Ring Construction by Palladium(0)-Catalyzed C(sp³)–H Activation

Abstract

The catalytic activation and functionalization of unactivated C(sp)-H bonds of alkyl groups has undergone intense development in recent years. In particular, a variety of directing groups as well as native functional groups have been employed in combination with palladium(II) catalysis in order to perform a variety of intermolecular, and to some extent intramolecular reactions. In parallel, inspired by precedents in C(sp)-H arylation, our group and others have developed a different approach, which is the focus of this Account. This strategy relies on the use of oxidative addition of a carbon-leaving group bond to palladium(0) to induce intramolecular C(sp)-H activation and the subsequent formation of a C(sp)-C(sp) or C(sp)-C(sp) bond. Since our first publication in 2003, the construction of olefins and, more interestingly, of an array of valuable monocyclic and polycyclic systems has been reported according to this principle. (Hetero)aryl bromides were initially employed as reactants, but the scope was later expanded to include (hetero)aryl chlorides and triflates, alkenyl bromides, carbamoyl chlorides and α-chloroamides. Mechanistic studies enabled a better understanding of the C-H activation step, which was proposed to occur through ambiphilic metal-ligand activation-6 (AMLA-6), also known as concerted metalation deprotonation (CMD), and a better rationalization of the observed selectivity patterns. Moreover, the wealth of accumulated experimental data indicate that the number of atoms separating the C-H bond from Pd and the type of C-H bond are the main factors controlling the site-selectivity of the C-H bond cleavage. Recent efforts have been devoted to the development of enantioselective reactions. To this purpose, two different strategies have been employed: a chiral ancillary ligand in combination with an achiral base, and a chiral base in combination with an achiral ligand, and allowed for the achievement of high enantioselectivities in the construction of both tri- and tetrasubstituted stereocenters. On the other hand, the current C-H activation-based ring-forming method was applied to the synthesis of pharmacologically active substances and agrochemicals, as well as complex natural products such as the aeruginosins, thereby demonstrating its great potential for step-economical organic synthesis.

Redox‐Neutral Coupling between Two C(sp3)−H Bonds Enabled by 1,4‐Palladium Shift for the Synthesis of Fused Heterocycles

“…[9] Moreover,i tw as shown that aryl bromides 3 (Scheme 1c)tend to undergo 1,4-Pd shift through carbonate or carboxylate-mediated proton transfer to generate alkylpalladium complex C. [9] Moreover,i tw as shown that aryl bromides 3 (Scheme 1c)tend to undergo 1,4-Pd shift through carbonate or carboxylate-mediated proton transfer to generate alkylpalladium complex C.…”

Electrochemical Transition‐Metal‐Catalyzed C−H Bond Functionalization: Electricity as Clean Surrogates of Chemical Oxidants

“…C(sp 3 )−H bonds are difficult to functionalize, relative to analogous C(sp 2 )−H bonds, because of the high bond dissociation energy . Recently, the groups of Mei and Sanford, by using oxime as a directing group, independently reported electrochemical palladium‐catalyzed C(sp 3 )−H oxygenation (Table ).…”

Silicon-Tethered Strategies for C–H Functionalization Reactions

“…Importantly, employment of LiOAc was curial for the success of the second C–H oxygenation event, which indicates that the reaction follows a concerted metalation–deprotonation (CMD) pathway. 16 The scope of this symmetrical double-fold C–H oxygenation methodology was found to be quite general, as substrates possessing both electron-donating and -withdrawing substituents produced their respective symmetrical bis-pivaloxylated products in excellent yields (Scheme 13). It is believed that the efficient formal three-step bis- o,o ′-oxygenation of 4-iodo-bromobenzene ( 63 → 64 ) via this approach represents a novel type of synthetic disconnection.…”