Enantioselective alkylation of aldehydes catalyzed by a highly active titanium complex of 3-substituted unsymmetric BINOL

Article abstract of DOI:10.1021/ol061407x

A titanium complex derived from 3-(3,5-diphenylphenyl)-BINOL exhibits an enhanced catalytic activity in the asymmetric alkylation of aldehydes, allowing the reduction of the catalyst amount to less than 1 mol % without deterioration in enantioselectivity.

Full text of DOI:10.1021/ol061407x

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3817-3819
Enantioselective Alkylation of Aldehydes
Catalyzed by a Highly Active Titanium
Complex of 3-Substituted Unsymmetric
BINOL
Toshiro Harada* and Kousou Kanda
Department of Chemistry and Materials Technology, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
harada@chem.kit.ac.jp
Received June 9, 2006
ABSTRACT
A titanium complex derived from 3-(3,5-diphenylphenyl)-BINOL exhibits an enhanced catalytic activity in the asymmetric alkylation of aldehydes,
allowing the reduction of the catalyst amount to less than 1 mol % without deterioration in enantioselectivity.
Titanium(IV) complexes of 1,1′-bi-2-naphthol (BINOL, 1)
and its derivatives are one of the most versatile chiral Lewis
acid catalysts employed in a number of useful asymmetric
processes.1 Much effort has been directed toward the
modification of the parent BINOL to optimize catalysts to
specific enantioselective reactions. In 1997, Nakai and Chan
et al. reported that the reaction of aldehydes with diorga-
nozincs enantioselectively gave the alkylation products in
the presence of a catalytic amount of BINOL and a
stoichiometric amount of titanium tetraisopropoxide.2 Since
these initial reports, a variety of BINOL derivatives have
been examined as chiral ligands for the reaction.3,4 Although
considerable improvements in enantioselectivity have been
achieved by the modification of the parent BINOL frame-
work, 10-20 mol % of catalysts need to be used. Because
these modified BINOLs are less accessible, a reduction in
the amount of catalysts remains an important issue for the
practicality of this useful asymmetric transformation.
Herein, we wish to report that the titanium catalysts
derived from 3-substituted unsymmetric BINOLs 25 exhibit
an enhanced activity allowing the reduction of the catalyst
amount. Enantioselectivities comparable to or higher than
(3) (a) Zhang, F.-Y.; Chan, A. S. C. Tetrahedron: Asymmetry 1997, 8,
3651. (b) Hu, Q.-S.; Pugh, V.; Sabat, M.; Pu, L. J. Org. Chem. 1999, 64,
7528. (c) Shen, X.; Guo, H.; Ding, K. K. Tetrahedron: Asymmetry 2000,
11, 4321. (d) Lipshutz, B. H.; Shin, Y.-J. Tetrahedron Lett. 2000, 41, 9515.
(e) Chen, Y.; Yekta, S.; Martyn, J. P.; Zheng, J.; Yudin, A. K. Org. Lett.
2000, 2, 3433. (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)
Hua, J.; Lin, W. Org. Lett. 2004, 6, 861.
(1) (a) Brunel, J. M. Chem. ReV. 2005, 105, 857. (b) Mikami, K. In
Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; John
Wiley and Sons: New York, 1995; Vol. 1, p 397. (c) Pu, L. Chem. ReV.
1998, 98, 2405. (d) Mikami, K.; Nakai, T. In Catalytic Asymmetric Synthesis,
2nd ed.; Ojima, I., Ed.; John Wiley and Sons: New York, 2000; p 543.
(2) (a) Mori, M.; Nakai, T. Tetrahedron Lett. 1997, 38, 6233. (b) Zhang,
F.-Y.; Yip, C.-W.; Cao, R.; Chan, A. S. C. Tetrahedron: Asymmetry 1997,
8, 585.
(4) For the enantioselective addition of dialkylzincs to aldehydes in
general, see: (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl.
1991, 30, 49. (b) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833. (c) Pu, L.;
Yu, H.-B. Chem. ReV. 2001, 101, 757.
10.1021/ol061407x CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/18/2006

20 mol % of the parent BINOL can be achieved by using
less than 1 mol % of the (3,5-diphenyl)phenyl derivative 2f.
and 2f, respectively. In addition to the enhanced reaction
rate, these unsymmetric BINOLs, 2f in particular, exhibited
an improved enantioselectivity. It should be noted that the
enhanced activity was observed only for the monosubstituted
unsymmetric derivatives. The reaction using 3,3′-diphenyl-
BINOL 3 was sluggish and nonselective (entry 9).
A satisfactory reaction rate and high enantioselectivity
were obtained even by using less than 2 mol % of the 3,5-
diphenylphenyl derivative 2f (Table 2). Reductions in the
Asymmetric ethylation of benzaldehyde was examined at
low catalyst loading (eq 1, Table 1). The reactions were
Table 2. Asymmetric Ethylation of Benzaldehyde with
Unsymmetric BINOL 2fa
conversion (%)
entry
mol %
temp (°C)
after 1 h
after 5 h
ee (%)
Table 1. Asymmetric Ethylation of Benzaldehyde with
BINOLs 1, 2a-g, and 3a
1
2
3
4
5
6
7
8c
9d
2
1
0.5
0.1
0
2
1
2
2
0
0
0
0
0
>95
96
81
32
<5
95
64
33
56
93
94
93
82
0
95
94
89
92
>98b
>98
92
15
-20
-20
-20
-20
>98b
>98
87
conversion (%)
entry ligand
R
after 1 h after 5 h ee (%)
>98
1
2
3
4
5
6
7
8
9
1
H
39
44
55
55
65
91
>98
32
94
>98
>98
>98
>98
>98b
85
84
81
79
87
90
93
83
9
2a
2b
2c
2d
2e
2f
2g
3
PhCtC
Br
Me
a Unless otherwise noted, reactions were carried out with 2f, Et2Zn (3
equiv), and Ti(OiPr)4 (1.4 equiv) in CH2Cl2. b After 2 h. c BINOL 1 was
used. d Ph-BINOL 2d was used.
Ph
3,5-Me2C6H3
3,5-Ph2C6H3
2,6-Me2C6H3
catalyst loading to 0.5 mol % were possible without lowering
the enantioselectivity (entries 2 and 3). Decreased enantio-
selectivity upon further reduction (0.1 mol %, entry 4) is
most probably attributed to a competing titanium tetraiso-
propoxide-promoted background reaction judging from its
rate estimated from a control experiment (entry 5). By virtue
of the rate enhancement, reactions could be carried out at
-20 °C by using 1-2 mol % of 2f, affording products with
slightly higher ee’s (entries 6 and 7). The higher activity of
the catalyst derived from 2f was again shown in comparing
the conversion after 1 h with those of a parent BINOL and
phenyl derivative 2d (entry 6 vs entries 8 and 9).
83
94c
< 5
a Unless otherwise noted, reactions were carried out in the presence of
the (R)-BINOL derivatives (2 mol %) with Et2Zn (3 equiv) and Ti(OiPr)4
(1.4 equiv) in CH2Cl2 at 0 °C for 5 h. b After 3 h. c After 48 h.
carried out in the presence of (R)-BINOL derivatives 1, 2a-
g, and 3 (2 mol %) with diethylzinc (3 equiv) and titanium
tetraisopropoxide (1.4 equiv) in CH2Cl2 at 0 °C. Under these
conditions, the reaction with the parent BINOL did not attain
the full conversion after 5 h, affording (R)-1-phenylpropanol
in lower enantioselectivity (85% ee) than reported for the
reaction at 20 mol % catalyst loading (92% ee)2b (entry 1).
The reaction with 3-substituted unsymmetric BINOLs 2a-
d, on the other hand, was completed within 5 h (entries 2-5).
The conversion of benzaldehyde after 1 h revealed the
following order in the reaction rate for the R group on the
BINOL moiety: Ph > Me ≈ Br > PhCtC > H, suggesting
that BINOL derivatives with sterically more demanding
substituents would afford a higher turnover frequency.
Although the highly hindered 2,6-dimethylphenyl derivative
2g did not show an anticipated reactivity (entry 8), the 3,5-
dimethylphenyl derivative 2e and 3,5-diphenylphenyl deriva-
tive 2f were found to be highly efficient (entries 6 and 7).
The reactions were accomplished within 3 and 1 h with 2e
The addition of diethylzinc to other aldehydes was
examined by using 2f under condition A (1 mol % at 0 °C)
and B (2 mol % at -20 °C) (Table 3). For aromatic
aldehydes, the reactions were accomplished within 2 h even
with the low catalyst loadings to give the corresponding
ethylation products in high enantioselectivity (90-96% ee)
(entries 1-10). Under condition A, 2f exhibited enantiose-
lectivities comparable to or higher than those reported for
BINOL (20 mol % at 0 °C).2b A further albeit small
improvement in enantioselectivity was observed by carrying
out the reaction at -20 °C (condition B). Although an
aliphatic aldehyde was less reactive and less enantioselective
(entry 11), a high enantioselectivity as well as turnover
efficiency was observed for an R,â-unsaturated aldehyde
(entries 12 and 13).
(5) For unsymmetrically substituted binaphthyl ligands in enantioselective
catalysis, see: Kocovsky, P.; Vyskocil, S.; Smrcina, M. Chem. ReV. 2003,
103, 3213.
In a recent study on the mechanism of asymmetric
alkylation catalyzed by BINOL-derived titanium complexes,
3818
Org. Lett., Vol. 8, No. 17, 2006

Scheme 1
Table 3. Asymmetric Ethylation of Aldehydes Catalyzed by a
Titanium Complex Derived from Unsymmetric BINOL 2fa
entry
aldehydes
conditionsa yield (%)b ee (%)c,d
1
2
3
4
5
6
7
8
9
10
11e
12
13
p-MeC6H4CHO
A
B
A
B
A
B
A
B
A
B
B
A
B
94
89
91
94
74
72
95
82
93
84
53
96
92
92 (88)
94
94 (94)
95
77 (69)
80
95 (94)
96
90 (81)
91
85
92
93
m-MeOC6H4CHO
o-ClC6H4CHO
1-naphthylCHO
2-naphthylCHO
PhCH2CH2CHO
PhCHdCHCHO
precursor of the reactive intermediate 6, to reduce the overall
catalyst efficiency. The introduction of a substituent (R1) at
the 3-position of the naphtholate moiety may cause a
destabilizing interaction in 1:2-aggregate 5, thereby main-
taining the sufficient concentration of 4 even at the lower
catalyst loadings. The very low activity observed for 3,3′-
diphenyl derivative 3 (Table 1, entry 9) is consistent with
this rationale because aggregate 4, as well as aggregate 6,
should be destabilized by the additional substituent (R2) at
the 3′-position. Judging from the rate of the background
reaction, the enantioselectivity of BINOL derivatives 2 seems
to be determined primarily by the extent of the background
reaction and might not be influenced much by the structure
of the substituents. The observation is also in accord with
the catalytic reaction through 6 where substituent R1 locates
distal to the reaction site.
In summary, we have demonstrated that the titanium
complexes derived from 3-substituted unsymmetric BINOLs
2 exhibit enhanced catalytic activity in the asymmetric
alkylation of aldehydes. Less than 1 mol % of the 3,5-
diphenylphenyl derivative 2f is enough to obtain a compa-
rable or higher enantioselectivity than reactions using 20 mol
% of the parent BINOL.
a Unless otherwise noted, reactions were carried out for 1-2 h. Condition
A: 2f (1 mol %) at 0 °C. Condition B: 2f (2 mol %) at -20 °C. b Isolated
yield. c Determined by chiral stationary phase HPLC; Chiralcel OB (entries
5 and 6) or Chiralcel OD (other entries). d Values in parentheses refer to
the ee reported for the reaction using BINOL (20 mol %) under otherwise
identical conditions.2b e The reaction was carried out for 5 h.
it was shown that the ethyltitanium species formed in
equilibrium from diethylzinc and titanium tetraisopropoxide
is an active alkylating agent.6 A large excess of titanium
tetraisopropoxide is required with respect to the ligand to
obtain the sufficient concentration of the alkyltitanium
species. At the low catalyst loading, BINOL and a large
excess of titanium tetraisopropoxide most probably form a
mixture of 1:1-aggregate 4 and 1:2-aggregate 5 (Scheme 1;
R1 ) H).7,8 If we assume that the asymmetric alkylation
proceeds through complex 66a with a five-coordinate titanium
center but not through six-coordinate titanium complex 7,
the presence of 5 diminishes the concentration of 4, the
(6) (a) Balsells, J.; Davis, T. J.; Carroll, P.; Walsh, P. J. J. Am. Chem.
Soc. 2002, 124, 10336. (b) Waltz, K. M.; Carroll, P.; Walsh, P. J.
Organometallics 2004, 23, 127.
(7) Aggregates 4 and 5 were characterized by X-ray crystallography.6a
(8) The solution mixture of BINOL and tetraisopropoxide was studied
by NMR spectroscopy: Pescitelli, G.; Bari, L. D.; Salvadori, P. Organo-
metallics 2004, 23, 4223. Although they did not observe the formation of
aggregate 5 up to 10 metal equiv (corresponding to the reaction with 14
mol % of BINOL), it is plausible to assume such an aggregate in the reaction
with lower catalyst loading (e.g., 70 metal equiv for 2 mol % reaction).
Supporting Information Available: The preparation of
ligands and a representative reaction procedure. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL061407X
Org. Lett., Vol. 8, No. 17, 2006
3819