Isoquinolinium salts nucleophilic addition

The Zincke salt (A -(2,4-dmitrophenyl) salt) of isoquinoline is easily transformed into chiral isoquinolinium salts on reaction with chiral amines - an ANRORC sequence in which the ninogen of the chiral amine ends up as the nitrogen of the isoquinolinium product - nucleophilic addition of Grignard reagents to these salts shows good stereoselectivity. ... 

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. 

The use of solvents more polar and nucleophilic than benzene, e.g. ethanol, increases the electrophilicity of the sterically more-accessible position 3 because of the interaction of the cation with the solvent, and the addition of primary amines occurs in position 1. Thus, one may conclude that decarboxylation of salts 62 in the reaction with primary amines occurs by a preliminary addition of nucleophile, whereas the decarboxylation of isoquinolinium salts 161 to 162 proceeds by a ylide mechanism as is shown here. As known, the latter pathway requires the use of stronger bases and more elevated temperatures (79MI3). 

Interestingly, a-carboxy-substituted monocyclic pyrylium salts 195, probably because of a lower tendency towards nucleophilic addition in comparison with 2-benzopyrylium salts (Section III,C,1), react via two pathways. One is similar to reactions of 2-benzopyrylium salts (a), and the other resembles the behavior of isoquinolinium salts (b) (Section III, C,4,a,ii). In this case, monocyclic five-membered acyloins 198 were obtained in 15-40% yield. Obviously, their formation occurs by initial addition of amine (pathway a). The difficultly obtainable a-unsubstituted py-... 

The tendency for relatively easy nucleophilic addition to the pyridinium ring in isoquinolinium salts is echoed in the cycloaddition (shown above) of electron-rich dienophiles such as ethoxyethene, which is reversed on refluxing in acetonitrile. "... 

More practically significant, are the many examples of nucleophilic addition to salts in which an N-substituent conjugates with the nitrogen, and thus stabilizes the product - Reissert compounds were the first examples. These are produced by cyanide addition to an iV -acyl-quinolinium or -isoquinolinium salt in the classical process the acylating agent is benzoyl chloride. Reissert compounds are traditionally prepared using a dichloromethane-water two-phase medium improvements include utilising phase-transfer... 

Nucleophilic intramolecular addition of a carbon-silicon bond onto a carbon-nitrogen iminium ion is the key step of a berbine synthesis <82CC769,83H(20)417>. Thus, treatment of the isoquinolinium salt (235) with caesium fluoride in ethanol afforded (+)-xylopinine (237), presumably via the betaine (236) (Scheme 45). A silicon-directed intramolecular cyclization of a A-acyliminium ion (238) was also the key step of Speckamp s synthesis of (+)-epilupinine as shown in Scheme 46 <85JOC40I4>. 

The Zincke salt of isoquinoline is easily transformed into chiral isoquinolinium salts on reaction with chiral amines.Nucleophilic addition of Grignard reagents to these salts shows good stereoselectivity. " ... 

The predominant property of these salts is the ease with which nucleophiles add to the quinolinium-2-and the isoquinolinium-1-positions. Such additions are favoured in these bicyclic compounds since the products retain a complete aromatic benzene ring. Hydroxide, hydride and organometaUic nucleophiles aU add with facility, though the resulting dihydroaromatic products require careful handling if they are not to disproportionate or be oxidised. " This approach can give 2-nifluoromethyl-quinolines CFj carbanion (from trifluoro(trimethylsilyl)methane and fluoride) is added to an A -(para-methoxybenzyl)-quinolinium salt, then the A -substituent is removed and oxidation to the aromatic level achieved with ceric ammonium nitrate. ... 

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