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.
2018 04 19 Additions to alkynes SI