5-Endo-trig Radical Cyclizations:  Disfavored or Favored Processes?

Abstract

Relative kinetic data were determined for the 5-endo-trig cyclization of radical 12 compared to hydrogen abstraction from (TMS)(3)SiH in the temperature range of 344-430 K, which allows for the estimation of a rate constant of 2 x 10(4) s(-)(1) at 298 K with an activation energy of ca. 9 kcal/mol for the cyclization process. The 5-endo-trig cyclization of a variety of radicals that afford five-membered nitrogen-containing heterocycles was addressed computationally at the UB3LYP/6-31G level. The 5-endo vs 4-exo mode of cyclication and the effect of delocalization of the unpaired electron in the transition state were investigated. Because the ring formed during cyclization contains five sp(2) centers, electrocyclization via a pentadienyl-like resonance form was also considered. For comparison, similar calculations were performed for 4-penten-1-yl and related radicals. The factors that affect the activation energies of homolytic 5-endo-trig cyclization were determined. In the absence of steric or conformational effects, the endo cyclization to form the five-membered ring was strongly favored over exo cyclization to form the four-membered ring not only on thermodynamic grounds but also kinetically. When a substituent on the double bond was able to delocalize the unpaired electron in the transition state of the 4-exo path, the two modes of cyclization became kinetically comparable. These results have an important bearing on the generalization of the Baldwin-Beckwith rules, which classified the 5-endo-trig radical cyclization as a "disfavored" process.

Cyclization of an α,β‐Unsaturated hydrazone catalyzed by a BINOL‐phosphoric acid: Pericyclic or not?

“…This notion is supported by the NBO analysis that reveals a strong donation from the lone pair at N1–C5 at the TS: the E(2) donor–acceptor interaction is 84.2 kcal/mol for TS‐ trans and 103.8 kcal/mol for TS‐ cis , respectively. This scenario would resemble a 5‐ endo ‐trig reaction which is assumed to be disfavored according to Baldwin's rules, which are, however, only qualitative and may be less reliable for systems containing heteroatoms . Recently, Johnston et al demonstrated that also all‐carbon systems may preferentially cyclize in a 5‐ endo ‐trig manner .…”

“…This scenario would resemble a 5-endo-trig reaction which is assumed to be disfavored according to Baldwin's rules, [33] which are, however, only qualitative and may be less reliable for systems containing heteroatoms. [34][35][36][37] Recently, Johnston et al demonstrated that also all-carbon systems may preferentially cyclize in a 5-endotrig manner. [38] They probed by DFT computations whether an electrocyclization is reasonable but had to exclude this pathway.…”

The Fascinating Chemistry of α‐Haloamides

“…In 2016 Clark and co‐workers reported a fruitful method for achieving four‐membered lactams based on a Cu(0) (copper wire)‐mediated stereoelectronically favored 4‐ exo‐trig ring closure of the unsaturated α‐bromo amide A (Scheme ).…”

A DFT study on a mutipathways, one product reaction: Initially divergent radical reactions reconverge to form a single product

“…In a multichannels reaction, there are two or more major products in general. It is always thought that if there is no selectivity in the initially divergent step, the overall reaction will not be selective . As illustrated in Scheme , when two diastereotopic groups X and X′ exist in the precursor, they will convert into different substituents A and B in the initially divergent step.…”