Microwave- and Thermally Promoted Iminyl Radical Cyclizations: A Versatile Method for the Synthesis of Functionalized Pyrrolines

Abstract

A detailed study of iminyl radical cyclizations of O-aryloximes tethered to alkenes is reported. The reactions can be triggered by either microwave irradiation or conventional heating in an oil bath. A variety of radical traps can be employed, enabling C–C, C–N, C–O, C–S, or C–X bond formation and producing a diverse array of functionalized pyrrolines. Substrates containing an allylic sulfide furnish terminal alkenes by a tandem cyclization–thiyl radical β-elimination pathway. Cyclizations of hydroxylated substrates exhibit moderate diastereoselectivity that in some cases can partially be attributed to intramolecular hydrogen bonding. Computational studies suggested a possible role for thermodynamics in controlling the stereochemistry of cyclizations. The reaction temperature can be lowered from 120 to 100 °C by employing O-(p-tert-butylphenyl)oximes instead of O-phenyloximes as substrates, and these second-generation iminyl radical precursors can be used in a one-pot oxime ether formation–cyclization that is promoted by conventional heating. The functionalized pyrrolines obtained from these reactions can be conveniently transformed in several different ways.

Photochemical and Single Electron Transfer Generation of 2′-Deoxycytidin-N4-yl Radical from Oxime Esters

“…Oxime ethers and esters are useful precursors for σ-type iminyl radicals (Scheme ). The weak N–O bond (BDE ∼ 35 kcal/mol) enables one to generate iminyl radicals via thermolysis although the temperatures required are typically significantly greater than 100 °C. , Direct UV-irradiation (Pyrex filtered light) also yields iminyl radicals. , There are also numerous examples of iminyl radical generation via single electron transfer, particularly for utilization in organic synthesis. , Organometallic catalysts and increasingly photoredox systems have been employed to generate the iminyl radicals from oxime esters via single electron transfer. , We recently generated dC· via direct UV-irradiation from oxime ether 1 . Although experiments with 1 provided insight regarding the reactivity of dC·, they were complicated in the presence of O 2 , a necessary component when studying DNA reactivity under biologically relevant conditions.…”

“…The weak N−O bond (BDE ∼ 35 kcal/mol) enables one to generate iminyl radicals via thermolysis although the temperatures required are typically significantly greater than 100 °C. 34,35 Direct UV-irradiation (Pyrex filtered light) also yields iminyl radicals. 36,37 There are also numerous examples of iminyl radical generation via single electron transfer, particularly for utilization in organic syn- thesis.…”

Synthesis of the Indolizidine Core of Virosinine A via a Microwave-Promoted Cascade Cyclization Involving Iminyl Radicals

“…The proposed cascade cyclization is depicted in Scheme . Based on our prior work, we reasoned that microwave irradiation of O -aryloxime 5 would trigger N–O homolysis, 5- exo - trig iminyl radical cyclization, and thiyl radical elimination . Cyclization via a chairlike Beckwith–Houk transition state should furnish dihydropyrrole A as the major diastereomer.…”

Formal γ-C(sp3)–H Activation of Ketones via Microwave-Promoted and Iminyl-Radical-Mediated 1,5-Hydrogen Atom Transfer

“…Recently, we generated a variety of pyrrolines via 5- exo - trig iminyl radical cyclizations. The latter reactions could be triggered by either microwave irradiation or conventional heating . The lack of SET events and redox cycles has enabled a broad range of radical traps to be employed in both fragmentations and the cyclizations.…”

“…We commenced our efforts by selecting O -phenyloxime 1a as the test substrate and TEMPO as the radical trap (Table ). We elected to trigger iminyl radical formation via microwave irradiation rather than conventional heating due to the rapid rates inherent to this technique. − Reactions performed without additives were low-yielding and afforded complex mixtures; therefore, we evaluated the use of Brønsted or Lewis acids. Various carboxylic acids promoted γ-C–H activation (entries 1–5), with chloroacetic acid delivering the best yield of ketone 2a (entry 3).…”