Palladium‐Catalyzed Formal Hydroalkylation of Aryl‐Substituted Alkynes with Hydrazones

Abstract

We have developed an unprecedented Pd-catalyzed formal hydroalkylation of alkynes with hydrazones, which are generated in situ from naturally abundant aldehydes, as both alkylation reagents and hydrogen donors. The hydroalkylation proceeds with high regio-and stereoselectivity to form (Z)-alkenes, which are more difficult to generate compared to (E)-alkenes. The reaction is compatible with a wide range of functional groups, including hydroxy, ester, ketone, nitrile, boronic ester, amine, and halide groups. Furthermore, latestage modifications of natural products and pharmaceutical derivatives exemplify its unique chemoselectivity, regioselectivity, and synthetic applicability. Mechanistic studies indicate the possible involvement of Pd-hydride intermediates. Alkenes are basic functionalities and highly desirable building blocks. They are not only frequently used as versatile synthetic intermediates but are also prevalent among organic molecules with a wide range of applications. [1] Therefore, the exploration of efficient methods for their synthesis has been a continuous pursuit throughout the history of organic chemistry. [2] Among the many efforts toward alkene syntheses, the transition-metal-catalyzed "formal" hydrofunctionalization of simple and readily available alkynes is considered one of the most straightforward and versatile stereocontrolled approaches to access various alkenes. [3, 4] Despite requiring a stoichiometric amount of reductant or organometallic reagent, transition-metal-catalyzed "formal" hydroalkylation reaction between alkynes and alkyl halides, pseudohalides, or boranes is considered an appealing strategy in this field and has attracted great interest (Scheme 1 a). [5-8] Without using halides and other functional groups, C(sp 3)ÀH bond alkenylation represents a promising method for conversion of alkynes to alkenes, and some elegant examples have been disclosed involving the direct C À H activation [9] and radical processes (Scheme 1 b). [10] Very recently, MacMillan and Rueping independently developed Ir and Ni dual-catalytic photoredox decarboxylative hydroalkylation reactions with carboxylic acids as the alkyl donors (Scheme 1 c). [11] Although much progress has been made, a number of challenges remain unsettled in this field. For example, most methods require stoichiometric reductant/organometallic reagents, oxidants, or directing groups, and the alkyl donors are limited to alkyl halides, pseudohalides, boranes, carboxylic acids, and compounds with activated C(sp 3)ÀH bonds. As the synthetic community is placing increasing emphasis on more sustainable, versatile, and operationally simple chemical syntheses, the development of new alkylation reagents that are readily derived from naturally abundant chemical feedstocks with harmless byproducts is highly desirable. Recently, our group developed the easily available umpolung carbonyls as nucleophiles in a series of transformations with unsaturated compounds, including carbonyls, [12] imines, [13] carbon dioxide, [14] and activated alkenes ...

Alkyl Formates as Transfer Hydroalkylation Reagents and Their Use in the Catalytic Conversion of Imines to Alkylamines**

“…Interestingly, the group of Li sought after the use of N 2 as a gaseous linker and employed hydrazones as transfer hydroalkylating reagents for imines in presence of a Ru‐based catalyst (Scheme 1c) [11] . The authors then extended the scope of the unsaturated coupling partner, using carbonyl, [12] activated alkenes, [13] or alkynes [14] . Although interesting from an atom‐economical point of view, the handling of hydrazone might however limits its use on large‐scale syntheses.…”

Syntheses, Characterization, and Multifaceted Coordination Chemistry of Hydrazonido Titanium Complexes

“…In the past, hydrazones were indirectly used to analyze aldehydes and ketones via the DNP test with 2,4-dinitrophenylhydrazine (DNPH) to form crystalline hydrazones with sharp melting points . Nowadays, they are used as substrates in homogeneous catalysis for hydrogenation − and hydroalkylation − reactions or as a precursor for the catalytic synthesis of heteroaromatics. , Hydrazone-based metal complexes are of recent interest and have various catalytic, , analytical, , and biomedical , applications. Hydrazido ligands are structurally related to the hydrazonido ligands, and there are many examples of hydrazido complexes .…”