Electrophilic Addition to the Nitrogen Atom

The lone-pair electron on the nitrogen is responsible for electrophilic reactions on its side. Thus, heterocyclic nitrogen atom of quinoline and isoquinolines react with electrophiles, as alkyl halides, alkyl sulfates, alkyl-toluene-p-sulfonates, etc., providing quinolinium and isoquinolinium salts. 

This method was used for the late introduction of ethyl group on nitrogen atom of quinoline core in the synthesis of oxolinic acid antibacterial.  

Another reaction affording the hydrazine function on quinoline or isoquinoline core is feasible by the nucleophilic attack of nitrogen atom to 2,4-dinitrophenyl 0-hydroxylamine in the presence of potassium carbonate, as this was well presented in the synthesis of amifloxacin antibiotic.  

Reaction of peracids with quinolines and isoquinolines affords the corresponding A-oxides. Typical conditions are treatment of heterocycles with RCO2H in the presence of H2O2 at -100 C or /w-CPBA at 0 C. The quinoline/isoquinoline nitrogen atom reacts less readily with peracids than the tertiary amines. Large substituents and electron-withdrawing groups slow the reaction. 

Whenever an appropriate electrophile is present in the reaction mixture along with an alkyne, the W-alkylated product reacts with the electrophile, producing an intermediate prone for intramolecular nucleophilic cyclization to the quinolinium or isoquinolinium salt as this is demonstrated in the synthesis of pyrrole-isoquinolines through die formation of mesoanionic intermediates. 

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