Isoquinolinium salts borohydrides

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. 

Sodium borohydride reduction of 4-substituted isoquinolinium salts led to vinylogous cyanamides, ureas, and urethanes, as well as the corresponding tetrahydroquinolines (640). Hydrogenation of /8-acylpyridinium salts (641) to vinylogous ureas was exploited in syntheses of alkaloids (642), leading, for instance, to lupinine, epilupinine, and corynantheidine (643, 644). Similarly, syntheses of dasycarpidone and epidasycarpidone were achieved (645) through isomerization of an a,/0-unsaturated 2-acylindole and cyclization of the resultant enamine. 

Dihydrogambirtannine (337) has been achieved via two routes from N-[2-(indol-3-yl)ethyl]isoquinolinium salts. Wenkert and co-workers (183) first synthesized the stable intermediate 339, which could be hydrolyzed, decarboxy-lated, and cyclized in one step by the use of aqueous alkali to ( )-337. In a very similar approach, Beisler (184) caused the isoquinolinium salt 340 to react with sodium borohydride and sodium cyanide, and the resulting intermediate 341 was immediately treated with strong acid. This one-pot reaction gave ( )-di-hydrogambirtannine in an overall yield of 83%. 

Nucleophilic addition takes place at C-1, and this is considerably enhanced if the reaction is carried out upon an isoquinolinium salt. Reduction with lithium aluminium hydride [tetrahydroaluminate(III)] in THF (tetrahydrofuran), for example, gives a 1,2-dihydroisoquinoline (Scheme 3.15). These products behave as cyclic enamines and if isoquinolinium salts are reacted with sodium borohydride [tetrahy-droboronate(III)] in aqueous ethanol, further reduction to 1,2,3,4-tetrahydroisoquinolines is effected through protonation at C-4 and then hydride transfer from the reagent to C-3. 

Sodium borohydride is the reagent of choice for the reduction of the pyridine ring in isoquinolinium salts. It reacts so rapidly that even the carbonyl group of a 1-aroyl substituent can survive (equation 154) (63JCS2487). A 1,2-dihydro intermediate has been isolated during the cyclization of (253) to 2,3-dimethoxyberbine by sodium borohydride, which suggests that a similar mechanism to that described above is operative here (equation 155) (60JOC90). 

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... 

When isoquinolinium salts are reduced with sodium borohydride (NaBH4) under the usual aqueous-ethanolic solvent conditions, tetrahydroisoquinolines (8) are produced. The 1,2-dihydroisoquinoline (6) is formed first, and this can14 be protonated by the solvent to 7... 

With some 4-substltuents reduction with borohydride does not proceed past the dihydro adduct even in protic solvents. Certain l-(2-nitrophenylmethyl)isoquinolinium salts, e.g. (73), have been found to undergo substituent cleavage on reduction with borohydride. ... 

However, l-benzyl-3-cyanoquinolinium bromide (168) gives a 75% yield of the 1,4-dihydro adduct 169 when reduced with NBH and allowed to equilibrate in the presence of the parent quinolinium salt. 1,4-Dimethyl-2-methylaminoquinolinium iodide (170) undergoes hydride attack at the 2 position with borohydride to give the product 171 as an unstable yellow oil. Alstonilin or benz[ ]indolo[2,3-fl]chinolizidine-type alkaloids (173) have been successfully prepared in high yields from the isoquinolinium salt 172 via hydride reduction. ... 

A shorter and neater synthesis of (+ )-dihydrogambirtannine involved the multiple-phase reduction of the isoquinolinium salt 78 with sodium borohydride in a methanol-ether—water system in the presence of a high concentration of cyanide ion. The intermediate, presumably the cyanide (79) formed by trapping of the initially generated dihydroisoquinoline derivative by nucleophilic cyanide ion, was not isolated but was converted directly into ( )-dihydrogambirtannine (67) by heating in dilute hydrochloric acid. Dehydrogenation of the stable hydrochloride of 67 by means of iodine and sodium acetate afforded an improved route... 

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