1,3-Dipolar and 1,3,6-Tripolar Reactivity of 3-hydroxy- and 3-amino-1-N-arylazopropenes for Heterocycle Formation



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3-Alkoxy-1-N-aryl azopropene structural motifs in the Eschenmoser-Tanabe Fragmentation pathway have been known for almost 50 years, yet one unexploited feature of these intermediates is their putative 1,3-dipole. Described here is a transformation leveraging this reactivity to synthesize an important class of oxygen heterocycles, β,γ-fused bicyclic γ-lactones, by the simple combination of an ester or acyl pyrrole, an α-epoxy-2-nitrophenyl hydrazone, and a base. The products of this reaction, including those containing quaternary centers, are generated with high (up to >25:1) diastereoselectivity. Conveniently, both syn- and anti-fused bicyclic systems can be generated stereoselectively by simply changing the counter-ion of the base, LiHMDS and KHMDS, respectively.

This dissertation also describes the development of a new functional group, 3-amino-1-azopropene, and its use in novel annulation strategies leading to N-heterocycles, which are important structures found in drugs and biologically active natural products. The 3-amino-1-azopropene functional group possesses multiple nucleophilic sites and, as such, is expected to inspire the development of a wide range of new synthetic methods and/or find applications in the development of new drugs and materials.

Lastly, as part of the continuing effects to develop new reactions for the formation of saturated heterocycles, the conjugated π systems of azoalkenes in 3-hydroxy-azopropenes and 3-amino-1-azopropene were utilized in a [4+2] cyclization reaction in order to achieve ring closure. Compounds were prepared in high (up to >25:1) diastereoselectivity from a cascading Tsuji-Trost [4+2] cycloaddition, producing a wide array of fused tetrahydrofuran- and pyrrolidine- tetrahydropyridazine derivatives.



Eschenmoser-Tanabe Fragmentation, 1,3-dipole, 1,3,6-tripole, Oxygen heterocycles, Nitrogen heterocycles, 3-amino-1-azopropene, 3-hydroxy-azopropenes


Portions of this document appear in: Rastelli, Ettore J., Andrew A. Bolinger, and Don M. Coltart. "Stereodivergent Synthesis of β, γ-Fused Bicyclic γ-Lactones via a Multicomponent Ring-Expansion Cascade." Chem 4, no. 9 (2018): 2228-2238.