Atsuhiro Iimuro

Asymmetric Hydrogenation of Isoquinolinium Salts Catalyzed by Chiral Iridium Complexes: Direct Synthesis for Optically Active 1,2,3,4‐Tetrahydroisoquinolines

1,2,3,4-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. To date, synthetic efforts have focused on introducing chirality at the C1 position with configurational integrity by employing the following synthetic methodologies: 1) the formation of the six-membered ring through a Bischler–Napieralski cyclization/reduction or a Pictet– Spengler reaction, 2) the C1–Ca connectivity approach by attaching nucleophilic or electrophilic carbon units to the C1 position of tetrahydroisoquinoline derivatives, and 3) the asymmetric hydrogenation of alkylidene-1,2,3,4-tetrahydroisoquinoline derivatives. 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 1substituted THIQs, the synthesis of 3-substituted THIQs has rarely been achieved, although their unique structural and diverse biologic properties have been noted. Accordingly, the development of more general and straightforward synthetic methods toward 1and 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. Nonetheless, the recent development of an asymmetric hydrogenation of aromatic and heteroaromatic compounds was remarkable, 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). As part of our continuing interest in the asymmetric hydrogenation of N-heteroaromatic compounds using halogen-bridged dinuclear iridium(III) complexes, we previously reported the additive effect of aryl amine derivatives in the asymmetric hydrogenation of quinoxalines, 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 3phenylisoquinolinium salt 2 a-HCl with H2 (30 bar) and the catalyst [{Ir(H)[(S)-binap]}2(m-Cl)3]Cl (1a) in methanol at Scheme 1. Asymmetric hydrogenation of isoquinoline derivatives.

Tunable Ligand Effects on Ruthenium Catalyst Activity for Selectively Preparing Imines or Amides by Dehydrogenative Coupling Reactions of Alcohols and Amines

Selective dehydrogenative synthesis of imines from a variety of alcohols and amines was developed by using the ruthenium complex [RuCl2 (dppea)2 ] (6 a: dppea=2-diphenylphosphino-ethylamine) in the presence of catalytic amounts of Zn(OCOCF3 )2 and KOtBu, whereas the selective dehydrogenative formation of amides from the same sources was achieved by using another ruthenium complex, [RuCl2 {(S)-dppmp}2 ] [6 d: (S)-dppmp=(S)-2-((diphenylphosphenyl)methyl)pyrrolidine], in the presence of catalytic amounts of Zn(OCOCF3 )2 and potassium bis(trimethylsilyl)amide (KHMDS). Our previously reported ruthenium complex, [Ru(OCOCF3 )2 (dppea)2 ] (8 a), was the catalyst precursor for the imine synthesis, whereas [Ru(OCOCF3 )2 {(S)-dppmp}2 ] (8 d), which was derived from the treatment of 6 d with Zn(OCOCF3 )2 and characterized by single-crystal X-ray analysis, was the pre-catalyst for the amide formation. Control experiments revealed that the zinc salt functioned as a reagent for replacing chloride anions with trifluoroacetate anions. Plausible mechanisms for both selective dehydrogenative coupling reactions are proposed based on a time-course study, Hammett plot, and deuterium-labeling experiments.

Triply Halide‐Bridged Dinuclear Iridium(III) Complexes with Chiral Diphosphine Ligands as New Easy‐to‐Handle Iridium Catalysts for Asymmetric Hydrogenation of Imines and N‐Heteroaromatics

Iridium(III) complexes bearing chiral ligands have proved to be active species in asymmetric hydrogenation of C=N bonds, though there are only a few iridium(III) precursors. We prepared triply halide-bridged dinuclear iridium complexes bearing chiral diphosphine ligands by simple treatment of the iridium(I) precursor, chiral diphosphine, and aqueous hydrogen halide. The strong advantage of these dinuclear iridium complexes is that they are air and moisture stable, leading to easy handling in asymmetric synthesis. The dinuclear iridium complexes exhibited high catalytic activity toward asymmetric hydrogenation of imines and N-heteroaromatics. Moreover, we demonstrated the application of triply halide-bridged dinuclear ruthenium(II) and rhodium(III) catalyst precursors for the asymmetric hydrogenation of ketonic substrates and simple olefins, respectively.