Indium-mediated Barbier-type allylation of aldehydes as a convenient method for the highly enantioselective synthesis of homoallylic alcohols

Article abstract of DOI:10.1016/j.tetlet.2005.01.169

We report a general method for the indium-mediated Barbier-type enantioselective allylation of both aromatic and aliphatic aldehydes using commercially available (1S,2R)-(+)-2-amino-1,2-diphenylethanol as a chiral auxiliary. Using only two equivalents of allyl bromide, excellent yields and very good to excellent enantioselectivities are obtained. To our knowledge, the enantioselectivities reported herein are the highest obtained for indium-promoted allylations of carbonyl compounds.

Full text of DOI:10.1016/j.tetlet.2005.01.169

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2315–2318
Indium-mediated Barbier-type allylation of aldehydes as
a convenient method for the highly enantioselective
synthesis of homoallylic alcohols
Lacie C. Hirayama, Soya Gamsey, Daniel Knueppel, Derek Steiner,
Kelly DeLaTorre and Bakthan Singaram*
Department of Chemistry and Biochemistry, University of California at Santa Cruz, 1156 High St, Santa Cruz, CA 95064, USA
Received 22 January 2005; accepted 31 January 2005
This paper is dedicated to the memory of Professor Herbert C. Brown
Abstract—We report a general method for the indium-mediated Barbier-type enantioselective allylation of both aromatic and
aliphatic aldehydes using commercially available (1S,2R)-(+)-2-amino-1,2-diphenylethanol as a chiral auxiliary. Using only two
equivalents of allyl bromide, excellent yields and very good to excellent enantioselectivities are obtained. To our knowledge, the
enantioselectivities reported herein are the highest obtained for indium-promoted allylations of carbonyl compounds.
Ó 2005 Elsevier Ltd. All rights reserved.
The asymmetric allylation of aldehydes to form enantio-
merically pure homoallylic alcohols remains a method-
ology of increasing interest,1,2 as these products are
important synthetic building blocks for making an array
of chiral compounds.3,4 Indium-promoted reactions are
attractive because indium, as opposed to other metals, is
less air- and moisture-sensitive, significantly less toxic,
and able to tolerate numerous functionalities.5,6 It has
been reported that indium-mediated allylations of alde-
hydes using a sixfold excess of allyl halide can proceed
with good enantioselectivity when cinchonidine is used
as the chiral promoter.7 Herein, we report a simple
method for the enantioselective allylation of aldehydes
using a twofold excess of allyl bromide, a commercially
available chiral amino alcohol, and metallic indium.
study began by screening the various limonene-based
amino alcohols that have been developed in our labora-
tory.9 During these studies we discovered that adding a
stoichiometric amount of pyridine to the reaction in-
creased both the yield and enantiomeric excess of the
homoallylic alcohol product. Utilizing benzaldehyde,
2 equivof the limonene amino alcohol ligands, 2 equiv
of indium, and using a large excess of allylbromide as
recommended in the literature,7 the corresponding
homoallylic alcohol was obtained in very good yields,
but the maximum asymmetric induction achieved was
only 40%. Consequently, we screened a wide variety of
commercially available amino alcohols to assess their
efficiency as chiral directors in this reaction.
These studies revealed (1S,2R)-(+)-2-amino-1,2-diphen-
ylethanol (1a) to be an effective chiral promoter in
the allylation of benzaldehyde (Table 1, entry 1).
Encouraged by these preliminary results, we then looked
to optimize the reaction conditions. We began by reduc-
ing the amount of allyl bromide from 6 equivto 2 equiv
with respect to the aldehyde. To our delight, this change
resulted in 99% conversion and a notable increase in
enantioselectivity to 93% ee (Table 1, entry 2). Attempts
to further decrease the amount of allyl bromide lowered
both conversion and enantioselectivity (Table 1, entry
5). We also verified that the addition of pyridine was
We have previously shown that limonene-based amino
alcohols can serve as effective ligands for enantioselec-
tive diethylzinc additions to aldehydes,8 and we envi-
sioned extending their use as chiral auxiliaries for the
asymmetric allylation of aldehydes using indium. Our
Keywords: Indium; Allylation; Amino alcohol; Homoallylic alcohol;
Asymmetric.
*
Corresponding author. Tel.: +1 831 4593479; fax: +1 831 4592935;
e-mail: singaram@chemistry.ucsc.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.169

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L. C. Hirayama et al. / Tetrahedron Letters 46 (2005) 2315–2318
Table 1. Optimization of enantioselective allylation of benzaldehydea
Entry
In0
1a
Pyridine
Allylbromide
% Convb
% Eeb(S)c
1
2
3
4
5
6
2
2
2
1
2
1
2
2
2
2
2
1
2
2
0
2
2
1
6
2
2
2
1
1
99
99
65
50
55
50
76
93
60
66
70
79
a Table values refer to number of equivalents. Reactions run with benzaldehyde (0.5 mmol).
b Determined by chiral GC analysis.
c Absolute configuration determined by comparison of the optical rotation with literature value.7
Table 2. Screening of chiral auxiliaries for the enantioselective
allylation of benzaldehyde with allyl bromidea
study, we identified the optimal reaction conditions
and stoichiometry to be that shown in entry 2 (Table 1).
In an attempt to improve our system further, we
screened other structurally similar ligands under the
optimized reaction conditions. Norephedrine, ephed-
rine, and pseudoephedrine were found to be significantly
less effective as chiral promoters (Table 2, entries 7, 8,
and 9, respectively). In addition, a series of secondary
N-substituted derivatives of 2-amino-1,2-diphenyletha-
nol were synthesized and evaluated (Fig. 1). Use of the
N-methyl, N-isopropyl, N-a-methylbenzyl, and N-tosyl
derivatives resulted in decreased conversion and ee
(Table 2, entries 2, 3, 4, and 5, respectively). Interest-
ingly, when a tertiary amine (N-pyrrolidino) was used
as the chiral promoter, no product formation was
observed after 1.5 h (Table 2, entry 6).10 The results of
this study clearly show unmodified 1a to be the most
effective ligand for our system.
Entry
Ligand*
% Conversionb (S)
% Eeb,c
1
2
3
4
5
6
7
8
9
1a
1b
2a
1c
1d
2b
3a
3b
4
99
13
10
50
33
0
93(S)
62(S)
46(R)
8(S)
0
0
98
50
81
30(R)
34(R)
20(R)
a Reactions run with In0 (1.0 mmol), chiral auxiliary (1.0 mmol), pyri-
dine (1.0 mmol), allyl bromide (1.0 mmol), and benzaldehyde
(0.5 mmol) in THF/n-hexane at À78°C for 1.5 h.
b Determined by chiral GC analysis.
c Absolute configuration determined by comparison of the optical
rotation with literature value.7
To evaluate the generality of this reaction, we performed
the allylation on several different aldehydes (Table 3).
As can be seen from the summarized results, this method
is effective for a range of substituted aromatic aldehydes.
Additionally, excellent enantioselectivity is attained with
cyclohexylcarboxaldehyde (Table 3, entry 11), allowing
this system to be extended to aliphatic aldehydes as well.
These data also show that functionality on the aromatic
aldehyde is tolerated during the reaction (Table 3, en-
tries 2, 9, and 10). Upon close inspection of the data
in Table 3, we noticed that aldehydes with a strong elec-
tron-donating group in the para-position (Table 3,
advantageous (Table 1, entry 3), but that raising the
reaction temperature above À78°C decreased the
enantioselectivity in a linear fashion. Interestingly,
reducing the amount of either the indium or allyl bro-
mide in the reaction resulted in only 50% conversion
to the homoallylic alcohol product (Table 1, entries 4
and 6). This result suggests the possibility of the forma-
tion of a reactive dimer.5 Based on this optimization
Figure 1. Ligands used in the indium-mediated allylation of benzaldehyde with allyl bromide.

L. C. Hirayama et al. / Tetrahedron Letters 46 (2005) 2315–2318
Table 3. Enantioselective allylation using 1a as a chiral promotera
2317
References and notes
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1
Ph
90
92
94
97
92
97
90
92
94
99
93
93
89
88
79
87
78
80
93
76
80
93e
2
4-CH3O–C6H4
o-CH3–C6H4
m-CH3–C6H4
p-CH3–C6H4
2-Cl–C6H4
3-Cl–C6H4
4-Cl–C6H4
4-CH3O2C–C6H4
4-CN–C6H4
Cyclohexyl
3
4
5
6
7
8
9
10
11
a Reactions run with In0 (2.0 mmol), 1a (2.0 mmol), pyridine (2.0 mmol),
allyl bromide (2.0 mmol), and aldehyde (1.0 mmol) in THF/n-hexane
at À78°C for 1.5 h.
b Isolated yield of analytically pure product.
c Determined by chiral GC analysis.
d Absolute configuration determined by comparison of the optical
rotation with literature value,7 all others were assigned by analogy.
e
Enantiomeric excess determined by chiral GC analysis of the acetyl-
ated homoallylic alcohol.
entries 2 and 5) give a higher enantiomeric excess than
those with an electron-withdrawing group in the para-
position (Table 3, entries 9 and 10).11 Apparently, elec-
tron-withdrawing groups increase the reactivity of the
aldehyde functionality, therefore decreasing the enantio-
selectivity of the reaction.
In summary, we have demonstrated a general method for
the indium-promoted enantioselective allylation of both
aromatic and aliphatic aldehydes using commercially
available (1S,2R)-(+)-2-amino-1,2-diphenylethanol as a
chiral auxiliary and using only two equivalents of allyl
bromide. The homoallylic alcohol products are obtained
in high enantiomeric excesses and in excellent yields and
purity. Furthermore, the amino alcohol ligand can be
recovered via a simple acid–base extraction.12 We are
presently extending this method to functionalized allylic
halides, and studies to elucidate mechanistic details are
also currently underway.
Acknowledgements
The authors thank LubovPasumansky for her technical
support.
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Supplementary data
Experimental procedures and characterization data for
homoallylic alcohol products and synthesized ligands.
This material is available free of charge via the
WWW. Supplementary data associated with this article
can be found, in the online version at doi:10.1016/
j.tetlet.2005.01.169.
6. For recent examples see: (a) Paquette, L. A. Synthesis
2003, 765–774; (b) Loh, T.-P.; Yin, Z.; Song, H.-Y.; Tan,

2318
L. C. Hirayama et al. / Tetrahedron Letters 46 (2005) 2315–2318
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