A general continuous-flow procedure for direct reductive amination of secondary and primary amines with aromatic and aliphatic aldehydes as well as ketones is reported. The use of hydrogen gas and commercially available Pt/C as a heterogeneous catalyst is a key. In addition to exhibiting an excellent functional group tolerance, this method allows the fast formation of CÀN bonds without production of any hazardous chemical waste. Applications to the synthesis of key intermediates toward active pharmaceutical ingredients (Donepezil and Arformoterol/Tamsulosin) are also described.
While organic synthesis
carried out in most laboratories uses batch methods, there is growing
interest in modernizing fine chemical synthesis through continuous-flow
processes. As a synthetic method, flow processes have several advantages
over batch systems in terms of environmental compatibility, efficiency,
and safety, and recent advances have allowed for the synthesis of
several complex molecules, including active pharmaceutical ingredients
(APIs). Nevertheless, due to several reasons related to the difficulties
arising from byproduct formation during the flow process, such as
lower yields, poor selectivities, clogging of columns due to poor
solubility, catalyst poisoning, etc., successful examples of continuous-flow
synthesis of complex organic molecules are still limited. In order
to solve this bottleneck, the development of selective and atom-economical
continuous-flow organic transformations are needed. This perspective
highlights examples of atom-economical addition and condensation reactions
with heterogeneous catalysts under continuous-flow conditions and
their applications for the synthesis of complex organic molecules
such as natural products and APIs. In order to realize new continuous-flow
methodologies, based on addition and condensation reactions, in place
of substitution reactions, the development of novel reactions and
heterogeneous catalysts is required.
We
report a photochemical method for the chemoselective radical
functionalization of tryptophan (Trp)-containing peptides. The method
exploits the photoactivity of an electron donor–acceptor complex
generated between the tryptophan unit and pyridinium salts. Irradiation
with weak light (390 nm) generates radical intermediates right next
to the targeted Trp amino acid, facilitating a proximity-driven radical
functionalization. This protocol exhibits high chemoselectivity for
Trp residues over other amino acids and tolerates biocompatible conditions.
We describe the continuous‐flow synthesis of (R)‐tamsulosin, a blockbuster therapeutic drug employed for dysuria associated with urinary stones and benign prostatic hyperplasia, by utilizing sequential heterogeneous catalysis. Two heterogeneous catalysts have been developed for the synthesis, and the key step involves reductive amination of nitriles using dimethylpolysilane‐modified Pd on activated carbon/calcium phosphate. Overall, (R)‐tamsulosin was obtained in 60 % yield and 64 % ee (99 % ee after recrystallization) in a flow stream through four catalytic transformations without the need for the isolation or purification of any intermediates or byproduct.
A biomimetic procedure for the late functionalization of resinic acids is reported, implementing photooxygenation by singlet oxygen, using visible light and a photosensitized, combined to the Kornblum–DeLaMare reaction or the Hock rearrangement.
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