The hydroaminomethylation (HAM) is a tandem catalytic process involving four reagents: an alkene, an amine, carbon monoxide and hydrogen. The HAM process consists in three sequential reactions: first, the hydroformylation step in which an alkene reacts with carbon monoxide and hydrogen to give an aldehyde, then the condensation of the aldehyde with amine to give enamine or imine and, finally, the hydrogenation of the enamine resulting in a new amine. It is important to note that the HAM process perfectly aligns with the precepts of green chemistry. HAM allows to perform several chemical reactions in a single procedure in the same reactor with high selectivity to the product amines.
Amines represent a class of essential intermediates in the synthesis of drugs, agrochemicals, surfactants, and other fine chemistry products. Despite the various methods available, the direct synthesis of amines is difficult due to the large number of by-products formed and the need for protection and deprotection steps. In this work, using the HAM process, it was possible to synthesize several structurally complex amines with potential biological activity starting from biorenewable low-cost substrates. HAM reaction was applied to several hydroxyolefins (allylic and homoallylic alcohols), such as linalool, nerolidol, isopulegol and isoprenol. Several amines, such as 4-methylpiperidine, morpholine and 1,2,3,4-tetrahydroisoquinoline, were used as counterparts. [Rh(COD)(OMe)]2 was used as a catalyst precursor and triphenylphosphine, tributylphosphine, tricyclohexylphosphine and tris(2,4-di-tert-butylphenyl) phosphite as auxiliary ligands. Reaction parameters (catalytic precursor/ligand ratio, temperature, ligand nature, catalyst concentration and CO/H2 mixture pressure) were optimized to achieve high yields for the target products.
Several new amines were synthesized in a single one-pot procedure. In the absence of phosphorus ligands (unpromoted system) using high ratios of H2 in the CO/H2 mixture, the catalyst was effective in the hydrogenation of enamine, enabling to obtain linear amines as final products in good yields. As phosphorous ligands are known to stabilize the rhodium catalyst and facilitate its recycling, promoted catalytic systems were also developed to synthesize linear amines. In particular, in the systems with tricyclohexylphosphine, the hydrogenation of enamine becomes specially effective, enabling for the excellent yields of linear amines that can reach 99% depending on the substrate and initial amine nature. On the other hand, we have found that certain phosphorus ligands inhibit the hydrogenation of the intermediate enamines, allowing to obtain in excellent yields cyclic amines as final products. The formation of these cyclic amines occurred through the intramolecular cyclisation of the enamines before their hydrogenation. Thus, the developed method offers a convenient access to two different groups of amines (linear and cyclic). It is important that the selectivity control can be performed by a simple change in the nature of the auxiliary phosphorus ligand.