Quantitative reaction cascades of ninhydrin in the solid state

Crystalline ninhydrin (1) undergoes waste-free solid-state cascade reactions with dimedone, L-proline, three o-phenylenediamines, o-mercaptoaniline, two ureas, three thioureas, and methyl 3-aminocrotonate. The yields are quantitative and give pure crystalline products without workup just by milling stoichiometric mixtures of the crystalline reagents. The structures of the new and the previously obtained products with lower yields from solutions are established or confirmed by spectroscopic data and density functional calculations at the B3LYP/6-31G* level. The success of 3- and 4-cascade reactions in the crystal without melting is unusual and of unmatched atom economy. They are mechanistically investigated with atomic force microscopy techniques (AFM) on six different faces of 1 when o-phenylenediamine was the reagent (substitution, elimination, cyclization, elimination) and interpreted on the basis of known crystal structure data. Strict correlations to the crystal packings are observed. The characteristic surface features grow to microm heights in some cases at distances of 0.5 mm from the contact edge of the reacting crystals. The waste-free and easy syntheses of highly functionalized (C=O; O-H; C=N) heterocycles or of a tetraketone are also of interest for synthetic use.