3,3-Substituted oxindoles, synthesis

Another indole/oxindole synthesis achieves the critical ortho-substitution by Sommelet-Hauser rearrangement of an anilinosiilfonium ion intermediate. Use of P-thioketones (G = R, an alkyl group) generates 2-substituted indoles, whereas P-thioesters (G = OR) lead to oxindoles. In each case, a 3-thio substituent must be removed by desulfuri2ation. 

Reductive cyclization of o-nitrophenylacetic acids is a very general method of oxindole synthesis (see Section 3.06.2.1.1 for the application of this method to indoles in general). The main problem is efficient construction of the desired phenylacetic acid. One method involves base-catalyzed condensation of substituted nitrotoluenes with diethyl oxalate followed by oxidation of the 3-arylpyruvate (equation 200) (63CB253). Nucleophilic substitution of o-nitrophenyl trifluoromethanesulfonate esters, which are readily prepared from phenols, by dimethyl malonate provides another route (equation 201) (79TL2857). 

Intramolecular nucleophilic substitution by the anions of o-haloanilides is another viable oxindole synthesis. This is a special example of the category Ic process described in Section 3.06.2.3. The reaction is photo-stimulated and the mechanism is believed to be of the electron-transfer type SRN1 rather than a classical addition-elimination mechanism. The reaction is effective when R = H if 2 equivalents of the base are used to generate the dianion (equation 202) (80JA3646). 

Recent syntheses of indol-2-ones (oxindoles) include Chuang s p-toluenesulfo-nyl radical induced cyclization of allylsulfones and the oxidative free-radical reactions of a,a-dimethylsulfonyl substituted anilides [62], the tin-free synthesis of 3-aminoindolinones from O-benzyl oxime substituted amidocyclohexadienes [63], and Pudlo s 5-exo-trigl5-exo-trig tandem radical cyclization of acrylamides to give 3-pyrrolidinone substituted oxindoles, shown below [64]. 

The authors have found that nitronates 11 are derived from intramolecular nucleophilic displacement of the chloro atom with oxygen of the nitro group (Scheme 9). Moreover, the intramolecular VNS reactions of nitroarenes proved to be a successful procedure for the synthesis of various indole derivatives. For instance, cyclization of 3-nitrochloroacetanilide 12 caused by action of f-BuOK affords N-substituted oxindole 13, which is hardly accessible by other methods [28] (Scheme 10). 

After copper and palladium, rhodium is the third most important transition metal for the synthesis of the indole ring. For a 2007 review on this reaction, see Patil and Paiil [1], Some early examples (Scheme 1) are Alper s rhodium reaction of 2-aryl-2/7-azirines to give 2-styiylindoles (equation 1) [2], Watanabe s Rh-catalyzed Fischer indole synthesis (equation 2) [3], Ucciani s 3-methylindole synthesis via the hydroformylation of o-nitrostyrene (equation 3) [4], and Burst s preparation of 3-acetyl-2-hydrox-yindoles from the Rh-catalyzed decomposition and carbenoid aromatic C-H bond insertion (equation 4) [5]. Narasaka extended Alper s 2-aryl-2//-azirine reaction to a Rh(II)-catalyzed synthesis of 2,3-disubstituted indoles [6], and both Cenini [7] and Alper [8] stretched the deoxygenation of o-nitrostyrenes to give indoles. Burst s Rh-catalyzed decomposition of a-diazo carbonyl compounds was used by Bauban [9] and Jha [10] in the synthesis of substituted oxindoles. 

Generally, the reaction works well for electron-deficient anilines. A modified approach using in situ prepared chlorosulfonium salts is preferred for more electron-rich anilines. Substituted thiol derivatives can be used to produce 3-oxindoles, which can be further reduced to 3-indole derivatives that are not available via the Gassman indole synthesis. The reaction is equally useful for the preparation of isatin derivatives vide infra). Historically, the Gassman oxindole synthesis has found applications in the preparation of heterocycles with medical or insecticidal properties. The reaction also has potential applications for the synthesis of oxindole containing natural products. ... 

The preparation of 3-substituted oxindoles can be readily achieved by using alkylated derivatives of ethyl methylthioacetate." For example, reaction of aniline with compound 18 gave oxindole derivative 19 in 64% yield. Reduction of 19 with Raney nickel gave oxindole 20 in 70% yield, while reduction with LiAlH4 gave the corresponding indole 21 in 76% yield. The two-step route to indoles eomplements the Gassman indole synthesis. 

For important reviews abont 3,3 -disnbstitnted oxindole strnc-tural motif, see (a) F. Zhou, Y.-L. Liu, J. Zhou, Adv. Synth. Catal. 2010, 352, 1381-1407. Catalytic asymmetric synthesis of oxindoles bearing a tetrasubstituted stereocenter at the C-3 position, (b) J. J. BadiUo, N. V. Hanhan, A. K. Franz, Curr. Opin. Drug Discov. Dev. 2010, 13, 758-776. Enantioselective synthesis of substituted oxindoles and spirooxindoles with applications in drug discovery, (c) A. Kumar, S. S. Chimni, RSC Advances 2012, 2, 9748-9762. Catalytic asymmetric synthesis of hydroxyoxindole a potentially bioactive molecule, (d) S. Mohammadi, R. Heiran, R. P. Herrera, E. Marques-L6pez,... 

In 2013, Li et al. reported a novel synthesis of chiral six-memhered spir-ocyclic oxindoles bearing five consecutive stereocentres on the basis of an enantioselective three-component domino Michael-Michael-aldol reaction catalysed hy a combination of a chiral diphenylprolinol silyl ether and a chiral bifunctional quinine thiourea. " As shown in Scheme 2.26, the reaction between iV-substituted oxindoles, nitrostyrenes, and enals led to the corresponding highly substituted spirocyclic oxindoles in high yields, moderate diastereoselectivities of up to 44% de, and enantioselectivities of up to >99% ee. A large variety of substrates could be used well in this... 

The acid-catalysed Fischer indole synthesis is an electrophilic substitution, and the evidence suggests that it occurs less readily with pyridylhydrazones than with benzene derivatives. Some failures with derivatives of 2-pyridyl-hydrazine have been recorded but cyclohexanone and desoxybenzoin 2-pyridylhydrazones were cyclized in about 50 per cent yields with poly-phosphoric acid. Zinc chloride has been used successfully with methyl isopropyl ketone 2-pyridylhydrazone 82, The Brunner oxindole synthesis worked... 

Intramolecular Friedel-Crafts substitution has also figured prominently in the synthesis of oxindoles from cx-haloacelanilides. Typical reaction conditions for cyclizalion involve heating with A1CI,[13-17]. 

In the presence of tetramethyltin, 1-bromonauclefine reacts with CO in a Pd-catalyzed carbonylation to give the alkaloid naucletine [202], Dong and Busacca effected a new synthesis of tryptamines and tryptophols via a Rh-catalyzed hydroformylation of functionalized anilines that are prepared by a standard Heck reaction, as shown for the preparation of tryptamine sulfonamide 325 [423]. This reaction is applicable to ring-substituted tryptamines (Cl, Br, F. OMe, CF3). Likewise, the Rh-catalyzed carbonylation of o-alkynylanilines, which were prepared by a Pd-catalyzed Sonogashira coupling, leads to oxindoles (60-86% yields) [424],... 

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