Isoquinolinium salts aluminum hydrides

Lithium aluminum hydride reduction of pyridinium salts is very similar to sodium horohydride reduction and gives similar products, but the ratio of 1,2- and 1,4-dihydro- or tetrahydropyridines differs considerably (5). Isoquinolinium salts are reduced hy sodium borohydride or lithium aluminum hydride in a manner identical to pyridinium salts (5). Quino-linium salts are reduced by sodium borohydride to give primarily tetra-hydroquinolines (72) as shown by the conversion of 33 to 34 and 35. When lithium aluminum hydride is used, the product is usually the dihydroquinoline (73) as shown in the conversion of 36 to 37 and 38. 

The reduction of 2-substituted-isoquinolinium salts has been reported by Torossian65 with potassium borohydride in water, by Mirza,68 and by Durmand et al.,87,68 using sodium borohydride in aqueous methanol to yield 1,2,3,4-tetrahydroisoquinolines. The reduction of the second double bond appears to arise from a mechanism similar to that leading to tetrahydropyridines from pyridinium ions (see Section I). Mirza66 (see also Bose60) found that the reduction of berberine (60) with sodium borohydride could be stopped at the 1,2-dihydro-intermediate (61), and Karrer and Brook70 showed that the 1,2-dihydroisoquinoline formed by the lithium aluminum hydride reduction of l-phenyl-2-methylisoquinolinium iodide (62) could be further reduced to the 1,2,3,4-tetrahydroisoquinoline (63) with sodium borohydride in methanol. Awe et al.71,72 and Huffman73... 

B. Reduction of Isoquinolinium Salts with Lithium Aluminum Hydride... 

Isoquinolinium salts are reduced to 2-alkyl-1,2-dihydroisoquinoline derivatives by sodium dithionite,6 lithium aluminum hydride7,8 (LAH), or dialkyl aluminum hydrides.9 LAH is preferred7 to dithionite since it leads to purer products, and will reduce those salts that are inert to dithionite (e.g., papaverine methiodide). Isoquinoline itself10,11 and 3-methyl-6,7-methylenedioxyisoquinolinelz (5) can be reduced to the 1,2-dihydroisoquinoline with LAH, as can isoquinoline... 

Intramolecular cyclization. Reduction of a 2-(3-aminopropyl)isoquinolinium salt (1, n = 2) with lithium aluminum hydride in ether gives the new heterocycle... 

Hofmann degradation, styrene 468 was formed. Epoxidation of 468 with m-chloroperbenzoic acid from the less hindered side and lithium aluminum hydride reduction gave ( )-epicorynoline (469). Moreover, slow addition of the a-methoxystyrene 471 to isoquinolinium salt 470 gave cycloadduct 472 in 90% yield. The adduct was hydrolyzed by acid and the resultant aldehyde oxidized to naphthoic acid by Jones oxidation. Modified Curtius rearrangement of 473 with added benzyl alcohol afforded benzyl urethane 474, which was reduced by lithium aluminum hydride and formylated with chloral to give 0-methylarnottiamide (475) (Scheme 60). 

The success of the approach depends on the ability of lithium aluminum hydride to reduce the isoquinolinium salt LXXX smoothly to the corresponding 1,2-dihydroisoquinoline. The 1,2-dihydroisoquino-... 

A simple route to the berberine ring system has been described recently by Dyke and Brown (118, 119). Treatment of the isoquinolinium salt LXXXII (R = H) with aqueous base, and without isolation of the intermediates LXXXIII (R = H) and LXXXIV (R = H), gave on treatment with hydrochloric acid 2,3-dimethoxyberbine (LXXXI) and the lactam LXXXV (R = H). Evidence for the structure of the lactam was obtained from its reduction by lithium aluminum hydride to LXXXI and by its dehydrogenation to the isocarbostyril LXXXVI, which had been prepared by an independent route from LXXXI via LXXXVII, according to the scheme shown in Chart IV. The isolation of the lactam LXXXV from the reaction is interesting and illustrates an unusual acid-catalyzed cyclization of the intermediate isocarbostyril LXXXIII (R = H). By employing the simple modification of reducing this intermediate to LXXXIV (R = H) before cyclization, a 50% yield of 2,3-dimethoxyberbine was realized. 

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