Stereoselectivity and regioselectivity in nucleophilic ring opening in derivatives of 3-phenylisoxazolo[2,3-a]pyrimidine. Unpredicted dimerization and ring transformation. Syntheses of derivatives of pyrimidinylmethylamine, pyrimidinylmethylamino acid amides, and alpha-amino-2-pyrimidinylacetamides.
The nucleophilic ring opening of the isoxazolone ring in 2-oxo-3-phenylisoxazolo[2,3-a]pyrimidine derivatives by optically active amino acid amides and ephedrine led to pyrimidinylmethylamino acid amides. Using amides of different L-amino acids and (-)-ephedrine resulted in different degrees of stereoselectivity. The degree of streoselectivity depended mostly on the nucleophile used. When applying hydroxy amines such as ephedrine, the attack via the secondary amino group was found as the favored regioselectivity. Upon replacement of the oxo group in position 2 in the phenylisoxazolo[2,3-a]pyrimidine system by an imino group, it was expected that the spontaneous decarboxylation that follows the ring opening would not take place, thus achieving amino acid amide derivatives of 2-pyrimidinylacetamide, which are closely related to pyrimidoblamic acid, an important constituent of Bleomycins, used in cancer therapy. However, by heating 5,7-dimethyl-2-imino-3-phenylisoxazolo[2,3-a]pyrimidine in solution, it underwent an unprecedented dimerization process that involved both the phenyl and the imino group. After protecting the imino group by acetylation, the ring opening by nucleophiles was possible, resulting in the formation of derivatives of 2-pyrimidinylacetamide. 2-Acetylimino-5,7-dimethyl-3-phenylisoxazolo[2,3-a]pyrimidine also underwent a ring transformation, yielding an interesting indolone derivative. Selectivity in ring opening and mechanisms of dimerization and ring transformation are discussed.
Zvilichovsky
Gury
G
Department of Organic Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. gury@vms.huji.ac.il
Gbara-Haj-Yahia
Isra
I
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry; D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry*; D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry; D019281:Dimerization; D008744:Methylamines / Q000138:chemical synthesis* / Q000737:chemistry*; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism
C490013:2-oxo-3-phenylisoxazolo(2,3-a)pyrimidine; D000577:Amides; D000588:Amines; D000596:Amino Acids; D008744:Methylamines; D010080:Oxazoles; D011743:Pyrimidines; C490014:pyrimidinylmethylamine