Heterocyclic Compounds Ring Expansion Reaction

In this thesis , a general procedure for the ring enlargement of N-heterocycles with the net result of -CH₂- insertion was improved. The procedure involved three consecutive steps: the preparation of the N-cyanomethyl quaternary ammonium salts by N-alkylation of the N-heterocycles with BrCH₂CN or ICH₂CN, Stevens rearrangement of the N-cyanomethyl quaternary ammonium salts by NaH in anhydrous THF, and the reductive decyanization of the intermediate α-amino nitrile by NaBH₄ in EtOH.When the general procedure was tested on such N-heterocycles as 7,8,13,13a-tetrahydro-5H-isoindolo[1,2-b][3]benzazepine analogs, brucine, strychnine , (±)-tetrahydroberberine , 5,7,11b,12-tetrahydroisoindolo [1,2-b] [3] isoquinoline analogs ,2-methyl-2,3-dihydroisoindole and 2-methyl-2,3-dihydro-1H-isoindole-1-spiro-2'-indan analogs , expected results were obtained . In some cases, competitive reactions such as Hofmann elimination or Stevens rearrangement with cyanomethyl migration occurred.When the general procedure was tested on such N-heterocycles as Hydrastine ,no ring enlaregement occurred.Based on the general procedure, three synthetic routes to four kinds of alkaloid analogs were designed. In each route, the key intermediate 5,7,11b,12-tetrahydroisoindolo[1,2-b][3]isoquinoline was obtained in four steps from catechol ,and the aimed molecules were obtained from the key intermediate via ring enlargement. For the 5,7,11b,12-tetrahydroisoindolo[1,2-b][3]isoquinoline analogs lead only to 7,8,13,13a-tetrahydroisoindolo[1,2-b][3]benzazepine analogs , only three kind of alkaloid analogs were obtained. Thus, 7,8,13,13a-tetrahydro-2,3,10,11-tetramethoxy-5H-isoindolo[1,2-b][3]isoquinoline (27) was obtained via seven steps, 5,6,8,9,14,14a-hexahydro-2,3,11,12-tetramethoxyisoquino[1,2-b][3] benzazepine (32) via ten steps, and 2-methyl-1,2,3,4-tetrahydro-4',5',6,7-tetramethoxy-1H-isoquinoline-1-spiro-2'-indan (37) via 9 steps.The key intermediate a-amino nitrile and some by-products were also examined by elemental analysis, MS, ¹HNMR and ¹³CNMR, the mechanism of the ring enlargement was also investigated.