Experimental and computational study of BF3-catalyzed transformations of ortho-(pivaloylaminomethyl)benzaldehydes: an unexpected difference from TFA catalysis.

Previously, we have studied the trifluoroacetic acid (TFA)-catalyzed rearrangements of unsubstituted and alkoxy-substituted ortho-(pivaloylaminomethyl)benzaldehydes and revealed the formation of rearranged, regioisomeric aldehydes along with dimer-like products ("TFA dimers"). In the present study, related reactions of ortho-(pivaloylaminomethyl)benzaldehydes are described with the difference that boron trifluoride diethyl etherate (BF3·OEt2) is used as the catalyst. Although in these reactions the formation of the same "TFA dimers" can be observed after a couple of hours reaction time, during further stirring these are transformed into a new dimer-like keto compound ("BF3 dimer") that gradually becomes the main product. Apart from this, an oxoindene-type by-product is also formed. The new products are characterized by detailed NMR studies and two of them also by single-crystal X-ray diffraction. DFT calculations support the mechanism proposed for the transformations and explain the differences observed in the product distribution.

Rearrangement of o-(pivaloylaminomethyl)benzaldehydes: an experimental and computational study.

Treatment of alkoxy-substituted o-(pivaloylaminomethyl)benzaldehydes under acidic conditions resulted in the formation of the regioisomeric aldehydes and/or dimer-like products. Detailed NMR studies and single-crystal X-ray measurements supported the structure elucidation of the compounds. DFT calculations were also carried out to clarify the reaction mechanism, and to explain the observed product distributions and structural variances in the dimer-like products. Studies on the transformation of unsubstituted o-(pivaloylaminomethyl)benzaldehyde under similar conditions were presented as well.

A novel tool for structure assignment of hydroxylated metabolites of (arylpiperazinylbutyl)oxindole derivatives based on relative HPLC retention times.

Incubation of oxindole derivatives containing an arylpiperazine pharmacophore in rat liver microsomes in vitro formed several metabolites hydroxylated at various positions of the aromatic rings of the oxindole carbocycle or the arylpiperazine moiety. In order to substitute the sites of metabolic attack on these positional isomers, the exact structure of the molecules had to be identified. As polarities of the compounds depend on the site of hydroxylation, we measured retention times of the metabolites using reversed-phase HPLC. It was noted that the relative retention times (RRT, the ratio of the retention time of the metabolite and the parent compound) fell into distinct narrow ranges for metabolites identified by MS spectra as positional isomers. These RRT ranges correlated with the positions of hydroxylation. The hypothesis was validated by synthesis of hydroxy compounds of known structure and by determination of their RRT values. Change in the chromatographic parameters such as column type, eluent, gradient time and temperature did not impede the identification of the sites of hydroxylation as the RRT pattern remained similar to the original one. The new empirical method proposed in our study can be used for tentative identification of hydroxy metabolites and orient the direction of efforts to synthesize metabolically stable compounds.