CuII -Catalyzed Oxidative Formation of 5-Alkynyltriazoles.

In an alcoholic solvent under the catalysis of Cu(OAc)2 ⋅H2 O, organic azide and terminal alkyne could oxidatively couple to afford 5-alkynyl-1,2,3-triazole (alkynyltriazole) at room temperature under an atmosphere of O2 in a few hours. The involvement of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) is essential, without which the redox neutral coupling instead proceeds to produce 5-H-1,2,3-triazole (protiotriazole) as the major product. Therefore, DBN switches the redox neutral coupling between terminal alkyne and organic azide, the copper-catalyzed "click" reaction to afford protiotriazole, to an oxidation reaction that results in alkynyltriazole. The organic base DBN is effective in accelerating the copper(II)-catalyzed oxidation of terminal alkyne or copper(I) acetylide, which is intercepted by an organic azide to produce alkynyltriazole. The proposed mechanistic model suggests that the selectivity between alkynyl- and protiotriazole, and other acetylide or triazolide oxidation products is determined by the competition between copper(I)-catalyzed redox neutral cycloaddition and copper(II)/O2 -mediated acetylide oxidation after the formation of copper(I) acetylide.

Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5.

This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu5 NAM clinical candidate that failed in non-human primate (NHP) 28 day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp3 character, uniform CYP450-mediated metabolism across species, good functional potency and high CNS penetration. Key to the optimization was a combination of matrix and iterative libraries that allowed rapid surveillance of multiple domains of the allosteric ligand.

Design and Synthesis of mGlu2 NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core.

Herein, we detail the optimization of the mGlu2 negative allosteric modulator (NAM), VU6001192, by a reductionist approach to afford a novel, simplified mGlu2 NAM scaffold. This new chemotype not only affords potent and selective mGlu2 inhibition, as exemplified by VU6001966 (mGlu2 IC50 = 78 nM, mGlu3 IC50 > 30 µM), but also excellent central nervous system (CNS) penetration (Kp = 1.9, Kp,uu = 0.78), a feature devoid in all previously disclosed mGlu2 NAMs (Kps ≈ 0.3, Kp,uus ≈ 0.1). Moreover, this series, based on overall properties, represents an exciting lead series for potential mGlu2 PET tracer development.

Cu(II)-Catalyzed Oxidative Formation of 5,5'-Bistriazoles.

Copper(II) acetate under aerobic conditions catalyzes the formation of 5,5'-bis(1,2,3-triazole)s (5,5'-bistriazoles) from organic azides and terminal alkynes. This reaction is an oxidative extension of the widely used copper-catalyzed azide-alkyne "click" cycloaddition. The inclusion of potassium carbonate as an additive and methanol or ethanol as the solvent, and in many instances an atmosphere of dioxygen, promote the oxidative reaction to afford 5,5'-bistriazole at the expense of 5-protio-1,2,3-triazole (5-protiotriazole). If needed, tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) as a ligand additive further accelerates the formation of 5,5'-bistriazoles. A convenient procedure to prepare TBTA is also reported to facilitate the adoption of this method for preparation of 5,5'-bistriazoles. Aromatic azide-derived 5,5'-bistriazoles possess rigid axially chiral structures with a broad distribution of dihedral angles, which may be explored as chiral ligands in enantioselective catalysis if decorated with proper functional groups.

On the Mechanism of Copper(I)-Catalyzed Azide-Alkyne Cycloaddition.

The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction regiospecifically produces 1,4-disubstituted-1,2,3-triazole molecules. This heterocycle formation chemistry has high tolerance to reaction conditions and substrate structures. Therefore, it has been practiced not only within, but also far beyond the area of heterocyclic chemistry. Herein, the mechanistic understanding of CuAAC is summarized, with a particular emphasis on the significance of copper/azide interactions. Our analysis concludes that the formation of the azide/copper(I) acetylide complex in the early stage of the reaction dictates the reaction rate. The subsequent triazole ring-formation step is fast and consequently possibly kinetically invisible. Therefore, structures of substrates and copper catalysts, as well as other reaction variables that are conducive to the formation of the copper/alkyne/azide ternary complex predisposed for cycloaddition would result in highly efficient CuAAC reactions. Specifically, terminal alkynes with relatively low pKa values and an inclination to engage in π-backbonding with copper(I), azides with ancillary copper-binding ligands (aka chelating azides), and copper catalysts that resist aggregation, balance redox activity with Lewis acidity, and allow for dinuclear cooperative catalysis are favored in CuAAC reactions. Brief discussions on the mechanistic aspects of internal alkyne-involved CuAAC reactions are also included, based on the relatively limited data that are available at this point.