5.6- Disubstituted quinazoline-2,4-diones

The trimethyluracil (193) reacts with DMFDMA to afford the enamine (194), which reacts with dienophiles to give 5,6-disubstituted quinazoline-2,4-diones (195), via [4 + 2] cycloaddition followed by elimination of dimethylamine, and oxidative aromatization, as shown in Scheme 45 (89CB1673). 

Quinazoline is oxidized rapidly by xanthine oxidase to quinazolin-4(3//)-one which subsequently is oxidized more slowly to quinazoline-2,4(l//,3//)-dione. Quinazoline is also oxidized to quinazolin-4(3//)-one by rabbit liver aldehyde oxidase but the reaction ceases within a short time it appears that quinazoline is able to inactivate the aldehyde oxida.se, Quinazolin-4(3//)-one is rapidly oxidized by aldehyde oxidase to quinazoline-2,4(l//,3//)-dione. Various 6-substituted and 6,7-disubstituted quinazolin-4(3//)-ones are quantitatively oxidized to the respective quinazoline-2,4(l//,3//)-diones by buttermilk xanthine o.xidase, ° Biotransformation of quinazoline by a mutant strain of the bacterium Pseudomonas putida gives quinazolin-4(3//)-one, c(s-5,6-dihydroquinazoline-5,6-diol, and cis-5,6,7,8-tetrahydroquinazoline-5,6-di-... 

Several examples are known of the ring-expansion reactions that transform isatins into quinazolines. iV-Carbamoyl isatins rearrange in the presence of amines into derivatives of 4-carboxy-4-hydroxy-3,4-dihydroquinazolin-2(lH)-ones, and iV-carbamoyl-3-(dicyano)methylene oxindoles provided 4-(dicyano)methylene-3,4-dihydroquinazolin-2(l//)-ones. The two isomeric A-oxides 102 and 103 underwent ring expansion on photolysis and produced the same 1,3-disubstituted quinazoline-2,4-diones (104) among other products, which include isatins. The ratio of products was sensitive... 

In contrast, the 2-position of 2,4-dichloroquinazoline is more reactive than the 4-position for the attack by tertiary amines. The reaction of 2,4-dichloroquinazoline with A -substituted cyclic amines thus affords cyclic A,iV-disubstituted 4-chloroquinazolin-2-amines 9 and, in the case of A -methylpyrrolidine, the ring-opened derivative 10. The regioselectivity of this reaction is considered to be determined by the steric nature of 2,4-dichloroquinazoline and is in good accord with that of the reaction of quinazoline-2,4(l//,3//)-dione with A-substituted cyclic amines in combination with phosphoryl chloride (cf. p 121). 

In the past year, reviews on 1,8-naphthyridines, perimidines, polyazaphen-anthrenes, 3-azabicyclo[3.3.1]nonanes, and 1,2- and 2,1-benzothiazines have appeared. Reviews on specialist aspects of pyridine chemistry are devoted to the reactions of newly available pyridines, a,a -disubstituted pyridines, the reactions of pyridines with nucleophiles, the electrochemistry of IjT-disubstituted 4,4 -bipyridinium ions (the viologens such as paraquat), dihydropyridines, and 4-aryl-dihydropyridines (a new class of calcium antagonists). Reviews have been published on the cyclization of oximes and amides to quinolines and isoquinolines, quinoline- and isoquinoline-diones, benzo[fl ]- and benzo[c]-quinolizinium ions, azachrysene preparation, quinazolines with plant-growth-regulating and biocidal activities, quinazolines in pharmaceutical research, isotopic hydrogen exchange in... 

Benzoxazines, such as acetylanthranil (177), are sometimes isolated as fleeting intermediates in the conversion of the o-disubstituted benzenes to annelated pyrimidines and hence serve to connect this section with preceding ones. The origin of acetylanthranil and its ready conversion to 2-methyl-quinazoline-2,4-dione have been dealt with in Section VIII,B,3. Related examples include the conversion of other types of benzoxazine to quinazo-lines (Sections VIII,A,6 and VIII,B,3 and of pyridooxazines to pyri-dopyrimidines (Section VIII,A,3), as well as of pyrazolothiazines to pyrazolopyrimidines (Sections VI,B,1 and 2). 

Smil996a Smith, A.L., Thomson, C.G. and Leeson, P.D., An Efficient Solid Phase Synthetic Route to 1,3-Disubstituted (1H,3H)-Quinazoline-2,4-diones Suitable for Combinatorial Synthesis, Bioorg. Med. Chem. Lett., 6 (1996) 1483-1486. 

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