Quinazoline-4-cyano groups

CN/CC replacements were also observed when the pyrimidine ring is part of a bicyclic system. Reaction of quinazoline with active methylene compounds, containing the cyano group (malonitrile, ethyl cyanoacetate, phenylacetonitrile) gave 2-amino-3-R-quinoline (R = CN, C02Et, Ph) (72CPB1544) (Scheme 12). The reaction has to be carried out in the absence of a base. When base is used, no ring transformation was observed only dimer formation and SnH substitution at C-4 was found. 

The treatment of iminodithiazole 96 with alcohol and a base gives quinazoline-2-carbonitriles 97 in good yield (Equation 18). A reasonable mechanism would appear to be addition of alkoxide ion to the cyano group and cyclization with the attack on C-5 of 1,2,3-dithiazole ring followed by elimination of S2 and HCI <1998T6475>. 

The cyano group in position 4 of quinazolines behaves like a halogen towards nucleophilic reagents and can be displaced by a hydroxide anion, alkoxides, amines, hydrazines, and various carbon nucleophiles, o.g. ketones, a-keto esters, dialkyl malonates, nitroalkanes, Gri-gnard reagents, and enamines, to give 4-substituted quinazolines 1. The cyano group of quin-azoline-2-carbonitriles is less reactive for nucleophilic substitution but its displacement has not been intensively studied. Alkaline or acid hydrolysis of quinazoline-4-carbonitriles affords quinazolin-4(3// )-oncs. ... 

The methyl group of 2-cyano-3-methyl-5-phenyl-5,6-dihydro-l//-pyrido-[1,2-a]quinazoline-l, 6-dione condensed with aromatic aldehydes in boiling ethanol in the presence of one drop of piperidine for 5 h to give 3-styryl derivatives (93CCC1953). 

The reaction of various substituted 2-fluorobenzonitriles 1 with guanidine carbonate affords quinazoline-2.4-diamines 2 in excellent yields. It is proposed that this cyclization reaction proceeds by the reversible addition of guanidine to the cyano function followed by nucleophilic displacement of fluoride. The reaction possesses considerable generality and is successful even when electron-donating groups are present at position 6 of the educt... 

The five-membered homolog of 390 (R = R = H, = 0) gave the dimethylaminomethylene derivative 381 upon treatment with dimethyl-amine. The formyl compounds 390 = 0,1) and the dimethylaminomethylene derivatives 392 were transformed by amines, hydrazines, and hydroxylamine into the corresponding 3-aminomethylene derivatives of type 394. - ° The dimethylaminomethylene compound 381 and the formyl derivative 390 (R = R = H, = 0) afforded cyano derivatives 395 on treatment with acetone cyanohydrin. - Compound 395 (R = NMe2) was hydrolyzed to the acetic acid derivative 396 in concentrated hydrochloric acid. Treatment of the (dimethylaminomethylene) pyrrolo-[2,l-i ]quinazoline 381 with formic acid furnished the bis derivative 397. The formyl and dimethylaminomethylene groups of compounds... 

The addition of water (see Section II,B) and other nucleophiles across the 3,4-double bond of quinazoline is well established. More recently other nucleophiles, such as dimedone, have given isolable 3,4-adducts. ° Similarly, malononitrile and other compounds with active methylene groups added across the 3,4-double bond of quinazoline, but in this case the reaction proceeded further with ring opening and formation of 2-amino-3-cyano-quinoline. The dimedone adduct was also made to react further in the presence of alkali to form the acridone 38. ... 

Treatment of the N-cyano-imidates (257) with o-hydrazinobenzoic acid gives triazolo[l,5-a]quinazolines (258). The hydrazine attacks the imidate carbon initially, rather than the nitrile group this contrasts with the preferential reaction at the nitrile function of the similar A -cyano-amidines (221) by amines (see p. 253) (Scheme 103). ... 

A mixture of o-hydrazinobenzoic acid hydrodiloride, ethyl 2-cyano-3-ethoxy-acrylate, ethanol, and water heated 10 min. on a steam bath, and allowed to stand overnight at room temp. ethyl pyrazolo[l,5-a]quinazolin-5(4H)-one-3-carboxylate. Y 85%. F. e., also with amino and cyano in place of alkoxy leaving groups, s. J. B. Wright, J. Heterocyclic Chem. 6, 947 (1969). 

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