Angewandte
Chemie
Substitution at the position ortho to the ketone proved
sensitive to steric factors. Both OMe- and F-containing
substrates underwent clean reaction (6m–6q), but Me
substitution was unfavorable (30% and 20% of 6r and 6s,
respectively), and an ortho-CF3 group shut down the reaction
completely (see the Supporting Information).
À
Substitution at the arene ring adjacent to the second C H
functionalization was more broadly tolerated, with OMe, F,
CF3, and Me groups affording indanones in 60–68% yields
(6t, 6v–6x). The strongly electron-withdrawing ortho-NO2
group was an exception, slowing the reaction down to give
a 35% yield of 6u after 50% conversion over 24 h. Finally, we
were able to construct the quaternary-center-containing
indanones 6y and 6z starting from a-methyl,a-phenyl aceto-
phenone. The additional methyl substituent promoted the
formation of tetracycles 7y and 7z, possibly by increasing the
À
ratio of cis diastereoisomer present after the first double C H
functionalization.
1-Indanones are versatile building blocks in medicinal and
materials chemistry. To demonstrate the applicability of the
ruthenium-catalyzed tandem process, we conducted further
transformations on compounds 6t and 6u (Scheme 2b).
Reduction of the nitro group in 6u with zinc gave an aniline,
which cyclized in situ to give the dihydroindenoindole 8 in
high yield. The dihydroindeno benzofuran 10 was prepared in
an analogous fashion from 6t through demethylation and
acid-mediated condensation. Fused dihydroindeno hetero-
cycles have been widely studied for their biological activity,[11]
as well as applications in organic electronics[12] and organo-
metallic chemistry (ligands for polymerization catalysts).[13]
We then turned our attention to the tetracycle compound
series 7. Compound 7a appears to arise from an oxidative
intramolecular arylation reaction of the minor cis stereoiso-
mer of 6a, a process that would formally involve four separate
Scheme 3. Indeno indene synthesis.
observed small amounts of the lactone 13a being formed as
a side product, the production of which could be increased to
a 26% yield of isolated product on increasing the amount of
HBF4 to one equivalent. The initial cyclized indanone prod-
À
uct 6 undergoes oxidative oxyacylation at the enolic C H
position, a transformation that has been reported on simpler
substrates by using hypervalent iodine oxidants,[14] peroxide
oxidation of enamine-type intermediates,[15] and heavy-metal
oxidants such as Tl(OAc)3 and Pb(OAc)4.[16] Oxidative oxy-
acylation by using simple CuII salts and a Brønsted acid has
not been reported, so we were pleased to find that yields
could be considerably enhanced by using a silver catalyst as
additive in the initial cyclization as before, and then adding
a second charge of Cu(OAc)2·H2O/HBF4 (aq) to the reaction
vessel and heating for a further 16 h. This one-pot, two-step
procedure gave a 61% yield of 13a (structure established by
X-ray analysis) from phenyl acetophenone 4a (Scheme 4).
Substrate-scope exploration established the oxidative lacto-
nization step to be efficient, with yields of isolated 13 only
slightly lower than those obtained for the corresponding
indanones 6 in most cases. Exceptions were noted for strong
electron-withdrawing groups in the neighboring arene ring,
with substrates containing ortho-nitro or para-CF3 groups
failing in the reaction. The efficiency of the oxidative
oxyacylation reaction was confirmed by reacting purified 1-
indanone 6a with HBF4 (aq) and Cu(OAc)2·H2O (1.5 equiv),
which resulted in the production of lactone 13a in 72% yield.
Control experiments established that neither Cu(OAc)2·H2O
or HBF4 (aq) alone were effective for oxyacylation from 6a
and the combination of the two of them was necessary to
access the lactone structure.
À
C H functionalizations starting from acetophenone 4a and
methyl acrylate 5a. We resubjected 6a (trans/cis = 10:1) to the
reaction conditions and observed only a trace of 7a, thus
suggesting that epimerization under the reaction conditions is
not capable of providing sufficient cis isomer to undergo
further reaction. To encourage formation of the tetracycle, we
prepared diarylated acetophenone substrates 11a–11d to
eliminate the cis/trans stereorelationship. Using the same
optimized reaction conditions as before, we were pleased to
À
observe sequential C H functionalization with a range of
Michael acceptors to form the pentacycles 12a–12k in
generally excellent yields (Scheme 3).
X-ray analysis of 12a confirmed the indeno indene
structure and the exo stereochemistry of the ester group.
None of the analogous monocyclized 1-indanone products
were isolated from the reaction, thus indicating that the
oxidative arylation step is highly efficient for the doubly
arylated acetophenone substrates 11. The overall efficiency of
the process is notable, with carbocycles 12 being produced in
high yields, as single diastereoisomers, through four succes-
Preliminary mechanistic experiments in the 1-indanone
and indeno indene pathways led to the outline mechanism
shown in Scheme 5. We found that simple acetophenones
stopped at the alkenylation stage, in line with observations
from Jeganmohan and Padala indicating that the phenyl
À
sive C H functionalization events.
À
We uncovered a third, orthogonal mode of cascade C H
functionalization from observations made in the optimization
of the initial monocyclization reaction. On using aqueous
HBF4 in lieu of silver catalysis (Table 1, entry 10), we had
À
group is essential to activate the a-Csp3 H bond for further
Angew. Chem. Int. Ed. 2014, 53, 1529 –1533
ꢀ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1531
Mehta, Vaibhav P.
