Synthesis of Fluoro Analogues of 3,4-(Methylenedioxy)amphetamine (MDA) and Its Derivatives

The role of the metabolism of the entactogen 3,4-(methylenedioxy)methamphetamine (MDMA; 1b) in neurotoxic or psychopharmacologic action is widely discussed, but not yet fully understood. To prompt further investigation into the role of MDMAmetabolism, six new 3,4-(difluoromethylenedioxy) analogues of MDMA (1b) were prepared and characterized. Although electronically very different, the fluoro analogues 3 ± 5 should be sterically very similar to the non-fluorinated parent compounds. The F-atoms may prevent the formation of toxic metabolites produced via a radical pathway (Scheme 1). Different theories regarding MDMA-induced neurotoxicity are briefly reviewed and discussed. The novel compounds 3 ± 5may help to verify the hypothesis that MDMA-induced neurotoxicity is the result of the formation of metabolites lacking the methylenedioxy bridge. Introduction. ± 3,4-(Methylenedioxy)amphetamine (MDA; 1a)1) and its deriva-tives 1b,c and 2a,b are ring-substituted analogues of amphetamine that possess unique pharmacological properties. Due to their ability to cause feelings of closeness, a desire to socialize, and an enhanced feeling of empathy, they are called −empathogens × or −entactogens × [1]. Especially MDMA (1b) has attracted considerable interest becaus