Bifunctional catalysts containing discrete metal pi-acid and amine sites were designed and investigated for the direct intermolecular addition of aldehydes and ketones to unactivated alkynes. Despite prior reports of intramolecular (Conia-ene-type) reactions and confirmation here that Cu(I)-based catalysts are effective, NMR studies indicated that a dual catalytic approach using separate amine and pi-acid catalysts may not be feasible for intermolecular reactions due to undesirable enamine competition with alkynes for metal complexation. Bifunctional precatalysts were designed with tridentate ligands and potentially hemilabile heterocyclic spacers, expected to be suitable for the binding of pi-acidic metals such as copper (I) and silver (I). The structures of the designed catalysts were computed using density functional theory (DFT), and the relative energies of putative catalytic intermediates were estimated. The calculated free energy changes upon carbon–carbon bond formation were used to prioritize catalyst designs, and several modular precatalysts were selected and prepared, with a focus on thiazole-containing systems synthesized via a 9-step sequence. Catalysts were screened for the direct addition of aldehydes and ketones to several internal and terminal alkynes. The precatalysts were combined with several different transition metal salts, and their structures studied with ¹H NMR and x-ray crystallography. Despite the lack of observed intermolecular reactions, DFT calculations of putative catalyst intermediates appears to be a promising strategy for the design and prioritization of bifunctional catalysts for C–C bond formation, and the combined results suggest that more rigid complexes may be necessary to catalyze direct intermolecular additions of aldehydes/ketones to alkynes.

Bifunctional catalysts containing discrete metal pi-acid and amine sites were designed and investigated for the direct intermolecular addition of aldehydes and ketones to unactivated alkynes. Copper(I)-based catalystswere prioritized based on intramolecular (Conia-ene type) reactions, and complexes were designed with tridentate ligands and potentially hemilabile heterocyclic spacers. The structures of the designed catalysts were computed using density functional theory (DFT), and the relative energies of putative catalytic intermediates were estimated and used to prioritize catalyst designs. Novel bifunctional precatalysts containing a thiazole spacer were synthesized via a 9-step sequence and combined with transition metals before screening for the direct addition of aldehydes and ketones to several internal and terminal alkynes. Despite the lack of desired intermolecular reactions, DFT calculations of putative catalyst intermediates appears to be a promising strategy for the design and prioritization of bifunctional catalysts for C C bond formation.

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A set of novel Kv7.2/7.3 (KCNQ2/3) channel blockers was synthesized to address several liabilities of the known compounds XE991 (metabolic instability and CYP inhibition) and the clinical compound DMP 543 (acid instability, insolubility, and lipophilicity). Using the anthrone scaffold of the prior channel blockers, alternative heteroarylmethyl substituents were installed via enolate alkylation reactions. Incorporation of a pyridazine and a fluorinated pyridine gave an analog (JDP-107) with an optimal combination of potency (IC₅₀= 0.16 𝜇M in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp assay, and drug-like properties.

A set of novel Kv7.2/7.3 (KCNQ2/3) channel blockers was synthesized to address several liabilities of the known compounds XE991 (metabolic instability and CYP inhibition) and the clinical compound DMP 543 (acid instability, insolubility, and lipophilicity). Using the anthrone scaffold of the prior channel blockers, alternative heteroarylmethyl substituents were installed via enolate alkylation reactions. Incorporation of a pyridazine and a fluorinated pyridine gave an analog (JDP-107) with an optimal combination of potency (IC₅₀= 0.16 𝜇M in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp assay, and drug-like properties.