Many oxetane-carboxylic acids were found to be unstable. They easily isomerized into new (hetero)cyclic lactones while being stored at room temperature or slightly heated. Chemists should keep in mind the high instability of these molecules, as this could dramatically affect the reaction yields and lead to negative results (especially in those reactions that require heating).

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.

We unexpectedly discovered that popular oxetane-carboxylic acids are intrinsically unstable. They easily isomerize into lactones under storage at rt, or under slight heating. Chemists should keep in mind the high instability of these common molecules, as this could dramatically affect the reaction yields and lead to negative results (especially in those reactions that require heating).