Pteridines nucleophilic substitution

In contrast to electrophilic reagents, the highly -tt-deficient character of the pteridine nucleus is responsible for its vulnerability towards nucleophilic attack by a wide variety of reagents. The direct nucleophilic substitution of pteridine itself in a Chichibabin-type reaction with sodamide in diethylaniline, however, was unsuccessful (51JCS474). Pteridin-6-one, on the other hand, yielded pteridine-6,7-dione under the same conditions, via a still unknown reaction mechanism. 

The synthesis of deoxysepiapterin (82) has been recently achieved by homo-lytic nucleophilic substitution of the pteridine nucleus by acyl radicals (505). Since this substitution arises preferentially at the most electron-deficient 7 position, protection at 7 position is necessary for nucleophilic attack at the 6 position. 2,4-Diamino-7-methylthiopteridine (597) and 2-amino-4- -pentyloxy-7-n-pro-pylthiopteridine (600), protected by the thio function, can be used as starting materials. Homolytic acylation of 597 with the system propionalde-hyde/Fe2+//ert-butylhydroperoxide afforded 6-propionylpteridine (598) in good yields, which could be transformed to deoxysepiapterin (82) by selective hydrolysis followed by deprotection of the thio function (Scheme 75). Deoxysepiapterin (82) can also be prepared by a similar procedure from 600. 

The introduction of substituents into position 7 of a 2,4-disubstituted pteridine can be effected very cleanly by the use of acyl radicals typically and has been known for many years. Treatment of aldehydes with /-butyl hydroperoxide and iron(ll) generates acyl radicals which add selectively to the 7-position. A recent exploitation of this chemistry has provided a large number of new examples including both aryl and alkyl acyl radicals as reagents <2004PTR129> pA , data have been compiled (Section 10.18.4) and many nucleophilic substitution reactions of the 7-acylated pteridines and functional group modifications have been described (Section 10.18.7.2). 

In modern medicinal chemistry, the creation of diversity on a structural framework is important. In principle, diversity at positions 2, 4, 6, 7, and 8 of pteridines can be achieved using such solid-phase chemistry. This prototype solid-phase synthesis involved nitrosation of the resin-bound pyrimidine, reduction of nitroso group with sodium dithionite, and subsequent cyclization with biacetyl to afford pteridines 114 and 115. Cleavage from the resin by nucleophilic substitution of the oxidized sulfur linker using w-chloroperbenzoic acid or DMDO led to the pteridine products 116 and 117 (Scheme 23). 

The alteration of nucleophilic reactivity by the intervention of covalent hydration and analogous nucleophilic additions needs to be borne in mind for many polyazanaphthalenes. Covalent hydration has been observed in several bicyclic azines besides pteridine and quinazoline (Section IV, B) and is related to nucleophilic substitution in activation and in proceeding through the same first stage as 8 Ar2 reactions. The Bucherer interconversion of naphthols and naphthylamines involves exchange of oxygen and nitrogen substituents in a covalent adduct produced by bisulfite ion. ... 

The nucleophilic substitution, amination, aldol-type condensation, oxidation, and hydrolysis of the l//-pyrazino[2,3-c][l,2,6]thiadiazine 2,2-dioxide system, structurally related to pteridine, were studied in detail <03HCA139>. Chlorinated pyrazines were directly oxidized to their corresponding iV-oxides using dimethyldioxirane in a completely regioselective fashion <03HEC221 >. 1,6-Dibenzoyl-5//, 10//-diimidazo[ 1,5-a 1, 5 -[Pg.374]

Pteridine, and substituted pteridines, are generally very thermally stable. However, because of the ready reaction with water, and other nucleophilic species, pteridines are unstable in hot solutions. Pteridine undergoes ring fission of the pyrimidine ring in aqueous acid to yield 3-aminopyrazine-2-carbaldehyde 11 (aqueous base yields 10). Such ring fission has been reviewed,28,29 and is discussed further in Section 7.3.1.4.7.2. 

The 7t-electron deficiency of pteridine should greatly aid nucleophilic substitution, but complications arise because of the ready nucleophilic covalent addition reactions referred to previously. However, nucleophilic displacement of halo substituents occurs very easily, except in the presence of electron-donating groups such as amino, etc. Increasing the number of such substituents increases the difficulty of carrying out nucleophilic substitutions. The kinetics for the aminolysis of 2,4,6,7-tetrabromopteridine shows that the order of reactivity for bromo substituents is 7 > 6 > 2 > 4.30,19 It is probable that 2,4,6,7-tetrachloropteridine shows the same pattern of reactivity and that generally bromo- and chloropteridines react similarly. 

The nucleophilic substitution of 4-chloro-5-nitropyrimidines by a-aminocarbonyl compounds, followed by cyclization and oxidation, is also a useful, and widely applicable, method for the synthesis of pteridines (in place of the 5-nitro substituent aryldiazenyl or nitroso moieties can also be used). This reaction is sometimes known as the Polonovski-Boon synthesis.130,131 The use of aminoacetaldehyde diethyl acetal gives 6,7-unsubstituted pteridines, whilst amino ketones, aminonitriles, and amino esters give 6-alkyl-, 6-amino-, and 6-oxopteridines, respectively. 

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