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.