Chiral 1,2,3,4-tetrahydroisoquinolines are ubiquitous structural motifs in many natural alkaloids and biologically active compounds. [1] Among the various catalytic methods developed for the construction of chiral tetrahydroisoquinolines during the past decades, [2] 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 [3] for substrates such as quinolines, [4] quinoxalines, [5] indoles, [6] pyrroles, [7] pyridines, [8] furans, [9] imidazoles, [10] thiophenes [11] and aromatic carbocyclic rings. [12] 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. [13] Very recently, an enantioselective hydrogenation of 3,4-disubstituted isoquinolines employing catalyst activation was successfully described, [14] 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 1-and 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. [15] As part of our ongoing efforts to promote the development of asymmetric hydrogenation of heteroaromatic compounds, [3a,b] 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 1-Scheme 3. Mechanistic investigation of the iridium-catalyzed asymmetric hydrogenation of 1-and 3-substituted isoquinolinium salts.Scheme 4. Proposed hydrogenation mechanism.Scheme 5. Synthesis of the chiral drug (+)-solifenacin. Angewandte Chemie
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.B iomimetic approaches of asymmetric-transfer hydrogenation (ATH) reactions have emerged as a preeminent synthetic method for the preparation of chiral molecules in the chemists' repertoire. 1 Since pioneering reports in the 1980s, Hantzsch ester (HEH) or related compounds 2,3 were the only superior biomimetic hydride source for a long time, until Akiyama and co-workers demonstrated another hydride transfer reagent, benzothiazoline ( Figure 1). 4 However, in ordinary, stoichiometric or excessive amount of HEH or benzothiazoline was needed and a substantial number of dehydrogenation wastes generated in these transformations, which obviously limits the application of these specific hydrogen sources in both industry and academia. Consequently, the development of ATH reactions with regenerable hydrogen source is strongly desired.Very recently, our group discovered that Hantzsch ester 5 or dihydrophenanthridine (DHPD) 6 could be regenerated in situ by Ru(II) complexes under hydrogen gas, which had been employed in the biomimetic asymmetric hydrogenation of heteroaromatics and cyclic imines with excellent enantioselectivities. Remarkably, the demand for hydrogen source could be reduced to a catalytic amount (10 mol %). Although such progress has been achieved, the harsh regeneration conditions of HEH and limited derivatization possibility of DHPD impelled us to seek for easy tunable and regenerable versatile hydrogen sources.The foregoing results have demonstrated that development of a regenerable biomimetic hydrogen source should fulfill the following requirements: (i) regenerate under mild conditions as well as with high hydride transfer ability and (ii) easy control of the reaction enantioselectivity and simultaneously with various derivatization possibilities. Based on these guidelines, we began our studies through investigating the transfer hydrogenation ability of 4,5-dihydropyrrolo[1,2-a]quinoxalines, which are easily obtained through the mild partial hydrogenation of corresponding pyrrolo[1,2-a]quinoxalines (Scheme 1). In addition, the latter compounds could be easily prepared and derived from the simple starting materials. 7 The readily available imine 3-phenyl-2H-benzo [b][1,4]-oxazine 3a 8 was selected as the model substrate for condition optimization (Table 1). Gratifyingly, the exposure of ketimine 3a with pyrrolo[1,2-a]quinoxaline 1a (10 mol %) in the presence of chiral phosphoric acid 5a and [Ru(p-cymene)I 2 ] 2 at room temperature furnished amine 4a with 88% ee and 75% of conversion (entry 1). Notably, the reaction failed to proceed in the absence of 1a (entry 7). Through screening the reaction
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