CARBONAZIDATE-INITIATED CASCADE REACTIONS: SYNTHESIS OF BRIDGED AZACYCLES, PROPELLANES AND -OXO-N-VINYLIMIDATES VIA HUISGEN CYCLIZATION/CARBENE CASCADE REACTIONS AND ACYL OXAZOLINONES VIA AN OXIDATIVE NITRENE/ALKYNE CASCADE REACTION

Date

2021-05

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Abstract

This dissertation covers four projects utilizing carbonazidate-initiated cascade reactions. Both the first and second projects are based on Huisgen cyclization/carbene alkyne cascades. By using this method of initiation, bridged azacycles, propellanes, or -oxo-N-vinylimidates could be selectively synthesized. The third project arises from an alternate mechanistic path. Starting with nitrene generation, followed by cyclization and oxidation, acyl oxazolinones were successfully formed. The last project focuses on an experimental mechanistic study, which provided evidence to support proposed intermediates found by the collaborative computational study. A Huisgen cyclization/carbene alkyne cascade reaction terminating in C–H bond insertion to form functionalized bridged azacycles is presented in Chapter 2. Accessible nitrene precursors were assessed, and carbonazidates were found to be the only effective initiators. Substrates with different ring sizes as well as different aryl and heteroaryl groups were also explored. Examples incorporating stereocenters on the initiator tether demonstrated diasteroselectivity in the formation of the bridged ring and two new stereocenters. Additionally, propellanes can be obtained from the bridged azacycles in an acid-promoted rearrangement. Alternatively, via Huisgen cyclization/carbene cascade, -oxo-N-vinylimidates could be directly obtained by intermolecular trapping of esters (Chapter 3). Mechanistic control experiments suggested that a reversible dipole formation by ester addition to the carbene and nitrogen attack on the ester carbonyl was irreversibly followed by stereoselective decarboxylative elimination to give the Z-vinyl imidate product. The potential reactivity of the cross-conjugated enone, imidate, and enamine functional groups in the cascade product offers novel synthetic pathways to functionalized oxazoles. High polarity aprotic solvents as well as Cu(II) catalysts can facilitate nitrene generation from carbonazidates, which allow an oxidative nitrene/alkyne cascade reaction to form 4-acyl-oxazolinone (Chapter 4). Computational investigations revealed several novel potential intermediates for these Huisgen cyclization/carbene alkyne cascade reactions like triplet carbenes, a vinylidene, and a Si–N cyclobutene containing enamine. Combining computational and experimental mechanistic studies revealed novel intermediates and plausible reaction pathways were validated (Chapter 5).

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Keywords

carbene, nitrene, cascade, bridged polycycles, imidates

Citation

Portions of this document appear in: Wang, Qinxuan, and Jeremy A. May. "Synthesis of bridged azacycles and propellanes via nitrene/alkyne cascades." Organic letters 22, no. 8 (2020): 3039-3044; and in: Wang, Qinxuan, and Jeremy A. May. "Formation of β-Oxo-N-vinylimidates via Intermolecular Ester Incorporation in Huisgen Cyclization/Carbene Cascade Reactions." Organic Letters 22, no. 24 (2020): 9579-9584.