Combined Experimental and Computational Mechanistic Investigation of the Palladium-Catalyzed Decarboxylative Cross-Coupling of Sodium Benzoates with Chloroarenes.

Reported herein is a mechanistic investigation into the palladium-catalyzed decarboxylative cross-coupling of sodium benzoates and chloroarenes. The reaction was found to be first-order in Pd. A minimal substituent effect was observed with respect to chloroarene, and the reaction was zero-order with respect to chloroarene.

4-Methyl-1,2,3-Triazoles as -Acetyl-Lysine Mimics Afford Potent BET Bromodomain Inhibitors with Improved Selectivity.

The bromodomain and extra terminal (BET) protein family recognizes acetylated lysines within histones and transcription factors using two N-terminal bromodomains, D1 and D2. The protein-protein interactions between BET bromodomains, acetylated histones, and transcription factors are therapeutic targets for BET-related diseases, including inflammatory disease and cancer. Prior work demonstrated that methylated-1,2,3-triazoles are suitable -acetyl lysine mimetics for BET inhibition.

Ti-catalyzed ring-opening oxidative amination of methylenecyclopropanes with diazenes.

The ring-opening oxidative amination of methylenecyclopropanes (MCPs) with diazenes catalyzed by pyTiCl(NR) complexes is reported. This reaction selectively generates branched α-methylene imines as opposed to linear α,β-unsaturated imines, which are difficult to access other methods. Products can be isolated as the imine or hydrolyzed to the corresponding ketone in good yields.

A cascade reaction of cinnamyl azides with vinyl sulfones directly generates dihydro-pyrrolo-pyrazole heterocycles.

This report describes the direct synthesis of dihydro-pyrrolo-pyrazole heterocycles from allylic azides and methyl vinyl sulfone. The product results from a complex cascade reaction that is operationally straightforward, with aromatization being the result of a concomitant elimination step. A variety of azides could participate in this reaction (12 examples) and the isolated yields of the desired product ranged from 51%-72%.

Enantioselective Nickel-Catalyzed Alkyne-Azide Cycloaddition by Dynamic Kinetic Resolution.

The triazole heterocycle has been widely adopted as an isostere for the amide bond. Many native amides are α-chiral, being derived from amino acids. This makes α--chiral triazoles attractive building blocks.

Silver Mediated Banert Cascade with Carbon Nucleophiles.

The Banert cascade of propargylic azides can be promoted by simple silver salts, and the triazafulvene intermediate can be intercepted by carbon nucleophiles. Various indoles (>25 examples, up to 92% yield) and electron-rich heterocycles were effective. The Mayr nucleophilicity parameter () was found to correlate to the reaction efficiency, which enabled the formation of C-C and C-C bonds under otherwise identical conditions from structurally dissimilar nucleophiles.

Enhanced Affinity for 3-Amino-Chromane-Derived σ Receptor Ligands.

The σ receptor is implicated in regulating a diverse range of physiology and is a target for developing therapies for cancer, pain management, neural degradation, and COVID-19. This report describes 36 phenethylamine-containing 3-amino-chromane ligands, which bind to σ with low nM affinities. The family consists of 18 distinct compounds and each enantiomer was independently assayed.

Gold Catalyzed Decarboxylative Cross-Coupling of Iodoarenes.

This report details a decarboxylative cross-coupling of (hetero)aryl carboxylates with iodoarenes in the presence of a gold catalyst (>25 examples, up to 96% yield). This reaction is site specific, which overcomes prior limitations associated with gold catalyzed oxidative coupling reactions. The reactivity of the (hetero)aryl carboxylate correlates qualitatively to the field effect parameter ().

A Cascade Reaction of Cinnamyl Azides with Acrylates Directly Generates Tetrahydro-Pyrrolo-Pyrazole Heterocycles.

Developing reactions to generate complex and modular building blocks in a concise and direct fashion remains a contemporary synthetic challenge. This work describes a stereoselective cascade reaction between allylic azides and acrylates that directly generates tetrahydro-pyrrolo-pyrazole ring systems. These products contain up to four contiguous stereocenters, two of which may be tetrasubstituted carbon atoms attached to a nitrogen atom.

Gram-Scale Synthesis of 2,5-Difluoro-7,7,8,8-tetracyanoquinodimethane (F-TCNQ).

The molecule 2,5-difluoro-7,7,8,8-tetracyanoquinodimethane (F-TCNQ) is an organic semiconductor with many promising properties, including high charge mobility (μ). However, an efficient gram-scale synthesis of F-TCNQ has not been fully documented. Herein, we report a synthesis of F-TCNQ via a three-step sequence that affords F-TCNQ in 58% cumulative yield.

Divergent Mechanisms of the Banert Cascade with Propargyl Azides.

Triazoles are privileged heterocycles for a variety of applications. The synthesis of 1-triazoles can be accomplished by the Banert cascade from propargylic azides. Depending on the substrate and conditions, the Banert cascade can proceed by either a sigmatropic or prototropic mechanism.

3-Amino-chromanes and Tetrahydroquinolines as Selective 5-HT, 5-HT, or σ Receptor Ligands.

The phenethylamine backbone is a privileged substructure found in a wide variety of G protein-coupled receptor (GPCR) ligands. This includes both endogenous neurotransmitters and active pharmaceutical agents. More than 20 structurally unique heterocyclic phenethylamine derivatives were broadly evaluated for GPCR affinity.

Double-click enables synthesis of chemical libraries for drug discovery.

Operationally simple chemical reactions, termed click reactions, are widely used in many scientific fields. A streamlined synthesis of compounds called azides looks set to expand the role of click chemistry still further. See Letter p.

Systematically Mitigating the p38α Activity of Triazole-based BET Inhibitors.

The Bromodomain and Extra Terminal (BET) family of proteins recognize post-translational -ε-acetylated lysine modifications, regulating transcription as "reader" proteins. Bromodomain inhibitors are interesting targets for the development of potential cancer, inflammation, and heart disease treatments. Several dual kinase-bromodomain inhibitors have been identified by screening kinase inhibitor libraries against BET proteins.

On the Winstein rearrangement: equilibrium and mechanism.

Allylic azides are underutilized in organic synthesis when compared to other organic azides or other allylic functionality. This is likely because allylic azides rearrange at room temperature, resulting in a potentially complex mixture of azides. This rearrangement has been termed the Winstein rearrangement.

Additive-Free Palladium-Catalyzed Decarboxylative Cross-Coupling of Aryl Chlorides.

The cross-coupling of sodium (hetero)aryl carboxylates with (hetero)aryl chlorides proceeds with 1 mol % palladium catalyst and does not require inorganic base, silver salts, or copper salts. This coupling uses two low energy partners, and the only stoichiometric byproducts are carbon dioxide and sodium chloride. The substrate scope includes less activated aryl chlorides and carboxylates (>25 examples).

Kinetic Resolution of Cyclic Secondary Azides, Using an Enantioselective Copper-Catalyzed Azide-Alkyne Cycloaddition.

An enantioselective copper-catalyzed azide-alkyne cycloaddition (E-CuAAC) is reported by kinetic resolution. Chiral triazoles were isolated in high yield with limiting alkyne (up to 97:3 enantiomeric ratio (er)). A range of substrates were tolerated (>30 examples), and the reaction was scaled to >1 g.

Allylic azides: synthesis, reactivity, and the Winstein rearrangement.

Organic azides are useful synthetic intermediates, which demonstrate broad reactivity. Unlike most organic azides, allylic azides can spontaneously rearrange to form a mixture of isomers. This rearrangement has been named the Winstein rearrangement.

Enantioselective Copper Catalyzed Alkyne-Azide Cycloaddition by Dynamic Kinetic Resolution.

The copper(I) catalyzed alkyne-azide cycloaddition (CuAAC), a click reaction, is one of the most powerful catalytic reactions developed during the last two decades. Conducting CuAAC enantioselectively would add a third dimension to this reaction and would enable the direct synthesis of α-chiral triazoles. Doing so is demanding because the two precursors have linear geometries, and the triazole product is a flat heterocycle.

"It's a (Kinetic) Trap!" - Selectively Differentiating Allylic Azide Isomers.

Allylic azides are known to undergo the Winstein rearrangement and are often isolated as an equilibrating mixture of isomers. While this process has been known for almost 60 years, very few synthetic applications of this process have been reported. The absence of methods exploiting these intermediates likely stems from a paucity of approaches for gaining the required selectivity to differentiate the isomers.

Catalytic Racemization of Activated Organic Azides.

The first detailed description of the catalytic racemization of activated benzylic and allylic azides under mild conditions is reported. A kinetic analysis of the observed racemization indicates a first-order dependence on azide, a first-order dependence on catalyst, and that the rate of racemization correlates to σ. A variety of azides with varying substitution patterns undergo facile racemization, and catalyst selection can tune this process.

Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor.

As regulators of transcription, epigenetic proteins that interpret post-translational modifications to N-terminal histone tails are essential for maintaining cellular homeostasis. When dysregulated, "reader" proteins become drivers of disease. In the case of bromodomains, which recognize N-ε-acetylated lysine, selective inhibition of individual bromodomain-and-extra-terminal (BET)-family bromodomains has proven challenging.

Palladium-catalyzed salt-free double decarboxylative aryl allylation.

This report describes a palladium-catalyzed decarboxylative aryl allylation between unactivated benzoic acids and allylic carbonates. This transformation successfully couples a variety of carbonates and benzoic acids in good yield (up to 94%) using 1 mol% palladium. This salt free allyl-arylation proceeds without added base, copper, or silver.

Evidence for a Sigmatropic and an Ionic Pathway in the Winstein Rearrangement.

The spontaneous rearrangement of allylic azides is thought to be a sigmatropic reaction. Presented herein is a detailed investigation into the rearrangement of several allylic azides. A combination of experiments including equilibrium studies, kinetic analysis, density functional theory calculations, and selective N-isotopic labeling are included.