A simple, modular method to prepare highly substituted pyridines is disclosed. The method employs a cascade reaction comprising (1) a novel N-iminative, Cu-catalyzed cross-coupling of alkenylboronic acids at the N-O bond of α, β-unsaturated ketoxime O-pentafluorobenzoates, (2) electrocyclization of the resulting 3-azatriene, and (3) air oxidation affording highly substituted pyridines in moderate to excellent isolated yields (43-91%). Starting materials are readily available and functional group tolerance is very good.The careful tuning of metal catalysts and mediators to specific bond types can lead to new synthetic transformations possessing significant chemoselectivity in functionally complex systems. Molecules bearing N-O bonds are fruitful candidates for beneficial tuning to metal catalysts and mediators, and such systems have the potential to deliver new, chemoselective methods for C-N bond formation under non-basic and non-oxidative conditions. 1 To exemplify this concept, we report herein a versatile synthesis of highly substituted pyridines that takes place through a reaction cascade comprised of (a) a novel and mild C-N crosscoupling of alkenyl boronic acids at the N-O bond of an oxime O-carboxylate generating 3-azatrienes, (b) electrocyclization, and (c) aerobic oxidation (Scheme 1).Substituted pyridines are important components of biologically active molecules 2 making the development of mild, efficient, and modular methods for the synthesis of substituted pyridines Construction of a substituted pyridine ring by the thermal electrocyclization of 1-, 2-, and 3-azatrienes has been previously demonstrated. 5 The recently disclosed N-imination of boronic acids and organostannanes under neutral reaction conditions via a copper-catalyzed C-N crosscoupling at the N-O bond of oxime carboxylates 1a could provide a mild, modular, and novel route to variously substituted 3-azatrienes, if practiced on α,β-unsaturated oxime Ocarboxylates and alkenylboronic acids. After in situ thermolysis and oxidation, this new chemistry would provide a simple, straightforward, and potentially powerful method for the modular construction of substituted pyridines with flexible control over the substitution pattern (Scheme 1). The neutral pH reaction conditions could allow broad functional group tolerance and therefore provide access to diverse substitution patterns about the pyridine core.α,β-Unsaturated ketoxime O-pentafluorobenzoates are easily prepared by the condensation of an α,β-unsaturated ketone with hydroxylamine followed by acylation with pentafluorobenzoyl chloride. As a probe experiment, a mixture of 1,3-diphenyl-2-propen-1-one oxime Opentafluorobenzoate (1.4:1, E/Z unassigned) and commercially available trans-1-hexen-1-ylboronic acid in DMF was exposed to 10 mol % Cu(OAc) 2 at 50°C for 1 h open to air. Both starting materials disappeared and a new spot was observed on TLC. 6 The reaction mixture was then heated at 85 °C for 3 h transforming the uncharacterized intermediate into 5-nbutyl-2,4-diphenylpyridine i...
