Sequential-Flow Synthesis of Donepezil: A Green and Sustainable Strategy Featuring Heterogeneous Catalysis and Hydrogenation.

An atom-economical sequential-flow synthesis of donepezil, a widely prescribed drug for Alzheimer's disease, was accomplished using inexpensive, commercially available precursors. This achievement was made possible by reconfiguring the synthetic route to include only heterogeneous catalytic addition and condensation reactions, with a particular emphasis on skeletal transformation and bond formation through hydrogenation processes. Notably, water was the sole byproduct in this synthesis. A crucial aspect of this work was the development of appropriate continuous-flow processes to achieve a one-flow synthesis. This was accomplished by implementing in-line treatments of the main reaction stream to eliminate inhibitory factors that could affect catalyst performance in the hydrogenation steps.

Structure-Directed Quaternary Ammonium Hydroxide Resins: High-Performance Heterogeneous Base Catalysts for Continuous-Flow Carbon-Carbon Bond-Forming Reactions.

Quaternary ammonium hydroxide resins are widely recognized for their effectiveness as immobilized bases and are frequently utilized as commodity chemicals for anion-exchange applications. However, despite their accessibility, chemically controlling their properties has proven challenging, hindering research and development efforts toward their use as solid base catalysts. This study investigates the synthetic factors that are crucial for achieving high functional performance in polystyrene resins. Using commercially available resin as a benchmark and the continuous-flow Henry reaction as a model system, we explore and evaluate newly synthesized resin catalysts to maximize their basic catalytic activity.

Continuous-flow synthesis using a column reactor packed with heterogeneous catalysts: A convenient production of nitroolefins by using amino-functionalized silicagel.

A continuous-flow synthesis of ß-nitroolefins by using heterogeneous base catalysts has been developed. Although the use of an excess amount of nitro-donor such as nitromethane is required in conventional methods, nearly equimolar amounts of nitro-donors and carbonyl compounds are sufficient for high-yielding production of nitroolefins. Catalysts for this flow protocol are inexpensive and abundant, and high durability and high productivity were also realized by using an appropriate second support.

Design of chiral bis-phosphoric acid catalyst derived from (R)-3,3'-di(2-hydroxy-3-arylphenyl)binaphthol: catalytic enantioselective Diels-Alder reaction of α,ß-unsaturated aldehydes with amidodienes.

Chiral bis-phosphoric acid 1 was designed to identify a new class of structural features in chiral Brønsted acid catalysts. X-ray diffraction analysis revealed the single atropisomer 1, bearing S axial chirality at 3,3'-biaryl substituents on (R)-binaphthyl and intramolecular hydrogen bonding between the two phosphoric acid moieties. The newly designed bis-phosphoric acid 1 was evaluated in the Diels-Alder reaction of α,ß-unsaturated aldehydes 4 with 1-N-acylamino-1,3-butadienes 3. After systematic variation of the catalyst substituents, as well as the N-acyl substituents of 1,3-butadiene, the use of an N-Cbz amidodiene 3a in the presence of bis-phosphoric acid 1e with a 2,4,6-tri-isopropylphenyl group was found to be optimal to yield the 1S,6R enantiomeric product 5aa in a Diels-Alder reaction of acrolein (4a). Application of this method to substituted substrates was found to be an efficient approach to the enantioselective synthesis of 3- and 3,6-substituted cyclic formylcarbamates 5. The specific character as well as the utility of 1e was further established by comparing its enantioselectivity, absolute stereochemistry, and catalytic efficiency with those of mono-phosphoric acid 2.

Enantioselective Sequential-Flow Synthesis of Baclofen Precursor via Asymmetric 1,4-Addition and Chemoselective Hydrogenation on Platinum/Carbon/Calcium Phosphate Composites.

Continuous-flow synthesis of baclofen precursor (2) was achieved using achiral and chiral heterogeneous catalysts in high yield with high enantioselectivity. The key steps are chiral calcium-catalyzed asymmetric 1,4-addition of a malonate to a nitroalkene and chemoselective reduction of a nitro compound to the corresponding amino compound by using molecular hydrogen. A dimethylpolysilane (DMPS)-modified platinum catalyst supported on activated carbon (AC) and calcium phosphate (CP) has been developed that has remarkable activity for the selective hydrogenation of nitro compounds.