Giancarlo Fabrizi

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.

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.

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.

Palladium Catalysis in the Construction of the Benzo[b]furan and Furan Rings from Alkynes and Organic Halides or Triflates

Three general processes leading to the construction of functionalized benzo[b]furan and furan rings are reviewed: 1) the coupling-cyclization methodology, involving the palladium-catalyzed coupling of terminal alkynes with o-iodophenols, or the alternative palladium-catalyzed coupling of terminal alkynes containing proximate oxygen nucleophiles with aryl and vinyl halides or triflates, followed by the cyclization of the resultant coupling intermediates; 2) the oxypalladation-reductive elimination domino reaction, based on the trans addition of the oxygen and an organopalladium complex across the carbon-carbon triple bond, followed by a reductive elimination step; 3) the carbopalladation-cyclization reaction, based on the syn addition of an organopalladium complex, containing an oxygen nucleophile, to the carbon-carbon triple bond, followed by the cyclization of the resultant carbopalladation adduct.

2-Substituted-3-allenyl-benzo[b]furans through the palladium-catalysed cyclization of propargylic o-(alkynyl)phenyl ethers

Abstract The reaction of propargylic o-(alkynyl)phenyl ethers in the presence of Pd(PPh3)4 and K2CO3 affords 2-substituted-3-allenylbenzo[b]furans in good yields. Depending on the nature of the starting alkyne, variable amounts of isomeric 2-substituted-3-propargylbenzo[b]furans have been isolated.

Sonogashira cross-coupling of arenediazonium salts.

Arenediazonium salts represent an attractive alternative to aryl halides or triflates because of their higher reactivity, their tolerance of milder conditions, their availability from inexpensive anilines, and because additional base is not required in several applications. Arenediazonium salts have been used in a variety of palladium-catalyzed reactions, including Mizoroki–Heck reactions, Suzuki–Miyaura and Stille crosscoupling reactions, and carbonylation reactions, in the synthesis of sulfinic acids and boronic esters; their use in hydroarylation reactions has also been described. Nevertheless, the alkynylation of arenediazonium salts continues to represent a challenge. After the seminal works of Sonogashira et al. , Heck and Dieck, and Cassar on the alkynylation of aryl iodides and bromides, a great deal of work has been done to extend the scope of the reaction to include an even wider range of reactants; however, the extension of the reaction to arenediazonium salts remains unresolved. To the best of our knowledge, the sole attempt to involve arenediazonium salts in the formation of arylacetylenes was made by GenÞt and co-workers, who obtained only small amounts of the desired cross-coupling derivative by palladium-catalyzed reaction of potassium 1-hexenyltrifluoroborate with para-toluenediazonium tetrafluoroborate. We investigated the reaction using phenylacetylene (1a) and 4-methoxybenzenediazonium tetrafluoroborate (2a) as the model system. No evidence of the formation of cross-coupling product 3a was found using [Pd2(dba)3] (dba = dibenzylideneacetone) or Pd(OAc)2 with a variety of phosphine (PPh3, Xphos, HP(tBu)3BF4) or carbene ligands, generated from 1,3bis(2,6-diisopropylphenyl)imidazolium chloride in the presence of base; a screen of different solvents (MeOH, THF, DME, DMF), in the presence or absence of base (iPr2NEt, K2CO3, Bu4NOAc) and CuI at temperatures ranging from room temperature to 60 8C also afforded no cross-coupled product. In all cases, complex reaction mixtures were obtained, and anisole and 1,4-diphenyl-1,3-diyne were frequently the main by-products. To overcome this limit of the palladium-based chemistry of arenediazonium salts, we reasoned that a strategy in which arylacetylenes are formed by an iododediazoniation reaction, followed by a Sonogashira cross-coupling might be successful. Iododediazoniation is a well-established reaction, and recently remarkable advances have been reported in this area. Nevertheless, no examples of its utilization in a sequential process with a palladium-catalyzed reaction have yet been described. Herein, we show that such a sequential process is indeed possible and report the first utilization of arenediazonium salts in Sonogashira cross-coupling reactions. An initial screen using [PdCl2(PPh3)2], CuI, and Et2NH in MeCN at room temperature showed that 3a could be isolated in 48 % yield in the presence of nBu4NI (1.5 equiv) or NaI (2 equiv; Table 1, entries 1 and 2). Optimization studies were then performed by changing the nature and number of equivalents of the base.

Phosphine-Free Perfluoro-Tagged Palladium Nanoparticles Supported on Fluorous Silica Gel: Application to the Heck Reaction†

The immobilization of phosphine-free perfluoro-tagged palladium nanoparticles Pd-1 on fluorous silica gel (FSG) and their utilization in the Heck reaction have been investigated. High yields of vinylic substitution products have been obtained. Recycling studies have shown that the solid-supported palladium catalyst can be readily recovered and reused several times without significant loss of activity. Reactions and recovery of the solid-supported palladium catalyst system can be carried out in the presence of air, without any particular precaution.

One-pot gold-catalyzed synthesis of azepino[1,2-a]indoles.

Indoles from scratch: A gold(I)/N-heterocyclic carbene complex (IPr=1,3-di(isopropylphenyl)imidazol-2-ylidene) was found to be particularly effective as a catalyst, enabling the one-pot synthesis of tricyclic azepinoindoles by an unprecedented cascade reaction. Readily available substrates, high chemoselectivity, good yields, and water as the only stoichiometric by-product are some of the main advantages of this method.

The Heck Reaction of Allylic Alcohols Catalyzed by Palladium Nanoparticles in Water: Chemoenzymatic Synthesis of (R)‐(−)‐Rhododendrol

The use of phosphine‐free perfluoro‐tagged palladium nanoparticles immobilized on fluorous silica gel (FSG), either through fluorous–fluorous interactions or covalent bonding, in the Heck reaction of aryl iodides with allylic alcohols under aerobic conditions in water is described. 4‐(4‐Methoxyphenyl)‐butan‐2‐one, an important fine chemical, is readily accessed by this procedure. A two‐step one‐pot process, involving a Heck reaction followed by an enantioselective enzyme‐catalyzed reduction, to form chiral alcohols is applied to the synthesis of (R)‐(−)‐rhododendrol. The palladium catalysts can be recycled several times, both in the Heck reaction and in the one‐pot chemoenzymatic process.