Metal-Free-Visible Light C–H Alkylation of Heteroaromatics via Hypervalent Iodine-Promoted Decarboxylation

Abstract

A metal-free photoredox C-H alkylation of heteroaromatics from readily available carboxylic acids using an organic photocatalyst and hypervalent iodine reagents under blue LED light is reported. The developed methodology tolerates a broad range of functional groups and can be applied to the late-stage functionalization of drugs and drug-like molecules. The reaction mechanism was investigated with control experiments and photophysical experiments as well as DFT calculations.

Beyond Friedel and Crafts: Innate Alkylation of C−H Bonds in Arenes

“…Under these conditions, various heteroarenes could be readily alkylated using a large excess (10 equivalents) of primary, secondary, and tertiary acids, as well as amino and fatty acids, thereby providing the desired alkylated products in fair to good yields (Scheme ). More recently, a similar transformation, based on the use of 9‐mesityl‐10‐methylacridinium perchlorate and PIFA as photoredox catalyst and oxidant, was also reported . The use of 1,2,3,5‐tetrakis(carbazol‐9‐yl)‐4,6‐dicyanobenzene (4‐CzIPN) under irradiation with a blue LED was also described for the Minisci‐like alkylation of azines (and some azoles) via the intermediacy of in situ generated N ‐(acyloxy)phthalimides .…”

Beyond Friedel and Crafts: Directed Alkylation of C−H Bonds in Arenes

“…Other reagents have indeed been exploited for the selective alkylation of CÀHb onds in electron-deficient heteroarenes:t hey include alcohols, [70][71][72][73] carboxylic acids, [74][75][76][77][78][79][80][81][82][83] peroxides, [84,85] aldehydes, [86][87][88] acyl chlorides, [89] as well as some less common reagents such as pyridinium salts, [90] dihydropyridines, [91] N-tosylhydrazones, [92] N-(acyloxy)phthalimides, [93,94] a-diazocarbonyl derivatives, [95] a-carbonyl alkylsulfones, [96] carboxylic xanthates, [97,98] cycloalkanols, [99,100] and Wittig reagents. [101] Theu se of alcohols as remarkably attractive alkylating agents was elegantly exploited by MacMillan in 2015 for the direct alkylation of pyridine derivatives by using as trategy that combines photoredox catalysis and hydrogen atom transfer catalysis.…”

“…[78] Finally,the use of visible-light photoredox catalysis also permitted the direct alkylation of various nitrogen-containing heteroarenes by using {Ir[dF(CF 3 )ppy] 2 (dtbbpy)}PF 6 and (NH 4 ) 2 S 2 O 8 as photoredox catalyst and oxidant, under irradiation with ab lue LED,a sdescribed by Glorius. [80] Theu se of 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4-CzIPN) under irradiation with ablue LED was also described for the Minisci-like alkylation of azines (and some azoles) via the intermediacyofinsitugenerated N-(acyloxy)phthalimides. More recently,asimilar transformation, based on the use of 9mesityl-10-methylacridinium perchlorate and PIFAasphotoredox catalyst and oxidant, was also reported.…”

“…More recently,asimilar transformation, based on the use of 9mesityl-10-methylacridinium perchlorate and PIFAasphotoredox catalyst and oxidant, was also reported. [80] Theu se of 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4-CzIPN) under irradiation with ablue LED was also described for the Minisci-like alkylation of azines (and some azoles) via the intermediacyofinsitugenerated N-(acyloxy)phthalimides. [81] Finally,t wo recent processes have been reported for the visible-light-initiated photoredox catalyst-free alkylation of N-heterocycles with primary,s econdary,a nd tertiary alkyl carboxylic acids, [82] and for the photoredox-mediated Minisci alkylation of N-heteroarenes using Ru(bpy) 3 Cl 2 as photoredox catalyst.…”

Neue Entwicklungen auf dem Gebiet der Minisci‐Reaktion

“…[41] ¾hnlich zu den von Glorius beschriebenen Ansätzen wird hier davon ausgegangen, dass die Radikalerzeugung durch Homolyse des Acylhypoiodits 14 erfolgt, [42] das aus dem entsprechenden Carboxylatanion und elektrochemisch erzeugtem molekularem Iod erhalten wird. [44] Dazu nutzten sie den von Fukuzumi beschriebenen, organischen Photokatalysator Mes-Acr (9-Mesityl-10-Methylacridinium) [45] zur Initiierung der vermutlichen Kettenreaktion (siehe mechanistische Überlegungen). Interessanterweise beobachteten die Autoren fürein Substrat zudem Unterschiede in der Regioselektivitätz wischen ihrem Syntheseprotokoll und den klassischen Minisci-Bedingungenmit Silbersalzen und starken Oxidationsmitteln.…”