Oppolzer-type intramolecular Diels-Alder cycloadditions via isomerizations of allenamides

Article abstract of DOI:10.1021/ol2010227

A new approach to Oppolzer's intramolecular Diels-Alder cycloaddition (IMDA) through γ-isomerization of readily available N-tethered allenamides is described. These IMDA reactions are carried out in tandem with the allenamide isomerization or 1,3-H shift,

Full text of DOI:10.1021/ol2010227

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3114–3117
Oppolzer-Type Intramolecular
DielsꢀAlder Cycloadditions via
Isomerizations of Allenamides
John B. Feltenberger and Richard P. Hsung*
Division of Pharmaceutical Sciences and Department of Chemistry,
University of Wisconsin, Madison, Wisconsin 53705, United States
rhsung@wisc.edu
Received April 17, 2011
ABSTRACT
A new approach to Oppolzer’s intramolecular DielsꢀAlder cycloaddition (IMDA) through γ-isomerization of readily available N-tethered
allenamides is described. These IMDA reactions are carried out in tandem with the allenamide isomerization or 1,3-H shift, leading to complex
nitrogen heterocycles in a highly stereoselective manner.
Intermolecular DielsꢀAlder cycloadditions of 1-amino- or
1-amido-dienes1ꢀ7 have proven to be a powerful reaction
manifold, with some notable examples shown in Scheme 1.
Although Oppolzer8,9 had elegantly demonstrated the
concept of N-tethered 1-amido-dienes in intramole-
cular DielsꢀAlder cycloadditions (IMDA),10 relative to
the intermolecular pursuit, it has shown limited applications
Scheme 1. Oppolzer’s IMDA via Allenamide Isomerization
(1) For reviews on chemistry of dienamides, see: (a) Overman, L. E.
Acc. Chem. Res. 1980, 13, 218. (b) Petrzilka, M.; Grayson, J. I. Synthesis
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€
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r
10.1021/ol2010227
Published on Web 05/25/2011
2011 American Chemical Society

in the past 40 years in part due to a lack of efficient synthetic
access to these cycloaddition precursors.10,11 We recently
reported12 that γ-isomerizations of allenamides 1 provide a
facile entry to 1-amido-dienes 3 via a stereoselective 1,3-H
shift (Scheme 1).13 This finding provokes a unique synthetic
design in which the allenamide isomerization could be ren-
dered in tandem with the Oppolzer-type intramolecular
DielsꢀAlder cycloaddition when using N-tethered allena-
mides 4. If successful (4 f 5 f 6), such an endeavor would
allow rapid assembly of structural complexity from simple
allenamides and further underscores the significance of devel-
oping chemistry of allenamides.14ꢀ16 We communicate here
an Oppolzer-type IMDA through γ-isomerizations of
allenamides.
Table 1. Tandem γ-IsomerizationꢀOppolzer-Type IMDA
Scheme 2. Facile Assembly of N-Tethered Allenamides
a All reactions were run in screw-cap vials with Teflon-coated caps.
Concentration = 0.05 M, except for entries 1ꢀ3 and 10 where concen-
tration = 0.02 M. b Isolated yields for 15 or 16. c The only product was
N-tethered 1-amido-diene 13 in 78% yield. d The respective secondary
amide was isolated in 15% yield as a result of hydrolysis along with 26%
of 13. e A complex mixture. f Mostly decomposition of 12.
of starting allenamides. Other amine bases, inorganic bases,
or drying agents screened were not effective (entries 15ꢀ20).
In addition, a p-nosyl substituent on the nitrogen atom
provided higher yield of the respective cycloadduct 16
(entry 14), relative to cycloadduct 15 containing an N-Ts
group (entry 13). Diastereoselectivity or the endo:exo ratio
for 16 (dr = 10:1) was also slightly higher than that of 15
(dr = 8:1). Relative stereochemistry of the major isomer of
While the general plan is laid out concisely in Scheme 2
with allenamides 11 and 1217 readily attainable through
amidative cross-coupling1f,18 of allenyl iodide 7 with re-
spective amides 8 and 9, developing an effective γ-isomer-
ization in conjunction with Oppolzer’s IMDA was not
trivial; a wide range of conditions had to be examined
(Table1). Whilethemodest yieldsattainedunderanumber
of conditions (entries 2ꢀ8) could still be considered useful
given the context of constructing multiple bonds and
stereocenters in a tandem sequence, ultimately it appeared
that a base, optimally being a proton sponge (entry 11) or
Et3N (entry 14), was needed to avoid significant hydrolysis
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D. J., Jr. J. Am. Chem. Soc. 1979, 101, 7110. (b) Witiak, D. T.; Tomita, K.;
Patch, R. J.; Enna, S. J. J. Med. Chem. 1981, 24, 788. (c) Keck, G. E.;
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Org. Lett., Vol. 13, No. 12, 2011
3115

acid-catalyzed isomerization of allenamide 12 gave N-
tethered 1-amido diene 14 in near quantitative yield. The
ensuing cycloaddition using either Et3N or a proton
sponge as the additive led to cycloadduct 16 with a
combined yield for either condition very comparable to
those attained in a tandem manner (in italics).
Figure 1. X-ray structure of 16.
16 was unambiguously assigned using single crystal X-ray
structure (Figure 1), thereby suggesting a favored endo-
transition state with respect to the carbon tethering.
Figure 2. Tandem γ-isomerizationꢀOppolzer-type IMDA. All
reactions were run for 40ꢀ48 h in screw-cap vials with Teflon-
coated caps at 165ꢀ175 °C using the xylene/decane mixed
solvent system and 3.0 equiv Et3N as additive. Cycloaddition for
preparing 23 was run at 210 °C. The diastereomeric ratios were
determined using 1H and/or 13C NMR.
Scheme 3. Sequential Pursuit versus Tandem Process
Having established the feasibility, various examples
could be readily produced including tricycles 21ꢀ23 (see
product Figure 2). In general, the p-nosyl substitution
gave better yields, and both stereoselectivity and overall
yields are in the synthetically useful range and could be
considered excellent in the context of constructing multi-
ple bonds and stereocenters. It is noteworthy that addi-
tional substitutions on the olefin such as a Ph group
could be included, leading to cycloadduct 23 with an
endo:exo ratio of 10:3 (the endo isomer was assigned
using NOE experiments). In addition, the original cis
configuration of the olefin was preserved during the
cycloaddition.
A quick comparison was drawn through pursuing this
Oppolzer-type IMDA sequentially in conjunction with the
γ-isomerization of allenamides. As shown in Scheme 3,
(15) Also see: (a) Lohse, A. G.; Hsung, R. P. Chem.;Eur. J. 2011, 17,
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Leider, M. D.; Ghosh, S. K. J. Org. Chem. 2011, 76, 3246. (b) Faustino,
Scheme 4. Unexpected Enamide 1,4-Addition
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3116
Org. Lett., Vol. 13, No. 12, 2011

We then turned our attention toward constructing het-
erocycles with greater complexity. However, when using
allenamide 24 containing a cinnamate motif in an attempt
to prepare indolines through the tandem γ-isomerizationꢀ
IMDA sequence, we encountered an unexpected enamide
1,4-addition (see 25), leading to the formation of amido
diene 27 (Scheme 4). This new diene was only fully rec-
ognizedafter we were attempting anaromatization process
using DDQ, which led to another DielsꢀAlder cycload-
duct 28.
Scheme 6. Rapid Constructions of Quinolines
Scheme 5. Assembly of Indolines
The power of this tandem sequence can be manifested in
thequinoline synthesis. Asshown inScheme 6, anumberof
quinolines such as 41ꢀ43 could be accessed rapidly in an
efficient manner from simple N-allyl-aniline 37 in four steps.
These rapid assemblies feature aza-Claisen, copper-catalyzed
amidative cross-coupling and tandem γ-isomerizationꢀ
Oppozler-type intramolecular DielsꢀAlder cycloaddition. In
particular, the tandem sequence is stereoselective for the
synthesis of the tetracyclic quinoline 43, which was isolated
in 74% yield with a diastereomeric ratio of 10:1. The major
isomer of 43 was concisely assigned using a NOE experiment.
We have described here an Oppolzer-type intramolecu-
lar DielsꢀAlder cycloaddition (IMDA) through γ-isomer-
ization of readily available N-tethered allenamides. These
IMDA reactions are carried out in tandem with the
allenamide isomerization, which consists of a 1,3-H shift,
leading to complex nitrogen heterocycles in a highly
stereoselective manner. Applications of this new tandem
process in alkaloid synthesis are underway.
Contemplating taking advantage of this new observa-
tion we prepared allenamide 29 containing an alloc group
with the hope that another IMDA could take place
through diene 30 leading to tetracycle 31 (Scheme 5).
Surprisingly, we found that 1,4-addition was even occur-
ring prior to the allenamide isomerization, leading to the
formation of cyclobutane 33. Cyclobutane 33 most likely
was derived from two consecutive 1,4-additions with the
latter involving vinyl iminium ion 32. On the other hand,
although the major product, 1-amido-diene 30 did not
undergo further IMDA to give the anticipated tetracyclic
quinoline 31. Fortuitously, this issue could be circum-
vented by using allenamide 34 and 340, which gave respec-
tiveindolines36and 360 inmodestoverall yield throughthe
expected sequence of tandem γ-isomerizationꢀOppolzer-
type IMDA. Unfortunately, the endo:exo ratios for these
cases were not high.
Acknowledgment. Authors thank NIH (GM066055)
for support and Dr. Victor Young, University of Minne-
sota for X-ray structural analysis.
Supporting Information Available. Experimental pro-
cedure sand NMR spectra, characterizations, and X-ray
structural files. This material is available free of charge
via the Internet at http://pubs.acs.org.
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3081. Also see: (c) Persson, A. K. A; Johnston, E. V.; Backvall, J.-E.
€
Org. Lett. 2009, 11, 3814.
Org. Lett., Vol. 13, No. 12, 2011
3117