Homoallyllic nitrone isomerization: Convenient enantioselective synthesis of homoallylic nitrones and homoallylic hydroxylamines

Article abstract of DOI:10.1021/ol800925v

(Chemical Equation Presented) An α-regioselective synthesis of homoallylic nitrones from aldehydes is reported on the basis of [3,3]-sigmatropic rearrangement. The products are obtained in up to 99% enantioselectivity and up to 80% yield under environment

Full text of DOI:10.1021/ol800925v

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2805-2807
Homoallyllic Nitrone Isomerization:
Convenient Enantioselective Synthesis
of Homoallylic Nitrones and Homoallylic
Hydroxylamines
Hin-Soon Cheng, Ai-Hua Seow, and Teck-Peng Loh*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, Singapore 637616
teckpeng@ntu.edu.sg
Received April 22, 2008
ABSTRACT
An r-regioselective synthesis of homoallylic nitrones from aldehydes is reported on the basis of [3,3]-sigmatropic rearrangement. The products
are obtained in up to 99% enantioselectivity and up to 80% yield under environmentally benign and mild reaction conditions.
Homoallylic amines are versatile synthons in synthetic
chemistry since the allyl group can be readily converted
into a wide variety of synthetically useful compounds.1
Among the many methods available, enantioselective
allylation of imines is one of the most straightforward and
efficient methods to obtain homoallylic amines.1,2 How-
ever, enantioselective imine allylation has its drawbacks as
the allylation of enolizable imines can be complicated with
side reactions (Figure 1).2b,c Furthermore, the allylations were
mostly γ-regioselective, affording branched homoallylic
amines. As far as we know, there has been no report on
R-regioselective imine allylation with good enantioselecti-
vity.
Based on our recent work on 2-oxonia-[3,3]-sigmatropic
rearrangement in the synthesis of linear homoallylic
alcohols,3 we envisage that the 2-aza-[3,3]-sigmatropic
rearrangement of the corresponding nitrones, easily ob-
Figure 1. Challenges in imines allylation.
tained from hydroxylamines, will afford the synthetically
versatile linear homoallylic hydroxylamines/nitrones.4
Herein, we report a synthesis of linear homoallylic nitrones
(3) (a) Loh, T. P.; Tan, K. T.; Hu, Q. Y. Angew. Chem., Int. Ed. 2001,
40, 2921. (b) Loh, T. P.; Tan, K. T.; Yang, J. Y.; Xiang, C. L. Tetrahedron
Lett. 2001, 42, 8701. (c) Cheng, H. S.; Loh, T. P. J. Am. Chem. Soc. 2003,
42, 4990. (d) Nokami, J.; Yoshizane, K.; Matsuura, H.; Sumida, S. J. Am.
Chem. Soc. 1998, 120, 6609. (d) Sumida, S.; Ohga, M.; Mitani, J.; Nokami,
J. J. Am. Chem. Soc. 2000, 122, 1310. (e) Rychnovsky, S. D.; Marumoto,
S.; Jaber, J. J. Org. Lett. 2001, 3, 3815. (f) Marumoto, S.; Jaber, J. J.; Vitale,
J. P.; Rychnovsky, S. D. Org. Lett. 2002, 4, 3919. (g) Marumoto, S.; Jaber,
J. J.; Vitale, J. P.; Rychnovsky, S. D. Org. Lett. 2002, 4, 3919.
(1) For reviews, see: (a) Yamamoto, Y.; Asao, N. Chem. ReV. 1993,
93, 2207. (b) Hall, D. G.; Kennedy, J. W. J. Angew. Chem., Int. Ed. 2003,
42, 4732. (c) Lu, Z.; Ma, S. Angew. Chem., Int. Ed 2008, 47, 258.
(2) (a) Kleinman, E. F.; Volkmann, R. A. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: New York, 1991;
Vol. 2, p 975. (b) Ding, H.; Friestad, G. K. Synthesis 2005, 2815. (c) Merino,
P.; Tejero, T.; Delso, J. I.; Mannucci, V. Curr. Org. Synth. 2005, 2, 479
.
10.1021/ol800925v CCC: $40.75
Published on Web 06/07/2008
2008 American Chemical Society

using the branched homoallylic nitrone generated in situ
from aldehyde and branched homoallylic hydroxylamines.
Initial studies were done by subjecting the readily available
branched homoallylic hydroxylamine 25 with hydrocin-
namaldehyde 1a in the presence of Lewis acids or
Brønsted acids under various reaction conditions. The
results are summarized in Table 1.
result is in contrast to the reaction involving the 2-oxonia-
[3,3]-sigmatropic rearrangement.3
With this result in hand, we proceeded to investigate
the asymmetric version of this new hydroxylaminoally-
lation reaction. A readily available optically pure starting
material, syn-R-2,6 was subjected to the optimized reaction
conditions.
In all cases, the desired linear homoallylic nitrones were
obtained in good yields with excellent enantioselectivities.
Even with enolizable aldehydes, the products were obtained
in good yields with excellent enantioselectivities of up to
99% (Table 2, entries 1-2 and 5-7). The rate of reaction
was affected by the steric bulkiness of the aldehydes. While
the reactions with primary and secondary aldehydes pro-
ceeded smoothly at room temperature, the reactions involving
tertiary and aromatic aldehydes were very slow at room
temperature and heating was necessary to drive the reactions
to completion.
Table 1. Rearrangement of Branched Homoallylic Nitrones
Generated in Situ To Form Linear Homoallylic Nitrones
2/equiv
(syn/anti)
acid/0.2
equiv
entry
solvent
time/h yielda/%
b
1
3.0 (50:50)
3.0 (50:50)
1.1 (50:50) CSA
1.1 (50:50)
1.1 (50:50)
1.1 (100:0) CSA
In(OTf)3
CSA
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
THF
iPrOH
iPrOH
iPrOH
4
5
5
72
12
7
70
85
81
5
54
80
82
0
2
Table 2. Asymmetric Synthesis of Nitrones
3c
4
CSA
CSA
5
6d
7e
8f
1.1 (0:100)
1.1 (50:50)
CSA
-
4
120
a Isolated yield. b 0.1 equiv of In(OTf)3 was used. c 1H NMR monitoring
showed that the rate of reaction of the anti isomer is faster than that of the
syn isomer. d Syn isomer of 2 was used. e Anti isomer of 2 was used. f No
acid was added.
This reaction worked well in the presence of Lewis acid
or Brønsted acid catalysts to afford the desired product
in moderate to good yields (Table 1). The reaction was
found to proceed smoothly under both protic and aprotic
solvents (Table 1, entries 2-7). To our surprise, regardless
of the stereo geometry of the starting material 2, all the
products obtained were exclusively the E-isomers. This
a Isolated yield. b Absolute stereochemistry was confirmed by matching
chiral HPLC data with known product. c Heated at 50 °C for 48 h after
12 h at rt. d Heated at 50 °C for 72 h after 12 h at rt. e anti-R-2 was used
in place of syn-R-2. f S-Isomer was obtained.
(4) (a) Horowitz, R. M.; Geissman, T. A. J. Am. Chem. Soc. 1950, 72,
1518. For a review, see: (b) Przheval’skii, N. M.; Grandberg, I. I. Usp.
Khim. 1987, 56, 814. (c) Overman, L. E. Acc. Chem. Res. 1992, 25, 352.
(d) Wuts, P. G. M.; Jung, Y. W. J. Org. Chem. 1988, 53, 1957. (e)
Kobayashi, S. M.; Mori, C.; Kobayashi, S. J. Am. Chem. Soc. 2006, 128,
11038.
Remarkably, the only product obtained, 3′′, possessed
E-geometry, which stereochemically corresponded to the
minor product, 3o′′, in the 2-oxonia-[3,3]-sigmatropic rear-
rangement,3 while 3′ was not observed although it stere-
ochemically corresponded to the major product in the
2-oxonia-[3,3]-sigmatropic rearrangement (Figure 2). The
E-geometry of one of the products, 3d, was confirmed by
X-ray crystallography. The absolute stereochemistry of this
compound was determined by comparing HPLC retention
times.7
(5) Synthesized from benzaldehyde oxime. See the Supporting Informa-
tion for details.
(6) Readily obtained in gram-scale from nitrone. See the Supporting
Information for details.
Furthermore, when the [3,3]-sigmatropic rearrangement of
optically active homoallylic nitrone N1 was studied, it was
found that the enantiomeric excess of product N2 dropped
significantly. This observation differed from a previous report
on 2-aza-[3,3]-sigmatropic rearrangement,4e where the enan-
tiomeric excess was maintained.4d
2806
Org. Lett., Vol. 10, No. 13, 2008

the methyl group is crucial in determining the conformer of
the transition states and hence directed the stereochemical
outcome of this [3,3]-sigmatropic rearrangement.
Scheme 2. Synthetic Applications of Nitrone
Figure 2.
2-Aza- and 2-oxonia-[3,3]-sigmatropic rearrangements.3
We have also demonstrated the versatility of the homoal-
lylic nitrone 3a (Scheme 2). It can be readily converted into
linear homoallylic amine 6, which is widely used in
synthesis.2 More importantly, 3a can be readily converted
into homoallylic hydroxylamine 5, a valuable synthon which
can easily be transformed into a diverse array of nitrones
for various 1,3 dipolar reactions.9
In conclusion, a direct access to linear homoallylic nitrones
has been realized under very mild reaction conditions
affording good yields and excellent enantioselectivities.
Further application of this methodology in both divergent
synthesis and the synthesis of alkaloids is in progress.
Hence, the following transition states are proposed to
account for the outcome in stereochemistry and exclusive E
selectivity (Scheme 1), based on the fact that oximes readily
Scheme 1. Proposed Mechanism
Acknowledgment. We thank Nanyang Technological
University for the generous financial support and thank the
Singapore Millennium Foundation Ltd. for its scholarship
support of H.-S.C.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL800925V
(7) 3dx was converted from 3d. The HPLC retention time matches well
with the literature value. Aggarwal, V. K.; Guang, Y. F.; Schmidt, A. T.
J. Am. Chem. Soc. 2005, 127, 1642. See the Supporting Information for
details.
go through both chair and boat conformers in their
Zimmermann-Taxler transition states.8
While the [3,3]-sigmatropic rearrangement of nitrone
anti-4 clearly goes through the most stable chair transition
state, the rearrangement of syn-4 has to proceed via the boat
transition state, thus avoiding the unfavorable 1,3-diaxial
interaction, to afford the E-isomer. The stereochemistry of
(8) Hoffmann, R. W.; Endesfelder, A. Liebigs Ann. Chem. 1987, 215.
(9) Two isomers were isolated with stereochemistry undetermined. For
examples of intramolecular 1,3-dipolar cycloaddition, see: (a) Looper, R. E.;
Williams, R. M. Angew. Chem., Int. Ed. 2004, 43, 2930. (b) Budzinska,
A.; Wojciench, S. Tetrahedron 2001, 57, 2021. (c) Lumma, W. C., Jr. J. Am.
Chem. Soc. 1969, 91, 2920.
Org. Lett., Vol. 10, No. 13, 2008
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