Synthesis of chiral primary amines: diastereoselective alkylation of N-[(1E)-alkylidene]-3,5-bis[(1S)-1-methoxyethyl]-4H-1,2,4-triazol-4-amines and N-4-N-exocyclic bond cleavage in the resulting 1,2,4-triazol-4-alkylamines

• Published in: Tetrahedron: asymmetry Vol. 19; no. 23; pp. 2682 - 2692
• Main Authors: Serradeil-Albalat, Muriel, Roussel, Christian, Vanthuyne, Nicolas, Vallejos, Jean-Claude, Wilhelm, Didier
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier 01.12.2008
• Subjects: Chemistry; Chemistry, Inorganic & Nuclear; Chemistry, Organic; Chemistry, Physical; Physical Sciences; Science & Technology; HYDRAZONES; ASYMMETRIC-SYNTHESIS; NUCLEOPHILIC 1,2-ADDITION; ENANTIOSELECTIVE SYNTHESIS; ORGANOMETALLIC REAGENTS; ACETALS; ADDITIONS; N-N; GRIGNARD-REAGENTS; 1,2,4-TRIAZOLE
• ISSN: 0957-4166
• DOI: 10.1016/j.tetasy.2008.12.015

Enantiomerically pure 3,5-bis[(1S)-1-methoxyethyl]-4H-1,2,4-triazol-4-amine 14a and 3,5-bis[(1S)-1-ethoxyethyl]-4H-1,2,4-triazol-4-amine 14b were used as chiral auxiliaries to obtain enantiomerically enriched alpha-aminoacetals, primary alkyl and arylalkyl amines (ee ranging from 40% to 90%). The different stages of the process were imine formation from the corresponding aldehydes, diastereoselective addition of a Grignard reagent, quaternization of the triazole auxiliary and cleavage of the N-4-N-exocylic bond by LiBH4. The mechanism of the cleavage of the N-4-N-exocyclic bond is supported by the use of deuterated metal hydride. The absolute configurations of the new stereogenic centres were established by X-ray analyses of the enantiomerically pure stereomers isolated by semi-preparative liquid chromatography on a chiral support. (C) 2008 Elsevier Ltd. All rights reserved.