Iridium‐Catalyzed Asymmetric Hydrogenation of Pyridinium Salts

Abstract

As one of the most straightforward and powerful approaches for the preparation of optically active compounds, asymmetric hydrogenation has been successfully used for different types of aromatic compounds, including quinolines, isoquinolines, quinoxalines, indoles, pyrroles, furans, imidazoles, and aromatic carbocyclic ring, with excellent enantioselectivities. [1][2][3][4][5][6][7][8][9] Despite these advances, direct hydrogenation of simple pyridines is still a challenge. The inherent problems are apparent: First, substrates and corresponding products that possess strong coordination ability might cause the deactivation of catalysts. Second, pyridines have a stabilizing aromatic structure that might impede the reduction. Therefore, only limited examples of hydrogenation of specific pyridine derivatives bearing powerful electron-withdrawing substituent at the 2-or 3-position have been previously described. In 2000, Studer et al. reported the first homogeneous rhodium-catalyzed asymmetric hydrogenation of pyridines, but only poor enantioselectivity was obtained. [10] Zhang and co-workers described an efficient three-step rhodium-catalyzed asymmetric hydrogenation of nicotinates.[11] Subsequently, the group of Rueping documented the first enantioselective organocatalytic transfer hydrogenation of 3-cyano-or carbonyl-substituted pyridines using Hantzsch esters as hydrogen sources, [12] and our group also employed [{Ir(cod)Cl} 2 ]/(S)-MeO-biphep/I 2 catalyst system for asymmetric hydrogenation of specific pyridines with excellent enantioselectivities.[13] Additionally, an elegant asymmetric hydrogenation of activated pyridines, that is, N-iminopyridinium ylides, was developed by Charette et al. [14] As chiral piperidines are important building blocks for the synthesis of biologically active molecules and natural products, [15] the development of an efficient strategy for the highly challenging hydrogenation of the simple pyridines is still of great significance.Iminium salts generally exhibit higher activity than the corresponding imines in hydrogenation, [15b-l, 16] therefore we envisioned that the activation of simple pyridines as the corresponding N-benzyl-pyridinium bromides would effectively eliminate coordination ability of the substrate and thus the reactivity could be greatly enhanced. Moreover, the stoichiometric amount of hydrogen bromide generated in situ would effectively inhibit the coordination ability of the desired product through the formation of its piperidine hydrogen bromide salt (Scheme 1). Also, the benzyl protecting groups could be conveniently removed by hydrogenolysis. Herein, we disclose the iridium-catalyzed asymmetric hydrogenation of 2-substituted pyridinium salts with excellent enantioselectivity.Our investigation started with the asymmetric hydrogenation of N-benzyl-2-phenylpyridinium bromide using [{Ir(cod)Cl} 2 ]/(R)-MeO-biphep as the catalyst (Table 1). To our delight, when CH 2 Cl 2 was employed as the solvent, the reaction proceeded smoothly to give the target product in 84 % y...

Enantioselektive Hydrierung von Isochinolinen

“…und Mashima et al. berichteten nahezu gleichzeitig über die Ir‐katalysierte, enantioselektive Hydrierung von 3,4‐disubstituierten Isochinolinen3 sowie 1‐ oder 3‐substituierten Isochinolinium‐ und Pyridiniumsalzen 4–6. In den letzten beiden Jahren wurden vier entscheidende Fortschritte auf dem Gebiet der asymmetrischen Hydrierung von Isochinolinen erzielt (Schema ):3–5…”

“… die Entwicklung von aktiveren (und dennoch selektiven) Katalysatoren ermöglichte nicht nur die partielle, sondern auch die vollständige Hydrierung; geringer aktivierte Substrate konnten verwendet werden (neutrale Isochinoline); die Substratbandbreite wurde vergrößert (von monosubstituierten hin zu unterschiedlich substituierten Substraten); die Aktivierungsstrategien wurden auf die Hydrierung von noch anspruchsvolleren Pyridinen ausgeweitet 6 …”

“…die Aktivierungsstrategien wurden auf die Hydrierung von noch anspruchsvolleren Pyridinen ausgeweitet 6…”

The Use of Phosphite‐Type Ligands in the Ir‐Catalyzed Asymmetric Hydrogenation of Heterocyclic Compounds

“…3,6 Several promising attempts in the metallocomplex asymmetric hydrogenation of heterocyclic compounds using expensive biphosphine ligands have been reported, providing acceptable results in terms of enantioselectivity and activity of catalysts. 3,[7][8][9][10][11] Besides chiral bisphosphine-type ligands, other types of diphosphorus ligands including phosphinephosphinites, phosphine-phosphites, diphosphinites, and diphosphonites have also been found to work well in iridiumcatalyzed asymmetric hydrogenation of heterocyclic compounds. [12][13][14][15][16] Recently, Feringa and co-workers 17 employed the less expensive monodentate BINOL-derived phosphoramidite (S)-PipPhos ligand to the iridium-catalyzed enantioselective hydrogenation of quinolines.…”

Enantioselective Synthesis of Alcohols and Amines by Iridium‐Catalyzed Hydrogenation, Transfer Hydrogenation, and Related Processes

“…[51] In another protocol by the same group, various 2-substituted pyridinium salts (11) could be hydrogenated to provide chiral piperidines with high yield and enantioselectivity (Scheme 18d). [52] Chan, Fan, and co-workers reported a highly air-stable…”