Useful approach for O-functionalization of trifluoromethyl-substituted spirotetracyclic isoxazolines, and their application in the synthesis of 1,2,3-triazole derivatives

Helio G. Bonacorso, Alex Ketzer, Wilian C. Rosa, Tainara P. Calheiro, Melissa B. Rodrigues, Nilo Zanatta, Marcos A.P. Martins, Clarissa P. Frizzo

Index: 10.1016/j.jfluchem.2018.03.012

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Abstract

The present paper describes first an efficient methodology for an easy O-functionalization (alkylation) of tetracyclic hydroxyisoxazolines 1 applied to the synthesis of eight examples of new 3-(alkoxy)-3-(trifluoromethyl)-3,3a-dihydrospiro[chromeno [4,3-c]isoxazole-4,1'-cycloalkanes] (6-9) at 61–84 % yields, in which the alkoxy substituents were methoxy, benzyloxy, allyloxy, or prop-2-yn-1-yloxy; while the cycloalkanes were 5-, 6-, and 7-membered carbocycles, as well as 4’-methyl- and 4’-t-butyl-cyclohexane. The reaction medium used 1, four alkyl halides (2-5), K2CO3, and KI in DMF at room temperature. The selected 3-(prop-2-yn-1-yloxy)-substituted isoxazolines 6 were successfully used as a CC-fragment in the construction of another series of five examples of 3-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-3-(trifluoromethyl)-3,3a-dihydrospiro[chromeno[4,3-c]isoxazole-4,1'-cycloalkanes] (10), at 36–84% yields, through a regioselective 1,3 dipolar cycloaddition reaction catalyzed by copper iodide (CuAAC), using benzyl azide as an NNN-building block (Click Chemistry).