Regioselective Synthesis of Pyrroles from Alkyne‐Isocyanide Click Reactions: An Angle Strain‐Induced Bond Migration Approach

Abstract

Thed irect regioselective synthesis of highly functionalized pyrrolesw ith twod ifferent electron-withdrawing groups has been developed using an angle strain-induced 1,2-shift of an electron-withdrawing group in 2H-pyrroles.T he preferential migration aptitude of an electron-withdrawing group over alkyla nd aryl groups is believed to be the result of the orbital overlap between the internal alkene and the electron-withdrawing group. Then ewly developed regioselective synthesis of pyrroles featuresawide substrate scope,s imple reaction set-up, andh igh yields( 60-82%), capturing the essence of alkyne-isocyanide "click" reactions.Scheme1.Alkyne-isocyanide "click" reactions and angle strain-induced bond migration to substituted pyrroles.

Substituted Pyrrololactams via Ring Expansion of Spiro-2H-pyrroles from Intermolecular Alkyne–Isocyanide Click Reactions

“…A control experiment confirmed the inactivity of t -BuOK in the formation of pyrrololactam 3a . Interestingly, unlike the cases with 2,2-disubstituted 2 H -pyrroles, the products from alkyne–isocyanide [3 + 2] cycloaddition reactions, the formation of spiro-2 H -pyrrole 4a , a possible precursor to 3a , was not observed during the reaction…”

“…Cycloaddition reactions between alkynes and isocyanides provide a regiodivergent synthesis of highly substituted pyrroles . Utilizing the “click chemistry” feature of the alkyne–isocyanide [3 + 2] cycloaddition reactions, we have recently disclosed an angle strain-induced bond migration of 2,2-disubstituted-2 H -pyrroles to the regioselective synthesis of pyrroles . This approach readily allows for the facile regioselective synthesis of 2,3,4-substituted pyrroles with two different EWGs at the 3- and 4-carbon atoms.…”

Catalytic Atropenantioselective Heteroannulation between Isocyanoacetates and Alkynyl Ketones: Synthesis of Enantioenriched Axially Chiral 3‐Arylpyrroles

“…In 2005, Yamamoto and de Meijere reported independently a metal catalyzed heteroannulation of isocyanoacetates 1 with activated alkynoates 2 for the synthesis of 2,3,4‐trisubstituted pyrroles 3 (EWG=COOR, CN, Scheme b). This chemistry has subsequently been extended to terminal alkynes and α‐substituted α‐isocyanoacetates . Mechanistically, it was proposed that the reaction was initiated by the Michael addition of metallated species A to the alkynoate 2 to afford B which, upon cyclization, provided intermediate C .…”

Recent Advancements in Pyrrole Synthesis

“…A wide collection of reactions have been reported between 2014-2019 that showcase the use of triple bonds as starting materials for pyrroles synthesis. [36][37][38][39][40][41] A number of transition metal catalysts, such as Au, Pd, Cu, Rh, and Ru, have been reported to catalyze reactions between substituted alkynes and amines, enaminones, or oxime to generate pyrroles. In addition, a few reagent-driven syntheses have also been reported.…”