Iridium‐Difluorphos‐Catalyzed Asymmetric Hydrogenation of 2‐Alkyl‐ and 2‐Aryl‐Substituted Quinoxalines: A General and Efficient Route into Tetrahydroquinoxalines

Abstract

A highly efficient and general iridium-difluorphos-catalyzed asymmetric hydrogenation of diverse 2-alkyl-and 2-aryl-substituted quinoxalines into biologically and pharmaceutically relevant 2-substituted-1,2,3,4-tetrahydroquinoxaline units has been developed. High isolated yields and excellent enantioselectivities of up to 95% for 2-alkyl-substituted quinoxalines and of up to 94% for 2-aryl-substituted quinoxalines were obtained.

Activation of a (cyclooctadiene) rhodium(i) complex supported by a chiral ferrocenyl phosphine thioether ligand for hydrogenation catalysis: a combined parahydrogen NMR and DFT study

“…When the pyridine excess was 75 fold, the experimental rate constant for the H e→c and H e→d processes (10 → 9) were indistinguishable at 31 s −1 . In contrast the corresponding rate constant for H e→a and H e→b (10 → 8) was zero, as was mutual H e -H f interchange (10). These values decrease from 31 s −1 to 20 s −1 to 3 s −1 as the pyridine excess falls from 75 fold through 42 fold to 15 fold.…”

“…2 Complexes of the type [MCl(diene)] 2 or [M(diene) 2 ] + [M = Rh or Ir], and particularly those of iridium, have also proven suitable as precatalysts for the ionic hydrogenation of polar substrates such as ketones and imines in the presence of appropriate ligands, mostly diphosphines. [3][4][5][6][7][8][9][10] A notable example of this is provided by Ir I -catalyzed imine hydrogenation as used in the multi-ton scale industrial production of the herbicide metolachor. 11,12 In one of our laboratories, chiral ferrocene-based phosphine thioether ligands (P,SR in Scheme 1) 13 have been developed and shown to be particularly efficient in terms of both activity and enantioselectivity for the hydrogenation of aromatic ketones when combined with [IrCl(COD)] 2 .…”

Quinoxaline as a potent heterocyclic moiety

“…High isolated yields and excellent enantioselectivities of up to 95% for 2-alkyl-substitutedquinoxalines and of up to 94% for 2-arylsubstituted quinoxalines were obtained. [23] 13. Pawar et al synthesized quinoxaline derivatives in high to excellent yields in the presence of thiamine hydrochloride (VB1) as an inexpensive, nontoxic and metal ion free catalyst at ambient temperature.…”

Asymmetric Hydrogenation of 2- and 2,3-Substituted Quinoxalines with Chiral Cationic Ruthenium Diamine Catalysts

“…The 1,2,3,4-tetrahydroquinoxaline ring system is a useful key structural unit in many therapeutically and biologically active compounds . Optically pure tetrahydroquinoxalines have shown great potential for drug development. − Consequently, increasing research efforts have been devoted to the asymmetric synthesis of these compounds over the past decades. − Among the reported different methods, asymmetric hydrogenation (AH) of the corresponding readily available quinoxalines represents one of the most convenient and straightforward approaches for attaining such optically active heterocyclic compounds.…”

“…In recent years, great progress in the metal-catalyzed AH of heteroaromatic compounds, particularly quinolines, has been made. However, despite the great importance of tetahydroquinoxalines, few successful examples of AH of quinoxalines have been reported so far in the literature . The first AH of 2-methyl-quinoxaline with a Rh-DIOP catalyst was reported by Murata in 1987, however with only 3% ee .…”