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16.13.1.1.2.2.3 Method 3: From Anthranilic Acid Derivatives and Nitriles

DOI: 10.1055/sos-SD-016-00745

Kikelj, D.Science of Synthesis, (200416586.

2-Substituted quinazolin-4(3H)-ones 5 are conveniently obtained by reaction of anthranilic acids, alkyl anthranilates, or 2-aminobenzamides with a variety of nitriles, e.g. alkyl and aryl nitriles,[‌192‌‌196‌] haloacetonitriles,[‌192‌,‌197‌] aryl cyanates,[‌172‌,‌198‌] cyanamides,[‌199‌‌201‌] alkyl cyanoformates,[‌202‌] dicyan,[‌203‌] and alkyl dicyanoacetates[‌81‌] (Scheme 15). In the older variations of this method, anthranilic acid and a nitrile are heated in a sealed tube at 200°C alone[‌204‌] or in the presence of an anhydride[‌205‌] or carboxylic acid.[‌206‌] The drawbacks of this older variation are moderate yields (usually below 50%) and lack of specificity, since the substituent at position 2 in 5 may originate from the nitrile or from the carboxylic component. An improved method utilizes hydrogen chloride as an acid catalyst or makes use of a basic catalyst, e.g. sodium methoxide[‌197‌] or lithium diisopropylamide.[‌193‌] The reaction presumably proceeds via nucleophilic attack of the amino group of 35 on the nitrile or on a reactive species derived from a nitrile (under hydrochloric acid catalysis, presumably an imidoyl chloride or a nitrilium halide[‌207‌]) to give the ortho-substituted amidine derivative which cyclizes to the corresponding fused pyrimidin-4-one 5. 2-Aryl- and 2-benzylquinazolin-4(3H)-ones are readily accessible in fair yields by reaction of N,N-diethyl-2-nitrobenzamide with appropriate aryl and benzyl halides in the presence of samarium(II) iodide, which selectively reduces the nitro group in the presence of nitriles and thus generates 2-aminobenzamide in situ.[‌208‌]

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