Aminopyrimidines, condensation with

The 5,7-dioxopyrimido[4,5-rf]pyrimidine-5,7-dione (254) can be obtained by fusion of the amide (253) with urea (68JMC568). This amide is prepared by hydrolysis of the corresponding cyanopyrimidine in concentrated sulfuric acid. 4-Aminopyrimidine-5-carboxamides can also be condensed with alkyl and aryl esters to give pyrimido[4,5-d]pyrimidin-4-ones... 

In a series of publications (75JOC2600, 70JOC1965, 73JOC3087), Potts and coworkers have reported that cyclic amidines (290) readily condense with trichloromethylsulfenyl chloride (329) to yield the sulfenamides (330 Scheme 119). Treatment of the latter compounds with aromatic amines in the presence of triethylamine results in cyclization, possibly via an intermediate such as (331), to produce bicyclic products of type (332). Heterocycles (290) which have been used successfully in this reaction include 2-amino-l,3,4-thiadiazoles, 3-aminopyridazines, 2-aminopyrimidines, 2-aminopyrazines, 2-aminopyridines, 3-aminoisoxazoles and 5-amino-1,2,4-thiadiazoles. The sulfenamide derivative (330) of 2-aminopyridine also was found to react with sodium sulfide and with diethyl malonate to produce (333) and (334) respectively. Attempts to hydrolyze (332) to (295) under acidic conditions failed. 

Solid-supported a-bromoketone 148 was condensed with various 2-aminopyridines or 2-aminopyrimidine derivatives to give imidazo[l,2-a]pyridines or imidazo[l,2-fl]pyriniidine derivatives 149 after cleavage with acid <03TL6265>. An abnormal aza-Wittig reaction on solid-phase parallel synthesis of 3-aryl-2,4-dioxo-l,3,5-triazino[l,2-a]benzimidazoles was observed <03TL3705>. New spiroimidazolidinone derivatives 151 were prepared Irom SynPhase lanterns from dipeptides anchored on the solid-supports 150 <03JCO356>. 

Analogous condensation with guanidine gave 2-aminopyrimidines (e.g. 28 a) reaction with benzamidine gave 2-phenylpyrimidines (e.g. 28b). 

The amino-ketone (292) dimerised when liberated from its salt, giving a dihydropyrazine air-oxidation gave the pyrazine (293), which exhibited characteristic u.v. and c.d. features n — k and tt —> 7t ). ° Some novel fused heterocycles have been obtained by suitable condensations of 3-oxo- and 7-oxo-steroids with nitrogenous compounds cyanoguanidine, for example, affords diamino-pyrimidines (294), and 2,4,5,6-tetra-aminopyrimidine reacts with a 2-bromo-3-oxo-steroid to give a diamino-pteridine. 

Besides formyl, other acyl groups such as acetyl or benzoyl in the 5-position of the pyrimidine nucleus have been used for cyclizations. Thus, 5-acyl-6-aminopyrimidin-4(3//)-ones condense with malononitrile in refluxing pyridine to give the corresponding 7-amino-4-oxo-3,4-dihydropyrido[2,3-(7]pyrimidine-6-carbonitriles 21.171... 

But-2-enal condenses with 5-aminouracil and its 1,3-dimethyl derivative,443 or with 2,5-di-aminopyrimidin-4(3//)-one (8)444 in the presence of hydrochloric acid to give the corresponding 6-methy lpyrido[3,2-rf]pyrirnidine-2,4(1/7,3/7)-diones 7 and 9, respectively. Because of the hydrolysis of the methoxy groups, the same procedure with 2,4-dimethoxypyrimidin-5-amine also yields 6-methylpyrido[3,2-c/]pyrimidine-2,4(1/7,3//)-dione, whereas with acetic acid as catalyst the methoxy groups are retained.443... 

Aminopyrimidine-5-carboxamidcs can also be condensed with diethyl carbonate leading to pyrimido[4,5-r/]pyrimidine-2,4-diols, by treatment with sodium ethoxide/ethanol at reflux for 1 -6 hours.109 The analogous reaction with alkyl or aryl carboxylic acid esters gives alkyl- or arylpyrimido[4,5-t/]pyrimidin-4-ols 23.130... 

Like 2-aminopyridines and 2-aminopyrimidine, 2-aminopyrazine (39) (Scheme 29) has been converted into the nitroso compound (121) by reaction with dimethyl sulfide and NCS followed by deprotonation of the resulting sulfonium salt with sodium methoxide to the 5, 5-dimethylsulfilimine and then oxidation with MCPBA <82JOC552>. The extremely reactive nitrosopyrazine (121) condenses with 1,3-dienes to give 3,6-dihydro-1,2-oxazines and with aromatic amines in the presence of acid to gives azo compounds, and is smoothly oxidized with ozone or sodium hypochlorite to 2-nitropyrazine (122). Methyl 3-aminopyrazinecarboxylate reacts with thiophosgene to produce the... 

Nucleophilic addition to a nitrile instead of a carbonyl group can provide aminopyrimidines. Condensation of thiourea with a variety of pyridyinitriles 27 produced aminopyrimidines 28 in good yields as reported by Kumar and co-workers <01HC52>. 

The original Hilbert-Johns on reaction has been modified using trimethylsilyl protected pyrimidine as aglycons to condense with glycosyl acetate and has been applied extensively to the synthesis of a variety of nucleoside derivatives. In addition, the substitution of 2-alkyl pyrimidine for 2-methylthio-protected pyrimidine allows the preparation of 2-oxo, 2-thio, and 2-aminopyrimidine nucleosides. 

C10H10N4O2S. White powder, which darkens on exposure to light m.p. 255-256 C. Prepared by condensing p-acet-amidobenzenesulphonyl chloride with 2-aminopyrimidine and subsequent hydrolysis. Soluble sulphadiazine is the sodium salt. Sulphadiazine is the least toxic of the more potent sulphonamides. ... 

Triamterene (31) is a diuretic that has found acceptance because it results in enhanced sodium ion excretion without serious loss of potassium ion or significant uric acid retention. Tautomerism of aminopyrimidines (e.g., 27a and 27b) serves to make the "nonenolized" amine at the 5 position more basic than the remaining amines. Thus, condensation of 27 with benzaldehyde goes at the most basic nitrogen to form 28. Addition of hydrogen cyanide gives the a-aminonitrile (29). Treatment of that intermediate with base leads to the eyelized dihydropirazine compound (30). This undergoes spontaneous air oxidation to afford triamterene (31). ... 

Reaction of 3-formyM/7-pyrido[ 1,2- ]pyrimidin-l-ones with hydroxylamine O-sulfonic acid at 5 °C, then 50 °C yielded 3-nitriles <2003T4113>. Treatment of 2-hydroxy-3-(dimethylamono)methyF4//-pyrido[l,2- ]pyrimidin-4-one with Mel, then with KCN gave the 3-cyanomethyl derivative <2004MI215>. A condensation product was obtained from 5-amino-l-ethyl-6-hydroxy-l,3-dihydrobenzimidazol-2-one and 3-lbrmyl-2-hydroxyA//-pyndo[ 1,2- ]pynmidin-l-one <2002W002/38549>. l-(2-Aminopyrimidin-4-yl)-8-phenyl-l,2,3,4-tetrahydro-6//-pyrido[l,2- ]pyrimidin-6-ones were prepared from l-(2-methylthiopyrimidin l-yl)-8-phenyl-l,2,3,4-tetrahydro-6//-pyrido[l,2- ]pyrimidin-6-one by treatment with MCPBA, and then with aralkylamines <2005W005/070932>. 

Compound 642, obtained by condensation of glyoxal with benzotriazole and morpholine undergoes interesting [2+3] cyclocondensation with 2-aminopyridine to give imidazo[l,2- ]pyridine 643 (Equation 15) <2003JOC4935>. Similar derivatives of piperidine and pyrrolidine are also described. 2-Amino- and 6-aminopyrimidines react similarly to give imidazo[l,2- ]- and imidazoll - pyrimidines, respectively. 

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