Ran-Ning Guo

Enantioselective Iridium-Catalyzed Hydrogenation of 1-and 3-Substituted Isoquinolinium Salts

Chiral 1,2,3,4-tetrahydroisoquinolines are ubiquitous structural motifs in many natural alkaloids and biologically active compounds. Among the various catalytic methods developed for the construction of chiral tetrahydroisoquinolines during the past decades, asymmetric hydrogenation of isoquinolines unquestionably serves as one of the most straightforward and powerful methods. So far, significant progress on the asymmetric hydrogenation of aromatic compounds has been implemented successfully for substrates such as quinolines, quinoxalines, indoles, pyrroles, pyridines, furans, imidazoles, thiophenes and aromatic carbocyclic rings. However, the development of the enantioselective hydrogenation of isoquinolines has met with limited success, probably owing to lower reactivity and strong coordination to the catalyst. In 2006, our group reported the first iridium-catalyzed asymmetric hydrogenation of isoquinolines, which were activated by chloroformates, with moderate enantioselectivity and yield. Very recently, an enantioselective hydrogenation of 3,4-disubstituted isoquinolines employing catalyst activation was successfully described, nevertheless, this strategy is not suitable for 1substituted isoquinolines. Moreover, there is no report on the asymmetric hydrogenation of 3-substituted isoquinolines heretofore. Therefore, the development of a general and efficient strategy for asymmetric hydrogenation of 1and 3substituted isoquinolines is still a very valuable and challenging area of chemical research. Recently, our group successfully documented the iridiumcatalyzed asymmetric hydrogenation of simple pyridinium salts, which were formed by using benzyl bromide and possess higher reactivity than the corresponding pyridines. As part of our ongoing efforts to promote the development of asymmetric hydrogenation of heteroaromatic compounds, and considering the similar structure of pyridine to isoquinoline, we envisioned that activating isoquinoline as the N-benzyl isoquinolinium salt would effectively improve the reactivity to facilitate hydrogenation (Scheme 1). Herein, we report the iridium-catalyzed asymmetric hydrogenation of 1and 3-substituted isoquinolinium salts with up to 96 % ee, as well as the application of the method to the synthesis of the chiral drug (+)-solifenacin. To begin the study, N-benzyl-1-phenyl isoquinolinium bromide (1; Ar = Ph) was chosen as a model substrate for the iridium-catalyzed asymmetric hydrogenation (Table 1). The reaction occurred smoothly in CH2Cl2 to give the desired product with moderate enantioselectivity and yield (entry 1). Further assessment of solvent revealed that the transformation was very sensitive to the reaction medium. The protic polar solvents displayed lower reactivity and enantioselectivity (entries 4 and 5). Gratifyingly, the mixed solvent system of THF/CH2Cl2 (1:1) gave the best result in terms of enantioselectivity and yield (entry 7). Subsequently, exploration of various commercially available bisphosphine ligands showed that (Rax,S,S)-C3*-TunePhos was the best ligand with respect to the yield and enantioselectivity (entry 13), whereas (R)-Binap gave lower enantioselectivity despite with high reactivity. Replacement of the bromide counterion by the trifluoromethanesulfonate anion resulted in no reactivity. In particular, when the CO2iPr group was introduced at the 2position of the benzyl group [1; Ar = 2-(iPrCO2)C6H4], the enantioselectivity was increased slightly, possibly because of its steric bulk and/or interaction with the iridium atom (entry 13 versus 16). With the optimized reaction conditions in hand, we turned our attention to investigate the scope of 1-substituted isoquinolinium salts, and the results are summarized in Table 2. It is noteworthy that various 1-substituted isoquinolinium salts proved to be good substrates under the standard reaction conditions. The transformation proceeded with excellent enantioselectivity and yield regardless of the Scheme 1. General strategy for asymmetric hydrogenation of 1and 3substituted isoquinolines. BCDMH= 1-bromo-3-chloro-5,5-dimethylhydantoin.

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 12] 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.

Chiral phosphoric acid-catalyzed asymmetric transfer hydrogenation of quinolin-3-amines.

A chiral phosphoric acid catalyzed asymmetric transfer hydrogenation of aromatic amines, quinolin-3-amines, was successfully developed with up to 99% ee. To supplement our previous work on the Ir-catalyzed asymmetric hydrogenation of 2-alkyl substituted quinolin-3-amines, a number of 2-aryl substituted substrates were reduced to provide a series of valuable chiral exocyclic amines with high diastereo- and enantioselectivities.

4,5-Dihydropyrrolo(1,2‑a)quinoxalines: A Tunable and Regenerable Biomimetic Hydrogen Source

A series of tunable and regenerable biomimetic hydrogen sources, 4,5-dihydropyrrolo[1,2-a]quinoxalines, have been synthesized and applied in biomimetic asymmetric hydrogenation of 3-aryl-2H-benzo[b][1,4]oxazines and 1-alkyl-3-aryl-quinoxalin-2(1H)-ones, providing the chiral amines with up to 92% and 89% ee, respectively.

Synthesis of Chiral Exocyclic Amines by Asymmetric Hydrogenation of Aromatic Quinolin‐3‐amines

Asymmetric hydrogenation of aromatic quinolin-3-amines was successfully developed with up to 94 % enantiomeric excess (ee). Introduction of the phthaloyl moiety to the amino group is crucial to eliminate the inhibition effect caused by the substrate and product, to activate the aromatic ring, and to improve the diastereoselectivity. This new methodology provides direct and facile access to chiral exocyclic amines. Notably, this report is the first on the highly enantioselective hydrogenation of aromatic amines.

Iridium-catalyzed asymmetric hydrogenation of dibenzo[ b,f ][1,4]thiazepines

Highly enantioselective hydrogenation of substituted dibenzo[b,f][1,4]thiazepines was achieved with up to 96 % ee (enantiomeric excess) using [Ir(COD)Cl]2/(R)-SynPhos complex as catalyst in the presence of iodine. This method provides an efficient access to optically active 11-substituted-10,11-dihydrodibenzo[b,f][1,4]thiazepines.

Synthesis of Fluorinated Heteroaromatics through Formal Substitution of a Nitro Group by Fluorine under Transition‐Metal‐Free Conditions

An efficient and transition-metal-free approach was developed to access a series of fluorinated heteroaromatics in moderate to excellent yields. This one-pot procedure features a triple-relay transformation of rapid dearomatization, fluorination, and rearomatization processes, which represents a conceptually novel strategy of combining partial hydrogenation and electrophilic fluorination.