Difunctionalization of Acrylamides through C–H Oxidative ... · functionalization involving the intramolecular Heck coupling of o-haloanilines has been developed for accessing oxindoles

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R.-J. Song et al. ReviewSyn thesis

SYNTHESIS0 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 X© Georg Thieme Verlag Stuttgart · New York2015, 47, 1195–1209review

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Difunctionalization of Acrylamides through C–H Oxidative Radical Coupling: New Approaches to OxindolesRen-Jie Song Yu Liu Ye-Xiang Xie Jin-Heng Li*

State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan Univer-sity, Changsha 410082, P. R. of [email protected]

N

R2

O

R3

R1R4

H

N

R2

R3C

R1 O

C Z C

Y

R4

initiator = peroxide, K2S2O8, hypervalent iodine, t-BuONO

N

R2

R3Y

R1 O

R4

N

R2

R3C

R1 O

R4

H

N

R2

R3Y

R1 O

R4

H

Z = H, C, SO2Na, TMS, NHNH2

Y = N, S, PZ = TMS, Na, t-Bu, NHNH2, OH, H

initiator

Y Zinitiator

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Received: 31.12.2014Accepted after revision: 28.01.2015Published online: 31.03.2015DOI: 10.1055/s-0034-1379903; Art ID: ss-2014-e0784-r

Abstract Oxindoles are an important class of heterocycles with uniquebiological activity that are found prevalently in numerous natural prod-ucts and biologically active compounds. For these reasons, much atten-tion has been given to the development of efficient methods for thepreparation of such compounds. Traditionally, the practical approachesfor the synthesis of oxindoles include the condensation of anilines withcarbonyl compounds, such as diethyl ketomalonate, oxalyl chloride, orchloral hydrate, mediated by strong acids or bases. Recently, a step- andatom-economic C–H activation strategy was illustrated to access oxin-doles through the difunctionalization of activated alkenes for these pur-poses. However, many of these transformations suffer from the cost ofthe transition-metal catalytic systems and/or limited substrate scope.In this review, we describe the recent studies of the difunctionalizationof activated alkenes for the synthesis of diverse functionalized oxindolesthat involves C–H oxidative radical coupling in the presence of an oxi-dant. These transformations are initiated either by the carbon radicalresulting from the split of the carbon–hydrogen bond (1,2-dicarbofunc-tionalization) or by the carbon or heteroatom radical arising from thecleavage of the carbon–heteroatom (1,2-dicarbofunctionalization) orheteroatom–heteroatom bond (1,2-carboheterofunctionalization). Im-portantly, these C–H oxidative radical coupling transformations aregenerally performed with readily available oxidants and/or inexpensiveiron or copper catalysts under neutral reaction conditions.1 Introduction2 Synthesis of Oxindoles via 1,2-Dicarbofunctionalization of Alkenes2.1 1,2-Alkylarylation2.2 1,2-Aryltrifluoromethylation2.3 1,2-Carbonylarylation3 Synthesis of Oxindoles via 1,2-Carboheterofunctionalization of Alkenes3.1 1,2-Azidoarylation or 1,2-Arylnitration3.2 1,2-Arylsulfonylation3.2 1,2-Arylphosphorylation4 Conclusion

Key words oxindoles, difunctionalization, C–H oxidative radical cou-pling, radical reaction, alkenes

1 Introduction

Oxindoles, an important class of heterocycles with awide range of biological properties, are a key structural mo-tif in numerous natural products and biologically activecompounds (Figure 1).1 Additionally, oxindoles are import-ant synthetic intermediates that have elicited considerablesynthetic interest principally because of their importantapplications in asymmetric synthesis, library design anddrug discovery.2 As a result, efficient methods for oxindolesynthesis have been the subject of extensive studies.Among these methods, the recently developed transition-metal-catalyzed or metal-free oxidative difunctionalization

Figure 1 Examples of important oxindoles

NO

SO2Ar

ClR2NCOO

MeO

NO

H2N

O

Cl

HOF3C

NH

O

MeO

MeN

NMe

O

NH

O

O

alstonisine

horsfiline

H

SM-130686

NEt2·HCl

NH

O

N

MeNHN

H

HO

strychnofoline

NH

O

N

spirotryprostain A

MeO

N

O

O H

H

© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1195–1209

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of activated alkenes is a particularly fascinating approach tobuilding diversely functionalized oxindoles, owing to itshigh step- and atom-economy, and easy incorporation ofmany functional groups (e.g., cyano, carbonyl, hydroxyl,phosphoryl, trifluoromethyl, azidyl, and nitro) into the ox-indole framework.

The difunctionalizations of alkenes have been signifi-cantly developed and have already played vital roles in or-ganic syntheses.3 In particular, the applications of difunc-tionalization of alkenes for the synthesis of important bio-

active heterocyclic compounds has proven to be a powerfulalternative to the traditional approaches. Recent studieshave illustrated that these transformations, such as arylal-kylation, aminooxygenation, diamination, and dioxygen-ation of unsaturated hydrocarbons, could be used efficient-ly to allow the formation of diverse chemical bonds. In1999, the Grigg research group reported a palladium-cata-lyzed difunctionalization of alkenes with aryl iodides andcarbon monoxide through an intramolecular Heck–carbon-ylation reaction for the synthesis of oxindoles and their de-

ly p

roh
Biographical Sketches
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Ren-Jie Song was born in
1983. He received his B.S. in2006 from College of Chemistryand Chemical Engineering atHunan Normal University (P. R.of China). Then he continued hisstudies at the same university

and obtained his Ph.D. in 2011under the supervision of Profes-sor Jin-Heng Li. In 2011, hemoved to Hunan University withProfessor Jin-Heng Li as a post-doctoral follow. In 2013, he be-came a research assistant in

College of Chemistry andChemical Engineering at HunanUniversity. His current researchinterests include the develop-ment of new synthetic method-ologies and heterocyclesynthesis.

Yu Liu was born in Hunan, P. R.of China, in 1985. He receivedhis B.S. (in 2008) and M.S. de-grees (in 2011) from College ofChemistry and Chemical Engi-

neering at Hunan Normal Uni-versity. He is currently studyingtowards a Ph.D. at Hunan Uni-versity under the supervision ofProfessor Jin-Heng Li. His cur-

rent research interests are fo-cused on 1,n-enyne oxidativeradical cyclization reactions.

Ye-Xiang Xie was born in Hu-nan, P. R. of China, in 1975. Shereceived her B.S. degree in 1999from Hunan Agricultural Univer-sity and M.S. degree in 2007from Hunan Normal University.

From 2010 to 2014, she under-took Ph.D. studies at HunanUniversity under the supervi-sion of Professor Jian-Nan Xiangand Professor Jin-Heng Li. Cur-rently, she is a lecturer at Hunan

University. Her research inter-ests are focused on transition-metal-catalyzed C–H oxidativearylation reactions.

Jin-Heng Li was born in Hunan,P. R. of China, in 1971. He re-ceived his B.S. in 2006 from Col-lege of Chemistry and ChemicalEngineering at Hunan NormalUniversity. From 1997 to 2010,he studied at Guangzhou Insti-tute of Chemistry, ChineseAcademy of Sciences, where heobtained his M.S. degree underthe supervision of Professor

Huanfeng Jiang. After complet-ing his Ph.D. studies at Universi-ty of Science and Technology ofChina in 2013 under the super-vision of Professor HuanfengJiang and Professor Ming-CaiChen, he continued his studiesas a postdoctoral fellow withProfessor Dan Yang at the Uni-versity of Hong Kong (P. R. ofChina). In 2002, he joined the

faculty at Hunan Normal Uni-versity as a professor. Since2011, he has worked as a pro-fessor in College of Chemistryand Chemical Engineering atHunan University. His currentresearch interests are focusedon C–H oxidative coupling reac-tions, cross-coupling reactions,and cycloaddition reactions.


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rivatives in good yield (Scheme 1).4 Following on these re-sults, a similar version of palladium(0)-catalyzed alkene di-functionalization involving the intramolecular Heckcoupling of o-haloanilines has been developed for accessingoxindoles and their derivatives.5

In 2007, the Zhu research group expanded the palladi-um-catalyzed domino intramolecular Heck coupling proto-col to assemble 3-substituted 3-cyanomethyl-2-oxindoles(Scheme 2),6 in which K4[Fe(CN)6] was employed as a trap-ping agent for the π-alkylpalladium intermediate. The reac-tion was applicable to a wide range of o-haloaniline sub-strates with different electronic properties. In addition, aconcise synthesis of physostigmine utilizing this key domi-no process for the construction of the core framework wasaccomplished. Importantly, an enantioselective version ofthis domino process was also examined. However, thesetransformations also suffer from the cost of the palladium–ligand catalytic system and the requirement of expensiveand unavailable o-haloaniline substrates.

To make the palladium-catalyzed domino methodsmore useful, Neuville and Zhu and their co-workers discov-ered a new palladium(II)/(diacetoxy)iodobenzene catalyticsystem for use in the domino cyclization of ortho-unsubsti-tuted anilines through the C(sp2)–H oxidative Heck-typecoupling (Scheme 3).7 This method represents a new palla-dium-catalyzed oxidative carboheterofunctionalization ofortho-unsubstituted anilines via C(sp2)–H oxidative activa-tion, and provides a facile and highly atom-economic accessto oxindoles.

The Liu research group described new palladium-cata-lyzed oxidative difunctionalization reactions of alkeneswith acetonitriles8a or trimethyl(trifluoromethyl)silane8b

for the synthesis of functionalized oxindoles through C–Hoxidative activation under neutral conditions (Scheme 4).

The mechanism for the palladium-catalyzed oxidative1,2-difunctionalization of alkenes with acetonitriles involv-ing a palladium(II)/palladium(IV) catalytic cycle, outlined in

Scheme 5, was proposed on the basis of kinetic isotopic ef-fect studies. The reaction is initiated by coordination of theolefin to palladium(II) (intermediate A), followed by nucleo-philic attack of the tethered arene to give the palladiumcomplex B. The C(sp3)–H bond activation of the acetonitriletakes place in the presence of di(pivaloyloxy)iodobenzeneand silver fluoride, thus generating the palladium(IV) com-plex C. Finally, reductive elimination of intermediate C af-fords the desired oxindole. The formation of the palladiumcomplex B is supported by HRMS analysis.

These palladium-catalyzed oxidative difunctionaliza-tion transformations involving C–H activation are more at-tractive because it extends the substrate scope to ortho-un-substituted anilines and can introduce additional function-al groups into the oxindole framework. However, the use ofthe highly expensive palladium–hypervalent iodine reagentsystems still limits the applicability of the reaction. Thus,the development of new C–H oxidative coupling strategiesfor alkene difunctionalization, especially using inexpensivemetal catalysts or no metal at all, is desirable.

Scheme 1 Palladium-catalyzed domino intramolecular Heck–carbon-ylation reaction

N

R

O+ CO + HN n

Pd(OAc)2 (10 mol%)Ph3P (20 mol%)

Tl2CO3 (2 equiv)toluene, 95 °C

57–69%N

R

O

NO n

R = Me, Bn

Pd(0)

N

R

OPdI CO

N

R

O

OPdI

n = 1–3

I

Scheme 2 Possible mechanism for the palladium-catalyzed domino in-tramolecular Heck–cyanation reaction.

N

R

O+

Pd(OAc)2 (15 mol%)

Na2CO3 (1 equiv)DMF, 120 °C

R = Me, Bn

Pd(OAc)2

L, base

Pd0Ln

R1

K4[Fe(CN)6]

N

CN

R

OR1

I

N O

I

N O

LnIPd

N

PdLnI

O

N

PdLnCN

O

N

CN

O

Scheme 3 Palladium-catalyzed oxidative 1,2-carboheterofunctional-ization of alkenes

N O

R2

R1

NHTs

H

Pd(OAc)2

PhI(OAc)2

R1

N

NHTs

R2

OOAc

PdCl2R1

N

NTs

O

R2

AcOH, 100 °CR1 = H, R2 = alkyl

43–85%

MeCN, 80 °CR1, R2 = alkyl

37–58%


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Scheme 5 Possible mechanism for the palladium-catalyzed oxidative alkylarylation of alkenes with acetonitriles

This review focuses on the construction of oxindoles bythe difunctionalization of activated alkenes through C–Hoxidative radical coupling using inexpensive iron or coppercatalysts as well as under metal-free conditions. It shouldbe noted that the mechanisms of these alkene difunctional-ization reactions through C–H oxidative radical couplingare still unclear and remain to be studied. These transfor-mations are classified, according to the difunctionalizationprocess, into two types (Scheme 6): synthesis of oxindolesvia 1,2-dicarbofunctionalization of alkenes (route a: the ad-dition of carbon radicals across the carbon–carbon doublebond, followed by arylation), and synthesis of oxindoles via

1,2-carboheterofunctionalization of alkenes (route b: theaddition of heteroatom and carbon radicals across the car-bon–carbon double bond, followed by arylation; heteroat-oms include N, S and P). The scope and limitations of thesedifunctionalization reactions are discussed, as well as theirmechanisms.

Scheme 6 Difunctionalization of activated alkenes through C–H oxida-tive radical coupling

2 Synthesis of Oxindoles via 1,2-Dicarbo-functionalization of Alkenes

It is well known that carbon–carbon bond-forming re-actions are the most common processes in chemistry be-cause they are important in the production of many usefulchemicals such as pharmaceuticals and plastics.9 Among

Scheme 4 Palladium-catalyzed oxidative 1,2-difunctionalization of alkenes with acetonitriles or trimethyl(trifluoromethyl)silane

N

R2

O

R3

R1

Pd(OAc)2 (5 mol%)

PhI(OPiv)2 (1.1 equiv)AgF (4 equiv), MgSO4 (40 mg)

MeCN (2 mL), 80 °C

N

R2

R3

R1+ R4 CN

CN

O

N

Ph

CN

O

98%

N

CN

O

98%

Cl

N

CN

O

92%

OAc

N

CN

O

83% (dr = 1.1:1)

N

N N

N(7.5 mol%)

selected products

N

Ph

CF3

O

82%

N

CF3

O

89%

I

N

CF3

O

81%

OAc

N

CF3

O

72%

N

R2

O

R3

R1

Pd(OAc)2 (5 mol%)Yb(OTf)3 (20 mol%)

L (15 mol%)

PhI(OAc)2 (2 equiv)CsF, EtOAc, r.t.

N

R2

O

R3CF3

R1TMSCF3+

selected products

N

OO

N

L

OMe

Ph

NO

CF3

81%

R4

H

H

PdIIL2(OAc)2

N

R2

O

R3

R1

H

PdL2(OAc)

N

R2

O

R3

R1

H

+

N

R2

R3PdIIL2

R1 O

+

A

N

R2

R3

R1

CN

OR4

N

R2

R3PdIVL2

R1 O

CN

X

X = OPiv or F

HOAcPhI(OPiv)2AgF, MeCN

B

C

N

R2

O

R3

R1R4

H

N

R2

R3C

R1 OC

Y

R4

a

b

N

R2

R3Y

R1 O

R4

N

R2

R3C

R1 O

R4

H

N

R2

R3Y

R1 O

R4

H

Y = N, S, P


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the numerous reported carbon–carbon bond-formationmethods, those involving C–H functionalization are partic-ularly significant and remain challenging.

2.1 1,2-Alkylarylation

Encouraged by the results of the Neuville/Zhu and Liuresearch groups, Li and co-workers chose to use ethers –compounds containing the activated C(sp3)–H bond adja-cent to the oxygen atom – in the presence of oxidants (oftenperoxides) to realize the 1,2-difunctionalization of alkenes(Scheme 7).10 In the presence of iron(III) chloride, tert-butylhydroperoxide (TBHP) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), a variety of activated alkenes reacted successful-ly with an aryl C(sp2)–H bond and a C(sp3)–H bond adjacentto a heteroatom, giving functionalized 3-(2-oxoethyl)indo-lin-2-ones in moderate to high yields. This oxidative 1,2-al-kylarylation was catalyzed by the economical and environ-mentally benign metal iron, and was the first example ofmetal-catalyzed 1,2-difunctionalization of an alkene withan aryl C(sp2)–H bond and a C(sp3)–H bond adjacent to aheteroatom for the simultaneous formation of two carbon–carbon bonds. Interestingly, the dual C–H oxidative radicalcoupling protocol was applicable to thioethers and tertiaryalkylamines 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 kineticisotope effect (kH/kD = 1.0) in the intramolecular or inter-molecular experiments (Scheme 8). These observations im-

plied that the iron-catalyzed alkene oxidative difunctional-ization may proceed via either the SEAr mechanism or thefree-radical mechanism. The results of the experiment withtetrahydrofuran and tetrahydrofuran-d8 (kH/kD = 1.0) sup-ported the free-radical mechanism. To verify this mecha-nism, two radical inhibitors, TEMPO and 2,6-di-tert-butyl-phenol, were added to the difunctionalization reaction: astoichiometric amount of radical inhibitor resulted in noconversion of amide; however, diethyl ether was trans-formed by TEMPO into 1-(1-ethoxyethoxy)-2,2,6,6-te-tramethylpiperidine in 91% yield, suggesting that the reac-tion includes a diethyl ether radical.

Scheme 8 Control experiments

Consequently, Li and co-workers proposed the radicalmechanism outlined in Scheme 9 for the iron-catalyzed1,2-alkylarylation of alkenes with C(sp3)–H bonds adjacentto a heteroatom. Initially, tert-butyl hydroperoxide is splitby iron(II) into a tert-butoxy radical and a hydroxy-iron(III)species. In the presence of a tert-butoxy radical, diethylether, with its C(sp3)–H bonds adjacent to oxygen, is readilytransformed into alkyl radical intermediate D. Addition ofalkyl radical intermediate D to the carbon–carbon doublebond of N-arylmethacrylamide results in the formation ofradical intermediate E, which undergoes the intramolecularcyclization with the C(sp2)–H bond in the N-aryl ring togenerate radical intermediate F. Finally, hydrogen abstrac-tion by the hydroxy-iron(III) species takes place to affordthe oxindole.

The Guo and Duan11a and the Liang11b research groupshave independently reported metal-free tert-butyl hydro-peroxide mediated oxidative hydroxyalkylarylation of acti-vated alkenes with C(sp3)–H bonds adjacent to a hydroxygroup (secondary or tertiary alcohols) for the assembly ofhydroxy-containing oxindoles (Scheme 10). Mechanisticstudies revealed that the α-hydroxy carbon radical is ini-tially formed from the α-C(sp3)–H bond cleavage, followedby intramolcular cyclization involving the aromatic C(sp2)–H radical coupling. Notably, the obtained hydroxy-contain-ing oxindoles can be used for further transformations togive diverse indole-alkaloid structural motifs.

Y

Y = O, S, N

H

+

FeCl3 (5 mol%)DBU (10 mol%)TBHP (2 equiv)

benzene120 °C, Ar

selected products

85% 78%

52%

76% (dr = 2.2:1)

51%40%

N

R2

O

R3

R1

HN

R2

R3

R1

Y

O

R4

R4

N

O

O

NO

O

NO

O

O

NO

O

NO

S

NO

N

77%

N

O

O

81%

N

PhO

O

intermolecular KIE experiment intramolecular KIE experiment

N O+

kH/D = 1

N O

D

kH/D = 1

N O+

THF

+

THF-d8

FeCl3 (5 mol%)DBU (10 mol%)TBHP (2 equiv)

benzene, 120 °C, ArkH/D = 1

N

R

O

NO

D

H D

D

D

D

H

O

(D)H(D)H H(D)

H(D)H(D)

(D)H H(D)

78%


1200


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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 oxi-dative radical coupling protocol to simple benzylic C(sp3)–Hbonds. As expected, in the absence of metal catalysts, thereactions of activated alkenes with benzylic C(sp3)–H bondsand di-tert-butyl peroxide (DTBP) were successful, albeitwith lower yields (Scheme 11).12 It was found that Lewisacids could improve the reaction, and iridium(III) chloridewas preferred. Meanwhile, the Guo and Duan researchgroup reported a similar version of the 1,2-alkylarylation ofalkenes with benzylic C(sp3)–H bonds using a catalytic sys-tem comprised of copper(I) oxide and tert-butyl peroxy-benzoate (TBPB).13

A novel copper-catalyzed oxidative 1,2-alkylarylation ofalkenes with a range of simple alkanes, including cyclic al-kanes, linear alkanes and arylmethanes, by using dicumylperoxide (DCP) as oxidant has been reported by Liu and co-workers (Scheme 12).14 This method not only provided auseful method for the synthesis of alkyl-substituted oxin-doles, but also presented a new strategy for selective func-tionalization of simple alkanes by way of a free-radical cas-cade process.

Remarkably, Guo, Duan and Wang documented that al-kyl radicals could be generated by C–H oxidative cleavagewith a new oxidative system, comprised of silver nitrateand potassium persulfate, that was thus not limited to per-oxide oxidants (Scheme 13).15 In this reaction, the 1,2-alkyl-arylation of activated alkenes with the α-C(sp3)–H bonds of1,3-dicarbonyl compounds was successful in furnishing ox-indoles in good yields. Notably, the same reaction condi-tions were also extended to the reaction with simple ke-tones.

Scheme 9 Possible mechanism for the Fe-catalyzed 1,2-alkylarylation of alkenes with a C(sp3)–H bond adjacent to a heteroatom

tBuOOHO

tBuOH

O

Fe2+Ln Fe3+(OH)Ln

L = DBU N O

N O

O

tBuO

H

HN

O

ON

O

O

H

EF

D

+N

R2

O

R3

R1

HN

R2

R3

R1 O

R4

R4TBHP (2 equiv)

100 °C

OH

R5R6

R5

OH

R6

2° and 3° alcoholsR5, R6 = alkylR1 = alkyl, ester

R2 = H, alkylR3 = alkylR4 = H

24–91%Scheme 11 1,2-Alkylarylation of alkenes with benzylic C(sp3)–H bonds

+

selected products

N

R2

O

R3

R1

HN

R2

R3

R1

R5

OAr

R4

R4

NO

NO

NO

Ar

R5H

IrCl3 (3 mol%)DTBP (1.2 equiv)

120 °C

83% (without IrCl3: 53%) 86% 73%

79% 77% 68%

N

NO

S

NO

NO

Scheme 12 1,2-Alkylarylation of alkens with simple alkanes

93% 90%

83%

H

+

selected products

N

R2

O

R3

R1

H

N

R2

R3

R1 O

R4

R4 Cu2O (5 mol%)DCP (3 equiv)

110 °C

NO

NO

NO

NO

Ph

Cl

66% (1/2/3 = 1:6:4)

1

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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 pro-ceeds through a sequential intermolecular radical additionand intramolecular radical substitution (Scheme 14). Withthe aid of silver nitrate and potassium persulfate, one of theα-C(sp3)–H bonds of the 1,3-dicarbonyl compound is splitinto alkyl radical intermediate G via a single-electron-transfer (SET) process, followed by addition across thealkene to produce intermediate H. Cyclization of H occurs toafford intermediate I. Finally, hydrogen-abstraction of in-termediate I with the silver catalyst gives the desired oxin-dole.

Scheme 14 Possible mechanism for the silver-catalyzed 1,2-alkylaryla-tion of alkenes with 1,3-dicarbonyl compounds

They subsequently found that the alkyl radical interme-diate G could be formed from the oxidation of 1,3-dicarbon-yl compounds with potassium persulfate in the absence ofsilver salts, thus extending the method to build diverselyfunctionalized spirooxindoles (Scheme 15).16 In the pres-ence of potassium persulfate, hydroxymethylacrylamidessuccessfully underwent the oxidative spirocyclization with1,3-dicarbonyl compounds leading to the desired spirooxin-doles. This process exhibited significant functional-grouptolerance and high atom-economy.

Scheme 15 Silver-free oxidative alkylspirocarbocyclization of hy-droxymethylacrylamides with 1,3-dicarbonyl compounds

The 1,2-alkylarylations of alkenes with other carbonradicals that are not generated from the cleavage of the C–Hbonds have also been extensively explored. The singleC(sp2)–H oxidative radical coupling initiated by other car-bon radicals are particularly fascinating because they opena new opportunity to incorporate various functional groupsinto the oxindole system through a radical strategy. In 2012,the Liu research group established a new radical strategyfor the introduction of alkyl groups into the oxindole sys-tem by the decarboxylation of the (dialkylcarbonyloxyio-do)benzene [PhI(OCOR)2] (Scheme 16).17 The resultsshowed that the addition of an organocatalyst significantlyimproved the reaction yield. The reason may be that or-ganocatalysts can stabilize radical intermediates J and K,and make the deprotonation of intermediate K successful.

Scheme 16 1,2-Alkylarylation of alkenes with (dialkylcarbonyloxy-iodo)benzenes

+

selected products

N

R2

O

R3

R1

H

N

R2

R3

R1 O

88% 94% (dr = 1.3:1)

80% 96% (dr = 1:1)

O

R5

OR4

R5

AgNO3 (5 mol%)K2S2O8 (1 equiv)

H2O, 50 °C

O

R4

O

NO

O

O

NO

O

OPh

NO

NO

O

OEt

OO

OH

N O N O

H H

AgNO3K2S2O8 OO

O

O

NO

H

NO

Ag(II)

Ag(I)

O

O

OO

G

O

O

H

H

H I

+N

R2

O

R1

H

R3

O

R4

OK2S2O8 (2 equiv)

MeCN–H2O (1:1)50 °C N

O

R2

O

R3R4

O

R1

OH

R1 = alkyl, aryl, esterR2 = alkyl

R3, R4 = alkyl26–94%

N

R2

O

R3

R1

H

PhI(OCOR)2

CaCO3, addtivePhOMe, 110 °C N

R2

R3R

R1 Oorganocatalyst

NN

organocatalystR = alkyl

PhI(OCOR)2heat

PhI + CO2

R

N

R2

O

R3

R1

H

R

N

R2

R3R

R1 O

H+

H

KJ

R1 = alkyl, PhR2 = R3 = Me

47–86%


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Recently, the Zhu research group merged visible-lightphotoredox catalysis with C–H oxidative radical coupling toachieve 1,2-alkylarylation with alkyl acids, in which oxida-tive decarboxylation of the alkyl acid by (diacetoxy)iodo-benzene produced the alkyl radical (Scheme 17).18 Themethod was shown to be general and applicable to a rangeof readily available primary, secondary and tertiary aliphat-ic carboxylic acids. For example, bioactive lithocholic acidwas a viable substrate for the tandem decarboxylation and1,2-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 cou-pling

Peroxides are usually used as the radical initiators or ox-idants in organic synthesis, and are easily decomposed intodifferent radical species under heating. However, methodsto trap the radical species from peroxides are scare. TheLi19a and Cheng19b research groups independently reportedthat peroxides as alkyl sources underwent the 1,2-alkylary-lation with activated alkenes (Scheme 18). The method al-lowed 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 animportant pharmacophore that can enhance the metabolicstability, lipophilicity, and bioavailability of the parent mol-ecule.20 Considerable efforts have been paid to the develop-ment of methods for the incorporation of the trifluoro-methyl group into bioactive molecules. As previously men-tioned (Scheme 4), in 2012, Liu and co-workers reported apalladium-catalyzed oxidative aryltrifluoromethylation ofactivated alkenes for the construction of a variety of bioac-tive molecules containing trifluoromethylated oxindolemoieties. The protocol included trimethyl(trifluorometh-yl)silane with cesium fluoride as the source of the trifluoro-methyl group, and (diacetoxy)iodobenzene as oxidant.8b

Their preliminary mechanistic studies indicated that the re-action proceeds through initial arylpalladation of thealkene, followed by sequential oxidation and reductiveelimination of C(sp3)−trifluoromethylpalladium(IV) speciesto provide the oxindole products.

In recent years, much attention has been given to theuse of the trifluoromethyl radical in the preparation of tri-fluoromethyl-containing compounds; however, successfulexamples are rare. In light of this, the 1,2-aryltrifluoro-methylation of alkenes with the trifluoromethyl radical hasbeen developed using different trifluoromethyl radical re-sources, such as sodium triflinate (the Langlois reagent)and trimethyl(trifluoromethyl)silane (Scheme 19).21 Inter-estingly, Tan and co-workers expanded the scope ofreagents to include zinc difluoromethanesulfinate(ZnSO2CF2H) for the synthesis of difluoromethyl-containingoxindoles.22 The Wang research group also employed iodo-difluoromethyl phenyl sulfone (PhSO2CF2I) to generate the(phenylsulfonyl)difluoromethyl radical to access (phenyl-sulfonyl)difluoromethyl-containing oxindoles using thegreener combination of ferrocene as catalyst and hydrogenperoxide as oxidant.23 Notably, these radical 1,2-aryltrifluo-romethylation approaches not only exhibit high chemose-lectivity for this transformation but also expand the sub-strate scope that is difficult to access by known transition-metal-catalyzed methods, thus reflecting the synthetic util-ity of these transformations.

Scheme 19 1,2-Aryltrifluoromethylation of alkenes with the trifluoro-methyl radical

N

R2

O

R3

R1

H

DMF, r.t.visible light N

R2

R3R4

R1 O

R4 = alkyl

+ R4 COOH

PhI(OAc)2fac-Ir(ppy)3

H

H H

AcO

R

N

O

DMF, r.t.visible light

N O

HPhI(OAc)2fac-Ir(ppy)3

HO2C

= R

R1, R3 = alkylR2 = alkyl, Ph

48–90%

52%

N

R2

O

R3

R1

HN

R2

R3R

R1 O

alkyl peroxide

our conditions: Fe(OAc)2, DABCO, DMSO, 120 °C 46–66%Cheng conditions: FeCl2, benzene, 135 °C 49–84%

R = Me, EtR1, R2 = alkylR3 = alkyl, Ph

O

Me

R5

Me

O R6

Fe(OAc)2 (5 mol%)DABCO (10 mol%)

DMSO, Ar, 120 °C

62% 66%63%

N

R2

O

R3

R1R4

HN

R2

R3Me

R1 O

R4

N

R2

Me

O

N

Ph Me

O

N

Me

O

Phselected products

N

Et

O

36%

N

R2

O

R3

R1

HN

R2

R3CF2R

R1 O+ CF2R

NaSO2CF3/CuCl/TBHP (the Lei group)

NaSO2CF3/K2S2O8 (the Wang group)

NaSO2CF3/Cu(NO3)2/TMEDA/TBHP (the Lipshutz group)

TMSCF3/PhI(OAc)2/base(the Fu/Zou group and theTan/Liu group)

NaSO2CF3 or [ZnSO2CF2H)2]/AgNO3/(NH4)2S2O8 (the Tan group)

PhSO2CF2I/FeCp2/H2O2(the Wang group)


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Following the increased interest in the trifluoromethylradical strategy, Nevado and co-workers described a newcopper-catalyzed sequential trifluoromethylation, 1,4-arylmigration, desulfonylation and C(sp2)–N bond formation,involving conjugated tosyl amides and Togni’s reagent asthe reaction partners for the synthesis of trifluoromethyl-containing oxindoles (Scheme 20).24 The chemoselectivitydepended on the N-substituent. The desired oxindoles wereassembled when N-alkyl tosyl amides were used. A cross-over experiment was designed to determine whether thearyl migration is an intra- or intermolecular process, andthe results showed that this method proceeds via intramo-lecular 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 acti-vate Togni’s reagent, generating a highly reactive trifluoro-methyl- and copper(II)-containing radical intermediate Lwhich interacts with the activated alkene to give a newC(sp3)−CF3 bond and α-alkyl radical intermediate M(Scheme 21). A 5-ipso cyclization then takes place on thesulfonyl aromatic ring, generating aryl radical N, followedby rapid desulfonylation to form the key amidyl radical in-

termediate O with a new C(sp2)−C(sp3) bond. Hydrogen ab-straction of amidyl radical O occurs to give the trifluoro-methylated amide, a process that seems to be favored forsubstrates with an aryl group (the substituent R2) on the ni-trogen. In contrast, a more electron-donating alkyl moietyon the nitrogen triggers the oxidation of the radical to givecopper enolate P, and subsequent trapping by the aromaticring leads to the oxindole.

2.3 1,2-Carbonylarylation

Carbonyl C(sp2)–H bonds are highly reactive chemicalbonds that are widely utilized in synthesis,25 and carbonyl-containing oxindoles are common structural motifs inpharmaceutical agents and natural products as well as be-ing versatile intermediates in organic synthesis. Li and co-workers reported a metal-free 1,2-difunctionalization ofalkenes with a range of carbonyl C(sp2)–H bonds, namelyaldehydes, formates and formamides (Scheme 22).26 In thepresence of tert-butyl hydroperoxide, the oxidative tandemcouplings of activated alkenes with carbonyl C(sp2)–Hbonds and aryl C(sp2)–H bonds were carried out smoothly,offering 3-(2-oxoethyl)indolin-2-ones in good yields.

To understand the mechanism, inter- and intramolecu-lar kinetic isotope experiments were performed (Scheme23): the arylation step may be compatible with either theSEAr mechanism or the free-radical mechanism because nokinetic isotope effect was observed (kH/kD = 1.0). The free-radical mechanism was supported by the control experi-ments carried out with radical inhibitors: a stoichiometricamount of radical inhibitor, such as TEMPO or 2,6-di-tert-butylphenol, was added to the difunctionalization reactionmixture, and no reaction took place. A large kinetic isotopeeffect (kH/kD = 5.0) was observed in the reaction of amide

SO O

N

O

R2

O

N

H

R2

CF3

R1

R1

H

N

R2

CF3

R1 O

R2 = alkyl

R2 = aryl

2,2'-bipyridine

OIF3C

O Cu(MeCN)3PF6

70–75%

40–85%

Cu2O

Scheme 21 Possible mechanism for the 1,2-aryltrifluoromethylation of alkenes through 1,4-aryl migration and desulfonylation

OIF3C

O[CuI]

ICF3

CO2[CuII]

SO O

N

O

R2

R1

H

[CuII]

SO O

N

O

R2

R1

HCF3

– SO2

O

N

H

CF3

R1

O

N

R2

CF3

R1

R2

R2 = aryl

R2 = alkyl

N

S

R2 O

CF3

R1O

O

[CuII]N

R2

CF3

R1 O

F3COCu

N

R2

R1

[CuI]

Togni's reagent LM N

O

P


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with N,N-dimethylformamide and N,N-dimethylforma-mide-d7, suggesting that the cleavage of the carbonyl car-bon–hydrogen bond is the rate-limiting step.

Accordingly, the radical mechanism outlined in Scheme23 was proposed for this 1,2-carbonylarylation. The aldehy-dic hydrogen is easily abstracted by an alkyloxy or hydroxyradical, generated in situ from tert-butyl hydroperoxide un-der heating, to yield aldehydic radical Q. Addition across thecarbon–carbon double bond affords radical intermediate R,then intramolecular cyclization with an aryl ring takesplace to give radical intermediate S. Finally, abstraction ofan aryl hydrogen by tert-butyl hydroperoxide delivers the3-(2-oxoethyl)indolin-2-one.

Prompted by these results, and because primary alco-hols can be easily oxidized into the corresponding alde-hydes, Li and co-workers turned their attention to the oxi-dative tandem coupling of activated alkenes with primaryalcohols. As expected, 1,2-carbonylarylation of N-arylacryl-amides with alcohols was achieved in the presence ofiron(II) acetate and tert-butyl hydroperoxide (Scheme 24).27

Notably, the desired oxindole was constructed in 28% yieldeven without the iron catalyst.

Guo, Duan and Wang showed that carbonyl radicalswere produced from the oxidative decarboxylation of α-oxocarboxylic acids using the catalytic system comprised ofsilver and potassium persulfate (Scheme 25).28 In the pres-ence of silver nitrate and potassium persulfate, a widerange of carbonyl-containing oxindoles were constructed ingood to excellent yields through the radical decarboxylative1,2-carbonylarylation of alkenes with easily available α-oxocarboxylic acids. This transformation proceeded wellunder mild reaction conditions and exhibited excellentfunctional-group tolerance.

A possible mechanism was postulated for this tandemreaction (Scheme 26). Initially, the α-oxocarboxylic acid isconverted into the corresponding aldehydic radical Q, andthe remaining steps are similar to those in the 1,2-carbonyl-arylation between alkenes and carbonyl C(sp2)–H bonds.23

Scheme 22 1,2-Carbonylarylation of alkenes with carbonyl C(sp2)–H bonds

+

selected products

N

R2

O

R3

R1

H

N

R2

R3

R1

O

OR5

R4

R4

NO

NO

76%

71%

NO

O

TBHP (2 equiv)R5

H O

R5 = aryl, alkyl, OEt, NR2

EtOAc, 105 °C

77%

75%

52%

O

OMe

O

O

NO

67%

OEt

O

NO

N

O

NO

N

O

O

Scheme 23 Control experiments and possible mechanism for the 1,2-carbonylarylation of alkenes with carbonyl C(sp2)–H bonds

t-BuOOH

R

O

H

t-BuOH/H2O

R

O/ HO

H2O+

t-BuOOH

N O

H

N O

O R

H

N

R

OO

N

R

OO

H

QR

S

N O

+

D

D

D

D

D

N O

intermolecular KIE experiment

43% yield (11 h), kH/D = 1.0

N O

intramolecular KIE experiment

D76% yield (36 h), kH/D = 1.0

NO

N

N O

+

O

75%

TBHP, EtOAc

105 °C, 36 h

NO

O

OMe

OH

MeO

trace

TBHP, EtOAc105 °C, 36 h

TEMPO+

OMe

OON

85%

DMF+

DMF-d7

CH(D)3

CH(D)3

kH/D = 5.0

t-BuO

t-BuO

Scheme 24 Iron-catalyzed 1,2-carbonylarylation of alkenes with pri-mary alcohols

+N O

HN

O

OPh

PhHO

77% (without Fe: 28%)

Fe(OAc)2 (10 mol%)TBHP (2 equiv)

EtOAc, 110 °C, 24 h

Scheme 25 Silver-catalyzed 1,2-acylarylation of alkenes with α-oxo-carboxylic acids

N

R2

O

R3

R1

HN

R2

R3

R1 O+R4

O

OH

O

AgNO3 (10 mol%)K2S2O8 (1 equiv)

H2O, 50 °C

O

R4

R1 = alkyl, aryl, esterR2 = alkylR3 = alkyl, Ph

44–92%


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Scheme 26 Possible mechanism for 1,2-acylarylation of alkenes with α-oxocarboxylic acids

In recent studies by Li, Du and co-workers29a and byChen, Yu and co-workers,29b the alkoxycarbonyl radicalswere formed readily by the oxidative cleavage of the car-bon–nitrogen bond of a carbazate (Scheme 27). They usedcarbazates as easily accessible and safe alkoxycarbonyl radi-cal precursors for the 1,2-alkoxycarbonylarylation of N-arylacrylamides. The method provides a general and practicalmethod for the construction of alkoxycarbonylated oxin-doles. Moreover, the use of economical and environmental-ly benign iron as the catalyst makes this transformationmore sustainable and practical.

Scheme 27 Iron-catalyzed 1,2-alkoxycarbonylarylation of N-aryl acryl-amides with carbazates

3 Synthesis of Oxindoles via Carbohetero-functionalization of Alkenes

3.1 1,2-Azidoarylation or 1,2-Arylnitration

The C(sp2)–H oxidative radical coupling strategy is ap-plicable to the carbo-heterofunctionalization of alkeneswith two type of nitrogen radicals: azidyl and nitro radical.In 2013, Antonchick and co-workers reported an unprece-dented metal-free azidoarylation of alkenes with azidylradicals that were generated by the oxidation of azido-trimethylsilane in the presence of hypervalent iodine(III)reagents at ambient temperature (Scheme 28).30 In thepresence of phenyliodine bis(trifluoroacetate) and azido-trimethylsilane, a variety of N-arylacrylamides deliveredthe corresponding azide-containing oxindoles in goodyields. It was noted that 2-oxindoles with an appended

azide group could be used to create further molecular com-plexity around the privileged scaffold of 2-oxindoles, orcould be applied for bioorthogonal transformation underphysiological conditions.

Scheme 28 Metal-free azidoarylation of alkenes with azidotrimethylsi-lane

The reaction is thought to proceed through a double li-gand exchange between phenyliodine bis(trifluoroacetate)and azidotrimethylsilane to afford intermediate T (Scheme29). The latter is not stable and easily undergoes thermalhomolytic cleavage to form an azide radical, which then at-tacks the alkene to give radical U. Intramolecular trappingwith the arene gives rise to intermediate V, which then un-dergoes rearomatization to produce the oxindole.

Scheme 29 Possible mechanism for the azidoarylation of alkenes with azidotrimethylsilane

Around that same time, the Yang31a and Jiao31b researchgroups independently documented a new strategy for theformation of the azidyl radical through the oxidation of azi-dotrimethylsilane with silver nitrate and oxidizing reagentssuch as zirconium nitrate or cerium(IV) sulfate (Scheme30). Through their methods, various azide-containing oxin-doles were prepared smoothly in moderate to good yields.

R

O

CO2

R

O

Ag(II)

N O

H

N O

O R

H

N

R

OO

N

R

OO

H

QR

S

OH

O

AgNO3, K2S2O8

Ag(I)

N

R2

O

R3

R1

HN

R2

R3CO2R4

R1 O

Li/Du conditions: FeCl2•4H2O, TBHP, MeCN, 60 °C 41–94%

H2NHN

O

OR4+

Chen/Yu conditions: FeCl2•4H2O, 4-cyanopyridine, TBHP, EtOAc, 80 °C 40–92%

R1 = alkyl, aryl, esterR2, R3 = alkyl

N

R2

O

R3

R1

HN

R2

R3N3

R1 O+ TMSN3CH2Cl2, r.t.

PhI(OCOCF3)2

R1, R2 = alkyl, arylR3 = alkyl, H

32–90%

N O

N3

N3

I

Ph

N3

I

OCOCF3

PhOCOCF3

I

N3

PhN3

2 TMSN3

2 CF3CO2TMS

N O

H

N

R3N3

O

R4

H

N

N3

O

HUV

T

Scheme 30 Possible mechanism for the silver-catalyzed azidoarylation of alkenes with azidotrimethylsilane

TMSN3

AgNO3 (10 mol%)Zr(NO3)4•5H2O (0.8 equiv)

MeCN, 110 °C

H

OAr

H

OAr

OArN3

O

azide

N3cat. N3

N

R2

O

R3

R1

H

R4

N

R2

R3N3

R1 O

R4

R1, R3 = alkyl, arylR2 = alkyl

39–89%


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Very recently, Zhang and Qiu reported a metal-free car-boazidation of acrylamides with sodium azide in the pres-ence of potassium persulfate as oxidant. This transforma-tion exhibited excellent functional-group tolerance.32

Nitro compounds are important structural features ofpharmaceuticals and functional materials, as well as beingversatile intermediates in synthesis.33 A nitro radical for the1,2-carbonitration of alkenes was first introduced by Yangand co-workers in 2013 (Scheme 31).34 This protocol pro-vided a new shortcut for the assembly of nitro-containingoxindoles, in which the nitro radical is formed from the oxi-dation 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 nitriteas the nitrogen dioxide source for the carbonitration ofalkenes, and were successful in accessing nitro-containingoxindoles under metal-free conditions (Scheme 32).35

Mechanistic studies indicated that both the nitric oxideradical (·NO) and the nitrogen dioxide radical (·NO2) addi-tion across the carbon–carbon double bond were involvedin this transformation, and that nitrogen dioxide radical ad-dition occurred prior to nitric oxide radical addition. Nota-bly, this reaction was applicable to unactivated alkenes.

Scheme 32 Metal-free 1,2-arylnitration of alkenes with tert-butyl ni-trite

3.2 1,2-Arylsulfonylation

The important roles of sulfur-containing compounds inpharmaceuticals and agrochemicals have inspired chemiststo continue developing mild and efficient carbon–sulfurbond-forming methods.36 A pioneering work on the difunc-tionalization of alkenes with sulfonyl radicals was pub-lished in 2013 by Li, Xu and co-workers (Scheme 33).37 Theoxidative 1,2-arylsulfonylation of activated alkenes with p-

toluenesulfonyl hydrazine proceeded using potassium io-dide as catalyst, THBP as oxidant and 18-crown-6 as pro-moter, thus affording sulfonated oxindoles in satisfactoryyields. This method uses the readily available p-toluenesul-fonyl hydrazine as sulfonyl source by way of a radical strate-gy, and represents an environmentally benign access to ox-indoles by using nontoxic potassium iodide as catalyst andwater as medium.

Scheme 33 1,2-Arylsulfonylation of activated alkenes with p-toluene-sulfonyl hydrazine

Both potassium iodide and 18-crown-6 were proposedto accelerate the decomposition of tert-butyl hydroperoxideinto the tert-butoxy radical (Scheme 34). The resultant ab-straction of hydrogen from p-toluenesulfonyl hydrazine bythe tert-butoxy radical generates a sulfonyl radical via therelease of molecular nitrogen from intermediate radical W.The addition of the sulfonyl radical to the alkene offers in-termediate X, and subsequent intamolecular cyclizationwith the arene produces intermediate Y. Hydrogen abstrac-tion of intermediate Y by tert-butyl hydroperoxide affordsthe sulfonated oxindole.

Scheme 34 Possible mechanism for the 1,2-arylsulfonylation of acti-vated alkenes with p-toluenesulfonyl hydrazine

A similar conversion was subsequently illustrated byKuang and co-workers, starting from N-arylsulfonylacryl-amides (Scheme 35).38 In the presence of copper(II) triflateand potassium persulfate, p-toluenesulfonyl hydrazine wasconverted into the arenesulfonyl radical, thus achieving the1,2-arylsulfonylation of N-arylsulfonylacrylamides througha sulfonylation, 5-ipso-cyclization, aryl migration, desulfo-nylation and amidyl radical cyclization cascade.

A example using sulfinic acids to form the sulfonyl radi-cals was developed by the Wang research group (Scheme36).39 An important feature of this strategy is that only po-tassium persulfate was employed to oxidize the sulfinic

H

N

R2

O

R3

R1R1

N

R2

O

R3

NaNO2

NO2+

K2S2O8 (2 equiv)

MeCN, 120 °C

R1 = alkyl, arylR2, R3 = alkyl

32–88%

H

N

R2

O

R3

metal-freecarbonitrationR1

R1

N

R2

O

R3

t-BuONONO2

N

R2

O

R1

C–N bond formation

R3

NO2

radical cyclization

C–C bond formation

H

t-BuONO

NO + NO2

O2 t-BuOH

R1 = alkyl, aryl, esterR2, R3 = alkyl, aryl

31–81%

N

R2

R3Ts

R1 O

KI (20 mol%)18-crown-6 (20 mol%)

TBHP (3 equiv)

H2O, 80 °CTsNHNH2

N

R2

O

R3

R1

H

+


40–82%

H2O

t-BuO

+

t-BuOOH

N O

H

N O

Ts

HN

Ts

ON

Ts

O

H

TsNHNH2Ts N N

N2

t-BuOOH

KI1/2 I2 + KOH

W

XYt-BuO

Ts


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acid to produce the sulfonyl radical. Direct 1,2-arylsulfo-nylation of the N-arylacrylamide then led to the sulfonatedoxindole.

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 activatedalkenes with [(trifluoromethyl)thio]silver in the presenceof potassium persulfate as oxidant (Scheme 37).40 Thismethod allowed for the oxidative conversion of [(trifluoro-methyl)thio]silver into (trifluoromethyl)thio radical by theoxidant, 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 wasproposed for this reaction (Scheme 38). Initially, oxidationof [(trifluoromethyl)thio]silver by potassium persulfategives [(trifluoromethyl)thio]silver(II), which then forms thekey (trifluoromethyl)thio radical Z. The latter undergoes asequential radical addition and cyclization with N-aryl-acrylamide to form the final oxindole by way of radical in-termediates AA and AB.

3.3 1,2-Arylphosphorylation

Organophosphorus compounds are a prominent molec-ular class in organic chemistry and are widely distributed inpharmaceuticals and agrochemicals; considerable efforthas been devoted to the development of new convenientand flexible methods for the formation of carbon–phospho-rus bonds.41 The first application of the phosphine oxideradicals for the carbophosphorylation of alkenes was re-ported in 2013 by Yang and co-workers (Scheme 39).42 Anumber of phosphorylated oxindoles were synthesized byusing a catalytic system comprised of silver nitrate andmagnesium nitrate hexahydrate to trigger the radical car-bophosphorylation of N-arylacrylamides with phosphineoxides.

Scheme 39 Silver-catalyzed 1,2-arylphosphorylation of alkenes with phosphine oxides

Mechanistically, the Ph2P(O)Ag intermediate AD, whichis formed from the reaction of silver(I) with diphenylphos-phine oxide, is proposed to play a crucial role in the alkene1,2-arylphosphorylation process (Scheme 40). It may takeplace through two paths: one proceeds by the formation ofdiphenylphosphinoyl radical from AD and its additionacross the alkene to produce AF (path A), the other involves

Scheme 35 1,2-Arylsulfonylation of activated alkenes with p-toluene-sulfonyl hydrazine through aryl migration and desulfonylation

ArSO2NHNH2

Cu(OTf)2 (20 mol%)K2S2O8 (3 equiv)

+MeCN–H2O (2:1)

Ar, 80 °C

SO O

N

O

R3R2

R1

H N

R2

R3SO2Ar

R1 O

R1 = alkyl, arylR2, R3 = alkyl

42–83%

N

R2

R3S

R1 ON

R2

O

R3

R1

H

+

K2S2O8 (1 equiv)

MeCN–H2O (1:2), 80 °CR4S

OH

O

O O

R4

R1, R3 = alkylR2 = Me, Ph

R4 = aryl 54–93%

N

R2

R3SCF3

R1 ON

R2

O

R3

R1

H

+MeCN, 75 °C

AgSCF3

K2S2O8 (3 equiv)HMPA (0.5 equiv)


30–91%

Scheme 38 Possible mechanism for the silver-catalyzed 1,2-aryltrifluoromethylthiolation of alkenes

N O

H

N O

SCF3

H

N

SCF3

ON

SCF3

O

H

AA

AB

AgSCF3

S2O82–

SO42– SO4

–+

Ag(II)SCF3

F3CSSCF3

F3CS

Ag+

Z

N

SCF3

O

H

AC

β-H emiminationAg+ Ag2+

S2O82–

N

R2

O

R3

R1

H

+ HPR4R5

O

R1

N

R2

O

R3

PR4R5

OAgNO3 (5 mol%)

Mg(NO3)2•6H2O (0.5 equiv)

MeCN, 100 °C


19–87%


1208


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s do

cum

ent w

as d

ownl

oade

d fo

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al u

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dis

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pro

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ted.

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-arylphos-phorylation of alkenes with phosphine oxides

The Ph2P(O) radical could also be formed from the oxi-dation of phosphine oxides by potassium persulfate in theabsence of a silver catalyst (Scheme 41).43 This arylphosphi-nation of N-arylacrylamides with phosphine oxides wasused to assemble various phosphorus-containing oxindolesin 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-difunctional-ization reactions involving a C–H oxidative coupling processhave been widely used in the synthesis of heterocyclic com-pounds, in particular oxindoles and their derivatives. Thisreview summarized recent efforts along these lines. Thesenew methods are triggered by carbon or heteroatom radi-cals, thus easily incorporating many functional groups, in-cluding alkyl, hydroxyl, carbonyl, trifluoromethyl, azidyl,nitro, sulfonyl, (trifluoromethyl)thio and phosphoryl

groups, into the oxindole framework. Owing to their highefficiency, high step- and atom-economy, excellent func-tional-group tolerance and broad substrate scope, the cur-rent C–H oxidative radical coupling reactions will havewidespread applications in the pharmaceutical, agrochemi-cal and materials fields.

Despite significant progress in the use of C–H oxidativeradical coupling for the synthesis of oxindoles, oxidant de-pendence is very prominent in the alkene difunctionaliza-tion transformations, and stoichiometric amounts of non-green oxidants, such as peroxides, potassium persulfate,hypervalent iodines or tert-butyl nitrite, are necessary in allcases. Moreover, the substrate scope in many cases is limit-ed to activated alkenes, and the related mechanisms need tobe explored in more detail. Therefore, the development ofnew, efficient C–H oxidative radical coupling strategies in-volving the use of green oxidants (e.g., O2, hydrogen perox-ide or other sustainable oxidants) is highly desirable. Theimportant opportunities and challenges in this field will in-volve determining how to achieve selective coupling of un-activated alkyl or aryl C–H bonds. In addition, more newfunctional radicals also need to be designed and discovered,in order to initiate research into further unexplored C–Hoxidative radical coupling methods.

Acknowledgment

This research was supported by the NSFC (Nos. 21402046, 21172060and 21472039) and Hunan Provincial Natural Science Foundation ofChina (No. 13JJ2018). Dr. R.-J. S. also thanks the Fundamental Re-search Funds for the Central Universities.

References

(1) For selected reviews and papers, see: (a) Lin, H.; Danishefsky, S.J. Angew. Chem. Int. Ed. 2003, 42, 36. (b) Emura, T.; Esaki, T.;Tachibana, K.; Shimizu, M. J. Org. Chem. 2006, 71, 8559.(c) Dalpozzo, R.; Bartoli, G.; Bencivenni, G. Chem. Soc. Rev. 2012,41, 7247. (d) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104.(e) Shen, K.; Liu, X.; Lin, L.; Feng, X. Chem. Sci. 2012, 3, 327.(f) Ohmatsu, K.; Ando, Y.; Ooi, T. J. Am. Chem. Soc. 2013, 135,18706.

(2) For selected examples, see: (a) Hennessy, E. J.; Buchwald, S. L.J. Am. Chem. Soc. 2003, 125, 12084. (b) Galliford, C. V.; Scheidt,K. A. Angew. Chem. Int. Ed. 2007, 46, 8748. (c) Jia, Y.-X.; Kündig,E. P. Angew. Chem. Int. Ed. 2009, 48, 1636. (d) Piou, T.; Neuville,L.; Zhu, J. Angew. Chem. Int. Ed. 2012, 51, 11561.

(3) For selected reviews on difunctionalization of alkenes, see:(a) Kolb, H. C.; van Nieuwenhze, M. S.; Sharpless, K. B. Chem.Rev. 1994, 94, 2483. (b) Beccalli, E. M.; Broggini, G.; Martinelli,M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318. (c) Jacques, B.;Muniz, K. In Catalyzed Carbon-Heteroatom Bond Formation;Yudin, A. K., Ed.; Wiley–VCH: Weinheim, 2010, 119.(d) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011, 111,2981. (e) Chen, J.-R.; Yu, X.-Y.; Xiao, W.-J. Synthesis 2015, 47,604.

(4) Evans, P.; Grigg, R.; Ramzan, M. I.; Sridharan, V.; York, M. Tetra-hedron Lett. 1999, 40, 3021.

N

R2

O

R1

R3

PPh2R1

N

R2

O

R3

PR4R5

OO

AF

O

Ag

HNO3

AgNO3 HPPh2

O

N

R2

O

R3

R1

H

+

path Apath B

O

N

R2

O

R1

R3

PPh2

OAg

Ag(0)

Ag(0)

AE

AD

Ph2P

Ph2P

HP(O)Ph2

K2S2O8 (3 equiv)+

MeCN, 90 °CN

R2

O

R3

R1

HN

R2

R3PPh2

R1 O

O


25–95%


1209


Thi

s do

cum

ent w

as d

ownl

oade

d fo

r pe

rson

al u

se o

nly.

Una

utho

rized

dis

trib

utio

n is

str

ictly

pro

hibi

ted.

(5) Anwar, U.; Casaschi, A.; Grigg, R.; Sansano, J. M. Tetrahedron2001, 57, 1361.

(6) Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem. Eur. J. 2007, 13, 961.(7) Jaegli, S. P.; Dufour, J.; Wei, H.-L.; Piou, T.; Duan, X.-H.; Vors, J.-

P.; Neuville, L.; Zhu, J. Org. Lett. 2010, 12, 4498.(8) (a) Wu, T.; Mu, X.; Liu, G. Angew. Chem. Int. Ed. 2011, 50, 12578.

(b) Mu, X.; Wu, T.; Wang, H.-Y.; Guo, Y.-L.; Liu, G. J. Am. Chem.Soc. 2012, 134, 878.

(9) (a) Murakami, M.; Ito, Y. In Topics in Organometallic Chemistry;Vol. 3; Murai, S., Ed.; Springer-Verlag: New York, 1999, 97–129.(b) Rybtchinski, B.; Milstein, D. Angew. Chem. Int. Ed. 1999, 38,871. (c) Sundermann, A.; Uzan, O.; Milstein, D.; Martin, J. M. L.J. Am. Chem. Soc. 2000, 122, 7095. (d) Gao, X.; Woo, S. K.;Krische, M. J. J. Am. Chem. Soc. 2013, 135, 4223. (e) Del Valle, D.J.; Krische, M. J. J. Am. Chem. Soc. 2013, 135, 10986. (f) Barroso,R.; Valencia, R. A.; Cabal, M.-P.; Valdés, C. Org. Lett. 2014, 16,2264.

(10) Wei, W.-T.; Zhou, M.-B.; Fan, J.-H.; Liu, W.; Song, R.-J.; Liu, Y.;Hu, M.; Xie, P.; Li, J.-H. Angew. Chem. Int. Ed. 2013, 52, 3638.

(11) (a) Meng, Y.; Guo, L.-N.; Wang, H.; Duan, X.-H. Chem. Commun.2013, 49, 7540. (b) Zhou, Z.-Z.; Hua, H.-L.; Luo, J.-Y.; Chen, Z.-S.;Zhou, P.-X.; Liu, X.-Y.; Liang, Y.-M. Tetrahedron 2013, 69, 10030.

(12) Zhou, M.-B.; Wang, C.-Y.; Song, R.-J.; Liu, Y.; Wei, W.-T.; Li, J.-H.Chem. Commun. 2013, 49, 10817.

(13) Zhou, S.-L.; Guo, L.-N.; Wang, H.; Duan, X.-H. Chem. Eur. J. 2013,19, 12970.

(14) Li, Z.-J.; Zhang, Y.; Zhang, L.-Z.; Liu, Z.-Q. Org. Lett. 2014, 16, 382.(15) Wang, H.; Guo, L.-N.; Duan, X.-H. Chem. Commun. 2013, 49,

10370.(16) Wang, H.; Guo, L.-N.; Duan, X.-H. Org. Lett. 2013, 15, 5254.(17) Wu, T.; Zhang, H.; Liu, G. Tetrahedron 2012, 68, 5229.(18) Xie, J.; Xu, P.; Li, H.; Xue, Q.; Jin, H.; Cheng, Y.; Zhu, C. Chem.

Commun. 2013, 49, 5672.(19) (a) Fan, J.-H.; Zhou, M.-B.; Liu, Y.; Wei, W.-T.; Ouyang, X.-H.;

Song, R.-J.; Li, J.-H. Synlett 2014, 25, 657. (b) Dai, Q.; Yu, J.; Jiang,Y.; Guo, S.; Yang, H.; Cheng, J. Chem. Commun. 2014, 50, 3865.

(20) (a) Smart, B. E. Chem. Rev. 1996, 96, 1555. (b) Shimizu, M.;Hiyama, T. Angew. Chem. Int. Ed. 2005, 44, 214. (c) Muller, C. K.;Faeh, C.; Diederich, F. Science 2007, 317, 1881. (d) Purser, S.;Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008,37, 320. (e) Wang, F.; Wang, D.-H.; Mu, X.; Chen, P.-H.; Liu, G.-S.J. Am. Chem. Soc. 2014, 136, 10202.

(21) (a) Egami, H.; Shimizu, R.; Sodeoka, M. J. Fluorine Chem. 2013,152, 51. (b) Li, L.; Deng, M.; Zheng, S.-C.; Xiong, Y.-P.; Tan, B.;Liu, X.-Y. Org. Lett. 2014, 16, 504. (c) Yang, F.; Klumphu, P.;Liang, Y.-M.; Lipshutz, B. H. Chem. Commun. 2014, 50, 936.(d) Fu, W.; Xu, F.; Fu, Y.; Xu, C.; Li, S.; Zou, D. Eur. J. Org. Chem.2014, 709. (e) Wei, W.; Wen, J.; Yang, D.; Liu, X.; Guo, M.; Dong,R.; Wang, H. J. Org. Chem. 2014, 79, 4225. (f) Lu, Q.-Q.; Liu, C.;Peng, P.; Liu, Z.-L.; Fu, L.-J.; Huang, J.-G.; Lei, A.-W. Asian J. Org.Chem. 2014, 3, 273.

(22) Liu, J.-D.; Zhuang, S.-B.; Gui, Q.-W.; Chen, X.; Yang, Z.-Y.; Tan, Z.Eur. J. Org. Chem. 2014, 3196.

(23) Wang, J.-Y.; Zhang, X.; Bao, Y.; Xu, Y.-M.; Cheng, X.-F.; Wang, X.-S. Org. Biomol. Chem. 2014, 12, 5582.

(24) (a) Kong, W.-Q.; Casimiro, M.; Merino, E.; Nevado, C. J. Am.Chem. Soc. 2013, 135, 14480. (b) Kong, W.-Q.; Merino, E.;Nevado, C. Angew. Chem. Int. Ed. 2014, 53, 5078. (c) Fuentes, N.;Kong, W.-Q.; Fernández-Sánchez, L.; Merino, E.; Nevado, C.J. Am. Chem. Soc. 2015, 137, 964.

(25) (a) Chan, C.-W.; Zhou, Z.; Chan, A. S. C.; Yu, W.-Y. Org. Lett. 2010,12, 3296. (b) Jia, X.; Zhang, S.; Wang, W.; Luo, F.; Cheng, J. Org.Lett. 2009, 11, 3120. (c) Tang, B.-X.; Song, R.-J.; Li, J.-H. J. Am.Chem. Soc. 2010, 132, 8900. (d) Wu, Y.; Li, B.; Mao, F.; Li, X.;Kwong, F. Y. Org. Lett. 2011, 13, 3258.

(26) Zhou, M.-B.; Song, R.-J.; Ouyang, X.-H.; Liu, Y.; Wei, W.-T.; Deng,G.-B.; Li, J.-H. Chem. Sci. 2013, 4, 2690.

(27) Ouyang, X.-H.; Song, R.-J.; Li, J.-H. Eur. J. Org. Chem. 2014, 3395.(28) Wang, H.; Guo, L.-N.; Duan, X.-H. Adv. Synth. Catal. 2013, 355,

2222.(29) (a) Xu, X.; Tang, Y.; Li, X.; Hong, G.; Fang, M.; Du, X. J. Org. Chem.

2014, 79, 446. (b) Wang, G.; Wang, S.; Wang, J.; Chen, S.-Y.; Yu,X.-Q. Tetrahedron 2014, 70, 3466.

(30) Matcha, K.; Narayan, R.; Antonchick, A. P. Angew. Chem. Int. Ed.2013, 52, 7985.

(31) (a) Wei, X.-H.; Li, Y.-M.; Zhou, A.-X.; Yang, T.-T.; Yang, S.-D. Org.Lett. 2013, 15, 4158. (b) Yuan, Y.; Shen, T.; Wang, K.; Jiao, N.Chem. Asian J. 2013, 8, 2932.

(32) Qiu, J.; Zhang, R.-H. Org. Biomol. Chem. 2014, 12, 4329.(33) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:

Weinheim, 2001. (b) Feuer, H.; Nielson, A. T. Nitro Compounds:Recent Advances in Synthesis and Chemistry; VCH: Weinheim,1990. (c) Barrett, A. G. M.; Graboski, G. G. Chem. Rev. 1986, 86,751.

(34) (a) Li, Y.-M.; Wei, X.-H.; Li, X.-A.; Yang, S.-D. Chem. Commun.2013, 49, 11701. (b) Li, Y.-M.; Shen, Y.; Chang, K.-J.; Yang, S.-D.Tetrahedron Lett. 2014, 55, 2119.

(35) Shen, T.; Yuan, Y.; Jiao, N. Chem. Commun. 2014, 50, 554.(36) (a) Napier, C.; Stewart, M.; Melrose, H.; Hopkins, B.; McHarg, A.;

Wallis, R. Eur. J. Pharmacol. 1999, 375, 61. (b) Petrov, K. G.;Zhang, Y.; Carter, M.; Cockerill, G. S.; Dickerson, S.; Gauthier, C.A.; Guo, Y.; Mook, R. A.; Rusnak, D. W.; Walker, A. L.; Wood, E.R.; Lackey, K. E. Bioorg. Med. Chem. Lett. 2006, 16, 4686.

(37) Li, X.; Xu, X.; Hu, P.; Xiao, X.; Zhou, C. J. Org. Chem. 2013, 78,7343.

(38) Tian, Q.; He, P.; Kuang, C. Org. Biomol. Chem. 2014, 12, 6349.(39) Wei, W.; Wen, J.; Yang, D.; Du, J.; You, J.; Wang, H. Green Chem.

2014, 16, 2988.(40) Yin, F.; Wang, X.-S. Org. Lett. 2014, 16, 1128.(41) (a) Van der Jeught, S.; Stevens, C. V. Chem. Rev. 2009, 109, 2672.

(b) George, A.; Veis, A. Chem. Rev. 2008, 108, 4670. (c) Bialy, L.;Waldmann, H. Angew. Chem. Int. Ed. 2005, 44, 3814.(d) Alexandre, F.; Amador, A.; Bot, S.; Caillet, C.; Convard, T.;Jakubik, J.; Musiu, C.; Poddesu, B.; Vargiu, L.; Liuzzi, M.; Roland,A.; Seifer, M.; Standring, D.; Storer, R.; Dousson, C. B. J. Med.Chem. 2011, 54, 392.

(42) Li, Y.-M.; Sun, M.; Wang, H.-L.; Tian, Q.-P.; Yang, S.-D. Angew.Chem. Int. Ed. 2013, 52, 3972.

(43) Li, Y.-M.; Shen, Y.; Chang, K.-J.; Yang, S.-D. Tetrahedron 2014, 70,1991.


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