Synthesis of 5-(Fluoroalkyl)isoxazole Building Blocks by Regioselective Reactions of Functionalized Halogenoximes
| Autor: | Oleksandr V. Borysov, Iulia Bakanovych, Yurii S. Moroz, Oleksandr O. Grygorenko, Yulia V Fil, Bohdan A. Chalyk, Kateryna V. Hrebeniuk, Pavlo S. Lebed, Bohdan V. Vashchenko, Alexander B. Rozhenko, Angelina V. Biitseva, Konstantin S. Gavrilenko |
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| Rok vydání: | 2019 |
| Předmět: |
Molecular Structure
010405 organic chemistry Organic Chemistry Regioselectivity Stereoisomerism Alcohol Isoxazoles 010402 general chemistry 01 natural sciences Combinatorial chemistry Article Cycloaddition 0104 chemical sciences chemistry.chemical_compound chemistry Cyclization Reagent Yield (chemistry) Oximes Nucleophilic substitution Isoxazole |
| Zdroj: | J Org Chem |
| ISSN: | 1520-6904 0022-3263 |
| Popis: | A comprehensive study on the synthesis of 5-fluoroalkyl-substituted isoxazoles starting from functionalized halogenoximes is reported. One-pot metal-free [3 + 2] cycloaddition of CF3-substituted alkenes and halogenoximes bearing ester, bromo, chloromethyl, and protected amino groups was developed for the preparation of 5-trifluoromethylisoxazoles. The target 3,5-disubstituted derivatives were obtained in a regioselective manner in good to excellent yield on up to 130 g scale. 5-Fluoromethyl- and 5-difluoromethylisoxazoles were synthesized by late-stage deoxofluorination of the corresponding 5-hydroxymethyl or 5-formyl derivatives, respectively, in turn prepared via metal-free cycloaddition of halogenoximes and propargylic alcohol. An alternative approach based on nucleophilic substitution in 5-bromomethyl derivatives was found to be more convenient for the preparation of 5-fluoromethylisoxazoles. Reaction of isoxazole-5-carbaldehydes with the Ruppert-Prakash reagent was used for the preparation of (β,β,β-trifluoro-α-hydroxyethyl)isoxazoles. Utility of described approaches was shown by multigram preparation of side-chain functionalized mono-, di-, and trifluoromethylisoxazoles, for example, fluorinated analogues of ABT-418 and ESI-09. |
| Databáze: | OpenAIRE |
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