Solvent selection in synthesis of 4-(1-arylfluoroethoxy)quinazolines and thienopyrimidines

•Solvent and base selection studied for coupling of 2-fluorinated 1-arylethanols with quianzolines and thienopyrimidines.•Environmental benign conditions can be used for coupling of fluoro containing alcohols giving high yields.•The 4-(1-arylfluoroethoxy)quinazoline products had higher stability towards base than the non-fluorinated analogues.•The 4-(1-arylfluoroethoxy)quinazolines and the non-fluorinated analogues had comparable low stability towards acid.•No racemisation issues detected during synthesis.

The nucleophilic aromatic substitution of 4-chloroquinazoline and 6-bromo-4-chlorothieno[2,3-d]pyrimidine with 1-aryl-2-fluoroethanols as nucleophilies has been studied focusing on the use of carbonate bases in combination of environmental acceptable solvents. The conversion rate depended on the solvent properties, the acidity of the nucleophile and the nature of the base. By using acetonitrile as reaction medium and K2CO3 as base, 2,2,2-trifluoro-, 2,2-difluoro-, and 2-fluoro-1-phenylethanol could efficiently be coupled to 4-chloropyrimidines. Alternatively, employing Cs2CO3, allowed for shorter reaction time for these substrates, and also couplings of the non-fluorinated alcohols proceeded well. tert-Butanol was also found to be a suitable reaction medium in transformation of the fluoro alcohols. Testing of hydrolytic stability of the 4-alkoxypyrimidines revealed that the fluorinated and non-fluorinated derivatives were labile under acidic conditions, whereas in basic media the fluoroalkoxy derivatives were more stable than their non-fluorinated counterparts.

Graphical abstractCoupling of fluoro containing alcohols to chloropyrimidines can be performed under milder and more environmental friendly conditions than their non-fluorinated counterparts. The product 4-(fluoroalkoxy)pyrimidines in basic medium possesses higher stability than the parent compound.Figure optionsDownload full-size imageDownload as PowerPoint slide