Direct asymmetric iodination of aldehydes using an axially chiral bifunctional amino alcohol catalyst

Article abstract of DOI:10.1021/ja074003o

A direct asymmetric iodination reaction of aldehydes with NIS was found to be catalyzed by the novel axially chiral bifunctional amino alcohol (S)-1d. This method represents the rare example of the catalytic and highly enantioselective synthesis of optically active α-iodoaldehydes. Copyright

Full text of DOI:10.1021/ja074003o

Published on Web 03/06/2008
Direct Asymmetric Iodination of Aldehydes Using an Axially Chiral
Bifunctional Amino Alcohol Catalyst
Taichi Kano, Mitsuhiro Ueda, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Received June 2, 2007; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Development of organocatalytic reactions is one of the most
exciting topics in practical organic synthesis because of its
operational simplicity, mild reaction conditions, and environ-
mental consciousness.1 In this area, various asymmetric R-func-
tionalization reactions of aldehydes and ketones were found to be
successfully catalyzed by chiral pyrrolidines (e.g., proline) and their
equivalents through their enamine intermediates.2 Such highly
nucleophilic and basic pyrrolidine-type catalysts, however, might
Table 1. Organocatalytic Direct Asymmetric Iodination of
3-Methylbutanal with NISa
not be appropriate for some specific asymmetric R-functionalizaion
reactions such as iodination of aldehydes due to the undesired side
reactions including self-aldol reaction and racemization of the
product.3 On the other hand, while a less nucleophilic and less
entry
catalyst
solvent
% conversionb
% eec
basic binaphthyl-based amine is supposed to suppress such side
reactions, its enamine is occasionally not reactive enough to undergo
the R-functionalizaion reactions (Scheme 1). We have therefore
been interested in the activation of certain electrophiles by
introducing hydroxyl groups on such an amine catalyst to promote
the desired R-functionalization with suppressing side reactions.
An asymmetric iodination of aldehydes was chosen to exemplify
this concept. Although some organocatalytic asymmetric R-halo-
genation reactions of aldehydes have been reported,4-6 examples
of asymmetric synthesis of R-iodoaldehydes as a member of
synthetically valuable R-haloaldehydes are especially scarce despite
their characteristic features including the high leaving group ability
and the steric bulk of the iodo group.6,7 Herein we wish to report
a direct asymmetric R-iodination of aldehydes using a novel axially
chiral bifunctional amino alcohol catalyst.
1
2
3
4
5
6
7
8
9
10
11
12
13d
pyrrolidine
THF
THF
THF
THF
THF
THF
THF
MeCN
DMF
CH2Cl2
toluene
Et2O
39
32
2
L-proline
(S)-diphenylprolinol
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S)-1d
(S)-1d
(S)-1d
-14
47
-10
-1
-26
80
12
45
32
76
14
23
67
28
46
23
73
65
48
94
(S)-1d
(S)-1d
(S)-1d
94
99
Et2O
a
The reaction of 3-methylbutanal and NIS (1.1 equiv) was carried out
in the presence of an amine catalyst (5 mol %) at 0 °C for 4 h. b Determined
by GC analysis using decane as an internal standard. c Determined by GC
analysis using chiral capillary column. Details are given in Supporting
Information. d Benzoic acid (5 mol %) was added.
Scheme 1
results (entries 2 and 3). The reaction using less nucleophilic
binaphthyl-based amine (S)-1a gave only a small amount of the
product as expected (entry 4). We then examined bifunctional
catalysts (S)-1b-d, which would activate NIS through hydrogen
bonding with hydroxylmethyl groups at 3,3′-positions. When (S)-
1b is used,8 the R-iodination was accelerated to give the R-iodoal-
dehyde in low yield with almost no enantioselectivity (entry 5).
With (S)-1c,8 the R-iodoaldehyde was obtained in moderate yield
albeit with low enantioselectivity (entry 6). To our surprise, use of
(S)-1d, which has sterically more congested and more acidic tert-
alcohol moieties at 3,3′-positions, afforded the iodination product
with the opposite enantiomer predominating (entry 7). We then
examined the solvent effects using (S)-1d (entries 7-12), and ether
was found to be the choice of solvent in terms of enantioselectivity
(entry 12). When 5 mol % of benzoic acid was employed as an
additive,6 a further increase in both yield and enantioselectivity was
observed (entry 13).
We first investigated R-iodination of 3-methylbutanal with
N-iodosuccinimide (NIS) in THF in the presence of 5 mol % of an
amine catalyst of type 1 at 0 °C, and the results are shown in Table
1. The use of pyrrolidine as a catalyst6 afforded the R-iodoaldehyde
in moderate yield along with the self-aldol byproducts (entry 1),
and chiral pyrrolidines, L-proline and (S)-diphenylprolinol gave poor
With the axially chiral bifunctional amino alcohol catalyst (S)-
1d in hand, the direct asymmetric R-iodination reaction of several
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J. AM. CHEM. SOC. 2008, 130, 3728-3729
10.1021/ja074003o CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Direct Asymmetric Iodination of Various Aldehydes with
NIS Catalyzed by (S)-1da
entry
R
% yieldb
% eec
entry
R
% yieldb
% eec
Figure 1. Transition state model for the direct asymmetric iodination
reaction catalyzed by (S)-1d.
1
i-Pr
Cy
Et
93 (36)
86 (34)
76 (32)
99
98
98
95
5
6
7
benzyl
CH2Cy
81 (80) 92f (R)
2d
3
74 (64) 90f
On the basis of the observed stereochemistry, a plausible
transition state is proposed (Figure 1). The activated and directed
NIS by hydroxyl group on (S)-1d approaches the Re face of the
enamine. Hence, the reaction of an aldehyde with NIS catalyzed
by (S)-1d provides R isomer predominantly.
In summary, we have developed a direct asymmetric iodination
reaction of aldehydes catalyzed by the novel axially chiral
bifunctional amino alcohol catalyst (S)-1d. This method represents
a rare example of the catalytic and highly enantioselective synthesis
of optically active R-iodoaldehydes. We are currently investigating
further application of R-iodoaldehydes by taking advantage of the
characteristic features of iodine containing compounds.
CH2 OBn 97 (30) 93f (R)
4 d,e allyl 98 (31)
a The reaction of an aldehyde and NIS (1.1 equiv) was carried out in
Et2O in the presence of (S)-1d (5 mol %) and benzoic acid (5 mol %) at
0 °C for 4 h. b Determined by GC analysis using an internal standard
technique. The numbers in parentheses are isolated yields of the corre-
sponding methyl esters. c Determined by GC analysis using chiral capillary
column. Details are given in Supporting Information. d Use of 10 mol %
of (S)-1d. e The reaction was carried out for 1 h. f Enantiomeric excess was
determined by conversion to the corresponding methyl ester and GC or
HPLC analysis.
other aldehydes with NIS was examined, and selected results are
shown in Table 2. In general, these direct asymmetric R-iodination
reactions proceeded smoothly to give the corresponding R-iodoal-
dehydes in good yields with excellent levels of enantioselectivities.
In order to assign the absolute configuration of the obtained
R-iodoaldehyde and to extend the synthetic utility of this transfor-
mation, an optically enriched R-iodoaldehyde 2 was converted to
the corresponding R-amino acid derivative (Scheme 2). Thus,
treatment of the R-iodoaldehyde 2 with KMnO4, followed by
addition of TMSCHN2, resulted in clean formation of the corre-
sponding methyl ester 3. By treatment with NaN3, the resulting
methyl ester 3 was transformed to the R-azido ester 4, which can
be readily reduced to the corresponding R-amino ester.5b By
comparison of optical rotation of the R-azido ester 4 with the
literature value the absolute configuration of the R-iodoaldehyde 2
was determined to be R.
Acknowledgment. This paper is dedicated to Professor E. J.
Corey on the occasion of his 80th birthday. This work was partially
supported by a Grant-in-Aid for Scientific Research on Priority
Areas “Advanced Molecular Transformation of Carbon Resources”
from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan. M.U. thanks the Japan Society for the Promo-
tion of Science for Young Scientists for Research Fellowships.
Supporting Information Available: Experimental details and
characterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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Scheme 2. Transformation of R-Iodoaldehyde
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(3) For instance, an optically active R-iodoaldehyde in ether is partially
racemized by a catalytic amount of pyrrolidine at 0 °C, while almost no
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see Supporting Information for detail.
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Furthermore, since silylcyanation of aldehydes with TMSCN is
known to be catalyzed by I2,9 we examined the one pot silylcya-
nation of the R-iodination product with TMSCN in the presence
of I2 generated from slightly excess NIS. The R-iodination product
2 was found to be smoothly converted to the corresponding
silylcyanation product 5 with high diastereoselectivity, probably
due to the steric bulk of the iodo group.10
(9) Yadav, J. S.; Reddy, B. V. S.; Reddy, M. S.; Prasad, A. R. Tetrahedron
Lett. 2002, 43, 9703.
(10) Under similar conditions the corresponding R-chloroaldehyde was silyl-
cyanated with low diastereoselectivity (9% de).
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J. AM. CHEM. SOC. VOL. 130, NO. 12, 2008 3729