José Barluenga

Tosylhydrazones: new uses for classic reagents in palladium-catalyzed cross-coupling and metal-free reactions.

Tosylhydrazones are useful synthetic intermediates that have been used in organic chemistry for almost 60 years. The recent discovery of a palladium-catalyzed cross-coupling reaction involving a tosylhydrazone coupling partner has triggered renewed interest in these reagents. This reaction shows nearly universal generality with regard to the hydrazone and can be employed for the preparation of polysubstituted alkenes. In the course of this research, novel metal-free C-C and C-O bond-forming reactions have been discovered. Since tosylhydrazones are readily prepared from carbonyl compounds, these transformations offer new synthetic opportunities for the unconventional modification of carbonyl compounds. This Minireview discusses all of these new reactions of a classic reagent.

Recent Advances in the Synthesis of Indole and Quinoline Derivatives through Cascade Reactions

Indoles and quinolines are ubiquitous structural motifs in many natural products and biologically active pharmaceuticals. The pursuit of synthetic efficiency has stimulated the design and development of new synthetic strategies to construct these heterocycles. One of the most effective ways of achieving efficiency is to implement reaction cascades, enabling multiple bond-forming and bond-cleaving events to occur in a single synthetic operation, thus circumventing the waste associated with traditional stepwise synthesis. In general, cascade reactions offer the opportunity to access highly functionalized final products from simple starting materials. For all these reasons, it is not a surprise that most of the recently reported methods for the synthesis of indoles and quinolines are based on the use of cascade reactions. In this Focus Review we discuss some of the most representative and interesting recent reports on the synthesis of indoles and quinolines through cascade reactions.

Metal-free carbon-carbon bond-forming reductive coupling between boronic acids and tosylhydrazones.

The formation of carbon–carbon bonds is a fundamental transformation in organic synthesis. In spite of the myriad methods available, advantageous methodologies in terms of selectivity, availability of starting materials, operational simplicity, functional-group tolerance, environmental sustainability and economy are in constant demand. In this context, the development of new cross-coupling reactions that use catalysts based on inexpensive and non-toxic metals is attracting increasing attention. Similarly, efficient processes that do not require a metal catalyst are of extraordinary interest. Here, we report a new and efficient metal-free carbon–carbon bond-forming coupling between tosylhydrazones and boronic acids. This reaction is very general and functional-group tolerant. As the required tosylhydrazones are easily generated from carbonyl compounds, it can be seen as a reductive coupling of carbonyls, a process of high synthetic relevance that requires several steps using other methodologies. New economic and environmentally benign methods for achieving carbon–carbon bond formation are in constant demand. Here, a remarkably efficient and functional-group-tolerant, metal-free reductive cross-coupling of carbonyl compounds with boronic acids is described.

Pyridine Activation via Copper(I)-Catalyzed Annulation toward Indolizines

The copper(I)-catalyzed regioselective [3 + 2] cyclization of pyridines toward alkenyldiazoacetates leading to functionalized indolizine derivatives is reported. A broad range of pyridine derivatives (including quinoline and isoquinoline) is compatible with this cyclization reaction. The process represents the first successful example of metal-catalyzed cyclization of a π-deficient heterocyclic system with alkenyldiazo compounds.

Modular Synthesis of Indoles from Imines and o-Dihaloarenes or o-Chlorosulfonates by a Pd-Catalyzed Cascade Process

A detailed study of the scope of a new Pd-catalyzed synthesis of indoles from 1,2-dihaloarenes and o-halobenzene sulfonates and imines is described. The cascade reaction comprises an imine alpha-arylation followed by an intramolecular C-N bond-forming reaction promoted by the same Pd catalyst. The reaction with 1,2-dibromobenzene shows wide scope and allows the introduction of aryl, alkyl, and vinyl substituents at different positions of the five-membered ring of the indole. The regioselective synthesis of indoles substituted in the six-membered ring can be carried out by employing o-dihalobenzene derivatives with two different halogens, taking advantage of the different reactivities of I, Br, and Cl in oxidative addition reactions. This paper also introduces a method for the efficient cleavage of the N-t-butyl group, thus allowing for the preparation of N-H indoles through the same methodology. Finally, the reaction with o-halosulfonates has been studied. The best substrates are o-chlorononaflates, which lead to indoles in very high yield. The reaction is particularly appropriate for the synthesis of the challenging 6-substituted indoles. In view of the availability of o-chlorophenols, which are direct precursors of the chlorononaflates, this reaction represents an efficient entry into indoles substituted in the six-membered ring. The concept is illustrated by the preparation of a 4,6-disubstituted indole from naturally occurring anethole.

Synthesis of Polysubstituted Olefins by Pd-Catalyzed Cross-Coupling Reaction of Tosylhydrazones and Aryl Nonaflates

Aryl nonaflates are employed as electrophiles in the Pd-catalyzed cross-coupling with tosylhydrazones affording di-, tri-, and tetrasubstituted olefins. Fine tunning of the reaction conditions are required to accomplish the coupling successfully, including the addition of LiCl and the presence of small amounts of water. Under the optimized conditions, the reactions proceed with high yield and also high stereoselectivity depending on the nature of the coupling partners.

Gold-Catalyzed Intermolecular Hetero-Dehydro-Diels-Alder Cycloaddition of Captodative Dienynes with Nitriles : A New Reaction and Regioselective Direct Access to Pyridines

For the first time, nitriles are used as 2pi electron component in a gold-catalyzed intermolecular hetero-dehydro-Diels-Alder cycloaddition with captodative enynes leading to the regioselective formation of pyridines.

Cu(I)-catalyzed regioselective synthesis of polysubstituted furans from propargylic esters via postulated (2-furyl)carbene complexes.

Polysubstituted furan derivatives are regioselective obtained from (bis-alkynyl)methyl carboxylates in the presence of catalytic amounts of copper(I) salts. This multistep process is consistent with the intermediacy of a copper(I) (2-furyl)carbene complex which is intercepted by suitable trapping reagents.

Intramolecular Diamination of Alkenes with Palladium(II)/Copper(II) Bromide and IPy2BF4: The Role of Halogenated Intermediates

The oxidative intramolecular diamination of alkenes with tethered ureas and related groups as the nitrogen source has been investigated both with the iodonium reagent IPy(2)BF(4) (Py=pyridine) and under palladium catalysis in the presence of copper(II) bromide as a reoxidant. For terminal alkenes, the two procedures enable selective and high-yielding transformations. Studies with deuterated material led to the conclusion that the reactions proceed through different stereochemical pathways. An advanced protocol for palladium-catalyzed diamination through six-membered-ring annulation was also developed, and the first examples of the intramolecular diamination of internal alkenes are described. In this case, the same stereochemical outcome was observed for the iodonium-promoted and palladium-catalyzed transformations. On this basis, it was possible to determine the importance of aminohalogenated intermediates in both diamination reactions. Overall, the disclosed procedures broaden significantly the synthetic applicability of the oxidative intramolecular diamination of alkenes.

[1,5]‐Hydride Transfer/Cyclizations on Alkynyl Fischer Carbene Complexes: Synthesis of 1,2‐Dihydroquinolinyl Carbene Complexes and Cascade Reactions

processes the first and rate-limiting step comprises of a hydride migration from the carbon atom, a to the hetero atom, to the electrophilic position of the vinyl group. Thus, suitable systems for the tandem reaction must feature a heteroatom, to stabilize the carbocation that develops upon hydride migration, and a strong electron-withdrawing group on the terminal position of the double bond. More recently, this strategy has been extended to functionalize the a position of ethers and carbamates, and even tertiary benzylic C H bonds in processes promoted by Lewis acid catalysts (Figure 1b). To the best of our knowledge, there is no precedent for analogous hydride-transfer-promoted cyclizations involving triple bonds, despite the synthetic power of this type of cascade isomerization. In contrast, ortho-alkynyl anilines undergo metal-catalyzed 5-endo-dig cycloisomerizations leading to indole derivatives. As a part of our work on the chemistry of alkynyl Fischer carbene complexes, we turned our attention to the study of chromium ortho-aminophenylalkynyl complexes (1; Scheme 1). Alkynyl carbene complex 1a was synthesized by standard procedures, and it was stable at room temperature, however, when a solution of 1a in THF was heated at 90 8C in a sealed tube, new carbene complex 2a was isolated in 98% yield after the workup (Scheme 1).