Mild Aerobic Oxidative Palladium (II) Catalyzed C−H Bond Functionalization:  Regioselective and Switchable C−H Alkenylation and Annulation of Pyrroles

Abstract

A palladium catalyzed C-H bond functionalization system that operates under ambient and aerobic conditions can be used to alkenylate pyrroles with control of regioselectivty. A steric and electronic control strategy can be used to influence positional control in the C-H bond functionalization process that results in either the C2 or C3 alkenylated products. Air, molecular oxygen, or tBuOOBz can be used as reoxidant in this mild process, and the reaction works on a range of substrates. Finally a catalytic aerobic annulation strategy is described that can be controlled to produce cyclization at either the C2 or C3 positions, thus forming diverse pyrrole products.

Direct transition metal-catalyzed functionalization of heteroaromatic compounds

“…102 Further, Gaunt disclosed a method for C-2 and C-3 regioselective intermolecular C-H alkenylation and annulation of pyrroles 198 and 199 (Scheme 69). 103 Notably, the regiochemistry in this mild and high-yielding aerobic protocol can be completely controlled via sterically and electronically tuned N-protecting groups to obtain either C-2 or C-3 functionalized products 199 and 200 selectively. In intramolecular series, introduction of an electron-withdrawing protecting group at 201, such as N-Ac, N-Boc, or N-Ts results in C-2-substitution to give 202 (electronic control).…”

“…In contrast, N-TIPS pyrroles afford C-4-substituted products 203 exclusively, which was attributed to the shielding effect of sterically-demanding TIPS group, disfavoring C-2-palladation (steric control) (Scheme 69). 103 The direct C-H addition of heterocycles to electron-deficient olefins in the presence of Au catalysts was investigated by He (Scheme 70). 104 Indoles, furans and benzofurans 204 were shown to undergo the gold(III)-catalyzed formal alkylation with functionalized alkenes and alkynes.…”

C–H bond functionalizations with palladium(II): intramolecular oxidative annulations of arenes

“…17 In a general reaction scheme, indole 35 would cyclize onto a tethered olefin to afford annulated indole 36 (Scheme 6). A reaction of this type would be highly useful to the synthetic community.…”

Catalyst‐Switchable Regiocontrol in the Direct Arylation of Remote CH Groups in Pyrazolo[1,5‐a]pyrimidines

“…Ap hosphinecontaining palladium catalyst promotes the direct arylation at the most acidic position (C7), whereas ap hosphine-free catalyst targets the most electron-rich position (C3).The direct CÀHa rylation of heterocyclics ubstrates (Scheme 1) is ap owerful synthetic tool for the construction of functionalized heterocycles.I tm aintains the expediency associated with simple cross-coupling reactions,b ut with greater step economy and lower waste production.[1] In heterocycles with multiple C À Hg roups,i tw ould be highly advantageous to be able to choose which CÀHg roup is functionalized, ideally with complete selectivity and with the ability to "switch" regioselectivity at will.[2] Seminal examples of this approach include the vinylation or arylation of pyrroles and indoles at either C2 or C3, where the outcome is driven by achange in substrate derivatization, [3,4] solvent, [5] or oxidant.[6]In these cases,the site selectivity is typically controlled by prohibiting or encouraging migration between positions C3 and C2. By contrast, we were interested to find out whether site selectivity could be engendered in the arylation of remote CÀHg roups,a nd whether catalyst "tuning" could be employed to drive this selectivity.…”