Construction of 3-oxyindoles via hypervalent iodine mediated tandem cyclization-acetoxylation of o-acyl anilines

Article abstract of DOI:10.1039/c0cc01911a

An efficient tandem cyclization-acetoxylation of o-acyl anilines mediated by the combination of iodobenzene diacetate with tetrabutylammonium iodide provides a new convenient and useful route to 2-acetoxy indolin-3-ones, which are ready to be converted into other 2-substituted 3-oxyindole derivatives.

Full text of DOI:10.1039/c0cc01911a

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Construction of 3-oxyindoles via hypervalent iodine mediated tandem
cyclization–acetoxylation of o-acyl anilinesw
Yi Sun and Renhua Fan*
Received 16th June 2010, Accepted 6th July 2010
DOI: 10.1039/c0cc01911a
An efficient tandem cyclization–acetoxylation of o-acyl anilines
mediated by the combination of iodobenzene diacetate with
tetrabutylammonium iodide provides a new convenient and
useful route to 2-acetoxy indolin-3-ones, which are ready to be
converted into other 2-substituted 3-oxyindole derivatives.
In past decades, the versatility of hypervalent iodine organic
compounds has been well recognized, and attracted especially
Scheme 1
active interest due to their benign environmental character and
ready availability.1 In addition to the very useful oxidizing
properties, a notable feature of the hypervalent iodine com-
pounds is their capability to undergo ligand exchange and
reductive elimination reactions like transition metals. For
example, Moriarty and co-workers have reported the use of
the combination of PhI(OAc)2/KOH/MeOH in the synthesis
of a wide range of heterocycle structures.1f The process
involves the ligand exchange reaction of the hypervalent iodine
compound with the corresponding substrate and a subsequent
reductive elimination of PhI and the generation of desired
carbon–carbon, hetero–heteroatom, or carbon–heteroatom
bonds without extra chemical transformations.2
reaction condition screening. Our earlier examination of the
iodine(III)-mediated oxidative cyclization of 1a employing the
reaction system of PhI(OAc)2/KOH/MeOH was unsuccessful
(Scheme 1). a-Methoxylation of the phenyl ketone was
observed. When the reaction was conducted in polar or
nonpolar aprotic solvents, although a-methoxylation was
inhibited, no cyclization product was obtained. To generate
a more reactive hypervalent iodine species, some salts were
added.9 While the introduction of Bu4NBr, KBr, or KI had no
effect on the reaction, the reaction with Bu4NI afforded a
1
major product.10 However, the H NMR spectrum indicated
that the isolated product was not the expected compound 2a,
but 2-methyl-3-oxo-1-tosylindolin-2-yl acetate 3a. As control
experiments, replacements of PhI(OAc)2 by PhIO and
PhI(OCOCF3)2 resulted in complicated reactions, and no
cyclized product was obtained. When Bu4NI was introduced
into the reaction with PhI(OAc)2/KOH/MeOH, only the
a-methoxylation product was isolated. When the a-methoxyl-
ation product was treated with the combination of PhI(OAc)2/
Bu4NI/NaOAc, no reaction occurred.
As important heterocyclic compounds, 3-oxyindoles are widely
distributed in natural products and synthetic compounds.3
Possessing a variety of biological activities, they have found
applications as COX-2 inhibitors4a and Mcl-1 inhibitors in the
design of novel antitumor agents.4b Meanwhile, they are key
building blocks for the potent peroxisome proliferator-activated
receptor g modulators.4c Despite the considerable amount of
effort that has been expended in the preparation of 3-oxyindoles,5
new and straightforward methods to access these heterocycles are
always highly desirable. Fistulosin, which was isolated from the
root of the Welsh onion by Tomita’s group in 1999, exhibits
antifungal activities against the wilt-producing fungus Fusarium
oxysporum.6 Nishida and co-workers reported the first synthesis
of fistulosin using the ruthenium catalyzed cycloisomerization of a
diene as a key step.7 Recently, we have investigated hypervalent
iodine mediated oxidative cyclizations and have developed a
practical method for the synthesis of a variety of cyclic
compounds.8 We envisioned that the indolin-3-one structure of
fistulosin might be constructed via iodine(III) mediated oxidative
cyclization of the corresponding o-acyl aniline derivatives.
Product 3a has the same core structure as fistulosin.
Meanwhile, its acetal structure provides a possibility to access
some other indolin-3-one derivatives. Motivated by the
synthetic potential of the method, the reaction was further
optimized by examining various reaction conditions. To
promote the possible a-acetoxylation, KOH was replaced by
NaOAc, and the yield of product 3a was improved to 50%. In
the control experiment without AcONa, the yield decreased to
17%. The best ratio of substrate, PhI(OAc)2, Bu4NI, and
NaOAc was 1 : 3 : 2.5 : 1, with which the yield increased to
62%. The screening of solvents revealed dioxane as the best
choice, in which product 3a was formed in 89% yield after 1 h.z
A higher temperature (40 1C) resulted in a complicated reaction,
while the reaction proceeded sluggishly at 0 1C.
To test our hypothesis, we selected 4-methyl-N-(2-propionyl-
phenyl)benzenesulfonamide 1a as the model substrate for
Further investigation indicated that N-Ts protection for
o-acyl aniline was essential to the oxidative cyclization
(Table 1, entries 1–6). This reaction was evaluated using
different o-acyl aniline derivatives. Either electron-donating
or -withdrawing substituted o-propionyl anilines were success-
fully converted to the cyclized products in good to excellent
Department of Chemistry, Fudan University, 220 Handan Road,
Shanghai 200433, China. E-mail: rhfan@fudan.edu.cn;
Fax: 86-21-6510-2412; Tel: 86-21-6564-2019
w Electronic supplementary information (ESI) available: Experimental
1
procedures, characterization data, copies of H NMR and 13C NMR
spectra of new compounds. See DOI: 10.1039/c0cc01911a
c
6834 Chem. Commun., 2010, 46, 6834–6836
This journal is The Royal Society of Chemistry 2010

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Table 1 PhI(OAc)2/Bu4NI mediated oxidative cyclization of o-acyl
anilines
substrate 1g was recovered after 1 h, the reaction afforded
a-acetoxy indolin-3-one 3g and indolin-3-one 2g in 24% and
31% yield. When indolin-3-one 2g was treated with PhI(OAc)2
and Bu4NI again, it was converted into 2-acetoxy indolin-3-
one 3g quantitatively (Scheme 2).
On the basis of this observation and the literature evidence,11
the following plausible mechanism can be formulated
(Scheme 3). Under the basic conditions, the enolate of the
substrate reacts with the generated highly reactive iodine(III)
Entry
R1
R2
R3
Product
Yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
H
H
H
H
H
H
Ts
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
89
0
0
0
0
CH3SO2
CF3CO
CH3CO
PhCO
PhCH2
Ts
Ts
Ts
Ts
Ts
Table 2 Friedel–Crafts reaction of a-acetoxy indolin-3-one
0
CH3
(CH3)2CH
CH3O
Cl
Br
H
CH3
86
92
88
90
90
50
75
3j
3k
3l
Yield (%)a
Ts
Ts
Entry
1
Product
CH2Ph
3m
a
Isolated yield based on 1.
84
yields (Table 1, entries 7–11). With respect to the acyl moiety,
acetyl and phenylpropanoyl derivatives were also found to be
suitable substrates, and the corresponding products were
isolated in moderate to good yields (Table 1, entries 12 and 13).
When compound 1n was employed as the substrate, no desired
2-acetoxy indolin-3-one derivative was formed, but a cyclo-
propanation product 4n was isolated in 90% yield.8c
2
3
4
85 (37 : 63)b
91 (33 : 67)b
85
ð1Þ
5
80
To gain insight into the mechanism, a reaction was carried
out with 1 equivalent of PhI(OAc)2 and Bu4NI. While 35% of
6
7
8
9
82 (20 : 80)b
81
84
84
Scheme 2
10
86
11
52 (33 : 67)b
a
b
Isolated yield based on 3l. The ratio was determined by H NMR
1
spectroscopy.
Scheme 3 Hypothesized reaction pathway.
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 6834–6836 6835

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species to form an a-hyperiodination intermediate, which is
ready to undergo an intramolecular attack by the nitrogen
atom to yield indolin-3-one 2 accompanied by the reductive
elimination of PhI. After the second a-hyperiodination and
subsequent reductive elimination, a-acetoxy indolin-3-one 3 is
formed. The generation of the unreactive I2 from the reaction
of PhI(OAc)2 with Bu4NI makes it necessary to use 3 equi-
valents of PhI(OAc)2 and 2.5 equivalents of Bu4NI.
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To explore the use of the resultant 2-acetoxy indolin-3-one,
we next investigated its Friedel–Crafts reaction. To activate
the acetal structure, a variety of Lewis and Brønsted acids
were examined. Trifluoromethanesulfonic acid (TfOH) was
finally found to be the best catalyst for the Friedel–Crafts
reaction of a-acetoxy indolin-3-one 3l with benzene. In the
presence of 1 equivalent of TfOH, the reaction completed in
15 min at 0 1C and afforded product 5a in 84% yield (Table 2,
entry 1). The scope of the Friedel–Crafts reaction with respect
to the aromatic compound was then investigated. Reactions of
electron-rich aromatic compounds with alkoxy or alkyl
substitutions proceeded smoothly, and gave rise to the
corresponding 2-aryl indolin-3-ones 5 in good to excellent
yields (Table 2, entries 2–10). The electron-poor chloro-
benzene was also a suitable substrate, albeit that a moderate
yield of the product was obtained.
When 2-aryl indolin-3-one 5d was treated with a catalytic
amount of K2CO3 in MeOH, it was converted into the
corresponding 3H-indol-3-one 6 in 74% yield (eqn (1)). The
N-oxides of 3H-indol-3-one have been found to have useful
biological activities against a range of bacteria, mycobacteria
and fungi.12
ð2Þ
In conclusion, we have developed an efficient method for
the construction of 2-acetoxy indolin-3-ones via a tandem
oxidative cyclization–acetoxylation of o-acyl anilines using
the combination of PhI(OAc)2/Bu4NI/AcONa. The resultant
2-acetoxy indolin-3-one is ready to be converted into other
2-substituted 3-oxyindole derivatives. The current direction
for future research is aimed at extending the scope and
potential synthesis applications.
Financial support from the National Natural Science
Foundation of China (20702006) is gratefully acknowledged.
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Notes and references
z Representative experimental procedure: a mixture of 1a (61 mg,
0.2 mmol), PhI(OAc)2 (193 mg, 0.6 mmol), and NaOAc (16 mg, 0.2 mmol)
in dioxane (1 mL) was treated with Bu4NI (185 mg, 0.5 mmol). The
reaction was allowed to stir at 25 1C for 1 h. Upon completion by
TLC, the reaction mixture was quenched with saturated Na2S2O3
(25 mL), and extracted using ethyl acetate (25 mL ꢀ 3). The organic
layer was dried over Na2SO4, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (15% ethyl
acetate in hexanes) to provide 2-methyl-3-oxo-1-tosylindolin-2-yl
acetate 3a in 89% yield.
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c
6836 Chem. Commun., 2010, 46, 6834–6836
This journal is The Royal Society of Chemistry 2010