Catalytic asymmetric alkylation of aldehydes by using trialkylboranes

Article abstract of DOI:10.1002/ejoc.200800561

Triethylborane can be used in the asymmetric alkylation of aldehydes by using a 3-(3,5-diphenylphenyl)-H₈-BINOL-derived titanium(IV) catalyst in the presence of an excess amount of titanium tetraisopropoxide. The reaction proceeds with a low catalyst loading (2 mol-%), exhibiting high enantioselectivity for aromatic and unsaturated aldehydes. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800561

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800561
Catalytic Asymmetric Alkylation of Aldehydes by Using Trialkylboranes
[a]
[a]
Takahiro Ukon and Toshiro Harada*
Keywords: Asymmetric catalysis / Alkylation / asymmetric synthesis / Boron / Titanium
Triethylborane can be used in the asymmetric alkylation of
aldehydes by using a 3-(3,5-diphenylphenyl)-H -BINOL-de-
rived titanium(IV) catalyst in the presence of an excess
amount of titanium tetraisopropoxide. The reaction proceeds
with a low catalyst loading (2 mol-%), exhibiting high
8
enantioselectivity for aromatic and unsaturated aldehydes.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
literature precedent, the direct use of trialkylboranes with-
out converting into alkylzinc species would significantly ex-
pand the scope of the catalytic asymmetric alkylation of
aldehydes.
The catalytic asymmetric addition of organometallic rea-
gents to aldehydes and ketones is a reaction of fundamental
importance in modern synthetic organic chemistry. The re-
sulting enantiomerically enriched chiral alcohols are valu-
able intermediates, for example, in the production of phar-
macologically active compounds. Generally, diorganozinc
reagents have been utilized for this transformation in com-
Herein, we wish to report the asymmetric alkylation of
aldehydes with a mixture of triethylborane and titanium tet-
raisopropoxide catalyzed by a titanium complex derived
from 3-(3,5-diphenylphenyl)-H -BINOL (DPP-H -BINOL
8
8
4). High enantioselectivity (up to 97%ee) could be obtained
bination with a variety of catalyst systems.[
nately, however, few organozinc reagents are commercially
available and their preparation is not always straightfor-
ward.
1–3]
at a low catalyst loading (2 mol-%) by a simple reaction
procedure.
Unfortu-
To circumvent such limitations, most recently, attention
has been focused on the use of other organometallic rea-
Results and Discussion
[
4–7]
gents.
For asymmetric arylation reactions, the scope of
When a mixture of 1-naphthaldehyde, triethylborane
[
11]
aryl groups that could be introduced has been extended sig- (1.5 equiv.), (R)-BINOL (1;
5 mol-%), and titanium tet-
nificantly by the use of arylboronic acids and their deriva- raisopropoxide (5.6 equiv.) in THF was heated under reflux
tives either through in situ transformation to arylzinc rea- for 2 h, the corresponding ethylation product (R)-5a was
[4]
gents with diethylzinc or through direct catalysis by chiral obtained in 78% yield and in 84%ee [Equation (1); Table 1,
[5]
rhodium complexes. A recent report from this labora- Entry 1). The minor formation of a reduction product, 1-
[
8]
tory showed that readily available alkyl Grignard reagents naphthylmethanol, (8%) was observed. Encouraged by this
can be employed in the asymmetric alkylation of aldehydes result, we surveyed other BINOL derivatives. Improved
by using a titanium(IV) catalyst derived from 3-(3,5-di- enantioselectivity of 89%ee was obtained with (R)-H
-BI-
ex-
8
[13]
[
12]
phenylphenyl)-BINOL (DPP-BINOL 3) in the presence of NOL (2;
Table 1, Entry 2). (R)-DPP-BINOL (3)
an excess amount of titanium tetraisopropoxide.[
9]
hibited better enantioselectivity of 91%ee either under re-
Because a variety of alkylboranes are commercially avail- fluxing conditions or at room temperature (Table 1, En-
able and can be readily prepared by hydroboration of al- tries 3 and 4). We recently reported that (R)-DPP-H -BI-
8
kenes, they are also promising candidates for practical al- NOL (4) showed enantioselectivity higher than DPP-BI-
kylating reagents. Indirect use of trialkylboranes in asym- NOL (3) in the asymmetric alkylation of aldehydes with
[
14]
metric alkylation reactions has been reported by a boron– Et
Zn. The best result of 97%ee was obtained with this
Although there has been no ligand (Table 1, Entry 5).
With this ligand, the catalyst loading and the amount of
2
zinc exchange reaction.[
10,3d]
titanium tetraisopropoxide could be reduced to 2 mol-%
and 3 equiv., respectively, without degrading the enantio-
selectivity and yield of the product (Table 1, Entry 7). Fur-
ther reduction of the catalyst loading resulted in degraded
enantioselectivity and an increase in the formation of the
reduction product (Table 1, Entry 11). The amount of the
[
a] Department of Chemistry and Materials Technology, Kyoto In-
stitute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585,
Japan
Fax: +81-75-724-7514
E-mail: harada@chem.kit.ac.jp
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
Eur. J. Org. Chem. 2008, 4405–4407
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4405

T. Ukon, T. Harada
SHORT COMMUNICATION
Table 2. Asymmetric alkylation of aldehydes with Et
3
B catalyzed
by the DPP-H
8
-BINOL derived titanium complex.[
a]
Entry
Aldehyde
Product
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
1-Naphthyl-CHO
PhCHO
5a
5b
5c
5d
5e
5f
83
93
85
87
74
87
73
94
49
90
83
73
37
28
96
96
96
93
96
97
94
97
84
96
57
85
92
92
p-MeC
p-PhC
p-ClC
6
H
H
4
H
4
4
-CHO
-CHO
-CHO
-CHO
-CHO
-CHO
-CHO
6
6
p-FC
p-CF
6
H
4
C
3
6
H
4
H
5g
5h
5i
m-MeOC
o-ClC H
4
6
4
6
10
11
12
13
14
2-Naphthyl-CHO
2-Furyl-CHO
PhCH=CHCHO
5j
5k
5l
PhCH
2
CH
2
-CHO
5m
3
Table 1. Asymmetric ethylation of 1-naphthaldehyde with Et B
catalyzed by titanium complexes derived from BINOL derivatives
[b]
[c]
1-Naphthyl-CHO
6
[
a]
1
–4.
[
a] Unless otherwise noted, reactions were carried out with Et
(1.5 equiv.), DPP-H -BINOL (2 mol-%), and Ti(OiPr) (3 equiv.) in
THF at 66 °C for 2–3 h. [b] The reaction was carried out with
nBu B (1.5 equiv.) for 5 h. [c] 6: 1-(Naphthalen-1-yl)pentan-1-ol.
3
B
Red.[b]
[%]
8
4
Entry
Ligand
Ti(OiPr)
[equiv.]
4
Yield
[%]
ee
[%]
(mol-%)
3
1
2
3
1 (5)
2 (5)
3 (5)
3 (5)
4 (5)
4 (5)
4 (2)
4 (2)
4 (2)
4 (2)
4 (1)
– (0)
5.6
5.6
5.6
5.6
5.6
3.0
3.0
1.2
0.1
0.0
3.0
3.0
78
70
73
76
86
73
83
70
0
84
89
91
91
97
97
96
96
–
8
12
4
11
3
7
6
12
9
8
11
6
To gain insight into the mechanism of the present asym-
metric alkylation reaction, several control experiments were
carried out. In the absence of ligand 4, a slow alkylation
reaction of 1-naphthaldehyde was observed with a mixture
of triethylborane and titanium tetraisopropoxide (3 equiv.;
[
c]
4
5
6
7
8
9
1
1
1
[15]
[
16]
Table 1, Entry 12).
In the presence of 4 (2 mol-%), the
0
1
2
0
74
21
–
93
–
ethylation reaction with triethylborane did not proceed at
all either with a catalytic amount of titanium tetraisopro-
poxide or without it (Table 1, Entries 9 and 10). Although
transmetalation of a trialkylborane to give alkyltitanium
compounds has not been reported,
titanium tetraisopropoxide in more than a stoichiometric
amount suggests that the active alkylating reagent of the
[
6
a] Reactions were carried out with Et
6 °C for 2–3 h. [b] The yield of a reduction product, 1-naph-
thylmethanol. [c] The reaction was carried out at room temperature
for 24 h.
3
B (1.5 equiv.) in THF at
[
17]
the requirement of
byproduct was also increased when the amount of titanium
tetraisopropoxide was reduced to 1.2 equiv. (Table 1, En-
try 8).
Under the optimized conditions with 2 mol-% of DPP-
H -BINOL (4; Table 1, Entry 7), a variety of aromatic alde-
8
present reaction is EtTi(OiPr) , or its aggregate with
3
Et B(OiPr), generated in equilibrium. EtTi(OiPr) has been
2
3
demonstrated to be an active alkylating reagent in BINOL-
ate-Ti-catalyzed asymmetric alkylation reactions with
[
15a]
Et Zn.
2
The above supposition is also in accord with the
hydes underwent a smooth reaction with triethylborane to
give the corresponding ethylation products 5a–k in high
enantioselectivity (93–97%ee) except for the reaction of o-
chlorobenzaldehyde and 2-furaldehyde [Equation (2);
Table 2, Entries 1–11). Lower, still acceptable, enantio-
selectivity was obtained in the reaction of an α,β-unsatu-
rated aldehyde (Table 2, Entry 12). The reaction of an ali-
phatic aldehyde was sluggish, affording the ethylation prod-
uct in low yield but with high enantioselectivity (Table 2,
Entry 13). When tributylboron was used instead of trieth-
ylborane, the reaction was also sluggish (Table 2, Entry 14).
The reaction of 1-naphthaldehyde after 5 h afforded (R)-1-
observed trends in enantioselectivity for various aldehydes
that are similar to those observed with Et Zn by using
2
[
14]
DPP-H -BINOL (4).
8
Conclusions
We demonstrated that triethylborane can be used in
asymmetric alkylation of aldehydes by using a DPP-
BINOL-derived titanium(IV) catalyst in the presence of an
excess amount of titanium tetraisopropoxide. The reaction
proceeds with a low catalyst loading (2 mol-%), exhibiting
high enantioselectivity for aromatic and unsaturated alde-
hydes. Work is in progress to investigate the full scope of
the reaction.
(naphthalen-1-yl)pentan-1-ol (6) in 92%ee and 28% yield. 1-
Naphthylmethanol (49%) was obtained as a major product.
Experimental Section
Preparation of (R)-1-Naphthalen-1-ylpropan-1-ol (5a) as a Represen-
tative Procedure for the Asymmetric Alkylation Reaction: A solution
4406
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4405–4407

Catalytic Asymmetric Alkylation of Aldehydes by Using Trialkylboranes
of triethylborane (1  in THF, 0.75 mL, 0.75 mmol) was added to
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O (3ϫ).
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2
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11b]
(
R)-BINOL as a ligand[
(Table 1, Entry 7).
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Eur. J. Org. Chem. 2008, 4405–4407
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4407