GC-MSn analysis of the crude reaction mixtures from Friedel Craft acylation: unambiguous identification and differentiation of 3-aroylbenzofurans from their 4- and 6-regioisomers

Michela Begala

First

;Michele Mancinelli

Second

;Elias Quezada

Penultimate

;Giovanna Lucia Delogu

Last

2021-01-01

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Abstract

Rationale 3‐Aroylbenzofurans and their 2‐nitrophenyl derivatives constitute fundamental intermediates for the synthesis of target compounds with pharmaceutical properties. However, their preparation by 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 the crude reaction mixture using gas‐chromatography coupled to multiple stage mass spectrometric (GC‐MSn) analysis performed in CID mode. Results Upon Electron Ionization (EI), each sets of isomers displayed nearly identical mass spectra. Multiple stage tandem mass spectrometry revealed fragmentation pattern that varied on 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 to ascertain 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 the 18O labelled 3‐benzoyl derivative. Conclusions The method allows to obtain rapid characterization of the crude reaction mixture of benzoyl benzofurans using solely GC‐MSn analysis, simplifying the workflow of extensive isolation and purification for structures elucidation.