Iron-catalyzed aerobic difunctionalization of alkenes: A highly efficient approach to construct oxindoles by C-S and C-C bond formation

Article abstract of DOI:10.1039/c4cc00401a

A novel iron-catalyzed efficient approach to construct sulfone-containing oxindoles, which play important roles in the structural library design and drug discovery, has been developed. The use of readily available benzenesulfinic acids, an inexpensive iron salt as the catalyst, and air as the oxidant makes this sulfur incorporation protocol very efficient and practical. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc00401a

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Iron-catalyzed aerobic difunctionalization of
alkenes: a highly efficient approach to construct
oxindoles by C–S and C–C bond formation†
Tao Shen,a Yizhi Yuan,a Song Songa and Ning Jiao*ab
Cite this: Chem. Commun., 2014,
50, 4115
Received 17th January 2014,
Accepted 26th February 2014
DOI: 10.1039/c4cc00401a
www.rsc.org/chemcomm
A novel iron-catalyzed efficient approach to construct sulfone-
containing oxindoles, which play important roles in the structural
library design and drug discovery, has been developed. The use of
readily available benzenesulfinic acids, an inexpensive iron salt as
the catalyst, and air as the oxidant makes this sulfur incorporation
protocol very efficient and practical.
Sulfone-containing molecules exhibit important functions in
materials, synthetic intermediates, and pharmaceuticals.1 The
significance of organosulfur compounds has inspired chemists
to develop efficient C–S bond-formation transformations.2
Scheme 1 Difunctionalization of alkenes with benzenesulfinic acids.
In the past few decades, through a radical process, the addition cascade C–S and C–C bond formation for rapid building of
of sulfonyl radicals to carbon–carbon unsaturated bonds repre- sulfone-containing oxindoles (b, Scheme 1).
sents a particularly useful strategy for sulfone synthesis.3,4
To the best of our knowledge, this is a novel aerobic oxidative
Despite the significances of these methods,4 some precursors such sulfonyl-carbocyclization of activated alkenes to construct sulfonyl
as sulfonyl halides, cyanides, selenides, azides, and hydrazides are substituted oxindoles. Molecular oxygen is employed as a green
employed to generate the sulfonyl radicals by treatment with oxidant and plays a very important role in initiating this trans-
radical initiators or photolysis. They cause atom transfer radical formation, which makes this protocol very easy to handle. An
additions to multiple bonds in the presence of a stoichiometric inexpensive iron salt is employed as the catalyst. This observa-
amount of oxidants such as copper(II), TBHP, and cerium(IV) salts. tion represents an efficient approach to construct sulfone-
Nevertheless, these processes are limited to the scope of substrates containing oxindoles by employing simple and readily available
which are sometimes unstable in the presence of the oxidants.
Recently, the group of Lei developed oxysulfonylation of
sulfinic acid as the sulfur source.
We began our study by examining the reaction of N-methyl-
alkenes by employing simple and readily available benzene- N-arylacrylamide 1a and benzenesulfinic acid 2a for the direct
sulfinic acids as the sulfonyl radical precursor using dioxygen sulfonylation and cyclization. Interestingly, 3aa was obtained in
as the oxidant5 (a, Scheme 1). 3-Substituted oxindoles play 77% yield by using 10% Fe(NO3)3ꢀ9H2O as a catalyst in MeCN
important roles in the structural library design and drug (entry 1, Table 1). To our delight, when the loading of PhSO2H
discovery.6 Therefore, the sulfone-containing oxindoles should 2a was reduced to 1.5 eq., the yield of 3aa increased to 94%
be in high demand due to the potential unique biological (entry 2, Table 1). When the reaction was performed under Ar,
activity of the products. Herein we report a novel and direct only 38% yield of 3aa was obtained (entry 3), which indicates that
Fe catalyzed aerobic difunctionalization of activated alkenes via O2 may be an oxidant involved in this sulfon-carbocyclization
process. Other solvents such as DCE, CHCl3 and THF did not
a State Key Laboratory of Natural and Biomimetic Drugs, Peking University,
Xue Yuan Rd. 38, Beijing 100191, People’s Republic of China.
E-mail: jiaoning@bjmu.edu.cn; Fax: +86-010-8280-5297
perform well (see ESI†). Other transition metal catalysts such as
FeCl3, AgNO3, Cu(NO3)2, Pd(OAc)2, and AuCl3 showed low
efficiencies, respectively (entry 4, Table 1, and ESI†). Notably,
some organic radical catalysts such as TEMPO and NHPI did
not work (entries 5 and 6, Table 1). 3aa was obtained only in
b State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, People’s Republic of China
† Electronic supplementary information (ESI) available. CCDC 981556. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc00401a 16% yield in the absence of any catalyst (entry 7, Table 1).
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Table 1 Optimization for the direct sulfon-carbocyclization of activated
alkenesa
Entry
Cat. (mol%)
Yield of 3aab (%)
1
2
3
4
5
6
7
Fe(NO3)3ꢀ9H2O (10)
Fe(NO3)3ꢀ9H2O (10)
Fe(NO3)3ꢀ9H2O (10)
FeCl3 (10)
TEMPO (10)
NHPI (10)
77
94c
38d
Trace
Trace
Trace
16
Scheme 3 Iron-catalyzed aerobic sulfon-carbocyclization of activated
alkenes. These reactions were carried out at 100 1C under air for 12 h.
Isolated yields. a 0.6 mmol of MeSO2H was used. b 0.4 mmol of EtSO2H
was used. c 0.3 mmol of 2 was used.
None
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), solvent (2 mL),
b
c
and stirred at 100 1C under air for 12 h. Isolated yields. 0.3 mmol
PhSO2H (2a) was used. The reaction was carried out under Ar.
d
in high yield (3ra, Scheme 2). Various protected a-hydroxymethyl
derivatives provided the oxysulfonylation products in moderate
yields (3sa and 3ta, Scheme 2). When N-methyl-N-(naphthalen-
1-yl)-methacrylamide was employed, the desired two isomers were
obtained in 55% and 21% yields (3wa and 3wa0, Scheme 2).
Interestingly, various substituted sulfinic acids could be
smoothly converted into expected sulfonated oxindoles in moderate
to excellent yields (Scheme 3). Substrates with a highly unstable
group such as cyclopropyl could also smoothly produce the
desired product in excellent yield (3ad, Scheme 3). Besides,
various benzene sulfinates with different substituents (e.g., Me,
Cl, NHAc) were well tolerated (3ae–3ag, Scheme 3).
Furthermore, this chemistry was applied in the synthesis
of more complicated rings. Notably, the current protocol
allows the formation of aza-2-oxindole derivatives in good yield
(eqn (1)).
When 1y was employed as a substrate, the six-membered-
ring product 3ya was obtained in 81% yield (eqn (2)). Tetra-
hydroisoquinoline and dibenzazepine structural motifs are
commonly encountered in many biologically active compounds.
Interestingly, tricyclic sulfonated oxindole derivative 3za was
obtained in 74% yield from the corresponding tetrahydro-
quinoline substrate (eqn (3)). Notably, a larger tetracyclic oxindole
derivative was successfully prepared in 68% yield using this
protocol (eqn (4)).
With the optimized reaction conditions in hand, the sub-
strate scope of this aerobic sulfon-carbocyclization of alkenes
was investigated. Various N-arylacrylamides were subjected to
the optimized reaction conditions (Scheme 2). N-arylacrylamides
containing both electron-donating and electron-withdrawing
groups at the aryl ring executed smoothly to produce the corre-
sponding products in good to excellent yields. Generally, sub-
strates with an electron-withdrawing group could afford higher
yields. It is noteworthy that the N-methyl-N-phenylmethacryl-
amides with halo-substituents (F, Cl, Br, and I) were tolerated
under these mild reaction conditions leading to the corres-
ponding halo-substituted oxindoles in excellent yields (88–96%,
3ca–3fa). N-protected N-phenylmethacrylamides could be smoothly
converted into the desired oxindoles in excellent yields (3ma–3oa,
Scheme 2). Interestingly, the N-arylacrylamide substrate with substi-
tuents at the meta position, highly regioselective, provided oxindoles
(1)
(2)
(3)
Scheme 2 Iron-catalyzed aerobic sulfon-carbocyclization of activated
alkenes. Reaction conditions: see entry 2, Table 1. a 0.3 mmol PhSO2H
was used. b The reaction mixture was stirred for 24 h.
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Fe(II) could be easily oxidized to Fe(III) to complete the
catalytic cycle.
(5)
(6)
(7)
Scheme 4 Range of reactions of the sulfonated oxindoles.
(8)
(4)
In summary, we have developed a novel iron-catalyzed aerobic
difunctionalization of alkenes for the construction of C–S and
C–C bonds. This protocol provides an efficient approach to form
sulfone-containing oxindoles, which play important roles in the
structural library design and drug discovery. The use of readily
available benzenesulfinic acids, an inexpensive iron salt as the
catalyst, and air as the oxidant makes this sulfone incorporation
protocol environmentally benign and practical. Further studies on
the synthetic application of this chemistry are underway.
Financial support from the National Science Foundation of
China (No. 21325206, 21172006), the National Young Top-notch
Talent Support Program, and the PhD Programs Foundation of
the Ministry of Education of China (No. 20120001110013) are
greatly appreciated. We thank Miancheng Zou in this group for
reproducing the results of 3ma and 3ae.
Oxindoles with an appended sulfonyl group obtained by the
presented methodology can be used to create a focused com-
pound library. After obtaining the model product 3aa in 76%
yield on a gram scale under standard conditions (eqn (5)), we
embarked upon exploring the diverse synthetic transformations
of sulfonyl oxindoles (Scheme 4). 3aa could be reduced by
LiAlH4 to give 2H-indole 6 in 81% yield. Moreover, the synthetic
utility of the sulfonated oxindoles was exemplified by the
alkylation reaction to produce 7, 8, and 9 in good to excellent
yields. In addition, the halogenation of 3aa with CBr4 and CCl4
provided oxazoline 10 and 11, respectively (Scheme 4).
The reaction was completely suppressed in the presence of
TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) (eqn (6)). Moreover,
the intramolecular and intermolecular kinetic isotope effects (KIE)
were investigated (the intramolecular kH/kD = 1.3 and inter-
molecular kH/kD = 1.1) (eqn (7) and (8)), which indicates that C–H
bond cleavage may not be the rate-determining step.7
Based on the above results, a possible mechanism is proposed
(Scheme 5). Initially, the sulfonyl radical could be easily initiated
by O2.5 Subsequent radical addition to activated alkene 1a
generates radical intermediate A. Then the intramolecular
carbocyclization of radical intermediate A affords radical inter-
mediate B,8 which is oxidized by Fe(III) to form cationic inter-
mediate C via a SET process. Intermediate C finally produces
terminal product 2a via a deprotonation step. In the presence of O2,
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