,4-Tetrahydroisoquinolines (THIQs), a class of highly important molecular skeletons abundant in natural alkaloids and biologically active compounds, are often used as key intermediates for the synthesis of pharmaceutical drugs and drug candidates.[1] To date, synthetic efforts have focused on introducing chirality at the C1 position with configurational integrity by employing the following synthetic methodologies:[2] 1) the formation of the six-membered ring through a Bischler-Napieralski cyclization/reduction [3] or a PictetSpengler reaction, [4] 2) the C 1 -C a connectivity approach by attaching nucleophilic or electrophilic carbon units to the C1 position of tetrahydroisoquinoline derivatives, [5] and 3) the asymmetric hydrogenation of alkylidene-1,2,3,4-tetrahydroisoquinoline derivatives.[6] However, these methods have some limitations, such as a limited substrate scope and the need for stoichiometric amounts of a chiral auxiliary. In contrast to 1-substituted THIQs, the synthesis of 3-substituted THIQs has rarely been achieved, [7] although their unique structural and diverse biologic properties have been noted.[8] Accordingly, the development of more general and straightforward synthetic methods toward 1-and 3-substituted THIQs is in high demand. Although asymmetric hydrogenation of substituted isoquinolines is considered the most attractive and straightforward synthetic protocol, isoquinoline is regarded as the most challenging substrate in asymmetric hydrogenation. An efficient catalytic system has not even been found for the reduction of isoquinolines in a nonenantioselective manner. [9] Nonetheless, the recent development of an asymmetric hydrogenation of aromatic and heteroaromatic compounds was remarkable, [10][11][12][13][14][15][16][17][18][19][20] and Zhou and co-workers reported the catalytic asymmetric hydrogenation of isoquinolines, although the substrate scope is limited and an activating reagent is sometimes required (Scheme 1). [21] As part of our continuing interest in the asymmetric hydrogenation of N-heteroaromatic compounds using halogen-bridged dinuclear iridium(III) complexes, [22] we previously reported the additive effect of aryl amine derivatives in the asymmetric hydrogenation of quinoxalines, [22d] where the addition of more-basic aliphatic amines retarded the reaction, presumably because of their tight coordination to the iridium center. These findings strongly suggested that the difficulties of catalytic hydrogenation of isoquinolines upon catalysis by iridium complexes might be due to the strong basicity of the corresponding THIQs. This hypothesis prompted us to study the asymmetric hydrogenation of isoquinolinium chlorides to give the corresponding tetrahydroisoquinolinium chlorides, thus avoiding the deactivation of the iridium catalyst and providing a direct transformation of isoquinolines to THIQs in an enantioselective manner by a simple basic workup (Scheme 1).We first examined the asymmetric hydrogenation of the 3-phenylisoquinolinium salt 2 a-HCl with H 2 (30 bar) and ...

Asymmetric hydrogenation of quinazolinium salts was catalysed by halogen-bridged dinuclear iridium complexes bearing chiral diphosphine ligands, yielding tetrahydroquinazoline and 3,4-dihydroquinazoline with high enantioselectivity. A derivative of chiral dihydroquinazoline was used as a chiral NHC ligand.

Asymmetric hydrogenation of 1- and 3-substituted and 1,3-disubstituted isoquinolinium chlorides using triply halide-bridged dinuclear iridium complexes [{Ir(H)(diphosphine)}2 (μ-Cl)3 ]Cl has been achieved by the strategy of HCl salt formation of isoquinolines to afford the corresponding chiral 1,2,3,4-tetrahydroisoquinolines (THIQs) in high yields and with excellent enantioselectivities after simple basic work-up. The effects of salt formation have been investigated by time-course experiments, which revealed that the generation of isoquinolinium chlorides clearly prevented formation of the catalytically inactive dinuclear trihydride complex, which was readily generated in the catalytic reduction of salt-free isoquinoline substrates. Based on mechanistic investigations, including by (1) H and (31) P{(1) H} NMR studies and the isolation and characterization of several intermediates, the function of the chloride anion of the isoquinolinium chlorides has been elucidated, allowing us to propose a new outer-sphere mechanism involving coordination of the chloride anion of the substrates to an iridium dihydride species along with a hydrogen bond between the chloride ligand and the N-H proton of the substrate salt.

,4-Tetrahydroisoquinolines (THIQs), a class of highly important molecular skeletons abundant in natural alkaloids and biologically active compounds, are often used as key intermediates for the synthesis of pharmaceutical drugs and drug candidates.[1] To date, synthetic efforts have focused on introducing chirality at the C1 position with configurational integrity by employing the following synthetic methodologies:[2] 1) the formation of the six-membered ring through a Bischler-Napieralski cyclization/reduction [3] or a PictetSpengler reaction, [4] 2) the C 1 -C a connectivity approach by attaching nucleophilic or electrophilic carbon units to the C1 position of tetrahydroisoquinoline derivatives, [5] and 3) the asymmetric hydrogenation of alkylidene-1,2,3,4-tetrahydroisoquinoline derivatives.[6] However, these methods have some limitations, such as a limited substrate scope and the need for stoichiometric amounts of a chiral auxiliary. In contrast to 1-substituted THIQs, the synthesis of 3-substituted THIQs has rarely been achieved, [7] although their unique structural and diverse biologic properties have been noted.[8] Accordingly, the development of more general and straightforward synthetic methods toward 1-and 3-substituted THIQs is in high demand. Although asymmetric hydrogenation of substituted isoquinolines is considered the most attractive and straightforward synthetic protocol, isoquinoline is regarded as the most challenging substrate in asymmetric hydrogenation. An efficient catalytic system has not even been found for the reduction of isoquinolines in a nonenantioselective manner. [9] Nonetheless, the recent development of an asymmetric hydrogenation of aromatic and heteroaromatic compounds was remarkable, [10][11][12][13][14][15][16][17][18][19][20] and Zhou and co-workers reported the catalytic asymmetric hydrogenation of isoquinolines, although the substrate scope is limited and an activating reagent is sometimes required (Scheme 1). [21] As part of our continuing interest in the asymmetric hydrogenation of N-heteroaromatic compounds using halogen-bridged dinuclear iridium(III) complexes, [22] we previously reported the additive effect of aryl amine derivatives in the asymmetric hydrogenation of quinoxalines, [22d] where the addition of more-basic aliphatic amines retarded the reaction, presumably because of their tight coordination to the iridium center. These findings strongly suggested that the difficulties of catalytic hydrogenation of isoquinolines upon catalysis by iridium complexes might be due to the strong basicity of the corresponding THIQs. This hypothesis prompted us to study the asymmetric hydrogenation of isoquinolinium chlorides to give the corresponding tetrahydroisoquinolinium chlorides, thus avoiding the deactivation of the iridium catalyst and providing a direct transformation of isoquinolines to THIQs in an enantioselective manner by a simple basic workup (Scheme 1).We first examined the asymmetric hydrogenation of the 3-phenylisoquinolinium salt 2 a-HCl with H 2 (30 bar) and ...

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What is the most significant result of this study?We report a conceptually novel six-membered outer sphere transition state for a hydride attack of an anionic iridium hydride complex to isoquinolinium chloride, in which a chloride atom coordinated to an iridium center forms a hydrogen bond with an NÀH proton of the substrate salt, clearly revealing the remarkably increased enantioselectivity for asymmetric hydrogenation of isoquinolines.What was the biggest surprise (on the way to the results presented in this paper)?We were surprised to find that the chloride anion of isoquinolinium chloride was able to coordinate to an iridium center to form an anionic iridium complex, because we had not thought that the chloride anion of the HCl salt of the N-heteroaromatics would coordinate. In addition, such coordination of the chloride atom plays a key role in achieving high enantioselectivity by the salt formation of the substrate in the asymmetric hydrogenation of isoquinolines catalyzed by halide-bridged dinuclear iridium complexes. What aspects of this project do you find most exciting?Asymmetric hydrogenation of N-heteroaromatics is one of the most straightforward and industrializable protocols to obtain optically active cyclic amine derivatives. This project, with its focus on mechanistic studies, provides insight to enhance scope and development in closely related research topics. In the case of the present project, chloride coordination to a metal center has potential application for not only hydrogenation of unsaturated bonds, but also other transformations using the combined catalytic system of both a metal and Brønsted acid.What is in your opinion an upcoming research theme likely to become one of the 'hot topics' in the near future?Asymmetric hydrogenation of unsaturated bonds is one of the most challenging and hot topics in terms of green chemistry and industrial applications. Our results elucidate a novel outer sphere mechanism that opens up a new era for suitable combinations of transition metal complexes and suitable chiral ligands with any Brønsted and Lewis acids.Invited for the cover of this issue is the group of Kazushi Mashima at Osaka University. The image depicts a novel six-membered outer sphere transition state-the substrate and product are represented by locomotives with a six-membered rail, and chiral induction by a signal. Read the full text of the article at

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Additive Effects on Asymmetric Hydrogenation of N-Heteroaromatics -[62 refs.]. -(MASHIMA*, K.; NAGANO, T.; IIMURO, A.; YAMAJI, K.; KITA, Y.; Heterocycles 88 (2014) 1, Special Issue, 103-127, http://dx.