Asymmetric conjugate addition of thioglycolate to a range of chalcones using tetrahydroisoquinoline (TIQ) N,N′-dioxide ligands

A series of novel TIQ based N,N′-oxide ligands were synthesised and screened for their catalytic activity in the enantioselective conjugate addition of thioglycolate to chalcones. Bulky groups on the side chain of the TIQ backbone provided the highest enantioselectivity of up to 88% with 10 mol % catalyst loading. It was also observed that these reactions proceeded optimally in the presence of dichloromethane as a solvent. Screening of various metals emphasized La(OTf)3 as the ideal pre-catalyst for this particular reaction.

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(S)-Benzyl 3-(o-tolylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylateC25H24N2O3[α]D20=-19.2 (c 0.78, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-Benzyl 3-(2,6-dimethylphenylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylateC26H26N2O3[α]D20=-32.0 (c 0.50, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-Benzyl 3-(2,6-diisopropylphenylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylateC30H34N2O3[α]D20=-11.3 (c 0.53, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-N-o-Tolyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamideC17H18N2O[α]D20=-60.0 (c 0.50, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-N-(2,6-Dimethylphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamideC18H20N2O[α]D20=-78.8 (c 0.33, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(S)-N-(2,6-Diisopropylphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamideC22H28N2O[α]D20=-58.3 (c 0.48, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (3S)

(3S,3′S)-2,2′-(Propane-1,3-diyl)bis(N-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide)C35H36N4O2[α]D20=-28.6 (c 0.35, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (3S,3′S)

(3S,3′S)-2,2′-(Propane-1,3-diyl)bis(N-o-tolyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide)C37H40N4O2[α]D20=-15.15 (c 0.33, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (3S,3′S)

(3S,3′S)-2,2′-(Propane-1,3-diyl)bis(N-(2,6-dimethylphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide)C39H44N4O2[α]D20=-35.7 (c 0.14, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (3S,3′S)

(3S,3′S)-2,2′-(Propane-1,3-diyl)bis(N-(2,6-diisopropylphenyl)-1,2,3,4-tetrahydroisoquinolin-e-3-carboxamide)C47H60N4O2[α]D20=-12.5 (c 0.16, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (3S,3′S)

(3S,3′S)-2,2′-(Propane-1,3-diyl)bis(N-benzyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide)C37H40N4O2[α]D20=-5.9 (c 0.17, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (3S,3′S)

(3S,3′S)-2,2′-(Propane-1,3-diyl)bis(3-(phenylcarbamoyl)-1,2,3,4-tetrahydroisoquinoline 2-oxide)C35H36N4O4[α]D20=-27.3 (c 0.11, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S,3′S)

(3S,3′S)-2,2′-(Propane-1,3-diyl)bis(3-(o-tolylcarbamoyl)-1,2,3,4-tetrahydroisoquinoline 2-oxide)C37H40N4O4[α]D20=-20.0 (c 0.10, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S,3′S)

(3S,3′S)-2,2′-(Propane-1,3-diyl)bis(3-(2,6-dimethylphenylcarbamoyl)-1,2,3,4-tetrahydroisoquinoline 2-oxide)C39H44N4O4[α]D20=-26.7 (c 0.15, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S,3′S)

(3S,3′S)-2,2′-(Propane-1,3-diyl)bis(3-(2,6-diisopropylphenylcarbamoyl)-1,2,3,4-tetrahydroisoquinoline 2-oxide)C47H60N4O4[α]D20=-38.5 (c 0.13, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S,3′S)

(3S,3′S)-2,2′-(Propane-1,3-diyl)bis(3-(benzylcarbamoyl)-1,2,3,4-tetrahydroisoquinoline 2-oxide)C37H40N4O4[α]D20=-22.2 (c 0.18, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (3S,3′S)