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

Transition-metal-catalyzed addition of heteroatom-hydrogen bonds to alkynes.

Several novel synthetic reactions of arenes and alkanes discovered and investigated in our laboratory are summarized here. These include olefin arylation, hydroarylation of alkynes, hydroxylation of arenes, carboxylation of arenes and alkanes, and aminomethylation and acetoxylation of alkanes. Most of these reactions are catalyzed by highly electrophilic transition metal cationic species generated in situ in an acid medium, involving electrophilic metalation of C−H bonds of arenes and alkanes which lead to the formation of aryl−metal and alkyl−metal σ-complexes.

Catalytic functionalization of arenes and alkanes via C-H bond activation.

Isolation and synthesis of biologically active carbazole alkaloids

Synthesis of Heterocycles via Palladium π-Olefin and π-Alkyne Chemistry

Palladium catalyzed reaction of 2-alkynylanilines with allyl chlorides. Formation of 3-allylindoles

Copulation cyclisante de pentyne-4oates de Li avec des halogenures d'allyle catalysee par PdCl 2 (CH 3 CN) 2

Palladium-catalyzed regio- and stereoselective cyclized coupling of lithium alkynoates with allyl halides

Carboxylative coupling of propargylic alcohols with allyl chloride

Palladium-Catalyzed Regio- and Stereoselective Cyclized Coupling of Lithium Alkynoates with Allyl Halides.

Pd(II) catalyzed reaction of N-carbomethoxy-2-alkynylanilines with allyl chlorides produces 2-alkyl-3-allyl-N-carbomethoxyindoles in the presence of oxirances; Aminopalladation of a N-carbomethoxy-2-alkynylaniline gives 3-(N-carbomethoxyindolyl)palladium intermediate, which regioselectively attacks on the γ position of chlorides to give 3-allyl-2-alkylindoles with concurrent regeneration of Pd(II) catalyst.

Koji Iritani

Papers

Palladium catalyzed reaction of 2-alkynylanilines with allyl chlorides. Formation of 3-allylindoles

Palladium-catalyzed regio- and stereoselective cyclized coupling of lithium alkynoates with allyl halides

Carboxylative coupling of propargylic alcohols with allyl chloride

Palladium-Catalyzed Regio- and Stereoselective Cyclized Coupling of Lithium Alkynoates with Allyl Halides.

Palladium Catalyzed Reaction of 2-Alkynylanilines with Allyl Chlorides. Formation of 3-Allylindoles.