Enabling Metallophotoredox Catalysis in Parallel Solution-Phase Synthesis Using Disintegrating Reagent Tablets

Abstract

Compressed tablets containing a mixture of a photocatalyst, a nickel catalyst, an inorganic base, and an inert excipient are employed as a fast, safe, and user-friendly chemical delivery system for two different metallophotoredox-catalyzed reactions. This delivery method simplifies the preparation of compound libraries using photoredox chemistry in a parallel setting. The reagent tablets were successfully applied to late-stage functionalization of drug-like intermediates. These tablets can be prepared with various reagents and catalysts in different sizes and be stored on the bench thanks to blister packaging.

ppm Pd‐Containing Nanoparticles as Catalysts for Negishi Couplings … in Water

“…Aside from the factors noted above, direct comparisons were made with both traditional approaches to Negishi couplings involving Pd [34] as well as recent protocols that rely on unsustainable and costly precious metals (e.g., 2-5 mol % Ir; see Table 6). Several include Ni in addition to Ir (entries 1-4), [35,36] or use of Ni alone (entry 5). [37] Most are from "big pharma" and hence, surprisingly, are run in environmentally egregious organic solvents such as watermiscible dioxane (entries 1 and 2) or dipolar aprotic DMA (entries 5 and 6).…”

At the Speed of Light: The Systematic Implementation of Photoredox Cross-Coupling Reactions for Medicinal Chemistry Research

“…As such, we were interested in developing a strategy to circumvent this disadvantage and developed tablets as an alternative chemical delivery system to capsules, where the "ingredients" were not separated from the reaction mixture by an encapsulating material. 45 As with the capsules, the preparation of tablets is straightforward and reduces the number of weighing steps significantly (dependent upon the number of reactions, Figure 7A, step 1). A Huxley Bertram machine (step 2) was used to prepare larger quantities of tablets (approximately 500 tablets/ h); however, tablet preparation can also be performed using a hand press.…”

“…A Huxley Bertram machine (step 2) was used to prepare larger quantities of tablets (approximately 500 tablets/ h); however, tablet preparation can also be performed using a hand press. 45 The final tablets should ideally be stored under an inert atmosphere to guarantee their integrity (step 3); however, sealing the tablets in aluminum blisters enables storage under standard benchtop conditions as well (step 4). Unlike the capsules, complete disintegration of the tablets can be observed within 15 min when using 1,4-dioxane as the reaction solvent, demonstrating the accessibility of the catalyst/ligand/base combination in the reaction mixture in a short period of time.…”

“…The dissolving process relies on a polar solvent and does not work in solvents with low polarity. As such, we were interested in developing a strategy to circumvent this disadvantage and developed tablets as an alternative chemical delivery system to capsules, where the “ingredients” were not separated from the reaction mixture by an encapsulating material . As with the capsules, the preparation of tablets is straightforward and reduces the number of weighing steps significantly (dependent upon the number of reactions, Figure A, step 1).…”

“…As with the capsules, the preparation of tablets is straightforward and reduces the number of weighing steps significantly (dependent upon the number of reactions, Figure A, step 1). A Huxley Bertram machine (step 2) was used to prepare larger quantities of tablets (approximately 500 tablets/h); however, tablet preparation can also be performed using a hand press . The final tablets should ideally be stored under an inert atmosphere to guarantee their integrity (step 3); however, sealing the tablets in aluminum blisters enables storage under standard benchtop conditions as well (step 4).…”