Understanding Cu(II)-based systems for C(sp3)-H bond functionalization: insights into the synthesis of aza-heterocycles.

Herein we report the synthesis of imidazo[1,5-a]pyridine heterocycles via a Cu(II)-mediated functionalization of α'-C(sp3)-H bonds of pyridinylaldimines and subsequent cyclization. This strategy exploits the inherent directing ability of heteroleptic aldimine and pyridine groups in the substrate yielding the C-H functionalization of α'-methylene groups in a regioselective fashion over distant methyl or methylene groups in ß or γ positions. The observed correlation between the nature of the anionic ligands (halide vs. carboxylate) bonded to copper and the chemoselectivity of the C(sp3)-H activation process points to a concerted metalation-deprotonation pathway prior to cyclization to furnish the corresponding imidazo[1,5-a]pyridine derivative. This copper-mediated C(sp3)-H bond functionalization reaction works for a variety of substrates incorporating linear alkyl chains (from 3 to 12 carbon atoms), and good functional group tolerance (aryl, ether and ester groups). Cu-Catalyzed C(sp2)-H cyanation on the imidazole ring can then take place selectively under oxidative conditions.

Copper nanocatalysts applied in coupling reactions: a mechanistic insight.

Copper-based nanocatalysts have seen great interest for use in synthetic applications since the early 20th century, as evidenced by the exponential number of contributions reported (since 2000, more than 48 000 works published out of about 81 300 since 1900; results from SciFinder using "copper nanocatalysts in organic synthesis" as keywords). These huge efforts are mainly based on two key aspects: (i) copper is an Earth-abundant metal with low toxicity, leading to inexpensive and eco-friendly catalytic materials; and (ii) copper can stabilize different oxidation states (0 to +3) for molecular and nanoparticle-based systems, which promotes different types of metal-reagent interactions. This chemical versatility allows different pathways, involving radical or ionic copper-based intermediates. Thus, copper-based nanoparticles have become convenient catalysts, in particular for couplings (both homo- and hetero-couplings), transformations that are involved in a remarkable number of processes affording organic compounds, which find interest in different fields (medicinal chemistry, natural products, drugs, materials, etc.). Clearly, this richness in reactivity makes understanding the mechanisms more complex. The present review focuses on the analysis of reported contributions using monometallic copper-based nanoparticles as catalytic precursors applied in coupling reactions, paying attention to those shedding light on the reaction mechanism.

Direct, Enantioselective, and Nickel(II) Catalyzed Reactions of N-Azidoacetyl Thioimides with Trimethyl Orthoformate: A New Combined Methodology for the Rapid Synthesis of Lacosamide and Derivatives.

A direct and highly enantioselective reaction of N-azidoacetyl-1,3-thiazolidine-2-thione with trimethyl orthoformate catalyzed by Tol-BINAPNiCl2 in the presence of TESOTf and 2,6-lutidine is reported. The heterocyclic scaffold can be easily removed by addition of a wide array of amines to give the corresponding enantiomerically pure 2-azido-3,3-dimethoxypropanamides in high yields. Appropriate manipulation of the N-benzyl amide derivative provides an efficient access to the antiepileptic agent lacosamide through a new enantioselective C-C bond-forming process. DFT computational studies uncover clues for the understanding of the remarkable stereocontrol of the addition of a nickel(II) enolate to a putative oxocarbenium intermediate from trimethyl orthoformate.