Quinolines nucleophilic substitution, regioselectivity

Reactions of benzodiazines show no exceptional features compared with the simple diazines. Reactivity towards electrophiles is less than in quinoline and isoquinoline. If S Ar reactions take place, they lead to substitution of the benzene ring. As a rule, nucleophilic substitution of benzodiazines occur in the diazine ring, particularly if substituted by halogen. The quinazoline system displays C-4 regioselectivity, e.g. in the reactions of 2,4-dichloroquinazoline with amines or alcohols ... 

By contrast, substitution in position 7 is much easier thanks to the well-known Minisci reaction, which involves a nucleophilic radical attack on a protonated quinoline [31]. Moreover, due to the unavailability of position 2 of the quinoline nucleus, the reaction shows complete regioselectivity. Minisci alkylation with an ethyl radical produced in situ by decarbonylation of propionaldehyde is a crucial step in the process of preparation of irinotecan (4) (Scheme 16.6) [32], whereas the same kind of reaction led to the semisynthesis (Scheme 16.7) of gimatecan (9)[33], silatecan (10)[34], and belotecan (ll)[35j. This last compound entered clinical practice in Korea in 2005. 

The reaction of nucleophilic radicals, under acidic conditions, with heterocycles containing an imine unit is by far the most important and synthetically useful radical substitution of heterocyclic compounds. Pyridines, quinolines, diazines, imidazoles, benzothiazoles, and purines are amongst the systems which have been shown to react with a wide range of nucleophilic radicals, selectively at positions a and 7 to the nitrogen, with replacement of hydrogen. Acidic conditions are essential because N-protonation of the heterocycle both greatly increases its reactivity and promotes regioselectivity towards a nucleophilic radical, most of which hardly react at all with... 

It has recently been demonstrated that bromo-tns-pyrrolidino-phosphonium hexafluorophosphate (PyBroP) can be functiOTiing as a mild activator of azine N-oxide providing regioselective addition of Ai-nucleophiles (amines, sulfonamides, and NH-heterocycUc compounds) to pyridine, quinoline, and isoquinoline N-oxides (Scheme 53) [112,113]. A strong regiochemical preference for the orf/io-substitution pattern in aU these cases is likely caused by specific electrostatic attraction of nucleophilic species and the intermediate phosphonium salt 76. This synthetic procedure was successfully extended for other types of nucleophilic reagents (phenols, thiols, malonates). 

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