.
Angewandte
Communications
[
4]
toward these compounds have also been described, includ-
[
5a]
ing our work.
The reversal of regioselectivity in the case of phalarine
implicated a different pathway. Danishefsky and co-workers
investigated the access to the benzofuro[3,2-b]indoline core
[3b]
6
a by direct coupling of phenol and indole without success.
They finally obtained this substructure through the rearrange-
ment of an azaspiroindolenine 5 or a stereospecific Pictet–
Spengler reaction to complete the total synthesis of phalarine
[
6]
(
Scheme 2b). Inspired by the palladium(II)-catalyzed intra-
molecular aminoalkoxylation of a stilbene derivative 7
[
7]
reported by Muniz, the group of Chen realized the formal
synthesis of phalarine through a similar transformation
mediated by a hypervalent iodine reagent to construct the
[
8]
expected polycycle 6 (Scheme 2b).
We recently engaged a program to explore new methods
for the direct coupling of indoles and phenols. In this line, we
disclosed the iron(III) chloride promoted C3-regioselective
hydroarylation of electrophilic N-acetyl indoles 8 by phenols
[
5]
or electron-rich (hetero)aromatic reagents. Subsequent
deacetylation and oxidation allowed us to obtain benzofuro-
[
2,3-b]indolines as well as related furoindolines, pyranoindo-
lines, pyrroloindolines, and piperidinoindolines. In continu-
ation of our efforts in this field, we sought to study a direct
[
9]
oxidative phenol–indole cross-coupling involving a radical
[
10]
process. We were inspired by two recent reports from the
[
11]
[12]
groups of Lei and Pappo, who described independently
the synthesis of 2,3-dihydrobenzofurans through an oxidative
cross-coupling of styrenes and phenols, mimicking polyhy-
[13]
droxystilbeneꢀs self-merging observed in nature.
Both
methods use an oxidant (2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ) or (tBuO) ) to oxidize electron-rich phenols
2
[
14]
into phenol radicals
and a catalytic amount of an iron
catalyst to promote the stabilization of the C radical over the
O radical. Our challenge was the addition of the electron-rich
C radical A to the electron-rich indole nucleus. During our
Scheme 3. Oxidative coupling between phenols and N-acetyl indoles
leading to benzofuro[3,2-b]indolines. [a] 1.5 equiv phenol, 1.5 equiv
[
15]
work on the C3-regioselective hydroarylation, the activation
DDQ, and 1.1 equiv FeCl ; [b] 3.0 equiv phenol, 3.0 equiv DDQ, and
3
[
16,17]
2.2 equiv FeCl ; [c] 4.0 equiv phenol, 4.2 equiv DDQ, and 2.2 equiv
of N-acetyl indole
with FeCl was decisive to turn the
3
3
FeCl3.
indole nucleus into an acceptor B of electron-rich aromatic
[5]
nucleophiles. We postulated that a similar activation will be
beneficial to our planned radical process. Therefore, the dual
activation of the N-acetyl indole and phenol radical by FeCl3
should act in synergy to favor the coupling between the two
species A and B (Scheme 2c). Two radical regioisomeric
adducts C and D could be expected leading to benzofuroindo-
lines 9 and 10, respectively.
and formyl (10ab; 51%) were the optimal activating groups
for the fine tuning of the reactivity of the indole nucleus to
[
20]
favor the synthesis of benzofuro[3,2-b]indolines 10.
It
seems reasonable to postulate that the complexation of
FeCl by the carbonyl oxygen (intermediate B, Scheme 2)
3
The investigation of the oxidative coupling was conducted
with N-acetyl-3-methylindole 8aa and p-methoxyphenol 1a
might break the aromaticity of the indole nucleus through
delocalization of the nitrogen lone pair into the carbonyl p
[5b]
(
1.5 equiv). It was found that the FeCl /(tBuO) system did
system. As a consequence, the C2=C3 bond would be less
electron-rich and prone to react with radical intermediate A
(Scheme 2).
3
2
not afford the desired products, whereas the association of
FeCl3 and DDQ led to the regioselective formation of
benzofuro[3,2-b]indoline 10aa with only traces of benzofuro-
Having discovered suitable conditions for the regioselec-
tive synthesis of benzofuroindoline 10aa from N-acetyl
skatole 8aa and p-methoxyphenol 1a, we wished to expand
the scope of this straightforward oxidative coupling
(Scheme 3). Indeed, electron-rich phenols such as p-ethoxy-
phenol, p-benzyloxyphenol, and 4-methoxynaphtol afforded
the desired benzofuroindolines 10b, 10c, and 10d in 62%,
42%, and 50%, respectively. Unfortunately the less electron-
[
18,19]
[
2,3-b]indoline 9aa.
DDQ or FeCl3 alone could not
promote the oxidative coupling, proving their synergetic
[
18]
effect. After further experimentations, we discovered that
it was optimal to run the reaction with stoichiometric amounts
of FeCl in a 0.1m dichloromethane solution at room temper-
3
ature to yield 52% of 10aa (Scheme 3). Evaluation of the
influence of the substituent on nitrogen proved that acetyl
2
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!
Tomakinian, Terry
