Condensed isoquinolines. 21. Condensation of o-bromomethylphenylacetonitrile with substituted anthranilic acids

Abstract

Keywords: anthranilic acid, o-bromomethylphenylacetonitrile, 7,12-dihydro-5H-isoquino[2,3-a]-quinazolin-5-one, enamine.We have previously developed a relatively simple procedure for the synthesis of isoquino[2,3-a]quinazoline system derivatives via the reaction of o-bromomethylphenylacetonitrile (o-BMPA) with the ester and nitrile of anthranilic acid. The properties of 7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-one (1) prepared by this method have been studied in a series of publications [1,[4][5][6][7][8][9][10]. Isoquinoquinazoline 1 shows high reactivity towards electrophilic reagents [4-8] being readily reduced by NaBH 4 to 6,6a,7,12-tetrahydro derivatives [4,9] and also readily oxidized to give aromatic derivatives [1, 5, 10]. All of these reactions affecting principally the N (6) -C (6a) -C (7) triad permitted preparation of a series of isoquino[2,3-a]quinazolines substituted at positions 6 and 7. We made attempts to carry out classical aromatic electrophilic substitution reactions. However, because of the high tendency of compound 1 to oxidize not depending on reaction conditions, these experiments led to tarring or to formation of a complex mixture of unidentified products. The only solution to this problem was the use of substituted starting reagents in the synthesis of the isoquinoquinazolines 1. With this in mind we have studied the interaction of o-BMPA with substituted anthranilic acids and their esters.The reactions were carried out by the previously reported method [2] of melting an equimolar mixture of reagents at 130-150ºC or by heating their solutions in 2-propanol. The use of the unsubstituted anthranilic acid 2c gives the 7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-one hydrobromide (1c) which was identical in constants and spectroscopic properties with that obtained before. The reaction in this case needed a longer heating time or higher melting temperature and the yield of the target product proved a little lower (by 15-20%) than when using the ester and this is fully consistent with the lowered reactivity when compared with the ester.

Condensed isoquinolines 25. Alkylation of 6,11-dihydro-13H-isoquino[3,2-b]quinazolin-13-one

“…It should be noted that in the case of isoquino [3,2-b]quinazoline 1 this reaction occurs quite easily (20-40 min at 120-150°C) and with high yield (60-80%). Whereas for other condensed 3-aminoisoquinolines -benzimidazo[1,2-b]isoquinolin-11(5H)-one, which exists predominantly in the "enamine" form [3] and 7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-one, which exists as a mixture of tautomers [7] -alkylation products were not formed with these olefins. One possible reason for this is the difference in reactivity of these heterocycles as proton donors in reaction with proton acceptors -anhydride and imides of dicarboxylic acids.…”