Late‐Stage Alkylation of Heterocycles Using N‐(Acyloxy)phthalimides

Abstract

Synthetic methods enabling late-stage modification of heterocycles hold tremendous importance in the pharmaceutical and agrochemical industry and drug discovery. Accordingly, efficient, functional group tolerant and selective late-stage alkylation of valuable molecular entities is of enormous significance and well-acknowledged in medicinal chemistry. Radical alkylation of heteroarenes employing carboxylic acids as the alkyl radical precursor represents one of the most direct ways of CÀ H functionalizations of heterocycles. Recently, the field has undergone a revolutionary development especially with regard to the generation of alkyl radicals under much milder conditions. In this regard N-(acyloxy)phthalimides (NHPI esters) have emerged as a suitable precursor of a diverse set of alkyl radicals allowing formal CÀ H alkylation of not only N-heteroarenes but a diverse set of non-aromatic heterocycles under visible light photocatalysis or electrochemical conditions. This review delineates all these discoveries and provides readers a comprehensive overview of this rapidly expanding field.

Visible Light-Induced Transition Metal Catalysis

“…The high regioselectivity observed across the scope highlights the advantage of this protocol over those operating via RPC scenario. 199 In 2018, the groups of Shang and Fu described the use of RAEs 74.1 as a source of alkyl radical 213,214 to produce desaturation products 74.2 upon β-H loss. 215 A dual ligand system was found to be crucial, as much lower yield was obtained without CyJohnPhos.…”

“…In 2018, the groups of Shang and Fu described the use of RAEs 74.1 as a source of alkyl radical , to produce desaturation products 74.2 upon β-H loss . A dual ligand system was found to be crucial, as much lower yield was obtained without CyJohnPhos.…”

Organophotoredox‐Catalyzed Late‐Stage Functionalization of Heterocycles

“…Recently, the readily available N ‐(acyloxy)phthalimides (NHPI esters) have emerged as a potent source of alkyl radicals under photochemical conditions [23] . The redox chemistry of NHPI esters have been successfully applied in an array of carbon‐carbon bond formation, and late‐stage functionalization of heterocycles and bioactive compounds [2c,24] . In 2018, Sherwood and co‐workers described a visible‐light organophotoredox‐catalyzed mono‐ and dialkylation of various heteroarenes 31 and elaborated the technique for the late‐stage functionalization of several drugs or drug‐like candidates (Scheme 7, condition A) [25] .…”

“…However, the chemo‐ and stereoselective functionalization at targeted sites of advanced molecular entities at a late‐stage rather than an early stage of a synthetic campaign still remains an uphill task and is highly demanded in medicinal chemistry and drug discovery [2d,4] . Furthermore, the employed reaction technologies allowing late‐stage functionalization (LSF) of advanced synthetic intermediates, APIs (active pharmaceutical ingredient) or functional materials ought to be milder, considering the presence of a variety of potentially non‐innocent functional groups on such molecular frameworks [2a,c,4b,5] …”

Hydroesterification and Difunctionalization of Olefins with N-Hydroxyphthalimide Esters

“…Pioneering studies from Okada and Odo revealed their propensity to undergo one-electron reduction, followed by N–O bond fragmentation to release alkyl radicals following decarboxylation . This reactivity underpinned the development of decarboxylative additions to olefins, arenes, and alkynes, as well as decarboxylative borylation, olefination, and cross-coupling. − Aryl N -(acyloxy)­phthalimides have been exploited in decarboxylative borylation reactions, but the decreased stability of aryl radicals, relative to alkyl radicals, hinders decarboxylative processes. For example, aryl phthalimide esters provided a source of benzoyl esters in a Ni-catalyzed oxidation of aryl zinc reagents .…”