Scalable Synthesis of <i>N</i>,<i>N</i>′-Di(2,3-dihydroxy-propyl)-1,4-naphthalenedipropanamide and Its 1,4-Endoperoxide as a Singlet Oxygen-Releasing Molecule

We report a greatly improved, operationally simple, and scalable three-step synthesis of the nonionic and water-soluble singlet oxygen (1O2) carrier molecule N,N′-bis(2,3-dihydroxypropyl)-1,4-naphthalenedipropanamide-1,4-endoperoxide (DHPNO2). Starting from 1,4-dibromonaphthalene, the developed sequence involves (1) a ligand-free Pd-catalyzed double Heck reaction with methyl acrylate, (2) Pd/C-catalyzed hydrogenation, and (3) amide formation by simple methyl ester aminolysis using 3-amino-1,2-propanediol to give N,N′-bis(2,3-dihydroxypropyl)-1,4-naphthalenedipropanamide (DHPN) in 70% overall yield (three steps). A solution of the corresponding endoperoxide DHPNO2 in D2O (storable at −20 °C), obtained by sensitized photo-oxidation of DHPN at 4 °C, is a valuable research tool allowing a controlled release of singlet oxygen (1O2) in aqueous biological systems at physiological temperatures.