O-alkylations and N-alkylations

Among reactions employed in the molecular construction for preparation of drug candidate products, heteroatom alkylations and arylations are the most common ones, representing the 19% of the total reactions. Of these, 57% are   N-Substitutions and 28% O-substitutions. The amines are usually used as building blocks in organic synthesis, in biological systems, material chemistry and medicinal chemistry, as evidenced by their presence into 200 drugs. The goals of improved sustainability and cost-competitivness in fine-chemical synthesis can be achieved by increasing the selectivity and hence yield of the reactions and by reducing the lead time of the entire production process by introducing multifunctional processes.



In this scenario, the direct reductive amination (DRA) of aldehydes and ketones, that is reactions in which the carbonyl compound and the amine are mixed with an appropriate reducing agent withou prior formation of the intermediate imine, is a highly attractive procedure in the synthesis of primary, secondary or tertiary amines.

Studies carried out at ISTM reveal that copper heterogeneous systems are effective for the synthesis of secondary amines. The synthesis takes place starting from an aromatic ketone through a one-pot DRA reaction over a slightly acidic pre-reduced Cu/SiOcatalyst.


Ether formation is an important reaction in organic synthesis, for both bulk and fine chemicals preparation, and it is traditionally performed with the Williamson reaction starting from an alcohol and a halide by using a strong base for the alkoxide formation.

The use of a heterogeneous copper catalyst supported over commercial mixed oxides have been developed for the one-pot transformation of an aromatic ketone and an aliphatic alcohol into the corresponding asymmetrical ether under very mild experimental conditions and without the need of any additive for water removal.

References:

[1] F. Zaccheria, R. Psaro, N. Ravasio, “Bifunctional copper catalysts for an atom efficient ether synthesis” , Tetrahedron Lett. , 2009, 50(37), 5221-5224.
[2] F. Santoro, R. Psaro, N. Ravasio, F. Zaccheria, “Reductive Amination of ketones or Amination of Alcohols over Heterogeneous Cu Catalysts: matching the Catalyst Support with the N-alkylating Agent”, ChemCatChem, 2012, 4(9), 1249-1254.

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