Synthesis of Pyrimidine-Fused Systems

Researchers found electron-rich iV-vinyl and iV-aryl amides proceeded to afford the corresponding pyrimidine derivatives at the ambient temperature however, less reactive substrates required heating for reactions to proceed. The use of epimerizable substrates provided the corresponding pyrimidine derivatives without any loss in optical activity. 

A Dakin-West reaction on plant scale is demonstrated by elaboration of a modified procedure avoiding uncontrolled release of carbon dioxide. It seems to be generally accepted that the mechanism involves dehydrative formation of an azlactone (oxazolinone), which is then C-acylated (in equilibria with G-acylation), undergoes ring-opening hydrolysis, and then decarboxylates to form the acylamino ketone. Pyrimidine ring formation is achieved in a simple one-pot reaction, which is followed by a simple isomerization. Laboratory experiments had made clear that the mechanism 

Vega developed an efficient synthesis of pyrazolo[3,4- /]pyrimidines based on the electrophilic properties of nitrilium salts formed by reaction of 5-aroylaminopyrazoles, nitriles and Lewis acids. Treating iminolyl halides with nitriles with SnCU gave rise of the nonisolated nitrilium salts, which underwent cyclization to generate the desired pyrazolo[3,4-i/]pyrimidines in moderate to good yields. A similar approach was extended to the preparation of 4-amino-2-phenylquinazolines via cyclization of V-arylbenzamides with cyanamide catalyzed by TiCU.  

A convenient synthesis of highly functionalized dihydropyrido[2,3-tfjpyrimidines via a double [5 + l]-annulations stoategy was developed. The double annulation route starts from easily available a-alkenoyl-a-carbamoyl ketene-(5,S)-acetals. 2-Amino-3-carbamoyl-5,6-dihydro-4-pyridones was firstly created in excellent yield by a formal [5C + IN] annulation reaction of ketene-(iS. 5)-acetals with ammonia. In the second step, 7,8-dihydropyrido[2,3-d]pyrimidin-4(3/f)-ones (when R = aryl) and 7,8-dihydropyrido[2,3-d]pyrimidines (when R = H), were prepared in good yields by reacting 2-amino-3-carbamoyl-5,6-dihydro-4-pyridones with excessive Vilsmeier reagent (DMF/POCI3) via a second [5 + 1] annulation step. 

The Baran group has reported an interesting one-step synthesis of 4-monosubstituted and 4,5-disubstituted pyrimidines. For example, 4,5-disubstituted pyrimidines are synthesized from the corresponding ketone in one step using inexpensive reagents, formamidine acetate, and /i-propanol. Contrasted to other methods, this process appears quite amenable to large-scale use in industrial settings. 

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