The development of a continuous diazomethane generator comprising a continuous stirred tank reactor (CSTR) cascade and membrane separation technology is reported. This reactor concept was applied for the telescoped three-step synthesis of a chiral α-chloroketone, a key building block for many HIV protease inhibitors, via a modified Arndt−Eistert reaction starting from N-protected L-phenylalanine. The initial mixed anhydride was generated in a coil reactor and directly introduced into the CSTR diazomethane cascade. The use of a semipermeable Teflon membrane (AF-2400) allowed the generation of anhydrous diazomethane, which diffuses through the membrane into the CSTR where it is immediately consumed by the anhydride to furnish the corresponding diazoketone. The subsequent halogenation with concentrated HCl was performed downstream in batch and allowed production of the α-chloroketone on a multigram scale, with a productivity of 1.54 g/h (5.2 mmol/h).
A safe and scalable
continuous flow strategy for Wolff–Kishner
reductions that employs methanol as the solvent has been developed.
The use of low-cost hydrazine as the reducing agent in combination
with a caustic base provides an atom-efficient, environmentally friendly
method for the deoxygenation of aldehydes and ketones to alkanes.
Because of the required harsh and corrosive reaction conditions (200
°C, 50 bar), reactor materials such as stainless steel, glass,
or any type of polymer have compatibility problems, rendering this
process problematic on a production scale. The use of corrosion-resistant
silicon carbide (SiC) as the reactor material opens up the possibility
of performing Wolff–Kishner reductions on scale with a considerably
improved safety profile. Methanol as the solvent significantly simplifies
the workup procedure compared with the generally employed high-boiling
solvents such as diethylene glycol. The continuous flow protocol was
applied to a number of substrates and provided the desired products
in good to high yields with space-time yields of up to 152 g L–1 h–1. In addition, a pharmaceutically
valuable active pharmaceutical ingredient precursor was synthesized
by employing this high-temperature/pressure Wolff–Kishner protocol.
Indium‐mediated reaction of a diversity of aldehydes with bromobutynols (II) proceeds under ultrasonication to give the corresponding allene products, e.g. (III), (VIII), (XI) or (XIV).
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