Application of Azide-Tetrazole Tautomerism and Arylsulfanyl Group Dance in the Synthesis of Thiosubstituted Tetrazoloquinazolines

Nucleophilic aromatic substitution reaction between 4-aryl-thio-2-chloroquinazolines and NaN3 takes place with an unusual sulfanyl group dance and leads to the formation of 5-(arylthio)tetrazolo[1,5- c]-quinazolines, which do not form the azide tautomer and do not undergo CuAAC reactions with alkynes. On the other hand, 5-azidotetrazolo[1,5-a]quinazoline (formally described as 2,4-diazidoquinazoline) undergoes regioselective nucleophilic aromatic substitution with thiols at C5 and forms 5-(alkyl/arylthio)tetrazolo[1,5-a]quinazolines, the structure of which has been proved by X-ray crystallography. The latter exist in tautomeric equilibrium with their 2-azidoquinazoline form, which provides possibility for copper-catalyzed azide-alkyne 1,3-dipolar cyclo-addition reaction, leading to the 4-alkyl/arylthio-2-(1H-1,2,3-triazol-1-yl)quinazolines.

Automated summary

The nucleophilic aromatic substitution reaction between 4-aryl-thio-2-chloroquinazolines and NaN3 leads to the formation of 5-(arylthio)tetrazolo[1,5-c]-quinazolines, which do not undergo CuAAC reactions with alkynes. On the other hand, 5-azidotetrazolo[1,5-a]quinazoline undergoes regioselective nucleophilic aromatic substitution with thiols at C5, forming 5-(alkyl/arylthio)tetrazolo[1,5-a]quinazolines. This allows for a copper-catalyzed azide-alkyne 1,3-dipolar cyclo-addition reaction to produce the 4-alkyl/arylthio-2-(1H-1,2,3-triazol-1-yl)quinazolines.