Synthesis of 3,3-Spiroindolines via FeCl3-Mediated Cyclization of Aryl- or Alkene-Containing 3-Substituted N-Ac Indoles

Article abstract of DOI:10.1021/acs.orglett.6b00174

We report the cyclization of 3-substituted N-acetylindoles for the straightforward synthesis of 3,3-spiroindolines via the Friedel-Crafts reaction of an appended aryl group or the formal [2 + 2] cycloaddition of an appended alkene. Our strategy involves a

Full text of DOI:10.1021/acs.orglett.6b00174

Letter
pubs.acs.org/OrgLett
Synthesis of 3,3-Spiroindolines via FeCl3‑Mediated Cyclization
of Aryl- or Alkene-Containing 3‑Substituted N−Ac Indoles
Raj Kumar Nandi, Regis Guillot, Cyrille Kouklovsky, and Guillaume Vincent*
́
Univ Paris Sud, CNRS, Universite
́
Paris-Saclay, Institut de Chimie Molec
́ ́
ulaire et des Materiaux d’Orsay (ICMMO),
Equipe Methodologie, Synthese et Molec
́
̀
́
ules Therapeutique (MS&MT), Bat. 410, 91405 Orsay, France
́
S
* Supporting Information
ABSTRACT: We report the cyclization of 3-substituted N-acetylindoles for the straightforward synthesis of 3,3-spiroindolines via
the Friedel−Crafts reaction of an appended aryl group or the formal [2 + 2] cycloaddition of an appended alkene. Our strategy
involves an Umpolung of the C2C3 bond of the indole nucleus during FeCl3-mediated hydroarylation or annulation reactions.
he 3,3-spiroindoline motif is found in several biologically
Scheme 1. Strategies for the Spiroarylation of Indoles
1
Tactive natural products such as spiroindimicin B or vindoline,
and it is a privileged scaffold for the design of medicinally relevant
compounds (Figure 1).2 For example, NITD609 is an anti-
malaria agent,2a XEN907 is a promising compound for the treat-
ment of pain,2b and SYN351 is an insecticidal2c (Figure 1).
Figure 1. 3,3-Spiroindolines of interest.
Various methods to access 3,3-spiroindolines have been
reported3 including dearomative cyclization of indoles.4−8
However, the access to 3-aryl-containing spiroindolines is less
encountered.9,2b In particular spirocyclization by 3-arylative
dearomatization of indole is uncommon (Scheme 1).10 Harrowven
reported one example of a radical spirocylization of a 2-iodoaryl-
containing 3-substitued indole 1 mediated by tin hydride to give
spiroindoline 2.11
Given our interest in arylative functionalization of indoles,14
we propose a mechanistically distinct approach to the synthesis
of arylated 3,3-spiroindolines.
The group of You12 and the group of Xu and Liang13 reported
a palladium catalyzed cyclization process from bromo or
iodoarenes 3−5 involving the intramolecular nucleophilic attack
of the C3 position of indole into an aryl palladium complex 6,
which led to 3,3-spiroindolenines 7.
Received: January 19, 2016
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.6b00174
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Organic Letters
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To access the spiroindoline framework 9 from substrates 8
(Scheme 1), we intend to deploy the FeCl3-mediated hydroarylation
reaction of the C3C2 bond of N−Ac indoles that we devel-
oped and reported recently in the intermolecular mode.14a,b,15
We believe that this reaction proceeds via both the activation of
the acetyl and the C2C3 bond of indole in intermediates 10a
or 10b, which would be electrophilic to trigger a Friedel−Crafts
type reaction and would indeed result in the transformation of a
C−H bond into a C−C bond.16
We then found that it is also possible to use a heterocyclic
substituent such as a thienyl to obtain heteroarylspiroindolines
9u,v in moderate yields (Scheme 4).
Scheme 4. Spirocyclization via Hydroarylation of N−Ac
Indoles: Use of a Heteroaryl and Substitution of the Tether
The hydroarylation cyclization proved to best proceed with
2.4 equiv of anhydrous FeCl3 in dichloromethane in dilute
conditions (0.05 M) at room temperature in air. The generality
of the reaction was evaluated, and we found that para- and
meta-methoxyphenyl as well as para-tolyl or phenyl substituents
on the C3-chain of the indole led efficiently to the desired
spiroindolines 9a−d (Scheme 2).
Scheme 2. Spirocyclization via Hydroarylation of N−Ac
Indoles: Substitution of the Aryl Group
Finally, we also introduced a gem-diester on the tether between
the indole and the phenyl parts (Scheme 4). We observed that
the conversion was incomplete at room temperature probably
due to sequestration of iron chloride by the ester groups.
However, performing the reaction at 80 °C in 1,2-dichloroethane
resulted in complete conversion of the starting indole and
isolation of the spiroindoline 9w in 62% yield. Unfortunately, no
conversion of 8x, the precursor of the 7-membered ring 9x, was
observed.17
X-ray crystallography of crystals of spiroindolines 9a, 9d,
and 9u allowed us to unambiguously assign their structures
(Figure 2).18
We then studied the substitution of the benzene part of
the indole (Scheme 3). We noticed that electrondonating
Scheme 3. Spirocyclization via Hydroarylation of N−Ac
Indoles: Substitution of the Indole Nucleus
Figure 2. X-ray structures of spiroindolines 9a, 9d, and 9u.
We next wished to evaluate other π nucleophiles to access the
spiroindoline framework. Therefore, we replaced the aryl group
on the C3-side chain by a terminal alkene. We believed that
activation of the C2C3 bond of indole 11 by FeCl3 would
trigger the addition of the alkene at C3 via intermediate 12 to
form a 3,3-spirocyclic compound 13 bearing an endo-cyclic
double bond (Scheme 5).9a
Scheme 5. Planned 3-Spirocyclization of an N−Ac Indole by
Intramolecular Addition of a Terminal Alkene
methoxy and methyl groups were well tolerated at the C5-position
and led to the respective formation of spiroindolines 9e−h
and 9i−l. Halogens were also tolerated since the 5-bromo-3,3-
spiroindolines 9m−p and the 6-chloro-3,3-spiroindolines 9q−t
were obtained.
B
DOI: 10.1021/acs.orglett.6b00174
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Scheme 6. Spirocyclization via a Formal [2 + 2] Cycloaddition
ACKNOWLEDGMENTS
■
The research leading to these results has received funding from
the People Programme (Marie Curie Actions) of the European
Union’s Seventh Framework Programme FP7/2007-2013/under
REA grant agreement no. 623422 (IIF-2013 postdoctoral
fellowship to R.K.N.). We also gratefully acknowledge the
́
ANR (ANR-12-JS07-0002), the Universite Paris Sud, and the
CNRS for financial support.
REFERENCES
■
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also a spirocyclic structure.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00174.
Additional experiment, experimental procedures, charac-
terizations, and 1H and 13C NMR spectra copies of all new
compounds (PDF)
Compound 9a(CIF)
Compound 9d(CIF)
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Compound 9u(CIF)
Compound 14(CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: guillaume.vincent@u-psud.fr.
Notes
The authors declare no competing financial interest.
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D
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