Facile synthesis of 3-aryloxindoles via Bronsted acid catalyzed friedel-crafts alkylation of electron-rich arenes with 3-diazooxindoles

Article abstract of DOI:10.1021/ol5010752

A simple metal-free method for the synthesis of 3-aryloxindoles via Bronsted acid catalyzed aromatic C-H functionalization of electron-rich arenes with 3-diazooxindoles is developed. In the presence of a catalytic amount of TfOH, a series of 3-aryloxindoles are synthesized as single regioisomers in good to excellent yields. This transformation is proposed to proceed through acid-catalyzed protonation of 3-diazooxindoles into diazonium ions followed by Friedel-Crafts-type alkylation of arenes.

Full text of DOI:10.1021/ol5010752

Letter
pubs.acs.org/OrgLett
Facile Synthesis of 3‑Aryloxindoles via Brønsted Acid Catalyzed
Friedel−Crafts Alkylation of Electron-Rich Arenes with
3‑Diazooxindoles
Changwei Zhai, Dong Xing,* Changcheng Jing, Jun Zhou, Chengjin Wang, Dongwei Wang,
and Wenhao Hu*
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, and Department of Chemistry, East
China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China
S
* Supporting Information
ABSTRACT: A simple metal-free method for the synthesis of
3-aryloxindoles via Brønsted acid catalyzed aromatic C−H
functionalization of electron-rich arenes with 3-diazooxindoles
is developed. In the presence of a catalytic amount of TfOH, a
series of 3-aryloxindoles are synthesized as single regioisomers
in good to excellent yields. This transformation is proposed to
proceed through acid-catalyzed protonation of 3-diazoox-
indoles into diazonium ions followed by Friedel−Crafts-type
alkylation of arenes.
3-Aryloxindoles are widely used precursors for the synthesis of
different types of 3,3-disubstituted oxindoles and indolines,
which constitute the core of a large number of biologically
active natural products and synthetic pharmaceutical agents.1,2
Over the past few decades, an array of methods have been
developed for the preparation of 3-aryloxindoles. The classical
ones include strong acid-promoted intramolecular Friedel−
Crafts cyclization,3 strong base-promoted cyclization,4 or
photoinduced cyclization of α-haloacetanilides (Scheme 1,
transition-metal catalysts are generally required. As a result, the
development of simple and convenient methods for the
synthesis of 3-aryloxindoles that can be implemented under
mild conditions without the use of metal reagents or transition-
metal catalysts is highly desirable. Herein, we describe the facile
synthesis of 3-aryloxindoles via a Brønsted acid-catalyzed
Friedel−Crafts type alkylation of arenes with 3-diazooxindoles
(Scheme 1, path f).
As an important class of reagents, diazo compounds have
been widely applied to different types of organic trans-
formations. Among them, it has been a well-established process
that diazo compounds undergo protonation to afford
diazonium ion under Brønsted acid catalysis.10 This process
has been involved in the earliest application of diazo
compounds for esterification of carboxylic acids11 and has
been applied to O−H insertions of water or alcohols12 as well
as certain types of rearrangement reactions.13 Surprisingly,
except for these achievements, such processes did not find
further synthetic applications in organic chemistry and have
been generally considered as the major competitive reactions in
transformations where Brønsted acid catalysts were used to
activate electrophiles to react with diazo compounds.14 As part
of our research program aimed at exploring the unique
reactivity of 3-diazooxindole for new transformations,15 we
envisioned that a diazonium ion generated from 3-diazoox-
indole in the presence of a Brønsted acid would undergo
Friedel−Crafts-type alkylation with arenes,16 therefore provid-
ing a metal-free strategy for the preparation of 3-aryloxindoles
starting from isatins (Scheme 2).17 However, since 3-
Scheme 1. Strategies for the Synthesis of 3-Aryloxindoles
path a).5 In recent years, the reaction of aryl Grignard reagents
with isatins followed by Pd/C or strong Lewis acid-promoted
reductive deoxygenation has become the most generally applied
method for the synthesis of 3-aryloxindoles (Scheme 1, path
b).2b,e,6 On the other hand, palladium-catalyzed intramolecular
α-arylation of amides7 (Scheme 1, path c), intermolecular α-
arylation of oxindoles with aryl halides8 (Scheme 1, path d), or
α-arylation of 3-diazooxindole with arylboroxines9 (Scheme 1,
path e) has also been developed as an elegant protocol for the
synthesis of 3-aryloxindoles. Among all of these methods,
however, harsh reaction conditions (strong acidic or basic
conditions) or the use of air-sensitive metal reagents or
Received: April 14, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
and 4). These results indicated that the acidity of Brønsted
acids is crucial for this transformation to successfully proceed.
Control experiments without the addition of TfOH did not give
any desired product (Table 1, entry 5). By applying TfOH as
the catalyst, further optimizations were conducted. Reducing
the loading of TfOH from 50 to 20 mol % still gave 3a in very
high yield (Table 1, entry 6). This reaction also run smoothly
when 5.0 equiv of toluene was used in different halogenated
solvent, while 1,2-dichloroethane (DCE) was the best solvent
to give 3a in 87% yield (Table 1, entries 7−9). However,
further reducing the amount of toluene from 5.0 to 3.5 equiv
resulted in a much reduced yield (Table 1, entry 10). The
addition of 4 Å molecular sieves caused a declined yield of 3a
(Table 1, entry 11), which indicated that the existence of slight
amount of water might be beneficial to this reaction. Moreover,
all reactions were carried out in open air with AR-grade
solvents, which means this transformation is very reliable and
easy to operate.
Scheme 2. Friedel−Crafts Alkylation of Arene with 3-
Diazooxindole via Diazonium Ion Intermediate
diazooxindole is a relatively less reactive diazo source,18 it
remains unclear whether the desired diazonium ion inter-
mediate would be efficiently generated under Brønsted acid
catalyzed conditions, and the generated diazonium ion may
undergo competitive hydrolysis and homocoupling, therefore
affecting the efficiency in affording the desired alkylation
product. On the other hand, when substituted arenes are used
as the substrates, the regioselectivity during the alkylation
process may also be a problem.
With these concerns, we started our initial investigation by
choosing N-benzyl-3-diazooxindole 1a and toluene as the
substrates wherein toluene was also used as the solvent. When
50 mol % of methanesulfonic acid (MsOH) (pKa = −2.6) was
used as the catalyst, 3-aryloxindole 3a was afforded in 61% yield
along with the formation of hydrolysis product as well as O−H
insertion product from MsOH as the major side products
(Table 1, entry 1). With this encouraging result, other Brønsted
With the optimized reaction conditions in hand, the scope of
3-diazooxindoles for this TfOH-catalyzed aromatic substitution
reaction was first investigated by choosing toluene as the arene
source as well as the solvent. In addition to N-benzyl-3-
diazooxindole 1a, N-methyl-3-diazooxindole also reacted with
toluene smoothly to afford the desired alkylation product in
good yield (Table 2, entries 1 and 2). An ester substituent on
a
Table 2. Scope of 3-Diazooxindoles
a
Table 1. Optimization of the Reaction Conditions
b,c
entry
R1
Bn
R2
3
yield (%)
1
2
3
4
5
H
3a
3b
3c
3d
3e
3f
96
66
78
74
68
60
85
74
72
Me
CO2Et
Bn
H
H
b
4-Cl
5-Cl
6-Cl
5-Br
5-Me
6-F
entry
cat.
X
solvent
equiv of 2a
yield (%)
Bn
1
2
MsOH
TfOH
CSA
50
50
50
50
toluene
toluene
toluene
toluene
toluene
toluene
DCM
61
98
<5
<5
<5
96
80
83
87
62
70
d
6
Bn
7
8
9
Bn
3g
3h
3i
3
Bn
4
TsOH
none
Bn
5
a
All reactions were conducted by adding 1 (0.2 mmol) in 1 mL of
6
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
20
20
20
20
20
20
toluene to the mixture of TfOH (20 mol %) in 0.7 mL of toluene via
syringe pump over 30 min, and the reaction mixture was stirred for
7
5.0
5.0
5.0
3.5
5.0
8
CHCl3
DCE
b
c
another 10 min. Isolated yield. Unless otherwise noted, the
9
regioisomeric ratio (para/ortho) is larger than 95:5 as determined by
d
1H NMR of the crude mixture. Para/ortho = 93:7.
10
DCE
c
11
DCE
a
Reactions were conducted by adding 1a (0.2 mmol) in 1 mL of the
solvent to the mixture of 2a and catalyst in 0.7 mL of the solvent via
syringe pump over 30 min. Isolated yield. With the addition of 100
mg of 4 Å MS.
nitrogen atom of 3-diazooxindoles was also applicable to this
transformation, providing the desired product in 78% yield
(Table 2, entry 3). N-Benzyl-3-diazooxindoles bearing different
substituents on the aromatic ring were also tested. With 4- or 5-
chloro-substituted 3-diazooxindoles as the substrates, the
desired alkylation products were afforded in good yields
(Table 2, entries 4 and 5). 5-Methyl- or 5-bromo-substituted
3-diazooxindoles gave the desired products in much higher
yields (Table 2, entries 7 and 8). Substrates bearing halogen
substituents at 6-position also underwent the desired alkylation
reaction, however, with slightly decreased efficiency (Table 2,
b
c
acid catalysts were further evaluated. When more acidic triflic
acid (TfOH) (pKa = −14) was used as the catalyst, 3a was
afforded in 98% yield as a single regioisomer (Table 1, entry
2).19,20 The use of weaker Brønsted acids such as
camphorsulfonic acid (CSA) (pKa = 1.2) or p-toluenesulfonic
acid (TsOH) (pKa = 3.9) as catalysts failed to decompose 1a,
and the formation of 3a was not observed (Table 1, entries 3
B
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Organic Letters
Letter
entries 6 and 9). For most cases, excellent regioselectivities
(para/ortho > 95:5) were observed.
The scope of arenes was further investigated by choosing
DCE as the solvent. When isobutyl-substituted benzene or
biphenyl was used as the substrate, the desired para-substituted
products were produced exclusively in good yields (Scheme 3,
smoothly alkylated with 1a, affording the desired products as
indistinguishable 2- and 3-substituted regioisomers in a
combined yield of 87% (Scheme 3, 3u).
To demonstrate the synthetic practicality of this TfOH-
catalyzed aromatic C−H substitution of arene with 3-
diazooxindole, a gram-scale reaction was carried out by
applying 1.50 g of 1a in toluene. In the presence of 10 mol
% of TfOH, this reaction proceeded smoothly at 0 °C to give
the desired product 3a in 75% yield (1.41 g) (Scheme 4).
a b
,
Scheme 3. Scope of Arenes
Scheme 4. Gram-Scale Synthesis of 3a
In accordance with our previous hypothesis, this aromatic
C−H functionalization is proposed to proceed through acid-
catalyzed protonation of 3-diazooxindole into a diazonium ion
followed by Friedel−Crafts alkylation of arenes with concurrent
loss of nitrogen (Scheme 2). From detailed kinetic experiments
and mechanistic investigations of Brønsted acid-catalyzed
hydrolysis of diazocarbonyl compounds,11 it has been shown
that the protonation of the diazo carbon atom for the
generation of the diazonium ion is the rate-determining step.
To gain more insights about this transformation, several
deuterium-labeling experiments were conducted. First, d8-
substituted toluene was allowed to react with 3-diazooxindole
1a in the presence of 20 mol % of TfOH. The deuterium-
substituted product (labeled with 38% deuterium at the C-3
position) was obtained in 70% yield (Scheme 5, eq 1). The low
content of deuterium in the product indicated that a direct
proton transfer from the aryl ring is unlikely involved. Reaction
between 1a and toluene in D2O-saturated DCE resulted in the
formation of deuterium-substituted product with 21%
deuterium in 78% yield (Scheme 5, eq 2). On the other
a
Unless otherwise noted, all reactions were conducted by adding 1a
(0.2 mmol) in 1 mL of DCE to the mixture of 2 (5.0 equiv) and TfOH
(20 mol %) in 0.7 mL of DCE via syringe pump over 30 min, and the
b
reaction mixture was stirred for another 10 min. Isolated yields.
c
d
e
Para/ortho = 87:13. 2 equiv of TfOH was used. Para/ortho = 92:8.
f
Undistinguished 2-/3-substituted regioisomers.
Scheme 5. Deuterium-Labeling Experiments
3j and 3k). When starting from anisole, the desired product was
obtained as a mixture of regioisomers (para/ortho = 87:13)
probably owing to the relatively high electron-donating ability
of methoxy group (Scheme 3, 3l). The use of acetanilide as the
substrate also provided the desired para-substituted product in
60% yield, wherein the use of 2 equiv of TfOH was required
(Scheme 3, 3m). Different disubstituted arenes were further
tested. When ortho-, meta-, or para-xylene were used, the
desired products were exclusively afforded as single re-
gioisomers in high yields (Scheme 3, 3n, 3o, and 3p). When
1,3-dimethoxybenzene reacted with 1a, the desired product was
afforded (para/ortho = 92:8) in 90% yield (Scheme 3, 3q).
When p-tert-butyl-substituted phenol was chosen as the
substrate, alkylation occurred at the ortho-position of the
hydroxy group, yielding 3r in 70% yield (Scheme 3, 3r). The
use of p-methyl-substituted thiophenol as the substrate also
afforded the desired product in good yield (Scheme 3, 3s).
Trisubstituted arene was also proven to be applicable to this
Friedel−Crafts alkylation with 3-diazooxindole, and the use of
mesitylene as the arene source gave the desired product in 95%
yield (Scheme 3, 3t). Heteroaromatic thiophene could also be
C
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Organic Letters
Letter
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resulted in 8% deuterated product, indicating a relatively low
rate of H/D exchange of the product (Scheme 5, eq 3).
Collectively, these results indicated that small amount of water
existed in the mixture may play as a proton shuttle for the acid-
catalyzed protonation process.21
In summary, we have developed a simple and efficient
method for the synthesis of 3-aryloxindoles by TfOH-catalyzed
Friedel−Crafts type alkylation of arenes with 3-diazooxindoles.
With this metal-free transformation, a series of 3-aryloxindoles
were obtained in good yields with high regioselectivities. This
reaction is carried out under simple and mild conditions with
nitrogen as the only waste and, therefore, shows great potential
for application to both laboratory and industrial synthesis.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Xing, D.; Jing, C.; Li, X.; Qiu, H.; Hu, W. Org. Lett. 2013, 15,
3578.
AUTHOR INFORMATION
■
Corresponding Authors
(16) Tayama and co-workers reported a Cu(II) and Brønsted acid
co-catalyzed aromatic C−H substitution of N,N-disubstituted anilines
with methyl phenyldiazoacetate. For several specially substituted
substrates in this work, it was found that TfOH or Tf2NH alone could
catalyze the transformation; see: Tayama, E.; Ishikawa, M.; Iwamoto,
H.; Hasegawa, E. Tetrahedron Lett. 2012, 53, 5159.
*E-mail: dxing@sat.ecnu.edu.cn.
*E-mail: whu@chem.ecnu.edu.cn.
Notes
The authors declare no competing financial interest.
(17) For detailed procedure for the preparation of 3-diazooxindoles
from isatins, see the Supporting Information.
ACKNOWLEDGMENTS
(18) For limited examples of cyclopropanation of 3-diazooxindoles,
see: (a) Muthusamy, S.; Gunanathan, C. Synlett 2003, 1599.
(b) Muthusamy, S.; Gunanathan, C.; Nethaji, M. J. Org. Chem.
2004, 69, 5631. (c) Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005,
127, 11505. (d) Cao, Z.-Y.; Wang, X.; Tan, C.; Zhao, X.-L.; Zhou, J.;
Ding, K. J. Am. Chem. Soc. 2013, 135, 8197. (e) Bonderoff, S. A.;
Padwa, A. Org. Lett. 2013, 15, 4114.
■
Financial support from NSF of China (20932003 and
21125209), the MOST of China (2011CB808600), STCSM
(12JC1403800), and CPSF (2013M540345) is greatly acknowl-
edged.
(19) Under the optimal reaction conditions, an array of other types
of diazocarbonyl compounds was also evaluated. However, only 3-
diazooxindole provided the desired product with satisfactory results in
terms of both the yield and regioselectivity (para vs ortho), indicating
the unique reactivity of 3-diazooxindole for this transformation. For
details, see Table S1 of the Supporting Information.
(20) On the other hand, in order to explore whether a metal−
carbene insertion process is also applicable for the synthesis of 3a from
1a and toluene, different transition-metal catalysts were tested;
however, in no case was 3a detected. For details, see Table S2 of
the Supporting Information.
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