Abstract
Rationale3‐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.MethodWe 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.ResultsUpon 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 18O‐labelled 3‐benzoyl derivatives.ConclusionsThe 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.
Highlights
Monitoring the reaction progress is of great interest in modern organic synthesis and drug research
Further differences in ion abundances were evidenced in the MS3 spectra of the m/z 221 ions (Figures 2C, 2F and 2I): all isomers exhibit the loss of CO molecules (m/z 193) followed by the typical abstraction of further CO from the 2-phenylbenzofuran nucleus (m/z 165),[19] only for isomer 1a does the ion at m/z 165 constitute the base peak (Figure 2C), whereas the ion at m/z 193 is the major peak for isomers 2a (Figure 2F) and 3a (Figure 2I)
GC/MS can be used for the rapid separation and identification of 3-benzoyl-2-phenylbenzofurans from their 4- and 6-benzoyl regioisomers directly in the crude reaction mixtures without the need of reference standards
Summary
Monitoring the reaction progress is of great interest in modern organic synthesis and drug research. This ion corresponds for all isomers to the loss of radical C6H5 from the benzoyl group, as supported by the mass shift to m/z 226 in the spectra of the deuterium analogues 1ad5–3ad[5] (Figures S1 and S2). The mass spectra of isomeric compounds 1b–3b, despite some minor differences in relative abundances of fragment ions, are nearly identical (Figures 3A, 3D and 3G).
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