Functionalization of C(sp3)-H bonds adjacent to heterocycles catalyzed by earth abundant transition metals

Functionalization of Alkyl Groups Adjacent to Azoles: Application to the Synthesis of α-Functionalized Carboxylic Acids

“…The resulting carbo-radical species subsequently undergoes either an oxidation event to form a benzylic cation that reacts with a nucleophile or a radical-radical coupling process to give the desired functionalized product (Scheme 1). 3 Scheme 1 Mode of activation of C-H bonds adjacent to benzazoles under transition metal catalysis…”

“…Thus, the reaction was proposed to involve an N-allylation leading to the formation of iminium ion complex 18, which subsequently led to the N-vinyl allylamine intermediate 19, followed by palladium catalyzed aza-Claisen rearrangement to furnish the desired product 22 (Scheme 7). Recently, we have reported a convenient synthesis of enenitrile compounds through the catalytic direct cyanomethylenation of C(sp 3 )−H bonds adjacent to benzazoles with a "CNCH=" equivalent. 18 In this process, DMF was used as a C-1 source ("=CH") and trimethylsilyl cyanide (TMSCN) was employed as the cyanating agent ("CN") to deliver enenitrile compounds via a one-step C=C double bond and C−CN bond formations in the presence of a palladium/copper bimetallic system.…”

“…However, due to smaller size, the catalytic activities of 3d transition metals differs considerably from that of a larger 4d or 5d metal catalysts. Among the 3d metals, copper and iron are known to serve as promising catalyst candidates for the functionalization of a C(sp 3 )-H bond adjacent to azoles. 3 The required C-H functionalization takes place via the formation of a C-centered radical that is stabilized by its Ncentered form as discussed in the previous sections.…”

“…Among the 3d metals, copper and iron are known to serve as promising catalyst candidates for the functionalization of a C(sp 3 )-H bond adjacent to azoles. 3 The required C-H functionalization takes place via the formation of a C-centered radical that is stabilized by its Ncentered form as discussed in the previous sections. These C-H functionalizations are of fundamental importance as many azole moieties act as masked form of carboxylic acids.…”

“…Nonetheless, the pKa value of those methylene C-H bonds is still high (>25 in DMSO) leading to inherently poor acidity. 3 As a consequence, the C-H abstraction with subsequent functionalization adjacent to an azole system calls for catalysis by a transition metal and involves an ionic or a…”