Salts isoquinolinium

Organometallic reagents react with iminium salts to give C-alkylated products. The reactions can be divided into two categories the reactions of pyridinium, quinolinium, and isoquinolinium salts and the reactions of... 

A review of the literature prior to 1953 on reactions of pyridinium, quinolinium, and isoquinolinium salts is available (31). The reactions will be described here only briefly. The initial observation was that of Freund et al. (32-37), who found that treatment of various derivatives of hydra-stinine (15) with Grignard reagents yielded addition products, such as 16. 

Since the initial discovery there have been several investigations that have examined the Grignard reaction with quinolinium and isoquinolinium salts... 

Tn general, quinolinium salts (21) give produets from addition at the 2 position (22) and isoquinolinium salts (23) give products from addition at the 1 position (24). 

The reaction of quinolinium and isoquinolinium salts with dialkyl cadmium has been observed to be slow and occurs in relatively poor yield. The structures of the products are the same as those obtained from reactior with Grignard reagents and the yields ranged from 0-20% (40). Leadini references to other observed reactions of quinolinium and isoquinoliniuir salts with Grignard reagents can be found in the above cited review (31). 

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 disproportionation reaction of isoquinolinium salts to 1,2-dihydro-isoquinolines and isocarbostyril derivatives (Scheme 16) was used by Brown and Dyke for the synthesis of berberine and 8-oxoberberine derivatives (277-279). 

The addition (150-157) of Grignard reagents, alkoxides, hydroxide, sulfides, cyanide, and enolate anions to pyridinium and isoquinolinium salts again provides a variety of cyclic enamines of potential synthetic use. 

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. 

Zincke-type salts derived from other aromatic nitrogen heterocycles also undergo Zincke reactions. The isoquinolinium salt 6 (Scheme 8.4.16) permitted incorporation of a phenyl ethylamine chiral auxiliary, providing salt 48. In this context and others (vide infra), Marazano and co-workers found that refluxing -butanol was a superior solvent system for the Zincke process. Additionally, the stereochemical integrity of the or-chiral amino fragment was reliably maintained. 

The same reaction with the isoquinolinium salt 338 (under the same conditions) furnishes l-acetyl-3-ethoxycarbonylpyrrolo[2,l-a]isoquinoline (339) in 72% yield. 

The lipophilicity (7 m value) and specific hydrophobic surface area of pyrido[l,2-a]pyrazinium-l-olates 342 and -3-olate 343, and l-(4-chlorophe-nyl)-l-hydroxy-l,2-dihydropyrazino[2,l-a]isoquinolinium salt (344) has been measured by reversed-phase thin-layer chromatography (98MI13). Partition coefficient (log/ ) of 9-bromo-5-[(A-phenylaminocarbonyl)-methyl]-l,2,3,5,6,7-hexahydropyrido[l,2,3- fc]quinoxaline-2,3-dione was calculated to be 2.78 (97JMC4053). 

Substituted 4-aryl-1 -oxo-1,2-dihydropyrazino[l, 2-i]isoquinolinium salts 402 were obtained when 3-substituted isoquinolines 401 were cleaved from a polymer by treatment 25% TFA (00MIP5). c/i-3,lla-H-3-Phenyl-1,2,3,4,11,11 fl-hexahydropyrazino[l, 2-i]isoquinoline-1,4-dione (404) formed when isoquinoline derivative 403 was cleaved from a resin with 25% TFA during an automated solid-phase synthesis (98BMCL2369). 

While 3-arylisoquinolin-l(2fl)-ones 87 are obtained by air oxidation of 3,4-dihydroisoquinolinium salts, the use of DDQ in dioxane results in a selective dehydrogenation to the corresponding -substituted isoquinolinium salts 88 <95T(51)12721>. 

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%. 

Two transformations should be discussed in more detail (1) presence of the amino group in 275 was utilized for the synthesis of the fused isoquinolinium salt 276 bearing the bicyclic heterocycle as an A-substituent <2003JHC1041> (2) selective nucleophilic substitution of 277 with pyrrolidine was reported <2001ZOR604> to yield only substitution on the phenyl substituent without formation of an amide from the ester group 278. 

Based on NMR evidence as well as analogy with results obtained with isoquinolinium salts, it appears certain that adducts (6) obtained from vinyl ethers invariably have the alkoxyl group turned away from the quaternary nitrogen or, in other words, are syn with respect to the... 

The most recent extension of the 4 + 2 cycloaddition to aromatic quaternary salts has been carried out with isoquinolinium salts (42), in effect, dispensing with ring A of the acridizinium ion. Although there was an earlier claim that the addition of an ynamine to 2-methyl-isoquinolinium iodide led to a 2 1 adduct, the assigned structure... 

When simple isoquinolinium salts without substituents in the 3-position are used, the adducts (e.g., 46) are more reactive to nucleophiles than is the starting material and, almost without exception, undergo attack by another mole of the alkene. In the light of these observations it would be desirable to have a reexamination of the products obtained by Fuks et al (by addition of ynamines to isoquinolinium salts) to make certain that the initial addition is really 2 + 2 and not 4 + 2. 

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). 

Stable anhydro bases, e.g. (64), can be formed from 1-alkyl- or 1-benzyl-isoquinolinium salts on treatment with alkali the reaction is reversed in acid. 9-Methylacridinium salts similarly form stable anhydro bases, e.g. (65 Scheme 52). 

Like acridinium salts, isoquinolinium salts disproportionate very easily in alkaline solution. In an extensive study. Bunting and Kabir (78JOC3662) investigated the crossed disproportionation of 166 with 167 to give 168 and 169 (Scheme 27). 

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. 

Homophthalaldehyde (188) gives isoquinoline, isoquinoline 2-oxide, 3,4-benzopyrylium salts, and 2-alkyl- and 2-aryl-isoquinolinium salts (189) by reaction with NH3, NH2OH, H+ or RNH2, respectively. 

Cyclization of 1-isoquinolyl derivatives (201) in a cold solution of perchloric acid or in cone, sulfuric acid at room temperature afforded 4-hydroxy-3,4-dihydro-2//-[l,3]thiazino[2,3-a]isoquinolinium perchlorates (202) and 2H-[l,3]thiazino[2,3-a]isoquinolinium salts (203), respectively (74IJC1242). Heating l-[(3-phenyl-3-hydroxypropyl)thio]isoquinoline in PPA yielded the l-phenyl-3,4-dihydro-2//-[l,3]thiazino[2,3-a]isoquin-olinium salt (74IJC1242). 6,7-Dihydro derivatives of 2//-[l,3]thiazino-[2,3-a]isoquinolinium perchlorate (203, R = Me) and 4-methyl-2,3,4,6,7, llh-hexahydro-[l,3]thiazino[2,3-a]isoquinoline were obtained by cyclization of the 3,4-dihydro derivative of 201 (R = Me) and 4-[(l,2,3,4-tetrahydroisoquinolin-l-yl)thio]-2-butanol, respectively, in cone, sulfuric acid or in PPA [81IJC(B)372],... 

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