A highly efficient friedel-crafts reaction of 3-hydroxyoxindoles and aromatic compounds to 3,3-diaryl and 3-alkyl-3-aryloxindoles catalyzed by Hg(ClO4)2·3 H2O

Article abstract of DOI:10.1002/asia.201100773

We report a highly efficient Friedel-Crafts reaction of 3-alkyl or 3-aryl 3-hydroxyoxindoles with a variety of aromatic and heteroaromatic compounds to unsymmetrical 3,3-diaryloxindoles or 3-alkyl-3-aryloxindoles, which are interesting medicinal targets and useful building blocks for the synthesis of natural products. Hg(ClO₄)₂·3 H₂O was identified as a powerful catalyst for this reaction, and is significantly more efficient than other screened metal perchlorate hydrates and Bronsted acids such as HOTf and HClO₄. The high catalytic property of Hg(ClO₄)₂·3 H₂O originates from the unprecedented dual activation effects of aromatic mercuration, which could generate a strong protic acid to facilitate the generation of a carbocation at the C3-position of oxindoles and simultaneously form the more reactive nucleophilic reaction partner.

Full text of DOI:10.1002/asia.201100773

DOI: 10.1002/asia.201100773
A Highly Efficient Friedel–Crafts Reaction of 3-Hydroxyoxindoles and
Aromatic Compounds to 3,3-Diaryl and 3-Alkyl-3-aryloxindoles Catalyzed by
HgACTHUNTGRNENUG(ClO4)2·3H2O
Feng Zhou, Zhong-Yan Cao, Jing Zhang, Hai-Bo Yang, and Jian Zhou*[a]
Abstract: We report a highly efficient
Friedel–Crafts reaction of 3-alkyl or 3-
aryl 3-hydroxyoxindoles with a variety
of aromatic and heteroaromatic com-
pounds to unsymmetrical 3,3-diarylox-
erful catalyst for this reaction, and is
significantly more efficient than other
screened metal perchlorate hydrates
and Brønsted acids such as HOTf and
HClO4. The high catalytic property of
HgACHTGNUTERNU(NG ClO4)2·3H2O originates from the
unprecedented dual activation effects
of aromatic mercuration, which could
generate a strong protic acid to facili-
tate the generation of a carbocation at
the C3-position of oxindoles and simul-
taneously form the more reactive nu-
cleophilic reaction partner.
indoles
or
3-alkyl-3-aryloxindoles,
which are interesting medicinal targets
and useful building blocks for the syn-
thesis of natural products. Hg-
Keywords: atom economy · carbo-
cations · Friedel–Crafts reaction ·
mercury · natural products
ACHTUNGTRENNUNG(ClO4)2·3H2O was identified as a pow-
Introduction
The 3,3-disubstituted oxindole
framework is present in many
biologically
active
natural
products and medicinal tar-
gets.[1] Of particular interest
are 3,3-diaryloxindoles and 3-
alkyl-3-aryloxindoles.
Both
subclasses are useful building
blocks for the total synthesis of
bioactive natural products,[2]
and have been studied as phar-
maceutically
active
com-
pounds.[3] Surprisingly, methods
for the synthesis of unsymmet-
rical 3,3-diaryloxindoles are
rare.[4] Most recently, Samma-
kia et al. reported the first ex-
ample of a palladium-catalyzed a-arylation of 3-aryloxin-
doles for the catalytic synthesis of unsymmetrical 3,3-diary-
loxindoles,[4e] thereby demonstrating the versatility of palla-
dium-catalyzed coupling reactions to prepare both frame-
Scheme 1. Methods to synthesize 3,3-diaryl and 3-alkyl-3-aryloxindoles.
works from 3-substituted oxindole iv[5a–g] or amide iii[5h–l]
(Scheme 1). However, as Pd0 species are involved, the prep-
aration of products with substituents sensitive to oxidative
addition—bromo groups, for example—has not been report-
ed by means of these coupling reactions.[5] Furthermore, the
introduction of hetereoaromatics to the C3-position of oxin-
doles to increase the structural diversity is less studied. Ac-
cordingly, it is highly desirable to develop new methods that
allow the efficient synthesis of both structural motifs, with
hindered all-carbon quaternary centers, in high structural di-
versity for biological evaluation and studies on the struc-
ture–activity relationship.
[a] F. Zhou, Z.-Y. Cao, J. Zhang, Prof. Dr. H.-B. Yang, Prof. Dr. J. Zhou
Shanghai Key Laboratory of
Green Chemistry and Chemical Processes
Department of Chemistry
East China Normal University, 3663N
Zhongshan Road, Shanghai 200062 (China)
Fax : (+86)21-6223-4560
E-mail: jzhou@chem.ecnu.edu.cn
The catalytic Friedel–Crafts reaction[6] of 3-hydroxyoxin-
doles 2 and aromatic compounds would be an atom-efficient
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100773.
Chem. Asian J. 2012, 7, 233 – 241
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233

FULL PAPERS
procedure[7] to construct both structural motifs, as it only
produces water as waste. In addition, compound 2 can be
prepared in a single step from isatins, whereas precursor iii
or iv for coupling reactions are usually obtained by two
steps from isatins or anilines.[8] The synthesis of symmetrical
3,3-diaryloxindoles from isatins and arenes in the presence
of a large excess amount of strong acids or superacids was
known.[4a,b] The reaction of 3-hydroxy-3-aryloxindoles and l-
tyrosine derivatives promoted by 5.0 equivalents of trifluor-
omethanesulfonic acid (TfOH) was developed by Nicolaou
et al. during the synthesis of diazonamide A.[2a] They also
found that the use of 20 mol% of TfOH or some metal tri-
flates led to the decomposition of starting materials.[2b] De-
spite their achievements, the catalytic versions of this reac-
tion were very limited, possibly because the formation of
the carbocationic intermediate was difficult due to the elec-
tron-withdrawing effect of the amide group of 3-hydroxyox-
indole 2. By now, only Lewis acid catalyzed arylation of isa-
tins with indoles or N,N-dimethylaniline to symmetric 3,3-
diaryl oxindoles, and the arylation of 3-indolyl-3-hydroxyox-
indoles by using indoles or pyrroles have been reported,[3-
ration. For example, Barron et al. reported that the forma-
tion of stabilized arene–mercury complexes significantly in-
creased the acidity of the aromatic protons of the coordinat-
ed arenes. The thus-obtained stable arene–mercury com-
plexes could serve as highly efficient catalysts for the H/D
exchange reaction of C6D6 with arenes in which the coordi-
nated arene protonated C6D6.[13] Nishizawa and co-workers
identified HgACHTNUTRGNEUNG(OTf)2 as a highly efficient catalyst for a
number of transformations, including hydration of alkynes,
À
C C bond-forming cyclizations initiated from alkynes or al-
lylic alcohols, and heterocycle synthesis.[14b–l] Deslongchamps
et al. also contributed greatly to mercury catalysis.[14m] The
high catalytic efficiency and mild reaction conditions made
these transformations very useful, particularly when applied
to natural product synthesis.[15]
Although aromatic mercuration has been extensively
studied and Olah et al. have suggested that mercury–arene
complexes might be the intermediates by NMR spectroscop-
ic studies,[16] most of these studies focused on the use of a
stoichiometric amount of mercury salts to convert aromatic
compounds to arylmercurials, which were used as versatile
synthons in transition-metal-catalyzed coupling reactions.[17]
Whereas Barron et al. reported a highly efficient H/D ex-
change reaction of C6D6 with arenes catalyzed by a stabi-
lized arene–mercury complex that resulted from aromatic
d,9a–e]
which involved the formation of reactive vinylogous
iminium intermediates.[9f,g] To increase the structural diversi-
ty for structure–activity relationship studies, the catalytic
synthesis of unsymmetrical 3,3-diaryl oxindoles by means of
Friedel–Crafts arylation of 3-aryl-3-hydroxyloxindoles that
cannot form vinylogous iminium intermediates is highly de-
sirable but is unprecedented.
mercuration,[13] the highly efficient catalytic C C bond-
À
forming reactions initiated by aromatic mercuration have
not been reported as far as we know.[17] Here we wish to
report the unprecedented dual activation effects of aromatic
mercuration, which could generate a strong protic acid to fa-
cilitate the generation of a carbocationic intermediate and
simultaneously activate the aromatics to form more nucleo-
philic aryl mercurials. This would contribute to a highly effi-
cient Friedel–Crafts reaction of 3-hydroxyoxindoles and a
variety of aromatic compounds to furnish the congested
quaternary carbon center at the C3-position of oxindole.
Recently, much effort has been devoted to the exploration
of new catalytic properties of inexpensive and easily avail-
able metal salts such as iron, bismuth, and copper salts in or-
ganic synthesis.[10] Mercury, as an “element of mystery,”[11]
however, has received very limited attention, mainly due to
the concern about its toxicity.[12a,b] This is to some extent per-
plexing because mercury still has numerous applications in
many areas nowadays.[12] In industrial applications, mercury
could be used for barometers, manometers, gauges, high-in-
tensity discharge (HID) lamps, and as an electrode in the
electrolytic production of chlorine and caustic soda from
saline, and in electrical switches widely used in automobiles.
The application of mercury to extract gold and silver from
their respective ores continues to this day. Furthermore,
mercury and its chemical compounds still have medical ap-
plications nowadays. For example, mercury amalgam princi-
pally with silver is widely used as a tooth filling, and there is
no convincing evidence that dental amalgam leads to ad-
verse health effects.[12a] Thimerosal is still used in vaccines in
many countries, and the current scientific consensus is that
no convincing scientific evidence to support the thimerosal
controversy that mercury-containing vaccines lead to the de-
velopment of autism and brain development disorders.[12a,b]
In view of the aforementioned facts, academic research
that aims toward the discovery of new catalytic properties of
mercury compounds is still needed, although unnecessary
usage of mercury compounds in organic synthesis should be
avoided. In particular, recent studies have shown that mer-
cury compounds had interesting properties worthy of explo-
Results and Discussion
In our efforts to synthesize 3,3-disubstituted oxindoles for
biological evaluation,[18] we speculated that the formation of
a reactive carbocation at the C3-position from oxindole 2
might be difficult owing to the electron-withdrawing amide
group, therefore we tried to develop a catalytic arylation of
3-hydroxyindoles 2 by using Lewis acids with weak-coordi-
nating counteranions that might enhance the catalytic prop-
erty of Lewis acids.[19] Given that inexpensive and easy-to-
handle metal perchlorate hydrates with a weak-coordinating
anion had been identified as powerful Lewis acids for a
number of reactions,[20] we first examined a series of metal
perchlorate hydrates in the reaction of 3-hydroxyoxindole
2b and N-methylindole 3a by using tetrahydrofuran (THF)
as the solvent in the presence of 10 mol% catalyst. Some
typical results are shown in Table 1.
It was found that InIII-, AlIII-, CrIII-, CuII-, ZnII-, CoII-, NiII-
, and AgI-derived metal perchlorate hydrates all failed to
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3,3-Diaryl and 3-Alkyl-3-aryloxindoles
Table 1. Optimization of the reaction conditions.
methods allowed the generation of a full-carbon quaternary
center adjacent to the C3-position of indole,[21] a number of
substituted indoles were first tried. The reaction of unpro-
tected 3-phenyl-3-hydroxyoxindole 2a and N-methyl indole
afforded product 4a in 86% yield. As the unprotected 3-
substituted hydroxyoxindoles dissolved poorly in CH3CN,
the N-methyl-protected ones were used subsequently. By
comparison, product 4b was indeed obtained at a much
faster rate. All the differently substituted indoles, even with
electron-withdrawing groups, worked well to afford the de-
sired products in good to excellent yield (4c–i). The struc-
ture of product 4i was also confirmed by X-ray analysis (see
the Supporting Information).[22] It should be noted that this
protocol allowed the retention of the bromo group, which
might be difficult in the palladium-catalyzed coupling reac-
tions shown in Scheme 1. The halogenated indole adducts
4g–k might be valuable synthons for use in conjunction with
organometallic technologies (e.g., Buchwald–Hartwig and
Stille couplings).[23] The substituent effect on the oxindole
framework was also examined, and the corresponding prod-
ucts 4j–q could also be obtained in good to excellent yield.
A variety of (hetero)aromatic compounds were then tried,
and 2-methyl-substituted furan or thiophene, para-tert-butyl-
phenol, and 1,3-dimethoxybenzene worked well to afford
the corresponding products (4r, 4s, 4u, 4w–y) in high yield.
However, N-methylpyrrole and N-acetylindoline were less
reactive, and the desired products 4t and 4v were obtained
in diminished yield.
Entry[a]
Catalyst
(ClO4)2·3H2O 10
(ClO4)3·xH2O 10
(ClO4)3·xH2O 10
(ClO4)2·3H2O 10
(ClO4)2·3H2O 10
X
Y
Solvent T [8C] t [h] Conv. [%][b]
1[c]
2[c]
3[c]
4[c]
5[d]
6[d]
7[d]
8[d]
Hg
N
2
2
2
2
2
THF
THF
50
50
120
120
120
120
4
90
25
<12
Fe
Fe
ACHTUNGTRENNUNG
A
CH3CN 50
CH3CN 50
CH3CN 80
Hg
Hg
Hg
Hg
Hg
100
100
E
5
2
5
1.5 CH3CN 80
1.5 CH3CN 80
1.2 CH3CN 80
1
8
100 (95)[e]
N
72 100 (82)[e]
T
8
100 (95)[e]
[a] On a 0.1 mmol scale. [b] Determined by H NMR spectroscopic analy-
sis of the crude mixture. [c] The concentration of 2b was 0.2m. [d] The
concentration of 2b was 0.5m. [e] On a 0.3 mmol scale, with isolated
yield.
catalyze the reaction. Only Hg
ACHTUGNTRNEN(UNG ClO4)2·3H2O and Fe-
ACHTUNGTRENNUNG
1
extent by H NMR spectroscopic analysis (Table 1, entries 1
and 2). Some typical Brønsted acids were also employed,
but only TfOH and HClO4 could slightly catalyze the reac-
tion (around 10% conversion; see the Supporting Informa-
tion for details). The counteranion effect of mercury salts
was also evaluated, and HgCl2 and HgSO4 both failed to cat-
alyze the reaction. We then compared the potency of Hg-
A
E
To demonstrate the generality of this method, we further
tried 3-hydroxyl-3-alkyloxindoles (Table 3). Previously, only
Padwa et al. reported that 3-hydroxy-3-methyloxindole
could react with anisole, furan, or thiophene in the presence
of 20 mol% of p-TsOH (TsOH=toluenesulfonic acid),
which was carried out in toluene heated to reflux tempera-
ture, by using 5.0 to 20.0 equivalents of aromatic com-
pounds.[5p] We found to our delight that both 3-methyl- and
3-allyl-substituted 3-hydroxyoxindoles could react with a
series of (hetero)aromatic compounds. Because of their low
boiling point, furan and anisole were used in three equiva-
lents to ensure a good yield of product 5a,b. 3-Allyl-3-hy-
droxyoxindoles were less reactive than 3-methyl ones, but
the corresponding products 5m–t were very useful for the
synthesis of a fused indoline ring system present in a multi-
tude of bioactive compounds according to literature meth-
ods.[2e,5m]
The broad substrate scope of this reaction was very im-
pressive: not only 3-alkyl and 3-aryl 3-hydroxyoxindoles
worked well as the electrophilic reaction partner, but also a
variety of aromatic and heteroaromatic compounds (includ-
ing halogenatedindoles) could serve as the nucleophilic reac-
tion partner. In addition, this reaction was carried out in air
by using an inexpensive and easy-to-handle Hg-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
CH3CN with low activity (Table 1, entries 2 and 3). In light
of this, we further optimized the reaction conditions by
using HgACHTUNGTRENNUNG(ClO4)2·3H2O as the catalyst. It was found that
when the reaction was carried out at 808C with the substrate
concentration increased from 0.2 to 0.5m, the reaction rate
could be greatly improved, and the reaction could finish
within four hours (Table 1, entry 4 and 5). By lowering the
catalyst loading to 5 mol% and the amount of N-methylin-
dole 3a to 1.5 equivalents, the reaction could still be com-
pleted after eight hours to afford product 4b in 95% yield
(Table 1, entry 6). Further lowering of the catalyst loading
to 2 mol% greatly slowed down the reaction rate (Table 1,
entry 7). With 5 mol% of catalyst, the amount of indole 3a
could be reduced down to 1.2 equivalents without obvious
influence on the reactivity to afford product 4b in 95%
yield (Table 1, entry 8).
Next, the substrate scope with respect to both the electro-
phile and nucleophile was investigated under the optimal
conditions to run the reaction in air at 808C and by using
CH3CN as the solvent in the presence of 5 mol% of Hg-
ACHTUNGTRENNUNG(ClO4)2·3H2O as the catalyst. A number of unsymmetrical
3,3-diaryloxindoles with enough diversity could be readily
obtained by this method (the right aryl group of the C3-po-
sition was from the nucleophilic reaction partner 3), as
shown in Table 2. As the indole framework is a “privileged”
structure or pharmacaphore, together with the fact that few
ACHTUGNTRNE(UNNG ClO4)2·3H2O catalyst. These facts made this method very
efficient for the synthesis of unsymmetrical 3,3-diaryloxin-
doles and 3-alkyl-3-aryloxindoles in sufficient diversity.
When benzene derivatives such as bromobenzene, benzene,
and toluene were used as the nucleophiles, only complex
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J. Zhou et al.
FULL PAPERS
Table 2. Synthesis of unsymmetrical 3,3-diaryloxindoles.
tained in 63% yield from hydroxyoxin-
dole 2a [Eq. (1)]. Compound 6 was more
potent than 3,3-diphenyloxindole in in-
ducing eIF2a phosphorylation and four
times more potent in inhibiting cancer-
cell growth, which further demonstrated
the importance of the preparation of 3,3-
diaryloxindoles and 3-alkyl-3-aryloxin-
doles in great diversity.
Product 3,3-diaryloxindoles 4[a–c]
Strong electronic effects were ob-
served in this reaction. For example, the
methoxy group at the C6-position of the
oxindole framework greatly accelerated
the reaction, so product 4m was ob-
tained at a much faster reaction rate
than 4n. The bromo group at the C5-po-
sition of oxindole slowed down the reac-
tion rate, and product 5r was obtained in
much lower yield than 5p. When enan-
tioenriched 3-hydroxyoxindole 7[24] react-
ed with 3a under the standard condi-
tions, product 8 was isolated in racemic
form [Eq. (2)]. These results provided
strong evidence that prochiral carbocat-
ionic intermediates were involved in the
reaction.
To understand the high catalytic effi-
ciency of HgACHTUNGTRNEUGN(ClO4)2·3H2O, we next con-
ducted some experiments to investigate
if the high reactivity realized by Hg-
AHCTUNGTERG(NNUN ClO4)2·3H2O in this reaction was related
to aromatic mercuration.[16] NMR spec-
troscopic studies were first employed. As
shown in Figure 1, after adding Hg-
AHCTUNGTREGUN(NN ClO4)2·3H2O (10 mol%) to a solution
of N-methylindole 3a in CD3CN, the in-
teraction could be immediately moni-
tored. Even in the presence of only
10 mol% of HgACHTUNGTRNEGNU(ClO4)2·3H2O, the char-
acteristic peaks of the protons at the C2-,
C3-positions, and the N-methyl group
were completely shifted from d=7.12,
6.42, and 3.73 ppm to d=7.29, 6.34, and
[a] On a 0.3 mmol scale. [b] Isolated yield. [c] The right aryl group at the C3-position of product 4
was from nucleophile 3.
mixtures were obtained with the full conversion of 3-hydrox-
yoxindoles, which was a limitation for this transformation.
This limitation might be to some extent compensated in the
synthesis of unsymmetrical 3,3-diaryloxindoles by using 3-
hydroxyoxindoles with different substituted phenyl groups
to react with electron-rich arenes, as shown in Table 2.
We also applied our method for the synthesis of Ca2+-de-
pleting translation initiation inhibitor 6,[3a] which was ob-
3.77 ppm by 1H NMR spectroscopic analysis, respectively.
Obvious changes were also observed by 13C NMR spectro-
scopic studies. The aromatic mercuration of N-methylindole
3a might arrive at a state of equilibrium after one hour, as
revealed by NMR spectroscopic analysis. The aromatic mer-
curation of other typical aromatics used in this reaction was
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Chem. Asian J. 2012, 7, 233 – 241

3,3-Diaryl and 3-Alkyl-3-aryloxindoles
Table 3. Synthesis of 3-alkyl-3-aryloxindoles.
took place the moment HgACTHUNRGTNEG(UN ClO4)2·3H2O
was added to the reaction mixtures, as
the characteristic peak of indole 3a im-
mediately shifted from d=6.43 to
6.30 ppm (c versus d–e in Figure 3).
However, the high reactivity of Hg-
Product 3-alkyl-3-aryloxindoles 5[a,b]
AHCTUNGTERG(NNUN ClO4)2·3H2O in this reaction could not
merely be explained by the formation of
arene–mercury complex as strong protic
acids, because even HClO4 alone cata-
lyzed the reaction at a much slower rate.
As shown in Figure 3, whereas Hg-
AHCTNUGRTEG(NNNU ClO4)2·3H2O could promote the reac-
tion to finish within 4 hours (Figure 3d–
f), only 83% conversion was obtained
after 40 hours when using HClO4 as the
catalyst (Figure 3g–i).
Based on the above information, espe-
cially the fact that HgACTHNUTRGNEUNG(ClO4)2·3H2O was
able to catalyze the reaction at a much
faster rate than HClO4, the high efficien-
cy that HgACTHNUTRGNEUNG(ClO4)2·3H2O exhibited in this
reaction was thought to be related to the
dual activation effects that resulted from
the aromatic mercuration of the elec-
tron-rich arene during the course of the
reaction, which could generate a strong
acid to facilitate the dehydration of 3-
substituted 3-hydroxyoxindole and simul-
taneously generate the aryl mercury
compound as the more reactive nucleo-
philic reaction partner.
As shown in Scheme 2, the aromatic
mercuration of aromatic compounds 3
[a] On a 0.3 mmol scale. [b] Isolated yield.
with HgACHTNUTRGNEUNG(ClO4)2·3H2O led to the forma-
also confirmed by NMR spectroscopic analysis (see the Sup-
porting Information). On the other hand, the coordination
of the hydroxy group of N-methyl-3-phenyl-3-hydroxyoxin-
dole 2b to HgII was not clear, although the characteristic
peak of hydroxy group shifted from d=4.46 to 3.53 ppm by
1H NMR spectroscopic analysis.
tion of arene–mercury complexes 9, which could serve as a
strong protic acid, as Barron et al. proposed,[13] to react with
3-hydroxyoxindole 2 to produce the carbocationic inter-
mediate 11, and simultaneously generate aryl mercury com-
pound 10. The reaction of 10 and 11 readily gave the desired
product 4 or 5, and regenerated the catalyst. Alternatively,
the aromatic mercuration might directly afford the aryl mer-
Because the use of a stoichiometric amount of Hg-
ACHTUNGTRENNUNG(ClO4)2·3H2O to interact with N-methylindole resulted in in-
soluble complexes unable to be characterized, we next tried
UV/Vis titration experiments to get more information about
the complex. The spectral changes of N-methylindole 3a
upon addition of HgACHTUNGTRNEGNU(ClO4)2·3H2O at 298 K are shown in
Figure 2. With the addition of Hg2+, the absorbance at
308 nm gradually developed and increased. A Job plot indi-
cated the formation of the 1:1 complex between N-methylin-
dole and Hg2+
.
To further understand the role of aromatic mercuration in
the course of the reaction, we monitored the reaction of
highly reactive oxindole 2p with N-methylindole 3a by
1H NMR spectroscopic studies, which proceeded smoothly
at 258C in CD3CN by using 10 mol% of Hg
ACHTUGNERTN(NUNG ClO4)2·3H2O.
The aromatic mercuration of N-methylindole 3a indeed
Scheme 2. Proposed reaction mechanism.
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J. Zhou et al.
FULL PAPERS
Figure 1. 1H NMR (400 MHz, CD3CN, 298 K) spectra of a) oxindole 2b; b),c) the mixture of 2b and 10 mol% of Hg
ACHTUNGRTNE(UNG ClO4)2·3H2O, the time as indicated;
d) N-methylindole 3a; e),f) the mixture of 3a and 10 mol% of HgACHTNUGTRNEG(UN ClO4)2·3H2O, the time as indicated.
benzylic cation that would then readily react with the acti-
vated nucleophile 10 to give product 4 or 5.
The formation of a strong protic acid in the course of the
reaction was also supported by the fact that basic N-methyl-
indoline failed to react with 3-hydroxyoxindoles under our
reaction conditions, although NMR spectroscopic studies
undoubtedly showed the occurrence of aromatic mercura-
tion. On the contrary, the less electron-rich N-acetyl indo-
line could react with 3-hydroxyloxindoles to give the desired
product 4v and 5j. As aromatic mercuration happened both
in the case of N-methylindoline and N-acetyl indoline (see
the Supporting Information), the failure of N-methylindo-
line to work with hydroxyoxindoles was possibly due to the
fact that the in situ-generated protic acid was caught by the
basic moiety of N-methylindoline, which prevented the for-
mation of carbocation.
Figure 2. UV/Vis spectral changes of N-methylindole 3a (1.0ꢁ10À4 m in
CH3CN) in response to the addition of Hg2+ ion at 298 K (0–2.0 equiv).
Inset: a) variation of absorbance at 308 nm of N-methylindole 3a using a
1:1 complexation model. b) Job plot showing a 1:1 complex of 3a and
Hg2+ ion (N-methylindole+Hg2+ =1.0ꢁ10À4 m in CH3CN).
Noticeably, aromatic mercuration in this reaction took
place under mild conditions to form stable mercury–arene
complexes, possibly on account of the high Lewis acidity of
HgACTHUNTGRNEUGN(ClO4)2·3H2O and the electron-rich nature of the aromat-
ics involved. This observation was interesting, because
Barron et al. used AlCl3 or GaCl3 to increase the Lewis
acidity of HgCl2 to form stabilized arene–mercury com-
plexes that were sensitive to moisture or coordinating sol-
vents.[13]
cury compound 10 and HClO4, similar to the mechanism
that Toste et al. proposed for the CuII-catalyzed cycloisome-
rization-indole addition reaction.[25] The HClO4 facilitated
the dehydration of hydroxyoxindole 2 to form a reactive
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3,3-Diaryl and 3-Alkyl-3-aryloxindoles
some
properties that are worthy of
exploration.[14b]
Experiments
interesting
catalytic
are now underway in our lab
to develop an asymmetric ver-
sion of this reaction and to ex-
plore the catalytic properties
of HgACHTUNTRGNEUNG(ClO4)2·3H2O in other
carbon–carbon and carbon–
heteroatom bond-forming re-
actions.
Experimental Section
HgACTHUNGRTNEUNG(ClO4)2·3H2O (6.8 mg,
0.015 mmol), oxindole 2 (0.30 mmol),
and anhydrous CH3CN (0.6 mL) were
added to a 5 mL vial, and then the ar-
omatic compounds
3 (0.36 mmol)
were quickly added. The resulting
mixture was stirred at 808C until
almost full conversion of 2 by TLC
analysis. After evaporating the sol-
vent under vacuum, the reaction mix-
ture was directly subjected to column
chromatography (10–20% EtOAc in
petroleum ether) to afford the de-
sired product 4 or 5.
Acknowledgements
Figure 3. 1H NMR (400 MHz, CD3CN, 298 K) spectra of a) N-methylindole 3a; b) oxindole 2p; c) the mixture
of 3a and 2p; d)–f) the reaction of 3a and 2p catalyzed by 10 mol% of HgACHTUNGTRNEG(UN ClO4)2·3H2O, the reaction time as
indicated; g)–i) the reaction of 3a- and 2p-catalyzed by 10 mol% of HClO4, the reaction time as indicated;
j) product 4z.
The financial support from the Na-
tional Natural Science Foundation of
China (20902025, 21172075), 973 pro-
gram (2011CB808600), Shanghai Pu-
jiang Program (10J1403100), Special-
ized Research Fund for the Doctoral
Conclusion
Program of Higher Education (20090076120007), and the Fundamental
Research Funds for the Central Universities (East China Normal Univer-
sity 11043) are highly appreciated.
In conclusion, we report for the first time that aromatic mer-
curation had dual activation effects, which allowed us to use
the inexpensive and easy-to-handle HgACHTNUGTRNEG(UN ClO4)2·3H2O as a
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The finding that aromatic mercuration of Hg-
ACHTUNGTRENNUNG(ClO4)2·3H2O and aromatic compounds takes place at room
temperature is very interesting, as it can be potentially ap-
À
plied to the development of C H functionalization reactions
because the thus-formed aryl mercury compounds would be
useful intermediates in palladium-catalyzed coupling reac-
tions.
The high catalytic property of HgACTHUNGTRNEG(UN ClO4)2·3H2O in this re-
action suggested that safe mercury compounds, other than
toxic organomercury compounds such as MeHgCl, have
Chem. Asian J. 2012, 7, 233 – 241
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
239

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Received: September 13, 2011
Published online: November 28, 2011
Chem. Asian J. 2012, 7, 233 – 241
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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