6,7-Dimethoxy-1,2,3,4-tetra hydroisoquinoline

A second degradative approach was more informative, for the products obtained accounted for all thirty-seven carbon atoms of the alkaloid. Permanganate oxidation of 0,0-dimethylliensinine (LXIV) afforded p-methoxybenzoic acid, l-oxo-2-methyl-6,7-dimethoxy-1,2,3,4-tetra-hydroisoquinoline, and a compound (O-methylliensinic acid) which was found to have structure LXX, mainly by degradation to 4,5,5 -tri-carboxy-2,2 -dimethoxydiphenyl ether. Similarly the permanganate oxidation of 0,0-diethylliensinine (LXV) yielded p-ethoxybenzoic acid and the acid LXXI (0-ethylliensinic acid). The above data revealed the constitution of the alkaloid to be as indicated in formula LXIII. 

The alkaloid was synthesized by the Ullmann condensation of l-(3 -bromo - 4 - benzyloxybenzyl) - 2 - methyl - 6,7 - dimethoxy -1,2,3,4 - tetra-hydroisoquinoline (XXXIV) and l-(4 -benzyloxybenzyl)-2-methyl-6-methoxy-7-hydroxy-l,2,3,4-tetrahydroisoquinoline (IX) followed by removal of the benzyl groups (40). 

Reaction of 2-cyanomethylpyridine with iV-(l-aryl-l-chloro-2,2,2-trifluoroethyl)-iV -(4-methylphenyl)carbodiimides, and with (1,1,2,2,2-pentachloro- and l,l-dichloro-2,2,2-trifluoroethyl)isocyanates or A-methoxycarbonyl-l,2,2,2-tetrachloro-, — l-chloro-2,2-trifluoroacetaldehyde imines afforded 3-aryl-4-cyano-l-(4-methylphenyl)imino-3-trifluoromethyl-2,3-dihydro-17/-pyrido[l,2-f]pyrimidines and 4-cyano-3-trichloro-, 4-cyano-3-trifluoro-17/-pyrido[l,2-4pyrimidin-l-ones, respectively <2004CHE47>. Refluxing 2-cyanomethylpyridine and iV-(l-aryl-l-chloro-2,2,2-trifluoroethyl)isocyanates in benzene furnished l-aryl-4-cyano-l-trifluoromethyl-l,2-dihydro-3//-pyrido[l,2-4pyrimidin-3-ones. However, when the solution of the isocyanate was added dropwise to the solution of 2-cyanomethylpyridine, and the reaction mixture was then treated with NEt at room temperature, the isomeric 3-aryl-4-cyano-3-trifluoromethyl-2,3-dihydro-l//-pyr-ido[l,2-dpyrimidin-l-ones were obtained. Reaction of l-(acetyl- and benzoylmethylene)-6,7-dimethoxy-l,2,3,4-tetra-hydroisoquinolines with PhCONCS yielded 1-acetyl-, 1 -benzoyl-9,10-dime thoxy-3-pheny 1-6,7-dihydro-2//-pyrimido[6,l- ]isoquinoline-2-thiones <2003SL2369>. 

The reduction of the isoquinolinium ring was shown to occur more rapidly than that of the carbonyl group of a 1-aroyl substituent. Thus the reduction of l-(3,4-dimethoxybenzoyl)-6,7-dimethoxy-2-methyl-isoquinolinium methosulfate (64) in aqueous sodium carbonate gave l-(3,4-dimethoxybenzoyl)-2-methyl-6,7-dimethoxy-l,2,3,4-tetra-hydroisoquinoline (65). In alcohol, both the ring and carbonyl groups underwent reduction.74... 

The alkaloid was found to contain two methylimino groups, seven methoxyl groups, and one diphenyl ether linkage. Oxidation of fetidine with permanganate gave l-oxo-2-methyl-6,7-dimethoxy-l,2,3,4-tetra-hydroisoquinoline. Reduction with sodium in liquid ammonia furnished (+ )-laudanosine (XLI) and (-I- )-laudanidine (XXXII). Thus it was concluded that the alkaloid is represented by formula LII, or a variation of this formula having the ether linkage attached to C-10 or C-14. 

Final proof of the structure of tetrandrine came when the alkaloid was subjected to the sodium in liquid ammonia reaction (127, 133). The two products d-l-(4 -methoxybenzyl)-V-methyl-6,7-dimethoxy-l, 2,3,4-tetra-hydroisoquinoline (XXXIX) and d-l-(4 -hydroxybenzyl)-iV-methyl-6-methoxy-7-hydroxy-l,2,3,4-tetrahydroisoquinoline (XL) were isolated. It is thus evident that the structure of tetrandrine must be represented by XXX. However it was also proved (126) that isotetrandrine is represented by the same structure (XXX) and that its cleavage products are... 

Oxidation with ceric nitrate has been developed as a new degradative procedure in the study of bisbenzylisoquinoline alkaloids. This reagent splits lau-danosine to veratric aldehyde and the N-methyl-6,7-dimethoxy-3,4-dihy-droisoquinolinium ion, isolated as veratryl alcohol and N-methyl-3,4-dimethoxytetrahydroisoquinoline after reduction. In the same way, tetrandrine, hernandezine, and O-methylmicranthine have been degraded to the bis-tetra-hydroisoquinolines (48 R = H), (48 R = OMe), and (49), the second product in each case being the diphenyl ether (50). ... 

A degassed soln. of 2-(o-acetoxybenzoyl)-6,7-dimethoxy-l-methylene-l,2,3,4-tetra-hydroisoquinoline in fert-butanol irradiated 1.5 hrs. in a Rayonet photoreactor with 3000 A lamps -V product. Y 80%. F. o-substituents, also with unsubst. enamides, s. G. R. Lenz, Tetrah. Let. 1973, 1963 elimination of methoxyl s. I. Ninomiya, H. Takasugi, and T. Naito, Heterocycles 1, 17 (1973). 

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