The dynamic progress in the multi-step continuous-flow synthesis of active pharmaceutical ingredients is part of the current industrial revolution. The recently implemented examples are the forerunners of safer and more...

Secondary phosphine oxides incorporating various aryl and alkyl groups were synthesized in racemic form, and these products formed the library reported in this study. TADDOL derivatives were used to obtain the optical resolution of these P -stereogenic secondary phosphine oxides. The developed resolution method showed a good scope under the optimized reaction conditions, as 9 out of 14 derivatives could be prepared with an enantiomeric excess (ee) ≥ 79% and 5 of these derivatives were practically enantiopure >P(O)H compounds (ee ≥ 98%). The scalability of this resolution method was also demonstrated. Noncovalent interactions responsible for the formation of diasteromeric complexes were elucidated by single-crystal XRD measurements. ( S )-(2-Methylphenyl)phenylphosphine oxide was transformed to a variety of P -stereogenic tertiary phosphine oxides and a thiophosphinate in stereospecific Michaelis–Becker, Hirao, or Pudovik reactions.

Aril azides are popular reagents in the laboratory, but their explosive properties prevent their larger-scale application. The safety risk is even greater for N-heterocyclic azides, which are rarely studied. Flow chemistry can be an effective tool in the synthesis and utilization of dangerous and explosive chemicals. In small-diameter flow reactors, good heat and mass transfer prevent local hot spots and side reactions, and since only small amounts of hazardous chemicals are present at any time, the potential danger is reduced in the event of an accident. In this work, the safe syntheses of 9 different 2-azidopyridine, 2-azidopyrimidine and 2 azidoquinoxaline derivatives were successfully achieved within the continuous-flow system. In most cases, simple work-up resulted in pure products. In-line extractive work-up was also implemented, which allowed us to transform 2-azidopyridine in a subsequent Staudinger reaction in a connected flow reactor, without manual handling of the hazardous azide.