Letter

Cite This: Org. Lett. XXXX, XXX, XXX-XXX pubs.acs.org/OrgLett

Radical-Mediated Dearomatization of Indoles with Sulnate

Reagents for the Synthesis of Fluorinated Spirocyclic Indolines
Dmytro Ryzhakov, Maxime Jarret, Regis Guillot, Cyrille Kouklovsky, and Guillaume Vincent*
Institut de Chimie Moleculaire et des Materiaux dOrsay (ICMMO), Equipe Methodologie, Synthese et Molecules Therapeutiques,
Univ. Paris Sud, CNRS, Universite Paris-Saclay, 15, rue Georges Clemenceau, 91405 Orsay, Cedex, France
*
S Supporting Information

ABSTRACT: The dearomative introduction of triuorometh-

yl and 1,1-diuoroethyl radicals, generated from their
corresponding sulnate salts, into the C2 position of indole
derivatives allows the diastereoselective synthesis of three-
dimensional 3,3-spirocyclic indolines over CH functionalized
indoles.

T he indole nucleus is the major constituent of a large

number of molecules with signicant biological activity,
including approved drugs or compounds in clinical trials.
Scheme 1. Radical-Mediated CH Functionalization versus
Dearomatization of Indoles

Therefore, the indole scaold is an important structural unit for

the discovery of new drug candidates.1 On the other hand,
uorine atoms and, in particular the triuoromethyl unit (CF3)
oer unique biological properties and are encountered in a high
number of commercial medicines.2 The 1,1-diuoroethyl group
is considered to be a metabolically stable bioisoster of the
methoxy group in drug discovery.3 Finally, the pharmaceutical
industry is in need of scaolds containing saturations (sp3
carbons); three-dimensional drug candidates are more likely to
succeed than at ones.4 For instance, the spiroindoline scaold
is encountered in several medicinally relevant molecules.5
Dearomatization reactions are perfectly suited to achieve this
goal, since they could transform rapidly achiral starting
materials into chiral compounds with an important increase
of complexity.6 Most of the time, dearomatization reactions rely
on the innate nucleophilic character of indoles which react with
electrophiles.5,7
We have recently described that the dearomatization of
indoles could be possible via the generation of electrophilic
indole intermediates.8 We now wish to study a radical-mediated
approach.9 Over the years, several functionalization reactions of
heteroarenes, including indoles, were reported which involve
the addition of free radicals into a heteroaromatic substrate 1
which delivers a dearomatized intermediate I with a radical on
the carbon adjacent to the newly formed bond (Scheme
1).1012 Usually, this radical is then oxidized by single electron
transfer (SET) into a carbocation II which is followed by a very
fast aromatization event via elimination of a proton to yield
functionalized heteroarene 2. In contrast, the challenge is to
intercept carbocation II by a nucleophile before the
aromatization step to obtain 2,3-difunctionalized indoline 3.
Few reports,13,14 including our work,14a described the addition
of radicals, generated from aziridines,13a oxaziridines,13b
azides,13c or phenols,14 at C2 of indoles followed by trapping
of the C3 resulting carbocations before the aromatization. In
order to introduce uorine-containing carbon-centered radicals
on the indole nucleus, we selected sodium triuoromethyl
sulnate,15 since sulnates are known to easily generate radicals
in mild oxidative conditions via homolytic cleavage of the
relatively weak CS bond and elimination of SO2 and are
therefore versatile reagents to perform CH functionalization
of arenes.12 This strategy would allow us to have general access
to original uorine-containing spiroindolines.16
We selected 3-(3-hydroxypropyl)-NCO2Et-indole 1a as a
model substrate to evaluate our approach (Table 1). In that
case, carbocation II would be intramolecularly intercepted by
an alcohol to yield spirofuranoindoline 3a. Dierent oxidative
systems to generate the triuoromethylene radical from sodium
triyl sulnate were investigated. With tert-butyl hydroperoxide,
only few amounts of 3a were detected, along with remaining
indole 1a and unidentied products (Table 1, entries 1 and 2).
Only traces of the desired 3a were obtained with hypervalent
iodine reagent PIFA (Table 1, entry 3). A catalytic amount of
silver nitrate and a sup-stoichiometric amount of potassium
persulfate at 80 C delivered 3a in 30% yield (Table 1, entry 4).
Manganese(III) acetate at 80 C in acetonitrile aorded 3a in a
gratifyingly 61% yield (Table 1, entry 5). Ceric ammonium
Received: October 10, 2017

XXXX American Chemical Society A DOI: 10.1021/acs.orglett.7b03155

Org. Lett. XXXX, XXX, XXXXXX
Organic Letters Letter

Table 1. Optimization of the 3-Oxy-2-triuoromethylation of Scheme 2. Synthesis of Fluorinated Spirocyclic Indolines

Indole 1a with Sodium Triuoromethyl Sulnate from Sulnate Reagents

temp 3a isolated yield

entry oxidant (equiv) solvent (C) (%)
1 t-BuOOH (5) CH3CN/H2O rt 10%
(2:1)
2 t-BuOOH (5) CH3CN rt traces
3 PIFAa (3) CH3CN rt traces
4 AgNO3 (0.1), CH3CN/H2O 80 30
K2S2O8 (2) (1:1)
5 Mn(OAc)3 (3) CH3CN 80 61
6 CANb (3) CH3CN rt 51
7 CANb (3) CH3CN 10 69
8 CANb (3) CH3CN 30 slow conversion
a
PhI(OCOCF3)2. b(NH4)2Ce(NO3)6.

nitrate (CAN) in acetonitrile at room temperature delivered 3a

in 51% yield and also CF3-containing indole 2a and
undetermined compounds (Table 1, entry 6). Performing the
reaction at 10 C allows the intramolecular trapping by the
alcohol of carbocation II to be favored over its aromatization,
and 3a was isolated in 69% yield (Table 1, entry 7). The
reaction proved to be too slow at 30 C (Table 1, entry 8).
Remarkably, indoline 3a was obtained as a unique diaster-
oisomer with the CF3 group at C2 and the oxygen at C3 in a
trans relationship as demonstrated by X-ray analysis of crystals
of 3a.17,18
Having found suitable conditions to perform our desired
dearomative 3-oxy-2-triuoromethylation of indoles, we
evaluated the scope of this reaction (Scheme 2).18 The
inuence of the substitution of the nitrogen of the indole
nucleus was rst studied. The Boc and acetyl groups were as
well permitted as the CO2Et since 3b17 and 3c were obtained in
74% and 78% yield, while a lower yield was obtained with a
tosyl group (3d, 43%). Dierent functional groups on the
benzene ring of the indole nucleus were then scrutinized.
Electron-donating groups, such as methoxy at the C5-position
(3e, 55%), methyl at the C5 (3f, 78%) and C7 (3g, 69%)
positions, or halogens such as uorine (3h, 60%), chlorine (3i,
71%), and bromine (3j, 61%) at C5, were well tolerated. The
reaction also operates with an electron-withdrawing group at
C5, such as a cyano group (3k, 57%).
Next, the nature of the nucleophile was investigated. A a
0.022 M in acetone. b2.5 equiv of MeCF2SO2Na and 4 equiv of CAN.
tertiary alcohol was as ecient as a primary one since indoline
3l was obtained in 70% yield. The carboxylic acid was also a
very good oxygenated nucleophile since 3m was isolated in 87% indolines containing, respectively, a methyl (3r, 70%),17 a
yield. Triuoromethylated-lactones containing a 5-methoxy methoxy (3s, 53%), and a uorine (3t, 61%) at the C5-position.
(3n, 72%), 7-methyl (3o, 80%), and 6-chlorine (3p, 35%)19 Finally, it was possible to introduce a 1,1-diuoroethyl group
group on the benzene part of the indole ring were also in lieu of the triuoromethyl by using the corresponding
obtained. To solubilize the starting carboxylic acids, the sodium sulnate.12e Gratifyingly, we obtained moderate yields
reaction leading to 3o and 3p were performed in acetone at of spirofuranoindoline 3u (28%) and spiropyrrolidinoindoline
a higher dilution. 3v (27%).20
Nitrogenated nucleophiles were also competent to deliver To further demonstrate the synthetic potential of this
spiropyrrolidinoindolines. The cyclization of indoles displaying dearomative method, a gram-scale experiment allowed 3f to be
a N-tosyl amine on the C3-side chain gave 3q in 66% yield and obtained in 73% yield.
B DOI: 10.1021/acs.orglett.7b03155
Org. Lett. XXXX, XXX, XXXXXX
Organic Letters
A mechanism involving free-radical intermediates is indeed
suggested by the incorporation of the triuomethyl group into
compounds 3 via desulfonation from the sulnate reagent.21 In
order to gain additional mechanistic insights, we submitted
indole 1b to the oxidative reaction conditions with CAN
without the presence of the triuoromethylative reagent, and in
that case, the starting indole was rapidly consumed into several
oxidation products, among which hydroxyl indoline 4 and
dimer 5 were isolated and their structures tentatively assigned
(Scheme 3). A radical cation such as III could be postulated to
Scheme 3. Control Experiment
explain the formation of such compounds. If both the indole 1
and the sulnate reagent could be oxidized by CAN,22 it is
presumed that the sulnate reagent should be oxidized faster
than indoles 123,24 and it supports the mechanism depicted in
Scheme 1. However, we cannot exclude an alternative
mechanism which involves the oxidation of 125 and the
sulnate reagent into, respectively, the radical cation III and the
triuoromethyl radical, followed by a radical recombination
event into carbocation II.26
In conclusion, we developed a diastereoselective dearomative
3,3-spirocyclization of indoles via the addition of uorinated-
carbon radicals, generated from sulnate reagents, at the C2-
position of indoles, in the presence of ceric ammonium nitrate
as the oxidant. The prominent feature of this strategy is the
interception of the transient carbocation at the C3-position
before aromatization into a C2-functionalized indole through
elimination of a proton. This protocol has a broad substrate
scope and tolerates various nucleophiles. We believe that this
method is potentially of high interest in the discovery of
biologically active compounds.
ASSOCIATED CONTENT
*
S Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03155.
Experimental procedures, characterizations, and NMR
spectra of all new compounds (PDF)
Accession Codes
CCDC 15753541575356 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
C DOI: 10.1021/acs.orglett.7b03155
Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail: Guillaume.vincent@u-psud.fr.
ORCID
Guillaume Vincent: 0000-0003-3162-1320
Notes
The authors declare no competing nancial interest.
ACKNOWLEDGMENTS
D.R. and M.J. thank respectively the MENESR and the ANR
for PhD fellowships. We also gratefully acknowledge the
Universite Paris Sud and the CNRS for nancial support.
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D DOI: 10.1021/acs.orglett.7b03155
Org. Lett. XXXX, XXX, XXXXXX