Pteridines, synthesis

A new pteridine synthesis is based on the reaction of 4-amino-5-nitroso-pyrimidines with the phosphonate carbanions (173 = C02Et, >... 

The synthetic strategy of preparing pyrazines by condensation of 2-keto aldoximes with a-amino nitriles is well represented by Taylor s pteridine synthesis, in which a variety of 2-amino-3-cyanopyrazine 1-oxides have been prepared by using aminomalononitrile <2002TL6747> as the amino nitriles. In the same fashion, some other a-amino nitriles, which are often the Strecker synthesis products, are converted into 2-aminopyrazine 1-oxides 160 (Scheme 44). The condensations are realized by treatment with iV-methylmorpholine <1993JOC7542>, and... 

Table 6 Pteridine synthesis by imidate condensation with 5,6-diaminopyrimidine (Scheme 18) <2006RJ0136>...

Table 7 Pteridine synthesis using 2-oxosuifonium sails as precursors (Scheme 25) <1996H(43)437>...

Table 9 Alkyloxymethyl pteridine synthesis from pyrazines (Scheme 31) <1996EJM273>...

In order to avoid unnecessary repetition, and to stress new, unusual or critical applications of synthetic methodology in this area of heterocyclic chemistry, some synthetic schemes will be discussed in greater detail than others. The preparation of essential, commonly employed intermediates such as 6-formylpterin, 2,4-diamino-6-bromomethylpteridine, 2-amino-3-cyano-5-halomethylpyrazines, etc. (see next section) will be discussed separately, and only once. Several often-used strategies, such as the Boon-Leigh pteridine synthesis, and the Waller three-component synthesis, will also be detailed in this introductory section, and then subsequently referred to without further discussion. 

The optically active precursor 87 was prepared by combination of usual synthetic transformations and the butyl protective group which could be easily removed by alkaline hydrolysis made the substrate and intermediates soluble in organic solvents and applicable to usual purification by silica-gel column chromatography. Therefore, there are various opportunities to apply modern synthetic reactions to this pteridine synthesis. 

Pteridine synthesis from pyrazine precursors are usually applied in such cases where the formation of special derivatives cannot be achieved easily by the pyrimidine approach. Methyl 3-amino-2-pyrazinecarboxylate (362) reacts with thiophosgene to give the corresponding 3-isothiocyanato derivative (363) which cyclizes with primary amines, arylalkylamines, aminoalcohols, amino acids,... 

Another key intermediate for pteridine synthesis was also seen in 2-amino-3-ethoxycarbonyl-5-phenylpyrazine 1-oxide which reacts with various amines to form the corresponding amides followed by cyclization with triethyl orthoformate giving 3-alkyl-6-phenyl-4(3/7)pteridinone 8-oxides <87JHC1109>. The synthesis of 2,4-diamino-6-methylpteridine 5-oxide (371) was achieved from 5-methyl-pyrazine-2-carboxamide (366) via the 4-oxide (367), a Hofmann degradation (368), bro-mination (369), and cyanation (370) followed by cyclization with guanidine to give (371) (Scheme 60) <93JHC841>. 

Table 1. Use of Glyoxal in the Gabriel Colman Pteridine Synthesis ...

The most common ester used for pteridine synthesis is ethyl glyoxylate which is commercially available as the ethyl hemiacetal (ethyl 2-ethoxy-2-hydroxyacetate) or as the diethylsulfanyl derivative. Both the pteridin-6-one and the pteridin-7-one may be obtained, and the ratio of isomers can be controlled to some extent by the choice of reaction conditions. This is well illustrated by condensations of pyrimidine-4,5-diamine with ethyl 2-ethoxy-2-hydroxyacetate. At pH 6 a mixture of products is obtained with the 7-isomer predominating. The products may be separated at pH 2 at which pteridin-7(8/7)-one is insoluble and may be collected, whilst the pteridin-6(5//)-one remains in solution as the 7,8-hydrate cation. If the condensation is carried out at pH 10 (2 M sodium carbonate under reflux), the 7-isomer is formed, almost exclusively, as the sodium salt.79 However, if the reaction is carried out at pH 0 (1 M sulfuric acid, 37 °C), the 6-isomer, as its stable covalent hydrate, is formed almost exclusively.80... 

Further examples of the use of diketones for pteridine synthesis are given in Table 5. 

A further method of pteridine synthesis from pyrimidine-4,5-diamine involves their reaction with aldehydes and hydrogen cyanide to give 5-(a-cyanoalkylamino)pyrimidines as intermediates which undergo cyclization to yield dihydropteridines which are subsequently oxidized to give the pteridines.118 In some cases the oxidation occurs spontaneously under the conditions of the cyclization. 

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