Visible-Light-Promoted Cyanoalkylation/Cyclization Cascade Reaction to Assemble Polyheterocycles in Continuous Flow

Abstract

This study describes a visible-light-induced cascade reaction for preparing cyanoalkyl-containing polyheterocycles initiated by the photoinduced radical cascade addition of N-arylacrylamide derivatives using cyclic oxime esters as radical sources followed by cyanoalkyl-mediated cyclization. This protocol features outstanding functional group compatibility, providing a variety of desired phenanthridine derivatives in moderate to good yields. Moreover, the application of a microflow technique enhanced these reactions compared with the equivalent batch reaction, significantly reducing reaction times to 10 min.

Cascade Cyclizations Triggered by Photochemically Generated Carbamoyl Radicals Derived from Alkyl Amines

“…23,34−36 Among methods that provide access to different derivatives of quinoline diones, a sulfonylative cyclization was reported by Yu and Li groups wherein the Yu group demonstrated a metal-free sulfonylative cyclization, 37 and the Li group utilized Cu-catalyzed sulfonylation 38 under conditions that were applicable to a larger selection of radicals for the annulation of 2-cyanoacrylamides. 39−43 Among other strategies for cyclization of acrylamide precursors, phosphorylation, 44,45 trifluoromethylation, 46 difluoromethylation, 40,47 azidation, 48 thiomethylation, and silylation 49 are methods 50 that have been well received by the scientific community. Our group has reported the visible light-mediated functionalization of C�C and C�N bonds 33,46,51 including the addition of carbamoyl radicals to quinone methides (Scheme 1b).…”

“…In this context, N -arylacrylamides are versatile precursors possessing the ability to generate a variety of molecular architectures depending on the functionality flanking the acrylamide moiety. The ortho -cyano-substituted acrylamide motif is being actively studied by the synthetic community as it leads to the quinoline dione substructure, which is present in a plethora of important biologically active molecules. ,− Among methods that provide access to different derivatives of quinoline diones, a sulfonylative cyclization was reported by Yu and Li groups wherein the Yu group demonstrated a metal-free sulfonylative cyclization, and the Li group utilized Cu-catalyzed sulfonylation under conditions that were applicable to a larger selection of radicals for the annulation of 2-cyanoacrylamides. − Among other strategies for cyclization of acrylamide precursors, phosphorylation, , trifluoromethylation, difluoromethylation, , azidation, thiomethylation, and silylation are methods that have been well received by the scientific community. Our group has reported the visible light-mediated functionalization of CC and CN bonds ,, including the addition of carbamoyl radicals to quinone methides (Scheme b).…”

Synthesis of ester-containing phenanthridinesviaphotoredox-catalyzed radical cascade cyclization ofN-arylacrylamides with alkyloxalyl chlorides

“…Recently, Sun, 10 Guo, 11 Fu, 12 and their co-workers reported the photoredox-catalyzed radical addition/nitrile insertion/cyclization of N -arylacrylamides for the synthesis of ester-, alkyl-, cyanoalkyl-, and CF 2 H-substituted phenanthridine derivatives. Despite these advances, the development of a versatile ester-containing phenanthridine derivative forming strategy that is (i) metal free, (ii) performed without additional oxidants, and (iii) compatible with diverse esters remains a challenging goal.…”

Ferrocene catalyzed redox-neutral difunctionalization of alkenes using cycloketone oxime esters: access to distal imido-nitriles

“…2 Zard's pioneering research 3 has sparked extensive exploration into the use of cycloketone oxime esters for synthesizing a broad range of functionalized alkylnitriles. 4 Recently, many transition metal or photoredox catalyzed difunctionalization of alkenes using cycloketone oxime esters have been reported. 5 However, in most of these reports, cycloketone oxime esters have only been used as sources of cyanoalkyl radicals and carboxylates released from these molecules have been neglected (Scheme 1A).…”