Pyrimidines cyanation

Undoubtedly these reactions proceed via an intermediate ureido or thioureido derivative. These compounds have been obtained by Dornow and Hahmann by the action of potassium cyanate or ammonium isothiocyanate on 2-amino-4,6-dimethylnicotinic acid (11), but whereas the urea (12, X = 0) was converted into the pyrido[2,3-li]-pyrimidine-2,4(lI/,3/7)-dione (13, X = 0) by the action of heat, the thiourea (12, X = S) was unchanged after similar treatment. 

The 6-methyl derivative (98, R = Me) was an important intermediate in the synthesis of analogs (e.g., 183) of folic acid. Korte has shown that 2-aminopyrido[3,2-guanidine carbonate with 3-aminopicolinic acid and that treatment of the same acid with ammonium thiocyanate or potassium cyanate yields the thioureido and ureido derivatives (100, X = S and X = 0). In contrast to the pyrido[2,3-d]pyrimidine system bsoth of these compounds could be cyclized by heat and the latter (100, X = O) is a likely intermediate in the synthesis of the dione (98) by the fusion with urea. 

Cyanations of quinoline 877 and isoquinoline N-oxide 879 in DMF or N-methyl-pyrrolidone provides the cyano compounds 878 and 880 in 90 and 79% yield, respectively (Scheme 7.4) it was expected, e.g., that pyrimidine N-oxides would react analogously [6]. 

Fig. 4.8 Suggested mechanisms for the synthesis of pyrimidines from cyanoacetaldehyde (CAA) and cyanate, urea or guanidine (Cleaves et al., 2007)...

The reaction of Ph 3P=CH2 with benzoyl isocyanate takes place in a 1 2 ratio with loss of benzene to afford the ylide 173 <71JOC2029> and treatment of either Ph3P=CHC02Me or Ph3P=CHC02Et with aryl cyanates, Ar-O-CN, results in formation of the pyrimidine ylides 174 <67CB187>. An alternative means of access to 171 (R = cyclohexyl) is provided by... 

It has been demonstrated in CHEC-II <1996GHEC-II(7)431> that halogen substituents as well as other good leaving substituents can be readily replaced by carbon nucleophiles, for example, cyanide ion or active methylene compounds. Also, direct cyanation of l-phenylpyrazolo[3,4-i/]pyrimidine was demonstrated. Since then, reactivity toward carbon nucleophiles has not received much attention. However, a few interesting reactions with carbon electrophiles have been reported in the last few years. Thus, reacting 154 with 155 affords 156 (Equation 9) <2002BML1687>. 

Mesoionic pyrido[2,l- >][1,3]oxazines (54) afforded 4-oxo-4//-pyrido[l,2-a]pyrimidin-l-iumolates (55) and 4//-quinolizin-4-one (56) with phenyl iso(thio)cyanates [78LA1655 79CB1585 82ZN(B)222] and dimethyl acetylenedicarboxylate (79CB1585), respectively. Reaction of 2-cyano-3-methyl-lH,6//-pyridol[l,2-a][3,l]benzoxazine-l,6-dione with ammonium acetate and hydroxylamine, hydrazines, primary aliphatic or aromatic amines, and (thio)ureas gave 5-unsubstituted and 5-substituted 2-cyano-3-methyl-l//,6H-pyrido[l,2-a]quinazoline-l,6-diones (93CCC1953). 

The prebiotic synthesis of the pyrimidine cytosine involves cyanoac-etylene, which is synthesized in good yield by sparking mixtures of CH4 + N2. Cyanoacetylene reacts with cyanate to give cytosine,29... 

As has already been pointed out, the Finkelstein reaction can be conducted in situ in the absence of solvents. For example, alkylations of purine and pyrimidine bases with alkyl halides and dimethyl sulfate have been carried out by solid/liquid phase-transfer catalysis in the absence of any additional solvent [48], as have cyanation of haloalkanes [49] and / -eliminations [50]. Noteworthy is the synthesis of glycosyl isothiocyanates by the reaction of potassium thiocyanate with molten glycosyl bromide at 190 °C [51]. 

The reaction of aromatic bis-cyanate with BMI has been investigated. The cy-anate trimerizes, giving a cyanurate ring but can also copolymerize with the maleimide double bond giving a pyrimidine ring (Fig. 19) during the cure cycle [70,71]. 

More complex, but still feasible, is the synthesis of pyrimidine bases from simple prebiotic substrates, although the reported yields of these reactions are relatively low. In this context, two main prebiotic precursors have been identified cyanoethine and a primary product of its hydrolysis, cyanoacetaldehyde. These compounds contain a preformed C-C bond which is incorporated in the C5-C6 position of the pyrimidine ring. In 1968 Ferris and co-workers reported that the reaction of cyanoethine with cyanate at 30 °C yields cytosine and, after its hydrolysis, uracil in acceptable yield [27]. trans-Cyanovinylurea was recovered as a key intermediate for this transformation. However, this reaction requires relatively high concentrations of cyanate (>0.1 mol/1), unlikely to occur in aqueous media due to its rapid degradation to carbon dioxide and ammonia. Cyanoethine also reacts with cyanate and yields cytosine and uracil at elevated temperatures. In this reaction urea or guanidine (also considered as prebiotic organic compounds) can easily replace cyanate (Figure 8.8) [26]. 

Ferris JP, Sanchez R, Orgel LE. Studies in prebiotic synthesis III. Synthesis of pyrimidines from cyanoacetylene and cyanate. J Mol Biol 1968 33 693-704. 

Cycloaddition of 2-(dicyanomethylene)piperidine with iso(thio) cyanates afforded 3-imino-4-cyano-2,3,5,6,7,8-hexahydro-l//-pyrido[l,2-c]pyrimidin-l-ones or -1-thiones (198, = H, X = O or S) (78MI1). When... 

The condensation of 3-aminopyridine-2-carboxylic acid with potassium cyanate or ammonium thiocyanate yields the corresponding ureas, which can be cyclized thermally to give pyrido[3,2-d]-pyrimidine-2,4(l//,3//)-dione (la) or 2-sulfanylpyrido[3,2-d]pyrimidin-4(3/7)-one (lb).432... 

Heating ethyl 3-aminopyridine-2-carboxylate with methyl or phenyl iso(thio)cyanate in pyridine gives the corresponding 3-substituted 2-sulfanylpyrido[3,2- ]pyrimidin-4(3//)-ones.430... 

The reactions of amino esters 97 (R =H, CH2Ph) with potassium cyanate afforded c/.y-cyclopenta[c/]pyrimidine-2,4-dione 98, while those with potassium thiocyanate led to cw-2-thioxocyclopenta[[Pg.291]

Pyrimidines are also formed by the reaction of cyanoacetylene and cyanoacetaldehyde with guanidine, cyanate and urea under a variety of reaction conditions (If 12). The observation of several potential sources of purines and... 

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