Studies on Reactive Pyridylketones Formed by Weinreb Transformations

Abstract

A method has been developed to allow the preparation of reactive pure vinylpyridylketones and activated vinylketones, in general, to be used in further reactions, such as cycloadditions. The process is based on the Weinreb's amide transformation and includes a quarternary ammonium intermediate and subsequent elimination. Additionally, based on our previous results on the malonate alkylation of 3-nitropyridines and subsequent synthetic applications, we present the studies on the transformation of pyridyl malonate derivative 3 via the Weinreb's amide 4 and reactive methylpyridyl-(17) and allylpyridyl-ketone (6) into bis-heterocyclic products 18 and 19, and 8, 20, and 21, respectively. J. Heterocyclic Chem., 49, 613 (2012). RESULTS AND DISCUSSIONWeinreb's amides, N-methoxy-N-methyl amides, formed by ester aminolysis [15], are useful intermediates © 2012 HeteroCorporation Scheme 2 Scheme 3 Scheme 1 Scheme 4

Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876—A Less Toxic and More Potent Analogue of Bedaquiline

“…Reagents and conditions: (i) vinylMgBr, THF, 0 • C then 20, H 2 O. Molecules 2020, 25, 1423 7 of 34This problem was overcome by isolating the vinyl ketone intermediate 12 from the reaction mixture instead of using it in situ, hence avoiding the presence of competing nucleophiles, such as cleaved N,O-dimethylhydroxylamine. By using a modified reported procedure [19], Mannich base 24 [14] was treated with methyl iodide for 72 h to form quaternary ammonium iodide salt which was washed with water and subsequent elimination liberated pure vinyl compound 12 (Scheme 7). With 12 isolated, it was dissolved in THF, added benzophenone imine 20 and stirred at r.t. for 30 min.…”