Mechanistic Studies on the Michael‐type Addition of Amines to 2‐Arylvinylidenebisphosphonates: Bisphosphonate Elimination <i>via</i> a Retro‐Aza‐Michael‐type Reaction

Abstract Encouraged by the potent inhibitory effect exhibited by long chain 2‐alkylaminoethyl‐1,1‐bisphosphonates against proliferation of the clinically more relevant form of Trypanosoma cruzi , the etiologic agent of American trypanosomiasis (Chagas disease), and against tachyzoites of Toxoplasma gondii , the responsible agent of toxoplasmosis, it was conceived a new series of structurally related 1,1‐bisphosphonates bearing a phenyl group at the C‐2 position of the title compounds. The synthetic approach to access these compounds employed a Michael‐type addition by reaction of tetraethyl 2‐phenylvinylidenebisphosphonate or substituted phenyl group with a suitable amine. To our surprise the reaction experienced a retro‐Michael type reaction resulting in an imine formation instead of the hypothetical and expected Michael‐type adduct. Obtainment of the imine derivatives was observed regardless of the nature of the substituent at the phenyl moiety. The source of the alkyl chain was the alkyl group of the amine substrate. Interestingly, when mercaptans were used as soft nucleophiles, the Michael‐type adducts were obtained in all cases.