A facile
synthetic route toward either 3- or 5-fluoroalkyl-substituted
isoxazoles or pyrazoles containing an additional functionalization
site was developed and applied on a multigram scale. The elaborated
approach extends the scope of fluoroalkyl substituents for introduction
into the heterocyclic moiety, and uses convenient transformations
of the side chain for incorporation of fluoroalkyl-substituted azoles
into the structures of biologically active molecules. The utility
of the obtained building blocks for isosteric replacement of alkyl-substituted
isoxazole and pyrazole was shown by the synthesis of fluorinated Isocarboxazid
and Mepiprazole analogues.
A novel chemical reagent – difluoromethyl nitrile oxide, CF2HCNO – was generated in situ for the first time. The synthesis commenced with ethyl difluoroacetate and included only two chemical steps. The difluoromethyl nitrile oxide smoothly participated in [3+2]‐cycloaddition reactions with alkynes and enamines to give CF2H‐isoxazoles; these products are promising cores for agrochemistry. A representative CHF2‐isoxazole was incorporated into the known fungicide Fluxapyroxad (BASF), and the synthesized analogue showed higher antifungal activity than the parent fungicide.
An efficient synthesis (up to a 200 g scale) of 3hydroxypyrrolidin-2-ones bearing alkyl substituents or functional groups at the C-5 position is described. The reaction sequence started from 1,3-dipolar cycloaddition of in situ generated nitrile oxides with (meth-)acrylates into 3-substituted isoxazoline-5carboxylates. The catalytic hydrogenolysis of the isoxazoline N−O bond was optimal upon using H 2 (1 atm) at rt, with the following order of the catalyst activity: Pd−C > Pd(OH) 2 −C > Pt−C. The reactions with Pt−C were more selective for the synthesis of pyrrolidones, while Pd−C provided the fastest conversion rates. The stirring efficiency had a positive impact on conversion rather than elevated temperatures (up to 40 °C) or pressure (up to 50 atm). The diastereoselectivity was governed mainly by steric factors, with a dr of 1:1 to 3:1 (cis-and trans-isomers could be separated). Higher homologues (isoxazolinylacetates and -propanoates) were suitable for the synthesis of 6-or 7-substituted 4-hydroxypiperidones and 5-hydroxyazepanones, respectively. The proposed methods are tolerant to functional groups, including CF 3 (but not CHF 2 or CH 2 Cl), ester, and most N-Boc-protected amines. The utility of hydroxyl groups in lactams was shown by functional group transformations. Hydrogenolysis of C(5)-functionalized isoxazolines, bearing trimethylsilyl, phosphonate, or sulfone groups, was also studied to demonstrate limitations.
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