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Synthesis of oxindoles

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A highly regioselective palladium-catalyzed cyclization converts α-chloroacetanilides to oxindoles in good to excellent yields with high functional group compatibility using 2-(di-tert-butylphosphino)biphenyl as ligand and triethylamine as a stoichiometric base.
E. J. Hennessy, S. L. Buchwald, J. Am. Chem. Soc., 2003, 125, 12084-12085.


With the proper choice of palladium catalyst, ligand, and base, five-, six-, and seven-membered rings are formed efficiently from secondary amide or secondary carbamate precursors.
B. H. Yang, S. L. Buchwald, Org. Lett., 1999, 1, 35-37.


Catalysts comprised of Pd(OAc)2 and either PCy3 or sterically hindered N-heterocyclic carbene ligands provide fast rates for a mild, palladium-catalyzed synthesis of oxindoles in high yields by amide α-arylation.
S. Lee, J. F. Hartwig, J. Org. Chem., 2001, 66, 3402-3415.


N-Heterocyclic nitrenium (NHN) salts, the analogues of N-heterocyclic carbenes, can serve as catalytic electron acceptors for charge transfer complex photoactivations. Under blue light irradiation, NHN salts catalyze the generation of aryl radicals from aryl halides.
K.-Q. Chen, B.-B. Zhang, Z.-X. Wang, X.-Y. Chen, Org. Lett., 2022, 24, 4598-4602.


A photocatalytic CTC strategy for hydroarylation of both activated and unactivated alkenes via single-electron reduction using thiolate as a catalytic electron donor enables the synthesis of various polycyclic heterocycle molecules from N-arylacrylamides, N-methacryloyl benzamides, and alkenyl-substituted quinazolinones.
Y.-Z. Ren, C.-Z. Fang, B.-B. Zhang, L. He, Y.-L. Tu, X.-Y. Chen, Org. Lett., 2023, 25, 3585-3589.


A catalyst generated from Pd(dba)2 and a bulky electron-rich phosphine ligand is effective for the α-arylation of oxindoles. Generation of the potassium-enolates of a range of oxindoles enables the coupling with aryl chlorides, bromides, and triflates.
M. J. Durbin, M. C. Willis, Org. Lett., 2008, 10, 1413-1415.


Trimethylsilyl tricyanopalladate complex generated in situ from trimethylsilyl cyanide and Pd(OAc)2 catalyzes the conversion of various diethyl phosphates derived from N-arylmandelamides into oxindoles in excellent yields. With a N,N-dibenzylamide as substrate, a benzo-fused δ-lactam was obtained.
H. Ece, Y. Tange, T. Yurino, T. Ohkuma, Synlett, 2021, 32, 935-939.


A Rh-catalyzed domino conjugate addition-arylation sequence enables the synthesis of 3-substituted oxindole derivatives in good yields via an intramolecular oxidative addition of a rhodium enolate.
Y. J. Jang, H. Yoon, M. Lautens, Org. Lett., 2015, 17, 3895-3897.


A new platinum-catalyzed oxoarylation of ynamides with nitrones gives oxoarylation products. A cascade sequences via NaBH3CN reduction of in situ formed oxoarylation products allows the synthesis of indolin-2-ones.
S. Bhunia, C.-J. Chang, R.-S. Liu, Org. Lett., 2012, 14, 5522-5525.


An organocatalyzed oxidative C-N bond formation of phenylpropanamide derivatives provides 3,3-disubstituted oxindole derivatives in very good yields. This highly efficient intramolecular reaction offers transition metal-free mild conditions and the ability to perform the reaction on a gram scale.
Y. Wang, M. Yang, Y.-Y. Sun, Z.-G. Wu, H. Dai, S. Li, Org. Lett., 2021, 23, 8750-8754.


A nickel-catalyzed aromatic C-H alkylation with tertiary or secondary alkyl-Br bonds enables the construction of indolones. The reaction tolerates various functional groups. Moreover, challenging secondary alkyl bromides can also be transformed. Radical trapping and photocatalysis conditions exhibited that a radical process is involved in this aromatic C-H alkylation.
C. Liu, D. Liu, W. Zhang, L. Zhou, A. Lei, Org. Lett., 2013, 15, 6166-6169.


Chiral N-heterocyclic carbene (NHC) ligands having a 2,2′-bisquinoline-based C2 symmetric skeleton exhibited good enantioselectivity in palladium-catalyzed intramolecular α-arylation of amides to give 3,3-disubsituted oxindoles.
L. Liu, N. Ishida, S. Ashida, M. Murakami, Org. Lett., 2011, 13, 1666-1669.


Potassium tert-butoxide-mediated intramolecular α-arylations of fluoro- and chloro-substituted anilides provide oxindoles in DMF at 80░C. Diversely substituted products have been obtained in good yields.
A. Beyer, J. Buendia, C. Bolm, Org. Lett., 2012, 14, 3948-3951.


A palladium catalyst derived from an air-stable secondary phosphine oxide enabled efficient intramolecular α-arylations of amides with aryl chlorides to give various substituted oxindoles and azaoxindoles in good yield.
L. Ackermann, R. Vicente, N. Hofmann, Org. Lett., 2009, 11, 4274-4276.


Excited-state palladium catalysis is an efficient process for the alkylation of diverse organic compounds via the generation of alkyl radicals from alkyl halides. An excited-state palladium-complex catalyzes the synthesis of oxindoles and isoquinolinediones via alkylation/annulation reaction with unactivated alkyl chlorides even at room temperature.
K. Muralirajan, R. Kancherla, A. Gimnkhan, M. Rueping, Org. Lett., 2021, 23, 6905-6910.


An efficient palladium-catalyzed alkylarylation of acrylamides with unactivated alkyl halides offers broad substrate scope and excellent functional group tolerance. In addition to alkyl halides, fluoroalkyl halides and benzyl bromides also participated well in this transformation. A radical pathway is probably involved in the cyclization process.
H. Wang, L.-N. Guo, X.-H. Duan, J. Org. Chem., 2016, 81, 860-867.


A facile method enables the construction of quaternary 3,3-disubstituted 2-oxindoles from 2-substituted indoles without a catalyst under mild conditions via an iminium-intermediate-triggered 1,2-rearrangement.
X. Jiang, J. Yang, F. Zhang, P. Yu, P. Yi, Y. Sun, Y. Wang, Org. Lett., 2016, 18, 3154-3157.


CBZ6, a redox-neutral non-donor-acceptor-type organo-photocatalyst, has a strong reductive potential and mediates both single-electron transfer and triplet energy transfer processes. The intramolecular hydroarylation of acrylamides provides both oxindoles as 5-exo-trig and dihydroquinolinones as 6-endo-trig cyclization products regiospecfically under mild conditions depending on the solvent used.
X.-P. Cai, B.-H. Han, F.-T. Cen, J.-P. Qu, Y.-B. Kang, Org. Lett., 2023, 25, 2863-2867.


A nickel-catalyzed domino Heck cyclization/Suzuki coupling reaction enables the synthesis of 3,3-disubstituted oxindoles bearing quaternary all-carbon centers. A wide range of electrophiles, such as aryl iodides, bromides, triflates, chlorides, and cheap aryl esters can be employed. This practical and sustainable reaction offers good yields and broad scope.
Y. Li, K. Wang, Y. Ping, Y. Wang, W. Kong, Org. Lett., 2018, 20, 921-924.


3-Monofunctionalized 2-oxindoles were conveniently synthesized from reactions between an anilide and phenyliodine(III) diacetate (PIDA) through hypervalent iodine mediated C(sp2)–C(sp2) bond formation followed by a subsequent deacylation. This metal-free method provides direct access to interesting oxindole intermediates, as exemplified by the total synthesis of horsfiline.
J. Lv, D. Zhang-Negrerie, J. Deng, Y. Du, K. Zhao, J. Org. Chem., 2014, 79, 1111-1119.


A chiral phosphine oxide catalyzes an asymmetric Staudinger-aza-Wittig reaction of (o-azidoaryl)malonates to provide chiral quaternary oxindoles in the presence of a silane reductant and an IrI-based Lewis acid. The reaction occurs under mild conditions, with good functional group tolerance, a wide substrate scope, and excellent enantioselectivity.
C. Xie, J. Kim, B. K. Mai, S. Cao, R. Ye, X.-Y. Wang, P. Liu, O. Kwon, J. Am. Chem. Soc., 2022, 144, 21318-21327.


A cross-dehydrogenative coupling enable a low-temperature procedure for the synthesis of 3,3-disubstituted 2-oxindoles. The use of a strong, nonreversible base effects a dramatic drop in reaction temperature. With iodine as an "oxidant", new evidence suggests that this transformation may occur via a transiently stable iodinated intermediate rather than by direct single-electron oxidation.
J. R. Donald, R. J. K. Taylor, W. F. Petersn, J. Org. Chem., 2017, 82, 11288-11294.


Highly efficient conditions for the preparation of 3,3-disubstituted oxindoles by a formal C-H, Ar-H coupling of anilides have been identified using catalytic Cu(OAc)2•H2O with atmospheric oxygen as the reoxidant in mesitylene or toluene as solvent; no additional base is required.
J. E. M. N. Klein, A. Perry, D. S. Pugh, R. J. K. Taylor, Org. Lett., 2010, 12, 3446-3449.


Sulfuryl chlorofluoride is a versatile reagent for controllable chlorination and chlorooxidation of simple unprotected indoles. Three types of products including 3-chloro-indoles, 3-chloro-2-oxindoles, and 3,3-dichloro-2-oxindoles could be selectively obtained in good to excellent yields by switching the reaction solvents. The convenient methods offer broad substrate scope and mild reaction conditions.
T. Ma, Y. Zheng, S. Huang, J. Org. Chem., 2023, 88, 4839-4847.


A catalyst-free halogenative cyclization of N-aryl diazoamides with N-halosuccinimides (NXS) provides 3-halooxindoles in good yields through a carbene-free mechanism under mild and catalyst-free conditions. This transformation is proposed to proceed through diazonium ion formation followed by intramolecular Friedel-Crafts alkylation.
C. Ma, D. Xing, W. Hu, Org. Lett., 2016, 18, 3134-3137.


Treatment of several 3-substituted indoles, including derivatives of tryptophan and serotonin, with Selectfluor in acetonitrile/water provides 3-substiuted 3-fluorooxindoles in very good yields.
Y. Takeuchi, T. Tarui, N. Shibata, Org. Lett., 2000, 2, 639-642.


A nickel-catalyzed reaction of acrylamides or enamides with diazoacetates provides indolin-2-ones or 1,4-dicarbonyl compounds in the presence of a peroxide and ethanol as hydrogen source and solvent.
J. Zhao, P. Li, Y. Xu, Y. Shi, F. Li, Org. Lett., 2019, 21, 9386-9390.


3-Alkyl-3-hydroxyoxindoles have antioxidant, neuroprotective, anticancer, and anti-HIV activities. α-Alkylation-α-hydroxylation of oxindoles with benzyl alcohols enables an economical synthesis without using any transition-metal catalysts in very good yields.
S. Wu. W. Song, R. Zhu, J. Hu, L. Zhao, Z. Li, X. Yu, C. Xia, J. Zhao, J. Org. Chem., 2022, 87, 5464-5471.


An intermolecular Ni-catalyzed reductive coupling of aryl iodides and isatins provides 3-hydroxyoxindoles in the presence of sec-butanol as a mild stoichiometric reductant. This formal 1,2-addition reaction is facilitated by a 1,5-diaza-3,7-diphosphacyclooctane (P2N2) ligand.
A. Nasim, G. T. Thomas, J. S. Ovens, S. G. Newman, Org. Lett., 2022, 24, 7232-7236.


Peroxy trichloroacetimidic acid, in situ generated from aqueous hydrogen peroxide and trichloroacetonitrile, acts as a competent electrophilic oxygenating agent for a direct enantioselective α-hydroxylation of oxindoles in the presence of a chiral 1,2,3-triazolium salt as a phase-transfer catalyst.
K. Ohmatsu, Y. Ando, T. Ooi, Synlett, 2017, 28, 1291-1294.


Chiral BINOL derivatives catalyze an enantioselective allylboration of isatins with 2-allyl-1,3,2-dioxaborolane to provide enantioenriched N-unprotected 3-allyl-3-hydroxy-2-oxindoles. This catalytic process is also effective for asymmetric crotylboration reactions, as well as for the enantioselective synthesis of homopropargylic alcohols.
J. Braire, A. MacÚ, R. Zaier, M. Cordier, J. Vidal, C. Lalli, A. Martel, F. Carreaux, J. Org. Chem., 2023, 88, 1457-1468.


A dimeric chiral quaternary ammoniums derived from quinine can be used as cationic inducer of an enantioselective Ag(I)-catalyzed alkynylation of isatin derivatives under mild conditions. The desired chiral 3-alkynyl-3-hydroxy-2-oxindoles can be obtained in good to high yields with excellent enantioselectivites.
X. Sun, C. Xiong, F. Zhou, K. Liang, C. Wu, X. Rao, Q. Chen, J. Org. Chem., 2023, 88, 7454-7462.


In a Pd-catalyzed domino cyclization and carboxylation reaction for synthesis of a variety of carboxylic acids, chloroform was used as convenient and safe carbon monoxide source. Heck cyclization leads in situ to a neopentylpalladium species, that can efficiently be trapped by dichlorocarbene to form a series of carboxylic acids.
X. Liu, B. Li, Z. Gu, J. Org. Chem., 2015, 80, 7547-7554.


A small library of α,β-unsaturated oxindoles was prepared by an efficient microwave-assisted one-pot sequence comprising an aromatic substitution followed by an ionic Horner-Wadsworth-Emmons olefination.
A. Teichert, K. Jantos, K. Harms, A. Studer, Org. Lett., 2004, 6, 3477-3480.


A [3 + 2] cycloadition of in situ generated arynes and (putative) aza-oxyallyl cations enables an unprecedented metal- and oxidant-free synthesis of N-alkoxy oxindoles. The versatility of this approach was demonstrated through valuable synthetic transformations.
R. Singh, K. Nagesh, D. Yugandhar, A. V. G. Prasanthi, Org. Lett., 2018, 20, 4848-4853.


A BF3-catalyzed atom-economical fluorocarbamoylation reaction of alkyne-tethered carbamoyl fluorides provides 3-(fluoromethylene) oxindoles and γ-lactams with excellent stereoselectivity. The catalyst acts as both a fluoride source and Lewis acid activator, thereby enabling the formal insertion of alkynes into strong C-F bonds through a halide recycling mechanism.
E. A. McKnight, R. Arora, E. Pradhan, Y. H. Fujisato, A. J. Ajayi, M. Lautens, T. Zeng, C. M. Le, J. Am. Chem. Soc., 2023, 145, 11012-11018.


N-Heterocyclic nitreniums (NHNs) catalyze a photohomolysis of CF3SO2Cl resulting in the CF3 radical for trifluormethylation of alkenes. This method is operationally simple and without using transition metals and oxidants.
X.-J. Ren, P.-W. Liao, H. Sheng, Z.-X. Wang, X.-Y. Chen, Org. Lett., 2023, 25, 6189-6194.