5.6- Disubstituted-pyrimidin-2,4-diones

Methyl 5-(3-fluorophenyl)-7-methyl-l,2,3,4,5,8-hexahydropyrido[2,3-tetrahydro derivative 137 by the action of sodium nitrite in acetic acid <1994T8085>. Oxidation of 2,7-disubstituted-5-trifluoromethyl-l,2-dihydropyrido[2,3-r/]pyrimidin (3//)-ones using active Mn02 in CH2CI2 gave the corresponding pyridopyrimidin-4(3//)-ones 138 <1995IJB587>. 

H NMR and IR data have been reported for 3,6-disubstituted 4-aminopyrimido-[5,4-cf]pyrimidine-2,8-diones. The NMR spectra of these compounds exhibit the presence of three NH protons which are exchangeable with deuterium oxide. One of these arises from the external nitrogen ca. S 11.3), and two result from the NH groups in the ring (ca. S 8.0 and 7.8) (78JOC3231). 

The electrophilic substitution reactions of 1,3-dimethylpyrrolo[3,2-coupling yield 7-substituted products. However, nitration in acetic acid gives primarily attack at position 6. In some reactions 6,7-disubstitution is observed [95CHE(30)1077]. 

A novel and versatile solid-phase synthesis of pyrimido[4,5- fJpyrimidine-2,4-diones has been reported <03S1739>. The key step is the reaction of the support-bound pyrimidine with isocyanates, involving formation of a carbamate intermediate, followed by a base-catalyzed intramolecular ring closure to give the polymer-bound pyrimidopyrimidines which are used in subsequent reactions providing 1,3-disubstituted 7-amino derivatives. 

Treatment of 2-substituted 3-amino-4-cyano-2,4a,5,6,7,8-hexahydro-l/f-pyrido[l,2-c]pyrimidin-l-ones (130) with acyl chlorides afforded tricyclic 3,5-disubstituted 2,5,6,8,9,10,ll,lla-octahydro-l//-pyrido[l,2-c]pyrimido[5,4-e]pyrimidine-l,6-diones (131) (90MI3 93MI1, 93MI3). 

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). 

Still other SAR studies included pyrimido[4,5-d]pyrimidine-2,4(l//,3//)dione and 2,4(l//,3//)-pteridinedione nucleosides as antiviral agents, 2-ary 1-6,8-disubstituted-quinazol-4(3//)-ones as fungicides <97IJHC51>, 3-N-substituted-thioureido-2-methyl-6-phenylthieno-[3,2-d]pyrimidin-4(3//)-ones <97JIC160> and 2-(dialkylamino, piperidino, morpholinomethyl)-... 

Sodium alkoxide-mediated reaction of 2,2-disubstituted [2- C]malonates with urea and thiourea produces (Figure 6.121), respectively, 5,5-disubstituted (lH,3H,5H)-[5- C]pyri-midine-2,4,6-triones 406 (or 5,5-disubstituted [5- " C]barbiturates) and the corresponding 2-thioxo-(l//,5fl)-[5- " C]pyrimidine-4,6-diones 407. some of which have been widely... 

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