REGIOCHEMICAL AND STEREOCHEMICAL STUDIES ON HALOCYCLIZATION REACTIONSOF UNSATURATED SULFIDES

The regiochemistry and stereochemistry for the halocyclization reactio ns of unsaturated benzyl sulfides have been examined as a function of tether length, type of unsaturation (carbon-carbon double bond versus carbon-carbon triple bond), substituents, and halogenating agent. Alke nyl sulfides were found to react with iodine or bromine at room temper ature to give five-membered ring cycloadducts exclusively over those h aving four-membered rings, while for larger systems, six-membered ring products are formed preferentially over their five-membered ring isom ers and exclusively over the seven-membered ring adducts. The endo- ve rsus exo-regioselectivity of these alkenyl sulfide ring closures most likely reflects the difference in thermodynamic stabilities of the bet a-halo sulfide cycloadducts, which are able to equilibrate via a commo n episulfonium intermediate. The efficiency of the cyclization process markedly drops off for these alkenyl sulfides as the tether length in creases beyond four intervening carbon centers. Thus, while the haloge nations of 3-butenyl sulfides and 4-pentenyl sulfides give high yields of cycloadducts, those of 5-hexenyl sulfides afford only small amount s of cyclized products and large quantities of acyclic dibromides. Con versely the reactions of acetylenic sulfides with iodine give uniforml y high yields and regiochemical control regardless of the tether lengt h. Thus, 3-butynyl and 4-pentynyl sulfides cyclize cleanly to the five -membered ring while 5-hexynyl sulfides give exclusively the six-membe red ring, The products arising from these alkynyl sulfide ring closure s are believed to be formed under kinetic control. The methodology has been applied to the synthesis of unusual bicyclic beta-lactams relate d to the penicillin family of antibiotics.