Condensed isoquinolines. 9. Alkylation of 7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones

Abstract

The alkylation of 7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-one (1) by methyl tosylate proceeds at N,,, to give quaternary salt 2a [3]. In a continuation of a study of isoquino[2,3-a]quinazolines, we investigated the alkylation of isoquinoquinazolone 1 by various alkylating agents under different conditions and attempted to study secondary alkylation of the monoalkylation products synthesized in the first step.The alkylation of isoquinoquinazolone 1 with excess ethyl iodide in acetonitrile proceeds also as alkylation at N,,, to give 6-ethyl-5-oxo-7,12-dihydro-5H-isoquino[2.3-a]quinazolinium iodide (2a). The action of triethylamine on salt 2b gave the corresponding anhydrobase identified as 6-ethyl-6,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-one (3b). The IR and *H NMR spectra of 2b and 3b are similar to the spectra of N-methyl analogs 2a and 3a synthesized in our previous work [3, 4], which confirnas their structure. On the other hand, fusion of isoquinoquinazolone 1 with a small excess of benzyl halides at 100-120~ unexpectedly gave hydrohalide salts of 7-benzyl-7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones (4a-4h.HX). Heating solutions of isoquinoquinazolone 1 with phenacyl bromides in acetonitrile at reflux gives hydrobromide salts of 7-phenacyl-7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones (4i.HBr and 4j.HBr). The reaction of isoquinoquinazolone 1 and methyl bromoacetate under the same conditions gave the methyl ester of (5-oxo-7,12-dihydro-5H-isoquino[2,3-a]quinazolin-7-yl)acetic acid (4k.HBr). These salts are converted by the action of triethylamine into free bases 4a-4k. These compounds were identified as C~,~-alkylation products using their *H NMR spectra (Tables 1 and 2), in which A2X and ABX spin systems are found lbr the protons of the CcT~H~CH,-R fragment. The proton at C~7~ in some of the salts such as 4i and 4j are readily exchanged by deuterium. Thus, the signal for this proton is lacking in the spectra of their freshly prepared solutions in deuterotrifluoroacetic acid, while the protons of the 7-CH, methylene group are seen as a two-proton doublet with 18 Hz geminal coupling constant. Complete deuterium exchange is observed for the other salts 4 after letting their solutions stand lbr several days. In all cases, the methylene protons at C~,,~ give two doublets with 16 Hz geminal coupling constant, which is a consequence of the molecular asy~mnetry of the C,7~-alkylation products.

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

“…In the 1 H NMR spectrum of 6,6-dibenzylisoquino[3,2-b]quinazoline 3 ( Table 2) the protons of the methylene groups of the benzyl groups were nonequivalent and were observed as an AB spin system with 2 J = 13.5 Hz. This results, as in the case of the isomeric 7,7-dibenzyl-7,12-dihydro-5H-isoquino(2,3-a)quinazolin-5-ones [4], from spatially restricted rotation of the bulky substituents around the C (6) -C (α′) and C (6) -C (α″) bonds.…”

“…The 6-benzoisoquino[3,2-b]quinazolines 2a-c were identical to those we had prepared previously [4]. In the 1 H NMR spectrum of 6,6-dibenzylisoquino[3,2-b]quinazoline 3 ( Table 2) the protons of the methylene groups of the benzyl groups were nonequivalent and were observed as an AB spin system with 2 J = 13.5 Hz.…”

“…It seemed of interest to investigate the characteristics of this reaction for the linear isomer -6,11-dihydro-13H-isoquino [3,2-b]quinaxolin-13-one (1) which had been shown previously [1] to be ambident as nucleophilic agent with the example of reactions with carbonyls. We had previously [4] obtained the hydrobromides of 6-benzyl-substituted derivatives of compound 1 by rearrangement of the corresponding compounds with an angular structure. However, under the reaction conditions (170-180°C) the process was accompanied by oxidation of both the starting materials and the final reaction products [6].…”

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We have previously studied alkylation, one of the characteristic reactions of enamines, using benzimidazo[1,2-b]isoquinolin-11(5H)-one [2, 3] and 7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-one [4,5] as examples. It seemed of interest to investigate the characteristics of this reaction for the linear isomer -6,11-dihydro-13H-isoquino[3,2-b]quinaxolin-13-one (1) which had been shown previously [1] to be ambident as nucleophilic agent with the example of reactions with carbonyls.

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

“…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].…”