3- indolin-2-ones synthesis

The Hegedus indole synthesis involves one of the earlier (formal) examples of olefin hydroamination. An ortho-vinyl or ortho-nllyl aniline derivative 1 is treated with palladium(II) to deliver an intermediate resulting from alkene aminopalladation. Subsequent reduction and/or isomerization steps then provide the indoline or indole unit 2, respectively. 

JPS 62,490(1973) gives an indoline synthesis which can be carried one step further (dehydrogenation described in this chapter) to give DMT derivatives. See JOC 41,1118(1976) for indoles from betaketosulfoxides. 

A one-pot synthesis of 3,3-disubstituted indolines was achieved by taking advantage of a sequential carbopalladation of allene, nucleophile attack, intramolecular insertion of an olefm and termination with NaBPh4 (Scheme 16.6) [10]. First, a Pd(0) species reacts with iodothiophene selectively to afford ArPdl, probably because the oxidative addition step is facilitated by coordination with the adjacent sulfur atom. Second, the ArPdl adds to allene, giving a Jt-allylpalladium complex, which is captured by a 2-iodoaniline derivative to afford an isolable allylic compound. Under more severe conditions, the oxidative addition of iodide to Pd(0) followed by the insertion of an internal olefm takes place to give an alkylpalladium complex, which is transmetallated with NaBPh4 to release the product. 

One of the major difficulties in the synthesis of these binary indole-indoline alkaloids is the necessity of generating the natural PARF (priority antireflective) (12) relative stereochemistry between C-14 and C-16, as well as the requirement for controlling the absolute stereochemistry at C-16, which must be (5). Other epimers at these positions lack the high cytotoxicity, with mitotic arrest at metaphase, that is the basis of the anticancer activity of these compounds (13,14). 

Sakamoto et al. reported the synthesis of hyellazole (245) and carazostatin (247) based on the benzannulation of indoles. This method involves an electrocyclization of the 3-(l,3-butadienyl)indoles 685, which derive from the indolin-3-one 686 and the phosphorus ylides 687 (Scheme 5.59). 

Dandia, A., Saha, M. and Taneja, H., Improved one-pot synthesis of 3-spiro indolines under microwave irradiation, Phosphorus, Sulfur Silicon, 1998, 139, 77-85. 

The Fischer indole synthesis. The Fischer acid-catalyzed conversion of an 7V-arylhydrazone 42 into an indole is one of the most powerful and versatile methods for the preparation of indoles . The mechanism involves a [3,3] sigmatropic Claisen-type rearrangement of a protonated enehydrazine tautomer 43 to give intermediate 44, which spontaneously cyclizes by loss of ammonia, probably via indoline 45, to an indole 46 (Scheme 27). For unsymmetrical ketones, two isomeric indoles are possible and the general result is that the indole derived from the more stable (usually the more highly substituted) enehydrazine is formed. 

The cascade sequence that affords bicyclic systems fails with the lithium derivatives of 2-bromo-iV,iV-diallylaniline. The methodology is useful for the synthesis of 3-substituted indolines and indoles, but the substrate undergoes only one anionic cyclization. Alkenyl vinyllithiums and alkenyl aryllithiums have also been employed in the preparation of alkylidenecyclopentanes and indanes. The intramolecular addition of vinyllithium reagents... 

Ji and co-workers [123] have reported a simple and efficient synthesis of spiro [indoline-3,4 -qumoUnes] 84 by a one-pot reaction of an isatin, malononitrile, and... 

Zhu S-L, Zhao K, Su X-M et al (2009) Microwave-assisted synthesis of new spiro[indoline-3, 4 -quinoline] derivatives via a one-pot multi-component reaction. Synth Commun 39 1355-1366... 

Fig. 12.9 Synthesis of 3- (indol-3-yl) -3-hydroxy indolin-2-ones in ionic hquids...

Rad-Moghadam K, Sharifi-Kiasaraie M, Taheri-Amlashi H (2010) Synthesis of symmetrical and unsymmetrical 3,3-di(indolyl)indolin-2-ones under controlled catalysis of ionic liquids. Tetrahedron 66 2316-2321... 

The synthesis of hippadine (44) and ungeremine (48) was performed by a combination of the directed ortho metallation and the modified Suzuki cross coupling reactions 134) (Scheme 15). (7-Bromo-5-mesyloxy)indoline reacted with (6-formyl-3,4-methylenedioxy)benzeneboronic acid under the modified Suzuki reaction conditions to give the pyrrolophenanthridone ring system 128, which was reduced with sodium bis(2-methoxyethoxy)alumi-num hydride (SMEAH) in boiling toluene to produce ungeremine (48) in 54% yield. Also, starting with 7-iodoindoline, a similar reaction sequence afforded anhydrolycorin-7-one (119), which was transformed to hippadine (44) in 90% yield by oxidation with DDQ. 

A related example involving a more complex substrate is found in Rapoport and Luly s formal synthesis of the 7-methoxymitosene (24). Again, decarbonylation of an a-tertiary amino acid chloride is employed to generate the iminium ion. The indoline acetal (23) produced in this way is essentially one diastereomer however, its stereochemistry was not established (Scheme 13). 

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