,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 ...

The additive effects of amines were realized in the asymmetric hydrogenation of 2-phenylquinoxaline, and its derivatives, catalyzed by chiral cationic dinuclear triply halide-bridged iridium complexes [{Ir(H)[diphosphine]}(2)(μ-X)(3)]X (diphosphine = (S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [(S)-BINAP], (S)-5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole [(S)-SEGPHOS], (S)-5,5'-bis(diphenylphosphino)-2,2,2',2'-tetrafluoro-4,4'-bi-1,3-benzodioxole [(S)-DIFLUORPHOS]; X = Cl, Br, I) to produce the corresponding 2-aryl-1,2,3,4-tetrahydroquinoxalines. The additive effects of amines were investigated by solution dynamics studies of iridium complexes in the presence of N-methyl-p-anisidine (MPA), which was determined to be the best amine additive for achievement of a high enantioselectivity of (S)-2-phenyl-1,2,3,4-tetrahydroquinoxaline, and by labeling experiments, which revealed a plausible mechanism comprised of two cycles. One catalytic cycle was less active and less enantioselective; it involved the substrate-coordinated mononuclear complex [IrHCl(2)(2-phenylquinoxaline){(S)-BINAP}], which afforded half-reduced product 3-phenyl-1,2-dihydroquinoxaline. A poorly enantioselective disproportionation of this half-reduced product afforded (S)-2-phenyl-1,2,3,4-tetrahydroquinoxaline. The other cycle involved a more active hydride-amide catalyst, derived from amine-coordinated mononuclear complex [IrCl(2)H(MPA){(S)-BINAP}], which functioned to reduce 2-phenylquinoxaline to (S)-2-phenyl-1,2,3,4-tetrahydroquinoxaline with high enantioselectivity. Based on the proposed mechanism, an Ir(I)-JOSIPHOS (JOSIPHOS = (R)-1-[(S(p))-2-(dicyclohexylphosphino)ferrocenylethyl]diphenylphosphine) catalyst in the presence of amine additive resulted in the highest enantioselectivity for the asymmetric hydrogenation of 2-phenylquinoxaline. Interestingly, the reaction rate and enantioselectivity were gradually increased during the reaction by a positive-feedback effect from the product amines.

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.

A salt formation strategy for asymmetric hydrogenation of pyridines is described. Poly-substituted pyridinium salts were successfully hydrogenated using chiral iridium dinuclear complexes to afford substituted piperidines with multiple stereogenic centers after a simple basic workup.Chiral piperidine is an important structural skeleton abundant in a vast array of natural products and biologically active organic compounds, and it is often embedded within scaffolds of privileged structures recognized by medicinal chemists.1 In this context, tremendous efforts have been focused on the development of synthetic protocols for such a prevalent motif.2 Among them, asymmetric hydrogenation of substituted pyridines is the most straightforward and atom-economical route to concurrently constructing multiple stereocenters, but it remains a difficult task despite the recent report of the asymmetric hydrogenation of Nheteroaromatics.3 Following the pioneering work by Studer et al. on the asymmetric hydrogenation of ethyl picolinate catalyzed by a rhodium complex with a chiral diphosphine ligand, 4 some synthetic studies have been devoted to the asymmetric hydrogenation of substituted pyridines.5 Specific pyridine derivatives were successfully hydrogenated, however, such as poly-substituted pyridines bearing a chiral auxiliary, 6 7,8-dihydroquinolin-5(6H)-ones, 7 N-iminopyridinium ylides, 8 and N-benzylpyridinium bromide.3q These systems have the potential to construct multiple stereocenters in a single operation, but there is only one case, reported by Glorius et al., in which both high ee and dr were accomplished through the hydrogenation of poly-substituted pyridines, although stoichiometric amounts of chiral auxiliary were required.6 Accordingly, it is imperative that the general system for asymmetric hydrogenation of pyridines is established as an efficient method to prepare structurally diverse piperidines with multiple stereocenters.We recently developed a series of asymmetric hydrogenations of N-heteroaromatics catalyzed by a halogen-bridged iridium dinuclear complex (Scheme 1). 9 In the course of our investigation, we found that salt formation of the substrate facilitated the asymmetric hydrogenation of isoquinolines with high enantioselectivity. 10 We achieved asymmetric hydrogenation of 1,3-disubstituted isoquinolinium salts to construct two stereocenters on a cyclic amine skeleton. Encouraged by this result, we examined the asymmetric hydrogenation of multisubstituted pyridine derivatives in which multiple stereogenic centers can be introduced to the piperidine skeleton in a single operation.We attempted the hydrogenation of 2-methyl-6-phenylpyridinium bromide (2a-HBr) using iridium dinuclear complex 1 as a catalyst in a mixed solution of 1,4-dioxane/i-PrOH at 100°C for 20 h under H 2 (10 bar), and the corresponding piperidine 3a was obtained in 80% conv. with 43% ee after a basic workup (eq 1), whereas un-ionized pyridine was not hydrogenated under the same reaction conditions (eq 2). It is noteworthy that 3a had ...

Selective dehydrogenative synthesis of imines from a variety of alcohols and amines was developed by using the ruthenium complex [RuCl (dppea) ] (6 a: dppea=2-diphenylphosphino-ethylamine) in the presence of catalytic amounts of Zn(OCOCF ) and KOtBu, whereas the selective dehydrogenative formation of amides from the same sources was achieved by using another ruthenium complex, [RuCl {(S)-dppmp} ] [6 d: (S)-dppmp=(S)-2-((diphenylphosphenyl)methyl)pyrrolidine], in the presence of catalytic amounts of Zn(OCOCF ) and potassium bis(trimethylsilyl)amide (KHMDS). Our previously reported ruthenium complex, [Ru(OCOCF ) (dppea) ] (8 a), was the catalyst precursor for the imine synthesis, whereas [Ru(OCOCF ) {(S)-dppmp} ] (8 d), which was derived from the treatment of 6 d with Zn(OCOCF ) 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.

We describe a most straightforward synthetic method for preparing neurokinin‐1 (NK1) receptor antagonist derivatives by asymmetric hydrogenation of 3‐amido‐2‐arylpyridinium salts using dinuclear iridium complexes with enantiopure diphosphine ligands, affording the corresponding chiral piperidines in high cis‐diastereoselectivity (>95:5) and moderately high enantioselectivity (up to 86%). Deprotection treatments afforded the NK‐1 receptor antagonist (+)‐CP‐99,994 (83% ee). In addition, we observed unique additive effects of 10‐camphorsulfonic acid in the asymmetric hydrogenation of 3‐amido‐2‐arylpyridinium salts.magnified image

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.

,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 ...