Pd-catalyzed cross-coupling reactions that form C–N bonds have become useful methods to synthesize anilines and aniline derivatives, an important class of compounds throughout chemical research. A key factor in the widespread adoption of these methods has been the continued development of reliable and versatile catalysts that function under operationally simple, user-friendly conditions. This review provides an overview of Pd-catalyzed N-arylation reactions found in both basic and applied chemical research from 2008 to the present. Selected examples of C–N cross-coupling reactions between nine classes of nitrogen-based coupling partners and (pseudo)aryl halides are described for the synthesis of heterocycles, medicinally relevant compounds, natural products, organic materials, and catalysts.

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

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

The coupling of aryl or vinyl halides with terminal acetylenes catalysed by palladium and other transition metals, commonly termed as Sonogashira cross-coupling reaction, is one of the most important and widely used sp2–sp carbon–carbon bond formation reactions in organic synthesis, frequently employed in the synthesis of natural products, biologically active molecules, heterocycles, molecular electronics, dendrimers and conjugated polymers or nanostructures. This critical review focuses on developments in the Sonogashira reaction achieved in recent years concerning catalysts, reaction conditions and substrates (352 references).

Recent advances in Sonogashira reactions

Late transition metal-catalyzed hydroamination and hydroamidation.

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Chemicals from Alkynes with Palladium Catalysts

A flexible, palladium-catalyzed indole and azaindole synthesis by direct annulation of chloroanilines and chloroaminopyridines with ketones.

Indazoles play an increasingly important role in drug discovery. They act as an efficient isostere for privileged structures such as indoles and benzimidazoles. Furthermore, this important scaffold is able to interact with a variety of diverse targets, as highlighted by the growing number of reports of biologically active indazole derivatives. However, only a limited number of approaches for the regioselective synthesis of N-substituted indazoles are available today. Most approaches afford the thermodynamically favored 1H-indazole or mixtures of 1Hand 2H-indazoles, whereas the regioselective formation of 2H-indazoles remains a very challenging task. The lack of a direct, efficient, and regioselective synthetic procedure for the construction of 2Hindazoles prevents their broader application in, for example, medicinal chemistry. Thus, there is an unmet need for the development of a simple and general synthesis of 2Hindazoles from readily available precursors. Herein we report a straightforward domino reaction sequence consisting of a regioselective coupling of monosubstituted hydrazines 2 with 2-halophenylacetylenes 1, followed by an intramolecular hydroamination through a 5-exo-dig cyclization and subsequent isomerization of the exocyclic double bond to give the aromatic 2H-indazole (Scheme 1). The first challenge in this strategy was the development of a regioselective transition-metal-catalyzed coupling of monosubstituted hydrazines 2 with 2-halophenylacetylenes 1 to afford the required N,N’-disubstituted hydrazines 4. Although a number of transition-metal-catalyzed coupling reactions of aryl halides with amides, amines, hydrazides, and hydrazones are known, only a few coupling reactions of hydrazines have been reported, and only one of the reported hydrazine couplings, for the formation of N,N-diaryl hydrazines, is regioselective. A second challenge in the development of our proposed strategy was the control of the hydroamination/ cyclization step to form the 1,2-dihydroindazole 5, as other possible cyclization pathways lead to other products, such as 1,2-dihydrocinnolines and N-azaindoles. The isomerization of the exocyclic double bond in dihydro-2H-indazole 5 to give the aromatic 2H-indazole 3 was expected to occur spontaneously under the reaction conditions and thus not to pose any problems. We initiated our investigation by screening for reaction conditions under which the coupling of 1-chloro-2-phenylethynylbenzene (1a) and phenylhydrazine (2a) would proceed efficiently to give the N,N’-diaryl hydrazine 4. Upon optimization of the reaction parameters (the transition metal, metal salt, ligand, base, solvent, and temperature), the desired coupling was found to proceed cleanly within just a few hours and with complete regioselectivity when the catalyst system [Pd2(dba)3]/PtBu3 (1:2) was used in toluene at 80 8C with NaOtBu as the base (dba = dibenzylideneacetone). This reaction is to our knowledge the first regioselective transition-metal-catalyzed coupling of monosubstituted hydrazines to give N,N’-disubstituted hydrazine products. We further optimized the reaction parameters to identify conditions that would promote the complete domino reaction of 1 a with 2a as a one-pot reaction (Table 1). We found that the use of polar solvents, such as DMF, NMP, or DMA, in combination with Cs2CO3 led to the formation of the desired 2H-indazole 3a in good yield (Table 1, entries 2–4), whereas Scheme 1. Proposed synthesis of 2H-indazoles.

A General and Mild Palladium‐Catalyzed Domino Reaction for the Synthesis of 2H‐Indazoles

Compounds of the formula I, in which R1, R2, R3, R4, R5, and R6 have the meanings given in the description, and their physiologically acceptable salts. The compounds are suitable for use, for example, as hypolipidemics.

Novel diphenylazetidinones, process for their preparation, medicaments comprising these compounds and their use

The invention relates to the compounds of the formula (I), wherein R1, R2, R3, R4, R5, and R6 have the cited meanings, and to their physiologically acceptable salts. The inventive compounds are suitable, for example, as hypolipidemics.

Novel 1,2-diphenzylazetidinones, method for producing the same, medicaments containing said compounds, and the use thereof for treating disorders of the lipid metabolism

Andreas Lindenschmidt

Papers

A flexible, palladium-catalyzed indole and azaindole synthesis by direct annulation of chloroanilines and chloroaminopyridines with ketones.

A General and Mild Palladium‐Catalyzed Domino Reaction for the Synthesis of 2H‐Indazoles

Novel diphenylazetidinones, process for their preparation, medicaments comprising these compounds and their use

Novel 1,2-diphenzylazetidinones, method for producing the same, medicaments containing said compounds, and the use thereof for treating disorders of the lipid metabolism

A general and mild domino approach to substituted 1-aminoindoles.