K. Orito*, M. Miyazawa, H. Suginome
1995
Citations
0
Influential Citations
3
Citations
Journal
Heterocyclic Communications
Abstract
e/7iAr»-l-(^Hydroxy-2-bromo-3,4-dimetho\ybenzyl)-6,7-dimethoxy-2-methyl-1^3,4-tetrahydroisoquinoline l a was almost quantitatively converted to 2,3,8,9-tetramethoxy-5,6-dihydroindolo[2,l-a]isoquinoline 2ä by heating with potassium carbonate in Ν,Ν-dimethylformamide. This one pot cyclization provides a new entry to the construction of indolo[2,l-a]isoquinoline skeleton characteristic of alkaloids, such as cryptaustoline and cryptowoline, isolated from Cryptocaria bowiei. Indolo[2,l-a]isoquinolines have a structural feature of alkaloids, such as cryptaustoline and cryptowoline, isolated from the bark of Cryptocarya bowiei (1). Syntheses of these unique tetracyclic compounds have been accomplished by several methods, such as a benzyne reaction (2) of l-(2-bromo-4,5-dialkoxybenzyl)isoquinbolines oxidative coupling of 1-benzylisoquinolines (3), and enamine photocyclization (4), which have been known to give either 9,10-dialkoxyindolo[2,l-a]isoquinolines or a mixture of 9,10and 10,11-dialkoxysubstituted derivatives. Our present method is able to produce 8,9-dialkoxyindoloisoquinolines selectively. In connection with our synthetic study of heterocyclic compounds involving aromatic metallation, erythro-1 -(^-hydroxy-2-bromo-3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline l a was treated with palladium diacetate, triphenyl phosphine and excess potassium carbonate in boiling DMF in an atmosphere of carbon monoxide for 3 days (5). However, the expected carbonylation leading to the formation of a phthalide ring did not occur at all, and instead, a new compound 2a having no N-methyl group was obtained. After careful examinations to clarify the reaction pathway, it was found that this reaction took place smoothly without CO gas, Pd(OAc)2 and PPI13. On the basis of the Ή and C NMR analysis in comparison with reported spectral data (2f), the structure of this exclusive product 2a was determined to be 2,3,8,9tetramethoxy-5,6-dihydroindolo[2,l-ö]isoquinoline 2a. This was also supported by measuring the Nuclear Overhauser Effect as follows. Irradiation of the signal of the proton at position 12 (δ 6.67) resulted in an enhancement of the signal areas of 1-H (20%, δ 7.18) and 11-H (10%, δ 7.24). Irradiation of the doublet signal of the proton at position 10 (δ 6.81) resulted in an enhancement of the signal areas of the aforementioned 11-H (19%) and the methoxy protons (14%, δ 3.95) at position 9. Methylenedioxy derivative lb (6) was also transformed to indoloisoquinoline 2b under the conditions described above in a good yield. Both N-H lc (6) and N-benzyl i d (5) derivatives remained unchanged. This reaction requires a fairly high nucleophilicity of the nitrogen atom but not a bulky N-substituent. Isoquinoline le, having no hydroxy group at its benzyl position, was unreactive. Isoquinoline 3a,b, having no alkoxyl group, at the 3' position was also unreactive, while the benzyne reaction converted them to 9,10-dialkoxyindoloisoquinolines (2a. d). In the preliminary experiments, when a mixture of 2a and its threo isomer (5) were subjected to the present cyclization, the threo isomer seemed to remain unchanged, although a small amount of the threo may have been consumed in the production of 2a through isomerization to the erythro l a (7). Thus,