Nickel-catalyzed Reductive Cleavage Research Articles

Nickel-catalyzed reductive defunctionalization of esters in the absence of an external reductant: activation of C-O bonds.

The nickel-catalyzed reductive cleavage of esters in the absence of an external reductant, which involves the cleavage of an inert acyl C-O bond in O-alkyl esters is reported. Various groups, such as N-containing heterocycles, esters, amides, and even arene rings can function as a directing group.

Nickel-Catalyzed Reductive Cleavage of Carbon–Oxygen Bonds in Anisole Derivatives Using Diisopropylaminoborane

The catalytic removal of a methoxy group on an aromatic ring allows this group to be used as a traceless activating and directing group for aromatic functionalization reactions. Although several catalytic methods for the reductive cleavage of anisole derivatives have been reported, all are applicable only to π-extended aryl ethers, such as naphthyl and biphenyl ethers, while monocyclic aryl ethers cannot be reduced. Herein, we report a nickel-catalyzed reductive cleavage reaction of C–O bonds in aryl ethers using diisopropylaminoborane as the reducing agent. Unlike previously reported methods, this reducing reagent allows effective C–O bond reduction in a much wider range of aryl ether substrates, including monocyclic and heterocyclic ethers bearing various functional groups.

Cross-Couplings Using Aryl Ethers via C-O Bond Activation Enabled by Nickel Catalysts.

Arene synthesis has been revolutionized by the invention of catalytic cross-coupling reactions, wherein aryl halides can be coupled with organometallic and organic nucleophiles. Although the replacement of aryl halides with phenol derivatives would lead to more economical and ecological methods, success has been primarily limited to activated phenol derivatives such as triflates. Aryl ethers arguably represent one of the most ideal substrates in terms of availability, cost, safety, and atom efficiency. However, the robust nature of the C(aryl)-O bonds of aryl ethers renders it extremely difficult to use them in catalytic reactions among the phenol derivatives. In 1979, Wenkert reported a seminal work on the nickel-catalyzed cross-coupling of aryl ethers with Grignard reagents. However, it was not until 2004 that the unique ability of a low-valent nickel species to activate otherwise unreactive C(aryl)-O bonds was appreciated with Dankwardt's identification of the Ni(0)/PCy3 system, which significantly expanded the efficiency of the Wenkert reaction. Application of the nickel catalyst to cross-couplings with other nucleophiles was first accomplished in 2008 by our group using organoboron reagents. Later on, several other nucleophiles, including organozinc reagents, amines, hydrosilane, and hydrogen were shown to be coupled with aryl ethers under nickel catalysis. Despite these advances, progress in this field is relatively slow because of the low reactivity of benzene derivatives (e.g., anisole) compared with polyaromatic substrates (e.g., methoxynaphthalene), particularly when less reactive and synthetically useful nucleophiles are used. The "naphthalene problem" has been overcome by the use of N-heterocyclic carbene (NHC) ligands bearing bulky N-alkyl substituents, which enables a wide range of aryl ethers to be coupled with organoboron nucleophiles. Moreover, the use of N-alkyl-substituted NHC ligands allows the use of alkynylmagnesium reagents, thereby realizing the first Sonogashira-type reaction of anisoles. From a mechanistic perspective, nickel-catalyzed cross-couplings of aryl ethers are at a nascent stage, in particular regarding the mode of activation of C(aryl)-O bonds. Oxidative addition is one plausible pathway, although such a process has not been fully verified experimentally. Nickel-catalyzed reductive cleavage of aryl ethers in the absence of an external reducing agent provides strong support for this oxidative addition process. Several other mechanisms have also been proposed. For example, Martin demonstrated a new possibility of the involvement of a Ni(I) species, which could mediate the cleavage of the C(aryl)-O bond via a redox-neutral pathway. The tolerance of aryl ethers under commonly used synthetic conditions enables alkoxy groups to serve as a platform for late-stage elaboration of complex molecules without any tedious protecting group manipulations. Aryl ethers are therefore not mere economical alternatives to aryl halides but also enable nonclassical synthetic strategies.

Nickel-catalyzed reductive cleavage of aryl alkyl ethers to arenes in absence of external reductant.

The reductive cleavage of the C-O bonds of aryl ethers has great potential in organic synthesis. Although several catalysts that can promote the reductive cleavage of aryl ethers have been reported, all such systems require the use of an external reductant, e.g., hydrosilane or hydrogen. Here, we report the development of a new nickel-based catalytic system that can cleave the C-O bonds of ethers in the absence of an external reductant. The hydrogen atom required in this new reductive cleavage reaction is provided by the alkoxy group of the substrate, which serves as an internal reductant. The absence of an external reductant enables the unique chemoselectivity, i.e., the selective reduction of an alkoxy group over alkenes and ketones.

Ni- and Fe-Catalyzed Cross-Coupling Reactions of Phenol Derivatives

This review describes our laboratory’s efforts to develop transition metal-catalyzed cross-couplings of several unconventional phenol-based electrophiles. Specifically, we highlight herein the following four key transformations: (a) nickel-catalyzed Suzuki–Miyaura couplings of aryl pivalates, carbamates, and sulfamates to construct sp2–sp2 C–C bonds; (b) iron-catalyzed Kumada couplings of aryl carbamates and sulfamates for the assembly of sp2–sp3 C–C bonds; (c) nickel-catalyzed amination reactions of carbamates and sulfamates to build aryl C–N bonds; and (d) nickel-catalyzed reductive cleavage reactions of aryl carbamates to achieve aryl deoxygenation and a rare method for cine substitution. We expect this review will enable the greater use of unconventional phenol-based cross-coupling electrophiles in industrial settings.

Nickel-Catalyzed Reductive Cleavage of Aryl Ethers

Nickel-Catalyzed Reductive Cleavage of Aryl Ethers

Entianin, a Novel Subtilin-Like Lantibiotic from Bacillus subtilis subsp. spizizenii DSM 15029 T with High Antimicrobial Activity

Lantibiotics, such as nisin and subtilin, are lanthionine-containing peptides that exhibit antimicrobial as well as pheromone-like autoinducing activity. Autoinduction is specific for each lantibiotic, and reporter systems for nisin and subtilin autoinduction are available. In this report, we used the previously reported subtilin autoinduction bioassay in combination with mass spectrometric analyses to identify the novel subtilin-like lantibiotic entianin from Bacillus subtilis subsp. spizizenii DSM 15029(T). Linearization of entianin using Raney nickel-catalyzed reductive cleavage enabled, for the first time, the use of tandem mass spectrometry for the fast and efficient determination of an entire lantibiotic primary structure, including posttranslational modifications. The amino acid sequence determined was verified by DNA sequencing of the etnS structural gene, which confirmed that entianin differs from subtilin at 3 amino acid positions. In contrast to B. subtilis ATCC 6633, which produces only small amounts of unsuccinylated subtilin, B. subtilis DSM 15029(T) secretes considerable amounts of unsuccinylated entianin. Entianin was very active against several Gram-positive pathogens, such as Staphylococcus aureus and Enterococcus faecalis. The growth-inhibiting activity of succinylated entianin (S-entianin) was much lower than that of unsuccinylated entianin: a 40-fold higher concentration was required for inhibition. For succinylated subtilin (S-subtilin), a concentration 100-fold higher than that of unsuccinylated entianin was required to inhibit the growth of a B. subtilis test strain. This finding was in accordance with a strongly reduced sensing of cellular envelope stress provided by S-entianin relative to that of entianin. Remarkably, S-entianin and S-subtilin showed considerable autoinduction activity, clearly demonstrating that autoinduction and antibiotic activity underlie different molecular mechanisms.

Nickel-catalyzed reductive cleavage of aryl–oxygen bonds in alkoxy- and pivaloxyarenes using hydrosilanes as a mild reducing agent

A nickel-catalyzed reductive deoxygenation of aryl alkyl ethers and aryl pivalates has been developed. Hydrosilanes serve as a mild reducing agent. The present protocol allows the use of a pivalate group as a robust and traceless steering group in arene functionalization reactions.