Microwave (MW) heating benefits organic synthesis by affording higher product yields in shorter time periods than conventional heating, yet it suffers from poor scalability and is limited to polar solvents in typical batch mode reactors. Herein, we report a microwave flow reactor using a solid-state semiconductor MW generator. The tunable, single-mode MW heating allows high efficiency, scalable organic synthesis, rapid reaction optimization and is applicable to non-polar solvents (o-Xylene and CPME can be rapidly heated to ca. 260 oC). Auto-frequency tuning compensates for changes in the microwave absorption properties (permittivity, epsilon) with increasing temperature, affording excellent temperature and process control. This technology unlocked unprecedented g/h productivity of C60/fullerene-indene monoadduct (IC60MA) and facilitated a novel, transition metal-free amide-styrene coupling reaction for synthesis of amide-containing pharmaceutical cores in up to 65 g/h (Figure 1). An ortho-Claisen rearrangement reaction was rapidly optimised.
Palladium enolates derived from β-ketocarbonyl compounds serve as key intermediates in various catalytic asymmetric reactions. We found that the palladium enolate formed from β-ketoamide is stable in air and moisture and we applied this property to develop a peptide purification system using β-ketoamide as a small affinity tag in aqueous media. A solid-supported palladium complex successfully captured β-ketoamide-tagged molecules as palladium enolates and released them in high yield upon acid treatment. Optimum conditions for the catch and release of tagged peptides from a mixture of untagged peptides were established. To demonstrate the value of this methodology in identifying the binding site of a ligand to its target protein, we purified and identified a peptide containing the ligand-binding site from the tryptic digest of cathepsin B labelled with a covalent cathepsin B inhibitor containing a β-ketoamide tag.
Abstract Fluorine is an attractive element in the field of pharmaceutical and agrochemical chemistry due to its unique properties. Considering the chiral environment in nature, where enantiomers often show different biological activities, the introduction of fluorine atom(s) into organic molecules to make chiral fluorinated compounds is an important subject. Herein, we describe the story of the development of our chiral carboxylate‐based phase‐transfer catalysts and their applications for asymmetric fluorocyclizations of alkenes bearing a carboxylic acid, an amide, and an oxime as an internal nucleophile with a dicationic fluorinating reagent, Selectfluor. We also describe dearomative fluorinations of indole derivatives, 2‐naphthols, and resorcinols.
The C-H alkylation of benzyl alcohols with α-ketoacid derivatives was achieved in the presence of thiobenzoic acid with or without Ru or Ir photoredox catalysts. The thiobenzoic acid serves as a photoexcited single-electron reducing reagent and a hydrogen atom transfer catalyst, while addition of the metal photoredox catalyst assists the electron transfer and improves the reaction efficiency. Various functional groups were tolerant of the reaction conditions, and sterically hindered diols were produced in good to high yield.
C-Alkylation of N-alkylamides with styrenes is reported, proceeding in ambient air/moisture to give arylbutanamides and other pharmaceutically-relevant scaffolds in excellent mass balance.
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