To pteridines

Another approach uses the reaction of 6-chloro-5-nitropyrimidines with a-phenyl-substituted amidines followed by base-catalyzed cyclization to pteridine 5-oxides, which can be reduced further by sodium dithionite to the heteroaromatic analogues (equation 97) (79JOC1700). Acylation of 6-amino-5-nitropyrimidines with cyanoacetyl chloride yields 6-(2-cyanoacetamino)-5-nitropyrimidines (276), which can be cyclized by base to 5-hydroxypteridine-6,7-diones (27S) or 6-cyano-7-oxo-7,8-dihydropteridine 5-oxides (277), precursors of pteridine-6,7-diones (278 equation 98) (75CC819). 

The degradation of more complex substances can be regarded as another route to pteridine derivatives. Already in 1895 tolualloxazine was oxidized by alkaline permanganate to lumazine-6,7-dicarboxylic acid, and further heating led in a stepwise decarboxylation to lumazine (3) (1895CB1970). 

In many cases, addition or removal of water proceeds sufficiently slowly that some of the physical properties of unstable species (such as hydrated neutral quinazoline or anhydrous 2-hydroxypteridine) can be observed. In these cases, reaction kinetics can also be examined. Addition of water to pteridine is of special interest in relation to studies of the formation and hydrolysis of Schiflf bases. The reaction proceeds in two reversible stages, 3 4 5 ... 

Iminophosphoranes have also proved to be key intermediates because they react with carbonyl compounds, isocyanates, isothiocyanates, acid chlorides, carbon dioxide, and carbon disulfide to give a wide range of imines and heterocumulenes, which are intermediates to pteridines. The preparation of iminophosphoranes has been investigated... 

Palladium-mediated cross-coupling reactions in pteridine chemistry provide for variation at position 6 using halogenated pyrazines or pteridines as substrates (see Section 10.18.7.4). The 6-bromopyrazine 168 is a versatile intermediate leading to pteridine 169 both compounds have been shown to be substrates for palladium-mediated cross-coupling reactions <2000J(P1)89> (Scheme 32). 

Other approaches to pyrimido[4,5- ][l,4]oxazines include the reaction of an ethanolamine derivative with a halopyrimidin-4-ol (Scheme 83), followed by ring closure <2006TL4437>. Formation of a pyrimido[4,5- ][l,4]-oxazine is also a competing reaction in a reported approach to pteridines (Equation 147) <1996T13017>. 

In many cases, the literature since CHEC-I of those systems in class (i) has been extensive, mainly because most are related to the purine nucleus by the inclusion of a further heteroatom for example azapurine derivatives which have shown pharmaceutical or physiological action. The methods of synthesis, except in a few cases, have not changed since the publication of CHEC-I and thus more emphasis has been placed on the physical properties, reactivity, and reactivity of substituents of compounds within these systems. In contrast, in most cases very little literature is available for systems of class (ii) and synthesis has assumed paramount importance. Only two reviews since the early 1980s are applicable to this chapter the conversion of [l,2,5]oxadiazolo[3,4- f]pyrimidines (9) to pteridines <82MI 713-01) and the chemistry and physical properties of 1,2,3-triazolo[4,5-djpyrimidines (7) <86AHC(39)l 17>. The incidence of publications relating to the use of Structures (1)-(50) in such applications as pharmaceuticals, agrochemicals, and even explosives has increased since the publication of CHEC-I and these are discussed in Section 7.13.10. 

An alternative method for the substitution of a hydrogen atom in -electron deficient heterocycles is using the nucleophilic character of radicals in homolytic aromatic displacement reactions <74AHC(16)123>. Acylation with acyl radicals derived from aldehydes is an especially important approach since Friedel-Crafts-type reactions are not applicable to pteridines. 

In a similar way, ethyl 3-amino-6-hydroxyiminomethyl-2-pyrazinecarboxylate 4-oxide (314) gave ethyl 3-amino-6-(5-phenylisoxazol-3-yl)-2-pyrazinecar-boxylate 4-oxide (315) (as before but using PhC=CH 55%) 836 also many analogues for elaboration to pteridines.836... 

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]

The oxidations of 2-amino-3-cyanopyrazine 1-oxides to the 1,4-dioxides are described in Section VIII.3A(4) and deoxygenations of some 2-amino-3-cyano-pyrazine 1-oxides and 1,4-dioxides with phosphorus trichloride or sodium dithionite in Section VIII.3C(4). Deoxygenation and chlorination of aminocyanopyrazine 1-oxides are reported in Section V.IG, and deoxygenation and acetoxylation or alkoxylation of 2-amino-3-cyano-5-methylpyrazine 1,4-dioxide in Section VIII.3C(5). Hydrolysis of cyanopyrazine Y-oxides to carbamoylpyrazine Af-oxides are given in Section 10A(3) and ring closure reactions of 2-amino-3-cyanopyrazine 1-oxides to pteridine 8-oxides in Section V11I.3C(3). 

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