Thiyl Radical-Mediated Cleavage of Allylic C−N Bonds: Scope, Limitations, and Theoretical Support to the Mechanism

Abstract

Thiols mediate the radical isomerization of allylic amines into enamines. The reaction results in the cleavage of the allylic C-N bond, after treatment with aqueous HCl. The mechanism involves the abstraction of an allylic hydrogen alpha to nitrogen by thiyl radical, followed by a return hydrogen transfer from the thiol to the carbon gamma to nitrogen in the intermediate allylic radical. The scope and limitations of the reaction with respect to the nature of the thiol, to the structure of the allylic chain, and to the nature of the substituents at nitrogen were investigated. The experimental results were interpreted on the ground of DFT calculations of the C-Halpha BDE in the starting allylic amines, and of the C-Hgamma BDE in the resulting enamines. The efficiency of the initial hydrogen transfer is the first requirement for the reaction to proceed. A balance must be found between the S-H BDE and the two above-mentioned C-H BDEs. The incidence of stereoelectronic factors was analyzed through NBO calculations performed on the optimized geometries of the starting allylic amines. Additional calculations of the transition structures and subsequent tracing of the reaction profiles were performed for the abstraction of Halpha from both the allyl and the prenyl derivatives by p-TolS(*). The latter allowed us to estimate the rate constant for the abstraction of hydrogen by thiyl radical from an N-prenylamine and an N-allylamine.

Photoinduced isomerization of allyl alcohols to carbonyl compounds using dendrimer disulfide as catalyst

“…The reaction mechanism of the reduction of diene was similar to the plausible mechanism of hydrogenation step of our isomerization. There could be alternative pathways, that is, direct isomerizations via the formation of cation radical of allyl alcohol by photoinduced SET process or the hydrogen atom donation from a thiol to an allyl radical instead of SET process [21,22]. However, since we observed the enone as an intermediate, the alternative pathway might be excluded.…”

Effect of Brønsted acids on the thiophenol-mediated radical addition–translocation–cyclization process for the preparation of pyrrolidine derivatives

“…This result was interpreted as a consequence of undesired hydrogen atom abstraction from the propargylic position leading to stabilized 1-aminosubstitued propargylic radicals. This degradation pathway is well established since Bertrand et al have described the isomerization of allylic amines under closely related reaction conditions [27,28].…”

Synthesis of (±)-Amathaspiramide F

“…The prenyl group of aminoester 78a was easily deprotected using radical isomerization conditions (Scheme 25). 19 In a three-step sequence, compound 81 was treated with trifluoroacetic acid to remove the MOM group and t-butyl ester group. The crude product was then treated with trimethylsilyldiazomethane to convert the acid to the methyl ester, followed by protection of the nitrogen 78a, Ar = 3-OMOM desired, major 71a, Ar = 3-OMe-4,6-Br 2 desired, minor Chapter 6 Synthesis of (AE)-Amathaspiramide F as the trifluoroacetamide.…”