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.

Metal‐free partner: No organometallic coupling partner is required for a Pd‐catalyzed cross‐coupling reaction that employs N‐tosylhydrazones as the nucleophilic component (see scheme; Ts=4‐toluenesulfonyl).

Ethers made easy: Heating a solution containing a tosylhydrazone and either a phenol or an alcohol in the presence of K2CO3 leads to the corresponding ethers (see scheme; MW=microwave, Ts=tosyl). The reaction is fairly general for the preparation of aryl alkyl and alkyl alkyl ethers, and represents a new method for the reductive etherification of carbonyl compounds.

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.

Two different combinations of coupling partners can be employed for the synthesis of conjugated dienes by palladium-catalyzed cross-coupling with tosylhydrazones: a,b-unsaturated ketone and aryl halide or alkenyl halide and non-conjugated tosylhydrazone. Depending on the substrate, a vinylogous hydride elimination is responsible for the formation of the final dienes.Keywords: cross-coupling; dienes; ketones; palladium; tosylhydrazonesThe discovery of new C À C bond forming reactions that work efficiently and selectively, based on easily available starting materials, is a field of constant interest in organic chemistry. Palladium-catalyzed crosscoupling reactions are among the most appealing methodologies for this purpose.[1] Their usefulness is reflected in a growing application for the synthesis of very complex organic molecules, [2] in drug discovery programs, and in industrial chemical processes.[3] Most of metal-catalyzed C À C bond forming transformations consist of the combination of an organic halide with an organometallic reagent. Nevertheless, great efforts have been devoted in the recent years towards the development of new processes for the creation of C À C linkages that do not employ stoichiometric organometallics. [4][5][6][7] In this context, we have recently uncovered a new Pd-catalyzed coupling reaction that employs N-tosylhydrazones as nucleophilic partner, suppressing the stoichiometric organometallic reagent (Scheme 1). [8,9] Since then, we have initiated a research program to evaluate the synthetic potential of this novel reaction.Continuing the study of the scope of this C À C bond forming reaction, we turned our attention to N-tosylhydrazones derived from a,b-unsatured ketones. We now report that this catalytic process is an excellent method to prepare dienic structures and, in particular, homoanular cyclic dienes. Moreover, during the progress of this research, we have discovered a new reaction pathway that proceeds through a formal d-hydride elimination. Preliminary studies of this new pathway show that it can be also employed in the preparation of conjugated dienes from tosylhydrazones and haloalkenes.Initially we selected the cross-coupling between the hydrazone 1a derived from 4,4-dimethyl-2-cyclohexen-1-one 4a and p-bromotoluene 2a. A screening of reaction conditions with variation of bases, ligands, and reaction temperatures was carried out. The optimal conditions found comprised [Pd 2 A C H T U N G T R E N N U N G (dba) 3 ] (2.5 mol%) as the metal source, Xphos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) as ligand, and LiO-t-Bu as base, in dioxane at 110 8C. Under these conditions, the diene 3a could be obtained in very good yield (Scheme 2). By decreasing either temperature or catalyst loading, apart from an increment of the reaction time, formation of the Bamford-Stevens by-product, that occurs through a competitive uncatalyzed thermal process, took place.We have previously demonstrated that the crosscoupling reaction can be carried out in a one-pot fashion d...

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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.

Chloroalkenes, important building blocks for cross-coupling reactions, are prepared in one step by the Suzuki reaction of 1,1-dichloroethylene and 1,2-dichloroethylene with alkenyl-and arylboronic acids. Under the proper reaction conditions, it is possible to obtain the monocoupling reaction to provide the corresponding chloroalkenes with good yields. This method represents an excellent route for the preparation of chloroalkenes and chlorodienes from commercially available starting materials.