4- Aminoquinazoline

The ultraviolet spectrum of 4-aminoquinazoline has been interpreted to support the amino structure. ... 

Morley and Simpson prepared quaternary salts from 4-phenoxy-quinazoline and 6- and 7-nitro-derivatives of 4-anilino- and 4-acet-amido-quinazohne. 6-Nitro-4-aminoquinazoline, however, could not be quatemized under the fairly mild conditions used by the... 

Aminoquinazoline was reacted with isopropylidene ethoxymethylene-malonate (422) in DMF at ambient temperature for 1 hr, then at 110°C for 10 min to give isopropylidene 4-quinazolinylaminomethylenemalonate in 69% yield (81EUP30156). 

Aminoquinazolines (R and R1 = H, Cl) were reacted with EMME at 150°C for 2 hr to give a mixture of 4-quinazolinylaminomethylene-malonates (1072) and pyrimido[l,2-c]quinazolinecarboxylates (1073) (81EUP30156). 

The application of the Chichibabin amination to effect a direct amination of quinazoline has been reported. It gives 4-aminoquinazoline (60MII) as well as 2,4-diaminoquinazoline (59GEP958197). No mechanistic details were discussed, but it can be expected (based on the experience with the amination with 4-phenyl- and 5-phenylpyrimidine) that amination of quinazoline would also involve, at least partly, participation of the Sn(ANRORC) mechanism. Amination with N-labeled potassium amide/liquid ammonia will certainly shed some light on the mechanism operative in this Chichibabin amination. 

Seijas, J. A., Vazquez-Tato, M. P., and Martinez, M. M. (2000) Microwave-enhanced synthesis of 4-aminoquinazolines. Tetrahedron Lett. 41, 2215-2217. 

Lapatinib, another 4-aminoquinazoline, is a dual ebB l/erbB2 kinase inhibitor. It is currently undergoing Phase III clinical trials for several cancers. 

Substituted 4-aminoquinazolines 847 can be prepared by combining 2-aminobenzonitriles 846 with nitriles under basic conditions <2000JME2227, 2005SC2481>, and a microwave-assisted procedure is now available that enables these compounds to be produced very efficiently <2000TL2215>. 

A one-pot procedure for the synthesis of 4-aminoquinazolines 771 from 2-aminobenzonitrile 770, ammonium acetate, and trialkyl orthoesters under solvent-free microwave conditions has been developed <2006JHC913>. Product yields are comparable to those obtained under thermal conditions, although reaction times are significantly shorter. An attempt to extend the method to include aromatic orthoesters was unsuccessful. 

A similar rapid microwave one-pot synthesis of substituted quinazolin-4-ones was also reported, which involved cyclocondensation af anthranilic acid, formic acid (or an orthoester) and an amine under solvent-free conditions (Scheme 3.37)61. A complimentary approach was adopted to synthesise 4-aminoquinazolines in very good yields, involving the reaction of aromatic nitrile compounds with 2-aminobenzonitrile in the presence of a catalytic amount ofbase (Scheme 3.38)62. The reactions were performed in a domestic microwave oven and required only a very short heating time. A microwave-assisted synthesis of a variety of new 3-substituted-2-alkyl-4-(3H)-quinazolinones using isatoic anhydride, 2-aminobenzimidazole and orthoesters has also been described (Scheme 3.38)63. 

Aminoquinazolin-2(l//)-one 1-oxide is obtained in the reaction of 2-isocyanatobenzonilrilc with hydroxylamine. ... 

Ethyl 2-(trichloroacetamido)bcnzoate and 2-(trichloroacetamido)benzonitrile 10 on treatment with ammonium acetate in dimethyl sulfoxide at 90-95 C undergo cyclization to quinazoline-2,4(1//,3-ff)-dione and 4-aminoquinazolin-2(l/7)-one 11, respectively. ... 

Aminoquinazolin-2(17T)-one 3-oxide undergoes a Dimroth rearrangement to give quin-azolin-2,4(l//,3//)-dione 4-oxime on heating in dimethylformamide. ... 

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-... 

A study of all the stages in the synthesis of 4-aminoquinazolines from isatoic anhydride, via anthranilamide and o-aminobenzonitrile, made possible the preparation of these compounds by a one-pot synthesis. The anhydride was treated with ammonia in dimethylformamide, nitrogen was then bubbled through the solution to remove excess of ammonia, phosphoryl chloride was added and heated at 40°-60°C for conversion into the nitrile, and finally the respective amine was added to yield the 4-(substituted-amino)-quinazolines in 44-79% yields. ... 

In a novel transformation the j8-oximes of isatins gave o-N, N -dimeth-ylaminomethyleneaminobenzonitriles (13) with the Vilsmeier reagent (Me2NCHO—POCI3), The nitriles were cyclized to 4-aminoquinazolines with ammonium acetate in 70-80% yields. ... 

The yields in the former reactions were generally higher. Intramolecular cyclization of o-unsubstituted aniline derivatives to give quinazolin-2(lH)-ones had never been reported. Recently, however, V-phenyl-V -acyl ureas (21) lacking in ortho-substituents in the benzene ring were cyclized to 4-substituted quinazolin-2(l//)-ones in polyphosphoric acid at 90°-130°C. 4-Aminoquinazolin-2(l//)-ones were prepared by a Chichibabin reaction (NaNHj) from quinazolin-2(l//)-ones. ... 

The kinetics of deamination of 4-aminoquinazoline to quinazolin-4(3H)-one was studied in detail at various potassium hydroxide concentrations. In 0.05-1.0 M potassium hydroxide the rate was first-order with respect to both the amine and hydroxide ion concentration, but in 1.0-3.0 M potassium hydroxide the rate increased more rapidly than was expected from a first-order dependence on the hydroxide ion concentration. " ... 

Methylation of 4-aminoquinazoline 3-oxide, prepared from 4-methoxy-quinazoline and hydroxylamine, produced a 1 1 mixture of 4-imino-3-methoxy-3,4-dihydroquinazoline (19%) and 3-methoxy-4-methylimino-3,4-dihydroquinazoline (18%). These were reduced with Raney nickel to 4-amino- and 4-methylaminoquinazoline, respectively. 

Aminoquinazolines are of considerable medicinal interest and may be synthesized by a one-pot reaction from isatoic anhydride (isatoic anhydride have been reviewed [3(X)8]. 

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