Isoquinoline ring reactivity

As in naphthalene, a fused benzene ring induces bond fixation. Hence, whereas substituents in the 1-position of isoquinoline (571 note numbering) behave like substituents in the 2-position of the pyridine nucleus, substituents in the 3-position of isoquinoline show reactivity less than that of true a-substituents and about midway between those of 2- and 3-substituents on pyridine (90AHC(47)390). 

Palladium-catalyzed reactions have been used to substitute the isoquinoline ring. With the differential reactivity of the 1- and 3-positions of 1,3-dichloroi.soquinoline regioselective arylation at the 3-position is possible <97JGS(P1)927>. The intramolecular Heck reaction of A-2-bromobenzoyl-1-methylene-1,2,3,4-tetrahydroisoquinoline via a 6-ent/o process provides an entry into the protoberberine ring system <97TL1057>. 

Halogenations of quinoline, isoquinoline, acridine, and phenanthridine will be discussed here. Reaction usually occurs in a homocyclic fused ring rather than in the 7r-deficient pyridine moiety, especially in acidic media. Relatively mild conditions suffice, but under more vigorous regimes radical involvement can result in heteroring halogenation. Substituents are able to modify reactivity and regiochemistry. 

The most reactive position for base-catalyzed hydrogen exchange of the 1-oxide derivatives of quinoline and isoquinoline is the position adjacent to the heteroatom and nearest the fused benzene ring. Thus for isoquinoline 1-oxide the positionalreactivity is given by 1 > >3 > > 4,... 

Quinoline and isoquinoline are benzopyridines. They behave by showing the reactivity associated with either the benzene or the pyridine rings. 

Indole is the fusion of a benzene ring with a pyrrole. Like quinoline and isoquinoline, indole behaves as an aromatic compound. However, unlike quinoline and isoquinoline, where the reactivity was effectively part benzene and part pyridine, the reactivity in indole is modified by each component of the fusion. The closest similarity is between the chemistry of pyrroles and indoles. 

Nucleophilic reagents attack pyridine at the a-position to form an adduct that rearomatizes by dissociation (Scheme 1). Only very strong nucleophiles, e.g. NH2-, RLi, LAH, Na-NH3, react, and for the second step to afford a substitution product (5), conditions that favour hydride loss are required. Adducts formed with hydride ions (from LAH) or carbanions (from lithium alkyls) are relatively more stable than the others at low temperature, and dihydropyridines (6) can be obtained by careful neutralization. Fusion of a benzene ring to pyridine increases reactivity towards nucleophiles, and attack is now found at both a- and y-positions in quinoline (7) and at C-l in isoquinoline (8). This may be attributed to a smaller loss of aromaticity in forming the initial adduct than in pyridine, and thus a correspondingly decreased tendency to rearomatize is also observed. Acridine reacts even more easily, but nucleophilic attack is now limited to the y -position (9), as attachment of nucleophiles at ring junctions is very rare. 

Electrophilic aromatic substitutions Quinoline and isoquinoline undergo electrophilic aromatic substitution on the benzene ring, because a benzene ring is more reactive than a pyridine ring towards such reaction. Substitution generally occurs at C-5 and C-8, e.g. bromination of quinoline and isoquinoline. 

In the following sections structure, thermodynamic aspects, theoretical calculations, spectroscopic properties, reactions, syntheses, and, more briefly, the uses of these tricyclic ring systems are discussed. Within the individual subsections of reactivity, synthesis, and applications, the pyrim-ido[l,2-6]isoquinolines, pyrido[2,l-6]quinazolines, pyrimido[l,2-a]quino-lines, pyrido[l,2-a]quinazolines, and pyrimido[2,l-a]isoquinolines are considered. 

The decreasing reactivity of the most familiar aromatic heterocyclic compounds with nucleophilic reagents may be illustrated by the following sequence quinoxaline > acridine > phenanthridine > isoquinoline > quinoline > pyridine. Acridine is alkylated in the 4-position, phenanthridine and quinoxaline in the a-position, isoquinoline in the 1-position, and quinoline and pyridine in the 2- or 4-positions. Weaker nucleophilic reagents seem to enter the 4-position of the pyridine and quinoline rings. If the addition occurs readily and in good yield, the intermediate dihydro derivative may sometimes be isolated otherwise, the product of the subsequent oxidation results. In synthetic work the dihydro derivative is usually directly oxidized. 

The reaction of the fused 5,7-dihalopyrimidine (19) to form the 7-methoxy derivative (20) also shows that the more readily displaced chlorine is next to the azole ring (67T675). Hydrazinolysis of the isoquinoline analogue (21) is stepwise with initial 4-substitution (22). The difference in reactivity at C-4 and C-6 in (22) is sufficient for selective acid hydrolysis of the hydrazino group in (22). Reductive cleavage of the hydrazino C—N bond is achieved in the usual manner by the reaction of its tosyl derivative with alkali (75JCS(Pi)2l90). 

Space restrictions mean that the reactivity of multiheteroatom systems or fused systems where both rings are heterocyclic cannot be covered in this section - the reader is referred to the relevant CHEC volumes. Space again dictates that the chemistries of oxygen- and sulfur-containing six-membered heterocycles, and the chemistry of monocyclic six-membered heterocycles with more than one heteroatom, are only briefly indicated alongside the description of pyridine/quinoline/isoquinoline chemistry, but especially where these are not shown by the pyridine prototypes, but again the reader should study the CHEC volumes for a full discussion. The inclusion of an extra heteroatom in a six-membered system exaggerates the effect of the first and so often it is possible to predict properties by extrapolation however, the same is not true for the five-membered systems, so these heterocycles with more than one heteroatom are considered in detail and separately. 

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