STUDY OF THE TRANSAMIDATIVE RING EXPANSION OF N-OMEGA-HALOGENOALKYL-BETA-LACTAMS OF ALKYL CHAIN LENGTHS 2-12 IN LIQUID-AMMONIA AND OTHER LIQUID AMINES - SYNTHESES OF 7-MEMBERED, 8-MEMBERED AND 9-MEMBERED 1,5-DIAZA CYCLIC-KETONES, INCLUDING ROUTES TO (+/-)-DIHYDROPERIPHYLLINE AND (+/-)-CELABENZINE

N-(3-Halogenopropyl)-4-phenylazetidin-2-ones undergo amination in liquid ammonia followed by transamidative ring expansion to give the eight-membered 4-phenyl-1,5-diazacyclooctan-2-one in excellent yield. Ring expansion of the amines in liquid ammonia is found to be much more effective than in hydrocarbon solvents. Formation of 7-, 8-, and 9-membered azalactams from the requisite omega-halogenoalkyl-beta-lactams is an excellent synthetic process, though it is not applicable to 10-membered rings. In the cases of rings of 13-, 15- and 17-members, although amination and apparent expansion takes place, the large rings appear not to be stable to ammonia and the final products are acyclic amides. N-[4-Halogenobut-2(Z)-enyl]-4-phenylazetidin-2-one satisfactorily forms a 9-membered (Z)-olefinic azalactam, but the (E)-isomer gives an acyclic amino amide. By using alkyl-substituted beta-lactam side-chains, C-substituted medium rings can be obtained; the relative instability of N-acyl beta-lactams to ammonia, however, leads to acylamino amides rather than expanded rings. Employing ethylamine in place of ammonia, it is shown that N-ethylated azalactams are formed satisfactorily, and using allylamine, N-allyl medium rings capable of further elaboration are obtained. The chemistry of these systems is discussed. Using transamidation in liquid ammonia, a short synthesis of the 9-membered spermidine alkaloid (+/-)-dihydroperiphylline is reported. Synthesis of key intermediates, whose transformation into the 13-membered alkaloids of the celabenzine group has already been effected, has been carried out. X-Ray single-crystal structure determinations for 4-phenyl-1,5-diazacyclononan-2-one, trans-4-phenyl-8-methyl-1,5-diazacyclooctan-2-one and (Z)-4-phenyl-1,5-diazacyclonon-7-en-2-one are reported, and comment is made on certain conformational features.