Late stage C―H activation of a privileged scaffold; synthesis of a library of benzodiazepines

A library of over twenty 5-(2-arylphenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ones has been formed by a microwave-mediated late-stage palladium-catalysed arylation of 1,4-benzodiazepines using diaryliodonium salts. This can also be applied to nordazepam (7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one), the active metabolite of diazepam, and subsequent N-alkylation and/or H/D exchange allows further diversification towards elaborated pharmaceuticals and their 3,3'-deuterated analogues

Combining Sanford arylations on benzodiazepines with the nuisance effect

5-Phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-ones react under palladium- and visible light photoredox catalysis, in refluxing methanol, with aryldiazonium salts to afford the respective 5-(2- arylphenyl) analogues. With 2- or 4-fluorobenzenediazonium derivatives, both fluoroaryl- and methoxyaryl- products were obtained, the latter resulting from a SNAr on the fluorobenzenediazonium salt (“nuisance effect”). A computational DFT analysis of the palladium-catalysed and the palladium/ruthenium-photocalysed mechanism for the functionalization of benzodiazepines indicated that in the presence of the photocatalyst the reaction proceeds via a low-energy SET pathway avoiding the high-energy oxidative addition step in the palladium-only catalysed reaction pathway

Synthesis of pyrazole containing α-amino acids via a highly regioselective condensation/aza-Michael reaction of β-aryl α,β-unsaturated ketones

A synthetic approach for the preparation of a new class of highly conjugated unnatural α-amino acids bearing a 5-arylpyrazole side-chain has been developed. Horner–Wadsworth–Emmons reaction of an aspartic acid derived β-keto phosphonate ester with a range of aromatic aldehydes gave β-aryl α,β-unsaturated ketones. Treatment of these with phenyl hydrazine followed by oxidation allowed the regioselective synthesis of pyrazole derived α-amino acids. As well as evaluating the fluorescent properties of the α-amino acids, their synthetic utility was also explored with the preparation of a sulfonyl fluoride derivative, a potential probe for serine proteases

Chemodivergent Manganese-Catalyzed C–H Activation: Modular Synthesis of Fluorogenic Probes

Bioorthogonal diversification of peptides is generally dependent on impractical prefunctionalization methods. Here, the authors develop a manganese(I)-catalyzed C–H fluorescent labeling with BODIPY probes, which enables the development of activatable fluorophores to image cell function

On-Resin Photochemical Decarboxylative Arylation of Peptides

Here we describe the application of photochemical decarboxylative arylation as a late-stage functionalization reaction for peptides. The reaction uses redox-active esters of aspartic acid and glutamic acid on the solid phase to provide analogues of aromatic amino acids. By using aryl bromides as arylation reagents, a wide variety of amino acids can be accessed without having to synthesize them individually in solution. The reaction is compatible with proteinogenic amino acids and was used to perform a structure–activity relationship study of a PRMT5 binding peptide