Experimental and theoretical study of the mechanism and rate constants of the sequential 5-exo-trig spirocyclization involving vinyl, aryl and N-alkoxyaminyl radicals

Abstract

In this research the sequential generation and cyclization of N-alkoxyaminyl radicals to produce 1-azaspiro[4.4]nonane, a prominent scaffold in organic and medicinal chemistry, was studied. Competition experiments in benzene at 80 °C with brominated oxime ethers using Bu₃SnH as chain transfer and AIBN as the initiator generated vinyl or aryl radicals which were captured by oxime ethers, allowing approximate 5-exo-trig cyclization constants at 4.6 × 10⁸ s⁻¹ and 9.9 × 10⁸ s⁻¹ respectively to be established. Similar results were obtained by kinetic studies using the transition state theory (TST) from ab initio calculations with density functional theory (DFT) using the M06-2X, B3LYP, mPW1PW91 and TPSSh functionals in combination with the 6-311+G(d, p) basis set. Additionally, it was found that the 5-exo-trig cyclization of the N-alkoxyaminyl radical onto CC double bonds is a reversible process whose constants were determined to be in the range of 6.2 × 10⁰ s⁻¹ and 3.5 × 10⁶ s⁻¹ at 80 °C, depending on the nature of the substituents. The calculation of the radical stabilization energy (RSE) shows that the N-alkoxyaminyl radical is a very stable species and its reactivity in the addition on alkenes is governed by its nucleophilic character and the stability of the carbon-centered radical formed after cyclization. The reduction constant of the N-alkoxyaminyl radical with Bu₃SnH in the gas phase at 80 °C was also estimated to be 3.4 × 10⁰ M⁻¹ s⁻¹ through computational calculations. This information facilitates the rational planning of cascades and other methodologies applied to the construction of carbocyclic and aza-heterocyclic compounds.