Purine from formamide

Formamide (45 g) was heated in an open vessel with a condenser for 28 h in an oil bath at 170-190 C. After removing excess formamide (32.1 g) by vacuum distillation, the residue was refluxed with MeOH. The MeOH solution was liltered, the solvent was removed from the filtrate by vacuum distillation and almost pure purine obtained yield 4.93 g (71 % calculated from formamide consumed). Crystallization (acetone) afforded purine as colorless crystals rap 218 "C. 

A rational synthesis of purine from 2-carbamimidoyl-2-(formylamino)acetamide with formamide gives hypoxanthine (8). Hypoxanthine (8) can also be prepared from 2-amino-2-carbamimi-doylacetamide and ethyl orthoformate. 

Adenine, C5H5N5, is formally a pentamer of hydrogen cyanide and indeed can be produced in the laboratory by the reaction of ammonia and hydrogen cyanide, although not with great efficiency. A related and more practical method involves the dehydration of formamide. Purine itself can also be obtained from formamide. ... 

The spontaneous, prebiotic formation of purines from hydrogen cyanide or formamide is a fascinating subject. Adenine is formally the pentamer of hydrogen cyanide. 

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... 

Purine derivatives were also synthesized starting from HCN derivatives. Yamada described in 1972 the one-pot synthesis of purine 12 obtained simply by heating neat formamide, a product of HCN hydrolysis [70,71] at 160 °C [72]. Adenine 1 was obtained as the main reaction product along with a low amount of 12 upon repetition of the reaction under similar experimental conditions in the presence of HCN (Scheme 7) [73,74], On the basis of 13C-NMR studies of the synthesis performed with the enriched substrate, three molecules of HCN and two molecules of formamide were found to be incorporated into the adenine scaffold by a C - N bond fission process. 

Purine has also been obtained by heating formamide alone (72CPB623) and detected in reactions involving hot formamide (77CPB1923). Interpretation of mechanisms of reactions carried out in formamide solution must clearly be made with care. However the distribution of and labels in purine derived from [ C, NJHCN and formamide has suggested the mechanism outlined (Scheme 55) (78TL4039). 

Acid amides have occasionally, like formamide, been used to produce 8-substituted purines. Acetamide and 2,4,5-triamino-6-oxo-l,6-dihydropyrimidine afforded 8-methyl-guanine (60JA2633) and 8-methyl- or ethyl-xanthines resulted from acetamide or propion-amide and 4,5-diamino-2,6-dioxo-l,2,3,6-tetrahydropyrimidine (53CB333). Diamides such... 

Purine (4) is also obtained from A -(cyanomethyl)phthalimide with jV,A, A -mcthylidynetris-formamide in formamide. " ... 

To formamide (20 mL) was added the crystalline sulfate of the appropriate pyrimidine-4,5-diamine (2.0 g). The sulfate salt was prepared in all cases by the addition of dil H2SO4 to an aqueous solution or suspension of the 4,5-diamine. The sulfate precipitated almost immediately in most instances however, in some cases, the salt crystallized slowly only after extended cooling of the aqueous solution. The formamide solution of the pyrimidine-4,5-diamine sulfate was refluxed for 20-25 min. A solution was rapidly obtained and precipitation of the purine occurred after 10 min. The solution was finally cooled, diluted with H O(10 mL) and allowed to remain overnight in the refrigerator, The crude product was removed by filtration from the neutral solution and washed with cold water. 

Acetamides are used analogously to formamide for the synthesis of 8-substituted purines, for example, 8-methylguanine (2) is obtained from a pyrimidinetriamine with acetamide. ... 

The reagents used for the completion of the purine heterocycle are essentially the same as those used for the Traubc synthesis. The purine ring is formed by condensation with derivatives of formic acid or other carboxylic acids. Alternatively, formylation of the amino group is accomplished by a mixture of formic acid and acetic anhydride followed by cyclization. Alkyl esters or trialkyl ortho esters are also versatile synthons for ring closure. Moreover, heating in formamide or cyclization with urea or thiourea provides a satisfactory route. Condensations with isothiocyanates show unusual versatility leading to 2-sulfanylpurin-6-ols. From carbonic acid derivatives, cyclization is reported with chlorocarbonic esters, diethyl carbonate or carbon disulfide. 

Purines can also be derived from simple acyclic building blocks. For instance, purine is formed by the thermolysis of formamide, or by interaction of iV-(cyanomethyl)phthalimide with tris(formamino)methane, or with formamidine acetate in formamide or butanol ... 

The synthesis of an imidazole C-nucleoside linked through C-4, namely 2-carbamoyl-4-(2 -deoxy-j5-D-ribofuranosyl)imidazole 1586, was achieved by way of a nine-step reaction sequence starting from 2-deoxy-3,5-di-0-p-tolyl-D-erythro-pentofuranosyl chloride. The isocyanide intermediate 1585 was obtained by dehydration of the corresponding formamide 1584 with phosphoryl chloride, affording the imidazole 1586 in a good yield of 86% based on formamide 1584. Substituted imidazole nucleotides play a vital role in purine biosynthesis, and some of them... 

Formamidines are interesting and important compounds that feature in the biosyntheses of imidazoles and purines. For the preparation of unsymmetrical formamidines, benzotriazol-l-ylalkyl isocyanides are versatile synthons [1208]. They are prepared from the corresponding formamides by dehydration with phosphoryl chloride in yields of 64-77%. 

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