Asymmetric indium-mediated synthesis of homopropargylic alcohols

Article abstract of DOI:10.1016/j.tetlet.2006.05.049

A method for the enantioselective synthesis of homopropargylic alcohols using indium under Barbier-like conditions is reported herein. Both aromatic and aliphatic aldehydes were successfully converted to the corresponding homopropargylic alcohols in good

Full text of DOI:10.1016/j.tetlet.2006.05.049

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Tetrahedron Letters 47 (2006) 5173–5176
Asymmetric indium-mediated synthesis of homopropargylic alcohols
Lacie C. Hirayama, Kevin K. Dunham and Bakthan Singaram*
Department of Chemistry and Biochemistry, University of California at Santa Cruz, 1156 High St,
Santa Cruz, CA 95064, United States
Received 14 April 2006; accepted 9 May 2006
Abstract—A method for the enantioselective synthesis of homopropargylic alcohols using indium under Barbier-like conditions is
reported herein. Both aromatic and aliphatic aldehydes were successfully converted to the corresponding homopropargylic alcohols
in good yield and high enantiomeric excesses using propargyl bromide, indium, and (1S,2R)-(+)-2-amino-1,2-diphenylethanol as a
chiral auxiliary.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Enantiomerically pure homopropargylic alcohols are
valuable synthetic intermediates used in the preparation
of complex molecules.1 Various asymmetric methodolo-
gies have been developed for the synthesis of homoprop-
argylic alcohols from aldehydes and allenylmetal
reagents.2 For example, it has recently been shown that
an air stable chiral allenylborane made from a Grignard
reagent can produce homopropargylic alcohols with
excellent enantioselectivity.3
by changing the solvent or substitution of the propargyl
halide.8 Chan and co-workers have studied the identity
of the organoindium species under various conditions.8c
Under the reaction conditions described herein (R = H),
the homopropargylic alcohol (1) is observed to be the
sole product.
Previously, we reported the highly enantioselective allyl-
ation of aldehydes using allyl bromide, indium, and
commercially available (1S,2R)-(+)-2-amino-1,2-diphen-
ylethanol as the chiral auxiliary. In this reaction, the
addition of a stoichiometric amount of pyridine not only
improved the yield of the reaction, but also increased the
ee of the homoallylic alcohol.9 Herein, we describe the
use of indium and (1S,2R)-(+)-2-amino-1,2-diphenyl-
ethanol (3) to mediate the asymmetric addition of prop-
argyl bromide to aldehydes under Barbier-like
conditions to synthesize homopropargylic alcohols in
high enantiomeric purity (Scheme 2).
Many researchers are now exploring the use of indium
in organic reactions.4 For instance, several examples of
asymmetric indium-mediated allylations have been re-
ported.5 However, only one example has been reported
for the asymmetric indium-mediated propargylation of
aldehydes.6
It is known that many allenylmetals can undergo a
metallotropic rearrangement resulting in either homo-
propargylic alcohol (1) or allenylic alcohol (2) upon
reaction with an aldehyde (Scheme 1).7 It has been
found that with indium, the ratio of 1:2 can be varied
Using 2 equiv of indium(0), 3, propargyl bromide, and
pyridine, the optimal temperature of the reaction was
LnIn
OH
R
OH
R
RCHO
In
+
+
Br
R
R
solvent
R
R
R
1
2
InLn
Scheme 1.
*
Corresponding author. Tel.: +1 831 459 3154/83; fax: +1 831 459 2935; e-mail: singaram@chemistry.ucsc.edu
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.049

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L. C. Hirayama et al. / Tetrahedron Letters 47 (2006) 5173–5176
Table 1. Temperature effects on the asymmetric indium-mediated
O
OH
In, 3
+
Br
propargylation of benzaldehydea
R
H
R
py, THF
Entry Time (h) Temperature (ꢁC) % Conversionb % eec
(isolated yield) (S)d
HO
Ph
NH2
Ph
1
2
3
4e
5
6
7
8
9
2
2.5
16
16
16
2.5
2.5
2.5
2.5
ꢀ78
58
87
91 (90)
>97
>97
87
89
88
48
76
74
88
89
77
84
83
84
89
ꢀ78 ! 25 (fast)
ꢀ78 ! 25 (slow)
3
ꢀ78 ! 25 (slow)
25
0
Scheme 2.
ꢀ20
ꢀ40
ꢀ60
investigated (Table 1). Although the enantioselectivity
of the reaction at ꢀ78 ꢁC for 2 h was 76% (Table 1, entry
1), the conversion to the homopropargylic alcohol was
only 58% based on unreacted aldehyde. By removing
the dry ice/acetone bath after a period of 2 h and letting
the flask warm to room temperature we were able to
increase the yield of the alcohol, without compromising
the enantioselectivity (Table 1, entry 2). Based on the
results of a temperature study (Table 1), we observed
the highest enantioselectivity (89% ee, entry 9) at
ꢀ60 ꢁC. However, cooling the flask to ꢀ78 ꢁC for the
addition of the aldehyde then allowing the flask to
slowly warm to room temperature overnight gave
comparable ee, but a much higher conversion to the
alcohol product (Table 1, entry 3). In addition, it is note-
a Reactions run with In0 (1.0 mmol),
3 (1.0 mmol), pyridine
(1.0 mmol), propargyl bromide (1.0 mmol), and aldehyde (0.5 mmol)
in THF.
b Percent conversion determined by 1H NMR.
c Determined by chiral GC analysis.
d Absolute configuration determined by comparison of the optical
rotation with literature value.3
e THF/hexanes 7:1.
worthy that we use only 2 equiv of propargyl bromide in
our reaction.6
In order to explore the generality of this reaction, we
screened a variety of structurally diverse aldehydes
Table 2. Enantioselective indium-mediated propargylation of aromatic aldehydesa
Entry
Aldehyde
Product
% Yieldb
90
% eec
O
OH
1
88 (S)d
H
O
OH
2
3
89
82
84 (S)
88 (S)
H
Cl
Cl
O
OH
H
MeO
MeO
O
OH
OH
4
5
75
90
83 (S)
H
NC
HO
NC
HO
O
85e (S)
H
O
O
OH
O
O
6
7
78
69
78 (S)
78 (S)
H
H
OH
O
O
a Reactions run with In0 (1.0 mmol), 3 (1.0 mmol), pyridine (1.0 mmol), propargyl bromide (1.0 mmol), and aldehyde (0.5 mmol) in THF (see Table
1, entry 3).
b Isolated yield.
c Determined by chiral GC analysis.
d Absolute configuration determined by comparison of the optical rotation with literature value.3 All others were assigned by analogy.
e Enantiomeric excess determined by chiral GC analysis of the diacetylated homopropargylic alcohol.

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L. C. Hirayama et al. / Tetrahedron Letters 47 (2006) 5173–5176
Table 3. Enantioselective indium-mediated propargylation of aliphatic aldehydesa
5175
Entry
Aldehyde
Product
% Yieldb
63
% eec
O
OH
1
74e (R)d
H
O
OH
OH
2
60
83 (S)
H
O
3
4
53
71
95e (S)
75 (S)
H
O
OH
H
a Reactions run with In0 (1.0 mmol), 3 (1.0 mmol), pyridine (1.0 mmol), propargyl bromide (1.0 mmol), and aldehyde (0.5 mmol) in THF (see Table
1, entry 3).
b Isolated yield.
c Determined by chiral GC analysis.
d Absolute configuration were assigned by analogy.
e Enantiomeric excess determined by chiral GC analysis of the acetylated homopropargylic alcohol.
under the optimized reaction conditions (Table 1, entry
3).10 The results of this study are shown in Tables 2 and
3. Both aromatic and aliphatic aldehydes are converted
to the corresponding homopropargylic alcohols in very
good yield and high enantioselectivities.
products are obtained in high yield, and with enantio-
meric excesses up to 95%. To our knowledge, the enantio-
selectivities reported herein are the highest obtained for
indium-promoted propargylations. Furthermore, the
amino alcohol ligand, which is commercially available
in either enantiomer, can be recovered via a simple
acid–base extraction.11
Various aromatic aldehydes have been propargylated in
high enantiomeric excesses and these results are shown
in Table 2. Benzaldehyde was converted to 4-phenyl-1-
butyn-4-ol in 90% isolated yield and 88% ee (entry 1).
Functionalized aldehydes were used in order to investi-
gate the chemoselectivity of this asymmetric propargyla-
tion reaction. Gratifyingly, comparable results were
obtained with the functionalized benzaldehyde
derivatives. 4-Chlorobenzaldehyde, p-anisaldehdye,
and 4-cyanobenzaldehdye gave the corresponding
homopropargylic alcohols in 84%, 88%, and 83% ee,
respectively (entries 2–4, respectively). Most notably,
3-hydroxybenzaldehdye also gave 85% ee, showing that
this reaction tolerates an unprotected phenol (entry 5).
Additionally, 2- and 3-furaldehdye both furnished the
homopropargylic alcohol in 78% ee (entries 6 and 7,
respectively).
Acknowledgements
The authors thank Soya Gamsey and Lubov Pasuman-
sky for their helpful discussions.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2006.05.049.
References and notes
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