Application of 1,4-Oxazinone Precursors to the Construction of Pyridine Derivatives by Tandem Intermolecular Cycloaddition/Cycloreversion

Abstract

This study reveals a new method for the preparation of 1,4-oxazinone derivatives by Staudinger reductive cyclization of functionalized vinyl azide precursors. The resulting oxazinone derivatives prepared in this manner were intercepted with terminal alkyne substrates through an intermolecular cycloaddition/cycloreversion sequence to afford polysubstituted pyridine products. Alkyne substrates bearing propargyl oxygen substitution showed good regioselectivity in the cycloaddition operation selectively affording 2,4,6-substituted pyridines. Application of this chemistry to the synthesis of an ErbB4 receptor inhibitor is also described.

Regioselective Formation of Pyridines by Cycloaddition/Cycloreversion of 1,4-Oxazinone Precursors with Bisalkyne Substrates

“…Oxazinone 6 and the symmetric TMS-bisalkyne 10a were reacted overnight in toluene at 110 °C (entry 1). We noticed that this thermal cycloaddition/cycloreversion reaction had a faster rate relative to other precursors previously explored 3 5 and the resulting product 11a was afforded in excellent yield (96%) as a single pyridine isomer. 8 In similar fashion, the bispropargyl ether 10b was also effective in the reaction sequence and gave pyridine 11b in 46% yield and as a 19:1 ratio of isomers (entry 2).…”

“…The greater reactivity of oxazinones enables reaction in both the inverse- and normal-electron-demand Diels–Alder modes; unactivated or electron-deficient alkynes represented by 2 may serve as the 2π reaction component. 3 The resulting [2.2.2]bicycloadducts 3 are generally not stable and undergo facile extrusion of CO 2 . In this way, pyridine products resembling 4 may be obtained in some cases at ambient temperatures.…”

Synthesis of Guaipyridine Alkaloids Rupestine M and L by Cycloaddition/Cycloreversion of an Intermediate 1,4-Oxazinone

“…We viewed the guaipyridine scaffold as an instructive model to explore our interest in the de novo synthesis of pyridines by domino reaction processes. 15 16 We saw an opportunity to advance new chemistry and explore the reactivity and selectivity of an oxazinone precursor in a cycloaddition/cycloreversion sequence. Our synthesis plan highlighted in Scheme 1 targeted rupestine L and M as our entry point to the guaipyridine alkaloid core.…”

“…General substructure analysis of the requisite oxazinone precursor 11 revealed that both 11 and 9 are at the same oxidation state and thus potential access might be achieved starting from acetylenedicarboxylate 9 . Methods to prepare oxazinones have been summarized elsewhere, 15 but the synthesis of oxazinone 11 from 9 was not known and would thus represent a new method to rapidly construct functionalized oxazinone precursors. Moreover, oxazinone 11 , which possesses a functional group (CO 2 R) at the position that corresponds to the oxygenated C8 position, could enable construction of target natural products 7 and 8 .…”

“…Spectroscopic analysis of oxazinone 17 revealed that the C3 alkene existed in the exocyclic (vinylogous urethane) form; none of the endocyclic isomer 17′ was apparent. Based on our experience with reactive oxazinone precursors, 15 we were unsure if 17 would engage in a productive cycloaddition/cycloreversion sequence. Although somewhat less reactive than other oxazinones we have worked with that reside in endocyclic tautomeric forms primed for cycloaddition, we found that 17 reacted with a model terminal alkyne, 5-hexynoate 18 , and gave both the 2,3- and 2,4-pyridine products 19a and 19b (ratio 1:1).…”