Second-Generation Palladium Catalyst System for Transannular C–H Functionalization of Azabicycloalkanes

Abstract

This Article describes the development of a second-generation catalyst system for the transannular C–H functionalization of alicyclic amines. Pyridine- and quinoline-carboxylate ligands are shown to be highly effective for increasing the reaction rate, yield, and scope of Pd-catalyzed transannular C–H arylation reactions of azabicyclo[3.1.0]hexane, azabicyclo[3.1.1]heptane, azabicyclo[3.2.1]octane, and piperidine derivatives. Mechanistic studies reveal that the pyridine/quinoline-carboxylates play a role in impeding both reversible and irreversible catalyst decomposition pathways. These ligands enable the first reported examples of the transannular C–H arylation of the ubiquitous tropane, 7-azanorbornane, and homotropane cores. Finally, the pyridine/quinoline-carboxylates are shown to promote both transannular C–H arylation and transannular C–H dehydrogenation on a homotropane substrate.

Model Complexes for the Palladium-Catalyzed Transannular C–H Functionalization of Alicyclic Amines

“…Two different alicyclic amine cores [3-azabicyclo[3.1.0]hexane ( A ) and 2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine ( B )] were selected for these studies based on their effectiveness as substrates for catalytic C–H arylation. 3a The reactions of A and B with various Pd II sources yielded complex mixtures that could not be definitively isolated or characterized (Scheme 2). We hypothesized that the palladium product(s) might be stabilized by the addition of a monodentate pyridine ligand to generate the pyridine adduct 1 .…”

“…2 In 2016, our group reported the transannular C–H arylation of piperidines and other alicyclic amine cores (Scheme 1). 3a Notably, this transformation enables highly selective functionalization of the C–H 4 bond in lieu of the more activated C–H bonds at the 2-position. 4 In our original report, 3a we proposed that this selectivity derives from bidentate coordination of the amine nitrogen and the tethered amide 5 of the substrate ( I ) at Pd II to form an intermediate of general structure II (Scheme 1, step i).…”

“…3a Notably, this transformation enables highly selective functionalization of the C–H 4 bond in lieu of the more activated C–H bonds at the 2-position. 4 In our original report, 3a we proposed that this selectivity derives from bidentate coordination of the amine nitrogen and the tethered amide 5 of the substrate ( I ) at Pd II to form an intermediate of general structure II (Scheme 1, step i). 3a Subsequent isomerization to the boat conformer then positions the C–H 4 bond proximal to the Pd II center for C(sp 3 )–H activation to form III (step ii), followed by functionalization with ArI and subsequent ligand exchange to release the product (step iii).…”

Diverse strategies for transition metal catalyzed distal C(sp3)–H functionalizations

“…The same group later outlined another protocol to transannular g-C-H arylation of azabicycloalkanes via a second generation Pd catalyst system. 13 In 2017, Yu and colleagues outlied another g-C(sp 3 )-H arylation approach of amines using nosyl (Ns) as the protecting group. 14 It is advantageous to utlize nosyl as the directing group due to its ease of removal.…”

Functionalization of Piperidine Derivatives for the Site‐Selective and Stereoselective Synthesis of Positional Analogues of Methylphenidate

“…[9] However,s electivef unctionalization at the remotep ositions of the piperidine moiety,t hat is, C3 and C4, is limited. [10,11] We have been exploring the rhodium-catalyzed reactions of donor/acceptor carbenes for catalyst-controlled CÀH functionalization. [6c,7f] Recently,w eh ave designed catalysts that are capable of selective functionalization of inactivated primary,s econdary, and tertiaryC ÀHb onds, [12] inactivated CÀH bondso ver electronically activated CÀHb onds, [13] and desymmetrization of alkylcyclohexanes.…”