An efficient and selective procedure was developed for the direct C2–H arylation of indoles using a Pd‐loaded metal–organic framework (MOF) as a heterogeneous catalyst and the nontoxic biomass‐derived solvent γ‐valerolactone (GVL) as a reaction medium. The developed method allows for excellent yields and C‐2 selectivity to be achieved and tolerates various substituents on the indole scaffold. The established conditions ensure the stability of the catalyst as well as recoverability, reusability, and low metal leaching into the solution.

Three different Pd0‐based heterogeneous catalysts were developed and tested in the Cassar–Heck reaction (i. e., copper‐free Sonogashira reaction) aiming at the definition of a waste minimized protocol. The cross‐linked polymeric supports used in this investigation were designed to be adequate for different reaction media and were decorated with different pincer‐type ionic ligands having the role of stabilizing the formation and dimension of palladium nanoparticles. Among the ionic tags tested, bis‐imidazolium showed the best performances in terms of efficiency and durability of the metal catalytic system. Eventually, aqueous acetonitrile azeotrope was selected as the reaction medium as it allowed the best catalytic efficiency combined with easy recovery and reuse. Finally, the synergy between the selected catalyst and reaction medium allowed to obtain highly satisfactory isolated yields of a variety of substrates while using a low amount of metal catalyst. The high performance of the designed POLymeric Ionic TAG (POLITAG)‐Pd0, along with its good selectivity achieved in a copper‐free process, also led to a simplified purification procedure allowing the minimization of the waste generated as also proven by the very low E‐factor values (1.4–5) associated.

Since their structural elucidation in 1935, the introduction and substitution of functional groups and the modification of the steroidal scaffolds have been a fertile ground of research for synthetic and medicinal chemists. The discovery of steroids with hormonal and pharmacological activity has stimulated tremendous efforts to the development of highly selective and efficient synthetic procedures. Despite the progress made, steroid chemistry remains challenging and the preparation of steroidal compounds of pharmaceutical interests and in clinical practice, often requires long and elaborated synthesis. In recent years, a new impetus in the field came with the advent of enabling chemical technologies, such as continuous flow chemistry, which are exploited to overcome problems that arise from batch synthesis. Although it is still a niche sector, the use of flow technology in steroid synthesis and functionalization holds the premise to empower methodology development and to provide innovative tactics also for many hitherto uncharted chemistries. In this review, scientific contributions are reported and discussed in terms of flow set‐up and advantages offered concerning process efficiency, optimization, waste minimization, safety improvement, easy scale‐up and costs. We also highlight the main challenges, key improvements and the future trajectory in the application of continuous flow chemistry and its implementation to different disciplines such as photochemistry and biocatalysis with the ultimate goal of streamlining steroid synthesis.magnified image

Heterocycles are ubiquitous structures in nature and can be found in many drugs and chemicals. Biocatalysts, alone or in combination with other metal catalysts, can be exploited for the construction of various heterocyclic rings under mild reaction conditions. This Short Review highlights the recent advances in the development of biocatalytic and chemo-enzymatic methods for the synthesis of both aliphatic and aromatic heterocyclic rings.1 Introduction2 Synthesis of Aliphatic Heterocycles2.1 Piperidines, Pyrrolidines and Piperazines2.2 Other Nitrogen-Containing Aliphatic Heterocycles2.3 Lactones and Lactams2.4 Other Oxygen-Containing Heterocycles3 Synthesis of Aromatic Heterocycles3.1 Pyrroles, Pyridines and Pyrazines3.2 Furans3.3 Bicyclic Aromatic Heterocycles4 Conclusion