Switchable Regioselective 6- endo or 5- exo Radical Cyclization via Photoredox Catalysis

Abstract

Controlling the regioselectivity of radical cyclizations to favor the 6-endo mode over its kinetically preferred 5-exo counterpart is difficult without introducing substrate prefunctionalization. To address this challenge, we have developed a simple method for reagent controlled regioselective radical cyclization of halogenated N-heterocycles onto pendant olefins. Radical generation occurs under mild photoredox conditions with control of the regioselectivity governed by the rate of hydrogen atom transfer (HAT). Utilizing a polarity-matched thiol-based HAT agent promotes the highly selective formation of the 5-exo cyclization product. Conversely, limiting the solubility of the HAT reagent Hantzsch ester (HEH) leads to selective formation of the thermodynamically favored 6-endo product. This occurs through an initial 5-exo cyclization, with the resulting alkyl radical intermediate undergoing neophyl rearrangement to form the 6-endo product. Development of this switchable catalysis strategy allows for two modes of divergent reactivity to form either the 6-endo or 5-exo product, generating fused N-heteroaromatic/saturated ring systems.

Figure 1.

Approach to selective 6-endo or 5-exo radical cyclization products.

Figure 2.

Mechanistic proposal explaining origins of reagent controlled switchable selectivity. aRatio determined by 1H NMR with internal standard.

Scheme 1.. Investigation of non-heteroaryl substrate

aConditions: 4CzIPN (1 mol%), substrate (1 equiv), mesna (20 mol%), sodium formate (5 equiv), formic acid (5 equiv), DMSO, blue LED, 23 oC, 16 h, isolated yields shown. bConditions: 3DPAFIPN (1 mol%), substrate (1 equiv), Hanztsch ester (1.5 equiv), H₂O:MeCN (1:1 v/v).