Formamide pyrimidines

Ai,A/-bis(hydroxymethyl) formamide [6921-98-8] (21), which in solution is in equiUbrium with the monomethylol derivative [13052-19-2] and formaldehyde. With ben2aldehyde in the presence of pyridine, formamide condenses to yield ben2yhdene bisformamide [14328-12-2]. Similar reactions occur with ketones, which, however, requite more drastic reaction conditions. Formamide is a valuable reagent in the synthesis of heterocycHc compounds. Synthetic routes to various types of compounds like imida2oles, oxa2oles, pyrimidines, tria2ines, xanthines, and even complex purine alkaloids, eg, theophylline [58-55-9] theobromine [83-67-0], and caffeine [58-08-2], have been devised (22). 

The best way to make pyrimidine in quantity is from 1,1,3,3-tetraethoxypropane (or other such acetal of malondialdehyde) and formamide, by either a continuous (58CB2832) or a batch process (57CB942). Other practical ways to make small amounts in the laboratory are thermal decarboxylation of pyrimidine-4,6-dicarboxylic acid (744), prepared by oxidation of 4,6-dimethylpyrimidine (59JCS525), or hydrogenolysis of 2,4-dichloropyrimidine over palladium-charcoal in the presence of magnesium oxide (53JCS1646). 

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). ... 

Pyrido[4,3-rf]pyrimidin-4(3/7)-oiie (138) was prepared from either ethyl 4-aminonicotinate or from 4-aminomcotinamide by fusion with formamide. A parallel to the pyrido[3,2-d]pyrimidines (cf. Section II,B, la) was demonstrated in the conversion of 2-methyl-pyrido[4,3-d][l,3]oxa7in-4-ones (139, Ri = Me) into the corresponding pyrido[4,3-d]pyrimidin-4(377)-ones (142) on treatment with a number of amines.There were certain limitations to the method in this series, however, and the intermediate diamides (140) were more conveniently prepared from the appropriate 4-amidonicotinate (141) and. .Ri... 

In the case of l-dimethylaminobut-l-en-3-yne no 4-methylpyrimidine was isolated because its boiling point is close to that of a side product, dimethylfor-mamide. The latter results from transamination of formamide by dimethylamine in the course of cyclization. The pyrimidines 156 were isolated and characterized as picrates (70ZOR1528). For easier isolation of pure 4-methylpyiimidine... 

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. 

Reaction of the aminouracil (55) with thionyl chloride in dimethyl-formamide produced the isothiazolo[3,4-[Pg.65]

A test library with three novel p38a inhibitory activity has been prepared, among them pyrazolo[3,4-c/]pyrimidine and pyrazolo[3,4-h]pyrazine with potent in vivo activity <06BMCL262>. A convenient route for the synthesis of pyrazolo[3,4-<7]pyrimidine involving Friedlander condensation of 5-aminopyrazole-4-carbaldehyde with formamide or benzamide has been reported <06JHC1169>. A facile synthesis of pyrazolo[3,4-<7]pyrimidines and pyrimido[4,5-<7]pyrimidin-4-one derivatives has been published <06SC2963>. 

Another multistep protocol that initially involves the formation of fused pyrimidines (quinazolines) has been described by Besson and coworkers in the context of synthesizing 8f-/-quinazolino[4,3-b]quinazolin-8-ones via double Niementowski condensation reactions (Scheme 6.250) [437]. In the first step of the sequence, an anthranilic acid was condensed with formamide (5.0 equivalents) under open-vessel microwave conditions (Niementowski condensation). Subsequent chlorination with excess POCl3, again under open-vessel conditions, produced the anticipated 4-chloro-quinazoline derivatives, which were subsequently condensed with anthranilic acids in acetic acid to produce the tetracyclic 8H-quinazolino[4,3-b]quinazolin-8-one target structures. The final condensation reactions were completed within 20 min under open-vessel reflux conditions (ca. 105 °C), but not surprisingly could also be performed within 10 min by sealed-vessel heating at 130 °C. 

Pyrazolo[5, l 3,4][l,2,4]triazino[5,6-d]pyrimidine 720 was prepared (89JHC853) by reaction of 716 with formamide. Treatment of 716 with aromatic amines gave 717, whose cyclization with triethyl ortho-... 

Bei der Synthese von Adenin-[8-18C] aus 4.6-Diamino-(5-formamido-[18C])-pyrimidin (I) durch Erhitzen in Formamid stellten Cavalieri imd Brown (44) einen erheblichen Austausch zwischen I und dem Formamid fest, was eine Umamidierung darstellt. Nur 25 % des 13C-t)berschusses von I wurden im Adenin wiedergefunden. Durch Verwendung anderer Losungsmittel an Stelle von Formamid kann der Austausch, der ins-besondere bei der Synthese hochradioaktiver, in 9-Stellung14C-markierter Purine sehr storend ist, vermieden werden [vgl. (215)]. 

Section 4.2.1 will be devoted to heterocycles, section 4.2.2 will cover other kinds of protomeric tautomeric equilibria (e.g., enol/ketone, formic acid, formamidine, etc.), and section 4.2.3 will discuss an example of a ring/chain tautomeric equilibrium. The order of presentation will be approximately by increasing molecular weight within each section. A review by Kwiatkowski et al. [267] covers work on formamide, pyridines, pyrimidines, purines, and nucleic... 

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... 

On the basis of the formal similarity between 1,8-diamino-naphthalene and 3,4-diaminothienothiophene (1) the latter might be able to form a fused pyrimidine system on reaction with orthoformic ester or formamide. However, heating dimethyl 3,4-diaminothieno[2,3-6]-thiophene-2,5-dicarboxylate with acetic anhydride gave the corresponding MiV -diacetyl derivative, while 3,4-diacyloxy derivatives resulted from analogous reaction of dimethyl 3,4-dihydroxythieno-[2,3-6]thiophene-2,5-dicarboxylate with orthoformic ester and acetic anhydride."... 

The reaction of acetophenone (19) with formamide is known to produce 21 after reduction of the imine and hydrolysis of the formate group. This is accompanied by a trace of pyrimidine 22 in the reaction mixture. Lejon and co-workers have optimized the production of 22 by adding CuCl, which is thought to oxidize the formate ion produced from the reaction of water with formamide, thereby minimizing the reduction of 20 and allowing the cyclocondensation with a second equivalent of formamide <99H611>. 

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>. 

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