Catalytic enantioselective alkylation and arylation of aldehydes by using grignard reagents

Article abstract of DOI:10.1246/bcsj.20090232

We have developed an efficient and practical method for the catalytic enantioselective alkylation and arylation of aldehydes by using Grignard reagents in combination with titanium tetraisopropoxide. Grignard reagents and titanium tetraisopropoxide are mixed in a molar ratio of ca. 1:2. In the presence of catalyst (24mol%), which is formed in situ from a BINOL ligand 4a and 4b and titanium tetraisopropoxide, the resulting mixed titanium reagents undergo addition to aldehydes with high enantioselectivities (typically >90% ee) and high yields. The method is applicable to various combination of aldehydes (R¹CHO; R¹ = aryl, heteroaryl, 1-alkenyl, and alkyl) and Grignard reagents (R²MgX; R² = primary alkyl and aryl). Thus, a variety of enantiomerically enriched secondary alcohols (R¹CH*(OH)R²) can be prepared. It has also been demonstrated that functionalized aryl Grignard reagents can be employed to generate highly functionalized diarylmethanols. The preparative utility of the method has been shown by the fact that the reaction is operationally simple, can be carried out on a 10-mmol scale without any difficulty, and the ligands can be readily recovered.

Full text of DOI:10.1246/bcsj.20090232

© 2010 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 83, No. 1, 19–32 (2010)
19
BCSJ Award Article
Catalytic Enantioselective Alkylation and Arylation of Aldehydes
by Using Grignard Reagents
Yusuke Muramatsu, Shinichi Kanehira, Masato Tanigawa, Yuta Miyawaki, and Toshiro Harada*
Department of Chemistry and Materials Technology, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto 606-8585
Received September 2, 2009; E-mail: harada@chem.kit.ac.jp
We have developed an efficient and practical method for the catalytic enantioselective alkylation and arylation of
aldehydes by using Grignard reagents in combination with titanium tetraisopropoxide. Grignard reagents and titanium
tetraisopropoxide are mixed in a molar ratio of ca. 1:2. In the presence of catalyst (2-4 mol %), which is formed in situ
from a BINOL ligand 4a and 4b and titanium tetraisopropoxide, the resulting mixed titanium reagents undergo addition to
aldehydes with high enantioselectivities (typically >90% ee) and high yields. The method is applicable to various
combination of aldehydes (R1CHO; R1 = aryl, heteroaryl, 1-alkenyl, and alkyl) and Grignard reagents (R2MgX;
R2 = primary alkyl and aryl). Thus, a variety of enantiomerically enriched secondary alcohols (R1CH*(OH)R2) can be
prepared. It has also been demonstrated that functionalized aryl Grignard reagents can be employed to generate highly
functionalized diarylmethanols. The preparative utility of the method has been shown by the fact that the reaction is
operationally simple, can be carried out on a 10-mmol scale without any difficulty, and the ligands can be readily
recovered.
The catalytic enantioselective addition of organometallic
reagents to aldehydes and ketones leading to enantiomerically
enriched secondary and tertiary alcohols is a reaction of
fundamental importance in modern synthetic organic chemis-
try. The development of efficient catalytic systems has received
widespread attention for a long time.1 In the early days,
attempts were made to employ Grignard reagents and organo-
lithium reagents in the presence of more than stoichiometric
amounts of chiral diamines or other chiral modifiers.2,3
However, the development of the catalytic reaction had been
hampered by the high reactivity of these organometallic
reagents. In 1984, Oguni and Omi discovered that diethylzinc
undergoes enantioselective addition to aldehydes in the
presence of chiral amino alcohols.4 In 1986, Noyori and co-
workers developed highly efficient DAIB catalyst, by which the
catalytic enantioselective alkylation of aldehydes was realized
for the first time with high enantioselectivity at low catalyst-
loading (2 mol %).1b,5 In the absence of catalysts, dialkylzincs
hardly react with aldehydes. These pioneering works clearly
showed that it is essential to use less reactive diorganozinc
reagents with the aid of ligand acceleration to realize efficient
catalytic enantioselective addition. Since then, remarkable
advances have been made in catalytic enantioselective
addition by using diorganozinc reagents, expanding the scope
of both nucleophiles (alkylation,1,6-9 arylation,10-13 alkynyla-
tion,14-16 and alkenylation17-19) and electrophiles (aldehydes
and ketones20-24).
The use of diorganozinc reagents in catalytic enantioselec-
tive addition has an inherent drawback critical to practical
applications. In their standard method for preparation, the
insertion of zinc metal to alkyl iodides leads to alkylzinc
iodides, which after distillation or sublimation, provide
dialkylzinc reagents (Scheme 1a).25 Due to the thermal
instability of higher homologs, the method is applicable only
to lower diorganozinc reagents. Indeed, only limited numbers
of them are commercially available.
(a)
R2-I
R'2Zn
R2-I
(b)
- R'I
Zn - ZnI2
R'2Zn
O
R2-H
(c)
R2-Zn-R2
- R'H
R1
H
(R2 = alkynyl)
OH
or
R2-Zn-R'
R1
R2
chiral catalyst
*
R'2Zn
R2-BY2
R' = Me, Et
(d)
(e)
- R'BY2
Me3Al - Me2AlCl
ZnX2
R2-M
R2-ZnCl
- MX2
(R2 = aryl)
(M = MgX, Li)
(f)
Scheme 1.
Published on the web December 23, 2009; doi:10.1246/bcsj.20090232

20
Bull. Chem. Soc. Jpn. Vol. 83, No. 1 (2010) BCSJ AWARD ARTICLE
Y
Y
To circumvent this intrinsic problem, several methods have
Ti(OiPr)2
O
OH
*
been developed for preparing diorganozinc reagents in situ
(Schemes 1b-1f) and employed in subsequent enantioselective
additions. Functionalized dialkylzinc reagents were prepared
by iodine-zinc exchange with neat Et2Zn (excess) and
used after the removal of ethyl iodide and surplus Et2Zn
(Scheme 1b).26 Recently, the catalytic enantioselective aryla-
tion of aldehydes with functionalized diarylzinc reagents
prepared in situ from a Li(acac)-catalyzed iodine-zinc ex-
change reaction with Et2Zn has been reported.27,28 Zincation
of terminal alkynes with Me2Zn or Et2Zn gives alkynylzinc
reagents, which have been used in the enantioselective
alkynylation of aldehydes and ketones (Scheme 1c).14-16
Alkyl- and alkenylboranes, prepared by hydroboration, were
converted into the corresponding zinc reagent by boron-zinc
exchange reaction and employed in enantioselective alkyla-
tion29 and alkenylation18c,19 (Scheme 1d).30 Similarly, func-
tionalized arylzinc reagents prepared in situ from arylboronic
acids or their derivatives have been used in catalytic enantio-
selective arylation.13,31 The in situ preparation of diorganozinc
reagents from Grignard and organolithium reagents by trans-
metalation with zinc salts (ZnX2; X = Cl, Br, and OMe) has
been also reported (Scheme 1e).32 In this method, concom-
itantly produced magnesium and lithium salts should be
removed as thoroughly as possible by their precipitation with
complexing agents and filtration or centrifugation. Otherwise,
enantioselectivity is degraded significantly by a competing
racemic reaction promoted by the salts. Recently it has been
shown that arylzinc chlorides can be converted to ArZnMe by
treatment with Me3Al (Scheme 1f).33 The resulting mixed
organozinc reagents selectively undergo aryl transfer and are
utilized in the enantioselective arylation of aldehydes.
Although major efforts have been made in the use of
diorganozinc reagents, organotitanium reagents have also
been employed as an alternative in catalytic enantioselective
addition. Seebach and co-workers showed that alkyl- and
aryltitanium reagents [R-Ti(OiPr)3] underwent enantioselective
addition to aldehydes through catalysis by TADDOLate-
Ti(OiPr)2.34,35 A variety of organotitanium reagents were
prepared from Grignard and organolithium reagents by trans-
metalation with Cl-Ti(OiPr)3 and used successfully after the
strict removal of magnesium and lithium salts.
Although being less apparent, organotitanium reagents have
been described as active organometallic species in catalytic
enantioselective additions using diorganozinc reagents in
combination with titanium tetraisopropoxide (Scheme 2).34b,36
In 1989, Yoshioka, Ohno, and Kobayashi reported a highly
efficient titanium catalyst based on bis(sulfonamide) 1.6 In the
presence of titanium tetraisopropoxide, the catalyst exhibits
excellent enantioselectivity at very low loadings (<2 mol %).
Subsequently, the mixed reagents of dialkylzincs and titanium
tetraisopropoxide have been applied successfully to a TADDOL
(2)-based catalyst by Seebach et al.7 and a BINOL (3a)-based
catalyst by Nakai et al. and by Chan et al.8 Followed by these
reports, many efficient chiral titanium catalysts have been
developed by using the mixed reagents of diorganozinc reagents
and titanium tetraisopropoxide.15c,15d,16d,16e,37 The enhanced
reactivity of the mixed reagents has been utilized especially in
the enantioselective addition to ketones.21a-21g,23c,24
+ Ti(OiPr)4
H
+
Et2Zn
EtZn(OiPr)
EtTi(OiPr)3
+
Ph
Ph
NHSO2Tf
NHSO2Tf
Y
Y
H
H
O
OH
OH
OH
OH
*
O
Ph
Ph
1
2
3a
2 mol %; 98% ee6 20 mol %; 98% ee7 20 mol %; 89% ee8a,b
Ph Ph
Ph
Ph
OH
OH
OH
OH
OH
OH
3b
20 mol %; 98% ee8c
4a
4b
2 mol %; 98% ee47
1 mol %; 94% ee46
Scheme 2.
In the presence of Ti(OiPr)4, organoaluminum38 and organo-
boron reagents39 have also been used in catalytic enantio-
selective additions. Gau and Wu reported the formation
of a bimetallic complex [Ar-Ti(OiPr)3¢Ar2Al(OiPr)] from
Ar3Al¢THF and titanium tetraisopropoxide in the enantiose-
lective arylation of aldehydes catalyzed by a titanium complex
derived from H8-BINOL (3b).38d A recent report from our
laboratory revealed that trialkylboranes can be used in
enantioselective alkylation of aldehydes in the presence of
DPP-BINOL (4a) or DPP-H8-BINOL (4b) (2 mol %) and
excess titanium tetraisopropoxide (3 equiv).39 It is most
probable that the alkyl group attached to a boron atom is first
transferred to a titanium atom and then reacts with aldehydes.
Given their popularity in organic synthesis, Grignard
reagents40 would be one of the most ideal organometallic
reagents for the catalytic enantioselective additions. Preparation
of large numbers of derivatives has been well established.
Some of them are commercially available. Moreover, recent
work by Knochel and co-workers shows that Grignard reagents
can tolerate many functionalities.41 In this regard the use
of Grignard reagents via transmetallation to diorganozinc
and organotitanium reagents (eqs 1 and 2) has significantly
expanded the scope of the catalytic enantioselective addition.
However, concurrent formation of magnesium salts compli-
cates the reaction procedure and impedes the reduction of
catalyst loading, making this approach less attractive for
practical applications.
2RMgX þ ZnX02 ! R2Zn þ 2MgXX0
ð1Þ
RMgX þ Cl-TiðOiPrÞ3 ! R-TiðOiPrÞ3 þ MgXCl ð2Þ
RMgX þ TiðOiPrÞ ! R-TiðOiPrÞ MgX
ð3Þ
4ꢀ
4

Y. Muramatsu et al.
Bull. Chem. Soc. Jpn. Vol. 83, No. 1 (2010)
21
Although not examined previously, Grignard reagents could
be employed in catalytic enantioselective addition by convert-
ing them to organotitanate reagents in situ by treatment with
titanium tetraisopropoxide (eq 3). Organotitanate reagents,
R-Ti(OR)4¢M (M = MgX and Li), have been known for a
long time42 while their precise structures have not been well
proven. The reagents exhibit characteristic reactivity against
carbonyl compounds distinct from Grignard and organotita-
nium reagents,43 and have been utilized in organic synthesis.44
The previous studies suggest strongly that the ate-complex
formation is an irreversible process. The reactivity of Grignard
reagents is anticipated to be reduced in the form of organo-
titanates. In addition, unlike transmetalation (eqs 1 and 2), ate-
complex formation (eq 3) is not accompanied by undesirable
magnesium salt-formation.
configuration of the major enantiomer was R as in the
enantioselective ethylation with Et2Zn.46 In order to suppress
a direct Grignard addition, the reaction procedure was modified
in such a way that the Grignard reagent was previously mixed
with titanium tetraisopropoxide. Thus, the addition of aldehyde
7a to a solution of the Grignard reagent (1.1 equiv), titanium
tetraisopropoxide (1.4 equiv), and ligand 4a (5 mol %) in
toluene at 0 °C afforded 9aa in 50% ee but in low yield (6%).
When 2.8 equiv of titanium tetraisopropoxide was employed
under these conditions, the selectivity and yield were improved
to 71% ee and 17%, respectively.
DPP-BINOL 4a
O
Ti(OiPr)4 (b equiv)
[EtMgCl + Ti(OiPr)4]
+
H
(a equiv)
8a
0 °C
We recently reported that titanium complexes derived from
DPP-BINOL (4a)45 and DPP-H8-BINOL (4b)46 exhibit a
remarkably enhanced catalytic activity in the enantioselective
alkylation of aldehydes with a mixed reagent of diethylzinc and
titanium tetraisopropoxide (Scheme 2). Low catalyst-loadings,
1 mol % of 4a and 2 mol % of 4b, are sufficient to achieve
high enantioselectivity superior to 20 mol % of parent BINOL
(3a)8a,8b and H8-BINOL (3b).8c Owing to a high molar ratio
of titanium tetraisopropoxide against BINOL ligands 4 at
the lower catalyst loadings, BINOLate-Ti(OiPr)2 complex 5
(R = H) might undergo aggregation with titanium tetraisoprop-
oxide to form a non-active 1:2 complex 6, which serves as a
catalyst sink to reduce overall catalyst activity (eq 4). The
enhanced activity of the titanium catalyst derived from 4a and
4b was rationalized by the inhibition of the aggregation to form
6 (R = 3,5-diphenylphenyl) by the aryl group at the 3-position.
Superior activity observed in the presence of excess titanium
tetraisopropoxide prompted us to examine catalysts derived
from 4a and 4b in the reaction employing Grignard reagents.
7a
OH
OH
Ar
+
+
ð5Þ
Ar
OH
OH
9aa
10a; Ar = 1-naphthyl
11
Further improvement in enantioselectivity was obtained by
the addition of a mixture of the Grignard reagent and titanium
tetraisopropoxide (Table 1). Slow addition of a mixture of 8a
(1.1 equiv) and titanium tetraisopropoxide (1.4 equiv) for 2 h to
a solution of 7a, 4a (5 mol %), and titanium tetraisopropoxide
(2.1 equiv) in toluene afforded 9aa in 90% ee (Entry 1). The
yield of 9aa increased by using CH2Cl2 as a solvent (Entry 2)
and with the increased amount of 8a (2.2 equiv) and titanium
tetraisopropoxide (4.4 equiv) (Entry 3). Solvent for the
Grignard reagent was influential. Excellent selectivity (95%
ee) as well as satisfactory yield (62%) was attained by the use
of 8a in Et2O (2 M) (Entry 4). Under these conditions, the
reaction could be carried out at a low catalyst loading (2 mol %)
without lowering the selectivity (Entry 5). On the other hand,
enantioselectivity was moderate (85% ee) when a parent
BINOL (3a) (5 mol %) was used (Entry 6).
R
R
OR'
R'O
R'O OR'
O
Ti
*
*
Ti(OiPr)4
O
O
ð4Þ
R'O Ti
R'O
R'O
O
+
OR'
Ti
Ti OR'
OR'
6; R' = iPr
A titanium reagent generated by treatment of titanium
tetraisopropoxide with excess (2-3 equiv) EtMgBr has been
R'O
OR'
5; R' = iPr
We herein report the full details of our development of a
catalytic enantioselective alkylation and arylation of aldehydes
with mixed titanium reagents derived from Grignard reagents
and titanium tetraisopropoxide. Titanium(IV) complexes of
BINOL derivatives 4a and 4b are demonstrated to catalyze
the reaction with high enantioselectivity at low loadings
(2-4 mol %). Application to the enantioselective preparation
of functionalized diarylmethanols by the employment of
functionalized Grignard reagents is also described.47
Table 1. Catalytic Asymmetric Ethylation of 1-Naphthalde-
hyde (7a) by Using EtMgCl (8a)a)
EtMgCl
Ti(OiPr)4
Entry
Yield/%b) ee/%
equiv Solvent
a
b
1c)
2
3
4
5d)
6e)
1.1
1.1
2.2
2.2
2.2
2.2
THF
THF
THF
Et2O
Et2O
Et2O
1.4
1.4
4.4
4.4
4.4
4.4
2.1
2.1
1.4
1.4
1.4
1.4
23
31
52
62
56
52
90
93
86
95
94
85
Results and Discussion
Examination of Reaction Parameters. We initiated our
investigation with ethylation of 1-naphthaldehyde (7a) by
using a THF (2 M) solution of EtMgCl (8a) (eq 5). When
Grignard reagent 8a (1.1 equiv) was added to a solution of 7a,
(R)-DPP-BINOL (4a) (5 mol %), and titanium tetraisoprop-
oxide (1.4 equiv) in toluene at 0 °C, ethylation product 9aa
was obtained in 52% yield and in 37% ee. The absolute
a) Unless otherwise noted, reactions were carried out by adding
a mixture of 8a and Ti(OiPr)4 (a equiv) in CH2Cl2 to a solution
of 7a, 4a (5 mol %), and Ti(OiPr)4 (b equiv) at 0 °C in CH2Cl2
for 2 h and quenched immediately in Entries 1 and 2 or after
1-h stirring in Entries 3-6. b) Isolated yield. c) The reaction
was carried out in toluene. d) 2 mol % of 4a was used.
e) 5 mol % of 3a was used.

22
Bull. Chem. Soc. Jpn. Vol. 83, No. 1 (2010) BCSJ AWARD ARTICLE
utilized in the reductive cyclopropanation of esters (the
Kulinkovich reaction) (Scheme 3).48,49 Olefin-titanium com-
plex 12 has been assumed to be a cyclopropanation agent.50
Complex 12 is thermally unstable and used at low temper-
atures. Decomposition of 12 produces low-valent (II and/or III)
titanium species. A pinacol coupling reaction induced by a
putative titanium species has been reported in which a
titanium(III) alkoxide might be formed by treatment of titanium
tetraisopropoxide with EtMgBr (1 equiv).51
conditions of Entries 4 and 5. The reductive side reactions were
significantly retarded in butylation of aldehydes employing
BuMgCl (8b). Thus, under the conditions optimized for
ethylation (Entry 5), the reaction of 7a (Ar = 1-naphthyl) with
a mixture of BuMgCl and titanium tetraisopropoxide gave the
butylation product 9ab (96% ee) in 90% yield with minor
formation of 10b (4%) and 11 (1%) (eq 6), indicating that the
mixed titanium reagents are stable enough to be used in the
slow addition procedure.
In the present ethylation reaction with a mixed reagent of
EtMgCl and titanium tetraisopropoxide, pinacol 10a and 1-
naphthylmethanol (11) were formed as major by-products. For
example, in Entry 5, 10a and 11 were formed in 22% and
4% yield, respectively. At ¹78 °C in CH2Cl2 and Et2O, a 1:2
mixture of EtMgCl and titanium tetraisopropoxide was color-
less solution. However, during slow addition in a syringe at
room temperature, it gradually turned black with evolution of a
small amount of gas, possibly ethane and ethylene. In spite of
the partial decomposition of the mixed titanium reagents, the
ethylation product was obtained in satisfactory yield under the
DPP-BINOL 4a
Ti(OiPr)4 (b equiv)
O
[BuMgCl + Ti(OiPr)4]
+
Ar
H
CH2Cl2
(a equiv)
8b
7a; Ar = 1-naphthyl
7b; Ar = Ph
OH
OH
Bu
+
ð6Þ
Ar
OH
10a,b
Ar
Ar
9ab,9bb
We then examined reaction parameters, such as ligands, time
for slow addition, temperature, and the amount of Grignard
reagent and titanium tetraisopropoxide, in the enantioselec-
tive butylation of benzaldehyde (7b) (eq 6, Ar = Ph). Slow
addition of a mixture of Grignard reagent 8b (2.2 equiv) and
titanium tetraisopropoxide (4.4 equiv) in CH2Cl2 for 2 h to a
solution of 7b, 4a (2 mol %), and titanium tetraisopropoxide
(1.4 equiv) in CH2Cl2 at 0 °C followed by additional 1 h stirring
afforded butylation product 9bb in 86% yield and in 93% ee
(Table 2, Entry 1). Under these conditions, DPP-H8-BINOL
4b also exhibited high enantioselectivity comparable to 1a
(Entry 2) whereas only modest selectivity was obtained with a
parent BINOL (3a) (Entry 3). Slow addition of the mixed
EtMgX (3 equiv)
O
Ti(OiPr)4 (1 equiv)
OH
R
OR'
R
-78 to 0 °C
Ti(OiPr)2
Ti(OiPr)2
12
Scheme 3.
Table 2. Catalytic Enantioselective Butylation of Benzaldehyde (7b) by Using BuMgCl (8b)a)
Ti(OiPr)4
9bb
Yield/%c)
10b
Yield/%c)
BuMgCl
/equiv
Time
/hb)
Temp
/°C
Entry
Ligand
a
b
ee/%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17d)
18d)
19d)
20d)
4a
4b
3a
4a
4a
4b
4a
4b
4b
4a
4b
4a
4b
4a
4a
4a
4a
4a
4b
4b
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2
1.5
1.2
2.2
2.2
2.2
2.2
4.4
4.4
4.4
4.4
4.4
4.4
4.4
4.4
4.4
4.4
4.4
4.4
4.4
3
3
2
4.4
4.4
4.4
4.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
0.7
0.7
0.2
0.2
1
1
2
1.4
1.4
1.4
1.4
2
2
2
0.1
3
3
2
2
2
2
2
2
2
2
2
2
2
3
2
3
0
0
0
0
0
86
86
78
71
75
85
75
60
81
85
82
83
87
71
57
65
91
78
86
83
93
92
79
86
95
95
94
91
84
93
94
91
84
89
94
93
95
97
96
97
4
13
7
14
8
8
13
3
8
7
7
5
10
12
1
7
5
3
8
11
0
¹20
¹20
20
0
0
0
0
0
0
0
0
0
0
0
a) Unless otherwise noted, reactions were carried out by adding a mixture of 8b (2 M in Et2O) and Ti(OiPr)4 (a equiv)
in CH2Cl2 to a solution of 7b, 4a (2 mol %), and Ti(OiPr)4 (b equiv) in CH2Cl2. The reaction mixture was stirred
further for 1 h before workup. b) Time for slow addition. c) Isolated yield. d) 4 mol % of ligands were used.

Y. Muramatsu et al.
Bull. Chem. Soc. Jpn. Vol. 83, No. 1 (2010)
23
titanium reagent was necessary to achieve high selectivity
(Entry 4). A longer addition time (3 h) led to a slight increase in
selectivity (95% ee) both for ligand 4a and 4b (Entries 5
and 6). Reactions at 0 °C were optimal. At ¹20 °C, the full
conversion of the aldehyde was not achieved (Entries 7 and 8).
The enantioselectivity decreased at 20 °C (Entry 9). The
amount of titanium tetraisopropoxide (b) used with ligands
4a and 4b could be reduced to 0.2 and 0.7 equiv, respectively,
without significant lowering of the product yield and selectivity
(Entries 10-13). On the other hand, the reduction in the amount
of titanium tetraisopropoxide (a) used with the Grignard
reagent caused decrease both in the selectivity and in the yield
(Entry 14). High enantioselectivity was retained in the reaction
using a reduced amount of the Grignard reagent, despite a
decrease in the yield (Entries 15 and 16). Enantioselectivity
was influenced by the amount of the chiral ligands. Although
2 mol % of 4a and 4b was sufficient to obtain high enantio-
selectivity (92-93% ee; Entries 1 and 2), still higher selectivity
(96-97% ee) could be achieved at a 4 mol %-catalyst loading
(Entries 17-20).
Reaction conditions established for the catalytic enantiose-
lective alkylation were then applied to arylation by using
PhMgBr (12a) (eq 7). Slow addition of a mixture of PhMgBr
(12a) (3 M in Et2O, 2.2 equiv) and titanium tetraisopropoxide
(4.4 equiv) in CH2Cl2 for 2 h to a solution of aldehyde 7a,
ligand 4a (2 mol %), and titanium tetraisopropoxide (1.4 equiv)
in CH2Cl2 at 0 °C followed by 1 h of additional stirring
afforded phenylation product 13aa in 86% ee and in high
yield (Table 3, Entry 1). The mixed titanium reagent derived
from 12a was stable and not accompanied by reductive side
reactions. Again, the use of PhMgCl in THF (3 M) resulted
in lower enantioselectivity (Entry 2). In butylation, DPP-H8-
BINOL (4b) exhibited enantioselectivity comparable to 4a
(Table 2). In contrast, the use of 4b in the phenylation
significantly improved the selectivity, affording 13aa in 94%
ee and in quantitative yield (Entry 3). Both BINOL (3a) and
H8-BINOL (3b) exhibited only moderate enantioselectivities
(Entries 4 and 5). Further optimization of the reaction
parameters revealed that the phenyl transfer could be carried
out with a small excess of the Grignard reagent (1.2 equiv) in
combination with a total 3 equiv (a = 2, b = 1) of titanium
tetraisopropoxide keeping high yield (97%) and selectivity
(95% ee) (Entry 7). Under these conditions, addition time
could be shortened to 0.5 h (Entry 8). Enantioselectivity was
decreased by further decrease in the amount of titanium
tetraisopropoxide (Entries 10 and 11).
7a
+
OH
ligand (2 mol %)
ð7Þ
[PhMgBr + Ti(OiPr)4]
Ti(OiPr)4 (b equiv)
CH2Cl2, 0 °C, 3 h
(a equiv)
12a
13aa
Scope and Limitations.
The catalytic enantioselective
alkylation was carried out for a variety of aldehydes and alkyl
Grignard reagents to clarify the scope and limitations (eq 8,
Table 4). Even with 2 mol % of 4a (method I), the reaction of
aromatic aldehydes with a mixed reagent of BuMgCl (2.2
equiv) and titanium tetraisopropoxide (4.4 equiv) afforded the
corresponding butylation products 9 in high yields (60-92%)
and in high enantioselectivities (91-96% ee) (Entries 3, 8, 15,
17, 20, 23, and 24). Superior selectivities (96-98% ee) could be
realized by employing 4 mol % of 4b (method II) (Entries 4, 10,
16, 18, and 21) and 4a (method III) (Entry 11). The reaction
is applicable to a range of benzaldehyde derivatives 7b-7f,
either with an electron-donating or -withdrawing substituent
at the para, meta, and ortho position, as well as to 1- and
2-naphthaldehyde 7a and 7g.
Method I; 4a (2 mol %)
Method II; 4b (4 mol %)
R2MgX; 8a-d
Method III; 4a (4 mol %)
O
OH
R2
(2.2 equiv)
+
Ti(OiPr)4 (1.4 equiv)
+
R1
H
R1
Table 3. Catalytic
Enantioselective
Phenylation
of
Ti(OiPr)4
(4.4 equiv)
ð8Þ
1-Naphthaldehyde (7a) by Using PhMgBr (12a)a)
CH2Cl2, 0 °C, 3 h
7
9
Ti(OiPr)4
PhMgBr
/equiv
Entry Ligand
Yield/%b) ee/%
The reactions of aromatic aldehydes 7a-7f with a mixed
a
b
reagent of EtMgCl (8a) and titanium tetraisopropoxide were
also enantioselective while the yields of the ethylation products
9 were moderate owing to the instability of the reagent (Entries
1, 2, 6, 7, 14, 19, and 22). Not only chloromagnesium reagent
8a but also bromomagnesium reagent 8a¤ could be employed
with comparable efficiency and selectivity (Entry 2 vs.
Entry 1). Enantioselectivities of ethylation by method I were
slightly lower than butylation. However, excellent selectivity
was obtained by applying method II (Entry 7). A mixed reagent
of PrMgCl (8d) and titanium tetraisopropoxide was stable
enough to be used in propylation, affording the corresponding
product 9bd in high yield and in high selectivity (Entries 12
and 13). A mixed titanium reagent derived from MeMgCl (8c)
was also stable, undergoing smooth addition to aldehyde 7a,
but exhibited only low enantioselectivity (Entry 5). Mixed
1
4a
4a
4b
3a
3b
4b
4b
4b
4b
4b
4b
2.2
2.2
2.2
2.2
2.2
1.2
1.2
1.2
1.2
1.2
1.2
4.4
4.4
4.4
4.4
4.4
2
2
2
2
2
1.4
1.4
1.4
1.4
1.4
2
1
1
1
0.2
0.2
94
96
98
99
99
98
97
94
97
99
90
86
73
94
73
81
92
95
95
78
91
87
2c)
3
4
5
6
7
8d)
9e)
10
11
1.5
a) Unless otherwise noted, reactions were carried out by slowly
adding a mixture of 12a (3 M in Et2O) and Ti(OiPr)4 (a equiv)
in CH2Cl2 for 2 h to a solution of 7a, ligand (2 mol %), and
Ti(OiPr)4 (b equiv) in CH2Cl2. The reaction mixture was stirred
further for 1 h before workup. b) Isolated yield. c) PhMgCl
(3 M in THF) was used. d) The mixed titanium reagent was
added for 0.5 h. e) The mixed titanium reagent was added at
once.
i
t
titanium reagents derived from PrMgCl, and BuMgCl were
very unstable at room temperature. Their reaction with 7b
resulted in the recovery of the aldehyde without the formation
of the corresponding alkylation products.

24
Bull. Chem. Soc. Jpn. Vol. 83, No. 1 (2010) BCSJ AWARD ARTICLE
Table 4. Catalytic Enantioselective Alkylation of Aldehydes by Using Alkyl Grignard Reagentsa)
Grignard
reagent
Yield
/%b)
ee
/%
Yield
/%b)
Entry
Aldehyde
Method
Product
By-product
1
2
3
4
5
EtMgCl (8a)
EtMgBr (8a¤)
BuMgCl (8b)
BuMgCl (8b)
MeMgCl (8c)
I
I
I
II
I
9aa; R = Et
9aa; R = Et
9ab; R = Bu
9ab; R = Bu
9ac; R = Me
56
63
90
83
89
94
93
96
98
28
10a
10a
10a
10a
10a
22
22
5
5
0
O
OH
H
R
7a
6
7
8
9c)
10
11
12
13
EtMgCl (8a)
EtMgCl (8a)
BuMgCl (8b)
BuMgCl (8b)
BuMgCl (8b)
BuMgCl (8b)
PrMgCl (8d)
PrMgCl (8d)
I
II
I
9ba; R = Et
9ba; R = Et
9bb; R = Bu
9bb; R = Bu
9bb; R = Bu
9bb; R = Bu
9bd; R = Pr
9bd; R = Pr
57
38
86
94
78
83
82
78
90
97
93
92
97
97
94
95
10b
10b
10b
10b
10b
10b
10b
10b
31
54
4
7
3
4
10
9
O
H
OH
R
7b
I
II
III
I
II
14
15
16
EtMgCl (8a)
BuMgCl (8b)
BuMgCl (8b)
I
I
II
9ca; R = Et
9cb; R = Bu
9cb; R = Bu
41
82
70
88
95
96
10c
10c
10c
44
9
8
O
O
OH
H
R
7c
Me
Me
17
18
BuMgCl (8b)
BuMgCl (8b)
I
II
9db
62
89
95
96
10d
10d
6
6
OH
Bu
H
7d
CF3
CF3
19
20
21
EtMgCl (8a)
BuMgCl (8b)
BuMgCl (8b)
I
I
II
9ea; R = Et
9eb; R = Bu
9eb; R = Bu
40
86
89
95
95
98
10e
10e
10e
26
6
9
O
OH
MeO
MeO
H
R
7e
22
23
EtMgCl (8a)
BuMgCl (8b)
I
I
9fa; R = Et
9fb; R = Bu
46
79
80
94
10f
10f
32
9
Cl
O
Cl
OH
H
O
R
7f
d)
24
BuMgCl (8b)
I
9gb
92
91
®
OH
H
Bu
7g
d)
25
26
27
BuMgCl (8b)
BuMgCl (8b)
BuMgCl (8b)
I
II
III
9hb
9hb
9hb
60
76
76
91
96
96
®
®
O
OH
Bu
d)
H
d)
®
7h
d)
28
29
30
BuMgCl (8b)
BuMgCl (8b)
BuMgCl (8b)
I
II
III
9ib
9ib
9ib
49
39
39
84
95
93
®
®
O
OH
d)
H
O
d)
Bu
®
7i
31
BuMgCl (8b)
I
9jb
36
92
10j
23
OH
H
Bu
7j
a) Unless otherwise noted, reactions were carried out by slowly adding a mixture of Grignard reagent 8a-8d (2.2 equiv) and Ti(OiPr)4
(4.4 equiv) in CH2Cl2 for 2 h to a solution of aldehyde 7 (1 mmol), ligand (2-4 mol %), and Ti(OiPr)4 (1.4 equiv) in CH2Cl2 at 0 °C.
The reaction mixture was stirred further for 1 h before workup. b) Isolated yield. c) The reaction was carried out on a 10 mmol-scale.
d) Not determined.
Catalytic enantioselective alkylation of ¡,¢-unsaturated
aldehydes 7h and 7i also proceeded in an efficient manner to
give allylic alcohols 9hb and 9ib with high enantioselectivity
(Entries 25-30).52 Enantioselectivity in the range of 93-95%
could be achieved by using 4 mol % of 4a and 4b (method II
or III). Aliphatic aldehyde 7j was less reactive in comparison

Y. Muramatsu et al.
Bull. Chem. Soc. Jpn. Vol. 83, No. 1 (2010)
25
Table 5. Catalytic Enantioselective Arylation of Aldehydes by Using Aryl Grignard Reagentsa)
Yield ee
/%b) /%
Entry
Aldehyde
Grignard reagent
Product
1
2
3
4
5
6
7b
p-MeC6H4MgBr (12b)
p-ClC6H4MgBr (12c)
p-FC6H4MgBr (12d)
o-MeOC6H4MgBr (12e)
2,4,6-Me3C6H2MgBr (12f)
2-ThienylMgBr (12g)
13bb; Ar = p-MeC6H4
13bc; Ar = p-ClC6H4
13bd; Ar = p-FC6H4
13be; Ar = o-MeOC6H4
13bf; Ar = 2,4,6-Me3C6H2
13bg; Ar = 2-thienyl
99
95
94
66
89
98
91
91
97
9
96
65
O
OH
H
Ar
7
8
9
10
11
12
13
7c; R = p-Me
7k; R = p-Cl
7l; R = p-F
7m; R = p-Ph PhMgBr (12a)
7n; R = p-CN PhMgBr (12a)
7e; R = m-MeO PhMgBr (12a)
PhMgBr (12a)
PhMgBr (12a)
PhMgBr (12a)
ent-13bb; R = p-Me
ent-13bc; R = p-Cl
ent-13bd; R = p-F
13ma; R = p-Ph
13na; R = p-CN
13ea; R = m-MeO
13fa; R = o-Cl
93
96
97
99
96
90
94
90
94
95
91
92
95
90
O
OH
Ph
H
R
R
7f; R = o-Cl
PhMgBr (12a)
14
7g
PhMgBr (12a)
13ga
96
91
O
O
OH
Ph
H
H
15
16
17c)
7a
PhMgBr (12a)
PhLi
PhLi
13aa
13aa
13aa
97
95
85
95
50
95
OH
Ph
18
19
7o; Y = O
7p; Y = S
PhMgBr (12a)
PhMgBr (12a)
13oa; Y = O
ent-13bg; Y = S
83
85
89
90
O
O
OH
Ph
Y
Y
H
H
20
7q
PhMgBr (12a)
13qa
82
82
OH
Ph
N
N
21
22
7i; R1 = Me,
R2 = H
PhMgBr (12a)
PhMgBr (12a)
13ia; R1 = Me,
R2 = H
87
78
97
86
O
OH
Ph
R2
H
R2
7r; R1 = H,
R2 = Me
13ra; R1 = H,
R2 = Me
R1
O
R1
22
23
7s
PhMgBr (12a)
PhMgBr (12a)
ent-9bb
88
86
88
80
OH
Bu
H
O
Bu
Ph
7t
13ta
OH
Ph
H
a) Unless otherwise noted, reactions were carried out by slowly adding a mixture of Grignard reagents 12 (1.2 equiv) (1.6-3 M in Et2O)
and Ti(OiPr)4 (2 equiv) in CH2Cl2 for 2 h to a solution of aldehyde 7 (1 mmol), 4b (2 mol %), and Ti(OiPr)4 (1 equiv) in CH2Cl2. The
reaction mixture was stirred further for 1 h before workup. b) Isolated yield. c) PhLi (1.2 equiv) was used after treatment with MgBr2
(1.2 equiv) in Et2O.
with aromatic and ¡,¢-unsaturated aldehydes, affording the
butylation product 9jb in low yield but with high selectivity
(Entry 31).
The catalytic alkylation reactions were carried out on a
1 mmol-scale by using a syringe pump for slow addition.
To demonstrate the preparative utility, the enantioselective
butylation of 7b was carried out on a 10 mmol-scale (Entry 9).
Slow addition of a mixed reagent of BuMgCl and titanium
tetraisopropoxide with a dropping funnel and Kugelrohr
distillation of the crude product gave 9bb (1.62 g, 94% yield)
in 92% ee. Ligand 4a was recovered quantitatively by flash
chromatography of the residue.
To investigate the scope and limitations of enantioselective
arylation, reactions were carried out for a variety of aldehydes
with mixed reagents derived from aryl Grignard reagents 12a-
12g (1.2 equiv) and titanium tetraisopropoxide (2 equiv) by
using ligand 4b (2 mol %) (eq 9). These results are summarized
in Table 5. High enantioselectivities (91-97% ee) and high
yields (89-99%) were obtained in the reaction of benzaldehyde
with substituted phenyl Grignard reagents 12b-12f except for

26
Bull. Chem. Soc. Jpn. Vol. 83, No. 1 (2010) BCSJ AWARD ARTICLE
o-methoxy derivative 12e (Entries 1-5). Addition of a sterically
hindered 2,4,6-trimethylphenyl group proceeded efficiently to
give diarylmethanol 13bf in 96% ee (Entry 5). Enantioselec-
tivity was moderate for the reaction with 2-thienyl Grignard
reagent 12g (Entry 6).
THF) at ¹40 °C (eq 10). The resulting Grignard reagent was
mixed with titanium tetraisopropoxide and used in the reaction
with 1-naphthaldehyde. The reaction gave diarylmethanol 16aa
in high yield but with low enantioselectivity (Table 6, Entry 2).
Since the use of a Grignard reagent in THF resulted in reduced
enantioselectivity in comparison with that in Et2O (Entries 1-3
in Table 1 and Entry 2 in Table 3), the preparation of 15a in
Et2O was then examined. At ¹20 °C in Et2O, iPrMgCl (2 M in
Et2O) underwent iodine-magnesium exchange reaction of 14a
rapidly within 1 h, judging from the exclusive formation of
benzonitrile after hydrolysis. However, treatment of the same
reaction mixture with I2 gave 14a contaminated by benzo-
nitrile, which was produced by in situ protonation of 15a most
probably by concurrently produced 2-iodopropane. To suppress
undesirable protonation, c-C5H9MgCl (2 M in Et2O) was used
for the iodine-magnesium exchange because iodocyclopentane
is less reactive toward Grignard reagents than 2-iodopropane.57
In accord with our anticipation, treatment of 14a with
c-C5H9MgCl at ¹20 °C for 0.5 h followed by treatment with
titanium tetraisopropoxide and subsequent use in the enantio-
selective arylation of 7a gave 16aa in 95% ee and in 91% yield
(Entry 1).
ArMgX; 12a-f
(1.2 equiv)
+
4b (2 mol %)
Ti(OiPr)4 (1 equiv)
O
OH
Ar
ð9Þ
+
R1
H
R1
Ti(OiPr)4
(2 equiv)
CH2Cl2, 0 °C, 3 h
7
13
As demonstrated in Entries 7-15, a variety of aromatic
aldehydes underwent phenylation with a mixed reagent derived
from PhMgBr in a highly efficient manner (90-97% ee, >90%
yield). Each enantiomer of diarylmethanols (13bb-13bd or ent-
13bb-13bd) could be prepared with the same ligand (R)-4b
by a proper combination of aldehydes and Grignard reagents
(Entries 1-3 vs. Entries 7-9). Slightly lower, but still accept-
able, selectivities (82-85% ee) were obtained for heteroaro-
matic aldehydes 7o-7q (Entries 18-20). Not only diaryl-
methanols, but also secondary allylic alcohols 13ia and
13ra and benzylic alcohols ent-9bb and 13ta could be
prepared enantioselectively (78-88% ee) in high yields by
the reaction of ¡,¢-unsaturated aldehydes 7i and 7r (Entries 21
and 22) and aliphatic aldehydes 7s and 7t (Entries 23 and 24),
respectively.
I
FG
FG
ClMg
RMgCl
14a-d
15a-d
Although the use of PhLi, instead of PhMgBr, resulted
in a significant reduction in enantioselectivity (Entry 16), the
organolithium reagent could be employed after conversion
into PhMgBr by treatment with MgBr2 (Entry 17). It should
be noted that the reaction was carried out without removing
concomitantly produced LiBr, simply by mixing PhLi (1.2
equiv) with MgBr2 (1.2 equiv) and titanium tetraisopropoxide
(2 equiv), to give 13aa in excellent enantioselectivity.
Catalytic Enantioselective Arylation Using Functional-
ized Grignard Reagents. Recently, considerable attention
has been focused on catalytic methods that allow enantio-
selective transfer of functionalized aryl groups to aromatic
aldehydes13,27,33,38d-38i,53 because the resulting highly function-
alized diarylmethanols are very much in demand as precursors
to many biologically active compounds.54 Arylboronic acids
and their derivatives are most often employed as precursors
to functionalized organozinc reagents in previous methods.
Although many functionalized boronic acids are commercially
available, their preparation requires several reaction steps,
generally involving borylation of organolithium or Grignard
precursors.55,56 Therefore, these methods have a problem with
overall atom economy for practical application. Recently,
Knochel and co-workers have demonstrated that thermally
unstable functionalized Grignard reagents can be prepared at
low temperatures by halogen-magnesium exchange of the
corresponding haloarenes.41 To develop a practical method for
the enantioselective synthesis of highly functionalized diaryl-
methanols, we examined the use of functionalized Grignard
reagents in the present catalytic enantioselective arylation
reaction.
1) Ti(OiPr)4 ,CH2Cl2
OH
ð10Þ
FG
2) 7a, 4b (2 mol%),
Ti(OiPr)4 (1 equiv)
CH2Cl2, 0 °C, 3 h
16
Aryl Grignard reagents 15b-15d bearing bromine, piperi-
dine-1-carbonyl, and t-butoxycarbonyl groups at the meta
position were prepared in Et2O by treatment of functionalized
iodoarenes 14b-14d with c-C5H9MgCl. The enantioselective
arylation of 7a using 15b-15d gave corresponding diaryl-
methanols 16 in high enantioselectivity (Entries 3-5).
There are some limitations to iodine-magnesium exchange
in Et2O. Since the reaction proceeded more slowly in Et2O than
in THF, reaction conditions, such as temperature, time, and the
amount of iodoarenes and c-C5H9MgCl, had to be carefully
optimized beforehand for each functional group. The prepara-
tion of m-(ethoxycarbonyl)phenylmagnesium chloride (15e) in
Et2O was unsuccessful because of the preferential attack of
c-C5H9MgCl to the carbonyl group. The exchange reaction was
hampered by low solubility of p-iodobenzonitrile (14f) in Et2O.
To overcome such limitations, we turned out our attention
again to functionalized Grignard reagents prepared in THF.
Grignard reagent 15f was prepared from 14f (1.5 equiv) in
THF and mixed with titanium tetraisopropoxide (2.5 equiv) in
CH2Cl2 at ¹78 °C (eq 11). Direct use of the resulting mixed
titanium reagent in the enantioselective arylation of benz-
aldehyde (7b) afforded diarylmethanol ent-13na in 55% ee
(Table 7, Entry 1). However, when it was used after the
removal of THF in vacuo followed by dissolution in CH2Cl2,
enantioselectivity was improved to 82% ee (Entry 2). Further
improvement was obtained by the use of the mixed titanium
According to the reported protocol,41b a THF solution of
m-cyanophenylmagnesium chloride (15a) was prepared by
i
treatment of m-iodobenzonitrile (14a) with PrMgCl (2 M in

Y. Muramatsu et al.
Bull. Chem. Soc. Jpn. Vol. 83, No. 1 (2010)
27
Table 6. Catalytic Enantioselective Arylation of Aldehydes by Using Functionalized Grignard Reagents Prepared in Et2Oa)
Entry
Iodoarene
equivb) Temp/°Cc) Time/hc)
Product
Yield/%d) ee/%
1
1.5
1.5
¹20
¹20
0.5
0.5
16aa
16aa
91
82
95
61
I
I
CN
OH
2e)
CN
Br
14a
3
4
2.0
1.5
0
0
2
1
16ab
16ac
85
73
92
92
Br
OH
14b
O
O
OH
O
I
I
N
N
O
14c
5f)
2.0
¹20
2
16ad
43
96
OH
OtBu
OtBu
14d
a) Unless otherwise noted, functionalized Grignard reagents 15 were prepared by treatment of iodoarenes 14 with
c-C5H9MgCl (2 M in Et2O) (1.1 equiv with respect to 14) in Et2O. A mixture 15 and Ti(OiPr)4 (1.7 equiv with respect to
14) in CH2Cl2 was slowly added for 2 h to a solution of 7a (1 mmol), 4b (2 mol %), and Ti(OiPr)4 (1 equiv) in CH2Cl2 at
0 °C. The reaction mixture was stirred further for 1 h before workup. b) Equivalent of 14. c) Conditions for the
i
preparation of 15. d) Isolated yield. e) The Grignard reagent was prepared in THF by using PrMgCl (2 M in THF).
f) Benzonitrile (4 equiv) was added in the preparation of the Grignard reagent.
Table 7. Catalytic Enantioselective Arylation of Aldehydes by Using Functionalized Grignard Reagents Prepared in THFa)
Entry
Iodoarene
Aldehyde
Product
Yield/%b)
ee/%
1c)
2d)
3e)
4
7b
7b
7b
7b
ent-13na
ent-13na
ent-13na
ent-13na
65
80
86
86
55
82
88
92
OH
I
I
CN
14f
CN
5
6
7
7a
7b
7a
16aa
16ba
16ae
90
96
97
93
87
95
CN
OH
OH
CN
14a
CN
O
O
OH
I
OEt
OEt
14e
8
9
7b
7n
16be
16ne
94
95
89
86
OH
OH
O
O
OEt
OEt
NC
a) Unless otherwise noted, reactions were carried out under conditions shown in eq 11. b) Isolated yield. c) The mixed
titanium reagent was used without removing THF in vacuo. d) The mixed titanium reagent was used after the removal of
THF in vacuo and dissolution in CH2Cl2. e) The mixed titanium reagent was used after the removal of THF in vacuo and
dissolution in CH2Cl2 and Et2O.

28
Bull. Chem. Soc. Jpn. Vol. 83, No. 1 (2010) BCSJ AWARD ARTICLE
reagent dissolved in CH2Cl2 and Et2O (Entry 3). Finally,
replacement of Ti(OiPr)4, partially lost in evacuation of THF,
afforded optimal selectivity of 92% ee as well as high product
yield (Entry 4).
with the observation that the enantioselectivity was not
sensitive to the amount of titanium tetraisopropoxide used
with chiral ligands 4a and 4b (Entries 10-12 in Table 2 and
Entry 10 in Table 3). It is more probable that a titanate
aggregate [R-Ti2(OiPr)8¢MgX] is the active species of the
present catalytic enantioselective reaction.
Conclusion
We have developed a highly efficient and practical method
for the catalytic enantioselective alkylation and arylation of
aldehydes by using Grignard reagents in combination with
Ti(OiPr)4. Titanium complexes derived from DPP-BINOL (4a)
and DPP-H8-BINOL (4b) are demonstrated to be excellent
catalysts for this transformation, providing secondary alcohol
products in high enantioselectivity at low catalyst loading (2-
4 mol %). Both Grignard reagents and aldehydes can be broadly
altered, permitting access to a wide range of enantiomerically
enriched secondary alcohols. The scope of the reaction has
been extended to include the enantioselective additions of
functionalized aryl Grignard reagents. The preparative utility of
the present method has been shown by the fact that the reaction
is operationally simple, can be carried out on a 10-mmol scale
without any difficulty, and the ligands can be readily recovered.
In spite of their popularity in catalytic enantioselective
addition, the use of diorganozinc reagents has several problems
critical to practical applications, such as a structural limitation
in available reagents and a complicated operation for their
in situ preparation. The successful use of Grignard reagents
provides a solution to these problems. Also noteworthy is the
high atom efficiency of the method especially in the aryl
transfer, in which aryl Grignard reagents in small excess (1.2-
1.5 equiv) are employed. Although titanium tetraisopropoxide
is required in excess, its low cost and benign nature of the by-
product (TiO2) make the present method attractive for prepar-
ative use.43a,43b Finally, the present study has demonstrated that
the highly reactive Grignard reagents can be tamed for the
catalytic enantioselective addition simply by mixing with
ca. 2 equiv of titanium tetraisopropoxide in the form of
organotitanates, in which even a labile carbonyl functionality is
well tolerated. The modified reactivity of the organotitanate
reagents could be exploited in other catalytic enantioselective
processes.
ð11Þ
Under these conditions, enantioselective transfer of the
m-cyanophenyl group also proceeded in an efficient manner
(Entries 5 and 6), exhibiting high enantioselectivity comparable
to that obtained by the previous method (Table 6, Entry 1). It
should be noted that Grignard reagent 15e bearing a labile
ethoxycarbonyl group could be used. The corresponding
functionalized diarylmethanols 16 were obtained in high
enantioselectivities (86-95% ee) (Entries 7-9).
Background Reaction and Plausible Active Titanium
Species. Diorganozinc reagents generally exhibit only low
reactivity toward aldehydes in the absence of catalysts.5 In
contrast, mixed titanium reagents employed in the present
catalytic enantioselective addition were found to undergo
addition to aldehydes without catalysis. Thus, when the
reaction of 7a with a mixed reagent of PhMgCl and titanium
tetraisopropoxide was carried out in the absence of ligand 4b
under otherwise identical conditions as in Entry 7 of Table 3,
racemic product rac-9aa was obtained in 76% yield and 7a
was recovered in 22%. Given the high enantioselectivity
(95% ee) observed in the presence of only 2 mol % of 4b, the
rate of noncatalytic background reaction is surprisingly fast.
Even so, the catalytic reaction proceeds overwhelmingly faster
as a result of extremely strong ligand acceleration.
Significant decrease in enantioselectivity (78% ee) was
observed when the reaction was carried out without applying
the slow addition procedure (Entry 9 in Table 3). Under these
conditions, the background reaction competed well with the
catalytic reaction, degrading the selectivity. Although the
catalytic cycle of the present enantioselective addition has not
yet been clarified, the result implies that a catalyst-turnover
step might be rate determining. By the addition of the mixed
titanium reagents slowly, at least for 0.5 h (Entry 8 in Table 3),
active catalyst is kept at sufficient concentration to exhibit high
enantioselectivity.
To obtain high enantioselectivity, it was necessary to employ
a ca. 1:2 mixture of Grignard reagents and titanium tetraiso-
propoxide. The enantioselectivity decreased with a decrease in
the amount of titanium tetraisopropoxide mixed with Grignard
reagents (Entry 14 in Table 2 and Entry 11 in Table 3). If we
assume that a titanate [R-Ti(OiPr)4¢MgX] is an active organo-
titanium species, the extra amount of titanium tetraisoprop-
oxide would be necessary to facilitate the rate-determining
catalyst turnover step. However, the possibility is not consistent
Experimental
General. Dichloromethane was dried and distilled over CaH2.
Et2O was distilled from sodium benzophenone ketyl. Aldehydes
and titanium tetraisopropoxide were used after distillation.
Ligand 4a was prepared according to a reported procedure.45
The following Grignard reagents were purchased from Aldrich and
used without titration; BuMgCl (2 M in Et2O), PrMgCl (2 M in
Et2O), EtMgCl (2 M in Et2O and 1.6 M in THF), EtMgBr (3 M in
Et2O), MeMgCl (3 M in THF), PhMgBr (3 M in Et2O), PhMgCl
(3 M in THF), p-MeC6H4MgBr (0.5 M in Et2O), p-ClC6H4MgBr
(1 M in Et2O), p-FC6H4MgBr (2 M in Et2O), o-MeOC6H4MgBr
i
(1 M in Et2O), 2,4,6-Me3C6H2MgBr (1 M in Et2O), PrMgCl (2 M
in Et2O and 2 M in THF), and c-C5H9MgCl (2.0 M in Et2O). PhLi
(0.98 M in cyclohexane and Et2O) was obtained from Kanto
Chemicals Co., Ltd. and used without titration. 2-Thienylmagne-
sium bromide was prepared in Et2O (0.8 M) from 2-bromothio-
phene and Mg.

Y. Muramatsu et al.
Bull. Chem. Soc. Jpn. Vol. 83, No. 1 (2010)
29
(R)-3-Bromo-2,2¤-dimethoxy-5,5¤,6,6¤,7,7¤,8,8¤-octahydro-1,1¤-
(R)-1-Phenylpentan-1-ol (9bb). Typical Procedure for
binaphthyl.
Bromine (0.19 M in dichloromethane, 9.8 mL,
Asymmetric Alkylation with a Grignard Reagent: Method I
(Table 4, Entries 8 and 9); To a solution of titanium tetra-
isopropoxide (1.30 mL, 4.4 mmol) in dry CH2Cl2 (16 mL) at
¹78 °C under argon atmosphere was added BuMgCl (2 M in
Et2O) (1.10 mL, 2.2 mmol). 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 CH2Cl2 (4 mL) solution of
4a (10.3 mg, 0.020 mmol), benzaldehyde (0.106 g, 1.0 mmol), and
titanium tetraisopropoxide (0.41 mL, 1.4 mmol) at 0 °C under
argon atmosphere. After being stirred further for 1 h, the reaction
mixture was quenched by the addition of aqueous 1 M HCl and
extracted three times with Et2O. The organic layers were washed
successively with aqueous 5% NaHCO3 and with brine, dried
(MgSO4), and concentrated in vacuo. Kugelrohr distillation
(150 °C/5 mmHg) gave 0.141 g (86% yield) of 9bb9a (93% ee).
Flash chromatography (silica gel, 10-50% ethyl acetate in hexane)
of the residue gave 6.1 mg (59% recovery) of 4a and 4.2 mg (4%
yield) of 1,2-diphenylethane-1,2-diol (10b)60 (meso:dl = 1.3:1).
The ee value of 9bb was determined by HPLC analysis using
a Chiralcel OD column (1.0 mL min¹1, 2% i-PrOH in hexane);
retention times: 11.8 min (major R enantiomer) and 14.7 min
(minor S enantiomer). The absolute structure of the product was
determined based on the reported retention times.61
1.86 mmol) was added to a solution of (R)-2,2¤-dimethoxy-
5,5¤,6,6¤,7,7¤,8,8¤-octahydro-1,1¤-binaphthyl58 (0.600 g, 1.86 mmol)
in dichloromethane (28 mL) at 0 °C. After being stirred for 5 min,
the red solution was poured into a 5% solution of NaHSO3,
and the mixture was extracted three times with dichloromethane.
The combined organic layers were dried (MgSO4) and concen-
trated in vacuo. The residue was purified by flash chromatography
on silica gel (1% ethyl acetate and 25% toluene in hexane) to
give 0.496 g (66% yield) of the bromide as an amorphous solid:
1H NMR (500 MHz, CDCl3): ¤ 1.58-1.73 (8H, m), 1.98-2.04 (2H,
m), 2.22 (1H, m), 2.35 (1H, m), 2.71-2.83 (4H, m), 3.46 (3H, s),
3.71 (3H, s), 6.76 (1H, d, J = 8.4 Hz), 7.08 (1H, d, J = 8.4 Hz),
7.29 (1H, s); 13C NMR (125.8 MHz, CDCl3): ¤ 22.7, 22.8, 23.0,
23.1, 26.8, 27.2, 29.3, 29.4, 107.8, 113.8, 124.8, 129.1, 129.7,
132.4, 132.7, 134.6, 136.6, 136.7, 151.9, 154.3; HRMS (EI) calcd
for C22H2579BrO2: 400.1038, found: 400.1042.
(R)-3-(3,5-Diphenylphenyl)-2,2¤-dimethoxy-5,5¤,6,6¤,7,7¤,8,8¤-
octahydro-1,1¤-binaphthyl. A mixture of bromide (R)-3-bromo-
2,2¤-dimethoxy-5,5¤,6,6¤,7,7¤,8,8¤-octahydro-1,1¤-binaphthyl (0.340
g, 0.847 mmol), (3,5-diphenyl)phenylboronic acid (0.256 g, 0.934
mmol),59 Pd(PPh3)4 (49 mg, 0.042 mmol), and Ba(OH)2¢8H2O
(0.294 g, 0.932 mmol) in water (2.17 mL) and 1,4-dioxane (6.23
mL) was heated under reflux for 18 h under argon atmosphere. The
reaction mixture was poured into water and extracted twice with
ethyl acetate. The combined organic layers were dried (Na2SO4)
and concentrated in vacuo. The residue was purified by flash
column chromatography (0.5% ethyl acetate and 25% toluene in
hexane) to give 0.433 g (93% yield) of the 3,5-diphenylphenyl
The above reaction was carried out on a 10.5 mmol-scale by
following the same procedure except that a dropping funnel was
used for the slow addition over 2 h. Kugelrohr distillation (120-
150 °C/5 mmHg) of the crude products gave 1.62 g (94% yield) of
25
(R)-9bb (92% ee) (½¡ꢁD +35.4 (c 3.03, C6H6)). Flash chromatog-
raphy (silica gel, 10-50% ethyl acetate in hexane) of the residue
gave 101.2 mg (98% recovery) of 4a and 76.2 mg (7% yield) of
10b (meso:dl = 1.4:1).
1
derivative as an amorphous solid: H NMR (500 MHz, CDCl3): ¤
1.64-1.86 (8H, m), 2.12-2.22 (2H, m), 2.36 (1H, m), 2.47 (1H, m),
2.78-2.94 (4H, m), 3.27 (3H, s), 3.76 (3H, s), 6.81 (1H, d, J = 8.4
Hz), 7.10 (1H, d, J = 8.4 Hz), 7.24 (1H, s), 7.38 (2H, t, J = 7.4
Hz), 7.48 (4H, t, J = 7.5 Hz), 7.72 (4H, dd, J = 1.0 and 8.0 Hz),
7.78 (1H, t, J = 1.7 Hz), 7.86 (2H, d, J = 1.7 Hz); 13C NMR (126
MHz, CDCl3): 23.05, 23.10, 23.15, 23.22, 27.0, 27.4, 29.4, 29.6,
55.3, 60.4, 107.9, 124.5, 125.8, 127.0, 127.28, 127.32, 128.73,
128.76, 129.6, 130.7, 131.4, 131.6, 132.8, 136.65, 136.68, 140.2,
141.4, 141.5, 152.9, 154.5; HRMS (EI) calcd for C40H38O2:
550.2872, found: 550.2864.
(R)-3-(3,5-Diphenylphenyl)-2,2¤-dihydroxy-5,5¤,6,6¤,7,7¤,8,8¤-
octahydro-1,1¤-binaphthyl (4b). To a solution of (R)-3-(3,5-
diphenylphenyl)-2,2¤-dimethoxy-5,5¤,6,6¤,7,7¤,8,8¤-octahydro-1,1¤-
binaphthyl (450 mg, 0.817 mmol) in dichloromethane (5.5 mL) at
¹10 °C under argon atmosphere was added boron tribromide
(0.77 mL, 8.17 mmol). The solution was stirred at this temperature
for 2 h. The reaction mixture was poured into water, and extracted
twice with ethyl acetate. The combined organic layers were dried
(Na2SO4) and concentrated in vacuo. The residue was purified by
flash chromatography on silica gel (20% ethyl acetate in hexane) to
Methods II and III (Entries 10 and 11); Reactions were
carried out by a procedure similar to Method I except that 4 mol %
of 4b and 4a were used in Methods II and III, respectively.
(R)-Naphthalen-1-ylphenylmethanol (13aa). Typical Pro-
cedure for Asymmetric Arylation with a Grignard Reagent
(Table 5, Entry 15): To a solution of titanium tetraisopropoxide
(0.59 mL, 2.0 mmol) in dry CH2Cl2 (8 mL) at ¹78 °C under argon
atmosphere was added PhMgBr (3 M in Et2O) (0.40 mL, 1.2 mmol).
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 CH2Cl2 (4 mL) solution of 4b (10.5 mg, 0.020 mmol),
1-naphthaldehyde (7a) (0.156 g, 1.0 mmol), and titanium tetraiso-
propoxide (0.30 mL, 1.0 mmol) at 0 °C under argon atmosphere.
After being stirred further for 1 h, the reaction mixture was
quenched by the addition of aqueous 1 M HCl and extracted
three times with ethyl acetate. The organic layers were washed
successively with aqueous 5% NaHCO3 and with brine, dried
(MgSO4), and concentrated in vacuo. Flash chromatography (silica
gel, 2-20% ethyl acetate in hexane) of the residue gave 0.226 g
(97% yield) of 13aa53e (95% ee). The ee value was determined by
HPLC analysis using a Chiralcel OD column (1.5 mL min¹1, 10%
i-PrOH in hexane); retention times: 26.8 min (major R enantiomer)
and 11.4 min (minor S enantiomer). The absolute structure of the
product was determined based on reported retention times.53e
Asymmetric Phenylation Using Phenyllithium (Table 5,
Entry 17). A two-layer mixture of MgBr2 in Et2O (2 mL) was
prepared by the reaction of magnesium turnings (29 mg, 1.2 mmol)
with 1,2-dibromoethane (1.2 mmol, 0.10 mL) under argon atmo-
sphere. To this was added CH2Cl2 (8 mL) at room temperature. To
the resulting solution of MgBr2 at ¹78 °C was added PhLi (0.98 M
25
give 409.1 mg (96% yield) of 4b as an amorphous solid: ½¡ꢁD
1
+69.7 (c 1.00, CHCl3); H NMR (500 MHz, CDCl3): ¤ 1.68-1.83
(8H, m), 2.21-2.30 (2H, m), 2.34-2.45 (2H, m), 2.78 (2H, t, J =
6.0 Hz), 2.85 (2H, t, J = 6.2 Hz), 4.71 (1H, br), 4.95 (1H, br), 6.87
(1H, d, J = 8.3 Hz), 7.09 (1H, d, J = 8.3 Hz), 7.30 (1H, s), 7.38
(2H, t, J = 7.4 Hz), 7.47 (4H, t, J = 7.5 Hz), 7.70 (4H, d, J = 7.2
Hz), 7.78 (1H, t, J = 1.6 Hz), 7.84 (2H, d, J = 1.6 Hz); 13C NMR
(126 MHz, CDCl3): ¤ 22.9, 23.0 (3C), 27.14, 27.19, 29.2 (2C),
113.0, 119.1, 119.8, 125.0, 125.8, 127.2, 127.4 (2C), 128.7, 130.2,
130.4, 131.1, 131.8, 137.0, 137.1, 138.8, 141.2, 141.9, 148.3,
151.3; HRMS (EI) calcd for C38H34O2: 522.2559, found: 522.2567.

30
Bull. Chem. Soc. Jpn. Vol. 83, No. 1 (2010) BCSJ AWARD ARTICLE
in cyclohexane and Et2O) (1.22 mL, 1.2 mmol). The resulting
suspension was stirred at room temperature for 15 min and then
cooled again at ¹78 °C. Titanium tetraisopropoxide (0.59 mL, 2.0
mmol) was added. 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 CH2Cl2 (4 mL) solution of 4b (10.5 mg, 0.020
mmol), 1-naphthaldehyde (7a) (0.156 g, 1.0 mmol), and titanium
tetraisopropoxide (0.30 mL, 1.0 mmol) at 0 °C. After being stirred
further for 1 h, the reaction mixture was quenched by the addition
of aqueous 1 M HCl and extracted three times with ethyl acetate.
The organic layers were washed successively with aqueous 5%
NaHCO3 and with brine, dried (MgSO4), and concentrated in
vacuo. Flash chromatography (silica gel, 2-20% ethyl acetate in
hexane) of the residue gave 0.199 g (85% yield) of 13aa (95% ee).
(R)-3-[Hydroxy(naphthalen-1-yl)methyl]benzonitrile (16aa).
Typical Procedure for Asymmetric Arylation Using Function-
alized Grignard Reagents Prepared in Et2O (Table 6, Entry 1):
To a solution of 3-iodobenzonitrile (14a) (0.344 g, 1.50 mmol) in
dry Et2O (3 mL) at ¹20 °C under argon atmosphere was added
c-C5H9MgCl (2 M in Et2O) (0.825 mL, 1.65 mmol). After being
stirred for 1 h at this temperature, the resulting suspension was
cooled to ¹78 °C and diluted with CH2Cl2 (10 mL). To the
suspension at this temperature was added titanium tetraisoprop-
oxide (0.74 mL, 2.5 mmol). 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 CH2Cl2 (4 mL) solution of
4b (10.5 mg, 0.020 mmol), 7a (0.156 g, 1.0 mmol), and titanium
tetraisopropoxide (0.30 mL, 1.0 mmol) at 0 °C under argon at-
mosphere. After being stirred further for 1 h, the reaction mixture
was quenched by the addition of aqueous 1 M HCl and extracted
three times with ethyl acetate. The organic layers were washed
successively with aqueous 5% NaHCO3 and with brine, dried
(MgSO4), and concentrated in vacuo. Flash chromatography (silica
gel, 12% ethyl acetate in hexane) of the residue gave 0.235 g (94%
yield) of 16aa (95% ee): 1H NMR (500 MHz, CDCl3): ¤ 2.51 (1H,
br), 6.52 (1H, d, J = 3.7 Hz), 7.42 (1H, t, J = 8.0 Hz), 7.43-7.57
(5H, m), 7.64 (1H, d, J = 7.9 Hz), 7.75 (1H, s), 7.83-7.91 (2H, m),
8.00 (1H, d, J = 8.0 Hz); 13C NMR (125.8 MHz, CDCl3): ¤ 73.5,
112.5, 118.8, 123.7, 125.30, 125.31, 125.9, 126.5, 129.0, 129.17,
129.24, 130.40, 130.42, 131.1, 131.2, 134.1, 137.8, 144.6; HRMS
(EI) calcd for C18H13NO: 259.0997, found: 259.1006. The ee value
was determined by HPLC analysis using a Chiralcel AD-H column
(1 mL min¹1, 9% i-PrOH in hexane); retention times: 36.2 min
(major R enantiomer) and 24.3 min (minor S enantiomer). The
absolute stereochemistry was assumed by analogy.
argon atmosphere. After being stirred further for 1 h, the reaction
mixture was quenched by the addition of aqueous 1 M HCl and
extracted three times with ethyl acetate. The organic layers were
washed successively with aqueous 5% NaHCO3 and with brine,
dried (MgSO4), and concentrated in vacuo. Flash chromatography
(silica gel, 3-5% ethyl acetate in toluene) of the residue gave
0.296 g (97% yield) of 16ae (95% ee): 1H NMR (500 MHz,
CDCl3): ¤ 1.37 (3H, t, J = 7.4 Hz), 2.45 (1H, d, J = 4.0 Hz), 4.36
(2H, d, J = 7.4 Hz), 6.60 (1H, d, J = 4.0 Hz), 7.38 (1H, t, J =
7.7 Hz), 7.43-7.50 (3H, m), 7.55 (1H, d, J = 7.9 Hz), 7.58 (1H, d,
J = 7.0 Hz), 7.83 (1H, d, J = 8.2 Hz), 7.88 (1H, m), 7.96 (1H, d,
J = 7.8 Hz), 8.05 (1H, m), 8.19 (1H, s); 13C NMR (125.8 MHz,
CDCl3): ¤ 14.3, 61.0, 73.4, 123.8, 124.9, 125.3, 125.7, 126.3,
128.1, 128.5, 128.81, 128.84 (2C), 130.6, 130.8, 131.3, 134.0,
138.4, 143.5, 166.5; HRMS (EI) calcd C20H18O3: 306.1256, found:
306.1249 (HPLC analysis using a Chiralcel AD-H column,
1 mL min¹1, 10% i-PrOH in hexane; retention times: 35.4 min
(major R enantiomer) and 28.8 min (minor S enantiomer). The
absolute stereochemistry was assumed by analogy.
This work was supported by KAKENHI (No. 20550095)
and by Kyoto Institute of Technology Research Fund.
Supporting Information
Characterization of products. This material is available free of
charge on the web at http://www.csj.jp/journals/bcsj/.
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