Alkoxyamine-Mediated Radical Synthesis of Indolinones and Indolines

Article abstract of DOI:10.1021/ol0358049

(Equation presented) Thermolysis of α-alkoxyamino propionanilides produces indolinones, whereas thermal reaction of N-allylaniline derivatives with various Tordo-type alkoxyamines results in formation of indolines in the radical regime.

Full text of DOI:10.1021/ol0358049

ORGANIC
LETTERS
2003
Vol. 5, No. 26
4943-4945
Alkoxyamine-Mediated Radical Synthesis
of Indolinones and Indolines
Corinne Leroi,† Denis Bertin,‡ Pierre-Emmanuel Dufils,‡ Didier Gigmes,‡
Sylvain Marque,‡ Paul Tordo,‡ Jean-Luc Couturier,§ Olivier Guerret,§ and
,†
Marco A. Ciufolini*
UniVersite´ Claude Bernard Lyon 1 and Ecole Supe´rieure de Chimie, Physique,
Electronique de Lyon, CNRS UMR 5622, 43, Bd du 11 NoVembre 1918, 69622
Villeurbanne, France, Laboratoire Structure et Re´actiVite´ des Espe`ces
Paramagne´tiques, case 521, CNRS UMR 6517, UniVersite´s d'Aix -Marseille I et III,
Centre de Saint-Je´roˆme, AVenue Escadrille Normandie-Niemen, 13397 Marseille Cedex
20, France, and Atofina SA, Centre de Recherche Rhoˆne-Alpes, Rue Henri Moissan,
69643 Pierre Benite, France
ciufi@cpe.fr
Received September 18, 2003
ABSTRACT
Thermolysis of r-alkoxyamino propionanilides produces indolinones, whereas thermal reaction of N-allylaniline derivatives with various Tordo-
type alkoxyamines results in formation of indolines in the radical regime.
We have recently described a new radical cyclization process
that relies on the reaction of the Tordo alkoxyamine, 1, with
a 1,6-diene, 2, leading to products 3 (Scheme 1).1 An even
Such alkoxyamine-based techniques suppress any need for
halogenated substrates and Sn/Si hydrides to promote C-C
bond formation in the radical regime, providing a relatively
environmentally benign alternative to traditional radical
methodology. Furthermore, the chain termination step in-
volves the capture of a carbon radical by a nitroxyl radical,
thereby introducing useful oxygenated functionality, instead
of simply reducing the radical intermediate through H-atom
transfer from a metal hydride.
Scheme 1. Alkoxyamine-Mediated Radical Cyclization
In an effort to extend this chemistry to the heterocyclic
domain, we have focused on the synthesis of indole deriva-
tives. Indeed, considerable activity has been recorded in the
area of indole synthesis through radical processes.3
more recent paper by Studer expands the scope of his earlier,
seminal studies to a like mode of reactivity with TEMPO-
derived alkoxyamines.2
In this paper, we disclose the alkoxyamine-mediated
assembly of indolinones and indolines through cyclization
of aniline derivatives 4 (Scheme 2).
† Universite´ Claude Bernard Lyon 1.
‡ Universite´s d'Aix -Marseille I et III.
§ Atofina SA.
(1) Leroi, C.; Fenet, B.; Couturier, J. L.; Guerret, O.; Ciufolini, M. A.
Org. Lett. 2003, 5, 1079.
The process that we envisioned involves the attack of a
radical species onto a benzenoid π system (cf. 6 and 7). This
general type of reaction is well documented,3e-h but in our
case, such an event would have to occur in the presence of
a free nitroxyl radical. A priori, it was not clear whether the
(2) Wetter, C.; Jantos, K.; Woithe, K.; Studer, A. Org. Lett. 2003, 5,
2899.
10.1021/ol0358049 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/22/2003

Scheme 2. Alkoxyamine-Mediated Avenue to Indole
Scheme 4. Indolines from Unsymmetrically Substituted
Derivatives
Anilines
reversible trapping of 6 by the nitroxyl radical would be
beneficial (or even critical) to the success of the reaction or
whether complications might arise as a result of this trapping.
Consequently, the feasibility of the transformation of Scheme
2 was initially explored through a study of the thermal
cyclization of preformed intermediates 11.4 These were
prepared by a coupling reaction between the stable free
nitroxyl radical 9 (“SG1”) and an alkyl radical generated in
situ through Cu(I)-mediated reduction of an appropriate alkyl
bromide 10 (Scheme 3).
a Conditions: 120 °C, 0.5 M in t-BuOH, 20 h. Chromatographed
Yields: 15% for 14s, 8% for 14t, 30% for 17. Bs = brosyl (4-
bromobenzenesulfonyl).
material was observed leading directly to compounds 12. No
products arising from trapping of the presumed radical
intermediate 7 by SG1 were detected in the reaction mixture.
Evidently, either 7 suffers H-atom transfer to the nitroxyl
radical or the product of its recombination with SG1
undergoes facile elimination to the ultimate 12. Some
examples of this transformation are provided in Table 1.
Scheme 3. Preparation of Alkoxyamines 11a
Table 1. Indolinone and Indoline Synthesis by Thermolysis of
Compounds 11
entry
R1
Me
Me
COOMe
R2
X, Y
T (°C)
yieldb
a PMDETA ) N,N,N′,N′′,N′-pentamethyldiethylenetriamine.
a
b
c
H
Me
H
O
O
H, H
120
80
120
68
63
75
When a solution of 11 in PhCl or t-BuOH was heated at
80-120 °C for 12 h, complete consumption of the starting
a Reactions were carried out as a 0.025 M solution in PhCl for entry a
and in t-BuOH for entries b and c. b Chromatographed.
(3) Cf. (a) Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc. 1994,
116, 3127. (b) Tokuyama, H.; Yamashita, T.; Reding, M. T.; Kaburagi, Y.;
Fukuyama, T. J. Am. Chem. Soc. 1999, 121, 3791. (c) Reding, M. T.;
Fukuyama, T. Org. Lett. 1999, 1, 973. (d) Yokoshima, S.; Ueda, T.;
Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fukuyama, T. J.
Am. Chem. Soc. 2002, 124, 2137. (e) Boivin, J.; Yousfi, M.; Zard, S. Z.
Tetrahedron Lett. 1994, 35, 9553. (f) Axon, J.; Boiteau, L.; Boivin, J.;
Forbes, J. E.; Zard, S. Z. Tetrahedron Lett. 1994, 35, 1719. (g) Ly, T. M.;
Quiclet-Sire, B.; Sortais, B.; Zard, S. Z. Tetrahedron Lett. 1999, 40, 2533.
(h) Quiclet-Sire, B.; Sortais, B. S.; Zard, S. Z. J. Chem. Soc., Chem.
Commun. 2002, 1692. (i) Rainier, J. D.; Kennedy, A. R.; Chase, E.
Tetrahedron Lett. 1999, 40, 6325. (j) Rainier, J. D.; Kennedy, A. R. J.
Org. Chem. 2000, 65, 6213.
The more challenging bimolecular mode of reactivity was
initially investigated with intermediates 4 wherein R2 ) X
) Y ) H or R2 ) H; X, Y ) O. Disappointingly, both types
of substrate failed to yield indolinones or indolines upon
thermal reaction with alkoxyamine 1. By contrast, com-
pounds 4 in which R2 ) COOMe and X,Y ) H proved to
be competent substrates. Presumably, the presence of the
ester function facilitates the addition of the radical produced
by the initial dissociation of the alkoxyamine to the olefinic
(4) This mode of reactivity constitutes a variant of the original Studer
cycloisomerization of alkoxyamines: see ref 2 and literature cited therein.
4944
Org. Lett., Vol. 5, No. 26, 2003

or symmetrically (para) substituted. Results of a brief study
of indoline formation from unsymmetrically substituted
anilines are presented in Scheme 3. Reaction of meta-
anisidine derivative 13s with alkoxyamine 1 led to a mixture
of regioisomers in which the major component was the para-
type cyclization product 14s. However, the product ratio was
a weak 2:1.7 On the other hand, pyridine derivative 15 reacted
with tert-butyl SG1 to furnish indoline 17 in 30% unopti-
mized yield. Compound 17 accounted for more than 90%
of the product mixture: regioisomer 18 was estimated (1H
NMR) to represent less than 10% of the total product (i.e.,
<3% chemical yield) and was not fully characterized. The
observed selectivity for attack of the presumed radical
intermediate 16 at C-2 of the pyridine nucleus is consistent
with precedent, notably with the work of Minisci on the
radical alkylation of electron-deficient nitrogen heterocycles.8
In summary, Tordo alkoxyamines, originally developed
as control agents in radical polymerization reactions,9 appear
to be valuable intermediates for the synthesis of indole
derivatives in the radical mode. Additional synthetic ap-
plications of alkoxyamines are under study and will be
described in due course.
Table 2. Indoline Synthesis by Alkoxyamine-Induced Radical
Cyclization
Acknowledgment. We thank Atofina SA (doctoral fel-
lowships to C.L.), the CNRS, the MENRT, and the Re´gion
Rhoˆne-Alpes for support of our research program. M.A.C.
is the recipient of a Merck & Co. Academic Development
Award.
Supporting Information Available: Detailed descrip-
tions of experimental procedures and full characterization
data for the compounds described herein. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0358049
(5) For a thorough discussion, see: Fischer, H.; Radom, L. Angew. Chem.,
Int. Ed. 2001, 40, 1340. An amide carbonyl may not provide sufficient
activation of the olefinic π system, explaining the failure of compounds 4
(X, Y ) O) to cyclize.
a All reactions were carried out as a 0.5 M solution in t-BuOH.
b Chromatographed. c Bs ) brosyl (4-bromobenzenesulfonyl).
(6) Alkoxyamines 5 where R3 ) CH3CHCOOMe or (CH3)e´CHCOOH
were prepared by the method detailed in Scheme 3. The tert-butyl analogue
was obtained by reaction of 2 equiv of free SG1 with commercial tert-
butylmagnesium chloride (55-60% yield).
(7) Yield of this reaction was not optimized due to the weak isomer
ratio observed.
(8) Cf., e.g.: Minisci, F.; Vismara, E.; Fontana, F. Heterocycles 1989,
28, 489.
(9) Review: Hawker, C. J.; Bosman, A. W.; Hart, E. Chem. ReV. 2001.
101, 3661.
π system.5 Representative examples with three Tordo-type
alkoxyamines6 are provided in Table 2.
The experiments summarized in Table 2 were carried out
with substrates in which the aryl group is either unsubstituted
Org. Lett., Vol. 5, No. 26, 2003
4945