Carlos Valdés

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.

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.

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.

[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).

Tosylhydrazide-promoted palladium-catalyzed reaction of β-aminoketones with o-dihaloarenes: combining organocatalysis and transition-metal catalysis.

One of the main challenges of current organic synthesis is the design of practically simple and increasingly efficient organic transformations. The sequential formation of various bonds through tandem or cascade reactions constitutes one approach to achieving this goal. In these types of reactions, high molecular complexity can be built from relatively simple starting materials in a single synthetic operation. Moreover, among the advantages of these processes are atom, solvent, and catalyst economy and operational simplicity, as isolation of intermediates is avoided. In the context of transition-metal-catalyzed reactions, processes in which a single, multifunctional metal catalyst promotes various individual reactions (auto-tandem catalysis) are of great interest. By taking advantage of the wide scope, high performance, and remarkable stability of state-ofthe-art Pd catalysts, a variety of Pd-catalyzed processes have been developed based on this principle. We have recently discovered a new Pd-catalyzed C C bond-forming reaction that employs N-tosylhydrazones as nucleophilic component in a new type of “stoichiometric organometallic-free” cross-coupling process. Moreover, the tosylhydrazone can be generated in situ from a carbonyl compound and tosylhydrazide, which implies that the carbonyl compounds can be directly employed in the crosscoupling reaction (Scheme 1). Following our interest in auto-tandem Pd-catalyzed processes, we decided to investigate whether the new C C bond-forming reaction with tosylhydrazones could be one of the processes promoted by a multifunctional catalyst. Following this idea, we designed a possible sequence employing hydrazones derived from b-aminoketones I and odihalobenzene derivatives II as starting materials. Thus, in the presence of the Pd catalyst two consecutive processes might occur: a C C cross-coupling reaction (arylation) to give intermediate III, followed by an intramolecular C N bondforming reaction (amination) affording substituted tetrahydroquinolines IV (Scheme 2). Moreover, taking into account that a variety of b-aminoketones are accessible in enantiomerically pure form through asymmetric organocatalyzed Mannich reactions, our ultimate goal would be to develop a heterocyclization process that would preserve the configurationally unstable stereogenic center in the a position to the carbonyl group.

Novel method for the synthesis of enamines by palladium catalyzed amination of alkenyl bromides

The intermolecular palladium catalyzed cross-coupling reaction between secondary amines and alkenyl bromides is described for the first time, giving rise to enamines with very high yields and regioselectivity.

Palladium catalyzed amination of vinyl chlorides: a new entry to imines, enamines and 2-amino-1,3-butadienes

Vinyl chlorides are employed for the first time in palladium catalyzed cross-coupling reactions with amines to furnish imines and enamines. The new methodology has been applied to the synthesis of 2-amino-1,3-butadienes, that could not be achieved from the corresponding bromides.

Synthesis of Polysubstituted Isoquinolines through Cross-Coupling Reactions with α-Alkoxytosylhydrazones

A Pd-catalyzed cross-coupling reaction of α-alkoxytosylhydrazones with sulfonates derived from salicyl aldehydes gives rise to protected 1,5-dicarbonyl compounds. Treatment with ammonium hydroxide readily transforms these alkenes into isoquinolines with diverse substitution patterns at positions 3 and 4. In a similar way, the employment of o-cyanononaflates in the coupling reaction, followed by treatment with an organometallic, provides isoquinolines that incorporate substitution also at position 1. The combination of both approaches represents a versatile method for the preparation of isoquinolines substituted at any position of the heterocyclic ring.

Synthesis of Chiral Pyrazoles: A 1,3‐Dipolar Cycloaddition/[1,5] Sigmatropic Rearrangement with Stereoretentive Migration of a Stereogenic Group

The reactions between terminal alkynes and α-chiral tosylhydrazones lead to the obtention of chiral pyrazoles with a stereogenic group directly attached at a nitrogen atom. The cascade reaction includes decomposition of the hydrazone into a diazocompound, 1,3-dipolar cycloaddition of the diazo compound with the alkyne, and [1,5] sigmatropic rearrangement with migration of the stereogenic group. This strategy has been successfully applied to the synthesis of structurally diverse chiral pyrazoles through α-chiral tosylhydrazones, obtained from α-phenylpropionic acid, α-amino acids, and 2-methoxycyclohexanone. Notably, the stereoretention of the [1,5] sigmatropic rearrangements represent very rare examples of this stereospecific transformation.