Isoquinolinium salts, reduction

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. 

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. 

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). 

Aporphines may be prepared through a similar ring closure. N-Methyl-l-(2 -iodobenzyl)isoquinolinium salts (69) can be reduced in acetonitrile126 at a potential more negative than the second peak, according to Eq. (57). The electron consumption is 2.0 Fmol-1, and two hydrogen atoms are expelled during the reaction, so that the net uptake of electrons is 0. Catalytic reduction of 70 produces aporphine. 

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

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... 

The reduction of isoquinolinium salts to 1,2-dihydroisoquinolines was first reported by Schmid and Karrer78,79 and has been exploited many times.80-82 The novel and practical application of this inter-... 

The reduction of isoquinolinium salts by complex metal hydrides... 

Methods of synthesis of bisbenzylisoquinoline alkaloids have been reviewed83 and the use of electrochemical methods for the reduction of the dihydro-isoquinolinium salts that result from Bischler-Napieralsky ring-closures in the synthesis of, for example, espinidine has been studied.84... 

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

Qulnolinium salts (68 Scheme 15) can undergo attack at either the 2- or 4-position. The former normally predominates and the latter leads to 1,2,3,4-tetrahydroquinolines (69). 3-Substituents generally produce mixtures of the 1,2- and 1,4-dihydro adducts. Isoquinolinium salts (70 Scheme 15) produce both 1,2-dihydrolsoqulnolines (71) and 1,2,3,4-tetrahydroisoquinolines (72). Reduction in protlc solvents normally produces the tetrahydro adducts, in anhydrous pyridine or dimethylformamide the reduction generally stops at the 1,2-dihydroisoquinoline. Reaction of the enamine system of 1,2-dihydroisoqui-nollnes with electrophiles has been used as a method for generation of 4-substituted isoquinolines. 

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. ... 

Quinolinium and isoquinolinium salts form predominantly 1,2-dihydro products with LAH reductions in aprotic solvents. With the latter the enamine system revealed is amenable to functionalization... 

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). 

Isoquinolinium saV., 3,4-dihydro-2-methyl-1-substituted reduction, 2, 44 i Isoquinolinium salts, 2-methyl-reactions... 

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. ... 

The reduction of isoquinolinium salts in aprotic solvents with LAH leads to the formation of 1,2-dihydroisoquinolines (195), in which the enamine system can undergo subsequent reaction with electrophiles. This type of reactivity has been exploited in the synthesis of alkaloids. ... 

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. 

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... 

Similar reduction-ring expansion was carried out with variously substituted isoquinolines, the acetic acid being replaced by propionic acid.176 Goeber et al.m expanded the ring of the isoquinolinium salt 183 (R = H, OMe A = OH) on treatment with phenyldiazomethane in methanol to prepare 35 (R1 = R2 = H R3 = Me R4 = Ph R6 = OMe R6 = H, Me R7, R8 = O-CHr-O). Similarly, 183 (R = H, A = C104) treated with diazomethane gave a mixture of 184 and 184a. The crude mixture of these... 

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