Asymmetric alkylation of aldehydes catalyzed by novel dinuclear bis-BINOLate titanium(IV) complexes

Article abstract of DOI:10.1016/j.tetasy.2004.11.008

Dinuclear bis-BINOLate titanium(IV) complexes catalyzes asymmetric alkylation of aldehydes even in the presence of a reduced amount of titanium tetraisopropoxide (0.2 equiv). Bis-BINOLs 1a,b in which two BINOL units are tethered by o- and m-phenylenebis(e

Full text of DOI:10.1016/j.tetasy.2004.11.008

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3879–3883
Asymmetric alkylation of aldehydes catalyzed by novel
dinuclear bis-BINOLate titanium(IV) complexes
Toshiro Harada,* Kousou Kanda, Yuuki Hiraoka,
Yasuhisa Marutani and Masashi Nakatsugawa
Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
Received 8 September 2004; accepted 1 November 2004
Available online 24 November 2004
Abstract—Bis-BINOLs 1a,b in which two BINOL units are tethered by o- and m-phenylenebis(ethynyl) groups form stable dinuclear
bis-BINOLate titanium(IV) complexes 2a,b by treatment with titanium tetraisopropoxide. In the presence of excess titanium tetra-
isopropoxide, 2a and 2b (2–20mol%) catalyze diethylzinc addition to aromatic and aliphatic aldehydes in an efficient manner to give
the ethylation products with high enantioselectivities. While more than 1equiv of titanium tetraisopropoxide (with respect to a sub-
strate aldehyde) is generally employed for obtaining high turnover frequency and selectivity in reactions catalyzed by a parent
(BINOLate)Ti(OiPr)2, the amount can be reduced as low as 0.2equiv in the reactions catalyzed by 2a,b.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
the enantioselectivity of the dimeric aggregate of a par-
ent BINOLate titanium(IV) complex is anticipated to be
obtained not obscured by the kinetic lability. Such study
will provide a basis for the development of dimeric
aggregate-based chiral Lewis acid catalysts.6
Titanium complexes of 1,10-bi-2-naphthol (BINOL) and
its derivatives stand for one of the most important and
versatile classes of chiral Lewis acid catalysts.1 In spite
of their synthetic importance, there is little information
regarding the structures of these titanium complexes.2,3
Of these, (BINOLate)Ti(OiPr)2 and its derivatives are
relatively well-characterized. The solid-state structure
of trimeric aggregate [(BINOLate)Ti(OiPr)2]3, with one
six-coordinate and two five-coordinate titanium centers,
has been established by X-ray crystallography.4 How-
ever, its structure in solution remains elusive owing to
the kinetic lability of titanium alkoxide ligands. More-
over, the aggregation phenomenon hampered the identi-
fication of active catalyst structures in enantioselective
reactions.
ð1Þ
We have recently reported the preparation and charac-
terization of intramolecular dimeric titanium(IV) aggre-
gates (R,R)-2a–c.5 These dinuclear complexes are
prepared by treatment of phenylenebis(ethynyl)-tethered
bis-BINOLs (R,R)-1a–c with titanium tetraisopropoxide
(Eq. 1). Their structures in solution have been estab-
lished unambiguously by NMR spectroscopy. By the
advantageous use of 2a–c as catalysts, information on
Asymmetric addition of diethylzinc to aldehydes cata-
lyzed by a titanium complex prepared from BINOL
and titanium tetraisopropoxide was first reported by
the groups of Nakai7 and Chan.8,9 Subsequently,
*
Corresponding author. Tel.: +81 75 724 7514; fax: +81 75 724
7580; e-mail: harada@chem.kit.ac.jp
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.008

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T. Harada et al. / Tetrahedron: Asymmetry 15(2004) 3879–3883
Table 2. Asymmetric ethylation of aldehydes 3b–e catalyzed by 2a and
2ba
titanium tetraisopropoxide/dialkylzinc system has been
examined with a variety of BINOL-based ligands. The
reaction is now recognized to be the primary testing
ground for new ligands to evaluate their utility in asym-
metric catalysis.10 Herein, we report the use of intramo-
lecular dimeric titanium(IV) aggregates 2a–c as catalysts
for the prototypical diethylzinc addition to aldehydes.
ð3Þ
Entry Aldehyde
Catalyst mol% Yieldb Eec
(%)
(%)
2. Results and discussion
1
3b; R = 1-naphthyl
2a
2a
1088
2
90
2
98
93
95
97
80
79
73
69
86
91
80
We first focused our effort on the asymmetric ethylation
of benzaldehyde catalyzed by 2a–c (Eq. 2, Table 1).
According to the reaction conditions reported by Chan
et al., reactions were carried out by using 3equiv of
diethylzinc in CH2Cl2 at 0°C for 19h in the presence
of excess titanium tetraisopropoxide. With a 20and
10mol% catalyst load, o-phenylenebis(ethynyl)-tethered
complex 2a exhibited high enantioselectivity comparable
to that reported for (BINOLate)Ti(OiPr)2 (entries 1 and
2).7,8 Even at a 2mol% catalyst loading, the reaction
proceeded smoothly with slightly diminished selectivity
(entry 3). m-Phenylenebis(ethynyl)-tethered complex 2b
also showed similar enantioselectivities at 2–20mol%
catalyst load (entries 4–6). In contrast to the high cata-
lytic activity of 2a and 2b, the reaction using sterically
hindered dimethyl derivative 2c was sluggish and nonse-
lective (entries 7 and 8). For comparison, we examined
reactions catalyzed by (3-phenylethynyl-BINOLate)-
Ti(OiPr)2 6 prepared from the corresponding ligand 5
(entries 9 and 10). This catalyst also exhibited enantio-
selectivities comparable to that reported for
(BINOLate)Ti(OiPr)2.
3
2b
2b
1089
2
91
80
83
67
76
81
86
4
5
3c; R = p-CH3C6H4 2a
2a
1089
2
6
7
2b
2b
1088
2
8
82
d
9
3d; R = p-CF3C6H4 2a
2a
1086
2
10
11
12
13
14
15
16
66d
d
2b
2b
1085
2
68d
76
3e; R = PhCH2CH2 2a
1073
2
2a
2b
2b
1069
2
75
a Reactions were carried out at 0°C for 19h in CH2Cl2 in the presence
of titanium tetraisopropoxide (0.9 and 1.0equiv for 10 and 2mol%
catalyst loading, respectively).
b Isolated yield.
c Unless otherwise noted, ee values were determined by HPLC using a
Chiralcel OD column.
d Determined by NMR analysis of the MTPA ester derivative.
thaldehyde 3b gave the corresponding ethylation
product with higher selectivities (90–91% ee) than benz-
aldehyde irrespective of the catalysts (entries 1–4). It is
noteworthy that relatively high ee was obtained even
at a 2mol% catalyst load of 2b. In the reactions of
substituted benzaldehydes 3c,d, enantioselectivities were
not attenuated even when 2mol% of the catalysts was
employed (entries 5–12). In comparison with aromatic
aldehydes, 3-phenylpropanal 3e was less reactive and
the reaction did not attain full conversion after 19h
(entries 13–16). When 2b (10mol%) was used, enantio-
selectivity comparable to that observed for benzalde-
hyde was obtained for 3e.
ð2Þ
The addition of diethylzinc to other aromatic and ali-
phatic aldehydes 3b–e was examined by using 2a and
2b at a 10and 2mol% catalyst load ( Table 2). 1-Naph-
Table 1. Asymmetric ethylation of benzaldehyde catalyzed by 2a–c
and 6a
Entry Catalyst mol% Ti(OiPr)4 Conversionc(%) Eed (%)
b
1
2a
2b
.8 200
.9 100
2
>98
>98
1.0>98
>98
>98
1.0>98
15
85
88
2
3
81
82
4
.8 200
.9 100
2
87
85
5
6
7e
8e
9
2c
6
.8 200
.9 100
.9 200
19
19
87
17
>98
In the previously reported asymmetric alkylation reac-
tions, more than 1equiv of titanium tetraisopropoxide
was usually employed for obtaining high turnover
frequency and high enantioselectivity.7,8,10 The use of
a reduced amount of titanium tetraisopropoxide, as
low as 0.2equiv with respect to the aldehyde, turned
out to give a similar level of selectivity in the reaction
of benzaldehyde using catalysts 2a and 2b (20mol%)
104 >98 1.0
86
a Unless otherwise noted, reactions were carried out with 3equiv of
diethylzinc at 0°C for 19h in CH2Cl2.
b Equivalents of titanium tetraisopropoxide used in excess with respect
to aldehyde 3a.
c Determined by GC.
d Determined by HPLC using a Chiralcel OD column.
e Reaction was carried out for 27h.

T. Harada et al. / Tetrahedron: Asymmetry 15(2004) 3879–3883
3881
Table 3. Effect of the amount of titanium tetraisopropoxidea
ence of excess titanium tetraisopropoxide.5 1H NMR
titration experiments demonstrated that 2a with o-phen-
ylenebis(ethynyl) tether is stable in the presence of up to
24equiv of titanium tetraisopropoxide (with respect to
2a) keeping the intramolecular dimeric structure.11 On
the other hand, m-phenylenebis(ethynyl)-tethered 2b is
relatively more labile in the presence of excess titanium
tetraisopropoxide, undergoing a reversible intramolecu-
lar deaggregation to form intermolecular aggregate 12
(Eq. 4). In the presence of 2equiv of titanium tetraiso-
propoxide (with respect to 2a), a ca. 1:1 mixture of 2b
Entry Catalyst Ti(OiPr)4 Time (h) Conversionc (%) Eed
b
(%)
1
2
2a
2b
6
0.8
0.4
0.2
0.1
0.8
0.4
0.2
0.1
0.8
19
19
19
19
19
19
15
23
19
>98
>98
>98
52
85
84
87
77
87
84
84
77
87
3
4
5
>98
>98
>98
>98
>98
6
7
8
1
9
and 12 was observed in the H NMR analysis while
complex 12 was a main component in the presence of
10equiv of titanium tetraisopropoxide.
.4
19100
11
12
>98
82
0.2
0.1
19
24
93
88
76
73
a Reactions of 3a and diethylzinc (3equiv) were carried out by using
20mol% of catalysts at 0 °C in CH2Cl2.
b Equivalents of titanium tetraisopropoxide used in excess with respect
to 3a.
c Determined by GC.
d Determined by HPLC using a Chiralcel OD column.
(Table 3). Thus, in the presence of 0.2equiv excess of
titanium tetraisopropoxide, the reaction catalyzed by
2a and 2b gave the ethylation product of 87% ee and
84% ee, respectively (entries 3 and 7). Further reduction
of titanium tetraisopropoxide amount resulted in re-
duced selectivity (entries 4 and 8). Catalyst 6 with a sin-
gle BINOLate unit, on the other hand, exhibited a
gradual deterioration of the ee by the decrease of tita-
nium tetraisopropoxide amount (entries 9–12).
ð4Þ
The structural lability of the intramolecular aggregate
2b and the fact that its enantioselectivity was compar-
able to that of 6 suggest that the reaction proceeded
through open structure 10 in the presence of titanium
tetraisopropoxide in excess (0.8–1.0equiv of with respect
to aldehyde 3). It has been reported that the introduc-
tion of substituents both at the 3 and 30 position of
BINOL significantly reduces the enantioselectivity of
the resulting titanium complexes.2b The results of 2b
and 6 suggest that, in accord with the proposed transi-
tion assembly 9, the mono substitution at the 3 position
is not influential to the enantioselectivity of the BINO-
Late titanium catalyst.
Recently, the mechanism of (BINOLate)Ti(OiPr)2 cata-
lyzed asymmetric alkylation has been extensively inves-
tigated by Walsh et al.4 Their study revealed that the
role of the dialkylzinc is not to add the alkyl group to
the carbonyl but rather to transfer the alkyl group to
titanium, which subsequently transfers it to the alde-
hyde. The possibility of BINOLate titanium oligomers
[(BINOLate)Ti(OiPr)2]n (n = 2,3) as active catalysts
was excluded because they undergo hetero-aggregation
with excess titanium tetraisopropoxide to form dinu-
clear and trinuclear aggregates 7 and 8 under the reac-
tion conditions. The possible transition-state assembly
shown in 9 was proposed for the reaction.
o-Phenylenebis(ethynyl)-tethered catalyst 2a also exhib-
ited a similar level of enantioselectivity in spite of the
stability of the intramolecular aggregate structure in
the presence of excess titanium tetraisopropoxide. The
concentration of an intermolecular aggregate, analogous
to 7, if formed in equilibrium, is very low. Provided that
the catalysis by 2a also proceeded through open struc-
ture 10, the activity of the catalyst with respect to a turn-
over frequency would be lowered in comparison with 2b
and 6. However the activity of 2a was not different from
that of 2b and 6. It is more likely that the catalysis by 2a
proceeded through transition assembly 11 maintaining a
closed structure. Comparable enantioselectivity ob-
served for 2a and 2b can be rationalized by similar lig-
and environment around the coordinating aldehyde in
10 and 11.
When a limited amount of titanium tetraisopropoxide
(0.4–0.1equiv with respect to an aldehyde) was used in
excess, the reaction of 2b might proceed also through
closed assembly 11. The enantioselectivity of 2a and 2b
was less sensitive to the reduction of the titanium tetra-
isopropoxide amount while that of 6 was lowered
gradually by the decrease of the amount (Table 3).
Although the origin of the difference is not yet clear,
Intramolecular dimeric titanium(IV) aggregates 2a and
2b show contrasting aggregation behaviors in the pres-

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T. Harada et al. / Tetrahedron: Asymmetry 15(2004) 3879–3883
the intramolecular aggregate structure of 2a,b might be
responsible to their insensitivity of enantioselectivity.
column chromatography (silica gel, 3% ethyl acetate in
toluene) to give 0.830g (80% yield) of 5 as an amor-
phous solid; H NMR (500MHz, CDCl3): d 4.95 (1H,
1
br, OH), 5.84 (1H, s, OH), 7.17 (2H, t, J = 8.0Hz),
7.25–7.42 (8H, m), 7.58 (2H, m), 7.88 (2H, m), 7.96
(1H, d, J = 8.9Hz), 8.24 (1H, s); 13C NMR
(125.8MHz, CDCl3): d 83.8, 96.2, 111.8, 112.3, 112.5,
117.7, 122.4, 123.7, 124.4, 124.6, 124.7, 127.1, 128.2,
128.29, 128.33, 128.5, 128.88, 128.94, 129.3,
130.9, 131.7, 133.3, 133.8, 134.0, 151.6, 152.0; IR (KBr
disk) 3490, 2360, 1010, 815, 750cmꢀ1; MS (EI) m/z
(relative intensity) 386 (M+, 1), 177 (38), 133 (67), 89
(100); HRMS calcd for C28H18O2: 386.1307, found:
386.1317.
3. Conclusion
In summary, it was demonstrated that dinuclear bis-
BINOLate titanium(IV) complexes 2a and 2b (2–
20mol%) catalyze diethylzinc addition to aromatic and
aliphatic aldehydes in an efficient manner to give the
ethylation products enantioselectively. In spite of the
general use of titanium tetraisopropoxide in excess to
obtain sufficient turnover frequencies and high enantio-
selectivities, the amount of excess titanium tetraisoprop-
oxide could be reduced to 0.2equiv in the reactions
catalyzed by 2a and 2b. It was proposed that o-phenyl-
enebis(ethynyl)-tethered 2a catalyzed the reaction
through transition-state assembly 11 keeping its closed
structure.
4.3. Asymmetric ethylation of aldehydes 3 catalyzed by
bis-(BINOLate)-Ti2 complexes 2a–c (a representative
procedure; Table 1, entry 2)
To a solution of bis-BINOL (R,R)-1a5 (34.7mg,
0.05mmol) in CH2Cl2 (4mL) at room temperature un-
der argon atmosphere was added titanium tetraisoprop-
oxide (0.16mL, 0.55mmol). The resulting solution of
catalyst 2a was stirred for 1h at room temperature.
To this at 0°C was added diethylzinc (1M in hexane,
1.5mL,3 1.5mmol) and stirring was continued for
20min. To the resulting mixture was added benzalde-
hyde (53mg, 0.5mmol) at 0°C. After being stirred for
19h, the reaction mixture was quenched by the addition
of aqueous 1M HCl and extracted twice with ethyl ace-
tate. The organic layers were washed with aqueous 5%
NaHCO3, dried (MgSO4), analyzed by capillary GC
(OV-1) to determine the conversion, and concentrated
in vacuo. The residue was purified by flash column
chromatography (silica gel, 15% ethyl acetate in hexane)
to give (R)-1-phenylpropanol of 88% ee. The enantiose-
lectivity was determined by HPLC analysis using a chi-
ral stationary phase column (Chiralcel OD; 1mL/min,
4. Experimental
4.1. General
GC analyses were performed with a capillary column:
(OV-1, 30m). Flash column chromatography was per-
formed using silica gel (Wakogel C-300) as absorbent.
Toluene was dried and distilled over Na–benzophenone
ketyl. Dichloromethane and triethylamine were dried
and distilled over CaH2.
4.2. (R)-3-Phenylethynyl-1,10-bi-2-naphthol 5
A mixture of phenylacetylene (0.204g, 2.0mmol),
(R)-2,20-bis(methoxy(methoxy))-3-iodo-1,10-binaphthyl
(1.10g, 2.2mmol), Pd(PPh3)4 (0.119g, 0.10mmol), and
CuI (38mg, 0.20mmol) in Et3N (10mL) and toluene
(9mL) was stirred at 60°C for 8h under argon atmos-
phere. The reaction mixture was filtered and the filtrate
was poured into aq 1N HCl and extracted twice with
ethyl acetate. The organic layers were dried (Na2SO4)
and concentrated in vacuo. The residue was purified
by flash column chromatography (silica gel, toluene)
to give 0.884g (93% yield) of 3-phenylethynyl-2,20-
bis(methoxy(methoxy))-1,10-binaphthyl as an amor-
3% i-PrOH in hexane, major
R
enantiomer;
t1 = 13.6min, minor S enantiomer; t2 = 15.5min). The
absolute structure of the product was determined by
comparing the retention time with that of an authentic
sample.
Reactions using 20or 10mol% of the catalysts were car-
ried out at 0.125M of a substrate in CH2Cl2. Reactions
at 2mol% catalyst load were performed at 0.25M.
1
phous solid; H NMR (500MHz, CDCl3): d 2.66 (3H,
s, CH3O–), 3.16 (3H, s, CH3O–), 4.94 (1H, d,
J = 5.9Hz, O–CH2–O), 5.01 (1H, d, J = 6.9Hz, O–
CH2–O), 5.05 (1H, d, J = 5.9Hz, O–CH2–O), 5.17
(1H, d, J = 6.9Hz, O–CH2–O), 7.17–7.29 (5H, m),
7.31–7.44 (4H, m), 7.55–7.61 (3H, m), 7.87 (2H, d,
J = 8.2Hz), 7.97 (1H, d, J = 9.0Hz), 8.22 (1H, s); IR
4.4. Determination of alcohol enantiomeric excesses
Unless otherwise mentioned, ee values of ethylation
products 4 were determined by HPLC analysis using a
chiral stationary phase column (Chiralcel OD). For
1-naphthyl-1-propanol [0.8mL/min, 10% i-PrOH in
hexane, minor (S)-enantiomer; t1 = 11.8min, major
(R)-enantiomer; t2 = 22.5min]; 1-(p-methylphenyl)-1-
propanol [1mL/min, 0.1% i-PrOH in hexane, major
(R)-enantiomer; t1 = 77.0min, minor (S)-enantiomer;
t2 = 90.0min]; 1-phenyl-3-pentanol [1mL/min, 3% i-
PrOH in hexane, major (R)-enantiomer; t1 = 15.0min,
minor (S)-enantiomer; t2 = 25.0min]. The ee value of
1-(p-trifluoromethylphenyl)-1-propanol was determined
by converting the alcohol to (S)-MTPA ester derivative;
(KBr disk) 3055, 2365, 1015, 810, 750cmꢀ1
.
To a mixture of the bis-MOM derivative (1.28g,
˚
2.7mmol) and molecular sieves 4A (2.5g) in CH2Cl2
(80mL) at 0 °C was added bromotrimethylsilane
(3.6mL, 27mmol).12 After being stirred for 6h at 0°C,
the reaction mixture was filtered. The filtrate was poured
into aqueous 5% NaHCO3 and extracted twice with
Et2O. The organic layers were dried (MgSO4) and
concentrated in vacuo. The residue was purified by flash

T. Harada et al. / Tetrahedron: Asymmetry 15(2004) 3879–3883
3883
1H NMR (500MHz, CDCl3): d 0.95 (3H, t, J = 6.4Hz,
CH3CH2), 1.83–2.02 (2H, m, CH3CH2), 3.48 (3H, br s,
CH3O), 5.87 (1H, t, J = 6.9Hz, Ar(CH3CH2)CH–O),
7.29–7.45 (7H, m), 7.56 (2H, d, J = 8.1Hz) [minor dia-
stereomer resonated at 3.47 (3H, br s, CH3O), and
5.96 (1H, t, J = 6.9Hz, Ar(CH3CH2)CH–O)].
Soc. 2000, 122, 2252; (d) Matsunaga, S.; Kumagai, N.;
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Harada, S.; Okada, S.; Sakamoto, S.; Yamaguchi, K.;
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7. Mori, M.; Nakai, T. Tetrahedron Lett. 1997, 38,
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