Enantioselective diethylzinc addition to the exocyclic CN double bond of some 4-arylideneamino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-one derivatives

4-Arylideneamino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones 2a–f have been evaluated as substrates in the enantioselective diethylzinc addition reaction in the presence of (1S,2R)-N-alkyl-N-benzylnorephedrines 3a–d as chiral ligands. The utility of using a dual catalytic system (amino alcohol/halosilane) for the diethylzinc addition reaction has been also examined. The addition products 4-(1-arylpropyl)amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones 4a–f were obtained in high yields and with enantiomeric excesses of up to 92%. The treatment of arylimines 2a–f with a diethylzinc reagent did not affect the hetero-ring opening although the CN double bond of the lateral chain did undergo an addition reaction to yield the C-ethylated products 4a–f. The reductive cleavage of the 1,2,4-triazinyl heterocyclic ring from addition products 4a–f led smoothly to the corresponding free primary amines 5a–f without a significant loss of enantiomeric purity.

Chiral 4-(1-arylpropyl)amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones 4 were synthesized easily through the enantioselective diethylzinc addition to the exocyclic CN double bond of 4-arylideneamino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones 2. Enantiomeric excess of up to 92% was obtained using (1S,2R)-N-methyl-N-benzylnorephedrine 3b as chiral ligand and TIPSCl as activator.Figure optionsDownload as PowerPoint slide

(S)-4-(1-Phenylpropyl)amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-oneC13H16N4OSEe = 84%[α]D25=-57.4 (c 1.03, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: S

(S)-4-[1-(2′-Methylphenyl)propyl]amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-oneC14H18N4OSEe = 79%[α]D25=-96.8 (c 0.98, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: S

(S)-4-[1-(4′-Methylphenyl)propyl]amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-oneC14H18N4OSEe = 87%[α]D25=-78.1 (c 1.28, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: S

(S)-4-[1-(2′-Methoxyphenyl)propyl]amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-oneC14H18N4O2SEe = 82%[α]D25=-94.5 (c 0.77, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: S

(S)-4-[1-(4′-Methoxyphenyl)propyl]amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-oneC14H18N4O2SEe = 88% (92% after crystallization)[α]D25=-34.6 (c 2.39, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: S

(S)-4-[1-(2′,4′,6′-Tri-methylphenyl)propyl]amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-oneC16H22N4OSEe = 72%[α]D25=-46.6 (c 0.98, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: S