4- Amino-2-phenylquinazolines

The substituent effect on tautomerism of benzene ring-substituted 4-amino-2-phenylquinazolines 91 has been studied by 1H NMR spectroscopy in DMSO-<7rt solution. It was shown that, in contrast to compounds with electron-donating substituents (R = 6-Me, 7-Me, 6-MeO, 7-MeO), which mainly occur in the imino form, aminoquinazolines with electron-withdrawing substituents (R = 6-N02, 7-N02, 6-Br, 6-C1) exist as amino-imino tautomeric mixtures (00M895). 

Nitriles can also be substituted for formamide. Benzonitrile and 2-aminobenzonitrile, autoclaved at 200°C, gave a moderate yield of 4-amino-2-phenylquinazoline (see 1). This reaction resembles, and is competitive with, the dimerization of aminonitriles discussed above it also proceeds by a similar mechanism. Other examples are the condensation of 3-cyanopyridine with 2-amino-3-cyanopyridine to give 2-(3-pyridyl)-4-aminopyrido[2,3-d]-pyrimidine (see 3) and of 5-cyano-l-methyl-4-aminoimidazole (see 18) with... 

Vega developed an efficient synthesis of pyrazolo[3,4- /]pyrimidines based on the electrophilic properties of nitrilium salts formed by reaction of 5-aroylaminopyrazoles, nitriles and Lewis acids. Treating iminolyl halides with nitriles with SnCU gave rise of the nonisolated nitrilium salts, which underwent cyclization to generate the desired pyrazolo[3,4-i/]pyrimidines in moderate to good yields. A similar approach was extended to the preparation of 4-amino-2-phenylquinazolines via cyclization of V-arylbenzamides with cyanamide catalyzed by TiCU. ... 

Amino-l-benzylindazole and NaH refluxed 16 hrs. under Ng in diethylene glycol dimethyl ether 4-amino-2-phenylquinazoline. Y 68%. N. Finch and H. W. Gsdiwend, J. Org. Chem. 36, 1463 (1971). 

It has been established that the conversion of 2-chloro-4-phenylquinazo-line into 2-amino-4-phenylquinazoline by treatment with potassium amide/liquid ammonia also occurs with ring opening (74RTC227).This was proved by the experimental result that in the 2-amino compound obtained from 2-chloro-4-phenyl[3- N]quinazoline, about 70% of the label is present in the amino group, i.e., formation of 2-[ N-amino]-4-phenylquina-zoline (83) see Scheme 11.36. 

Cyclization of quinazolin-4(3//)-one with an excess of methyl isocyanate gave the 1,3,5-triazino[ 1,2-u]quinazoline-1,3,6-trione (643) (84H501). A one-pot synthesis of 1,3,5-triazino[ 1,2-u ]quinazolines (645) was carried out by reacting 2-amino-4-phenylquinazolines (644) with chlorocarbonyl isocyanate (85S892). 

A suspension of 2-amino-A -benzoylbenzamidine (5, R = Ph 2.39 g, 10 mmol) in H O (20 mL) was acidified with a few drops of 10% aq HCl to give a clear yellow solution which changed to colorless after a few seconds. The solution was made alkaline and 2-phenylquinazolin-4-amine precipitated yield 2.20g (90%) mp 145-146"C overall yield (4 6) 79%. 

On treatment with ammonia or primary amines, 6-substituted 2-chloromethyl-4-phenylquin-azoline 3-oxides 1 undergo rearrangement to 2-amino derivatives of 7-substituted 5-phenyl-3//-1,4-benzodiazepine 4-oxide 2, Reaction with secondary amines proceeds without rearrangement with formation of the expected 2-(aminomethyl)-4-phenylquinazoline 3-oxides (cf. Section 6.3.1.1.10.3.). 2o. s2i... 

Haloquinazolines also react with amide ion in ammonia to give amino substitution products by an ANRORC process. Nitrogen labelling studies indicate that about half of the 4-aminoquinazoline resulting from 4-chloroquinazoline forms by an Sn(ANRORC) route. Amide ion must add to the unsubstituted 2 position prior to ring opening, Eq. (11).50 Similarly, 2-chloro-4-phenylquinazoline gives 2-amino-4-... 

Using ethanolic ammonia at 160 °C it was shown that, depending on the ammonia concentration, 34—67% of the 2-amino-4-phenylquinazoline produced from the chloro compound arises by a ring opening process. 2-Chloro- and 4-chloroquinazo-lines also undergo a ring opening substitution pathway in ethanol-ammonia.47 Thus, the Sn(ANRORC) mechanism is not limited to amide ion in ammonia. 

The copper acetate-catalyzed aerial oxidation of 4-substituted-amino-6-hydroxy-2-phenylquinazolines in methanolic solution containing piperidine or dimethylamine gave the 5,6-quinones (17) in 64-79% yields. Some of these were also formed when 6-acetoxy-4-chloro-2-phenylquinazoline was oxidized under similar conditions. The 5,6-quinones (17) can be hydrolyzed by base to the 6-hydroxy-5,8-quinones (18) in high yields. They dimerize to the intermediate 6,6 -biquinazolinyl-5,8-quinones on prolonged heating at 80°-90°C, and these cyclize to form benzofuran derivatives. ... 

Hydrazine transformed the 3-oxide 105 into the benzotriazocine 108, which was reduced to the corresponding 2-amino derivative with Raney nickel. The related 3JT-4,l,5-benzoxadiazocine-2-one oxime 109 was obtained from 106 by treatment with hydroxylamine but, unlike 108, ring-contraction occurred on reduction with Raney nickel, and 6-chloro-2-hydroxymethyl-4-phenylquinazoline was produced. ... 

Soon after he had discovered his synthesis of quinazolines from aminoal-dehydes, Bischler turned to the amino ketones to obtain quinazolines with alkyl or aryl substituents in the 4-position (see 1). He showed that JV-acyl derivatives of 2-aminobenzophenone, heated at 170°C with ethanolic ammonia, furnished 4-phenylquinazolines,96 and 2-aminoacetophenone behaved similarly.97 However, it was later found that such severe conditions were unnecessary, for 4-methylquinazoline was produced quantitatively from 2-formamidoacetophenone and ethanolic ammonia at 20°C in 18 hr, and 2,4-dimethylquinazoline was similarly prepared (from 2-acetamidoaceto-phenone) in 5 days.81... 

Amino-5-chlorobenzophenone oxime, stirred at 20°C with dimethyl acetylenedicarboxylate, gave a good yield of the dimethyl ester of 2-carboxy-6-chloro-l,2-dihydro-4-phenylquinazolin-2-acetic acid (96).116... 

Benzamidobenzamide was converted to 2-phenylquinazolin-4-one by heating at 250°C for 1 hr (no yield given).207 Difficulty in closing the ring was experienced when one or both of the amino groups were secondary.208... 

N-Methylformamide converted 2-aminopyridine-3-carboxylic acid to 3-methylpyrido[2,3-d]pyrimidin-4-one (5 hr at 180°C) in good yield.290 The same reagent also made 3-methyl-6-nitroquinazolin-4-one from 2-amino-5-nitrobenzoic acid in excellent yield some slowly reacting 2-aminobenzoic acids were assisted with phosphoryl chloride.291 A moderate yield of 3-phenylquinazolin-4-one was obtained from the action of formani-lide on 2-aminobenzoic acid (90 min at 140°C).282... 

Most of the work described here has been done with guanidine. In one of the few amidine examples, methyl anthranilate and N,jV -diphenylformami-dine gave 3-phenylquinazolin-4-one in excellent yield when heated at 155°C for 45 min. The authors state that the initial attack is on the amino group.282... 

Ethyl chloroformate and methyl anthranilate, heated 15 hr at 100CC, were converted quantitatively to methyl 2-ethoxycarbonyl aminobenzoate (181), which was converted to quinazoline-2,4-dione in excellent yield by heating in ethanolamine for 40 min at 160°C.341 Urethane (ethyl amino-formate) and ethyl JV-phenylanthranilate, when heated at 220°C for 1 hr, gave an excellent yield of l-phenylquinazoline-2,4-dione.342... 

The 1- and 3-(hydroxypropyl)-2-aminodihydroquinazolines are also cyclized to the angular and linear benzologue, respectively, by treatment with SOCI2. However, from 2-(3-hydroxypropyl-amino)quinazoline a mixture of (144) and (60) was formed in which (144) predominated (Equation (47)) <79CPB880>. Only the angular derivative was obtained from 6-chloro-2-(3-hydroxy-propylamino)-4-phenylquinazoline <73NKK1944>. 

A mixture of 2-amino-5-chlorobenzophenone s u-oxime, acetone, and a little cupric sulfate pentahydrate refluxed 2 hrs. crude 6-chloro-l,2-dihydro-2,2-dimethyl-4-phenylquinazoline 3-oxide (Y 80 ) suspended in 3 iV HCl, and stirred 2 hrs. at room temp. crude 2-amino-5-chlorobenzophenone anti-oxime (Y 80%). F. e. s. G. F. Field, W. J. Zally, and L. H. Sternbach, J. Org. Chem. 30,3 7 (1965). 

Quinazoline-2-carboxaldehydes. A suspension of 3-acetoxy-7-chloro-2-methyl-amino-5-phenyl-3H-1,4-benzodiazepine in dil. HGl stirred and heated 10 min. at 85° 6-chloro-4-phenylquinazoline-2-carboxaldehyde. Y 49%. F. e. s. L. H. Sternbach et al., J. Org. Ghem. 29, 332 (1964). 

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