Pyrimidine, oxidative amination

UV, 6, 652 <70BCJ3909) Oxazolo[5,4-d]pyrimidin-4-amine 5-oxide UV, 6, 652 <70BCJ3305)... 

Other approaches to related bicyclic systems include the reaction of 1,3-dicarbonyl compounds with l-amino-2(l//)-pyridin-2-amines or -pyrimidin-2-amines (Scheme 14) (94JHC1157] and the oxidation of 2- or 4-pyrimidinyl ketone arylhydrazones to yield triazolo[l,5-a - or -ll,5-c]pyrimidinium salts (Scheme 15). In this reaction 2,4,4,6-... 

The highly acidic conditions required to generate peracids in situ from carboxylic acids and hydrogen peroxide are usually not conducive to efficient amine oxidation. In situ generation from anhydrides in neutral solution or other acylated agents in alkali can be employed. In situ perphthalic or permaleic have been reported for pyrimidine oxidation.332... 

If the reaction of 9-halo-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l,2-a]pyri-midines and amines was carried out in the absence of air, the 9-amino-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidines were isolated, which could be oxidized by air to the 6,7-dihydro analogs. The latter were directly prepared from 9,9-dihalo-4-oxo-6,7,8,9-tetrahydro- or 9-hydroxy-4-oxo-6,7-dihydro-4/f-pyrido[l,2-a]pyrimidines ° with amines. 

The incorporation of a 3-carboxamidoxime group into the newly formed pyrimidine part of the pyrido[2,3-r(]pyrirnidine furnishes a 3-oxide function. Thus, 2-(benzoylamino)pyridine-3-carboxamidoxime (10) cyclizes in concentrated sulfuric or phosphoric acid to give 2-phenylpyrido[2,3-J]pyrimidin-4-amine 3-oxide (11).13... 

Phenylpyrido 2,3-[Pg.85]

The starting material used in the following method is prepared by converting 2-aminonicoti-nonitrile with dimethylformamide dimethyl acetal into 2-[(A,V-dimethylamino)methylamino]-pyridine-3-earbonitrile followed by hydroxylamine to give the 2-[(hydroxyimino)methylarnino]-pyridine-3-carboxamidoxime.14 Cyclization of the latter on heating with polyphosphoric acid yields pyrido[2,3-[Pg.86]

Pyrido[2,3-4[pyrimidin-4-amine 3-Oxide (12) Typical Procedure 14... 

A solution of NH2OH [prepared fromNH2OH HC1 (1.4 g, 20 mmol) and a solution of Na (0.46 g, 20 mmol) in MeOH (30 mL)] was treated with 2-[(dimethylamino)methylamino]pyridine-3-carbonitrile (0.87 g, 5 mmol). After standing overnight at rt the solvent was evaporated, the residue treated with some H20, and the product collected yield 0.7 g (72%) mp 190 205 °C (with cyclization into pyrido[2,3-4]pyrimidin-4-amine 3-oxide mp 270-275 CC). 

Vol. E 8c, p 513), may provide the C - N chain for ring-closure reactions.14 2-Aminonicotmami-doxime is cyclized with triethyl orthoformate to give pyrido[2,3-rf]pyrimidin-4-amine 3-oxide (12) or with acetic anhydride to give 4-(acetoxyamino)-2-methylpyrido[2,3-rf]pyrimidine (43).14... 

For the preparation of pyrido[2,3-d]pvrimidinc-2,4(l//,3//)-diones 28, an adaption of the Doebner-Miller quinaldine synthesis (cf. Houben-Weyl, Vol. E7a, p 363), can be used. The orientation of addition of oc,/5-unsaturated carbonyl compounds to pyrimidin-6-amines is governed by the attack of C5 of the pyrimidinamine at the carbon /5 to the carbonyl function.219 Besides pyrimidine-2,4,6-triamine,149 263 aminouracils are used as partners for the base-catalyzed reaction with a,/5-unsaturated ketones.148,219 264,570,571 Without the final oxidation step, which occurs mostly by air, the dihydro compounds are produced.265 Examples are the Michael additions of 4,4-dimethyl-l-phenylpent-l-en-3-one266 or of 1,3-diphenylprop-2-en-l-one264 to 6-amino-l,3-dimethylpyrimidine-2,4(l//,37T)-dione, which are followed by ring closure to give the corresponding pyrido[2,3-d]pyrimidme-2,4(l//,3//)-diones or their dihydro derivatives. 

Examples for the alkaline hydrolysis of acylated 2-amino groups are the formation of 6-bromo-l-methylpyrido[2,3-i/]pyrimidine-2,4(l//,3//)-dione (35) from 6-bromo-l-methyl-2-(pivaloylamino)pyrido[2,3-[Pg.151]

Heating pyrido[2,3-r/]pyrimidin-4-amine 3-oxide in water for 7 hours leads to the formation of 4-(hydroxyamino)pyrido[2,3-c/]pyrimidine as the main product.14 This compound apparently results from ring opening followed by ring closure involving the former 4-amino group. 

Ar-[(Ar,Ar-Dimethylamino)methylene]pyrido[2,3-c/]pyrimidin-4-amine 3-oxide (6) plays a central role as an educt for 3-(3-pyridyl)-l,2,4-oxadiazoles. Thus, it has been treated with carbon nucleophiles such as the anions of diethyl malonate, ethyl cyanoacetate, or pentanc-2,4-dione.417 After addition across the 2,3-bond, ring opening of the pyrimidine moiety with simultaneous 1,2,4-oxadiazole ring formation occurs. Evidently, the five-membered ring is formed easily through participation of the [(dimethylamino)methylene]amino and TV-oxide functions. 

Other ring openings of pyrido[2,3-r/]pyrimidin-4-amine 3-oxides with formation of 3-azolylpyri-dines are the reactions of pyrido[2,3-c/]pyrimidin-4-amine 3-oxide (7) with acetic anhydride to give yV-[3-(5-methyl-l,2,4-oxadiazol-3-yl)-2-pyridyl]formamide (8),14 or of 2-phenylpyrido-[2,3-r/]pyrimidin-4-amine 3-oxide (9) with hydrochloric acid to give A-p-fl, 2,4-oxadiazol-3-yl)-2-pyridyl]benzamide (10).13... 

Concomitant with the dehydration of 4-aminonieotinamide, the phosphoryl chloride/dimethyl-formamide reagent also converts the 4-amino substituent into the [(dimethylamino)-methylenejamino group, The resulting 4- [(7V,J V-dimethylamino)methylene]amino nieotino-nitrile (10) by cyclization with hydroxylamine hydrochloride at room temperature then yields pyrido[4,3-c/]pyrimidin-4-amine 3-oxide (11).452... 

Pyrido[4,3-d]pyrimidin-4-amine 3-Oxide (11) Typical Procedure 452... 

A partial aromatization of hexahydropyrido[4,3-potassium hexacyanoferrate(III).531 Starting from the hydrochloride of8-benzylidene-6-methyl-4-phenyI-3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidine-2-thiol, after methylation of the sulfanyl group, the oxidation gives 8-benzylidene-2-(methylsuIfanyI)-6-methyl-4-phenyl-5,6,7,8-tetrahydropy-rido[4,3-d]pyrimidine. In a similar way, several 4-aryl-8-arylidene-6-methyl-3,4,5,6,7,8-hexahy-dropyrido[4,3-rf]pyrimidin-2-amines have been partially aromatized.513... 

By cyclization with hydroxylamine hydrochloride at room temperature, 4- [(7V,/V-dimethy]-amino)methylene]amino pyridine-3-carbonitrile yields pyrido[4,3-rf]pyrimidin-4-amine 3-oxide.452 Due to traces of hydroxylamine hydrochloride, the attempted rccrystallization of the crude product from dimethylformamide furnishes 4-(hydroxyamino)pyrido[4,3-Dimroth rearrangement is avoided by removal of the impurities by suspending the crude product in water (see Section 7.2.2.4.1.1.1.). 

An example of this reaction is the synthesis of 4,6-dimethylpteridin-2-amine (1) from 2,4-dichloro-6-methyl-5-nitropyrimidine and aminoacetone. Initially 4-acetonylamino-2-chloro-6-methyl-5-nitropyrimidine is formed which, by reaction with ammonia, gives the corresponding pyrimidin-2-amine.132 This undergoes reductive cyclization to 4,6-dimethyl-7,8-dihydropteridin-2-amine, which may be subsequently oxidized (potassium permanganate) to l.133... 

The methods outlined, of course, are readily applicable to a wide variety of substituted heterocycles like the carboxyl, hydroxy and mercapto derivatives of pyridines, pyridine 1-oxides, pyrroles, etc. The application to amines and to diaza compounds such as pyrimidine, where the two centers are basic, is obvious except that now 23 takes the role of the neutral compound, 21 and 22 the roles of the tautomeric first conjugate bases, and 20 the role of the second conjugate base. Extensions to molecules with more than two acidic or basic centers, such as aminonicotinic acid, pyrimidinecarboxylic acids, etc., are obvious although they tend to become algebraically cumbersome, involving (for three centers) three measurable Kg s, four Ay s, and fifteen ideal dissociation constants (A ), a total of twenty-two constants of which seven are independent. 

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