Synthesis of tetrahydroisoquinoline-diamine ligands and their application in asymmetric transfer hydrogenation

The use of the tetrahydroisoquinoline scaffold is well documented in biologically active compounds. However, reports of the utilisation of tetrahydroisoquinoline compounds in asymmetric catalysis are limited. The synthesis of novel diamine ligands possessing the tetrahydroisoquinoline (tetrahydroisoquinoline) backbone and evaluation of their activity in the asymmetric transfer hydrogenation of acetophenone are presented. The diamine ligands in conjunction with i-PrOH as the hydrogen source and [RhCl2(Cp∗)]2 as the metal precursor proved to be the most effective of the tetrahydroisoquinoline derivatives for this catalytic system. Water was found to have a profound influence on the enantioselectivity of the reaction. Optimisation of the amount water, i-PrOH and catalytic loading content rendered the best result of 70% enantioselectivity for the (S)-1-phenylethanol isomer product.

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(S)-N-Benzyl-1-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanamineC17H20N2[α]D20=-70.9 (c 0.43, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-1,1-Diphenyl-N-((1,2,3,4-tetrahydroisoquinolin-3-yl)methyl)methanamineC23H24N2[α]D20=-55.8 (c 0.52, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-N-((1,2,3,4-Tetrahydroisoquinolin-3-yl)methyl)anilineC16H18N2[α]D20=-64.3 (c 0.14, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-N-Methyl-1-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanamineC11H16N2[α]D20=-1.3 (c 0.1, MeOH)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-N-((1,2,3,4-Tetrahydroisoquinolin-3-yl)methyl)propan-2-amineC13H20N2[α]D20=-8.3 (c 0.12, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(R)-1-Phenyl-N-(((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)methyl)ethanamineC18H22N2[α]D20=-43.55 (c 0.93, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S,1′R)

(S)-1-Phenyl-N-(((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)methyl)ethanamineC18H22N2[α]D20=-43.55 (c 0.93, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S,1′S)

N-Benzyl-1-((1R,3S)-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-yl)methanamineC25H28N2O2[α]D20=-26.8 (c 0.41, CH2Cl2)Source of chirality: l-DOPAAbsolute configuration: (1R,3S)

(S)-4-Methyl-N-((1,2,3,4-tetrahydroisoquinolin-3-yl)methyl)benzenesulfonamideC17H20N2O2S[α]D20=-13.8 (c 0.17, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-Benzyl 3-(benzylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylateC25H24N2O3[α]D20=-8.3 (c 0.12, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-Benzyl 3-(benzhydrylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylateC31H28N2O3[α]D20=-11.4 (c 0.36, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-Benzyl 3-(phenylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylateC24H22N2O3[α]D20=-38.1 (c 0.42, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-Benzyl 3-(methylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylateC19H20N2O3[α]D20=-6.4 (c 0.62, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-Benzyl 3-(isopropylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylateC21H24N2O3[α]D20=-3.4 (c 0.58, THF)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-Benzyl 3-((R)-1-phenylethylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylateC26H26N2O3[α]D20=+10.7 (c 1.03, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S,1′R)

(S)-Benzyl 3-((S)-1-phenylethylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylateC26H26N2O3[α]D20=-21.4 (c 0.70, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S,1′S)

(S)-N-Benzyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamideC17H18N2O[α]D20=-54.8 (c 0.42, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-N-Benzhydryl-1,2,3,4-tetrahydroisoquinoline-3-carboxamideC23H22N2O[α]D20=-105.7 (c 0.35, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-N-Phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamideC16H16N2O[α]D20=-144.7 (c 0.38, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-N-Methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamideC11H14N2O[α]D20=-222.5 (c 0.20, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-N-Isopropyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamideC13H18N2O[α]D20=-105.7 (c 0.35, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-N-((R)-1-Phenylethyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamideC18H20N2O[α]D20=-33.8 (c 0.34, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S,1′R)

(S)-N-((S)-1-Phenylethyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamideC18H20N2O[α]D20=-100.7 (c 0.36, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S,1′S)

(1R,3S)-Benzyl 3-(hydroxymethyl)-6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylateC26H27NO5[α]D20=+40.4 (c 0.26, CH2Cl2)Source of chirality: l-DOPAAbsolute configuration: (1R,3S)

(1R,3S)-Benzyl 3-formyl-6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylateC26H25NO5[α]D20=+41.5 (c 0.41, CH2Cl2)Source of chirality: l-DOPAAbsolute configuration: (1R,3S)

(1R,3S)-Benzyl 3-((benzylamino)methyl)-6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylateC33H34N2O4[α]D20=+27.3 (c 0.44, CH2Cl2)Source of chirality: l-DOPAAbsolute configuration: (1R, 3S)

(S)-Benzyl 3-carbamoyl-3,4-dihydroisoquinoline-2(1H)-carboxylateC18H18N2O3[α]D20=-2.3 (c 0.59, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-Benzyl 3-(aminomethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylateC18H20N2O2[α]D20=-15.0 (c 0.16, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S)