Parallel synthesis of 1,2,4-oxadiazoles using CDI activation

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 2, 1999, Pages 209-212

  Deegan, Tracy L ^a   Nitz, Theodore J ^b   Cebzanov, Diane ^b   Pufko, Denise E ^b   Porco Jr , John A ^a  

^a Argonaut Technologies   (United States)

^b ViroPharma Incorporated   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

OXADIAZOLE DERIVATIVE;

ACYLATION; ARTICLE; COUPLING FACTOR; DEHYDRATION; DRUG ISOLATION; DRUG SYNTHESIS; FILTRATION; LIQUID LIQUID EXTRACTION; PROTEIN PURIFICATION;

BENZAMIDINES; CARBOXYLIC ACIDS; IMIDAZOLES; OXADIAZOLES;

EID: 0033579847     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00712-4     Document Type: Article

References (17)

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12. Abbreviations: CDI: 1,1'-carbonyldiimidazole; DMF: dimethylformamide; DCM: dichloromethane; SPE: solid phase extraction. EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DCC: 1,3-dicyclohexylcarbodiimide.
13. Benzamidoximes were prepared according to a modification of the reported procedure: Eloy, F.; Lenaeres, R. Chem. Rev. 1961, 62, 155. Representative preparation of p-toluamidoxime: To a 250 mL round-bottom flask was added 10.2 g (87.0 mmol, 1.0 equiv) of p-tolunitrile, 12.4 g (191.5 mmol, 2.2 equiv) of hydroxylamine hydrochloride, and the solids dissolved in 150 mL of 95 % ethanol. 27.9 mL (200.2 mmol, 2.3 equiv) of triethylamine was added, and the reaction mixture stirred at 75 °C for 12 h. After cooling to rt, the mixture was filtered, diluted with 200 mL distilled water, and neutralized to pH 7 with cone HCl. The solution was placed on a rotovap at 40 °C bath temperature to remove the ethanol and precipitate the product. The solid product was filtered, washed three times with water, and dried in vacuo to afford 10.4 g (80 %) of p-toluamidoxime.
14. For a discussion of the cyclodehydration mechanism, see: Ooi, N. S.; Wilson, D. S.; J. Chem. Soc. Perkin Trans. II 1980, 1792.
15. Jones Chromatography, Lakewood, Colorado, USA. We have found that Florisil is also particularly effective at removing trace amounts of DMF that are contained in crude products.
16. 2: 266.25.
17. Initial attempts were made to precipitate the products in parallel using water. However, oxadiazoles derived from aliphatic acids were found to be non-crystalline which required us to utilize a liquid-liquid extraction procedure.