4-Aminoquinazoline , synthesis

The linearly fused benzologues, pyrimido[2,l-A]quinazolines, are most frequently synthesized from a 2-amino- or 2-iminoquinazoline. Synthesis from [6+0] atom fragments by bond formation 7 to the ring junction nitrogen takes place when the 2-aminoquinazoline bearing a suitable substituent at N-3 is cyclized. The 2-iminoquinazoline-3-propionates 197 cyclized on treatment with alkali to give 198 (Scheme 31) <1997EPP0778258>. 

The 2,3-dihydro-6/7-pyrimido[2,l-A]quinazolin-4(177)-ones 201 were obtained in a one-pot synthesis from the iminophosphorane 199 and isocyanate, through the 2-aminoquinazoline 200. Yields were good (R1 = H, Rz = c-hexyl) to excellent (R1 = Rz = Ph) (Equation 21) <1996TL9071>. 

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

Although 3-aminoquinazoline derivatives are normally prepared de novo from hydrazine starting materials, they can also be prepared by N-amination reactions. Thus, treatment of l-substituted-2,4(177,377)-quinazolinediones 32 with 0-aryl hydroxylamines under basic conditions gives 3-amino-l-substituted-2,4(177,377)-quinazolinediones 33 which are intermediates in the synthesis of 3-amino-2,4(l/7,3/7)-quinazolinedione antibacterial agents <20020PD230, 2005JHC669, 2006JME6435>. 

Aminoquinazolines can be prepared by the reaction of guanidine with 2-aminobenzaldehydes, although yields are only moderate, as shown by the synthesis of 2-amino-5-bromoquinazoline 841 which occurred in only an 18% yield <2003JA2084>. 

Cyanamide can also be used as a source of the C(2)-N(3) unit, to give 2-aminoquinazolines, and good results can be achieved in condensations with 2-aminoketones <2000BML1317, 2005JOC8764>, as shown by the 97% yield achieved in the synthesis of the 2-amino -piperidinyl derivative 845 from the aminoketone 844 <2000BML1317>. 

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. 

Cyclization of 3-aminoquinazoline-4-thiones (375) with carbon disulfide gave the zwitterionic l,3,4-thiadiazolo[3,2-c]quinazoline (376) (771JC(B)1110]. Synthesis from properly functionalized 1,3,4-thiadiazole precursors was also reported [83JCS(P1)2011], according to which the 2-(2-nitrophenyl)-l,3,4-thiadiazoles (377) were reduced and cyclized to 378. 1,3,4-Thiadiazoloquinazolines were shown to exhibit amebicidal... 

Synthesis according to the first approach requires quinazoline precursors with an appropriate subtituent on position 2 or 3 which, upon cyclization, forms the terminal pyrimidine ring. Thus, 2-aminoquinazolin-4(3//)-one (505) underwent cyclization with a,j8-unsaturated acids (78KGS105 80MI1) or their chlorides (87KGS1527) to the pyrimido... 

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. 

Cyclocondensation routes also provide access to pyrimidines. 2,3-Disubstituted pyrido[2,3-/i]-quinazolin-4(3//)-ones are obtained via cyclocondensation of 5-aminoquinoline-6-caiboxylic acid with acid chlorides <02SC235>. 5,6,8-Trialkyl-7-methoxy-2-aminoquinazolines are obtained from 1,3-dimethoxybenzenes via cyclocondensation of intermediate dihydrobenzenes with guanidine carbonate <02TL3295>. Diastereoselective intramolecular hetero Diels-Alder cyclization of a pyrazole carboxaldehyde condensed onto 1,3-dimethylbarbituric acid (101) gave polycyclic heterocycle 102 <02T531>. An efficient one-step synthesis of cyclobutene-annelated pyrimidinones 103 from methyl 2-chloro-2-cyclopropylideneacetate and amidines has been... 

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." ... 

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. ... 

Hie cyclic anhydride (80.4) reacts with trimethylsilyi azide under anhydrous conditions to give a mixture of I,3-oxazine-2,6-dione isomers, which was used without further purification to synthesis several extended purines. Reaction with formamidine acetate in DMF in effect replaced the furandione ring by a pyrimidinone. Cyanamide produced a new fiued 2-aminopyrimidin-4-one [in (80.5, R = NH )], while urea led to a pyrimidinedione. Isatoic anhydride similarly yields 2-aminoquinazolin-4-one on treatment with cyanamide-DMF. 

A common method for the preparation of 2,4(1//,3//)-quinazolinediones (627) consists of fusion of anthranilic acid derivatives with urea (Scheme 100). The benzene ring is frequently substituted . The most satisfactory synthesis of 2-aminoquinazoline (628) is by the reaction of guanidine carbonate with o-aminobenzaldehyde in boiling decalin. Cyanamide or dicyanamide can be used instead of guanidine carbonate . 

Niementowski reaction was also used in the first step of the synthesis of a series of 4-aminoquinazoline derivatives (54), which were evaluated for their anti-proliferative properties against several types of tumor cells. 

Scheme 61 Synthesis of 2-amino-4(3/f)-quinazolinones, 2-aminoquinazolines and 4-ammoqui-nazolines via Cul-catalyzed N-arylation of guanidines...

Fu et al. have extended the above strategy to the synthesis of 2-amino-4(3//)-quinazolinones 176 and 2-aminoquinazolines 177 by using guanidines 175 as the coupling partners [105], and assembly of 4-aminoquinazolines 178 by coupling amidine hydrochloride salts 172 with 2-bromobenzonitrile [106] (Scheme 61). 

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