Catalytic asymmetric aryl transfer reactions to aldehydes with grignard reagents as the aryl source

Article abstract of DOI:10.1002/chem.200801612

A study was conducted to demonstrate a practical and efficient method for asymmetric arylation of aldehydes, using aryl Grignard reagents in combination with titanium tetraisopropoxide. It was demonstrated that a variety of diarylmethanols can be obtained

Full text of DOI:10.1002/chem.200801612

DOI: 10.1002/chem.200801612
Catalytic Asymmetric Aryl Transfer Reactions to Aldehydes with Grignard
Reagents as the Aryl Source
Yusuke Muramatsu and Toshiro Harada*[a]
A straightforward synthesis of enantiomerically enriched
diarylmethanols involves the addition of an aryl–metal re-
agent to an aromatic aldehyde, through which a carbon–
carbon bond and a stereogenic center are produced simulta-
neously. Because these alcohols are important constituents
and precursors of biologically active compounds, catalytic
asymmetric arylation has attracted much attention in recent
years.[1] Seebach and Weber reported the first catalytic
A recent report from this laboratory[11] showed that
Grignard reagents can be used in the asymmetric alkylation
of aldehydes by using a titanium(IV) catalyst derived from
3-(3,5-diphenylphenyl)-BINOL (1) in the presence of excess
titanium tetraisopropoxide.[12,13] The reaction protocol in-
volves the slow addition of a mixture of an alkyl Grignard
reagent (2.2 equiv) and titanium tetraisopropoxide
(4.4 equiv) to a solution of an aldehyde, ligand 1 (2 mol%),
and titanium tetraisopropoxide (1.4 equiv) in CH2Cl2 at 08C.
In contrast to the high enanatioselectivity obtained in the
phenyl transfer reaction with [Ti
ACHTUNGTRENNUNG
transmetalation of PhLi with [TiClAHCUTNGTRENNUNG
removal of LiCl by centrifugation.[2] Since the works of
direct Ph2Zn addition by Fu et al.,[3] various catalysts have
been developed for enantioselective addition of aryl–zinc re-
agents.[4–6] The scope of aryl groups that can be introduced
has been extended significantly by the use of arylboronic
acids and their derivatives, either through in situ transforma-
tion to aryl–zinc reagents with diethylzinc[7] or through
direct catalysis by chiral rhodium complexes.[8] Most recent-
ly, Walsh and Kim[9] reported a one-pot method for the gen-
eration of aryl–zinc reagents by the reaction of the corre-
sponding aryl bromide with nBuLi followed by transmetala-
tion with ZnCl2 and precipitation of the resulting LiCl with
tetraethylethylene diamine, and their subsequent catalytic
asymmetric addition to aldehydes.[10]
Table 1. Asymmetric phenyl transfer reaction of 1-naphthaldehyde using
PhMgBr.[a]
Herein, we report a practical and efficient method for
asymmetric arylation of aldehydes by using aryl Grignard
reagents in combination with titanium tetraisopropoxide. A
variety of diarylmethanols can be obtained in high enantio-
selectivity by the reaction of aldehydes with the Grignard
reagents (1.2 equiv) in the presence of 3-(3,5-diphenylphen-
yl)-H8-BINOL (2; 2 mol%) and titanium tetraisopropoxide
(3 equiv).
Entry
Ligand
PhMgBr
[equiv]
Ti
A
G
Yield[b]
[%]
ee
[%]
A
G
1[c]
2
3
4
5
1
2
2
2
2
2
2.2
2.2
1.2
1.2
1.2
1.2
4.4
4.4
2.0
2.0
2.0
1.5
94
98
98
97
99
90
86
94
92
95
91
87
[a] Y. Muramatsu, Prof. Dr. T. Harada
Department of Chemistry and Materials Technology
Kyoto Institute of Technology, Matsugasaki
Sakyo-ku, Kyoto 606-8585 (Japan)
Fax : (+81)75-724-7514
6
[a] Reactions were carried out by adding a solution of PhMgBr (3m in
Et2O) and titanium tetraisopropoxide (a equiv) in CH2Cl2 (8 mL) to a so-
lution of 1-naphthaldehyde (1 mmol), ligand 1 or 2 (2 mol%), and titani-
um tetraisopropoxide (b equiv) in CH2Cl2 (4 mL), over 2 h at 08C. The
reaction mixture was stirred for a further hour before workup. [b] Yield
of isolated product. [c] Reference [11].
E-mail: harada@chem.kit.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801612.
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Chem. Eur. J. 2008, 14, 10560 – 10563

COMMUNICATION
Table 2. Catalytic asymmetric arylation of aldehydes with Grignard reagents.[a]
reaction with alkyl Grignard re-
agents, inferior selectivity was
observed in a phenyl transfer
reaction using PhMgBr. Thus,
under these conditions, the re-
action of 1-naphthaldehyde
with PhMgBr gave the corre-
sponding diarylmethanol 3a in
86% enantiomeric excess (ee)
(Table 1, entry 1). We have re-
cently reported that 2 showed
higher enantioselectivity than 1
in the asymmetric alkylation of
aldehydes
with
Et2Zn.[14,15]
Gratifyingly, the use of 2 as a
chiral ligand under similar con-
ditions significantly improved
the enantioselectivity, affording
3a in 94% ee and 98% yield
(Table 1, entry 2). Further ex-
amination of the reaction con-
ditions revealed that phenyl
transfer could be carried out
with an almost stoichiometric
amount of the Grignard reagent
(1.2 equiv) and with a total of
three equivalents of titanium
Entry
Aldehyde
ArM[b]
Product
Yield[c] [%]
ee [%]
1
2
3
4
5
6
7
8
PhCHO
PhCHO
PhCHO
PhCHO
p-MeC6H4MgBr
p-ClC6H4MgBr
p-FC6H4MgBr
o-MeOC6H4MgBr
2,4,6-Me3C6H2MgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
PhLi
PhLi
PhMgBr
PhMgBr
3b
3c
3d
3e
99
95
94
66
89
93
96
97
99
96
90
94
96
97
95
85
83
85
87
78
88
86
91
91
97
9
PhCHO
3 f
96
90
94
95
91
92
95
90
91
95
50
95
89
90
97
86
88
80
p-MeC6H4CHO
p-ClC6H4CHO
p-FC6H4CHO
p-PhC6H4CHO
p-NCC6H4CHO
m-MeOC6H4CHO
o-ClC6H4CHO
2-naphthylCHO
1-naphthylCHO
1-naphthylCHO
1-naphthylCHO
2-furylCHO
ent-3b
ent-3c
ent-3d
3g
3h
3i
3j
3k
3a
3a
3a
3l
3m
4a
4b
9
10
11
12
13
14
15
16[d]
17
18
19
20
21
22
tetraisopropoxide
(Table 1,
entry 4). High product yield
(97%) and high enantioselec-
tivity (95% ee) were obtained
under these optimized condi-
tions. Enantioselectivity was de-
creased by further reduction of
the amount of titanium tetraiso-
propoxide (Table 1, entries 5
and 6).
The results of the asymmetric
arylation of a variety of alde-
hydes by using aryl Grignard
reagents are summarized in
Table 2. High enantioselectivi-
2-thienylCHO
CH2=C(Me)CHO
MeCH=CHCHO
BuCHO
PhMgBr
PhMgBr
PhMgBr
PhMgBr
5a
5b
c-C6H11CHO
[a] Reactions were carried out on a 1 mmol scale with 2 (2 mol%) according to the procedure described in the
Experimental Section. [b] Commercial solution of the Grignard reagents in Et2O (1.6–3m) and PhLi in cyclo-
hexane and Et2O (0.98m) were used. [c] Yield of isolated product. [d] PhLi (1.2 equiv) was used after treat-
ment with MgBr2 (1.2 equiv) in Et2O. See the Supporting Information for more information.
ties and yields were obtained in the reaction of benzalde-
hyde with substituted phenyl Grignard reagents, except for
the o-methoxy derivative (Table 2, entries 1–5). Notably, ex-
cellent enantioselectivity was observed for sterically hin-
dered 2,4,6-Me3C6H4MgBr. As shown in Table 2, entries 6–
14, the reaction of aromatic aldehydes with PhMgBr gener-
ally proceeded in an efficient manner. Slightly lower, yet
still acceptable selectivity was obtained for heteroaromatic
aldehydes (Table 2, entries 17 and 18). Although the use of
PhLi, instead of PhMgBr, resulted in a significant reduction
in enantioselectivity (Table 2, entry 15), the organolithium
reagent could be employed after conversion into PhMgBr
by treatment with MgBr2 (Table 2, entry 16). Note that the
reaction was carried out without removing concomitantly
produced LiBr,[16] but was simply carried out by mixing
PhLi (1.2 equiv) with MgBr2 (1.2 equiv) and titanium tetra-
isopropoxide (2 equiv), to give 3a in excellent enantioselec-
AHCTUNGTRENNUNG
tivity. Not only diarylmethanols, but also secondary allylic
alcohols 4 and benzylic alcohols 5 could be synthesized
enantioselectively by the reaction of a,b-unsaturated alde-
hydes and aliphatic aldehydes, respectively (Table 2, en-
tries 19–22).
To expand the scope of the reaction, asymmetric transfer
of functionalized aryl groups was examined.[17] Recently,
Knochel and co-workers have developed a method for the
preparation of functionalized Grignard reagents by a halo-
gen–magnesium exchange reaction.[18] According to the re-
ported protocol,[17b] a solution of 3-cyanophenylmagnesium
chloride (7a) in THF was prepared by treating m-iodoben-
zonitrile (6a) with iPrMgCl (2m in THF) at À408C, and was
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10561

T. Harada and Y. Muramatsu
Table 3. Catalytic asymmetric transfer of functionalized aryl groups with Grignard reagents.
(0.226 g, 97%; 95% ee). The ee value
was determined by HPLC analysis
using
(1.5 mLminÀ1
hexane); retention times: 26.8 min
(major enantiomer) and 11.4 min
a
Chiralcel OD column
,
10% iPrOH in
R
(minor S enantiomer). The absolute
structure of the product was deter-
mined based on reported retention
times.[8d]
Entry
Iodide
RMgCl
Product
Yield [%]
ee [%]
1
2
3
6a
6a
6b
iPrMgCl[a]
8a
8a
8b
82
91
76
61
95
93
cC5H9MgCl[b]
cC5H9MgCl[b]
[a] Solution in THF. [b] Solution in Et2O.
Acknowledgements
This work was supported by KAKEN-
HI (20550095) and by the Kyoto Insti-
tute of Technology Research Fund.
used in the asymmetric arylation of 1-naphthaldehyde
(Table 3). The reaction gave diarylmethanol 8a in high yield
but with low enantioselectivity (61% ee; Table 3, entry 1).
In our previous study, the use of a Grignard reagent in THF
resulted in reduced enantioselectivity in comparison with
that in Et2O.[11] Although preparation of the requsite
Grignard reagent in Et2O was unsuccessful with iPrMgCl
(2m in Et2O), it could be prepared efficiently by the use of
cC5H9MgCl (2m in Et2O).[19] Subsequent use in the asym-
metric arylation reaction afforded 8a with a selectivity of
95% ee in 91% yield (Table 3, entry 2). Under similar con-
ditions, the reaction of 1-naphthaldehyde with 3-(piperidine-
1-carbonyl)phenylmagnesium chloride (7b) gave the func-
tionalized diarylmethanol 8b in high enantioselectivity
(Table 3, entry 3).
In summary, we have shown that Grignard reagents can
be used in asymmetric arylation of aldehydes in the pres-
ence of the chiral titanium catalyst derived from 2 and tita-
nium tetraisopropoxide. The reaction was accomplished
within 3 h with a low catalyst loading (2 mol%) and with a
slight excess (1.2 equiv) of Grignard reagents. The results
show high enantioselectivities and product yields for various
combinations of substrates and reagents, including those
with functional groups. Work is in progress to investigate
the full scope of the reaction.
Keywords: addition reactions
asymmetric catalysis · Grignard reaction · titanium
· alcohols · aldehydes ·
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Experimental Section
Typical procedure for asymmetric arylation with a Grignard reagent (3a;
Table 1, entry 4): PhMgBr (0.40 mL, 1.2 mmol; 3m in Et2O) was added to
a solution of titanium tetraisopropoxide (0.59 mL, 2.0 mmol) in dry
CH2Cl2 (8 mL) at À788C under an argon atmosphere. After being stirred
for 10 min at this temperature, the resulting mixture was slowly added
over a period of 2 h by using a syringe pump to a solution of 2 (10.5 mg,
0.020 mmol), 1-naphthaldehyde (0.156 g, 1.0 mmol), and titanium tetrai-
sopropoxide (0.30 mL, 1.0 mmol) in CH2Cl2 (4 mL) at 08C under an
argon atmosphere. After being stirred for a further hour, the reaction
mixture was quenched by the addition of a 1m solution of HCl and ex-
tracted three times with ethyl acetate. The organic layers were washed
successively with a 5% aqueous solution of NaHCO3 and brine, dried
(MgSO4), and concentrated in vacuo . Flash chromatography (silica gel,
2–20% ethyl acetate in hexane) of the residue gave 3a as a colorless oil
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Asymmetric Aryl Transfer Reactions
COMMUNICATION
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Received: August 5, 2008
Published online: October 29, 2008
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