Bioinspired direct access to benzofuroindolines by oxidative [3 + 2] annulation of phenols and indoles

Article abstract of DOI:10.1021/ol502820p

The straightforward entry to benzofuroindoline containing natural product-like scaffolds has been achieved by a challenging [3 + 2] oxidative coupling between phenols and indoles. The reaction proceeds by NIS-oxidation of the indole followed by the trapping of the resulting electrophilic intermediate by phenol.

Full text of DOI:10.1021/ol502820p

Letter
pubs.acs.org/OrgLett
Bioinspired Direct Access to Benzofuroindolines by Oxidative [3 + 2]
Annulation of Phenols and Indoles
Natacha Denizot, Annie Pouilhes, Melissa Cucca, Rodolphe Beaud, Regis Guillot, Cyrille Kouklovsky,
̀
́
́
and Guillaume Vincent*
Univ Paris Sud and CNRS, Institut de Chimie Molec
́
ulaire et des Mater
́
iaux d’Orsay (ICMMO), UMR8182, Equipe Met
́
hodologie -
Synthese & Molecules Therapeutiques (MS&MT), Bat. 410, 91405, Orsay, France
̀
́
́
S
* Supporting Information
ABSTRACT: The straightforward entry to benzofuroindoline
containing natural product-like scaffolds has been achieved by
a challenging [3 + 2] oxidative coupling between phenols and
indoles. The reaction proceeds by NIS-oxidation of the indole
followed by the trapping of the resulting electrophilic
intermediate by phenol.
ipleiophylline,1 voacalgine A,2 and pleiocraline3 are natural
between indoles and phenols, the biogenetic precursors of the
benzofuroindoline natural products.
4
Bproducts containing a benzofuro[2,3-b]indoline substruc-
Pioneered by Harran et al., few direct syntheses of
benzofuro[2,3-b]indolines via the oxidative coupling of indoles
and phenols mediated by hypervalent-iodine(III) reagents or
electrochemistry have been described.7 This strategy is
conceptually very attractive and elegant despite modest yields
and its substrate specificity.8 We have been recently interested
in the union of indoles and phenols in order to construct the
benzofuroindoline skeleton. In 2012, we reported a two-phase
approach: the C3-regioselective addition of phenols to
electrophilic N−Ac indoles activated by FeCl3, followed by
an oxidation which delivers the desired benzofuro[2,3-
b]indolines.9 More recently, we have uncovered the radical
coupling of phenols with N−Ac indoles in the presence of
DDQ and FeCl3 leading to regioisomeric benzofuro[3,2-
b]indolines.10
ture thought to be biogenetically produced by the oxidative
coupling of the indole alkaloid pleiocarpamine and a phenol
unit (Scheme 1).1−3 Synthetically mimicking this trans-
formation is known to be a particularly difficult endeavor
because it involves the union of two nucleophilic entities.5 We
therefore set our goal to achieve a direct [3 + 2] annulation6
Scheme 1. Benzofuroindoline Containing Natural Products
Derived from Pleiocarpamine
However, we found that none of these methods were suitable
to access structures of the bipleiophylline/voacalgine A series.
Therefore, to overcome these limitations, the design of an
alternative strategy was required. In contrast to the mentioned
methods, we planned to preoxidize the indole nucleus in order
to generate an electrophilic species at C3 before realizing the
coupling with a phenol.11
To meet this criterion, we turned our attention to 3-
halogenoindolines 4 which have been described to be involved
in reactions with nucleophiles,7b,12−14 including arene-
s.12a,b,13a−d However, the C-addition of phenols to halogen-
oindoline derivatives is unreported. Two pathways may be
envisioned for this coupling: the O-addition of the phenol 2 to
the imine of 4 followed by an intramolecular nucleophilic
substitution at C3 in 5 or the generation of a carbocation 6 in
alpha to the imine which would react with the phenol to form a
Received: September 24, 2014
Published: October 27, 2014
© 2014 American Chemical Society
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Letter
C−C bond (Scheme 2). The literature warned us against
competition pathways from halogenoindolines 4 which would
that side reactions could be operative. Mixing the two partners
with N-chloro- or N-bromosuccinimide (NCS and NBS) did
not lead to any of the desired benzofuroindoline (entries 1, 2).
Eventually, the reaction with N-iodosuccinimide (NIS) allowed
us to isolate the expected annulated compound 3a whether
indole 1a, phenol 2a, and NIS were added at the same time
(26%, entry 3) or the indole was first mixed with NIS to form
the iodoindoline 4 before phenol was added (28%, entry 4).
We reasoned that the addition of soluble silver salts to the
preformed iodoindoline 4 will allow the formation of a
carbocation such as 6, which would be more reactive toward
phenol 2a and hopefully increase the yield of 3a.12a,b,13a−d
However, the addition of silver tetrafluoroborate disappoint-
ingly yielded only 33% of 3a (entry 5). All the iodoindoline was
consumed, but traces of 7, which arose from the O-alkylation
pathway, were observed as well as other unknown byproducts.
In order to favor the C-alkylation, Lewis acids were screened
with the idea to form a complex between the hydroxyl of the
phenol and the Lewis acid. We observed that scandium triflate
(entry 6) and tin chloride (entry 7) were efficient to deliver
satisfactory yields (44% and 53%) of benzofuroindoline 3a. The
addition of sodium hydroxide in lieu of the Lewis acid was of
similar efficiency (52%, entry 9). In the absence of the silver salt
an important decrease in yield was noted with tin chloride
alone or sodium hydroxide alone (entries 8, 10). In both cases,
tetrahydrocarbazole 1a was recovered, and in the former case,
O-alkylation products were detected.
Scheme 2. Our Strategy via Preoxidation of Indoles
After the discovery of suitable conditions for the challenging
direct oxidative merging of tetrahydrocarbazole 1a and 4-
methoxyphenol 2a, we desired to explore in more detail the
scope of this reaction. Keeping 4-methoxyphenol 2a as a test
nucleophile, we engaged several 2,3-disubstituted indoles in the
NIS/AgBF4/SnCl4 conditions (Scheme 3). Changing the
result in the formation of undesired products.12c−h O-
Alkylation of phenol at C3 of the indoline could occur and
lead to compound 7 which may rearrange into the undesired
compound 8 through migration of the C2-substituent to the C3
position. Migration of the C2-substituent to the C3 position
from 5 may also be expected and deliver 9. Additions of arenes
or alcohols on the C2-substituents of the halogenoindoline are
also documented; therefore, isolation of indole 10 or 11 could
be expected.
Scheme 3. Oxidative Coupling between Phenols and
Indoles; Scope of Indoles
The investigation started by coupling tetrahydrocarbazole 1a
with 4-methoxyphenol 2a (Table 1), although we had in mind
Table 1. Investigation of the Oxidative Coupling of
Tetrahydrocarbazole 1a and 4-Methoxyphenol 2a
a
entry
oxidant
additive 1 (equiv)
additive 2 (equiv)
yield
b
1
NCS
NBS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
−
−
−
−
−
−
−
−
0%
0%
b
2
b
3
26%
28%
33%
43%
53%
<5%
52%
15%
4
5
AgBF4 (2.0)
AgBF4 (2.0)
AgBF4 (2.0)
−
−
6
Sc(OTf)3 (2.0)
SnCl4 (2.0)
SnCl4 (2.0)
NaOH (5.0)
NaOH (5.0)
7
8
substitution of the 2 and 3 positions of the indole from
tetrahydrocarbazole to cycloheptaindole resulted in benzofur-
oindoline 3b in 55% yield; 2-methyl-3-ethylindole led to
benzofuroindoline 3c in 43% yield. The electronic effects on
the benzene part of the indole nucleus were then evaluated.
Pleasantly, electron-donating groups (OMe, 3d, 40%; Me, 3e,
9
10
AgBF4 (2.0)
−
a
b
Isolated yields. The oxidant and the phenol were added at the same
time.
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Letter
53%;), an electron-withdrawing group (NO2, 3f, 46%;), and
halides (Cl, 3g, 48%; Br, 3h, 59%; 3i, 47%) afforded the
expected benzofuroindolines in appreciable yields given the
complexity of the transformation.
We next investigated phenols susceptible to participating in
the [3 + 2] annulation (Scheme 4). Indeed, 4-ethoxyphenol
4%), 12r (R = F, 6%), 12s (R = Br, 6%).15 Increasing the
electron density with 3,4,5-trimethoxyphenol resulted in the
major formation of regioisomeric benzofuro[3,2-b]indolines
12t (R = H, 37%) and 12u (R = Me, 32%)16 over the
benzofuro[2,3-b]indolines 3t (R = H, 2%) and 3u (R = Me,
8%). In this unexpected case, the O-alkylation of the phenol by
the indolenium ion 6 is probably predominant over the C-
alkylation, and then intramolecular C−C bond formation
between the C2 position of the indole and ortho position of the
phenol should occur and deliver benzofuro[3,2-b]indolines 12.
The structure of the natural product phalarine very interestingly
displays the benzofuro[3,2-b]indoline skeleton.17
Scheme 4. Oxidative Coupling between Phenols and
a
Indoles; Scope of Phenols
Our oxidative coupling was then tested with tetrahydrocarbo-
line 13. The reaction with 4-methoxyphenol and 3,4-
dimethoxyphenol afforded benzofuroindolines 14a and 14b
(Scheme 5). Encouraged by this result, we increased the level of
Scheme 5. Oxidative Coupling from Tetrahydrocarboline
Derivatives; Synthetic Approach to Voacalgine A
structural complexity and performed the reaction on the more
challenging tetracycle 15, which was synthesized in three steps.
The hexacyclic core 16 of voacalgine A/bipleiophylline was
thus obtained diastereoselectively in a very concise manner.16
In conclusion, we developed a method for direct access to
the benzofuro[2,3-b]indoline scaffold, which is found in several
natural products. The [3 + 2] oxidative coupling between
nucleophilic phenols and indoles which we designed was
inspired by the biogenesis of the benzofuroindoline containing
natural products. This transformation from unprotected indoles
and phenols is known to be a particularly difficult task. The
preoxidation of the indole nucleus by NIS to form an
electrophilic intermediate captured by phenol is the key to
the success of this procedure. Our method is conceptually the
reverse of the hypervalent iodine mediated coupling of indoles
and phenols developed by Harran in which the phenol is
oxidized before the coupling with the nucleophilic indole.7 Our
method features the bimolecular formation of a C−C bond
which is a great added value. We believe that the scope of the
reaction and the yields obtained complement the known
hypervalent-iodine mediated reaction favorably.7 Very interest-
ingly, particularly electron-rich 3,4,5-trimethoxyphenol led to
regioisomeric benzofuro[3,2-b]indolines, the scaffold of which
is found in the natural product phalarine. Finally, we have
achieved the straightforward synthesis (4 steps) of the
hexacyclic skeleton of voacalgine A.
a
K2CO3 was used instead of NaOH.
delivered the desired benzofuroindolines 3j (49%) and 3k
(60%) from tetrahydrocarbazole and cycloheptaindole. Less
electron-rich phenols were less reactive; however, 4-methyl-
phenol allowed the synthesis of 3l in 36% yield. Methox-
ynaphtol was also a suitable partner in the presence of NaOH,
and 3m was obtained (47%).
We then turned our attention to more electron-rich
dimethoxy or trimethoxy phenols and found that basic
conditions were more efficient than SnCl4 to promote the
reaction. We isolated benzofuroindolines 3n and 3o from 2,4-
dimethoxyphenol in 42% and 61% yields, respectively. With
3,4-dimethoxyphenol, a different trend appeared: along with the
expected benzofuro[2,3-b]indolines 3p (R = H, 40%), 3q (R =
Me, 52%), 3r (R = F, 45%), and 3s (R = Br, 42%) as the major
products, we observed the formation of the regioisomeric
benzofuro[3,2-b]indolines 12p (R = H, 25%), 12q (R = Me,
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterizations, and H and 13C
NMR spectra copies for all benzofuroindolines as well as X-ray
crystallographic data for compounds 12u and 16. This material
is available free of charge via the Internet at http://pubs.acs.org.
■
S
1
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: guillaume.vincent@u-psud.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the “Fondation pour le dev
ment de la chimie des substances naturelles et ses applications;
■
́
eloppe-
sous l’eg
́ ́
ide de l’Academie des Sciences” for a graduate
fellowship (N.D.), the ANR (ANR-12-JS07-0002; “programme
Tendoung, J.-J.; Treg
j.tet.2014.06.054.
́
uier, B. Tetrahedron, 2014, doi:10.1016/
JCJC 2012”; project name “CouPhIn”), the Universite
Sud, and the CNRS for financial support.
́
Paris
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