Sandro Cacchi

Copper-catalyzed C-C bond formation through C-H functionalization: synthesis of multisubstituted indoles from N-aryl enaminones.

Because of the economic attractiveness and good functional tolerance of copper-catalyzed methods and hence their potential in large-scale applications, during the past few years there have been remarkable advances in the use of copper catalysis in organic synthesis. An impressive number of Ullmann coupling reactions have been described starting from aryl halides and suitable reagents. Recent reports have shown that copper catalysis can also be used in the formation of C heteroatom and C C bonds through selective catalytic activation of aryl C H bonds, a topic of intense current interest that, for the most part, has witnessed the use of palladium-, rhodium-, and ruthenium-based catalysts. In particular, intramolecular copper-catalyzed ortho C H functionalizations through C N and C O bond-forming reactions have been shown to form benzimidazoles and benzoxazoles from amidines and anilides, respectively. Herein, we disclose a new synthesis of multisubstituted indoles from N-aryl enaminones that involves an intramolecular coppercatalyzed aryl C H functionalization through C C bond formation. The indole moiety is prevalent in a vast array of biologically active natural and nonnatural compounds. Consequently, despite the existence of numerous methods for the synthesis of indole derivatives, the development of new, more efficient procedures is a subject of great importance. N-Aryl enaminones 1 were readily prepared through Sonogashira cross-coupling of terminal alkynes with aroyl chlorides, followed by the conjugate addition of anilines with the resultant a,b-ynones. We initiated our study by examining whether the enaminone 1a could be converted into the corresponding indole 2a. Reactions were usually carried out under an atmosphere of air. After an initial screen of copper catalysts (CuSO4, CuCl2, CuI), we found that 2 a could be isolated in 63 % yield by using CuI, Li2CO3, and 1,10-phenanthroline (phen) in dimethyl acetamide (DMA) after 48 h (Table 1, entry 1). Optimization studies were then performed that varied the

The Aminopalladation/Reductive Elimination Domino Reaction in the Construction of Functionalized Indole Rings

The aminopalladation-reductive elimination tandem reaction of internal and terminal alkynes containing proximate nitrogen nucleophiles has been proved to be a powerful and useful tool for the construction of the substituted pyrrole nucleus of the indole system. The fact that the reaction can be carried out with a wide assortment of organopalladium precursors and readily available starting alkynes, the ease of execution and the tolerance of a wide range of functional groups highlights its importance and flexibility and may contribute toward its utilization in the synthesis of complex indole derivatives. The method may provide a versatile complement of well established classical methods such as the Batcho-Limgruber synthesis of indoles from o-nitrotoluenes and dimethylformamide acetals, the Fisher indole synthesis, the Gassman synthesis of indoles from N-halo anilines, the Madelung cyclization of N-acyl-o-toluidines, and the reductive cyclization of o-nitrobenzyl ketones.

Heterocycles via cyclization of alkynes promoted by organopalladium complexes

Two general classes of reactions leading to heterocycles are reviewed: the sequential hydroarylation(hydrovinylation)/cyclization of alkynes containing proximate nucleophilic and electrophilic centers, a process which combines the palladium-catalyzed cis addition of an aryl or vinyl unit and a hydrogen atom to the carbon–carbon triple bond with the formation of a new bond between the nucleophile and the electrophile; the palladium-catalyzed cyclization of alkynes containing proximate nucleophiles with organopalladium complexes, which is based on a trans heteropalladation/reductive elimination tandem reaction.

Palladium-catalysed coupling of aryl and vinyl triflates or halides with 2-ethynylaniline: An efficient route to functionalized 2-substituted indoles

Abstract The palladium(0)-catalysed coupling of aryl and vinyl triflates or halides with the easily available 2-ethynylaniline, followed by a palladium(II)-catalysed cyclization step, provides an efficient and very versatile procedure for the synthesis of functionalyzed 2-substituted indoles.

Palladium catalyzed triethylammonium formate reduction of aryl triflates. A selective method for the deoxygenation of phenols.

Abstract Phenols can be selectively deoxygenated by reduction of the corresponding aryl triflates with triethylammonium formate in the presence of a homogeneous palladium catalyst.

N-Propargylic β-Enaminones: Common Intermediates for the Synthesis of Polysubstituted Pyrroles and Pyridines

N-Propargylic beta-enaminones have been used as common intermediates for the synthesis of polysubstituted pyrroles and pyridines. Best results have been obtained using DMSO as solvent. In the presence of Cs(2)CO(3) N-propargylic beta-enaminones are cyclized to pyrroles in good to high yields, whereas omitting bases and using CuBr leads to the selective formation of pyridines.

Palladium-catalyzed carbonylation of aryl triplates. Synthesis of arenecarboxylic acid derivatives from phenols

Abstract Various aryl triflates derived from phenols were converted into aryl esters or amides in good yields by a palladium-catalyzed reaction with carbon monoxide and alcohols or amines.

Palladium-catalyzed carbonylation of enol triflates. A novel method for one-carbon homologation of ketones to α,β-unsaturated carboxylic acid derivatives

Abstract Ketones can be homologated to α,gb-unsaturated esters or amides via their enol triflates by a palladium-catalyzed reaction with carbon monoxide and alcohols or amines.

Palladium-catalyzed reduction of enol triflates to alkenes

Abstract Enol triflates react with trialkylammonium formate-palladium reagent to give alkenes.

Perfluoro-tagged, phosphine-free palladium nanoparticles supported on silica gel: application to alkynylation of aryl halides, Suzuki–Miyaura cross-coupling, and Heck reactions under aerobic conditions

The utilization of perfluoro-tagged palladium nanoparticles immobilized on fluorous silica gel through fluorous–fluorous interactions (Pdnp–A/FSG) or through covalent bonding to silica gel (Pdnp–B) in the alkynylation of aryl halides, in the Suzuki–Miyaura cross-coupling, as well as in the Heck reaction between methyl acrylate and aryl iodides is described. The reactions are carried out under aerobic and phosphine-free conditions with excellent to quantitative product yields in each case. The catalysts are easily recovered and reused several times without significant loss of activity. The alkynylation of aryl halides (under copper-free conditions) and the Suzuki–Miyaura cross-coupling are carried out in water. The Heck reaction of methyl acrylate with aryl iodides is best performed in MeCN. The utilization of Pdnp–B in the synthesis of 2,3-disubstituted indoles from 2-(alkynyl)trifluoroacetanilides and aryl halides is also reported.