Simple ruthenium-catalyzed reductive amination enables the synthesis of a broad range of primary amines

The development of efficient catalytic reactions for the selective and sustainable synthesis of amines from readily available and inexpensive starting materials by utilizing abundant and green reagents continues to be an important goal of chemical research1,2,3,4,5,6. In particular, the development of simple and easily accessible catalysts for reductive aminations is highly important because these reactions allow for the cost-efficient production of different kinds of amines7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30. Among reductive aminations, the reaction of carbonyl compounds with ammonia in presence of molecular hydrogen to produce primary amines is of central importance and continues to be a major challenge17,18,19,20,21,22,23,24,25,26,27,28,29,30. In general, amines are essential chemicals used widely in many research areas and industrial productions related to chemistry, medicine, biology, and material science1,2,3,4,5,6. The majority of existing pharmaceuticals, agrochemicals, biomolecules, and natural products contain amine functionalities, which constitute key structural motifs and play vital roles in their functions1,2,3,4,5,6. Among different kinds of amines, primary benzylic and aliphatic amines constitute valuable fine and bulk chemicals, that serve as versatile feedstocks and key intermediates for advanced chemicals, life science molecules and polymers1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34. Regarding their synthesis, catalytic reductive amination of carbonyl compounds (aldehydes and ketones) with ammonia in presence of molecular hydrogen represents a waste-free process to access various linear and branched benzylic and aliphatic amines17,18,19,20,21,22,23,24,25,26,27. In addition, catalytic amination of alcohols with ammonia also constitutes a sustainable methodology to produce primary amines35,36,37,38. Apart from transition metal-catalyzed aminations, the Leuckart-Wallach reaction39,40,41 and reduction of oxime ethers with borane42,43,44 have also been applied. Noteworthy, selective introduction of primary amine moieties in functionalized compounds by utilizing ammonia constitutes a benign and economic methodology17,18,19,20,21,22,23,24,25,26,27. Ammonia, which is produced in >175 million tons per year scale, is considered to be an abundant and green chemical used enormously for the large scale production of urea and other fertilizers as well as various basic chemicals45,46,47,48,49,50. Although ammonia is used extensively for the production of simple molecules, its reactions still encounter common problems such as the requirement of high temperatures or pressures and low selectivity towards the formation of a single desired product45,46,47,48,49,50. Hence, the development of more active and selective catalysts for an effective utilization of ammonia, especially for its insertion in advanced and complex molecules, is highly demanded and challenging.

Reductive amination for the preparation of primary amines, especially in industry, is mainly carried out using heterogeneous catalysts17,18,19,20,21,22,23. Compared to heterogeneous catalysts, homogeneous catalysis for amination of structurally diverse molecules is less studied and remains challenging24,25,26,27. Transition metal-catalyzed reactions involving ammonia are often difficult to perform or do not even occur. This problem is mainly due to the deactivation of homogeneous catalysts by the formation of stable Werner-type ammine complexes as well as due to the harsh conditions required for the activation of ammonia. In addition, common problems in reductive aminations, such as over alkylation and reduction to the corresponding alcohols, also affect catalyst viability. In order to utilize ammonia successfully and to overcome these problems, there is a need to develop highly efficient homogeneous catalysts, which is the prime task of this investigation. To date, a few catalysts based on Rh-24,25, Ir-25 and Ru-26,27 complexes were reported for the preparation of primary amines from carbonyl compounds and ammonia using hydrogen. Initially, Beller and co-workers24 have reported a [Rh(COD)Cl]2-TPPTS catalyst system for the synthesis of simple primary amines from aldehydes and aqueous ammonia using NH4OAc as additive. Following this work, Rh[(dppb)(COD)]BF4 and [Rh(COD)Cl]2-BINAS catalysts were also applied25. Next, [Ir(COD)Cl]2-BINAS was found to be able to catalyze the amination of a few simple ketones with ammonia25. Regarding Ru-catalysts, RuHCl(CO)(PPh3)3-xantphos/-dppe in presence of Al(OTf)3 is known to catalyze the preparation of simple primary amines from ketones26. Recently, RuHCl(CO)(PPh3)3-(S,S)-f-binaphane27 in presence of NaPF6 or NH4I using NH3, as well as Ru(OAc)2-C3-TunePhos30 using NH4OAc have been used for enantioselective reductive amination of ketones to obtain chiral primary amines. These homogeneous catalysts, however, have only been applied in (enantioselective) reductive aminations of simple substrates and have not been used for the preparation of functionalized amines. Despite these advances, the design of simpler yet efficient homogeneous catalysts for the preparation of a broad range of structurally diverse primary amines is highly desired and continues to be an important task from both a research and an industry perspective.

In a lot of cases, homogeneous catalysts applied for challenging reactions and advanced organic synthesis operations are based on sophisticated or synthetically demanding metal complexes and ligands. However, a fundamental and economically important principle is that to achieve a convenient and practical chemical synthesis, the catalyst must be simple, effective and commercially available and/or easily accessible. In this regard, triphenylphosphine (PPh3)-based metal complexes are found to be expedient and advantageous for catalysis applications, since PPh3 is a stable and comparatively cheap ligand51,52,53,54,55. Among PPh3-based Ru-complexes, RuCl2(PPh3)3 is considered to be the simplest and least expensive one and is also commercially available. Interestingly, RuCl2(PPh3)3 is known to catalyze a number of organic reactions56,57,58,59,60,61,62. Herein we demonstrate that RuCl2(PPh3)3 is an efficient and highly selective homogeneous precatalyst for reductive amination, allowing the preparation of a variety of primary amines of industrial importance. By applying this Ru-precatalyst and starting from inexpensive and readily available carbonyl compounds (aldehydes, ketones), ammonia and molecular hydrogen, we undertook the synthesis of functionalized and structurally diverse linear and branched benzylic, heterocyclic, and aliphatic amines including drugs and steroid derivatives. Another objective is to demonstrate up-scaling of the homogeneous amination protocol to gram-scale syntheses. Furthermore, efforts were also made to identify catalytically active species and reaction intermediates by performing kinetic and in situ NMR investigations. Based on these studies, a plausible reaction mechanism is proposed.

Post time: Oct-31-2018