Iridium‐Catalyzed Asymmetric Hydrogenation of Substituted Pyridines

Abstract

Abstract:We demonstrate here the asymmetric hydrogenation of orthosubstituted pyridines using an N,Pligated iridium catalyst. To facilitate this reaction, aromaticity of the pyridines was weakened by forming Niminopyridium ylides. The reactions gave very high conversions, and after a single recrystallization, excellent ee was obtained (up to 98%). This methodology lends itself to the synthesis of chiral piperidine building blocks.

Substrate Activation in the Catalytic Asymmetric Hydrogenation ofN‐Heteroarenes

“…On the basis of the superb enantioselectivities obtained in chelation‐assisted asymmetric rhodium‐mediated hydrogenations,9 it was envisaged that coordination between the substrate and the metal center would be beneficial for controlling enantioselectivity. Because an acyl group is the classical model system for achieving high enantioselectivity and reactivity in rhodium‐mediated hydrogenation, the groups led by Charette,30 Zhou,31–33 and Andersson34 also attached acyl motifs to various six‐membered heteroarenes to be hydrogenated in the presence of iridium‐based enantioselective catalysts. Examples of this strategy are shown in Scheme .…”

“…Eight substrates were explored, and the ee values of the hydrogenated products ranged from 10 to 90 % ee (Scheme , e). Substrate chelation proved to be beneficial in achieving high levels of stereoselection 34…”

HMPA-Catalyzed Transfer Hydrogenation of 3-Carbonyl Pyridines and Other N-Heteroarenes with Trichlorosilane

“…Piperidines are very important structural building blocks of numerous biologically active compounds, such as the Topo inhibitor, the Chk1 inhibitor, Tiagabine and Focalin XR [1]. The catalytic hydrogenation of pyridines provides one of the most straightforward methods to access piperidines [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18], although it is essential to overcome some inherent challenges presented by catalyst deactivation and pyridine dearomatization. In the last decade, various transition-metal catalyst systems have been studied for the direct hydrogenation of pyridines, but the metal-free catalytic reduction of pyridines is a great challenge [19,20,21,22,23,24].…”

Asymmetric Hydrogenation of Isoquinolines and Pyridines Using Hydrogen Halide Generated in Situ as Activator

“…Chiral piperidines and tetrahydroisoquinolines are common structural motifs present in biologically active compounds, and the development of efficient methods for their synthesis has attracted increasing attention . One of the most straightforward and atom-economic methods is direct asymmetric hydrogenation of the corresponding pyridines − and isoquinolines . However, the resonance stability and inhibiting effect of nitrogen atom on chiral catalyst impeded efficient asymmetric hydrogenation of these compounds.…”

“…In 2005, an elegant asymmetric hydrogenation of the N -iminopyridinium ylides was reported by Charette’s group . Next, the chloroformates, benzyl bromides, and Brønsted acids were successfully used as substrate activators for asymmetric hydrogenation of pyridines − and isoquinolines (Scheme ). However, installation and removal of activating groups are the major drawbacks for further synthetic applications.…”