Walking Metals for Remote Functionalization

Abstract

The distant and selective activation of unreactive C-H and C-C bonds remains one of the biggest challenges in organic chemistry. In recent years, the development of remote functionalization has received growing interest as it allows for the activation of rather challenging C-H and C-C bonds distant from the initiation point by means of a "metal-walk". A "metal-walk" or "chain-walk" is defined by an iterative series of consecutive 1,2- or 1,3-hydride shifts of a metal complex along a single hydrocarbon chain. With this approach, simple building blocks or mixtures thereof can be transformed into complex scaffolds in a convergent and unified strategy. A variety of catalytic systems have been developed and refined over the past decade ranging from late-transition-metal complexes to more sustainable iron- and cobalt-based systems. As the possibilities of this field are slowly unfolding, this area of research will contribute considerably to provide solutions to yet unmet synthetic challenges.

Figure 1

“Metal-walk” vs classical modes of activation: (a) general concept of remote functionalization; (b) directed C–H activation at close proximity; (c) metal-walk for remote functionalization.

Figure 2

Mechanistic intricacies of olefin isomerization: (a) 1,2-hydride shift mechanism; (b) 1,3-hydride shift; (c) 1,3-hydride shift with a ligand acting as a base; (d) 1,3-proton shift.

Figure 3

Zr complexes in remote functionalization: (a) zirconium-mediated C–H allylic activation–elimination sequence; (b) migratory hydrozirconation for enantioselectice copper-catalyzed 1,4-addition reaction; (c) zirconium-mediated allylic C–H bond activation followed by a selective ring-opening reaction.

Figure 4

Ru and Rh “chain-walking” via olefin isomerization: (a) isomerization of alkenyl alcohols with the alkene zipper catalyst; (b) tandem Ru-catalyzed isomerization–W-catalyzed olefin metathesis reactions; (c) tandem Rh-catalyzed isomerization–hydroformylation reaction and functionalization at the terminal position.

Figure 5

Rh or Ir “chain-walk”/C–C bond formation: (a) tandem Rh-catalyzed isomerization–conjugate addition reactions; (b) tandem Ir-catalyzed isomerization −allylation reactions.

Figure 6

Fe “chain-walking” hydroboration(hydrosilylation) of internal olefins.

Figure 7

Co-catalyzed “chain-walking” hydroboration events: (a) tandem Co-catalyzed isomerization–hydroboration reactions; (b) effect of the Co catalyst on the regioselectivity of the isomerization; (c) Co-catalyzed isomerization–hydroboration reactions with a N-phosphinoamidinate ligand.

Figure 8

Co-catalyzed “chain-walking” hydrosilylation.

Figure 9

Co-catalyzed “chain-walking” via olefin isomerization/C–C bond formation.

Figure 10

Pd-catalyzed “chain-walking” via C–C bond formations terminated by carbonyl formation: (a) Pd-catalyzed isomerization of alkenyl alcohols; (b) enantioselective Pd-catalyzed isomerization of alkenols; (c) enantioselective Heck reaction on trisubstituted alkenols; (d) palladium-catalyzed Heck isomerization as a trigger for selective ring-opening of cyclopropanes; (e) isomerization of unsaturated alcohols promoted by metal–hydride catalysts.

Figure 11

Pd-catalyzed “chain-walking” via C–C bond formation by nonterminating carbonyl formation: (a) Pd-catalyzed tandem isomerization–nucleophilic addition; (b) palladium-catalyzed tandem isomerization–cyclization reactions; (c) Pd-catalyzed isomerization–functionalization via either an initial C–H activation or oxidative addition reaction.

Figure 12

Ni-catalyzed “chain-walking” hydrosilylations of internal olefins: (a) Ni-pincer complex catalyzed isomerization–silylation reactions; (b) Ni-nanoparticle catalyzed isomerization–silylation reactions.

Figure 13

Ni-catalyzed “chain-walking” hydroarylation initiated by formal C–H activation: (a) Ni-catalyzed olefin isomerization–hydroarylation of alkenes; (b) tandem isomerization–hydroarylation reactions using a N-heterocyclic carbene Ni(0) complex.

Figure 14

Ni-catalyzed “chain-walking” hydroarylation with aryl halide counterparts: (a) Ni-catalyzed hydroarylation at benzylic sp³ C–H sites; (b) Ni-catalyzed hydroarylation with aryl bromides.

Figure 15

Ni-catalyzed “chain-walking” for remote carboxylation of hydrocarbons with CO₂: (a) Ni-catalyzed remote sp³ C–H carboxylation of unactivated alkyl bromides; (b) water as an inexpensive hydride source for the remote carboxylation of alkenes.