Synthesis of indoles via 6π-electrocyclic ring closures of trienecarbamates

Article abstract of DOI:10.1021/ja060282o

A new method for the preparation of indoles from readily available α-haloenones and α-(trialkylstannyl)enecarbamates is described. Following a Stille coupling, trienecarbamate 2 is electronically activated to undergo a facile 6π-electrocyclic ring closure

Full text of DOI:10.1021/ja060282o

Published on Web 03/30/2006
Synthesis of Indoles via 6π-Electrocyclic Ring Closures of Trienecarbamates
Thomas J. Greshock and Raymond L. Funk*
Department of Chemistry, PennsylVania State UniVersity, UniVersity Park, PennsylVania 16802
Received January 14, 2006; E-mail: rlf@chem.psu.edu
Indoles are arguably the most important of all the privileged
structures in drug discovery.1 Accordingly, the development of new
methods for the synthesis of indoles has been extensively investi-
gated.2 These strategies can be broadly categorized based upon the
order in which the individual aromatic substructures are introduced.
By far the most common approach (A, Figure 1) involves beginning
the synthesis with a substituted benzene ring. The venerable Fischer
indole synthesis is an example of this strategy wherein the indicated
C(3)-C(3a) and N-C(2) bonds are sequentially formed. A less
common approach to substituted indoles is through the annelation
of pyrroles (B, Figure 1), for example, the cycloaddition of 3-vinyl
pyrroles with dienophiles. The third and least explored strategy for
the construction of indoles is one in which both aromatic rings of
the indole are constructed in consecutive bond forming processes
from acyclic precursors. One of many hypothetical disconnections
is formulated in structure C. Indeed, the majority of the examples2b
of this overall strategy employ the implied intramolecular cycload-
dition3 as the key step in the construction of the substituted benzene
ring. We report herein a new approach to indoles which exploits a
Stille coupling to form the C(3a)-C(7a) bond of C followed by a
novel electrocyclic ring closure of the resulting trienecarbamate
which effects the connection of C(4) with C(5). Finally, condensa-
tion of a C(2) enolate upon a C(3) carbonyl completes the
heterocycle construction.
The feasibility of this strategic plan was easily demonstrated and
is detailed in Scheme 1. Thus, Stille coupling of R-(tributylstannyl)-
enecarbamate 14 with 2-iodocyclohexenone proceeded smoothly to
afford amidotriene 2. More importantly, triene 2 was found to
undergo an especially facile electrocyclic ring closure5 (110 °C, 1
h) to furnish cyclohexadiene 3. This closure is most likely facilitated
by a push/pull-type mechanism of the hydrogen bonded enecar-
bamate functionality with the proximal carbonyl group en route to
the resonance stabilized vinylogous imide product.6 Indeed, we
found that the electrocyclic ring closure of a triene analogous to 2
that lacks the carbonyl group and possesses an N-methyl substituent
requires higher temperatures and prolonged reaction times (120 °C,
12 h).7 Not surprisingly, the electron-rich cyclohexadiene 3 can be
easily oxidized to the protected aniline 4 by DDQ. This aromati-
zation can be conveniently accomplished in the same pot once the
electrocyclization is observed to be complete by TLC.
Figure 1. Strategies for indole synthesis.
Scheme 1
We next directed our attention to delineating the scope and
generality of this new indole annelation. Our proof-of-principle
example suggested that this method would be especially useful for
constructing indoles that are bridged at the C(3) and C(4) positions,
a substructure that complicates the synthesis of many indole natural
products. To that end, the corresponding R-iodocycloalkenones were
coupled with stannane 1 to afford trienecarbamates 7 and 10
(Scheme 2), and these substrates were subjected to the previously
described reaction sequence to afford the heretofore unknown
indole-containing ring systems 9 and 12, respectively. The triene-
carbamate 13 was also prepared from a methylated analogue of
stannane 1 and transformed to indole 15 in order to demonstrate
that additional substitution at C(5) is accessible by straightforward
adaptation of this strategy.
It was also of interest to determine whether the Råileanu closure
would tolerate the incorporation of substituents at N or C(2) of the
Scheme 2
Removal of the BOC group with TFA was uneventful, and a
reductive amination of the resultant aniline with glyoxylic acid
provided acid 5. It was hoped that this compound would cyclize to
an indole upon subjection to conditions (Ac2O, NEt3, 130 °C) that
were reported by Råileanu and co-workers8a for the cyclization of
the analogously substituted ortho-aminobenzaldehyde to N-acetyl-
indole. Indeed, this underutilized transformation proceeded smoothly
to deliver the desired N-acetylindole 6. This cyclization could
possibly be proceeding through a Perkin-type reaction of the mixed
anhydride derivative of acid 5 or, more likely, through a mu¨nchnone
intermediate generated from the acetylated derivative of aniline 5.8b,c
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10.1021/ja060282o CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
Scheme 5
product indole. With respect to the former question, the electrocyclic
ring closure of trienecarbamate 16 (Scheme 3) proceeded as
expected, although a longer reaction time (110 °C, 3 h) was required
in comparison to that of triene 2, presumably due to a lack of
hydrogen bonding of the enecarbamate with the proximal carbonyl.
After oxidation, removal of the BOC protecting group, and
alkylation with methyl iodoacetate, the resultant ester was hydro-
lyzed with 4 M NaOH. To our surprise, we obtained clean
conversion to the N-methyl indole 18 upon acidic workup with HCl.
Preparation of a 2-substituted indole was accomplished through
alkylation of the previously prepared aniline 19 (Scheme 1) with
methyl R-bromophenylacetate to afford ester 20. Saponification of
the ester, followed by subjection of the resultant acid to the Råileanu
conditions afforded the desired 2-phenyl indole 21, albeit lacking
the acetyl moiety, which suggests that a mu¨nchnone intermediate
may not be involved in this particular closure.
In addition to cyclic R-iodoenones, we have also employed
acyclic R-iodoenones as the starting materials in the annelation
sequence (Scheme 4). For example, the cis-phenyl ring did not
diminish the yield (90%) of the Stille coupling reaction leading to
trienecarbamate 22. However, the electrocyclization of trienecar-
bamate 22 required a higher temperature, perhaps due to a more
out-of-plane carbonyl in comparison to the conformationally locked
cyclic trienecarbamates (Schemes 1-3). Subsequent transformation
of 23 to the desired N-acetyl indole 24 was straightforward.
Thermolysis of the â,â-disubstituted acyclic enone 25 provided the
cyclohexadiene 27. This result was not entirely unexpected since
it is well-known that [1,7]-sigmatropic rearrangements are often
competitive with 6π-electrocyclic closures, in this case providing
the rearrangement product 26 followed by electrocyclic closure to
27. Our standard protocol then furnished the 3,4,6-trisubstituted
indole 29.
sequence with heterocyclic R-iodoenones or R-stannylenecarbam-
ates (Scheme 5). Thus, electrocyclization of triene 30 proceeded
smoothly with a negligible electronic/steric impact of the additional
carbamate substituent to afford a cyclohexadiene that was oxidized
(DDQ) in situ to the desired protected aniline 31. Completion of
the annelation afforded indole 32, a substructure embodied in several
biologically active natural products, such as the prianosins.9 Finally,
the modularity of this indole construction method is showcased in
the preparation of the unusual tetracyclic indole 35, which originates
from 4,4-dimethyl-2-iodocyclohexenone and the BOC-protected
3-vinyl-2-(trimethylstannyl)pyrroline.
In conclusion, we have shown that both of the aromatic rings of
indoles can be constructed from readily available R-haloenones and
R-(trialkylstannyl)enecarbamates using a five-step reaction sequence
that features facile electrocyclic ring closures of trienecarbamates.
The method may prove to be most useful for the preparation of
indoles possessing complex or difficult substitution patterns. The
syntheses of natural products of this type are underway.
Acknowledgment. We appreciate the financial support provided
by the National Institutes of Health (GM28553).
Supporting Information Available: Spectroscopic data and ex-
perimental details for the preparation of all new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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