Reductive Amination of Ketones or Amination of Alcohols over Heterogeneous Cu Catalysts: Matching the Catalyst Support with the N‐Alkylating Agent

Abstract

The goals of improved sustainability and cost-competitiveness in fine-chemicals 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. [1] In this context, 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 without prior formation of the intermediate imine, is a highly attractive procedure in the synthesis of primary, secondary, or tertiary amines. [2] However, this reaction is not straightforward. Water is produced during the in situ formation of the imine, which means that the reducing agent has to be stable in the presence of water. This limitation is why some preparation methods involve the use of drying agents, such as molecular sieves [3, 4] or TiCl4, [5] to bind water. Moreover, imine formation is acid-catalyzed; therefore, the reducing agent must also be stable under acidic conditions. Finally, the rate of reduction of the carbonyl compound must be slower than that of imine formation. [6] To meet these requirements, NaBH3CN and NaBH(OAc)3 have been widely used. However, NaBH3CN is highly toxic; thus, the disposal of byproducts and contamination of the products are an issue and it requires the use of a fivefold excess of the amine and long reaction times with aromatic ketones. NaBH(OAc)3 is less toxic but flammable, it reacts with water, and it has several limitations with aromatic, a,b-unsaturated, and sterically hindered ketones. [7] Other boron-based systems, such as a-picoline-borane, have shown the same limitations. [8] Recently, homogeneous Fe-based systems [9] and Leuckardttype DRA reactions with the formate derivatives of aldehydes and aliphatic ketones have also been reported. [10] A Lewis acid, Zn(ClO4)2· 6H 2O, in combination with a hydride donor, such as the InCl3/Et3SiH system, has been proposed. [11] However, in this case, aromatic ketones again displayed very low reactivity. Interestingly, fairly good yields were obtained for the amination of acetophenone by uniformly adsorbing the carbonyl compound and the amine onto the surface of activated silica gel, stirring the mixture until complete formation of the imine had occurred, and then adding a solution of ZnBH4. [12] Furthermore, Zn(OTf)2, in combination with poly(methylhydrosiloxane) (PMHS) as a hydride source, was reported to be an useful system for the amination of aldehydes. [13] Some drawbacks of these methods are related to the use of Lewis acids that cannot easily be recovered and reused. Moreover, the use of common hydride donors results in the production of large amounts of waste and inorganic salts that require time-consuming work-up and costly purification procedures. Conversely, the use of molecular hydrogen would lead to notable advantages in terms of efficiency. Heterogeneous catalytic hydrogenation reactions can be employed, of which, Raney Ni and Pd/C are the most-used catalysts, but they can give a mixture of products if the as-produced amine competes with the reactant amine in the carbonyl-condensation step. Therefore, a large excess of primary amine is required to give preferential formation of the secondary amine. [14] Sulfide catalysts, in particular platinum- and rhodium–sulfide catalysts, are used to minimize the reduction of the carbonyl group into an alcohol and to avoid hydrodehalogenation. These catalysts are much-less active than nonsulfide catalysts and require, for their economic use, elevated temperatures and pressures (50–1808C, 20–135 atm H2; 1 atm = 101.3 kPa). [15] Moreover, serious limitations arise when other reducible or hydrogenolyzable functional groups are present in the substrate. In particular, the reactions of primary amines with acetophenone require a very selective catalyst because the aromatic ketone is readily hydrogenolyzed into ethylbenzene.