Nickel-Catalyzed Three-Component 1,2-Carboacylation of Alkenes.

Ketones, prevalent in many biologically significant molecules, require the development of novel methods to synthesize these structures, which is a critical endeavor in organic synthesis. Transition metal catalysis has proven to be an effective method for synthesizing ketones. However, the scope of these substrates remains relatively limited, particularly due to their incompatibility with sensitive functional groups. Herein, we report a Ni-catalyzed three-component 1,2-carboacylation of alkenes, which activates secondary/tertiary alkyl bromides. This method offers significant advantages: simplicity of operation, ready availability of substrates, and broad substrate applicability. A series of experimental studies have helped clarify the key mechanistic pathways involved in this cascade reaction.

Nickel(II)-Catalyzed Formal [3+2] Cycloadditions between Indoles and Donor-Acceptor Cyclopropanes.

This article describes the development of a nickel-catalyzed regio- and diastereoselective formal [3+2] cycloaddition between N-substituted indoles and donor-acceptor cyclopropanes to synthesize cyclopenta[b]indoles. Optimized reaction conditions provide the desired nitrogen-containing cycloadducts in up to 93% yield and dr 8.6:1 with complete regioselectivity. The substrate scope showed high tolerance to various substituted indoles and cyclopropanes, resulting in the synthesis of six new cyclopenta[b]indoles and the isolation of five derivatives previously reported in the literature. In addition, a mechanistic proposal for the reaction was studied through online reaction monitoring by ESI-MS, allowing for the identification of the reactive intermediates in the Ni(II) catalyzed process. X-ray crystallography confirmed the structure and relative endo stereochemistry of the products. This method enables the fast and efficient construction of fused indolines from readily accessible starting materials.

Single step synthesis of ß- and γ- aryl-substituted ß- and γ-amino acid derivatives by electrochemistry.

Electrochemical transformations are a subject of increasing interest in early drug discovery due to its ability to assemble complex scaffolds under rather mild reaction conditions. In this context, we became interested in electrochemical decarboxylative cross-coupling (DCC) protocols of redox-active esters (RAEs) and halo(hetero)arenes. Starting with the one-step electrochemical synthesis of novel methylamino-substituted heterocycles we recognized the potential of this methodology to deliver a novel approach to ß- and γ- amino acids by starting from the corresponding RAEs. Our work finally resulted in the delivery of novel and highly valuable trifunctional building blocks based on ß- and γ-amino-acid scaffolds.

Harnessing Sulfur(VI) Fluoride Exchange Click Chemistry and Photocatalysis for Deaminative Benzylic Arylation.

While among the most common functional handles present in organic molecules, amines are a widely underutilized linchpin for C-C bond formation. To facilitate C-N bond cleavage, large activating groups are typically used but result in the generation of stoichiometric amounts of organic waste. Herein, we report an atom-economic activation of benzylic primary amines relying on the Sulfur(VI) Fluoride Exchange (SuFEx) click chemistry and the aza-Ramberg-Bäcklund reaction. This two-step sequence allows the high-yielding generation of 1,2-dialkyldiazenes from primary amines via loss of SO2. Excitation of the diazenes with blue light and an Ir photocatalyst affords radical pairs upon expulsion of N2, which can be coaxed into the formation of C(sp3)-C(sp2) bonds upon diffusion and capture by a Ni catalyst. This arylative strategy relying on a traceless click approach was harnessed in a variety of examples and its mechanism was investigated.

Nickel-Catalyzed Regioselective Intermolecular Dialkylation of Alkenylarenes: Generation of Two Vicinal C(sp3 )-C(sp3 ) Bonds Across Alkenes.

We disclose a Ni-catalyzed regioselective dialkylation reaction of alkenylarenes with α-halocarbonyls and alkylzinc reagents. The reaction produces γ-arylated alkanecarbonyl compounds with the generation of two new C(sp3 )-C(sp3 ) bonds at the vicinal carbons of alkenes. This reaction is effective for the use of primary, secondary and tertiary α-halocarboxylic esters, amides and ketones in conjunction with primary and secondary alkylzinc reagents as the sources of two C(sp3 ) carbons for the dialkylation of terminal and cyclic internal alkenes.

Synthesis of Sulfonated Polyphenylene Block Copolymers via In Situ Generation of Ni(0).

Proton exchange membranes (PEMs) fabricated from sulfonated polyphenylenes (sPP) exhibit superior proton conductivity and electrochemical performance. However, the Ni(0) catalyst required for Colon's cross-coupling reaction for the synthesis of sPP block copolymers is expensive. Therefore, in this study, we generated Ni(0) in situ from an inexpensive Ni(II) salt in the presence of the reducing metal Zn and NaI. The sPP block copolymers were synthesized from neopentyl-protected 3,5- and 2,5-dichlorobenzenesulfonates and oligo(arylene ether ketone) using the catalyst NiBr2(PPh3)2. The block copolymers synthesized using our strategy and the Ni(0) catalyst exhibited comparable polydispersity index values and high molecular weights. Thin, transparent, and bendable PEMs fabricated using selected high-molecular-weight sPP block copolymers synthesized via our strategy exhibited similar proton conductivities to those of the block copolymers synthesized using the Ni(0) catalyst. We believe that our strategy will promote the synthesis of similar multifunctional block copolymers.

Picolinamide Ligands: Nickel-Catalyzed Reductive Cross-Coupling of Aryl Bromides with Bromocyclopropane and Beyond.

The arylcyclopropane motif as the combination of aryl and cyclopropyl ring systems can be found in an increasing amount of approved and investigational drugs. Herein, we have developed a mild, efficient nickel-catalyzed reductive cross-coupling protocol, featuring a simple Ni(II) precatalyst and a novel picolinamide NN2 pincer ligand. A variety of (hetero)aryl bromides could successfully couple with cyclopropyl bromide to furnish the valued arylcyclopropanes in good to excellent yields. This method is applicable to other alkyl bromides as well. Notably, the reaction is tolerant of a broad range of functionalities including free amines. Furthermore, the synthesis of several significant intermediates of bioactive molecules was achieved in grams, proving the practicability of this method.

Ni-Catalyzed Cross-Coupling of 2-Iodoglycals and 2-Iodoribals with Grignard Reagents: A Route to 2-C-Glycosides and 2'-C-Nucleosides.

The synthesis of 2-C-glycals and 2-C-ribals was achieved in good yields using a nickel-catalyzed cross-coupling between 2-iodoglycals and 2-iodoribal respectively and Grignard reagents. The prepared 2-C-glycals and ribals were then transformed into 2-C-2-deoxyglycosides, 2-C-diglycosides and 2'-C-2'-deoxynucleosides. The developed method was applied to the synthesis of a 2-chloroadenine 2'-deoxyribonucleoside - a structural analogue of cladribine (Mavenclad®, Leustatin®) and clofarabine (Clolar®, Evoltra®), two compounds used in the treatment of relapsing-remitting multiple sclerosis and hairy cell leukemia.

Ni-Catalyzed Regio- and Stereoselective Alkylarylation of Unactivated Alkenes in γ,δ-Alkenylketimines.

We disclose a Ni-catalyzed vicinal alkylarylation of unactivated alkenes in γ,δ-alkenylketimines with aryl halides and alkylzinc reagents. The reaction produces γ-C(sp3)-branched δ-arylketones with the construction of two new C(sp3)-C(sp3) and C(sp3)-C(sp2) bonds. Electron-deficient alkenes play crucial dual roles as ligands to stabilize reaction intermediates and to increase catalytic rates for the formation of C(sp3)-C(sp3) bonds. This alkene alkylarylation reaction is also effective for secondary alkylzinc reagents and internal alkenes, and proceeds with a complete regio- and stereocontrol, affording products with up to three contiguous all-carbon all-cis secondary stereocenters.

Branched Sulfonimide-Based Proton Exchange Polymer Membranes from Poly(Phenylenebenzopheneone)s for Fuel Cell Applications.

Improved proton conductivity and high durability are now a high concern for proton exchange membranes (PEMs). Therefore, highly proton conductive PEMs have been synthesized from branched sulfonimide-based poly(phenylenebenzophenone) (SI-branched PPBP) with excellent thermal and chemical stability. The branched polyphenylene-based carbon-carbon backbones of the SI-branched PPBP membranes were attained from the 1,4-dichloro-2,5-diphenylenebenzophenone (PBP) monomer using 1,3,5-trichlorobenzene as a branching agent (0.1%) via the Ni-Zn catalyzed C-C coupling reaction. The as-synthesized SI-branched PPBP membranes showed 1.00~1.86 meq./g ion exchange capacity (IEC) with unique dimensional stability. The sulfonimide groups of the SI-branched PPBP membranes had improved proton conductivity (75.9-121.88 mS/cm) compared to Nafion 117 (84.74 mS/cm). Oxidation stability by thermogravimetric analysis (TGA) and Fenton's test study confirmed the significant properties of the SI-branched PPBP membranes. Additionally, a very distinct microphase separation between the hydrophobic and hydrophilic moieties was observed using atomic force microscopic (AFM) analysis. The properties of the synthesized SI-branched PPBP membranes demonstrate their viability as an alternative PEM material.

An Expedient Route to 9-arylmethylanthracene Derivatives via Tandem Ni-catalyzed Alkene Dicarbofunctionalization and Acid-promoted Cyclization-aromatization.

We report a nickel-catalyzed one pot synthesis of 9-arylmethylanthracene motifs, which find applications in medicinal and material chemistry. In this synthesis, we apply three component alkene dicarbofunctionalization of 2-vinylaldimines with aryl iodides and arylzinc reagent to generate a 1,1,2-diarylethyl scaffold, which then undergoes an acidpromoted cyclization followed by aromatization to furnish 9-arylmethylanthracene cores. With the new method, a number of differently-substituted 9-arylmethylanthracene derivatives can be synthesized in good yields.

Nickel-Catalyzed Heck-Type Monofluoroacetation of Styrenes for Facile Synthesis of Allylic Fluorides.

An efficient nickel-catalyzed Heck-type reaction between styrenes and fluoroalkyl iodine has been developed. This novel transformation has demonstrated a broad substrate scope, mild reaction conditions and excellent E-stereoselectivity. This efficient synthetic method has been applied to the late-stage monofluoroacetation of biologically active molecules. Mechanistic investigations indicate that a monofluoroalkyl radical is involved in the catalytic cycle.

Nickel-Catalyzed Oxidative C-H/N-H Isocyanide Insertion: An Efficient Synthesis of Iminoisoindolinone Derivatives.

Transition metal-catalyzed isocyanide insertion has served as a fundamental and important chemical transformation. Classical isocyanide insertion usually occurs between organohalides and nucleophiles, which normally involves tedious and non-atom-economical prefunctionalization processes. However, oxidative C-H/N-H isocyanide insertion offers an efficient and green alternative. Herein, a nickel-catayzed oxidative C-H/N-H isocyanide insertion of aminoquinoline benzamides has been developed. Different kinds of iminoisoindolinone derivatives could be synthesized in good yields by utilizing Ni(acac)2 as the catalyst. In this transformation, isocyanide serves as an efficient C1 connector, which further inserted into two simple nucleophiles (C-H/N-H), representing an effective way to construct heterocycles.

Synthesis of a polymerizable, bivalent glycan mimetic of the HIV envelope spike gp120.

A synthetic study on the creation of a bivalent, ROMP capable monomer has the ability to be polymerized into the corresponding neo-glycopolymer mimetic of the surface glycans on gp120 envelope spike of the HIV virus. In our approach, we have developed a new strategy for orthogonally attaching both the terminal Manα1-2Man disaccharide unit of the D1 arm of Man9GlcNAc2 of HIV gp120 and the terminal Manα1-2 unit of its D2 arm to a bivalent scaffold to produce the corresponding polymerizable monomer. The Manα1-2 saccharide moieties were assembled using a nickel catalyst, Ni(4-F-PhCN)4(OTf)2, to activate trihaloacetimidate donors under mild and operationally simple procedure.