Enantioselective iridium-catalyzed hydrogenation of 3,4-disubstituted isoquinolines.

The past decade has witnessed rapid progress in the field of asymmetric hydrogenation of aromatic compounds, a transformation, which is regarded as one of the most straightforward means for accessing enantiopure cyclic compounds. Extensive research has significantly expanded the substrate scope of this reaction, and substrates such as quinolines, quinoxalines, indoles, furans, pyrroles, pyridines, imidazoles, and aromatic carbocycles can now be transformed through asymmetric hydrogenation. Despite achievements made, the asymmetric hydrogenation of isoquinoline still remains an important unmet challenge. Hydrogenation reactions involving this substrate have been plagued by catalyst deactivation owing to the strong coordinating ability of the substrate and the product. So far, only one example of an enantioselective hydrogenation of isoquinoline has been reported by our research group. N-protected 1-substituted 1,2-dihydroisoquinolines were obtained in moderate yield and enantioselectivity in the presence of stoichiometric amounts of chloroformate as the substrate activator (Scheme 1). However, several obvious limitations remain, such as the need for a stoichiometric amount of activating reagent and inorganic base, and that current methods only lead to products containing one stereogenic center, which is usually the C1 position. Given the prevalence of the chiral 1,2,3,4-tetrahydroisoquinoline motif in natural alkaloids and pharmaceutical molecules, the development of an efficient method for the direct hydrogenation of isoquinolines is highly desirable. Herein, we describe a highly efficient direct enantioselective iridium-catalyzed hydrogenation of 3,4-disubstituted isoquinolines. Recent results from our research group and that of others have demonstrated that iodine can significantly improve the performance of an iridium catalyst in asymmetric hydrogenation. We wanted to investigate whether isoquinoline could be amenable to asymmetric hydrogenation catalyzed by an iodine-activated iridium complex. Initially, ethyl 3-methylisoquinoline-4-carboxylate 1a was chosen as model substrate. Upon exposure to 500 psi H2 in the presence of a chiral iridium complex, which is generated in situ from [Ir(cod)Cl]2/(R)-synphos and iodine at 50 8C, isoquinoline 1a underwent enantioselective hydrogenation to afford product 2a with full conversion, excellent diastereoselectivity (d.r.>20:1) and moderate enantioselectivity (59% ee ; Table 1, entry 2); when iodine was omitted, only the 1,2hydrogenation product was observed (Table 1, entry 1). Encouraged by this promising result, we initially investigated the effect of the identity of the solvent on the substrate conversion and enantioselectivity. The substrate conversion was, in most solvents, uniformly good, whereas the ee value of 2a exhibited a dramatic dependence upon the solvent identity (Table 1, entries 2–5). The use of toluene as the solvent was the most beneficial in terms of the enantioselectivity of the hydrogenation (80% ee, Table 1, entry 6). Next, the effect of the nature of the additive was investigated using various halogen sources (Table 1, entries 6–10). Each additive promoted this transformation, thus leading to full conversion of substrate and similar enantioselectivity. Among these additives, the use of 1-bromo-3-chloro-5,5-dimethyl-hydantoin (BCDMH) led to the isolation of product with slightly superior ee value (83% ee ; Table 1, entry 10). The effect of the nature of the ligand on the reaction was then investigated by employing BCDMH as the halogen source in combination with iridium catalysts that were generated from [Ir(cod)Cl]2 and a diverse array of commercially available ligands (Table 1, entries 10–13). Disappointingly, no ligand gave a better result than the ligand used in the initial screening of reaction conditions (L1). Dynamic kinetic resolution (DKR), which is a powerful tool for accessing enantioenriched compounds, has been successfully applied in asymmetric hydrogenation. In our previous research on asymmetric hydrogenation of 2,3-disubstituted quinolines and indoles, an interesting DKR phenomenon was also observed. 4h] For the asymmetric hydrogenation of 3,4-disubstituted isoquinolines, a dynamic kinetic resolution process was involved (see below). In Scheme 1. Asymmetric hydrogenation of isoquinoline.