Tungsten-catalyzed heterocycloisomerization approach to 4,5-dihydro-benzo[b]furans and -indoles

Article abstract of DOI:10.1021/ja3045647

A W(CO)₅·THF-catalyzed cycloisomerization of bicyclo[4.1.0] substrates to afford mono C4-substituted 4,5-dihydro-benzo[b] furans and -indoles is reported. The title compounds are versatile intermediates that lead to a range of fused bicycles including the cores of various furan-, benzofuran-, and indole-containing natural products. In many cases, the functionalization of the dihydro-benzo[b]furans and -indoles is orthogonal to that of the corresponding benzofurans and indoles and, thus, offers complementary approaches for synthesis.

Full text of DOI:10.1021/ja3045647

Communication
pubs.acs.org/JACS
Tungsten-Catalyzed Heterocycloisomerization Approach to 4,5-
Dihydro-benzo[b]furans and -indoles
Ethan L. Fisher, Sidney M. Wilkerson-Hill, and Richmond Sarpong*
Department of Chemistry, University of California, Berkeley, California 94720, United States
S
* Supporting Information
As a part of a general program aimed at the total synthesis of
ABSTRACT: A W(CO)5·THF-catalyzed cycloisomeriza-
tion of bicyclo[4.1.0] substrates to afford mono C4-
substituted 4,5-dihydro-benzo[b]furans and -indoles is
reported. The title compounds are versatile intermediates
that lead to a range of fused bicycles including the cores of
various furan-, benzofuran-, and indole-containing natural
products. In many cases, the functionalization of the
dihydro-benzo[b]furans and -indoles is orthogonal to that
of the corresponding benzofurans and indoles and, thus,
offers complementary approaches for synthesis.
benzofuran natural products such as tyrolobibenzyls A and B (1
and 2, respectively, Scheme 1)1 and furanoterpenoids including
Scheme 1. Potential Utility of 4,5-Dihydro-benzo[b]furans
and -indoles
he 4,5-dihydrobenzo[b]furans and the corresponding 4,5-
dihydroindoles (see boxed compound in Figure 1) may
T
hibiscone C (3),2 as well as indole natural products such as
verticillatine A (4),3 pibocin B (5),4 and the hapalindoles (e.g.,
6),5 we were drawn to the use of 4,5-dihydro-benzo[b]furan
and -indole derivatives as precursors. Specifically, we envisioned
a methylene carboethoxy substituent at C4 (see boxed
structures in Scheme 1) that could be transformed to a range
of groups including prenyl and reverse prenyl substituents. In
the context of indole alkaloid synthesis, this would be highly
significant given the expense and challenge associated with
accessing C4-prenyl and reverse prenyl substituents,6 which
form the basis of the synthesis of many indole alkaloids.7
Our inspection of the literature has revealed only one prior
report of a synthetically useful synthesis of mono C4-
substituted 4,5-dihydroindoles.8,9 Reported by Semmelhack
and co-workers in 1982, this preparation involved the
intermediacy of stoichiometric η6-Cr arene complexes, which
limits the practical utility of this route (especially for the large-
scale preparation of C4-substituted 4,5-dihydroindoles) for
complex molecule applications. To the best of our knowledge,
outside of the vacuum pyrolysis studies of Weber,9 there are no
prior examples of 4,5-dihydrobenzo[b]furans bearing a single
substituent at C4. In this manuscript, we report the preparation
Figure 1. Versatile reactions of 4,5-dihydro-benzo[b]furans and
-indoles.
represent versatile intermediates in the synthesis of complex
molecules. This is largely because multiple options for
functionalization of these bicyclic motifs could be possible as
shown in Figure 1, which could lead to the cores of myriad
natural products and pharmaceutical substances. For example,
dehydrogenation could yield benzofurans or indoles (A).
Alternatively, the double bond moiety may be selectively
engaged in various addition reactions to give functionalized
annelated furans or pyrroles (B). Of perhaps even greater
significance, the heteroaromatic portion of the 4,5-dihydro-
benzo[b]furans and -indoles may undergo reactions that are
either not possible (e.g., cycloadditions; see C) or are
complementary (see D) for the corresponding benzofurans
and indoles. As a result, dihydro-benzofurans and -indoles may
offer novel strategies for the synthesis of various substituted
fused bicycles including decalin derivatives, indoles, and
benzofurans.
Received: May 10, 2012
Published: June 4, 2012
© 2012 American Chemical Society
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Communication
of these versatile synthetic intermediates, which takes advantage
of a unique W(CO)5·THF-catalyzed heterocycloisomerization.
Furthermore, we demonstrate the conversion of the dihydro-
benzo[b]furan and -indole compounds to the value-added
products outlined in Figure 1, which could set the stage for
numerous applications in complex molecule synthesis.
Table 1. Substrate Scope of the Heterocycloisomerization
On the basis of well-established studies of metallo-vinylidene
formation from terminal alkynes,10 we envisioned that [4.1.0]
bicycles such as 7 could be transformed to 12 (Scheme 2). In
Scheme 2. Possible Cycloisomerization Mechanism for the
Formation of Dihydro-benzo[b]furans and -indoles
a
The standard conditions (10 mol % W(CO)5·THF, 3 equiv of Et3N,
b
rt, 12 h) were used unless otherwise stated. Reaction was conducted
using 20 mol % of W(CO)5·THF. The reported yield of N-alkoxy
c
indole 18 was obtained upon stirring the crude reaction product with
oxalic acid and SiO2 in wet CH2Cl2 for 3 h (see the Supporting
Information for more details).
the presence of an appropriate metal complex, 7 could first be
converted to metallo-vinylidene 8, which could then be
engaged by the proximal heteroatom (O or N) to provide
zwitterionic intermediate 9. Proto-demetalation of 9 could
potentially yield spiro-fused tricycle 10. At this stage, strain
release fragmentation of the cyclopropane to afford 11 (likely
assisted by the heteroatom), followed by proton transfer (and
concomitant aromatization), would provide the desired
dihydro-benzo[b]furans or -indoles. Several aspects of this
proposed sequence are noteworthy. First, remote C−H
functionalization β to the carbonyl or oxime group of 7a/b is
achieved in the overall transformation. Second, it is also
possible that the metallo-vinylidene moiety in 8 could undergo
a vinyl cyclopropane rearrangement,11 or be engaged by the
carboethoxy group (instead of X), which would lead to a
heteroatomic variant of the divinylcyclopropane rearrange-
ment.12 Third, although numerous reports have appeared in the
literature that describe cycloisomerization of cyclopropyl
ketones related to 7,13 to the best of our knowledge, the
previously reported transformations of bicyclo-1-(1-alkynyl)-
cyclopropyl ketones proceed with formal cleavage of the
endocyclic cyclopropane bond (i.e.,“b”, see 10).14 In contrast,
cleavage of bond “a” is required for our purposes. However, we
expected the presence of the carboethoxy group in 7 to make
Path A more favorable by better stabilizing the developing
negative charge (see 11).15
dihydrobenzo[b]furans in good to excellent yields (see 12a,
13−16). Both heteroatom (see 13, 15, and 16) and alkyl
substitution (see 14) are well tolerated. In addition, a
bicyclo[5.1.0] substrate readily participates in the cyclo-
isomerization to provide 17, illustrating the potential generality
of this transformation beyond dihydro-benzo[b]furans.21
Furthermore, N-alkoxy-4,5-dihydroindoles are also readily
accessed using this methodology (see 12b−d, 19, and 20).22
The scope of the N-alkoxy-4,5-dihydroindole formation is
generally analogous to that observed for the formation of 4,5-
dihydrobenzo[b]furans. One exception is the formation of N-
methoxy indole 18,23 where the ketal group of the crude
product (compare to 13) unravels upon purification on silica
gel, presumably because of the pronounced electron-rich nature
of the alkoxypyrrole group relative to the corresponding furan.
The versatility of the 4,5-dihydro-benzo[b]furans and
-indoles as synthetic intermediates is evident in the range of
reactions that they undergo as illustrated in Scheme 3. For
example, 12a is easily transformed to disubstituted benzofuran
23, which provides a starting point for the synthesis of
tyrolobibenzyl A (1, Scheme 1). The short sequence proceeds
from 12a in good overall yield (57% yield over 3 steps) by a
formal carbomethoxylation and DDQ-mediated oxidation. Also,
highly functionalized furans such as diol 24 are readily obtained
with good diastereoselectivity (9:1 d.r.)24 under standard
dihydroxylation conditions, which are selective for the double
bond over the furan moiety.25 In addition, methylation of
ketone 25 (obtained from 15)26,27 provides α-methyl ketone
26 (78% yield, 3.5:1 d.r.), which may serve as a starting point
for the synthesis of furanoterpenoids such as hibiscone C (3,
Scheme 1).
We initiated our studies with [4.1.0] bicycle 7a (prepared
from cyclohexenone in 61% yield over four steps),16 which was
subjected to a range of ruthenium and rhodium metal
complexes that have been established as catalysts for vinylidene
1 7
f o r m a t i o n , i n c l u d i n g R h C l ( P P h 3 ) 3
a n d
[RuCl2(cymene)]2.18,19 In the end, the conditions of Ohe
and Uemura,20 which employ a tungsten complex (10 mol %
W(CO)5·THF, 3 equiv of Et3N, rt, 12 h), were found to be the
most effective and general. As illustrated in Table 1 (only
products are shown), substrates bearing substitution on the six-
membered ring provide access to the corresponding 4,5-
N-alkoxyindoles (e.g., 27, Scheme 3), which may be
employed in the synthesis of indole alkaloids including pibocin
B (5, Scheme 1), can be realized from the dehydrogenation of
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intermediates that offer access to functionalized furans,
benzofurans, pyrroles, and indoles. In addition, one-pot
sequential additions involving the bicyclo[4.1.0] substrates
that proceed via the intermediacy of the 4,5-dihydrobenzo[b]-
furans can be achieved and proceed in high yield. A
comprehensive study of the reactivity of the mono C4-
substituted 4,5-dihydrobenzo[b]furan and 4,5-dihydroindole
compounds, as well as their applications in natural products
synthesis, is currently underway.
Scheme 3. Transformations of 4,5-Dihydro-benzo[b]furans
and -indoles
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
rsarpong@berkeley.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work was supported by the NSF (CAREER 0643264 to
R.S.) and a Research Scholar Grant from the American Cancer
Society (RSG-09-017-01-CDD to R.S.). R.S. is a Camille
Dreyfus Teacher Scholar. We are grateful to the NSF for a
graduate fellowship to S.M.W.-H. and Eli Lilly and Roche for
financial support.
the corresponding N-alkoxy-4,5-dihydroindoles (i.e., 12b).
Importantly, formal C2 indole functionalization is also easily
achieved, which is complementary to the normally observed C3
regioselectivity for N-alkoxyindoles,28 (see 12b → 28 for
sequential acylation/oxidation).
Significantly, several transformations may be carried out in
one pot from the precursor bicyclo [4.1.0] substrates without
isolation of, for example, the 4,5-dihydrobenzo[b]furan
intermediate. As shown in Scheme 4, decalin derivative 29 is
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