Mechanochemical Duff Reaction in Solid Phase for Easy Access to Mono- and Di-formyl Electron-Rich Arenes

A sustainable alternative to the century-old Duff reaction was developed by adopting a solid-phase mechanochemical route. A series of mono-formyl electron-rich arenes were prepared in high yields in silica as the solid reaction media using a combination of hexamethylenetetramine (HMTA) as the formyl source and a small amount of H₂SO₄ in a mixer mill. The use of toxic, costly, and low-boiling trifluoroacetic acid was avoided in the new mold of the mechanochemical Duff reaction. The mono-formyl phenols were obtained with exclusive ortho-selectivity, whereas unprecedented para-formylation was observed for other electron-rich aromatics. By controlling the stoichiometry of HMTA, the method offers easy access to di-formylated phenols as well. The scalability of the reaction was validated with selected substrates at the gram-scale level. In a case study, a mechanochemical tandem reaction was explored in the synthesis of a rhodol derivative. The solvent-free, metal-free mild method of formylation, with the absence of tedious work-up steps and shorter reaction times using an inexpensive mineral acid, is a sustainable alternative to the available methods for aromatic formylation.