GC/MSⁿ 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/MSⁿ ) analysis performed in collision-induced dissociation (CID) mode.

Results: Upon electron ionization, each set of isomers displayed nearly identical mass spectra. MSⁿ 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 NO₂ group. The origin of the diagnostic OH^• loss was investigated through MSⁿ experiments using ¹⁸ O-labelled 3-benzoyl derivatives.

Conclusions: The method allows the rapid characterization of crude reaction mixtures of benzoylbenzofurans using solely GC/MSⁿ analysis, simplifying the workflow of extensive isolation and purification for structure elucidation.