Pyrido triones

The most satisfactory method involving this type of intramolecular electrophilic cyclization was the thermal ring-closure of aminomethylenemalonates (e.g., 119, R = COOEt) to yield the pyrido[3,2-d]pyrimidine-2,4,8(l/7,3/f,5/f)-trione (120, R = COOEt). 

Reduction of 2,3,6,7-tetrahydro-177,5i/-pyrido[3,2,l-//]quinazoline-l,3,7-trione and 7-chloro-6-formyl-2,3-dihydro-177,5i/-pyrido[3,2,1 -(/]quinazo-line-l,3-dione with NaBH4 in THF in the presence of 60% aqueous solution of NaOH gave 7-hydroxy and 7-chloro-6-hydroxymethyl derivatives, respectively (01MI28). 

Treatment of pyrimidine-2-thione 193 with AICI3 in PhN02 yielded 2-(4-benzylphenyl)-6-oxo-6,7-dihydro-4//-pyrido[6,l-a]isoquinolin-4-thione (194) (98MI47). Cyclization of l-(2-carboxyethyl)-l,2,3,4-tetrahydroquina-zoline-2,4-dione (195) in PPA afforded l,2,3,5,6,7-hexahydropyrimido[3,2, l-//]quinazoline-l,3,7-trione (196) (97CHE96). 

Thermolysis of 3-alkyloxy- and 3-aroyloxy-5-phenyl-l,2,4-pyrrolo[l,2- ]quinoxaline-l,2,4-triones afforded 5-phenyl-9-(4-phenyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-6,8,10-trioxo-5,6,9,10-tetrahydro-87/-pyrido[l,2-tf ]quinoxaline-7,9-dicarboxylates <2000CHE615, 2004CHE1295> and 7-aroyl-8-aroyloxy-5-phenyl-9-(4-phenyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-5,6-dihydro-1077-pyrido[l,2- ]quinoxaline-6,10-diones <2002CHE498>, respectively. Thermolysis of 3-aryl-2-(5-aryl-2,3-dioxo-2,3-dioxo-4-furanyl)quinoxalines gave 7-aroyl-8-aroyloxy-6-aryl-9-(3-aryl-2-quinoxalyl)-10/7-pyrido[l,2- ]quinoxalin-10-ones <2001CHE1314, 2002RCB850>. 

Reaction of 3-(5-acetoxyhexyl)-6-amino-l-methyluracil with diketene in boiling dichloroethane gave the cyclized pyrido[2,3-,71pyrimidine-2,4,5-trione 501 <2002W02002094824>. Also, reaction of 6-amino-1-phenyluracil with methoxyvinyl cyanide gave 7-amino-tetrahydropyrido[2,3-,7]pyrimidinedione 502 <2001EPP1145716>. The cyano... 

Heating tetrahydropyrrolo[l,2-rz]quinoxaline-l,2,4-trione 456 in decane at 172-173 °C provided 5,6-dihydro-10H-pyrido[l,2-a]quinoxaline-6,10-dione 459 via the [4+2] cycloaddition of primarily formed ketene 457 followed by the 1,3-migratiom of the COR group of 458 (05RJ01081). 

The syntheses of 1,3-dipropyl-l//,3//-pyrazino-, pyrid0 5 pynmido-, and pyrrolo[2,1 /]purine-2,4-diones starting from 5,6-diamino-l,3-dipropylpyrimidine-2,4-dione and 6-chloro-l,3-dipropyl-pyrimidine-2,4-dione have been described (Scheme 15) <94JHC8l>. A new route to 1,3-dipropyl-1H, 3/f-pyrido- (or pyrazino-) [T,2 -l,2]pyrimidino[4,5-d]pyrimidino-2,4,5-triones has also been developed (Scheme 16). 

Alkylation of pyrido[4,3-isopropyl iodide gave the corresponding 5-alkyloxy derivatives <86GEP3502590>. Also, alkylation of pyrido[2,3-. Alkylation of 2-thiooxo-... 

The acrylic acid ester side chain may also be introduced by the Wittig reaction of 6-chloro-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carbaldehyde with the appropriate ylide. Subsequent conversion to a 6-amino compound and ring closure in the presence of triethyl-amine gives 8-alkyl-l,3-dimethylpyrido[2,3-t/]pyrimidine-2,4,7(l//,3//,8W)-triones 9. 45 146 Exclusive formation of pyrido[2,3-t/]pyrimidines is achieved by refluxing the acrylic acid esters in a mixture of triethylamine and dimethylformamide in the presence of l,5-diazabicyclo[4.3.0]-non-5-ene (DBN).147 55t... 

It is, however, possible to obtain either pyrido[2,3-rf]pyrimidine-2,4,7(1/7,377,8//)-triones or, to a lesser extent, py rido[2,3-acetic acid 99 affords ethyl 1,3-dimethyl-2,4,7-trioxo-l,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-6-carboxylate. Further examples of this pathway are the reaction of diethyl (ethoxymethylene)malonate with 6-amino-165 or 6-(methylamino)-l,3-dimethyluracil 222 neat at 220-230 °C, or with 6-amino-2-methoxypyrimidin-4(3/7)-one223 in acetic acid to yield the corresponding ethyl 2,4,7-trioxo-l, 2,3,4,7,8-hexahydropyrido[2,3-[Pg.118]

An example of the normal Gould - Jacobs pathway is the reaction of 6-amino-2-methoxypyrim-idin-4(3//)-ones with diethyl (ethoxymethylene)malonate in ethanolic sodium ethoxide to give the corresponding pyrido[2,3-d]pyrimidine-2,4,5(l//,3/7,8/7)-trione in low yield together with the diethyl [(pyrimidinylamino)methylene]malonate.223... 

Dimethyluracils substituted in the 5-position, preferably with electron-withdrawing groups, react as Michael acceptors with 6-aminouracils. By a base-catalyzed ring transformation, the C—C —C unit bearing the electron-withdrawing substituent builds up the C5-C6-C7 part of the final pyrido[2,3-t/]pyrimidine-2,4,7(1//,37/,8//)-trione 21.240,241... 

With 6-aminouracil, prop-2-ynal or 3-phenylprop-l-yn-3-one in aqueous alkali at 0°C reacts to furnish pyrido[2,3-phenyl derivative 232 similarly, methyl propiolate and l,3-dimethyl-6-aminouracil (33) in refluxing water give 1,3-dimethylpyrido[2,3-c/]pyrimidine-2,4,7(177,3//,8//)-trione (34).165 In protic media such as water or methanol, irrespective of the N1 substituent, the reaction with 6-aminouracils largely yields methyl 2,4,7-trioxo-l,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-5-carboxylates.I42,165,547,584... 

Aminouracil and its 1-inethyl derivative react with dimethyl allene-l,3-dicarboxylate in refluxing water by Michael attack of its C5 atom at the central allene carbon and subsequent ring closure to give the corresponding pyrido[2,3-<71pyrimidine-2,4,7(l //,37/.8/7)-triones 35.144... 

Amino-8-(phenylhydrazono)pyrido 4,3-rflpyTimidine-2,5,7(1 f/,6W)-trione Single Procedure 51 ... 

Pyrimidines 73 with dinucleophiles, such as 2-amino-pyridine, 1,3-dimethylbarbituric acid, 5,5-dimethylcyclohexa-l,3-dione and 4-hydroxy-6-methyl-pyran-2(lH)-one, were carried out in boiling acetic acid formed 4H-pyrido[l,2-fl]pyrimidin-4-one (76), lH-pyrano[2,3-d]pyrimidine-2,4,7(3H)-trione (77), 6H-chromene-2,5-dione (78) and pyrano[4,5-b]pyran-2,5-dione (79) in 30%, 67%, 56% and 73% yields, respectively (Scheme 26). 

This reaction has been much used for the synthesis of the pharmacologically important 1,4-benzodiazepin-2-ones by one of two routes as shown in the general scheme (Scheme 21) note that if the intermediates are not isolated this is a type ac synthesis. In an example the Z-glycineamide of 3-amino-4-benzoylpyridine (127) was cyclized under acidic conditions to 2,3-dihydro-5-phenyl-2/f-pyrido[3,4-e]-l,4-benzodiazepin-2-one (128) in 80% yield <87CJC1158>. ITie linear triamide (129 R = NMe2) itself could not be induced to cyclize to a diazepinetrione but on conversion into the phenylthioester (129 R = SPh) it underwent smooth cyclization on treatment with sodium hydride in hot toluene to hexahydro-6,6-diethyl-3,3-dimethyl-l,4-diazepine-2,5,7-trione (130) (Equation (4)) <85HCA465>. 

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