GC/MS(n) analysis of the crude reaction mixtures from Friedel-Crafts acylation: Unambiguous identification and differentiation of 3-aroylbenzofurans from their 4- and 6-regioisomers.

RATIONALE: 3-Aroylbenzofurans and their 2-nitrophenyl derivatives constitute fundamental intermediates for the synthesis of target compounds with pharmaceutical properties. However, their preparation via the Friedel-Crafts acylation of 2-phenylbenzofurans, using Lewis acid as catalyst, often leads to mixtures of regioisomeric aroylbenzofurans that can be challenging to distinguish, thus preventing the reaction characterization. METHOD: We report a method for the unambiguous identification and differentiation of the desired 3-benzoyl isomers from their 4- and 6-regioisomers in a crude reaction mixture using gas chromatography coupled to multiple-stage mass spectrometric (GC/MS(n) ) analysis performed in collision-induced dissociation (CID) mode. RESULTS: Upon electron ionization, each set of isomers displayed nearly identical mass spectra. MS(n) revealed fragmentation patterns that varied in the location of the benzoyl group on the benzofuran scaffold: CID experiments performed on the molecular ion allowed the distinction of the 3-acyl isomers from the 4- and 6-regioisomers; CID experiments on the [M - Ar](+) ion allowed the distinction of the 4-benzoyl from the 6-benzoyl regioisomer, when the nitro group is located on the 2-phenyl ring. Moreover, the unusual loss of OH(•) radical allowed ascertaining the position of the nitro group in 3-acyl regioisomers bearing the NO(2) group. The origin of the diagnostic OH(•) loss was investigated through MS(n) experiments using (18) O-labelled 3-benzoyl derivatives. CONCLUSIONS: The method allows the rapid characterization of crude reaction mixtures of benzoylbenzofurans using solely GC/MS(n) analysis, simplifying the workflow of extensive isolation and purification for structure elucidation.