limited access to the active
catalysts and their restricted degrees of freedom.1d
For the enantioselective carbonyl addition reactions, a number
of chiral ligands have been grafted on polymers and silicas since
the pioneering work by Frec
́ ̀
het3 and Soai.4,5 Recently, Pericas
and co-workers reported highly efficient, chiral amino alcohol
based, polymer-supported catalysts6 that can be successfully
employed under continuous flow conditions.7 Despite these
advances, and with very few exceptions,7b the reported
immobilized catalysts have been developed and evaluated for
the reaction of diorganozincs, particularly Et2Zn. Recently, we
have developed a heterogeneous titanium catalyst derived from
silica-supported 3-aryl (SSA-) H8−BINOL ligand (Scheme 1)
that exhibits high activity and enantioselectivity in the reactions
using not only Et2Zn but also Et3B and aryl Grignard reagents as
mixed titanium reagents with Ti(OiPr)4.8 It has been
demonstrated that the catalyst is robust enough to be reused
up to 14 times in batch conditions without appreciable
deterioration of the activity.
carbonyl arylation reactions using aryl Grignard reagents,
including functionalized derivatives, and PhLi under the batch
and flow conditions. Herein, we report the results of the study
together with the characterization of the immobilized ligands by
solid-state NMR spectroscopy.
SSA-H8−BINOL (R)-3 was prepared by grafting hydrosilane
precursor (R)-1 on the surface of amorphous silica (480 m2/g)
under B(C6F5)3 (6 mol %) catalysis9 and then capping the free
silanol groups of the resulting silica (R)-2 with EtMe2SiH under
similar conditions (Scheme 2).8 Thus, prepared grafted silica
(R)-3 was estimated to contain 0.072−0.114 mmol/g of the (R)-
H8−BINOL unit with a cap/ligand ratio (n) of 6.9−15
(depending on the runs) by elemental analyses.
In the present study, the potential of the SSA-H8−BINOL-
derived catalyst was further exploited in the enantioselective
Received: March 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00945
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Preparation of SSA-H8−BINOL (R)-3
Table 1. Enantioselective Arylation of Aldehydes Using a
a
Pipet Reactor Packed with SSA-H8−BINOL (R)-3
conversion
(%)
ee
(%)
b
c
entry
R1
R2
A
B
product
d
A1
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
0.2
0.2
0.2
0.2
1.25
2.5
6a
6a
6a
6a
77
71
57
89
92
92
87
92
87
89
83
88
89
84
85
84
83
85
91
87
88
94
85
87
A2
A3
A4
5.0
e,
f
g
2.5
72
−2 h
−4 h
−6 h
78
70
80
78
77
55
d
B1
m-MeO
m-MeO
m-MeO
m-MeO
0.4
0.4
0.4
0.4
1.25
2.5
6b
6b
6b
6b
B2
B3
H
H
5.0
e
,
f
g
B4
H
2.5
58
−2 h
−4 h
−8 h
59
61
59
79
74
68
e
C1
p-Cl
p-Cl
p-Cl
p-Cl
H
H
H
H
0.2
0.2
0.2
0.1
1.25
2.5
ent-6a
ent-6a
ent-6a
Figure 1. 29Si CP-MAS NMR spectrum of amorphous silica (a) and 13
C
C2
C3
NMR spectrum of (R)-1 (e) and 29Si and 13C CP-MAS NMR spectra of
silica grafted with EtMe2SiH (1.46 mmol/g) (b and f), (R)-2 (0.075
mmol/g) (c and g), and (R)-3 (0.073 mmol/g, n = 15) (d and h).
5.0
d
,
h
,
i
g
C4
5.0
65
−2 h
−4 h
−6 h
83
73
73
SSA-H8−BINOL (R)-3 was characterized further by 29Si and
13C CP-MAS NMR measurements (Figure 1). Before capping,
the grafted silica (R)-2 exhibited the 29Si resonance at 13.8 ppm
(c), which is a typical chemical shift for trialkylsilyloxy groups
(M; R3SiOSi) on the silica surface and 13C signals in aromatic
(110−160 ppm) and aliphatic (15−45 ppm) region (g) in accord
with the spectrum of precursor (R)-1 (e), thus indicating that the
chiral ligand was immobilized on the surface with Si−O bonding.
After capping, strong 13C resonances derived from EtMe2Si
group appeared from −8 to 12 ppm (h and f) in addition to the
aromatic and aliphatic signals. The ratio of the aliphatic 13C
signals (15−45 ppm) to those of the EtMe2Si group was
consistent with the cap/ligand ratio (n) of 15 determined by
elemental analyses. The 29Si resonance of EtMe2SiOSi over-
lapped with that of (R)-2 at 13.8 ppm (d and c). In comparison
with unmodified silica (a), the intensity of signals derived from Si
species Q2 (Si(OH)2(OSi)2) was decreased and that of Q4
(Si(OSi)4) was significantly increased in (R)-3 (d). The
observation showed that a large portion of the silanol groups
on the silica surface was silylated in SSA-H8−BINOL (R)-3 and
a
Unless otherwise noted, flow reactions were carried out consecutively
b
with the same pipet reactor. Molar concentration of aldehydes.
Unless otherwise noted, the concentration of mixed titanium reagents
is 0.5 times that of aldehydes. Flow rate (mL/h) of aldehydes. Unless
otherwise noted, the flow rate of mixed titanium reagents is four times
that of aldehydes. A new pipet reactor was used. A pipet reactor used
in previous entries was employed after washing and reactivation. For
c
d
e
f
details, see the text and the Supporting Information. Flow time is 8 h.
g
h
i
Isolated yield. Flow time is 9.1 h. Concentration and flow rate of the
mixed titanium reagent are 0.13 M and 7.5 mL/min, respectively. Flow
time is 7 h.
5 and Ti(OiPr)4 (Table 1).10 A disposable pipet (6 × 100 mm),
fitted with a rubber septum, was packed with 1.25 g (90 μmol) of
(R)-3 (0.072 mmol/g). A solution of a mixed reagent of p-
ClC6H4MgBr and Ti(OiPr)4 (1:2.5 molar ratio) in CH2Cl2 (0.1
M with respect to the p-chlorophenyl group) was first introduced
to the pipet reactor cooled at 0 °C with a syringe pump to prepare
a yellow, immobilized chiral titanium catalyst. The flow rate of
the mixed titanium reagent was adjusted as 5 mL/h, and then a
solution of benzaldehyde (4a) in CH2Cl2 (0.2 M) was
introduced additionally at 1.25 mL/h so that the molar ratio of
the reagent to the aldehyde is 2. The reaction mixture eluted from
the reactor for 0.5 h was quenched with aqueous 1 N HCl to give
p-chlorophenyl adduct (S)-6a in 89% ee with 77% conversion
(entry A1). The enantioselectivity was increased to 92% ee by the
1
that the cross-polarization effectively occurs from H nuclei of
the capping groups to 29Si of Q4 near the surface.
High turnover frequency, enantioselectivity, and robustness
observed in the previous recycle experiments8 prompted us to
use SSA-H8−BINOL (R)-3 under flow conditions in the
arylation of aldehydes with a mixed reagent of Grignard reagents
B
DOI: 10.1021/acs.orglett.8b00945
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
increase of a flow rate of the substrate (2.5 and 5.0 mL/h) and the
reagent (10 and 20 mL/h) albeit with concurrent lowering of the
conversion (entries A2 and A3). A preparative-scale experiment
was carried out under conditions similar to those of entry A2.
Continuous introduction of the aldehyde and reagent solution
for 8 h provided 0.65 g (72% yield) of (S)-6a in 87% ee (entry
A4). During this experiment, aliquots of the eluate were
withdrawn at 2, 4, and 6 h to monitor conversion and
enantioselectivity. As shown in entries A4-2 h, -4 h, and -6 h,
the conversion and selectivity remained almost constant
throughout the reaction. It should be noted that these four
experiments (entries A1−4) were performed in this order with
the same pipet reactor, which was washed successively with 0.5 N
HCl in 50% aqueous ethanol, ethanol, and CH2Cl2 and then
activated with the flow of the mixed titanium reagent before the
preparative experiment (entry A4).
Table 2. Enantioselective Arylation of Aldehydes Using
Functionalized Aryl Grignard Reagents
a
Another series of experiments were carried out with m-
anisaldehyde (4b) and PhMgBr at higher concentrations using a
new pipet reactor (entries B1−4). From an increase of a flow rate
of the aldehyde solution (0.4 M) and mixed titanium reagent
solution (0.2 M), the enantioselectivity of the corresponding
adduct (R)-6b was increased from 84% ee to 89% ee with
decreasing conversion (entries B1−B3). A preparative experi-
ment conducted under the conditions of entry B2 for 9.1 h
afforded 1.95 g (59% yield) of (R)-6b in 84% ee (entry B4).
Again, the activity of the catalyst was maintained throughout the
reaction judging from the result of aliquot monitoring (entries
B4−2 h, −4 h, and −8 h). Under the flow conditions, the reaction
of p-chlorobenzaldehyde (4c) (0.1 M) and a mixed titanium
reagent (0.13 M) derived from PhMgBr provided 0.49 g (65%
yield) of ent-6a (R enantiomer of 6a) in high enantioselectivity
(88% ee) (entry C4). The conversion and selectivity for this
reaction followed similar trends as those observed in entries A
and B (entries C1−C3).11
entry
aldehyde
7 (Y)
6
yield (%)
ee (%)
A1
A2
A3
A4
A5
A6
B1
B2
B3
B4
4d; R = 1-naphthyl
CN
CN
CN
CN
CN
CN
Br
6c
6c
6d
6d
6e
6e
6f
97
77
96
99
85
64
62
51
71
62
40
95
96
93
92
83
86
91
89
82
81
92
4d
4a; R = Ph
4a
4e; R = p-(CN)C6H4
4e
4d; R = 1-naphthyl
4d
Br
6f
4a; R = Ph
4a
Br
6g
6g
6c
Br
b
C
4d; R = 1-naphthyl
CN
a
Unless otherwise noted, reactions were carried out with aldehyde 4
(0.5 mmol), iodoarene 7 (2 equiv), c-C5H11MgCl (2.2 equiv),
Ti(OiPr)4 (4.7 equiv), and (R)-3 (10 mol %) in Et2O and CH2Cl2 at 0
b
°C for 5 h. The reaction was carried out under flow conditions using
a pipet reactor. For details, see the text and Supporting Information.
Optically active functionalized diarylmethanols are in demand
as synthetic precursors to many biologically active compounds.12
We recently reported an efficient method for the enantioselective
preparation of these alcohols that is based on the arylation of
aromatic aldehydes with functionalized Grignard reagents under
homogeneous chiral titanium catalysis.10b,13 It was shown the
thermally unstable functionalized reagents could be employed in
the enantioselective addition as a mixed titanium reagents with
Ti(OiPr)4. We examined the potential of the present
heterogeneous catalysis in the functionalized arylation first
under the batch conditions.
3-Iodobenzonitrile (7a) (2 equiv) was treated with c-
C5H9MgBr in Et2O at −40 °C, and the resulting Grignard
reagent 5 bearing a cyano group was mixed with Ti(OiPr)4 (3.3
equiv) (Table 2). The mixed titanium reagent was added to a
well-stirred mixture of 1-naphthaldehyde (4d), Ti(OiPr)4 (1.7
equiv), and (R)-3 (10 mol %) in CH2Cl2 at 0 °C for 3 h. After an
additional 2 h of stirring, centrifugation of the reaction mixture
and hydrolysis of the supernatant afforded the m-cyanophenyl
adduct (R)-6c in 97% yield and 94% ee (entry A1). The residual
silica-supported catalyst was used in the next run. Following this
method, we managed to run up to six cycles for three different
aldehydes 4d, 4a, and 4e with the same immobilized catalyst
keeping high selectivity (83−96% ee) and yield (64−99%)
(entries A2−A6). Under similar conditions, another series of
recycle experiments were carried out using 1-bromo-3-
iodobenzene (7b) as a source of the mixed titanium reagent
(entries B1−4). The four consecutive reactions of aldehydes 4d
and 4a exhibited high enantioselectivity (81−91% ee) albeit with
moderate yields (51−71%).
The functionalized arylation could be also carried out under
flow conditions using a pipet reactor packed with 1.34 g of (R)-3
(0.094 mmol/g). Simultaneous introduction of a functionalized
titanium reagent (0.1 M, 10 mL/h) generated from 7a and
aldehyde 4d (0.2 M, 3.1 mL/h mL/h) for 4 h afforded 0.25 g
(40% yield) of (R)-6c in high enantioselectivity (92% ee) (entry
C).
The chiral immobilized catalyst is also applicable to the
enantioselective addition of PhTi(OiPr)3 generated in situ from
PhLi (Table 3).14 Treatment of PhLi with ClTi(OiPr)3 in
CH2Cl2 and addition of the resulting PhTi(OiPr)3 (2 equiv) to a
CH2Cl2 solution of 1-naphthaldehyde (4d) and Ti(OiPr)4 (0.2
equiv) in the presence of (R)-3 (5 mol %) at 0 °C for 3 h
provided the phenyl adduct (R)-6h of 76% ee in 92% yield (entry
A1). In the following recycle experiments (entries A2−10), the
enantioselectivity of (R)-6h was improved by the increase of the
stirring rate, as shown in the second and the third cycle. With
vigorous stirring, high selectivities (86−92% ee) as well as the
quantitative yields were preserved up to the tenth cycle.
According to our previous study on a relevant homogeneous
catalyst system,14 PhTi(OiPr)3 is reactive enough to undergo
non-enantioselective addition to aldehydes. To realize high
enantioselectivity, the high activity of the catalyst system is
indispensable in overwhelming the background reaction. The
rapid stirring might promote material transfer on the surface of
C
DOI: 10.1021/acs.orglett.8b00945
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
Table 3. Enantioselective Phenylation of 1-Naphthaldehyde
(4d) with in Situ Generated Phenyltitanium Reagent
a
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a grant from KAKENHI (No.
15K05500) from the Ministry of Education, Culture, Sports,
Science, and Technology (MEXT), Japan.
entry
conversion (%)
ee (%)
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A5
A6
A7
A8
A9
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84
76
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88
93
92
91
87
90
91
86
95
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A pipet reactor packed with (R)-3 exhibited high performance
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generated PhTi(OiPr)3 (0.1 M, 10 mL/h) and 4d (0.2 M, 3.1
mL/h) provided 0.22 g (44% yield) of (R)-9h in excellent
enantioselectivity (95% ee) (entry B).
In summary, it has been demonstrated that well-characterized
silica-supported SSA-H8−BINOL-derived catalyst exhibits high
performance in enantioselective carbonyl arylation using
Grignard and organolithium reagents under the batch and flow
conditions.15 Even with a simple pipet reactor packed with the
heterogeneous catalyst, the enantioselective production of chiral
diarylmethanols has been realized through a continuous
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generated from the organometallic precursors. The synthetic
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00945.
■
S
(13) Itakura, D.; Harada, T. Synlett 2011, 2011, 2875−2879.
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Eur. J. 2016, 22, 12095−12105.
Experimental procedures and characterization of products
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: harada-t@kit.ac.jp.
ORCID
(15) For a proposed catalytic cycle for a relevant homogeneous
reaction, see ref 14b.
Toshiro Harada: 0000-0002-9818-5386
D
DOI: 10.1021/acs.orglett.8b00945
Org. Lett. XXXX, XXX, XXX−XXX