Activation and Deactivation Strategies Promoted by Medium Effects for Selective Aliphatic C−H Bond Functionalization

Abstract

Selective functionalization of unactivated aliphatic C-H bonds represents an important goal of modern synthetic chemistry. Differentiating between such bonds in organic molecules with high levels of selectivity remains a crucial issue, and a profound understanding of even the subtlest reactivity trends is needed. Among the methods that have been developed, those based on hydrogen atom transfer (HAT) have attracted considerable interest. Within this framework, medium effects have proved effective in altering the reactivity and site selectivity in synthetically useful C-H functionalization procedures. In this Review, the mechanistic features behind the available strategies are discussed. It is shown that hydrogen bonding and acid-base interactions can promote C-H bond activation or deactivation toward HAT reagents, thereby providing fine-control over the site selectivity and product chemoselectivity as well as useful guidelines for future development and applications.

Photoredox‐Catalyzed Site‐Selective α‐C(sp3)−H Alkylation of Primary Amine Derivatives

“…Computational studies suggest the nitrogen radical from at rifluoroacetamide is less stable than that from at riflamide. [8] Under phosphate conditions,t rifluoroacetamides lie toward heavily protonated, thus, a-C À H bond activation is minimized when compared to their triflamide counter partners.T he trifluoroacetamide nitrogen-centered radical will experience alarger driving force for intramolecular [1,5] HATd ue to nitrogen radical instability and the absence of activated a-C À Hb onds in solution (trifluoroacetamides in solution lie in the protonated state). Them ore stable nitrogen-centered radical present on triflamide acts as an intermolecular hydrogen-atom abstractor to deprotonated triflamides in solution, which possess highly activated a-CÀHb onds due to the anionic character.T his pivot in reactivity allows selective functionalization of both aand d-C À Hb onds depending on the installed nitrogen protecting group.…”

“…We reasoned that using amore acidifying functionality could pivot reactivity towards the activation of a-C(sp 3 ) À Hbonds by leveraging the following consequences: ac hange in the nature of the protecting group results in achange in the bond strength and the pK a value of the NH. [8] After surveying av ariety of amine protecting groups,w e gratifyingly observed promising reactivity and selectivity using trifluoromethanesulfonamides.W ew ere delighted to observe a-functionalization of 1a in 50 %y ield with benzyl acrylate in the presence of acarbonate base,the photocatalyst A,a nd blue light (Table 1, entry 1). As uperior yield was obtained when using [Ir(dF-CH 3 -ppy) 2 (dtbbpy)PF 6 ]( B) [9] as the photocatalyst, and subjecting quinuclidine to the reaction conditions (entry 6).…”

Recent trends in catalytic sp3 C–H functionalization of heterocycles

“…Second, we believe that as target-oriented research attempts to use C-H functionalization in more and more complex set- tings, issues of site-selectivity are going to become increasingly relevant. [215][216][217][218][219][220][221][222][223][224][225][226] Consider complex small molecules investigated in pharmaceutical applications, such as verucerfont or nizatidine ( Fig. 11).…”

Cytotoxic and antibacterial polyketide-indole hybrids synthesized from indole-3-carbinol by Daldinia eschscholzii

“…. Strategically, the generation of new PIHs usually includes cascade reactions such as C—C(N/O) bond formation 15 and selective functionalization of unactivated aliphatic C( sp 3 )—H bonds 16 . However, these reactions largely proceed in harsh reaction conditions 17 .…”

“…A presumable underlying reason for the PIH rarity arises from the fact that the PIH synthesis faces a suite of challenges, such as the complicated reaction steps (including iterative/inevitable procedures for protection and deprotection) and/or the utilization of toxic/expensive reagents13., 14.. Strategically, the generation of new PIHs usually includes cascade reactions such as C—C(N/O) bond formation 15 and selective functionalization of unactivated aliphatic C( sp 3 )—H bonds 16 . However, these reactions largely proceed in harsh reaction conditions 17 .…”