2-substituted quinazolines, amidine

Substituted quinazolines 970 have been prepared by treatment of dihydrotriazolines 968 with ammonia, in a process which involves initial thermal ring opening to an amidine 969, and cyclocondensation of the ammonia with... 

Kotsuki and co-workers used amidines to synthesize 2-substituted quinazolines. Reaction of 2-fluoro-5-nitro-benzaldehyde with 4-bromo-benzyl amidine gave the corresponding quinazoline in modest yield. This approach was subsequently used by Kotsuki and co-workers to generate a number of 5-nitro- and 5-cyanoquinazolines in modest yields. 

Lin and coworkers prepared 2-substituted quinazolines via a metal-free oxidative sp C—H/sp C—H cyclization of amidines (Scheme 23) (140L2822). Two methods were developed. Method A uses iodobenzene diacetate as a source of hypervalent iodine(lll) and a nonpolar solvent, toluene. In Method B potassium persulfate is used as the oxidant in the presence of a catalyst, TEMPO, and a polar solvent, acetonitrile. Both methods... 

Quinazolinones are an important class of fused heterocycles that have been reported with remarkable activities in biology and pharmacology such as anticancer, antiinflammatory, anticonvulsant, antibacterial, antidiabetic, hypolipidemic, and protein tyrosine kinase inhibitors. Alper and Zheng reported a palladium-catalyzed cyclocarbonylation of o-iodoanilines with imidoyl chlorides to produce quinazolin-4(3H)-ones in 2008. A wide variety of substituted quinazolin-4(3H)-ones were prepared in 63-91% yields (Scheme 3.27a). The reaction is believed to proceed via in situ formation of an amidine, followed by oxidative addition, CO insertion, and intramolecular cyclization to give the substituted quinazolin-4(3H)-ones. Later on, a procedure was established based on generating the amidine in situ by a copper-catalyzed reaction of terminal allq nes, sulfonyl azide and o-iodo-anilines. The desired quinazolinones can be produced by carbonylation with Pd(OAc)2-DPPB-NEt3-THF as the reaction system. In the same year, Alper s group developed a procedure for 2,3-dihydro-4(lH)-quinazolinone preparation. The reaction started with the reaction of 2-iodoanilines and N-toluenesulfonyl aldimines followed by palladium-catalyzed intramolecular... 

Acetates 5 with an acyl group at position 6 react with amidines, guanidine, C9-alkylisoureas, and 5-alkylisothioureas, respectively, in ethanol to give quinazolin-5-ols 6 in good yields. The synthesis is successful only with 2- and 4-substituted acetates and is especially useful for the preparation of 2-methoxy-, 2-(methylsulfanyl)-, and 2-aminoquinazolin-5-ols." ... 

The reaction with ethylenediamine822 gives 2-substituted imidazolines, which can be regarded as cyclic amidines. The reaction with anthranilic acid also leads to ring closure, since the final products are quinazolines.825... 

In a recent approach 5-acceptor-substituted 2-fluorobenzaldehydes 17 combine with amidines to give quinazolines 18 in an intramolecular SNAr ringclosure process [162]. 

On the other hand, nitriles are widely used as intermediates in the synthesis of many types of heterocycles [7] and other compounds of interest in medicinal chemistry, for example, 3,4-dihydroisoquinolines [8], imidazoles [9], indoles [10], lactim ethers [11], napthyridines [12], pyridones [13], pyridopyrimidi-nes [14], pyrimidines [15], quinazolines [16], quinazolones [17], quinolines [18], sydnones [19], 1,2,4,5-tetrazines [20], tetrazoles [21,22], 1,2,4-triazoles [20], N-substituted amides [23], amidines [24] and basic esters [25]. 

Scheme 60 Synthesis of 2-substituted quinazolinones and quinazolines via Cul-catalyzed N-arylation of amidines...

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