With Amides, Imidates, or Nitriles

Reactions That Give 4-Aminopyrimidines 1. With Amides, Imidates, or Nitriles 

The use of formamide, which was introduced in 1956,117-119 is exemplified by the conversion of 3-amino-4-cyanopyrazole (97) to 4-aminopyrazolo-[3,4-d]pyrimidine (98) in good yield by boiling with formamide for 30 min.118 The product was conveniently obtained by diluting the cooled mass with water. Here, as in most other applications of the reaction, the temperature is not specified. This introduces uncertainty, because formamide vigorously expels bubbles of ammonia and carbon monoxide at about 200°-210°C, decomposing rather than boiling. An addition of acetic anhydride to improve yields has been suggested.120 

One of the two undesired reactions is the formation of an JV-formyl derivative of the base accompanied by loss of the nitrogen atom that is required for position 3 in the nascent pyrimidine ring. 7r-Deficiency in the starting material, which disfavors this formylation, encourages dimerization.122 Thus, 2-aminopyridine-3-carbonitrile (101) dimerizes to 2,3 -(2 -amino-pyridyl)-4-aminopyrido[2,3-d]pyrimidine (102). 2-Aminobenzonitrile does not undergo this reaction, whereas its 5-nitro derivative does so readily. The reaction is the addition of the amino group of one molecule across the cyano group of another to form an intermediate amidine.122,4 

In spite of these sources of loss, the reaction is useful for both n-excessive and 7t-deficient nuclei. Thus, formamide has been used successfully to convert 

3- amino-4-cyano-2,5-dihydropyrroles (see 11) to 5,7-dihydropyrrolo[3,4-d]-pyrimidines (see 13),123 2-amino-3-cyanofurans (see 11) to furano[2,3-d]-pyrimidines (see 12),120 4-amino-5-cyanoimidazoles (see 18) to purines (see 19),124 2-amino-3-cyanopyridines to pyrido[2,3-d ]pyrimidines (see 3),12 5 and 

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