Divergent Synthesis of CF₃‐Substituted Allenyl Nitriles by Ligand‐Controlled Radical 1,2‐ and 1,4‐Addition to 1,3‐Enynes

Abstract

A ligand-controlled system that enables regioselective trifluoromethylcyanation of 1,3-enynes has been identified, which provides access to a variety of CF -containing tri- and tetrasubstituted allenyl nitriles. We disclose that the involved propargylic radicals can be selectively trapped by (Box)Cu cyanide, while the tautomerized allenyl radicals are trapped by (phen)Cu cyanide (Box= bisoxazoline, phen=phenanthroline). In addition, the reaction features broad substrate scope and excellent functional group compatibility. Moreover, this protocol represents a novel regioselectivity-tunable functionalization of 1,3-enynes via radicals, which we believe will have great implications for the development of catalytic systems for selectivity control in radical and organometallic chemistry.

The Persistent Radical Effect in Organic Synthesis

“…[290] c) Asymmetric cyanation and arylation by radical-metalc rossover reactions. [312,313] Angewandte Chemie…”

“…Thea lkyl radicals are generated by reductive cleavage of alkyl halides, [304] or by radical addition of N-centered radicals, [305] trifluoromethyl radicals, [306,307] and alkyl radicals [308,309] to alkenes,o rb y benzylic Habstraction using NFSI [310] or peroxides. [311] Recently,the group of Liu substantially contributed to the development of asymmetric variants of such transformations by using chiral bis(oxazoline) ligands.F or example,r adical alkene trifluoromethylation with concomitant b-cyanation [312] was accomplished with excellent enantioselectivity.I na nalogy,t rifluoromethylation and subsequent Cu-catalyzed stereoselective b-arylation [313] was reported (Figure 49 c). The addition of N-centered radicals [314,315] to styrenes and subsequent trapping with various chiral Cu complexes leading to enantioselective 1,2-difunctionalizations of arylalkenes was also achieved.…”

Nickel‐Catalyzed Carbofluoroalkylation of 1,3‐Enynes to Access Structurally Diverse Fluoroalkylated Allenes

“…Over the past few decades,agreat number of fluorinating and fluoroalkylating agents have been successfully developed, enabling facile synthesis of different kinds of fluorinecontaining molecules, [6] whereas the general approaches to access each fluoroalkylating building blocks typically require multistep syntheses.While such fluoroalkylating agents could only work in specific fluoroalkylation reactions,the development of efficient fluoroalkylation reactions,w hich are compatible with ab road array of fluorine-containing functional groups,w ill evidently offer ap erfect tactic for batch production of fluorinated products in medicinal chemistry. As part of our continuous efforts on nickel-catalyzed fluoroalkylation, [7] we envisioned that the addition of various in situ generated radicals from fluoroalkyl halides [6d] to 1,3enynes [8] would give allenyl radicals for nickel-catalyzed cross-coupling, [9] affording the allenes with structurally different fluorine-containing groups.I ndeed, such ar adical relay strategy was first used for 1,2-carbofluoroalkylation of alkenes by the group of Zhang,a nd then further illustrated by the group of Chu (Scheme 1). [10] However,a lkenes with chelating groups were essential for both transformations, possibly because of the unique catalytic reactivity of the nickel complex.…”

Der “Persistent Radical Effect” in der organischen Chemie

“…Beispielsweise wurden fürdie radikalische Tr ifluormethylierung mit anschließender b-Cyanierung exzellente Enantioselektivitäten erzielt. [312] In Analogie wurde von der Tr ifluormethylierung und der nachfolgenden stereoselektiven b-Arylierung [313] berichtet (Abbildung 49 c). Die Addition N-zentrierter Radikale [314,315] an Styrole und anschließendes Abfangen mit verschiedenen Cu-Komplexen lieferten enantioselektiv 1,2-difunktionalisierte Arylalkane.…”