Development of Regioselective Nitrene-Transfer [5+1] Cycloadditions as a Strategy for the Synthesis of Nitrogen Heterocycles

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Laudenschlager, Julie, Chemistry - Graduate School of Arts and Sciences, University of Virginia
Hilinski, Michael, AS-Chemistry (CHEM), University of Virginia

Nitrogen heterocycles appear in a majority of FDA-approved drugs with piperidine being the most prevalent. As such, synthetic chemists are searching for methods that would allow for the facile synthesis of these motifs since many current methods are limited to certain substitution patterns in the product. This potential area of study to address this problem is using nitrenes and metallonitrenes in nitrene-transfer catalysis. However, known examples of nitrene precursors in intermolecular cyclizations are restricted in the literature to only five-membered rings through [4+1] or [2+2+1] cycloadditions. Herein, in this dissertation, we present the first syntheses of six-membered rings via nitrene-transfer cycloaddition in a [5+1] fashion, using vinylcyclopropanes (VCPs) as the aliphatic backbone.

Rh(II) catalysts have long been used for both intra- and intermolecular amination and aziridination. As such, we have shown that Rh2(esp)2 – the DuBois catalyst – was effective for nitrene transfer of N-tosyloxycarbamates to biaryl VCPs, resulting in the formation of 2,5-tetrahydropyridine products – a substitution pattern that was previously non-existent in the literature. Furthermore, we were able to demonstrate the additional synthetic utility of these compounds through hydrogenation and selective epoxidation. We later investigated the use of a Rh2II,III dimer catalyst to not only improve the method in terms of time but also introduce pyridine rings as a viable substituent to VCPs. In addition, we explored how pyridine substituents could be amenable to using Rh2(esp)2 as a catalyst.

Through our initial investigations, we found that our substrate scope was quite limited. Thus, we explored other sources for nitrogen transfer for mono-arylated VCPs. Brønsted and Lewis acids were both found to be effective with this substrate class with Sc(OTf)3. In addition, cyclopropyl-substitution patterns not tolerable to the Rh-conditions were used in the Sc-conditions to provide the desired cycloadducts. The complementarity of both methods indicated that their respective mechanisms are different. Using the radical scavenger TEMPO, we were able to show that the acid-promoter method is undergoing a radical – not cationic – pathway. The development of this strategy further expanded the synthetic library of the [5+1] reaction.

PHD (Doctor of Philosophy)
Nitrene transfer, Cycloaddition, Vinylcyclopropane, Nitrogen heterocycle, Regioselectivity
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