Practical methodologies for the synthesis of indoles.

The substituted indole nucleus [indole is the acronym from indigo (the natural dye) and oleum (used for the isolation)] is a structural component of a vast number of biologically active natural and unnatural compounds. The synthesis and functionalization of indoles has been the object of research for over 100 years, and a variety of well-established classical methods are now available, to name a few of them, the Fisher indole synthesis, the Gassman synthesis of indoles from N-halo-anilines, the Madelung cyclization of N-acyl-o-toluidines, the Bischler indole synthesis, the Batcho-Leimgruber synthesis of indoles from o-nitrotoluenes and dimethylformamide acetals, and the reductive cyclization of o-nitrobenzyl ketones.1 In the last 40 years or so, however, palladiumcatalyzed reactions, generally tolerant of a wide range of functionalities and therefore applicable to complex molecules, have achieved an important place in the arsenal of the practicing organic chemist. Since the invention of an industrial process for the palladium-catalyzed production of acetaldehyde from ethylene in the presence of PdCl2 and CuCl2, an everincreasing number of organic transformations have been based on palladium catalysis. Almost every area of the organic synthesis has been deeply influenced by the profound potential of this versatile transition metal, modifying the way organic chemists design and realize synthetic processes.2,3 Because of its catalytic nature, palladium-catalyzed synthesis can provide access to fine chemicals, agrochemical and pharmaceutical intermediates, and active ingredients in fewer steps and with less waste than classical † In memory of Prof. Bianca Rosa Pietroni, a colleague and very close friend. * To whom correspondence should be addressed. Phone: + 39 (06) 4991-2785. Fax: + 30 (06) 4991-2780. E-mail: sandro.cacchi@ uniroma1.it. 2873 Chem. Rev. 2005, 105, 2873−2920

Synthesis and functionalization of indoles through palladium-catalyzed reactions

Over the last decade, substantial research has led to the introduction of an impressive number of efficient procedures which allow the selective construction of CC bonds by directly connecting two different CH bonds under oxidative conditions. Common to these methodologies is the generation of the reactive intermediates in situ by activation of both CH bonds. This strategy was introduced by the group of Li as cross-dehydrogenative coupling (CDC) and discloses waste-minimized synthetic alternatives to classic coupling procedures which rely on the use of prefunctionalized starting materials. This Review highlights the recent progress in the field of cross-dehydrogenative C sp 3C formations and provides a comprehensive overview on existing procedures and employed methodologies.

The Cross-Dehydrogenative Coupling of C sp 3H Bonds: A Versatile Strategy for CC Bond Formations

Occurrence, Biogenesis, and Synthesis of Biologically Active Carbazole Alkaloids

Advances in the chemistry of tetrahydroquinolines.

The title 2-substituted benzimidazoles are prepared by a highly efficient one-pot procedure, cyclodehydration of the corresponding accessible carboxylic acids and 1,2-arylenediamines, using polyphosphoric acid as the catalyst and solvent in a condensation of the type found in the Phillips benzimidazole synthesis. The method has been adapted and proved to be extremely useful for 1-alkyl-(1H- benzimidazol-2-yl)pyridinium tetrafluoroborates with a methylene and vinylene interannular moiety

An Advantageous Synthesis of 2-Substituted Benzimidazoles Using Polyphosphoric Acid. 2-(Pyridyl)-1H-benzimidazoles, 1-Alkyl-(1H-benzimidazol-2-yl)pyridinium Salts, their Homologues and Vinylogues

An indole-templated ring-closing metathesis or a 2-indolylacyl radical cyclization constitute the central steps of two alternative approaches developed to assemble the tricyclic ABC substructure of the indole alkaloid apparicine. From this key intermediate, an intramolecular vinyl halide Heck reaction accomplished the closure of the strained 1-azabicyclo[4.2.2]decane framework of the alkaloid with concomitant incorporation of the exocyclic alkylidene substituents.

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Total synthesis of the bridged indole alkaloid apparicine.

The dimethyltitanocene methylenation of N-acylamides derived from ortho-vinylanilines, ortho-allylaniline, and ortho-vinylbenzylamine provides the corresponding enamides, which upon exposure to the second generation Grubbs ruthenium catalyst give access to indoles, 1,4-dihydroquinolines, and 1,2-dihydroisoquinolines, respectively. This sequential protocol also allows the synthesis of dihydrobenzoazepines, although the ring-closing metathesis (RCM) step is complicated by the alkene isomerization processes. From certain substrates, the direct annulation is observed in the titanium-mediated step, which is likely to occur through an olefin metathesis−intramolecular olefination sequence.

Sequential N-Acylamide Methylenation−Enamide Ring-Closing Metathesis: Construction of Benzo-Fused Nitrogen Heterocycles

2-Indolylacyl radicals generated from the corresponding selenoesters under hexabutylditin−hν conditions undergo regioselective intramolecular reaction with unprotonated pyridines to give polycyclic indolylpyridyl ketones. For substrates bearing a (3-pyridyl)methyl moiety connected to the 3-position of the indole ring, the cyclization provides easy access to ellipticine quinones.

Tomas Roca

Papers

An Advantageous Synthesis of 2-Substituted Benzimidazoles Using Polyphosphoric Acid. 2-(Pyridyl)-1H-benzimidazoles, 1-Alkyl-(1H-benzimidazol-2-yl)pyridinium Salts, their Homologues and Vinylogues

Total synthesis of the bridged indole alkaloid apparicine.

Sequential N-Acylamide Methylenation−Enamide Ring-Closing Metathesis: Construction of Benzo-Fused Nitrogen Heterocycles

Regioselective intramolecular reactions of 2-indolylacyl radicals with pyridines : A direct synthetic entry to ellipticine quinones

Synthesis of 5-(sulfamoylmethyl)indoles