Practical and highly enantioselective alkylation of aldehydes catalyzed by a titanium complex of 3-aryl H8-BINOL

Article abstract of DOI:10.1016/j.tetasy.2007.10.012

A titanium complex derived from 3-(3,5-diphenylphenyl)-H₈-BINOL exhibits high catalytic activity and enantioselectivity in the alkylation of aldehydes. Enantioselectivities comparable to or higher than 20 mol % of the parent H₈-BINOL

Full text of DOI:10.1016/j.tetasy.2007.10.012

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2499–2502
Practical and highly enantioselective alkylation of aldehydes catalyzed
by a titanium complex of 3-aryl H8-BINOL
Toshiro Harada* and Takahiro Ukon
Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
Received 1 September 2007; accepted 4 October 2007
Available online 5 November 2007
Abstract—A titanium complex derived from 3-(3,5-diphenylphenyl)-H8-BINOL exhibits high catalytic activity and enantioselectivity in
the alkylation of aldehydes. Enantioselectivities comparable to or higher than 20 mol % of the parent H8-BINOL are obtained with
2 mol %-catalyst loadings. The reaction can be carried out without rigorous exclusion of water.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
realizing excellent enantioselectivity in the reaction of
aromatic aldehydes at 20 mol % catalyst loading.5
The asymmetric addition of organometallic reagents to
carbonyl compounds is a reaction of fundamental impor-
tance in modern synthetic organic chemistry.1 There has
been a continuing interest in developing 1,10-bi-2-naphthol
1 (BINOL) based titanium(IV) catalysts for the asymmetric
addition of diorganozincs to aldehydes (Scheme 1).
Following the seminal discovery of Nakai2 and Chan,3 a
variety of derivatives have been examined as chiral ligands
to improve the enantioselectivity of the parent BINOL.4 Of
these derivatives, H8-BINOL 3 is one of the best ligands for
We recently reported that the titanium catalysts derived
from 3-substituted unsymmetric BINOLs exhibit an
enhanced activity, allowing the reduction of the catalyst
amount.6,7 By using less than 1 mol % of 3-(3,5-diphenyl)-
phenyl-BINOL 2, enantioselectivities comparable to or
higher than 20 mol % of the parent BINOL were obtained.
The remarkable effect of the 3,5-diphenylphenyl group
prompted us to examine the corresponding H8-BINOL
derivatives 4 as a chiral ligand.
Herein we report a highly enantioselective alkylation of
aldehydes catalyzed by titanium(IV) complex derived from
3-substituted H8-BINOL 4. The practicality of the reac-
tion was demonstrated by excellent enantioselectivities
(94–98% ee) at a low catalyst loading (2 mol %) and by
the possible use of a commercial reagent and solvent as
received without rigorous exclusion of water.
BINOL derivatives 1-4
O
OH
Ti(OiPr)4 (1.4 equiv)
CH2Cl2, 0 ºC
+
Et2Zn
Ar
H
Ar
R
R
OH
OH
OH
OH
2. Results and discussion
Ligand (R)-4 was prepared from H8-BINOL (R)-3 in four
steps (Scheme 2). After protection of the phenolic oxygens
with a methyl group,8 treatment of the resulting dimethyl
derivative 5 with bromine (1.0 equiv) at 0 °C gave mono-
bromide 6. A Pd(PPh3)4-catalyzed coupling of bromide 6
with 3,5-diphenylphenylboronic acid9 followed by depro-
tection of the dimethyl derivative 6 with BBr3 furnished
(R)-4.
3; R = H (20 mol %)
4; R = 3,5-(C6H5)2C6H4 (2 mol %)
1; R = H (20 mol %)
2; R = 3,5-(C6H5)2C6H4 (< 1 mol %)
Scheme 1. Asymmetric alkylation of aldehydes catalyzed by titanium(IV)
complexes of BINOL derivatives.
*
Corresponding author. E-mail: harada@chem.kit.ac.jp
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.012

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T. Harada, T. Ukon / Tetrahedron: Asymmetry 18 (2007) 2499–2502
unsaturated aldehyde and an aliphatic aldehyde (entries 9
and 10).
Br
c, d
a
b
OMe
OMe
OMe
OMe
3
4
Another practical advantage of using ligand 4 is that the
reaction can be carried out without rigorous exclusion of
water. Reactions could be carried out with commercial tita-
nium tetraisopropoxide and dichloromethane as received
by using non-dried glassware to give products without a
noticeable deterioration in enantioselectivity (entries 2
and 7).11
6
5
Scheme 2. Preparation of H8-BINOL derivative (R)-4. Reagents and
conditions: (a) MeI, K2CO3, acetone;8 (b) Br2 (1 equiv), CH2Cl2 (66%); (c)
3,4-Ph2C6H3B(OH)2, Pd(PPh3)4 (5 mol %), Ba(OH)2Æ8H2O, aqueous diox-
ane (93%); (d) BBr3,CH2Cl2 (100%).
We have previously proposed6 that the high catalytic activ-
ity of the titanium complex derived from BINOL derivative
2 can be attributed to the steric inhibition of the formation
of six-coordinate titanium aggregates 8 and 10 based upon
recent mechanistic studies12 (Scheme 3; R0 = 3-(3,5-diphen-
yl)phenyl). It was assumed that the asymmetric alkylation
proceeds through complex 9 with a five-coordinate tita-
nium center, but not through six-coordinate titanium com-
plex 10. At low catalyst loading, a large excess of titanium
tetraisopropoxide with respect to BINOL 1 (and H8-BI-
NOL 3) might result in the formation of the 1:2-aggregate
8 (R0 = H), which can serve as a catalyst sink to reduce an
overall catalyst activity. The introduction of the aryl group
at the 3-position of BINOL 1 (and H8-BINOL 3) destabi-
lizes 8 and 10 sterically, thereby maintaining the sufficient
concentration of 7 and 9 even at the lower catalyst loading.
The enhancement of catalytic activity observed for the
complex derived from 3-substituted H8-BINOL 4 provides
additional support for our rationalization. The observation
that the high enantioselectivity of the parent compound 3
(20 mol %) is retained in 4 (2 mol %) is inconsistent with
the assumed activated complex 8, where the R0 substituent
locates far away from the reaction site.
The reaction of benzaldehyde with diethylzinc (3 equiv)
was carried out in CH2Cl2 at 0 °C in the presence of
(R)-4 (2 mol %) and titanium tetraisopropoxide (1.4 equiv)
(Table 1, entry 2). As we anticipated, the reaction pro-
ceeded rapidly under these conditions, and was complete
within 3.5 h to give (R)-1-phenylpropanol in 98% ee. Under
similar conditions, a control reaction using the parent
H8-BINOL 3 did not attain full conversion of the aldehyde
after 5 h, affording the product in lower enantioselectivity
(75% ee) than reported5a for the reaction at 20 mol % cata-
lyst loading (98% ee) (entry 1). A slightly decreased, but
still high, enantioselectivity (96% ee) was obtained in the
reaction with 1 mol % of 4 (entry 3). Judging from conver-
sions after 1 h, the turnover efficiency of the catalyst
derived from 4 is significantly improved by the introduc-
tion of the 3,5-diphenylphenyl group, while being slightly
inferior to a catalyst derived from 3-(3,5-diphenylphenyl)-
BINOL 2 (entries 2,3 vs entries 4,5).
The addition of diethylzinc to other aldehydes was exam-
ined by using ligand 4 (2 mol %) (Table 2).10 For all the
aromatic aldehydes examined, the reactions were accom-
plished within 5 h and the corresponding ethylation
products were obtained in excellent enantioselectivity
(94–98% ee) (entries 1–8). In comparison with 3-(3,5-diphen-
ylphenyl)-BINOL 2,6 4 consistently showed enhanced
enantioselectivity. The observed selectivities were compara-
ble to or higher than those obtained with 20 mol % of the
unsubstituted H8-BINOL 3.5 Ligand 4 exhibited slightly
lower, but acceptable selectivities in the reaction of an
3. Conclusion
In conclusion, we have shown the enhanced catalytic activ-
ity of the titanium complexes derived from the 3-substi-
tuted BINOL 4 in asymmetric alkylation of aldehydes.
The low catalyst loading, the excellent enantioselectivities,
and the ease of operation without the need for rigorous
exclusion of water attest to its practicality.
Table 1. Asymmetric ethylation of benzaldehyde with unsymmetric BINOL 4a
2, 3, or 4 (1-2 mol%)
Ti(OiPr)4 (1.4 equiv),
CH2Cl2, 0 ºC
OH
O
(1)
+
Et2Zn
Ph
Ph
H
Entry
Ligand
mol %
Conversion (%)
ee (%)
After 1 h
After 5 h
1
2
3
46
56
3
4
4
2
2
2
2
1
2
1
49
98
76
>98
96
80
>98b
>98
—
75
98
96
93
94
>98c
a Reactions were carried out with Et2Zn (3 equiv) and Ti(Oi-Pr)4 (1.4 equiv) in CH2Cl2 at 0 °C.
b After 3.5 h.
c After 2 h.

T. Harada, T. Ukon / Tetrahedron: Asymmetry 18 (2007) 2499–2502
2501
Table 2. Asymmetric ethylation of aldehydes catalyzed by titanium complex derived from H8-BINOL derivative 4a
4 (2 mol%)
Ti(OiPr)4 (1.4 equiv),
CH2Cl2, 0 ºC
OH
O
(2)
+
Et2Zn
R
R
H
Entry
Aldehyde
PhCHO
Yieldb (%)
eec (%)
3d
2e
1
2f
3
4
5
77
97
80
96
88
73
94
95
97
80
98
97
98
98
94
99
97
98
94
90
98
94
p-MeC6H4CHO
m-MeOC6H4CHO
o-ClC6H4CHO
92
96
92
98
92
95
77
95
6
1-NaphthylCHO
7f
8
2-NaphthylCHO
PhCH@CHCHO
PhCH2CH2CHO
—
—
—
90
92
85
9
10
a Reactions were carried out with Et2Zn (3 equiv) and Ti(Oi-Pr)4 (1.4 equiv) in CH2Cl2 at 0 °C for 3–5 h.
b Isolated yield.
c Determined by chiral stationary phase HPLC; Chiralcel OB (entry 5) or Chiralcel OD (other entries).
d Values refer to the ee reported for the reaction using H8-BINOL 3 (20 mol %).5a
e Values refer to the ee reported for the reaction using BINOL derivative 2 (1 mol %) under otherwise identical conditions.6
f The reaction was carried out with commercial Ti(Oi-Pr)4 and CH2Cl2 as received by using a non-dried glassware.
R'
3. Zhang, F.-Y.; Yip, C.-W.; Cao, R.; Chan, A. S. C. Tetra-
hedron: Asymmetry 1997, 8, 585.
R'
RO
RO
RO
O
Ti OR
OR
RO OR
*
4. (a) Hu, Q.-S.; Pugh, V.; Sabat, M.; Pu, L. J. Org. Chem. 1999,
64, 7528; (b) Shen, X.; Guo, H.; Ding, K. K. Tetrahedron:
Asymmetry 2000, 11, 4321; (c) Lipshutz, B. H.; Shin, Y.-J.
Tetrahedron Lett. 2000, 41, 9515; (d) Chen, Y.; Yekta, S.;
Martyn, J. P.; Zheng, J.; Yudin, A. K. Org. Lett. 2000, 2,
3433; (e) Shen, X.; Guo, H.; Ding, K. Tetrahedron: Asym-
metry 2000, 11, 4321–4327; (f) Yang, X.-W.; Sheng, J.-H.;
Da, C.-S.; Wang, H.-S.; Su, W.; Wang, R.; Chan, A. S. C. J.
Org. Chem. 2000, 65, 295; (g) Nakamura, Y.; Takeuchi, S.;
Ohgo, Y.; Curran, D. P. Tetrahedron Lett. 2000, 41, 57; (h)
Jayaprakash, D.; Sasai, H. Tetrahedron: Asymmetry 2001, 12,
2589; (i) Lee, S. J.; Hu, A.; Lin, W. J. Am. Chem. Soc. 2002,
124, 12948; (j) Jiang, H.; Hu, A.; Lin, W. J. Chem. Soc.,
Chem. Commun. 2003, 96; (k) Harada, T.; Hiraoka, Y.;
Kusukawa, T.; Marutani, Y.; Matsui, S.; Nakatsugawa, M.;
Kanda, K. Org. Lett. 2003, 5, 5059; (l) Hua, J.; Lin, W. Org.
Lett. 2004, 6, 861; (m) Harada, T.; Kanda, K.; Hiraoka, Y.;
Marutani, Y.; Nakatsugawa, M. Tetrahedron: Asymmetry
2004, 15, 3879; (n) Harada, T.; Nakatsugawa, M. Synlett
2006, 321.
*
Ti
O
O
O
OR
Ti
RO
Ti OR
OR
RO
RO
Ti
OR
OR
RO
7
8
R'
R'
RO
RO
Ti
OR
OR
Et
Ar
RO
Ti
OR
OR
Et
Ar
RO
*
*
Ti
O
O
O
O
RO
O
Ti
RO
RO
Ti
O
RO
OR
OR
H
H
10
9
*
5. (a) Zhang, F.-Y.; Chan, A. S. C. Tetrahedron: Asymmetry
1997, 8, 3651; (b) Chan, A. S. C.; Zhang, F.-Y.; Yip, C.-W.
J. Am. Chem. Soc. 1997, 119, 4080.
= BINOL or H8-BINOL, R = i-Pr
OH OH
Scheme 3. Plausible titanium aggregates.
6. Harada, T.; Kanda, K. Org. Lett. 2006, 8, 3817.
7. For unsymmetrically substituted binaphthyl ligands in enan-
tioselective catalysis, see: Kocovsky, P.; Vyskocil, S.; Smrci-
na, M. Chem. Rev. 2003, 103, 3213.
8. Schrock, R. R.; Jamieson, J. Y.; Dolman, S. J.; Miller, S. A.;
Bonitatebus, P. J., Jr.; Hoveyda, A. H. Organometallics 2002,
21, 409.
Acknowledgments
Financial support from the Ministry of Education, Science,
Sports and Culture of the Japanese Government [Grant-
in-Aid for Scientific Research (No. 17550101)] is gratefully
acknowledged.
9. Miller, T. M.; Neenan, T. X.; Zayas, R.; Bair, H. E. J. Am.
Chem. Soc. 1992, 114, 1018.
10. Representative procedure for asymmetric ethylation (Table 2,
entries 6 and 7): Titanium tetraisopropoxide (0.413 mL,
References
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a solution of 4 (10.5 mg,
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at room temperature under an argon atmosphere. The
resulting solution was stirred for 10 min at room temperature.
To this was added diethylzinc (1 M in hexane, 3 mL,
3.0 mmol) and stirring was continued for 10 min. To the
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2502
T. Harada, T. Ukon / Tetrahedron: Asymmetry 18 (2007) 2499–2502
resulting mixture was added 1-naphthaldehyde (0.156 g,
(R)-BINOL as a ligand. The above reaction was carried out in
a non-dried Schlenk flask with commercial titanium tetraiso-
propoxide and CH2Cl2 as received by following the same
procedure except that, after addition of diethylzinc, the
resulting mixture was stirred for 1 h at room temperature.
The reaction gave 0.175 g (94% yield) of (R)-1-(1-naphthyl)-1-
propanol (97% ee).
1.0 mmol) at 0 °C. After being stirred for 3 h, the reaction
mixture was quenched by the addition of aqueous 1 M HCl
and extracted twice with ethyl acetate. The organic layers
were washed with aqueous 5% NaHCO3, dried over MgSO4,
and concentrated in vacuo. The residue was purified by a
silica gel flash chromatography (5% ethyl acetate in toluene)
to give 0.136 g (73% yield) of (R)-1-(1-naphthyl)-1-propanol
(99% ee). The ee value as determined by HPLC analysis using
a Chiralcel OD column (0.8 mL/min, 10% i-PrOH in hexane);
9.9 min [minor (S)-enantiomer] and 16.8 min [major (R)-
enantiomer]. The absolute stereochemistry of the product was
determined by comparing the retention time with that of an
authentic sample prepared by asymmetric ethylation using
11. Under similar conditions, the reaction of 1-naphthaldehyde
with 2 (1 mol %) gave the corresponding ethylation product
in 94% ee and in 91% yield.
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Chem. Soc. 2002, 124, 10336; (b) Waltz, K. M.; Carroll, P.;
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