Abstract
Nitration of three regioisomers of bromo-fluorobenzaldehyde proceeds regioselectively, notably with H2SO4/HNO3 at 0 °C. The thereby synthesized tetrasubstituted aromatics, endowed with orthogonal substituents, can be elaborated via Pd-catalysed coupling, reduction and reductive amination reactions. As a test-case, these compounds were converted into EGFR inhibitors related to Gefitinib, whose activity was rationalised by docking studies.
Highlights
Tetrasubstituted aromatics are commonplace in drug discovery yet regioselective routes towards these compounds, which often contain orthogonal groups, are rather scarce.[1]
We show that these orthogonal groups can be modified in order to furnish useful drug-like fragments as well as tetrasubstituted units that can be incorporated into potential kinase inhibitors
Brominations on trisubstituted aromatics are an effective means for synthesising tetrasubstitued aromatic units containing orthogonal (e.g. MIDA and bromide) groups
Summary
Tetrasubstituted aromatics are commonplace in drug discovery yet regioselective routes towards these compounds, which often contain orthogonal groups, are rather scarce.[1]. We show that these orthogonal groups can be modified in order to furnish useful drug-like fragments as well as tetrasubstituted units that can be incorporated into potential kinase inhibitors. We sought a general method for reducing the nitro compounds 2 and we found that iron in acetic acid was an effective means for forming the anilines 3.
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