Simultaneous Formation of 8H‐Isoquino[2,1‐b][2,7]naphthyridin‐8‐ones and 13H‐Pyrido[4′,3′:3,4]pyrrolo[2,1‐b][3]benzazepin‐13‐ones, a Novel Potential Alkaloidal System

Abstract

155 16. Simultaneous Formation of 8H-Isoquino[2,1-b][2,7]naphthyridin-8-ones and 13H-Pyrido[4',3':3,4]pyrrolo[2,1-b ][3]benzazepin-l3-ones,Condensation of 3,4-dihydro-6,7-dimethoxyisoquinoline (4) with 4-methylnicotinoyl chloride (12) in refluxing pyridine gives 5,6,13,13a-tetrahydro-2,3-dimethoxy-8~-isoquino[2,l-b][2,7]naphthyridin-8-one (Il), along with some of its 13,13a-didehydro derivative 7. A similar reaction of 4 with 4-(chloromethyl)nicotinoyl chloride (14) affords, in addition to 7, the isomeric product 10,l l-dihydro-7,8-dimethoxy-13H-pyrido[4',3':3,4]pyrrolo[2,lb][3]benzazepin-13-one (3). Analogous pairs of products are obtained from 3,4-dihydro-6,7-(methylenedioxy)-and 3,4-dihydro-6,7,8-trimethoxy-isoquinolines (15 and 18, resp.). The structure of 3 was established by extensive NMR data and confirmed by single-crystal X-ray studies. Structure 7 has the ring system of the Alangium alkaloids like alangimarine (l), while the isomeric ring system 3 is predicted to be present in nature on biogenetic reasoning. Introduction. -The alkaloids of Alangium lumarckji THW. represented by alangimarine (1) [ 11 have the interesting 8H-isoquino[2,1-b][2,7]naphthyridin-8-one ring system isosteric with 8-oxoprotoberberines [2]. Alkaloids of the latter group like prechilenine, in the correct oxidation state, were found to rearrange in nature to the isomeric isoindolobenzazepines, e.g. chilenine [3]. Aporhoedane (2) having this ring system was known earlier [4] and was synthesized [5]. Similar biogenetic transformations of Alangium alkaloids can give rise to natural products with the pyrido-[4',3':3,4]pyrrolo[2,l-b][3]benzazepine ring system, typified by 3 which are hitherto unkown in nature or by synthesis.The first approach to the synthesis of isoquinonaphthyridines of type 1 predated the isolation of the alkaloids and involved the irradiation of the enamide of 3,4-dihydro-1methylisoquinoline with nicotinoyl chloride [6]. Subsequently, this reaction was shown to occur also thermally but found to suffer from nonregiospecificity [7]. Notwithstanding this handicap, the thermal cyclization approach was successfully applied to the synthesis of alamarine, isoalamarine, and alamaridine [8]. Alternative approaches which do not suffer from the problem of nonregiospecificity start from the 3,4-dihydro-6,7-dimethoxy-') Present address:

Creative research in the chemical industry – Four decades in retrospect

“…Although 93 and analogues have not been isolated so far from plants, there is reason to believe that they may be produced biogenetically in Alangium lamarcki by rearrangement of 92 and its congeners through a transformation with precedence in protoberberine chemistry. 72…”