Organic Base Enabled Nickel-Catalyzed Mono-α-Arylation of Feedstock Solvents.

We report on our successful development of the first metal-catalyzed mono-α-arylation of carbonyl compounds employing a soluble organic base. The scope of these Ni/DalPhos-catalyzed transformations encompasses a range of (hetero)aryl halides (Cl, Br, I) and phenol-derived electrophiles (sulfonates, carbonates, carbamates, sulfamates), including active pharmaceutical ingredients (chloroquine, clozapine), in combination with the typically problematic feedstock small molecule substrates acetone, dimethylacetamide, and for the first time with any metal catalyst/base, ethyl acetate.

Mapping Dual-Base-Enabled Nickel-Catalyzed Aryl Amidations: Application in the Synthesis of 4-Quinolones.

The C-N cross-coupling of (hetero)aryl (pseudo)halides with NH substrates employing nickel catalysts and organic amine bases represents an emergent strategy for the sustainable synthesis of (hetero)anilines. However, unlike protocols that rely on photoredox/electrochemical/reductant methods within NiI/III cycles, the reaction steps that comprise a putative Ni0/II C-N cross-coupling cycle for a thermally promoted catalyst system using organic amine base have not been elucidated. Here we disclose an efficient new nickel-catalyzed protocol for the C-N cross-coupling of amides and 2'-(pseudo)halide-substituted acetophenones, for the first time where the (pseudo)halide is chloride or sulfonate, which makes use of the commercial bisphosphine ligand PAd2-DalPhos (L4) in combination with an organic amine base/halide scavenger, leading to 4-quinolones. Room-temperature stoichiometric experiments involving isolated Ni0, I, and II species support a Ni0/II pathway, where the combined action of DBU/NaTFA allows for room-temperature amide cross-couplings.

Hydrostibination of Alkynes: A Radical Mechanism*.

The addition of Sb-H bonds to alkynes was reported recently as a new hydroelementation reaction that exclusively yields anti-Markovnikov Z-olefins from terminal acetylenes. We examine four possible mechanisms that are consistent with the observed stereochemical and regiochemical outcomes. A comprehensive analysis of solvent, substituent, isotope, additive, and temperature effects on hydrostibination reaction rates definitively refutes three ionic mechanisms involving closed-shell charged intermediates. Instead the data support a fourth pathway featuring open-shell neutral intermediates. Density-functional theory (DFT) calculations are consistent with this model, predicting an activation barrier that is in agreement with the experimental value (Eyring analysis) and a rate limiting step that is congruent with the experimental kinetic isotope effect. We therefore conclude that hydrostibination of arylacetylenes is initiated by the generation of stibinyl radicals, which then participate in a cycle featuring SbII and SbIII intermediates to yield the observed Z-olefins as products. This mechanistic understanding will enable rational evolution of hydrostibination as a synthetic methodology.

Hydrostibination.

A rigid naphthalenediamine framework has been used to prepare antimony hydrides that feature LUMO shapes and energies similar to those found in secondary boranes. By exploiting this feature, we introduce the first examples of uncatalyzed hydrostibination reactions of robust C≡C, C=C, C=O, and N=N bonds as new elementary hydrometalation reactions analogous to hydroboration. These results endorse the notion of a diagonal relationship between the lightest p-block element and the heaviest Group 15 elements and may lead to the conception of novel reaction chemistry.

Substrate-product analogue inhibitors of isoleucine 2-epimerase from Lactobacillus buchneri by rational design.

A rational approach that may be applied to a broad class of enzyme-catalyzed reactions to design enzyme inhibitors affords a powerful strategy, facilitating the development of drugs and/or molecular probes of enzyme mechanisms. A strategy for the development of substrate-product analogues (SPAs) as inhibitors of racemases and epimerases is elaborated using isoleucine 2-epimerase from Lactobacillus buchneri (LbIleE) as a model enzyme. LbIleE catalyzes the PLP-dependent, reversible, racemization or epimerization of nonpolar amino acids at the C-2 position. The enzyme plays an important role in the biosynthesis of branched-chain d-amino acids and is a potential target for the development of antimicrobial agents. 3-Ethyl-3-methyl-l-norvaline (Ki = 2.9 ± 0.2 mM) and 3-ethyl-3-methyl-d-norvaline (Ki = 1.5 ± 0.2 mM) were designed as SPAs based on the movement of the sec-butyl side chain of the substrate l-Ile during catalysis, and were competitive inhibitors with binding affinities exceeding that of l-Ile by 1.3- and 2.5-fold, respectively. Surprisingly, these compounds were not substrates, but the corresponding compounds lacking the 3-methyl group were substrates. Unlike serine, glutamate, and proline racemases, which exhibit stringent steric requirements at their active sites, the active site of LbIleE was amenable to binding bulky SPAs. Moreover, LbIleE bound the SPA 2,2-di-n-butylglycine (Ki = 11.0 ± 0.2 mM) as a competitive inhibitor, indicating that the hydrophobic binding pocket at the active site was sufficiently plastic to tolerate gem-dialkyl substitution at the α-carbon of an amino acid. Overall, these results reveal that amino acid racemases/epimerases are amenable to inhibition by SPAs provided that they possess a capacious active site.