In Search of Efficient 5-Endo-dig Cyclization of a Carbon-Centered Radical: 40 Years from a Prediction to Another Success for the Baldwin Rules

Abstract

Despite being predicted to be stereoelectronically favorable by the Baldwin rules, efficient formation of a C-C bond through a 5-endo-dig radical cyclization remained unknown for more than 40 years. This work reports a remarkable increase in the efficiency of this process upon beta-Ts substitution, which led to the development of an expedient approach to densely functionalized cyclic 1,3-dienes. Good qualitative agreement between the increased efficiency and stereoselectivity for the 5-endo-dig cyclization of Ts-substituted vinyl radicals and the results of density functional theory analysis further confirms the utility of computational methods in the design of new radical processes. Although reactions of Br atoms generated through photochemical Ts-Br bond homolysis lead to the formation of cyclic dibromide side products, the yields of target bromosulfones in the photochemically induced reactions can be increased by recycling the dibromide byproduct into the target bromosulfones through a sequence of addition/elimination reactions at the exocyclic double bond. Discovery of a relatively efficient radical 5-endo-dig closure, accompanied by a C-C bond formation, provides further support to stereoelectronic considerations at the heart of the Baldwin rules and fills one of the last remaining gaps in the arsenal of radical cyclizations.

Strain control in nucleophilic cyclizations: reversal of exo‐selectivity in cyclizations of hydrazides of acetylenyl carboxylic acids by annealing to a pyrazole scaffold

“…Now, the calculated cyclization barriers for the both competing cyclization of pyrazolyl reactants are in the order of 20 kcal/mol and both cyclizations are moderately endergonic. Similar effects of strain on the exo / endo selectivity have been reported for 4‐ exo /5‐ endo and 5‐ exo /6‐ endo radical cyclizations of alkynes. However, the exo ‐preference is even more pronounced for anionic cyclizations, so this switch in selectivity is more impressive.…”

The Baldwin rules: revised and extended

“…Surprised by the scarcity of radical 5‐endo‐dig cyclizations, we analyzed a variety of 4‐exo‐dig/5‐endo‐dig pairs computationally and found that the 4‐exo‐dig cyclization, unfavorable according to the rules and significantly less exothermic, is often faster than the alternative 5‐endo‐dig closure . Subsequent experimental work confirmed these predictions; only in the presence of an intramolecular interaction selectively stabilizing the 5‐endo TS could we obtain good yields of the 5‐endo products (Scheme ) ,…”

CO2 or SO2: Should It Stay or Should It Go?

“…Loss of SO2 can be a more selective process that loss of CO2. Due to applications of RSO2 radicals in synthesis, 52 the search for new approaches to their generations continues. 53 In this context, the reverse process, i.e.…”