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

Thirusangumurugan Senthamarai,Narayana V Kalevaru,Jacob Schneidewind,Matthias Beller,Helfried Neumann,Rajenahally V Jagadeesh,Kathiravan Murugesan,Paul C J Kamer,Wolfgang Baumann

doi:10.1038/s41467-018-06416-6

Thirusangumurugan Senthamarai, Narayana V Kalevaru + Show 7 more

Open Access

https://doi.org/10.1038/s41467-018-06416-6

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Journal: Nature Communications	Publication Date: Oct 8, 2018
Citations: 138	License type: open-access

Affiliation: Leibniz Institute for Catalysis

Abstract

The production of primary benzylic and aliphatic amines, which represent essential feedstocks and key intermediates for valuable chemicals, life science molecules and materials, is of central importance. Here, we report the synthesis of this class of amines starting from carbonyl compounds and ammonia by Ru-catalyzed reductive amination using H2. Key to success for this synthesis is the use of a simple RuCl2(PPh3)3 catalyst that empowers the synthesis of >90 various linear and branched benzylic, heterocyclic, and aliphatic amines under industrially viable and scalable conditions. Applying this catalyst, −NH2 moiety has been introduced in functionalized and structurally diverse compounds, steroid derivatives and pharmaceuticals. Noteworthy, the synthetic utility of this Ru-catalyzed amination protocol has been demonstrated by upscaling the reactions up to 10 gram-scale syntheses. Furthermore, in situ NMR studies were performed for the identification of active catalytic species. Based on these studies a mechanism for Ru-catalyzed reductive amination is proposed.

Highlights

The production of primary benzylic and aliphatic amines, which represent essential feedstocks and key intermediates for valuable chemicals, life science molecules and materials, is of central importance
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 challenge[17,18,19,20,21,22,23,24,25,26,27,28,29,30]
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 polymers[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34]

Summary

Introduction

The production of primary benzylic and aliphatic amines, which represent essential feedstocks and key intermediates for valuable chemicals, life science molecules and materials, is of central importance. 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 Ruprecatalyst 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.

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