Radical Alkene-Trifluoromethylation-Triggered Nitrile Insertion/Remote Functionalization Relay Processes: Diverse Synthesis of Trifluoromethylated Azaheterocycles Enabled by Copper Catalysis

Abstract

A copper-catalyzed alkene-trifluoromethylation-triggered nitrile insertion/remote functionalization relay process has been achieved, in which “interrupted” remote 1,n-difunctionalizations of alkenes with nitrile insertion can deliver iminyl radical intermediates instead of C-based radicals, followed by subsequent 1,n-HAT to furnish corresponding remote functionalization. This relay protocol enables a straightforward approach to streamline the assembly of structurally diverse trifluoromethylated azaheterocycles.

Recent advances in transition metal-mediated trifluoromethylation reactions

“…In the same year, Liao and co-workers disclosed the first example of the alkene-trifluoromethylation-triggered nitrile insertion/remote functionalization relay process under Cu-catalysis to access various trifluoromethylated N -containing cyclic frameworks (Scheme 9). 46 In this context, Togni's reagent II was used as the trifluoromethyl radical source in the transformation. Generation of common carbon-centered radical 9d formed from substrate 9a was obtained through the sequence of addition of a CF 3 radical onto the alkene, intramolecular radical cyclization and 1,5-HAT.…”

Sulfonyl radical-triggered two/three-component tandem bicyclization of CN-containing 1,6-enynes under transition metal- and base-free conditions

“…2 Traditionally, the general process of this reaction mode starts with the in situ generated radicals attacking the unsaturated bond of CN-containing compounds followed by an intramolecular cyclization to produce unstable iminyl radical intermediates. Further transformation of iminyl radical intermediates generally involves three pathways: hydrolysis, 3 nitrile insertion, 4 and remote cyano migration. 5 One of the most intriguing aspects of the transformations mentioned above is hydrolysis, which has been extensively explored to construct complex cyclic ketones in a one-step process.…”

Synthesis of imidazo[1,2-a]pyridinones via a visible light-photocatalyzed functionalization of alkynes/nitrile insertion/cyclization tandem sequence using micro-flow technology

“…[14][15][16][17][18][19][20][21][22][23] In this context, as a versatile class, iminyl radicals have been involved in a wide range of synthetic applications and have gained increasing attention recently in synthetic chemistry because of their promising potential in 1,n-HAT-mediated relay processes for the construction of N-containing cyclic molecules (Scheme 1a). [16][17][18][19][20][21][24][25][26][27][28] Recently, Liao and co-workers 29 reported a new copper-catalyzed alkene-trifluoromethylationtriggered nitrile insertion/remote functionalization relay process (Scheme 1b).…”