Formamide pyrimidines, 4-amino

Treatment of the symmetrical triaminopyrimidine (50-1) with sulfuryl chloride ties up the two adjacent amines in a thiadiazole ring, protecting those groups from attacks in subsequent reactions. Reaction of the product (50-2) with ortho difluorinated benzylamine (50-3) results in the replacement of the pyrimidine amino group by that in the reagent most hkely by an addition-elimination sequence to afford (50-4). That amino group is then converted to the formamide (50-5) with formic acid. Exposure of the product to Raney nickel leads to a loss of sulfur and the formation of the transient intermediate (50-6). This cyclizes to a purine... 

A combination of the preceding type of synthesis and of cyclization of 4-amino-5-arylazopyrimidine can be seen in the novel procedure of Richter and Taylor. Proceeding from phenylazomalonamide-amidine hydrochloride (180), they actually close both rings in this synthesis. The pyrimidine ring (183) is closed by formamide, the triazole (181) one by oxidative cyclization in the presence of cupric sulfate. Both possible sequences of cyclization were used. The synthetic possibilities of this procedure follow from the combination of the two parts. The synthesis was used for 7-substituted 2-phenyl-l,2,3-triazolo[4,5-d]-pyrimidines (184, 185). An analogous procedure was employed to prepare the 7-amino derivatives (188) from phenylazomalondiamidine (186). 

Acid chlorides, acetic anhydride,and formamide have also been used to synthesize pyrido[2,3-d]pyrimidines from 2-ammo-nicotinamides, although in the last case high temperatures were necessary. It is suspected that all the foregoing eyclizations proceed via initial acylation of the 2-amino group to yield an intermediate 2 - amidonicotinamide. 

Good yields of pyrido[2,3-d]pyrimidiries (37) were also oblaiiied by the action of formamide on o-amino nitriles (36). Reduction of 2-amino-4,6-dimethylnicotinitrilc yields the 3-aminomcthyl compound (38). Acylation to the 3-aoylaminomethyl derivative (39), followed by cyolization, by means of heat or phosphoryl chloride, yielded the dihydropyrido[2,3-d]pyrimidines (40). ... 

Alkylpyrimidines were obtained in 59-70% yield from higher 1-dimethyl-amino- and l-methoxyalk-l-en-3-ynes (R = Me, Et, -Pr) by their reaction with formamide (70ZOR2374). The exception was l-methoxy-5,5-dimethylhex-l-en-3-yne, from which the pyrimidine was obtained in 45% yield only, which is related to steiic hindrance for the attack at the acetylene bond. 

A similar route to the i -triazolo[4,5-d]pyrimidine ( 8-azapurine ) ring system has been developed. This involves reaction of 4-amino-l,2,3-triazole-5-carboxamide or its ring iV-alkyl derivatives with formamide (Scheme 46). - 232-234 pyrimidone derivatives thus... 

Having a cyano group and an amino group ortho to each other on a ring is another system that has led to the formation of fused pyrimidine ring systems. In this case, an aminopyrimidine is the result. Compound 42 in Scheme 5 is one such structure. Treatment of 42a with formamide leads to the amino derivative 43 <1999PS(155)175>. Alternatively 42b provides 44 after treatment with triethyl orthoformate followed by hydrazine <1999PS(155)175>. 

A further example of the formation of a fused pyrimidine by reaction of ortho amino/cyano groups is illustrated by condensation of 2-amino-4-(4-nitrophenyl)-3-thiophenecarbonitrile with formamide in the presence of PhsP at elevated temperature <2006T11311>. 

This synthesis involves Michael cycloaddition reaction of the readily available 4-hydroxycoumarine 1 with a cyanocrotonitrile 2 in ethanolic piperidine to afforded 2-amino-3-cyano-4-methyl-4H, 5H-pyrano-benzopyran-5-one (3). Treatment of 3 with acetic anhydride for 0.5 h and/or 3 h under reflux afforded N-acetyl and [l]benzopyrano[3/,4/ 5,6]pyrano(2,3-d) pyrimidine-6,8-dione derivatives (4) and (5a), respectively. Also, interaction of 3 with benzoyl chloride or formic acid gave the corresponding pyrimidine derivatives (5b,c) while its treatment with formamide afforded the aminopyrimi-dine derivative (6). 

The reaction of 5-aminopyrazole-4-carboxylates with amides affords pyrazolo[3,4-d]pyrimidines <79AP(312)703, 87MI 712-02). The synthesis of allopurinol (53) by reaction of ethyl ethoxymethyl-enecyanoacetate, hydrazine, and formamide probably proceeds via intermediacy of ethyl 5-amino-1 //-pyrazole-4-carboxylate which then condenses with formamide to yield intermediate (318) which readily cyclizes to allopurinol (53) <74NEP7507554>. 

Azine approach. 4-Amino-5-hydroxypyrimidine condenses with acid anhydrides or esters to form the corresponding 2-substituted oxazolopyrimidine system (77CPB491). Under relatively mild reaction conditions the nucleoside 6-amino-5-hydroxyuridine will undergo cyclocondensation with formamide under the influence of polyphosphate ester to form the oxazolo-fused nucleoside (230) both protected and non-protected pyrimidine nucleosides have been used in this reaction (73CPB1327). 

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