Pyrimidin-2 -ones, reaction with phosphoryl chloride

Formation of l,2,4-triazolo[l,5-c]pyrimidine-5(6//)-thiones or their 5(6//)-ones by the reaction of l,4,6-triaminopyrimidine-2(l//)-thiones (468) with the Vilsmeier reagent has been found to be dependent on the temperature. Thus, treatment of 468 with phosphoryl chloride and DMF at 0-5°C afforded mainly the thiadiazolopyrimidinium chloride 470 in addition to the thione 471, but at 25°C a mixture of 471 and 7-formamido-l,2,... 

When treated with phosphoryl chloride at room temperature, 4-phenyl-pyrimidine 1,3-dioxide (37) was chlorinated with the loss of one or two oxide functions. The reaction products were a function of temperature (see Scheme 37), and when there was a methyl group in the 5-position the ratio 2-chloro 3- 2-chloro 1-oxide became 3.5 1. If all of the positions a and y to the N-oxide functions were blocked, the usual Meisenheimer process did not occur instead lateral chlorination of the adjacent methyl groups was observed (81CHE383 83CPB4533). No 2- and 4-chloropyrimi-dines were formed on similar treatment of 2- and 6-methylpyrimidine 1-oxides deoxygenation and lateral chlorination only were noted [83H(20)991]. 

Later, it was also claimed that 3-(tetrazolyl)-4//-pyrido[ 1,2-u]pyrimidin-4-ones 159 were obtained in an one-step procedure by heating the appropriate 2-aminopyridine, ethyl (l//-tetrazol-5-yl)acetate, and triethyl orthoformate in dimethylformamide at 90°C for 1 hour, or in boiling tetra-hydrofuran for 6 hours followed by treatment with 1N potassium hydroxide at 50°C for 1 hour, or with anhydrous aluminum chloride under reflux for 6 hours (91EUP462834). 9-Methyl-3-( 1 //-tetrazolyl)-4//-pyrido[ 1,2-a]-pyrimidin-4-one 159 (R = 9-Me) could be prepared when 2-amino-3-meth-ylpyridine hydrochloride and sodium azide were suspended and stirred in dimethylformamide for 1 hour at room temperature, followed by the addition of ethyl ethoxymethylenecyanoacetate, ethoxymethylenemalo-nonitrile, ethyl cyanoacetate and triethyl orthoformate, or malononitrile and triethyl orthoformate and stirring at 90°C for 6-12 hours. Then the reaction mixture was treated with 1 N potassium hydroxide at 50°C for 1 hour, phosphoryl chloride at 90°C for 5 hours, or with concentrated hydrochloric acid at 110°C for 4 hours to give 26-62% yields. 

Chloro derivative 291 was obtained from dioxo derivative 70 by treatment of phosphoryl chloride in dimethylformamide at 100°C for 2 hours (80CPB3537). The treatment of chloro derivative 291 with methylhydra-zine in a mixture of ethanol and chloroform under reflux gave 2H-pyrido[ 1,2-a]pyrimidin-2-one 295 and rearranged pyridazino[3,4-6]-quinoxaline 296 in 4.8% and 78% yields, respectively (Scheme 21) (80CPB3537). 3,4-Dihydroquinoxalinone 70 could not be rearranged into pyridazino[3,4-6]quinoxaline 296 by treatment with methylhydrazine. When hydrazine hydrate was employed instead of methylhydrazine, tricyclic ethyl ester 297 (R1 = Et) was obtained. The latter reaction gave methyl ester 297 (R1 = Me) when carried out in a mixture of methanol and chloroform (80CPB3537). 

When 2-(3,4-Dimethoxyphenyl)-4//-pyrido[l, 2-a]pyrimidin-4-one 479 was boiled in phosphoryl chloride for 1 hour, the reaction mixture was evaporated and the residue was treated with 2,4,6-trimethylaniline at 100-120°C for 1 hour, 4-arylamino derivative 480 was obtained (86EUP168262). 

Methyl-6,7,8,9-tetrahydro-4//-pyrido[l,2-a]pyrimidin-4-ones 18 reacted with the iminium salt formed in situ from N-formylpiperidine, N-methylformanilide, N, A -diethylbenzamide, and phosphoryl chloride in 1,2-dichloroethane to yield 9-aminomethylene-6,7,8,9-tetrahydro or 9-acyl-l,6,7,8-tetrahydropyridopyrimidin-4-ones 556 and 557 (Scheme 36) (85JHC593). The iminium salt formed from N, /V-diethylacetamide and N, A/-ethylisobutyramide was unreactive under the above reaction condi-... 

The nitrogen atom necessary for ring closure to give the pyrido[3,2-c/]pyrimidine system may be introduced by heating methyl 3-acetamidopyridine-2-carboxylate with an arylamine in a free flame for a short time or refluxing the reaction partners in a benzene/phosphoryl chloride mixture.37 The reaction of the pyridine-2-carboxylate with hydroxylamine in methanol/water requires two days at room temperature and affords 3-hydroxy-2-methylpyrido[3,2-t/]-pyrimidin-4(3//>one (11).35... 

The 8-methylene carbon atom in 5,6,7,8-tetrahydroquinazoline was activated by the pyrimidine ring, and reacted with formamide and phosphoryl chloride (a Vilsmeier reagent) to form 8-formamidomethylene-5,6,7,8-tetra-hydroquinazoline.197 The latter was also obtained as a by-product in the synthesis of 5,6,7,8-tetrahydroquinazoline from cyclohexanone and trisform-amidomethane.1982-Phenyl-5,6,7,8-tetrahydroquinazoline-4(3//)-thione was synthesized from 1-morpholinocyclohex-l-ene and benzoylisothiocyanate. The thione group underwent the usual metathesis reactions.199 2-Methyl-5,6,7,8-tetrahydroquinazoline-4(3//)-thione was oxidized with potassium permanganate to 2-methyl-4-sulfo-5,6,7,8-tetrahydroquinazoline, which provided 2-methyl-5,6,7,8-tetrahydroquinazolin-4(3//)-one on hydrolysis.145... 

Amino-2-ethoxycarbonyl-4-methylpyrrole was converted to the di-methylaminomethyleneamino analog (178) with dimethylformamide and phosphoryl chloride. The product, set aside for 3 days with cold methanolic ammonia, gave 7-methylpyrrolo[3,2-rf]pyrimidin-4-one 179) in excellent yield.332 The corresponding reaction with methyl anthranilate gave quina-zolin-4-one quantitatively.333... 

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