A highly efficient metal-free catalytic system for the aerobic photocyanation of tertiary amines with visible light is reported. The use of air as terminal oxidant offers an improved safety profile compared with pure oxygen, the used compact fluorescent lamp (CFL) light sources are highly economical, and no halogenated solvents are required. This system not only proves to be effective for a wide variety of trialkylamines, pharmaceuticals, and alkaloids but remarkably also allows the lowest catalyst loading (0.00001 mol% or 0.1 ppm) ever reported for an organic dye. Bruylants reactions and C-alkylation/decyanations were performed on the obtained α-aminonitriles to demonstrate the postfunctionalization of complex molecules. The catalytic system is furthermore applied in the short and effective syntheses of the alkaloids (±)-crispine A and the tetraponerines T7 and T8.

There is an urgent demand for 5‐fluorocytosine (5‐FC) due to its activity against HIV‐induced fungal infections as well as its use as a key intermediate in the synthesis of the clinically highly important anti‐HIV drug emtricitabine (FTC). We report a simple, low‐cost five steps synthesis of 5‐FC starting from chloroacetamide. Overall yields up to 46 % were achieved and the route is devoid of any chromatographic purifications. The previously unknown key intermediate (Z)‐2‐cyano‐2‐fluoroethenolate is obtained through a Claisen‐type condensation from fluoroacetonitrile. As the direct cyclization with urea only gave poor yields, 5‐fluoro‐2‐methoxypyrimidin‐4‐amine, 5‐fluoro‐2‐(methylsulfanyl)pyrimidin‐4‐amine and 5‐fluoropyrimidine‐2,4‐diamine served as synthetic intermediates.

A short and practical synthesis for preparing the active pharmaceutical ingredient dolutegravir sodium was developed. The convergent strategy starts from (R)-3-amino-1-butanol and establishes the BC ring system in a 76% isolated yield over four steps. Ring A was constructed by a one-pot 1,4-addition to diethyl-(2E/Z)-2-(ethoxymethylidene)-3-oxobutandioate and subsequent MgBr2·OEt2-mediated regioselective cyclization. Amide formation with 2,4-difluorobenzylamine was either performed from the free carboxylic acid or through aminolysis of the corresponding ethyl ester. Final salt formation afforded dolutegravir sodium in a 48–51% isolated yield (HPLC purity of 99.7–99.9%) over six linear steps.

Bedaquiline is a crucial medicine in the global fight against tuberculosis, yet its high price places it out of reach for many patients. Herein, we describe improvements to the key industrial lithiation‐addition sequence that enable a higher yielding and therefore more economical synthesis of bedaquiline. Prioritization of mechanistic understanding and multi‐lab reproducibility led to optimized reaction conditions that feature an unusual base‐salt pairing and afford a doubling of the yield of racemic bedaquiline. We anticipate that implementation of these improvements on manufacturing scale will be facile, thereby substantially increasing the accessibility of this essential medication.

Di- tert -butyl oxymethyl phosphonates were investigated regarding their suitability for preparing the active pharmaceutical ingredient tenofovir (PMPA). First, an efficient and simple access to the crystalline di- tert -butyl(hydroxymethyl)phosphonate was developed. O-Mesylation gave high yields of the active phosphonomethylation reagent. For the synthesis of tenofovir, a two-step sequence was developed using Mg(O t Bu) 2 as the base for the alkylation of ( R )-9-(2-hydroxypropyl)adenine. Subsequent deprotection could be achieved with aqueous acids. (Di- tert -butoxyphosphoryl)methyl methanesulfonate showed to be the most efficient electrophile tested, affording PMPA in 72% yield on a 5 g scale. The developed protocol could also be applied for the preparation of the hepatitis B drug adefovir (64% yield/1 g scale).