1
Introduction
Figure 1 Examples of important oxindoles
Oxindoles, an important class of heterocycles with a wide range of biological properties,
are a key structural motif in numerous natural products and biologically active compounds
(Figure [1 ]).[1 ] Additionally, oxindoles are important synthetic intermediates that have elicited
considerable synthetic interest principally because of their important applications
in asymmetric synthesis, library design and drug discovery.[2 ] As a result, efficient methods for oxindole synthesis have been the subject of extensive
studies. Among these methods, the recently developed transition-metal-catalyzed or
metal-free oxidative difunctionalization of activated alkenes is a particularly fascinating
approach to building diversely functionalized oxindoles, owing to its high step- and
atom-economy, and easy incorporation of many functional groups (e.g., cyano, carbonyl,
hydroxyl, phosphoryl, trifluoromethyl, azidyl, and nitro) into the oxindole framework.
The difunctionalizations of alkenes have been significantly developed and have already
played vital roles in organic syntheses.[3 ] In particular, the applications of difunctionalization of alkenes for the synthesis
of important bioactive heterocyclic compounds has proven to be a powerful alternative
to the traditional approaches. Recent studies have illustrated that these transformations,
such as arylalkylation, aminooxygenation, diamination, and dioxygenation of unsaturated
hydrocarbons, could be used efficiently to allow the formation of diverse chemical
bonds. In 1999, the Grigg research group reported a palladium-catalyzed difunctionalization
of alkenes with aryl iodides and carbon monoxide through an intramolecular Heck–carbonylation
reaction for the synthesis of oxindoles and their derivatives in good yield (Scheme
[1 ]).[4 ] Following on these results, a similar version of palladium(0)-catalyzed alkene difunctionalization
involving the intramolecular Heck coupling of o -haloanilines has been developed for accessing oxindoles and their derivatives.[5 ]
Scheme 1 Palladium-catalyzed domino intramolecular Heck–carbonylation reaction
In 2007, the Zhu research group expanded the palladium-catalyzed domino intramolecular
Heck coupling protocol to assemble 3-substituted 3-cyanomethyl-2-oxindoles (Scheme
[2 ]),[6 ] in which K4 [Fe(CN)6 ] was employed as a trapping agent for the π-alkylpalladium intermediate. The reaction
was applicable to a wide range of o -haloaniline substrates with different electronic properties. In addition, a concise
synthesis of physostigmine utilizing this key domino process for the construction
of the core framework was accomplished. Importantly, an enantioselective version of
this domino process was also examined. However, these transformations also suffer
from the cost of the palladium–ligand catalytic system and the requirement of expensive
and unavailable o -haloaniline substrates.
Scheme 2 Possible mechanism for the palladium-catalyzed domino intramolecular Heck–cyanation
reaction.
To make the palladium-catalyzed domino methods more useful, Neuville and Zhu and their
co-workers discovered a new palladium(II)/(diacetoxy)iodobenzene catalytic system
for use in the domino cyclization of ortho -unsubstituted anilines through the C(sp2 )–H oxidative Heck-type coupling (Scheme [3 ]).[7 ] This method represents a new palladium-catalyzed oxidative carboheterofunctionalization
of ortho -unsubstituted anilines via C(sp2 )–H oxidative activation, and provides a facile and highly atom-economic access to
oxindoles.
Scheme 3 Palladium-catalyzed oxidative 1,2-carboheterofunctionalization of alkenes
The Liu research group described new palladium-catalyzed oxidative difunctionalization
reactions of alkenes with acetonitriles[8a ] or trimethyl(trifluoromethyl)silane[8b ] for the synthesis of functionalized oxindoles through C–H oxidative activation under
neutral conditions (Scheme [4 ]).
Scheme 4 Palladium-catalyzed oxidative 1,2-difunctionalization of alkenes with acetonitriles
or trimethyl(trifluoromethyl)silane
The mechanism for the palladium-catalyzed oxidative 1,2-difunctionalization of alkenes
with acetonitriles involving a palladium(II)/palladium(IV) catalytic cycle, outlined
in Scheme [5 ], was proposed on the basis of kinetic isotopic effect studies. The reaction is initiated
by coordination of the olefin to palladium(II) (intermediate A ), followed by nucleophilic attack of the tethered arene to give the palladium complex
B . The C(sp3 )–H bond activation of the acetonitrile takes place in the presence of di(pivaloyloxy)iodobenzene
and silver fluoride, thus generating the palladium(IV) complex C . Finally, reductive elimination of intermediate C affords the desired oxindole. The formation of the palladium complex B is supported by HRMS analysis.
These palladium-catalyzed oxidative difunctionalization transformations involving
C–H activation are more attractive because it extends the substrate scope to ortho -unsubstituted anilines and can introduce additional functional groups into the oxindole
framework. However, the use of the highly expensive palladium–hypervalent iodine reagent
systems still limits the applicability of the reaction. Thus, the development of new
C–H oxidative coupling strategies for alkene difunctionalization, especially using
inexpensive metal catalysts or no metal at all, is desirable.
Scheme 5 Possible mechanism for the palladium-catalyzed oxidative alkylarylation of alkenes
with acetonitriles
This review focuses on the construction of oxindoles by the difunctionalization of
activated alkenes through C–H oxidative radical coupling using inexpensive iron or
copper catalysts as well as under metal-free conditions. It should be noted that the
mechanisms of these alkene difunctionalization reactions through C–H oxidative radical
coupling are still unclear and remain to be studied. These transformations are classified,
according to the difunctionalization process, into two types (Scheme [6 ]): synthesis of oxindoles via 1,2-dicarbofunctionalization of alkenes (route a: the
addition of carbon radicals across the carbon–carbon double bond, followed by arylation),
and synthesis of oxindoles via 1,2-carboheterofunctionalization of alkenes (route
b: the addition of heteroatom and carbon radicals across the carbon–carbon double
bond, followed by arylation; heteroatoms include N, S and P). The scope and limitations
of these difunctionalization reactions are discussed, as well as their mechanisms.
Scheme 6 Difunctionalization of activated alkenes through C–H oxidative radical coupling
2
Synthesis of Oxindoles via 1,2-Dicarbofunctionalization of Alkenes
It is well known that carbon–carbon bond-forming reactions are the most common processes
in chemistry because they are important in the production of many useful chemicals
such as pharmaceuticals and plastics.[9 ] Among the numerous reported carbon–carbon bond-formation methods, those involving
C–H functionalization are particularly significant and remain challenging.
2.1
1,2-Alkylarylation
Encouraged by the results of the Neuville/Zhu and Liu research groups, Li and co-workers
chose to use ethers – compounds containing the activated C(sp3 )–H bond adjacent to the oxygen atom – in the presence of oxidants (often peroxides)
to realize the 1,2-difunctionalization of alkenes (Scheme [7 ]).[10 ] In the presence of iron(III) chloride, tert -butyl hydroperoxide (TBHP) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), a variety
of activated alkenes reacted successfully with an aryl C(sp2 )–H bond and a C(sp3 )–H bond adjacent to a heteroatom, giving functionalized 3-(2-oxoethyl)indolin-2-ones
in moderate to high yields. This oxidative 1,2-alkylarylation was catalyzed by the
economical and environmentally benign metal iron, and was the first example of metal-catalyzed
1,2-difunctionalization of an alkene with an aryl C(sp2 )–H bond and a C(sp3 )–H bond adjacent to a heteroatom for the simultaneous formation of two carbon–carbon
bonds. Interestingly, the dual C–H oxidative radical coupling protocol was applicable
to thioethers and tertiary alkylamines as well.
Scheme 7 Iron-catalyzed 1,2-alkylarylation of alkenes with the C(sp3 )–H bonds adjacent to a heteroatom
Control experiments indicated that there was no kinetic isotope effect (kH
/kD
= 1.0) in the intramolecular or intermolecular experiments (Scheme [8 ]). These observations implied that the iron-catalyzed alkene oxidative difunctionalization
may proceed via either the SEAr mechanism or the free-radical mechanism. The results
of the experiment with tetrahydrofuran and tetrahydrofuran-d
8 (kH
/kD
= 1.0) supported the free-radical mechanism. To verify this mechanism, two radical
inhibitors, TEMPO and 2,6-di-tert -butylphenol, were added to the difunctionalization reaction: a stoichiometric amount
of radical inhibitor resulted in no conversion of amide; however, diethyl ether was
transformed by TEMPO into 1-(1-ethoxyethoxy)-2,2,6,6-tetramethylpiperidine in 91%
yield, suggesting that the reaction includes a diethyl ether radical.
Scheme 8 Control experiments
Consequently, Li and co-workers proposed the radical mechanism outlined in Scheme
[9 ] for the iron-catalyzed 1,2-alkylarylation of alkenes with C(sp3 )–H bonds adjacent to a heteroatom. Initially, tert -butyl hydroperoxide is split by iron(II) into a tert -butoxy radical and a hydroxy-iron(III) species. In the presence of a tert -butoxy radical, diethyl ether, with its C(sp3 )–H bonds adjacent to oxygen, is readily transformed into alkyl radical intermediate
D . Addition of alkyl radical intermediate D to the carbon–carbon double bond of N -arylmethacrylamide results in the formation of radical intermediate E , which undergoes the intramolecular cyclization with the C(sp2 )–H bond in the N -aryl ring to generate radical intermediate F . Finally, hydrogen abstraction by the hydroxy-iron(III) species takes place to afford
the oxindole.
Scheme 9 Possible mechanism for the Fe-catalyzed 1,2-alkylarylation of alkenes with a C(sp3 )–H bond adjacent to a heteroatom
The Guo and Duan[11a ] and the Liang[11b ] research groups have independently reported metal-free tert -butyl hydroperoxide mediated oxidative hydroxyalkylarylation of activated alkenes
with C(sp3 )–H bonds adjacent to a hydroxy group (secondary or tertiary alcohols) for the assembly
of hydroxy-containing oxindoles (Scheme [10 ]). Mechanistic studies revealed that the α�-hydroxy carbon radical is initially formed
from the α-C(sp3 )–H bond cleavage, followed by intramolcular cyclization involving the aromatic C(sp2 )–H radical coupling. Notably, the obtained hydroxy-containing oxindoles can be used
for further transformations to give diverse indole-alkaloid structural motifs.
Scheme 10 1,2-Alkylarylation of alkenes with C(sp3 )–H bonds adjacent to a hydroxy group
Generally, benzylic C(sp3 )–H bonds are highly reactive. Therefore, Li and co-workers attempted to extend the
oxidative radical coupling protocol to simple benzylic C(sp3 )–H bonds. As expected, in the absence of metal catalysts, the reactions of activated
alkenes with benzylic C(sp3 )–H bonds and di-tert -butyl peroxide (DTBP) were successful, albeit with lower yields (Scheme [11 ]).[12 ] It was found that Lewis acids could improve the reaction, and iridium(III) chloride
was preferred. Meanwhile, the Guo and Duan research group reported a similar version
of the 1,2-alkylarylation of alkenes with benzylic C(sp3 )–H bonds using a catalytic system comprised of copper(I) oxide and tert -butyl peroxybenzoate (TBPB).[13 ]
Scheme 11 1,2-Alkylarylation of alkenes with benzylic C(sp3 )–H bonds
A novel copper-catalyzed oxidative 1,2-alkylarylation of alkenes with a range of simple
alkanes, including cyclic alkanes, linear alkanes and arylmethanes, by using dicumyl
peroxide (DCP) as oxidant has been reported by Liu and co-workers (Scheme [12 ]).[14 ] This method not only provided a useful method for the synthesis of alkyl-substituted
oxindoles, but also presented a new strategy for selective functionalization of simple
alkanes by way of a free-radical cascade process.
Scheme 12 1,2-Alkylarylation of alkens with simple alkanes
Remarkably, Guo, Duan and Wang documented that alkyl radicals could be generated by
C–H oxidative cleavage with a new oxidative system, comprised of silver nitrate and
potassium persulfate, that was thus not limited to peroxide oxidants (Scheme [13 ]).[15 ] In this reaction, the 1,2-alkylarylation of activated alkenes with the α-C(sp3 )–H bonds of 1,3-dicarbonyl compounds was successful in furnishing oxindoles in good
yields. Notably, the same reaction conditions were also extended to the reaction with
simple ketones.
Scheme 13 Silver-catalyzed 1,2-alkylarylation of alkenes with α-C(sp3 )–H bonds in 1,3-dicarbonyl compounds
They proposed that the silver-catalyzed reaction proceeds through a sequential intermolecular
radical addition and intramolecular radical substitution (Scheme [14 ]). With the aid of silver nitrate and potassium persulfate, one of the α-C(sp3 )–H bonds of the 1,3-dicarbonyl compound is split into alkyl radical intermediate
G via a single-electron-transfer (SET) process, followed by addition across the alkene
to produce intermediate H . Cyclization of H occurs to afford intermediate I . Finally, hydrogen-abstraction of intermediate I with the silver catalyst gives the desired oxindole.
Scheme 14 Possible mechanism for the silver-catalyzed 1,2-alkylarylation of alkenes with 1,3-dicarbonyl
compounds
They subsequently found that the alkyl radical intermediate G could be formed from the oxidation of 1,3-dicarbonyl compounds with potassium persulfate
in the absence of silver salts, thus extending the method to build diversely functionalized
spirooxindoles (Scheme [15 ]).[16 ] In the presence of potassium persulfate, hydroxymethylacrylamides successfully underwent
the oxidative spirocyclization with 1,3-dicarbonyl compounds leading to the desired
spirooxindoles. This process exhibited significant functional-group tolerance and
high atom-economy.
Scheme 15 Silver-free oxidative alkylspirocarbocyclization of hydroxymethylacrylamides with
1,3-dicarbonyl compounds
The 1,2-alkylarylations of alkenes with other carbon radicals that are not generated
from the cleavage of the C–H bonds have also been extensively explored. The single
C(sp2 )–H oxidative radical coupling initiated by other carbon radicals are particularly
fascinating because they open a new opportunity to incorporate various functional
groups into the oxindole system through a radical strategy. In 2012, the Liu research
group established a new radical strategy for the introduction of alkyl groups into
the oxindole system by the decarboxylation of the (dialkylcarbonyloxyiodo)benzene
[PhI(OCOR)2 ] (Scheme [16 ]).[17 ] The results showed that the addition of an organocatalyst significantly improved
the reaction yield. The reason may be that organocatalysts can stabilize radical intermediates
J and K , and make the deprotonation of intermediate K successful.
Scheme 16 1,2-Alkylarylation of alkenes with (dialkylcarbonyloxyiodo)benzenes
Recently, the Zhu research group merged visible-light photoredox catalysis with C–H
oxidative radical coupling to achieve 1,2-alkylarylation with alkyl acids, in which
oxidative decarboxylation of the alkyl acid by (diacetoxy)iodobenzene produced the
alkyl radical (Scheme [17 ]).[18 ] The method was shown to be general and applicable to a range of readily available
primary, secondary and tertiary aliphatic carboxylic acids. For example, bioactive
lithocholic acid was a viable substrate for the tandem decarboxylation and 1,2-alkylarylation
reaction.
Scheme 17 1,2-Alkylarylation of alkenes with alkyl acids: the merging of visible-light photoredox
catalysis with a C–H oxidative radical coupling
Peroxides are usually used as the radical initiators or oxidants in organic synthesis,
and are easily decomposed into different radical species under heating. However, methods
to trap the radical species from peroxides are scare. The Li[19a ] and Cheng[19b ] research groups independently reported that peroxides as alkyl sources underwent
the 1,2-alkylarylation with activated alkenes (Scheme [18 ]). The method allowed for the simultaneous formation of two carbon–carbon bonds
in the assembly of quaternary oxindoles.
Scheme 18 1,2-Alkylarylation of alkenes with peroxides
2.2
1,2-Aryltrifluoromethylation
The trifluoromethyl group has been recognized as an important pharmacophore that can
enhance the metabolic stability, lipophilicity, and bioavailability of the parent
molecule.[20 ] Considerable efforts have been paid to the development of methods for the incorporation
of the trifluoromethyl group into bioactive molecules. As previously mentioned (Scheme
[4 ]), in 2012, Liu and co-workers reported a palladium-catalyzed oxidative aryltrifluoromethylation
of activated alkenes for the construction of a variety of bioactive molecules containing
trifluoromethylated oxindole moieties. The protocol included trimethyl(trifluoromethyl)silane
with cesium fluoride as the source of the trifluoromethyl group, and (diacetoxy)iodobenzene
as oxidant.[8b ] Their preliminary mechanistic studies indicated that the reaction proceeds through
initial arylpalladation of the alkene, followed by sequential oxidation and reductive
elimination of C(sp3 )−trifluoromethylpalladium(IV) species to provide the oxindole products.
In recent years, much attention has been given to the use of the trifluoromethyl radical
in the preparation of trifluoromethyl-containing compounds; however, successful examples
are rare. In light of this, the 1,2-aryltrifluoromethylation of alkenes with the trifluoromethyl
radical has been developed using different trifluoromethyl radical resources, such
as sodium triflinate (the Langlois reagent) and trimethyl(trifluoromethyl)silane (Scheme
[19 ]).[21 ] Interestingly, Tan and co-workers expanded the scope of reagents to include zinc
difluoromethanesulfinate (ZnSO2 CF2 H) for the synthesis of difluoromethyl-containing oxindoles.[22 ] The Wang research group also employed iododifluoromethyl phenyl sulfone (PhSO2 CF2 I) to generate the (phenylsulfonyl)difluoromethyl radical to access (phenylsulfonyl)difluoromethyl-containing
oxindoles using the greener combination of ferrocene as catalyst and hydrogen peroxide
as oxidant.[23 ] Notably, these radical 1,2-aryltrifluoromethylation approaches not only exhibit
high chemoselectivity for this transformation but also expand the substrate scope
that is difficult to access by known transition-metal-catalyzed methods, thus reflecting
the synthetic utility of these transformations.
Scheme 19 1,2-Aryltrifluoromethylation of alkenes with the trifluoromethyl radical
Following the increased interest in the trifluoromethyl radical strategy, Nevado and
co-workers described a new copper-catalyzed sequential trifluoromethylation, 1,4-aryl
migration, desulfonylation and C(sp2 )–N bond formation, involving conjugated tosyl amides and Togni’s reagent as the reaction
partners for the synthesis of trifluoromethyl-containing oxindoles (Scheme [20 ]).[24 ] The chemoselectivity depended on the N-substituent. The desired oxindoles were assembled
when N -alkyl tosyl amides were used. A crossover experiment was designed to determine whether
the aryl migration is an intra- or intermolecular process, and the results showed
that this method proceeds via intramolecular migration.
Scheme 20 Copper-catalyzed 1,2-aryltrifluoromethylation of alkenes through 1,4-aryl migration
and desulfonylation
They proposed that the copper catalyst seemed to activate Togni’s reagent, generating
a highly reactive trifluoromethyl- and copper(II)-containing radical intermediate
L which interacts with the activated alkene to give a new C(sp3 )−CF3 bond and α-alkyl radical intermediate M (Scheme [21 ]). A 5-ipso cyclization then takes place on the sulfonyl aromatic ring, generating aryl radical
N , followed by rapid desulfonylation to form the key amidyl radical intermediate O with a new C(sp2 )−C(sp3 ) bond. Hydrogen abstraction of amidyl radical O occurs to give the trifluoromethylated amide, a process that seems to be favored
for substrates with an aryl group (the substituent R2 ) on the nitrogen. In contrast, a more electron-donating alkyl moiety on the nitrogen
triggers the oxidation of the radical to give copper enolate P , and subsequent trapping by the aromatic ring leads to the oxindole.
Scheme 21 Possible mechanism for the 1,2-aryltrifluoromethylation of alkenes through 1,4-aryl
migration and desulfonylation
2.3
1,2-Carbonylarylation
Carbonyl C(sp2 )–H bonds are highly reactive chemical bonds that are widely utilized in synthesis,[25 ] and carbonyl-containing oxindoles are common structural motifs in pharmaceutical
agents and natural products as well as being versatile intermediates in organic synthesis.
Li and co-workers reported a metal-free 1,2-difunctionalization of alkenes with a
range of carbonyl C(sp2 )–H bonds, namely aldehydes, formates and formamides (Scheme [22 ]).[26 ] In the presence of tert -butyl hydroperoxide, the oxidative tandem couplings of activated alkenes with carbonyl
C(sp2 )–H bonds and aryl C(sp2 )–H bonds were carried out smoothly, offering 3-(2-oxoethyl)indolin-2-ones in good
yields.
Scheme 22 1,2-Carbonylarylation of alkenes with carbonyl C(sp2 )–H bonds
To understand the mechanism, inter- and intramolecular kinetic isotope experiments
were performed (Scheme [23 ]): the arylation step may be compatible with either the SE Ar mechanism or the free-radical mechanism because no kinetic isotope effect was observed
(kH
/kD
= 1.0). The free-radical mechanism was supported by the control experiments carried
out with radical inhibitors: a stoichiometric amount of radical inhibitor, such as
TEMPO or 2,6-di-tert -butylphenol, was added to the difunctionalization reaction mixture, and no reaction
took place. A large kinetic isotope effect (kH
/kD
= 5.0) was observed in the reaction of amide with N ,N -dimethylformamide and N ,N -dimethylformamide-d
7 , suggesting that the cleavage of the carbonyl carbon–hydrogen bond is the rate-limiting
step.
Accordingly, the radical mechanism outlined in Scheme [23 ] was proposed for this 1,2-carbonylarylation. The aldehydic hydrogen is easily abstracted
by an alkyloxy or hydroxy radical, generated in situ from tert -butyl hydroperoxide under heating, to yield aldehydic radical Q . Addition across the carbon–carbon double bond affords radical intermediate R , then intramolecular cyclization with an aryl ring takes place to give radical intermediate
S . Finally, abstraction of an aryl hydrogen by tert -butyl hydroperoxide delivers the 3-(2-oxoethyl)indolin-2-one.
Scheme 23 Control experiments and possible mechanism for the 1,2-carbonylarylation of alkenes
with carbonyl C(sp2 )–H bonds
Prompted by these results, and because primary alcohols can be easily oxidized into
the corresponding aldehydes, Li and co-workers turned their attention to the oxidative
tandem coupling of activated alkenes with primary alcohols. As expected, 1,2-carbonylarylation
of N -arylacrylamides with alcohols was achieved in the presence of iron(II) acetate and
tert -butyl hydroperoxide (Scheme [24 ]).[27 ] Notably, the desired oxindole was constructed in 28% yield even without the iron
catalyst.
Guo, Duan and Wang showed that carbonyl radicals were produced from the oxidative
decarboxylation of α-oxocarboxylic acids using the catalytic system comprised of silver
and potassium persulfate (Scheme [25 ]).[28 ] In the presence of silver nitrate and potassium persulfate, a wide range of carbonyl-containing
oxindoles were constructed in good to excellent yields through the radical decarboxylative
1,2-carbonylarylation of alkenes with easily available α-oxocarboxylic acids. This
transformation proceeded well under mild reaction conditions and exhibited excellent
functional-group tolerance.
Scheme 24 Iron-catalyzed 1,2-carbonylarylation of alkenes with primary alcohols
Scheme 25 Silver-catalyzed 1,2-acylarylation of alkenes with α-oxocarboxylic acids
A possible mechanism was postulated for this tandem reaction (Scheme [26 ]). Initially, the α-oxocarboxylic acid is converted into the corresponding aldehydic
radical Q , and the remaining steps are similar to those in the 1,2-carbonylarylation between
alkenes and carbonyl C(sp2 )–H bonds.[23 ]
Scheme 26 Possible mechanism for 1,2-acylarylation of alkenes with α-oxocarboxylic acids
In recent studies by Li, Du and co-workers[29a ] and by Chen, Yu and co-workers,[29b ] the alkoxycarbonyl radicals were formed readily by the oxidative cleavage of the
carbon–nitrogen bond of a carbazate (Scheme [27 ]). They used carbazates as easily accessible and safe alkoxycarbonyl radical precursors
for the 1,2-alkoxycarbonylarylation of N -aryl acrylamides. The method provides a general and practical method for the construction
of alkoxycarbonylated oxindoles. Moreover, the use of economical and environmentally
benign iron as the catalyst makes this transformation more sustainable and practical.
Scheme 27 Iron-catalyzed 1,2-alkoxycarbonylarylation of N -aryl acrylamides with carbazates
3
Synthesis of Oxindoles via Carboheterofunctionalization of Alkenes
3.1
1,2-Azidoarylation or 1,2-Arylnitration
The C(sp2 )–H oxidative radical coupling strategy is applicable to the carbo-heterofunctionalization
of alkenes with two type of nitrogen radicals: azidyl and nitro radical. In 2013,
Antonchick and co-workers reported an unprecedented metal-free azidoarylation of alkenes
with azidyl radicals that were generated by the oxidation of azidotrimethylsilane
in the presence of hypervalent iodine(III) reagents at ambient temperature (Scheme
[28 ]).[30 ] In the presence of phenyliodine bis(trifluoroacetate) and azidotrimethylsilane,
a variety of N -arylacrylamides delivered the corresponding azide-containing oxindoles in good yields.
It was noted that 2-oxindoles with an appended azide group could be used to create
further molecular complexity around the privileged scaffold of 2-oxindoles, or could
be applied for bioorthogonal transformation under physiological conditions.
Scheme 28 Metal-free azidoarylation of alkenes with azidotrimethylsilane
The reaction is thought to proceed through a double ligand exchange between phenyliodine
bis(trifluoroacetate) and azidotrimethylsilane to afford intermediate T (Scheme [29 ]). The latter is not stable and easily undergoes thermal homolytic cleavage to form
an azide radical, which then attacks the alkene to give radical U . Intramolecular trapping with the arene gives rise to intermediate V , which then undergoes rearomatization to produce the oxindole.
Scheme 29 Possible mechanism for the azidoarylation of alkenes with azidotrimethylsilane
Scheme 30 Possible mechanism for the silver-catalyzed azidoarylation of alkenes with azidotrimethylsilane
Around that same time, the Yang[31a ] and Jiao[31b ] research groups independently documented a new strategy for the formation of the
azidyl radical through the oxidation of azidotrimethylsilane with silver nitrate and
oxidizing reagents such as zirconium nitrate or cerium(IV) sulfate (Scheme [30 ]). Through their methods, various azide-containing oxindoles were prepared smoothly
in moderate to good yields.
Very recently, Zhang and Qiu reported a metal-free carboazidation of acrylamides with
sodium azide in the presence of potassium persulfate as oxidant. This transformation
exhibited excellent functional-group tolerance.[32 ]
Nitro compounds are important structural features of pharmaceuticals and functional
materials, as well as being versatile intermediates in synthesis.[33 ] A nitro radical for the 1,2-carbonitration of alkenes was first introduced by Yang
and co-workers in 2013 (Scheme [31 ]).[34 ] This protocol provided a new shortcut for the assembly of nitro-containing oxindoles,
in which the nitro radical is formed from the oxidation of sodium nitrite by potassium
persulfate.
Scheme 31 1,2-Arylnitration of alkenes with sodium nitrite
Jiao and co-workers tested the use of tert -butyl nitrite as the nitrogen dioxide source for the carbonitration of alkenes, and
were successful in accessing nitro-containing oxindoles under metal-free conditions
(Scheme [32 ]).[35 ] Mechanistic studies indicated that both the nitric oxide radical (· NO) and the nitrogen dioxide radical (· NO2 ) addition across the carbon–carbon double bond were involved in this transformation,
and that nitrogen dioxide radical addition occurred prior to nitric oxide radical
addition. Notably, this reaction was applicable to unactivated alkenes.
Scheme 32 Metal-free 1,2-arylnitration of alkenes with tert -butyl nitrite
3.2
1,2-Arylsulfonylation
The important roles of sulfur-containing compounds in pharmaceuticals and agrochemicals
have inspired chemists to continue developing mild and efficient carbon–sulfur bond-forming
methods.[36 ] A pioneering work on the difunctionalization of alkenes with sulfonyl radicals was
published in 2013 by Li, Xu and co-workers (Scheme [33 ]).[37 ] The oxidative 1,2-arylsulfonylation of activated alkenes with p -toluenesulfonyl hydrazine proceeded using potassium iodide as catalyst, THBP as oxidant
and 18-crown-6 as promoter, thus affording sulfonated oxindoles in satisfactory yields.
This method uses the readily available p -toluenesulfonyl hydrazine as sulfonyl source by way of a radical strategy, and represents
an environmentally benign access to oxindoles by using nontoxic potassium iodide as
catalyst and water as medium.
Scheme 33 1,2-Arylsulfonylation of activated alkenes with p -toluenesulfonyl hydrazine
Both potassium iodide and 18-crown-6 were proposed to accelerate the decomposition
of tert -butyl hydroperoxide into the tert -butoxy radical (Scheme [34 ]). The resultant abstraction of hydrogen from p -toluenesulfonyl hydrazine by the tert -butoxy radical generates a sulfonyl radical via the release of molecular nitrogen
from intermediate radical W . The addition of the sulfonyl radical to the alkene offers intermediate X , and subsequent intamolecular cyclization with the arene produces intermediate Y . Hydrogen abstraction of intermediate Y by tert -butyl hydroperoxide affords the sulfonated oxindole.
Scheme 34 Possible mechanism for the 1,2-arylsulfonylation of activated alkenes with p -toluenesulfonyl hydrazine
A similar conversion was subsequently illustrated by Kuang and co-workers, starting
from N -arylsulfonylacrylamides (Scheme [35 ]).[38 ] In the presence of copper(II) triflate and potassium persulfate, p -toluenesulfonyl hydrazine was converted into the arenesulfonyl radical, thus achieving
the 1,2-arylsulfonylation of N -arylsulfonylacrylamides through a sulfonylation, 5-ipso -cyclization, aryl migration, desulfonylation and amidyl radical cyclization cascade.
Scheme 35 1,2-Arylsulfonylation of activated alkenes with p -toluenesulfonyl hydrazine through aryl migration and desulfonylation
A example using sulfinic acids to form the sulfonyl radicals was developed by the
Wang research group (Scheme [36 ]).[39 ] An important feature of this strategy is that only potassium persulfate was employed
to oxidize the sulfinic acid to produce the sulfonyl radical. Direct 1,2-arylsulfonylation
of the N -arylacrylamide then led to the sulfonated oxindole.
Scheme 36 1,2-Arylsulfonylation of activated alkenes with sulfinic acids
Very recently, Wang and co-workers reported a silver-mediated 1,2-aryltrifluoromethylthiolation
of activated alkenes with [(trifluoromethyl)thio]silver in the presence of potassium
persulfate as oxidant (Scheme [37 ]).[40 ] This method allowed for the oxidative conversion of [(trifluoromethyl)thio]silver
into (trifluoromethyl)thio radical by the oxidant, and provided a facile route to
trifluoromethylthiol-containing oxindoles.
Scheme 37 Silver-catalyzed 1,2-aryltrifluoromethylthiolation of alkenes with [(trifluoromethyl)thio]silver
A possible mechanism involving a radical process was proposed for this reaction (Scheme
[38 ]). Initially, oxidation of [(trifluoromethyl)thio]silver by potassium persulfate
gives [(trifluoromethyl)thio]silver(II), which then forms the key (trifluoromethyl)thio
radical Z . The latter undergoes a sequential radical addition and cyclization with N -arylacrylamide to form the final oxindole by way of radical intermediates AA and AB .
Scheme 38 Possible mechanism for the silver-catalyzed 1,2-aryltrifluoromethylthiolation of
alkenes
3.3
1,2-Arylphosphorylation
Organophosphorus compounds are a prominent molecular class in organic chemistry and
are widely distributed in pharmaceuticals and agrochemicals; considerable effort has
been devoted to the development of new convenient and flexible methods for the formation
of carbon–phosphorus bonds.[41 ] The first application of the phosphine oxide radicals for the carbophosphorylation
of alkenes was reported in 2013 by Yang and co-workers (Scheme [39 ]).[42 ] A number of phosphorylated oxindoles were synthesized by using a catalytic system
comprised of silver nitrate and magnesium nitrate hexahydrate to trigger the radical
carbophosphorylation of N -arylacrylamides with phosphine oxides.
Scheme 39 Silver-catalyzed 1,2-arylphosphorylation of alkenes with phosphine oxides
Mechanistically, the Ph2 P(O)Ag intermediate AD , which is formed from the reaction of silver(I) with diphenylphosphine oxide, is
proposed to play a crucial role in the alkene 1,2-arylphosphorylation process (Scheme
[40 ]). It may take place through two paths: one proceeds by the formation of diphenylphosphinoyl
radical from AD and its addition across the alkene to produce AF (path A), the other involves the addition of AD itself to the carbon–carbon double bond, leading to intermediate AE which is then oxidized to AF . Both paths proceed from intermediate AF .
Scheme 40 Possible mechanism for the silver-catalyzed 1,2-arylphosphorylation of alkenes with
phosphine oxides
The Ph2 P(O) radical could also be formed from the oxidation of phosphine oxides by potassium
persulfate in the absence of a silver catalyst (Scheme [41 ]).[43 ] This arylphosphination of N -arylacrylamides with phosphine oxides was used to assemble various phosphorus-containing
oxindoles in high yields.
Scheme 41 Transition-metal-free 1,2-arylphosphorylation of alkenes with phosphine oxides
4
Conclusion
In the last five years, activated alkene 1,2-difunctionalization reactions involving
a C–H oxidative coupling process have been widely used in the synthesis of heterocyclic
compounds, in particular oxindoles and their derivatives. This review summarized recent
efforts along these lines. These new methods are triggered by carbon or heteroatom
radicals, thus easily incorporating many functional groups, including alkyl, hydroxyl,
carbonyl, trifluoromethyl, azidyl, nitro, sulfonyl, (trifluoromethyl)thio and phosphoryl
groups, into the oxindole framework. Owing to their high efficiency, high step- and
atom-economy, excellent functional-group tolerance and broad substrate scope, the
current C–H oxidative radical coupling reactions will have widespread applications
in the pharmaceutical, agrochemical and materials fields.
Despite significant progress in the use of C–H oxidative radical coupling for the
synthesis of oxindoles, oxidant dependence is very prominent in the alkene difunctionalization
transformations, and stoichiometric amounts of non-green oxidants, such as peroxides,
potassium persulfate, hypervalent iodines or tert -butyl nitrite, are necessary in all cases. Moreover, the substrate scope in many
cases is limited to activated alkenes, and the related mechanisms need to be explored
in more detail. Therefore, the development of new, efficient C–H oxidative radical
coupling strategies involving the use of green oxidants (e.g., O2 , hydrogen peroxide or other sustainable oxidants) is highly desirable. The important
opportunities and challenges in this field will involve determining how to achieve
selective coupling of unactivated alkyl or aryl C–H bonds. In addition, more new functional
radicals also need to be designed and discovered, in order to initiate research into
further unexplored C–H oxidative radical coupling methods.
