FeCl3-mediated friedel-crafts hydroarylation with electrophilic N-acetyl indoles for the synthesis of benzofuroindolines

Article abstract of DOI:10.1002/anie.201206611

IRONic electrophilic indoles! The C3-regioselective hydroarylation of N-acetyl indoles with aromatic nucleophiles mediated by FeCl₃ features a rare example of the electrophilic reactivity of the indole core in a Friedel-Crafts reaction. This indole umpolung allows us straightforward access to the tetracyclic benzofuroindoline motif found in the natural product diazonamide A, which is a potent antitumor agent. Copyright

Full text of DOI:10.1002/anie.201206611

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DOI: 10.1002/anie.201206611
Indole Chemistry
FeCl3-Mediated Friedel–Crafts Hydroarylation with Electrophilic
N-Acetyl Indoles for the Synthesis of Benzofuroindolines**
Rodolphe Beaud, Rꢀgis Guillot, Cyrille Kouklovsky, and Guillaume Vincent*
The benzofuroindoline core is a unique motif found in the
natural products diazonamide A (1),[1a,b] bipleiophylline,[1c]
and azonazine (2, Scheme 1).[1d] From a biosynthetic point
of view, we can assume that the benzofuroindoline skeleton 3
arises from the oxidative coupling of an indole 4 and a phenol
5 (Scheme 1).
benzofuroindoline analogues as promising as the natural
product, but more synthetically accessible.
The attraction of the high antitumor activity of diazona-
mide A has launched impressive synthetic efforts worldwide
towards the benzofuroindoline skeleton, which had been
scarcely explored before.[3–5] Most of the methods developed
are neither straightforward nor general, and do not take
advantage of the biogenetically inspired direct oxidative
coupling between an indole and a phenol. Harran met this
objective with a modest yield during his total synthesis of
diazonamide A by the hypervalent-iodine(III)-mediated
intramolecular coupling between tryptophan and tyrosine
residues, presumably through the formation of a phenoxenium
ion.[4] The intermolecular version is little known and only with
low yields.[5] It is also highly substrate dependant, as the
corresponding coupling between skatole 4a and p-cresol 5a
unfortunately failed in our hands (Scheme 2).
Scheme 1. Benzofuroindoline-containing natural products.
The benzofuroindoline motif represents an opportunity
for the discovery of new antitumor agents. In fact, diazona-
mide A is a very potent anticancer agent that has received
considerable attention owing to its high antitumor activity
(IC50 < 5 nm) and its unique mode of action:[2] the inhibition
of a newly discovered role for the ornithine-d-aminotransfer-
ase (OAT).[2a] It is suggested that this natural product may
have clinical utility for cancer therapy because it is as active
in vitro as widely used antimitotic drugs such as taxanes and
vinca alkaloids, but does not have their toxicity in normal
dividing tissue, as has been demonstrated on mice.[2b] Owing
to the high potential of diazonamide A and its scarce
availability, it is highly desirable to identify simplified
Scheme 2. Towards benzofuroindolines from indoles and phenols.
Ac=acetyl.
Our goal was therefore to develop an oxidative intermo-
lecular process to couple indoles and phenols in order to
easily access a wide range of benzofuroindolines. We decided
to explore a two-step sequence wherein the two partners
would be assembled through the regioselective C3-hydro-
arylation of a 3-substituted indole (4) by a phenol (5) to
generate a 3,3-disubstituted indoline (6).[6] Oxidation of 6
should then yield the desired benzofuroindoline (3)
(Scheme 2).
[*] R. Beaud, Dr. R. Guillot, Prof.Dr. C. Kouklovsky, Dr. G. Vincent
Universitꢀ Paris-Sud and CNRS
Institut de Chimie Molꢀculaire et des Matꢀriaux d’Orsay (ICMMO),
UMR 8182, Laboratoire de Chimie des Procꢀdꢀs et Substances
Naturelles, Bat. 410, 91405 Orsay (France)
À
The hydroarylation of activated alkenes via C H func-
tionalization of arylating reagents is a well-known process,[7]
=
however the reaction at the more electron rich C2 C3 bonds
E-mail: guillaume.vincent@u-psud.fr
of indoles appears far more challenging, as indoles are well
known to behave as nucleophiles at C3.[8] The umpolung of
the indole[9–11] at C3 would therefore require fine tuning of
this core by carefully selecting the substituent of the nitrogen.
Interestingly, Nakatsuka et al. have reported the hydro-
arylation of N-acyl-3-alkyl indoles at C3 with aryl speciesin
Homepage: http://www.icmmo.u-psud.fr/Labos/LPSN/cv/guillau-
me_eng.php?ID=381
[**] We thank the CNRS and the Universitꢀ Paris-Sud (Fellowship to
R.B.) for financial support, and Didier Gori for HPLC analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206611.
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the presence of a very large excess of AlCl3.[12] Based on this
finding, we explored the coupling between N-acetyl skatole
7a and p-cresol 5a. Disappointingly, the use of up to six
equivalents of AlCl3 did not lead to any of the desired
product.
Fortunately, we rapidly discovered that 2.4 equivalents of
inexpensive and non-toxic iron(III) chloride[13] in dichloro-
methane at room temperature promoted the formation of
indoline 6a in 99% yield from 2 equivalents of 5a
(Scheme 3). A small amount of 3-arylated indoline 8a,
Scheme 3. Optimization of the 3-Hydroarylation of N-acetyl skatole 7a
with p-cresol 5a. [a] Yield of isolated product based on 7a; [b] Yield of
isolated 9 based on 5a. acac=acetylacetonate, Tf=trifluoromethane-
sulfonyl.
Scheme 4. Hydroarylation of 3-substituted N-acetyl indoles with phe-
nols. [a] 7 (2.2 equiv) and FeCl3 (2.4 equiv). [b] 7 (3.2 equiv) and FeCl3
(3.4 equiv). [c] About 15% of indoline resulting from meta attack of p-
OEt phenol was also detected.
which is linked at the para position of the phenol core, was
isolated. This probably results from an electrophilic ipso
aromatic substitution.[14] Polyphenol oxidative homocoupling
products (9) of p-cresol were also isolated.[15]
More electron rich p-OEt phenol allowed the synthesis of 6j.
Evaluation of 3-benzyl and 3-butyl N-acetyl indoles resulted
in 3-arylated indolines 6k–m in 92–51% yields. The more
hindered 3-phenyl N-acetyl indole gave 24% of indoline 6n.
N-acetyl tetrahydocarbazole, a 2,3-substituted indole, deliv-
ered cis hydroarylated indoline 6o as the major diastereomer
(d.r.: 6.5:1). Varying the electronics of the indole core resulted
in the isolation of bromoindoline 6p and ethyl ester indoline
6q from the more electron-poor indole rings, whereas
a electron-donating methoxy group on indole allowed the
synthesis of methoxyindoline 6r. Unsubstituted phenol
reacted in the para position to generate 8a,[16] whereas
2,4,6-trimethyl phenol delivered a mixture of the ipso
substitution para product 8s and compound 10, which results
Surprisingly, the screening of various Brønsted or Lewis
acids in lieu of FeCl3 did not lead to any coupling reaction.
Even more intriguing, other sources of iron(III) or iron (II)
leave N-acetyl skatole untouched. The reason why FeCl3 is so
exclusive in achieving this transformation is unclear at the
moment. Coordinating solvents, such as ethyl acetate, meth-
anol, acetone, or THF, were unsuited for this reaction, as they
probably sequester the iron promoter; moreover, only 37%
of 6a was obtained in heptane because of the low solubility of
the starting materials.
Very pleased to have in hand such delicate and mild
conditions to achieve the challenging hydroarylation of the
À
from meta attack of the phenol followed by an oxidative C C
=
usually nucleophilic C2 C3 double bond of indole by phenol,
bond formation (Scheme 4).
we turned our attention to the scope of the reaction. We
explored the reaction between N-acetyl skatole 7a and
different p-alkyl phenols (Scheme 4). The expected coupling
products 6a–e were isolated with yields of 62–99%. Halo-
genated phenols also furnished the expected indolines 6 f–i.
To gain insight into the stereochemical course of the
hydroarylation, the reaction of N-acetyl skatole 7a with the
deuterium-labeled phenol 2,6-D2-5a was performed. The two
deuterated indolines, [D]-6aa and [D]-6ab, which are epi-
meric at C2, were isolated in a 1.2:1 ratio, whereas the
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experiment between 7a and 5a in the presence of D2O
delivered 7% of a 3.2:1 ratio of [D]-6aa and [D]-6ab
(Scheme 5).
Scheme 7. Hydroarylation of substituted indoles with aromatic nucleo-
philes. [a] ArH (2 equiv) and FeCl3 (2.4 equiv). [b] ArH (3 equiv) and
FeCl3 (2.4 equiv). [c] ArH (3 equiv) and FeCl3 (3.4 equiv). [d] ArH
(7.2 equiv) and FeCl3 (7.6 equiv).
Scheme 5. Deuterium-labeling experiments.
We have also evaluated non-phenol aromatic nucleophiles
under our conditions (Scheme 7). Electron-rich anisole and
N-acetyl skatole 7a delivered 11a in 99% yield, whereas
indoline 12 was obtained in 65% yield from a phenol-
containing N-acetyl indole. Toluene and N-acetyl skatole 7a
produced 11b in 51% yield, whereas the less electron rich
chlorobenzene did not afford any of the desired coupling
product 11c. Heteroaromatic rings, such as N-tosyl indole,
thiophene, and furan, also proved to be useful nucleophiles
for 7a, as 3-arylated indolines 13, 14, and 15 were obtained in
64%, 52%, and 30% yields, respectively.
From a mechanistic point of view, we may postulate that
the formation of an iron–phenol complex[17] was the first
event to occur (Scheme 6). Although the formation of
polyphenol products 9 proved that some phenol radicals are
Our next task required the transformation of 3,3 disub-
stituted indolines 6 into the targeted benzofuroindolines 3
(Scheme 8). Therefore, we removed the N-acetyl substituent
of 6a by acidic hydrolysis, followed by oxidation of the crude
À
N H indolines with tetrapropylammonium perruthenate
(TPAP) and N-methyl morpholine-N-oxide (NMO),[19] and
we were pleased to isolate 56% of benzofuroindoline 3a.
Diisopropyl azodicarboxylate (DIAD) was also an effective
oxidant for this transformation, as 63% of 3a was
obtained.[20,21] The previously obtained indolines 6a–r were
converted into benzofuroindolines 3a–r using either TPAP/
NMO or DIAD in yields of 50–86%.[16,22]
Scheme 6. Mechanistic considerations.
formed by the oxidation of phenols with iron(III), we do not
believe that this is the operative species that accounts for the
hydroarylation of N-acetyl indoles. If this was the case, we
would have expected the addition of the phenols at the C2
position of the indoles.[6d,18] Moreover, the hydroarylation of
indoles is possible with non-phenol aromatic compounds
(Scheme 7), where the formation of radicals is unlikely.
Therefore, we believe that a Friedel–Crafts pathway occurs
We also desired to access the 3-arylchromenoindoline[23]
framework (Scheme 8), therefore indoline 12 was succes-
sively hydrolyzed and treated with a catalytic amount of
TPAP and 2.8 equivalents of NMO to deliver aryl chrome-
noindole 16.[16] The use of 1.2 equivalents of DIAD, to
prevent overoxidation, allowed the formation and isolation
of the expected chromenoindoline 17.[24]
To access enantioenriched benzofuroindolines, N-mesyl
proline[18] was employed as a chiral auxiliary on the nitrogen
of skatole (Scheme 9). The hydroarylation of 18 with 5a
delivers a 2.8:1 ratio of two C3 epimers. Separation on silica
gel yielded 63% of the major epimer, 19a, and 24% of the
minor epimer, 19b. Hydrolysis of 19a and DIAD oxidation
allowed the isolation of (À)-3a in 94% ee.
=
with N-acetyl indoles. Activation of the C2 C3 double bond
of the indole core with iron could lead to a benzylic tertiary
carbocationic species at C3, with the potential coordination of
the iron to the oxygen of the N-acetyl group. Nucleophilic
attack by the phenol could happen on the same side as the
iron, as in intermediate A1, or on the opposite face, as in B1
(Scheme 6). The deuterated experiments of Scheme 5 showed
that both possibilities are operative, but syn hydroarylation
seems preponderant, as deuteration of the iron intermediate
A2 should lead to [D]-6aa, whereas deuteration of B2 should
deliver [D]-6ab.
In conclusion, we have devised a method to construct
benzofuroindolines and chromenoindoline derivatives from
the 3-regioselective hydroarylation of N-acetyl indoles by
phenols with inexpensive and non-toxic FeCl3, followed by an
oxidation step. This process allows the intermolecular assem-
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Keywords: benzofuroindoline · diazonamide A · Friedel-Crafts ·
.
indoles · umpolung
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propylammonium perruthenate.
Scheme 9. Asymmetric version. Ms=methanesulfonyl.
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Received: August 16, 2012
Published online: November 5, 2012
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