Practical and innate carbon–hydrogen functionalization of heterocycles

Abstract

Nitrogen-rich heterocyclic compounds have had a profound impact on human health, as these chemical motifs are found in a large number of drugs used to combat a broad range of diseases and pathophysiological conditions. Advances in transition metal-mediated cross-coupling have simplified the synthesis of such molecules; however, the development of practical and selective C–H functionalization methods that do not rely upon prefunctionalized starting materials is an underdeveloped area.1–9 Paradoxically, the innate properties of heterocycles that make them so desirable for biological applications render them challenging substrates for direct chemical functionalization, such as limited solubility, functional group incompatibilities, and reagent/catalyst deactivation. Herein we report that zinc sulfinate salts9 can be used to transfer alkyl radicals to heterocycles, allowing for a mild, direct and operationally simple formation of medicinally relevant C–C bonds while reacting in an orthogonal fashion to other innate C–H functionalization methods (Minisci, borono-Minisci, electrophilic aromatic substitution, transition metal-mediated C–H insertion, C–H deprotonation).2–7,9 A toolkit of these reagents was prepared and reacted across a wide range of heterocycles (natural products, drugs, building blocks) without recourse to protecting group chemistry, and can even be employed in a tandem fashion in a single pot in the presence of water and air.

Cooperative dual palladium/silver catalyst for direct difluoromethylation of aryl bromides and iodides

“…Difluorination of benzylic C-H bonds that was promoted by visible light or silver catalyst generated difluoromethylarenes efficiently, yet selectivity is problematic for multi-alkylated arenes [13][14][15] . Baran and coworkers 16,17 reported a radical difluoromethylation of heteroarenes with zinc difluoromethanesulfinate, but reactions with arenes have not been reported. Several transition metal-catalysed difluoromethylation involved the using of difluoromethyl surrogates such as a-silyldifluoroacetate 18 and difluoromethylphenylketone 19 have emerged recently.…”

Palladium‐Catalyzed Intramolecular CH Difluoroalkylation: Synthesis of Substituted 3,3‐Difluoro‐2‐oxindoles

“…However, when BrettPhos (L6) was employed as the ligand, difluorinated oxindole 2a was isolated in high yield (78%, entry 6). The use of other monophosphine ligands, as well as bidentate phosphine ligands, such as PPh 3 , PCy 3 , P(tBu) 3 , dppe, BINAP and Xantphos, resulted in low to no conversion to the desired product (entries [7][8][9][10][11][12]. No conversion of the starting material was observed in the absence of either phosphine ligand or palladium source (entries 13 and 14).…”

“…However, these methods are limited by their scope, synthetic efficiency, or the accessibility of the required starting materials. A synthesis of difluorooxindoles through a palladium-catalyzed C-H difluoroalkylation process [11] would constitute a general and practical alternative to these previously reported methods.…”

Regioselective trifluoromethylation of N-heteroaromatic compounds using trifluoromethyldifluoroborane activator

“…These examples include the following: (1) directing groupassisted palladium 37,38 -or silver 39 -catalysed oxidative trifluoromethylation; (2) palladium 40 -or copper 41 -catalysed oxidative trifluoromethylation of heteroaromatic compounds; and (3) radical trifluoromethylation using NaSO 2 45,46 . The drawback to approach (1), however, is the requirement for directing groups that are not necessary in the target molecules 39 , and in approaches (2) and (3), regioselectivity is generally difficult to control, especially in the case of sixmembered heteroaromatic compounds except when using substrates with substituent(s) to block the possible reaction site(s) [40][41][42][43][44][45][46] . Specifically, trifluoromethylation reactions reported by Baran 42 and MacMillan groups 44 are of wide substrate scope.…”

“…Although CF 3 groups can be regioselectively introduced to aromatic rings in cross-coupling reactions, requirement of multiple steps for the preparation of aryl halides and boronic acids/esters and generation of stoichiometric amounts of metal salts decrease synthetic efficiency. To overcome such drawbacks, direct C-H trifluoromethylation recently received much attention; however, examples of aromatic C-H trifluoromethylations are still limited [35][36][37][38][39][40][41][42][43][44][45][46] . These examples include the following: (1) directing groupassisted palladium 37,38 -or silver 39 -catalysed oxidative trifluoromethylation; (2) palladium 40 -or copper 41 -catalysed oxidative trifluoromethylation of heteroaromatic compounds; and (3) radical trifluoromethylation using NaSO 2 45,46 .…”