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.

Radical Group Transfer of Vinyl and Alkynyl Silanes Driven by Photoredox Catalysis

“…Radical cyclizations are a powerful strategy to forge C–C bonds. These intramolecular processes benefit from very rapid kinetics, can generate multiple bonds in one transformation, and enable unique reactivity pathways for the synthesis of complex scaffolds. − Although radical processes have traditionally relied on harmful reagents and harsh conditions, photoredox catalysis has emerged as a method of choice for performing radical chemistry under mild, non-toxic conditions. , Radical cyclizations typically involve the addition of a carbon-centered radical to a C–C π bond, leading to cyclic products (Scheme a). , This strategy has been widely employed to produce both saturated and unsaturated all-carbon rings and heterocycles. ,, Stereoselective radical cyclizations, moreover, have been used to access enantioenriched cyclic frameworks, which feature, e.g., in many pharmaceuticals and natural products. − …”

A Traceless Heterocyclic Amine Mediator in Regioselectivity−Switchable Formal [1 + 2 + 2] Cycloaddition Reaction to 1,3,4- and 1,4,5-Trisubstituted Pyrazoles

“…Switchable strategies, with potential for converting the same starting materials into two or more different products by changing reaction conditions, have been indispensable tools in organic synthesis . Recently, by exploiting the in situ trapping of active 1,3-vinylimine ions intermediates obtained from enaminones and BrCF 2 CO 2 R, our group has developed a formal [1 + 2 + 3] cyclization reaction for building nitrogen heterocycles with the use of nucleophilic reagents .…”

Tuning the donor properties of bipyridyl-substituted phosphines by metal ion encapsulation & Photocatalytic synthesis of 6H-benzo[c]chromenes from S-aryl sulfonium salts

“…[204] An example of such a reaction is the recently published photocatalytic 5-exo radical cyclization by Jui, Blakey and co-workers. [205] Scheme 101: Photocatalytic 5-exo radical cyclization by Jui, Blakey (Condition slow HAT: [205] Photocatalyst 3DPAFIPN (1 mol%), Hantzsch ester (1.5 equiv. ), 50% H2O/MeCN, blue LED, 23 °C, 16h; Condition rapid HAT: [205,206] Photocatalyst: 4CzIPN (1 mol%), mesna (20 mol%), NaHCO2 (5 equiv.…”

“…[205] Scheme 101: Photocatalytic 5-exo radical cyclization by Jui, Blakey (Condition slow HAT: [205] Photocatalyst 3DPAFIPN (1 mol%), Hantzsch ester (1.5 equiv. ), 50% H2O/MeCN, blue LED, 23 °C, 16h; Condition rapid HAT: [205,206] Photocatalyst: 4CzIPN (1 mol%), mesna (20 mol%), NaHCO2 (5 equiv. ), HCO2H (5 equiv.…”

“…By using a different protocol [205,206] and a more efficient thiol-based HAT reagent mesna (an inexpensive alkyl thiol), the radical 309 can be trapped and thus the 5-exo product 314 can be selectively obtained. However, it should be noted that this is not a classical photocatalyzed reaction.…”