Iodo-carbocyclization of electron-deficient alkenes: Synthesis of oxindoles and spirooxindoles

Article abstract of DOI:10.1021/ol2005243

Chemical equations presented. Cyclisative carbo-iodination of N-alkyl-N-arylacrylamide derivatives (3) in the presence of PhI(OAc) ₂/I₂ afforded functionalized 3-(iodomethyl)-3-substituted- indolin-2-ones (4) in good to excellent yie

Full text of DOI:10.1021/ol2005243

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2244–2247
Iodo-Carbocyclization of Electron-
Deficient Alkenes: Synthesis of Oxindoles
and Spirooxindoles
Hai-Long Wei,† Tiffany Piou,† Jeremy Dufour,† Luc Neuville,*,† and Jieping Zhu*,†,‡
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 91198
Gif-sur-Yvette Cedex, France, and Institute of Chemical Sciences and Engineering, Ecole
ꢀ ꢀ
Polytechnique Federale de Lausanne, EPFL-SB-ISIC-LSPN, CH-1015 Lausanne,
Switzerland
jieping.zhu@epfl.ch; luc.neuville@icsn.cnrs-gif.fr
Received February 25, 2011
ABSTRACT
Cyclisative carbo-iodination of N-alkyl-N-arylacrylamide derivatives (3) in the presence of PhI(OAc)2/I2 afforded functionalized 3-(iodomethyl)-3-
substituted-indolin-2-ones (4) in good to excellent yields. With a suitably functionalized linear amide, spirooxindole 8 was prepared in a one-pot
fashion via a sequence of iodo-arylation followed by an in situ base-promoted intramolecular SN2 reaction.
Halonium-induced cyclizations of heteroatom-tethered
olefins have emerged as powerful methods for the con-
struction of heterocycles.1 On the other hand, halocarbo-
cyclization of polyenesisfar lessdeveloped,2 althoughsuch
processes are known in the biogenesis of halogenated
natural products.3 Notable recent achievements in this
field are as follows: (a) Ishiraha’s enantioselective cycliza-
tion of 1,5-dienes in the presence of chiral phosphorami-
dite-complexed N-iodosuccinimide (NIS);4 (b) Barluenga’s
bis(pyridine)iodonium tetrafluoroborate (Py2IBF4)/HBF4-
promoted iodoarylation of N-protected-N-allylanilines (1)
to afford 1,2,3,4-tetrahydroquinolines (2, Scheme 1, eq 1);5
and (c) Snyder’s BDSB (bromodiethylsulfonium bromo-
pentachloroantimonate) promoted cyclization of polyenes.6
In all of these examples, electron-rich olefins are used as
cyclization partners, and in the case of 1,5-dienes, formal
6-endo-trig cyclization is strongly favored over the alter-
native 5-exo-trig mode7 in accord with the Eschenmoserꢀ
Stork postulate (Scheme 1, eq 1).8 We report herein
that a combination of two reagents, PhI(OAc)2 and I2, is
capable of promoting the iodoarylation of R-substituted
† Centre de Recherche de Gif, Institut de Chimie des Substances Natur-
elles, France.
‡ Institute of Chemical Sciences and Engineering, Ecole Polytechnique
ꢀ ꢀ
Federale de Lausanne, Switzerland.
(1) Reviews: (a) Togo, H.; Iida, S. Synlett 2006, 2159–2175. (b)
Mphahlele, M. J. Molecules 2009, 14, 4814–4837. (c) Chen, G.; Ma, S.
Angew. Chem., Int. Ed. 2010, 49, 8306–8308. For a recent enantioselec-
tive oxylactonization, see: (d) Fujita, M.; Yoshida, Y.; Miyata, K.;
Wakisaka, A.; Sugimura, T. Angew. Chem., Int. Ed. 2010, 49, 7068–7071.
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alternative 6-endo-trig cyclization in iodonium-promoted cyclization
reactions of heteroatom-tethered alkenes in accord with the Baldwin’s
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r
10.1021/ol2005243
Published on Web 04/07/2011
2011 American Chemical Society

N-arylacrylamide derivatives (3) to afford 3,30-disubsti-
tuted oxindoles (4, Scheme 1, eq 2). To the best of our
knowledge, this work constitutes the first examples of
iodo-carbocyclization of electron-deficient olefins. The
unique cyclization mode is also noteworthy as it proceeds
via an unusual formal 5-exo-trig cyclization mode in sharp
contrast to the cyclization of structurally similar N-pro-
tected-N-allylanilines (1).9
anilides have been developed.13,14 We have been involved
in the development of a palladium-catalyzed synthesis of
oxindoles15 and have recently reported an oxidative palla-
dium-catalyzed carbo-heterofunctionalization of alkenes 3
involving a direct aromatic CꢀH functionalization step.16
Stimulated by the recent development of halonium-
mediated carbocyclization processes,4ꢀ6 we became inter-
ested in investigating the cyclization of 3 under metal-free
conditions using 3a as a model substrate.
As shown in Table 1, our initial survey of reaction
conditions using molecular iodine (I2), iodine monochlo-
ride (ICl), or Barluenga’s reagent (Py2IBF4/HBF4)17 as
iodonium sources showed them to be inefficient at promot-
ing the desired transformation. However, acombination of
oxidant [PhI(OAc)2, IBX (2-iodoxybenzoic acid), AgOAc,
or PhI(OCOCF3)2] with iodine in acetic acid (AcOH)
furnished in each case the oxindole 4a, with PhI(OAc)2/
I2 being the most effective.18 In sharp contrast to the
cyclization of 1 reported by Barluenga (eq 1, Scheme 1),5
a 5-exo-trig iodo-carbocyclization occurred in our case
leading to oxindole with concurrent iodination of the
aromatic ring.
Scheme 1. Different Cyclization Modes for Iodoarylation
Using PhI(OAc)2/I2 as an iodonium source, we next
investigated the solvent effect. The reaction was less effi-
cient in more acidic media (TFA, entry 8, Table 1) and
failed to take place in MeOH (entry 9). Among other
screened solvents [CH2Cl2, THF, EtOAc, 1,2-dichloro-
ethane (DCE), dioxane, MeCN, DMF, DMSO], aceto-
nitrile (MeCN) was found to be the most efficient one to
3,30-Disubstituted oxindoles are highly valuable syn-
thetic targets due to their presence in a wide range of
natural products, pharmaceuticals, and agrochemicals.10
Among known synthetic strategies, palladium-catalyzed
cyclization of ortho-functionalized anilides was particularly
successful.11 More recently, metal-catalyzed CꢀH activa-
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Org. Lett., Vol. 13, No. 9, 2011
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yield 4a in 88% yield (entry 15). We also checked that
neither iodine nor PhI(OAc)2 alone was capable of pro-
moting this transformation under otherwise identical con-
ditions. Itisinteresting tonotethatproductsresultingfrom
the alternative pathway, involving the participation of
MeCN, were not observed.19
Table 2. Scope of the Iodo-Carbocyclization: Substitution at the
Anilinesa
Table 1. Survey of Reaction Conditions
entry
iodonium source
I2
solvent
yield (%)a
1
AcOHc
AcOH
CH2Cl2
AcOH
AcOH
AcOH
AcOH
TFA
0
2
ICl
Trace
0
3b
4
IPy2BF4/HBF4
IBX/I2
34
5
PhI(OAc)2/I2
PhI(OCOCF3)2/I2
AgOAc/I2
66
6
58
7
62
8
PhI(OAc)2/I2
PhI(OAc)2/I2
PhI(OAc)2/I2
PhI(OAc)2/I2
PhI(OAc)2/I2
PhI(OAc)2/I2
PhI(OAc)2/I2
PhI(OAc)2/I2
PhI(OAc)2/I2
PhI(OAc)2/I2
40
9
MeOH
CH2Cl2
THF
N.R.
31
10
11
12
13c
14
15
16
17
Trace
24
EtOAc
DCE
47
Dioxane
CH3CN
DMF
Trace
88
Trace
18
DMSO
a General conditions: PhI(OAc)2 (1.5 equiv), I2 (1.5 equiv), CH3CN,
rt. b Isolated yield. c PhI(OAc)2 (3 equiv), I2 (3 equiv), CH3CN, rt.
d PhI(OAc)2 (1.0 equiv), I2 (1.0 equiv) at 0 °C. e 14% of starting marterial
was recovered.
a Isolated yield. b Reaction performed at 0 °C. c Reaction performed
at 80 °C.
With the optimum conditions [PhI(OAc)2 (1.5 equiv), I2
(1.5 equiv), in CH3CN at rt] in hand, we next examined the
scope of this process, and the results are presented in
Tables 2 and 3. Use of a tertiary amide was mandatory
to ensure the occurrence of the iodo-carbocyclization as no
oxindole was formed in the case of N-phenylmethacryla-
mide (entry 1, Table 2). The N-benzyl derivative afforded
oxindole 4c in 74% yield. It is worth mentioning that the
benzyl residue did not participate in the cyclization as no
1,2-dihydroisoquinolin-3(4H)-one was observed. The pre-
sence of an electron-donating or -withdrawing group at the
para-position of anilides was well tolerated (entries 3ꢀ6).
However, 3 equiv of PhI(OAc)2/I2 were required toachieve
full conversion of 4-cyano anilide (entry 4). Except for the
4-methoxy-substituted anilides, no additional iodination
of the aromatic ring was observed. When N-meta-tolyl-
methacrylamide was employed, an inseparable mixture of
regioisomers 4g and 4g0 (1.4:1 ratio) was isolated in
81% overall yield in favor of the 6-substituted oxindole
(entry 7). Ortho-substitution was also compatible as de-
monstrated by the formation of 4h (entry 8). Cyclization of
a tetrahydroquinoline derivative furnished tricyclic oxi-
ndole 4j in 75% yield (entry 9). A regioselective reaction
was also observed with the R- or β-naphthylanilide as
shown in entries 10 and 11 (Table 2).
Variation at the acrylamide residue was next evaluated
(Table 3). n-Butyl, i-propyl, phenyl, and benzyl groups
were tolerated at the R-position of the acrylamide provid-
ing the corresponding iodooxindoles in yields ranging
from 59 to 83% (entries 1ꢀ4, Table 3). Whereas iodination
was observed on the aniline aromatic ring in each case,
phenyl and benzyl groups at the R-position remained
untouched (entries 3 and 4). Silyloxyl and methyl ester
groups were compatible with the reaction conditions as
illustrated with the synthesis of compounds 4p and 4q
(entries 5 and 6). R,β-Disubstituted N-phenylacrylamides
were also subjected to the process affording the spiroox-
indoles in 40% yield (entry 7, Table 3). The reaction was,
however, limited to the synthesis of 3,30-disubstitued oxi-
ndoles as no desired product was observed for N-pheny-
lacrylamide (data not shown).
We finally evaluated the reactivity of anilide 5 bearing a
tosyl-protected alkylamine side chain at the R-position of
the acrylamide. Two possible reaction pathways, namely,
(19) Yeung, Y.-Y.; Gao, X.; Corey, E. J. J. Am. Chem. Soc. 2006, 128,
9644–9645.
2246
Org. Lett., Vol. 13, No. 9, 2011

relevant spiropyrrolidinyloxindole 8 (Scheme 2).21 Even-
tually, treatment of an acetonitrile solution of 5 with 3
equiv of PhI(OAc)2/I2 followed by addition of K2CO3
afforded directly the spirooxindole 8 in 71% yield. When
the addition of K2CO3 was omitted, oxindole 6 was
isolated in excellent yield at the expense of 7, indicating
that the iodo-arylation dominated over the alternative
iodo-sulfonamidation under these conditions.
Table 3. Scope of the Iodo-Carbocyclization: Substitution at the
Acrylatesa
In summary, we have developed a novel metal-free
synthesis of 3,30-disubstituted oxindoles via an iodine
monoacetate-promoted iodoarylation of anilides. The
salient features of the present halonium-induced cycli-
zation are as follows: (a) it involves, for the first time,
an electron-deficient olefin; (b) it proceeds via a unique
5-exo-trig cyclization mode in contrast to the more com-
mon 6-endo-trig mode observed for most of the halonium-
induced cyclizations of 1,5-dienes. While a few metal-
catalyzed cyclizations of anilides involving a CꢀH func-
tionalization step have been developed for the synthesis of
oxindoles, we believethat the present metal-free conditions
provided an attractive alternative to access this important
type of heterocycle. Efforts aiming at understanding the
reaction mechanism are ongoing.22
a General conditions: PhI(OAc)2 (1.5 equiv), I2 (1.5 equiv), CH3CN,
rt. b Isolated yield. c PhI(OAc)2 (3 equiv), I2 (3 equiv), CH3CN, rt. d Only
one diasteroisomer was isolated. The stereochemistry of 4r was tenta-
tively assigned based on a mechanistic hypothesis.
Acknowledgment. Financial support from CNRS,
ICSN, and ANR is gratefully acknowledged. H.L.W.
thanks the Government of China for a National
Graduate Student Program of Building World-Class
Universities.
Scheme 2. One-Step Synthesis of Spirooxindole
Supporting Information Available. Supporting Infor-
mation for this article, including experimental proce-
1
dures, product characterization. and copies of the H
and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(21) Jaegli, S.; Vors, J.-P.; Neuville, L.; Zhu, J. Tetrahedron 2010, 66,
8911–8921.
(22) One reaction pathway involved a 1,4-addition of an iodine
radical to the conjugated double bond followed by radical cyclization
onto the aromatic ring. However, the following results seemed to be
against this proposalin our case: (i) cyclization of 3a took place readily in
the dark to afford 4a in a similar yield; (ii) addition of benzoquinone did
not inhibit the reaction; (iii) although yield remained moderate, the
cyclization of (Z)- and (E)-N-2-dimethyl-N-phenylbut-2-enamide was
stereospecific affording two distinct diastereomers (cf. Supporting
Information). For radical based cyclization to oxindoles, see: (a) Teichert,
A.; Jantos, K.; Harms, K.; Studer, A. Org. Lett. 2004, 6, 3477–3480.
(b) Murphy, J. A.; Tripoli, R.; Khan, T. A.; Mali, U. W. Org. Lett. 2005, 7,
3287–3289.
iodo-arylation and iodo-sulfonamidation,20 could occur
leading to oxindole 6 and pyrrolidine 7, respectively. Both
6 and 7 could, in principle, be converted to the biologically
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rolidines, see: (a) Jones, D. A.; Knight, D. W.; Hibs, D. E. J. Chem. Soc.,
Perkin Trans. 2001, 1, 1182–1203. (b) Amjad, M.; Knight, D. W.
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Org. Lett., Vol. 13, No. 9, 2011
2247