4-Aminopyridines are valuable scaffolds for the chemical industry in general, from life sciences to catalysis. We report herein a collection of structurally diverse polycyclic fused and spiro-4-aminopyridines that are prepared in only three steps from commercially available pyrimidines. The key step of this short sequence is a [4 + 2]/retro-[4 + 2] cycloaddition between a pyrimidine and an ynamide, which constitutes the first examples of ynamides behaving as electron-rich dienophiles in [4 + 2] cycloaddition reactions. In addition, running the ihDA/rDA reaction in continuous mode in superheated toluene, to overcome the limited scalability of MW reactions, results in a notable production increase compared to batch mode. Finally, density functional theory investigations shed light on the energetic and geometric requirements of the different steps of the ihDA/rDA sequence.
Abstract The difluoromethyl group plays an important role in modern medicinal and agrochemistry. While several difluoromethylation reagents have been reported, these typically rely on difluoromethyl carbenes or anions, or target specific processes. Here, we describe a conceptually unique and general process for O−H, N−H and C−H difluoromethylation that involves the formation of a transient dithiole followed by facile desulfurative fluorination using silver(I) fluoride. We also introduce the 5,6‐dimethoxy‐1,3‐benzodithiole (DMBDT) function, which undergoes sufficiently rapid desulfurative fluorination to additionally support 18 F‐difluoromethylation. This new process is compatible with the wide range of functional groups typically encountered in medicinal chemistry campaigns, and the use of Ag 18 F is demonstrated in the production of 18 F‐labeled derivatives of testosterone, perphenazine, and melatonin, 58.0±2.2, 20.4±0.3 and 32.2±3.6 MBq μmol −1 , respectively. We expect that the DMBDT group and this 18 F/ 19 F‐difluoromethylation process will inspire and support new efforts in medicinal chemistry, agrochemistry and radiotracer production.
A continuous flow inverse-electron-demand Kondrat'eva reaction has been developed that provides direct access to cycloalka[c]pyridines from unactivated oxazoles and cycloalkenes. Annulated pyridines obtained by this one-step process are valuable scaffolds for medicinal chemistry.
Eine Vier-Puls-Version des gepulsten Doppel-Elektron-Elektron-Resonanz(DEER)-Experimentes wurde auf eine Serie von TEMPO-Diradikalen mit definierten Interradikalabständen im Bereich von 1.4 bis 2.8 nm angewendet (siehe Bild). Diese neue Pulssequenz ermöglicht es, breite Verteilungen von Elektron-Elektron-Abständen ohne Totzeitartefakte zu bestimmen.
Abstract Pyridine features prominently in pharmaceuticals and drug leads, and methods to selectively manipulate pyridine basicity or metabolic stability are highly sought after. A robust, metal‐free direct fluorination of unactivated pyridylic C−H bonds was developed. This convenient reaction shows high functional‐group tolerance and offers complimentary selectivity to existing C−H fluorination strategies. Importantly, this late‐stage pyridylic C−H fluorination provides opportunities to rationally modulate the basicity, lipophilicity, and metabolic stability of alkylpyridine drugs.
The synthesis of the highly fluorescent mono- and bis-silylated poly(1,4-phenylene vinylene) derivatives 1 and 2 is reported. The Gilch dehydrohalogenation polycondensation and the Horner synthesis of strictly alternating copolymers have been used to prepare the copolymers 8-11 and 14, 16-18, respectively, in which the tunability of various optoelectonic properties may be examined systematically.
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