Synthesis of highly substituted indolines and indoles via intramolecular [4 + 2] cycloaddition of ynamides and conjugated enynes

Article abstract of DOI:10.1021/ja051180l

Ynamides react with conjugated enynes in intramolecular [4 + 2] cycloadditions to afford substituted indolines that undergo oxidation with o-chloranil to furnish the corresponding indoles. The cycloaddition substrates are easily assembled from derivatives of 3-butynylamine by Sonogashira coupling with alkenyl halides followed by copper-catalyzed N-alkynylation with acetylenic bromides. Diynamides participate as particularly reactive 2π components in the cycloaddition, providing access to indolines with carbon substituents at the C-7 position. Enynamides serve as 4π components in a complementary version of the cycloaddition strategy which provides access to indoles and indolines substituted with carbon substituents at C-4. These enyne cycloadditions take place upon heating the substrates at 110-210 °C in toluene or 2,2,2-trifluoroethanol and in some cases can be achieved at 0 °C to room temperature in the presence of Lewis acids such as Me²AlCl. Copyright

Full text of DOI:10.1021/ja051180l

Published on Web 03/31/2005
Synthesis of Highly Substituted Indolines and Indoles via Intramolecular
[4 + 2] Cycloaddition of Ynamides and Conjugated Enynes
Joshua R. Dunetz and Rick L. Danheiser*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received February 24, 2005; E-mail: danheisr@mit.edu
The invention of new synthetic routes to indoles and indolines
continues to command wide interest due to the numerous natural
products and biologically significant compounds whose structures
incorporate these heterocyclic systems.1 A number of useful
strategies are now available for the synthesis of indoles substituted
on the five-membered ring, the majority of which involve the
elaboration of the heterocyclic system from an aniline, o-halo
aniline, or other 2-substituted aniline derivative. In contrast, few
existing methods provide efficient and regiocontrolled access to
indoles that are highly substituted on the benzenoid ring.
Intramolecular cycloaddition strategies provide a powerful vehicle
for the direct assembly of the bicyclic indole ring system from
acyclic precursors.2 Herein we report a new intramolecular [4 +
2] cycloaddition strategy that is particularly useful for the construc-
tion of indolines and indoles bearing multiple substituents on the
six-membered ring. This approach is highly modular and is
especially well-suited for the preparation of libraries of substituted
indole derivatives.
N-alkynylation8,9 reaction then provides access to the desired
substituted ynamides.10
Tables 1 and 2 delineate the scope of the [4 + 2] cycloaddition.
Thermal cycloadditions take place in toluene at temperatures ranging
from 110 to 210 °C, depending on the degree of activation of the
2π (“enynophile”) component. As noted previously,3 reactions
conducted in the presence of BHT proceed in somewhat improved
yield (Table 2, entries 1 and 2), although this additive has little
effect on the rate of reaction. BHT is believed to suppress
Table 1. [4 + 2] Cycloadditions of Conjugated Enynes with
Ynamides
The new indole synthesis is based on the extension of our earlier
work on enyne cycloadditions3-5 to include reactions of ynamide6
and enynamide derivatives as 2π and 4π cycloaddition components.
In a typical reaction, heating enynes of type 1 promotes a [4 + 2]
cycloaddition which generates a highly strained isoaromatic cyclic
allene that rearranges via proton or hydrogen atom transfer pathways
to afford the desired indoline (Scheme 1).7 An especially attractive
feature of this strategy is the ease with which the requisite enyne
cycloaddition substrates can be assembled via transition-metal-
mediated coupling reactions (vide infra).
Scheme 1
Initial feasibility studies were conducted using enynes such as
5, whose preparation illustrates our convenient modular approach
to the assembly of cycloaddition substrates. As outlined in eq 1,
3-butynylamine serves as a synthetic linchpin in this divergent
strategy. Sonogashira coupling of 4 with an alkenyl halide or
sulfonate generates the requisite enyne moieties with a variety of
substitution patterns, and our room-temperature copper-promoted
a Cycloadditions performed in toluene (0.05 M) with 1 equiv of BHT (3
equiv of BHT for Z ) Ts, Tf). b Isolated yields.
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10.1021/ja051180l CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. [4 + 2] Cycloadditions of Conjugated Enynamides with
Alkynes
was easily circumvented by carrying out the oxidation on the
deprotected indoline 38 (eq 2). In this case, hydride abstraction
from the C-2 position is a more facile process, and indole 39 was
obtained in excellent yield without over-oxidation.
Acknowledgment. We thank the National Institutes of Health
(GM 28273) and Merck Research Laboratories for generous
financial support.
Supporting Information Available: Experimental procedures and
characterization data for all indolines and indoles. Full details on the
synthesis of all cycloaddition substrates. This material is available free
of charge via the Internet at http://pubs.acs.org.
a Cycloadditions performed in toluene (0.05 M) with 1 equiv of BHT
unless otherwise indicated. b Isolated yields. c Reaction in the absence of
BHT. d Reaction in TFE (0.05 M) without BHT. e Reaction in the presence
of 2.5 equiv of Me2AlCl in CH2Cl2 (0.05 M) without BHT.
polymerization of the enyne substrates, but this phenol may also
serve as a proton and/or hydrogen atom donor facilitating the
isomerization of the intermediate cyclic allene 2 to the indoline
product 3. Trifluoroethanol, which can function as a non-nucleo-
philic proton donor, also proved to be an excellent solvent for the
cycloaddition in the absence of BHT. Finally, a noteworthy finding
is that Lewis acids have the capacity to serve as powerful promoters
of the cycloaddition in cases involving enynophiles with carbonyl
activating groups. For example, exposure of alkynyl ester 25 to
Me2AlCl in CH2Cl2 leads to efficient cycloaddition at 0-25 °C to
furnish the desired cycloadduct 30 in 78% yield. Significantly, no
reaction of alkynylsilane 27 was observed to take place under
identical conditions.
The facility of cycloadditions involving diynamides 11-14 as
enynophiles is particularly notable. These cycloadditions proceed
in refluxing toluene and give rise to indolines bearing carbon
substituents at the C-7 position. These reactions are also syntheti-
cally significant, since the cycloadducts can be easily elaborated
(e.g., by hydrogenation) to furnish indolines that are not available
in good yield directly via ynamide cycloadditions.11 To our
knowledge, these reactions represent the first synthetic applications
of diynamides, an interesting class of synthetic building blocks with
considerable potential in organic synthesis.
One significant limitation of the cycloaddition of conjugated
enynes with ynamides is that the indoline products necessarily bear
a hydrogen at the C-4 position. Access to indolines substituted at
this site can be gained, however, via the reactions of conjugated
enynamides. As summarized in Table 2, the cycloaddition of these
electron-rich enynes is unusually facile and provides an efficient
route to C-4 substituted indolines that is complementary to the
reactions outlined in Table 1.
Finally, oxidation of the indoline cycloaddition products was
conveniently achieved employing o-chloranil12 in benzene at room
temperature to afford indoles such as 35 and 36 in good yield. In
the case of indoline 30, however, partial dehydrogenation of the
cyclohexyl ring was observed under these conditions, and the
desired indole (37) was obtained in only modest yield. This problem
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