Nitropyrimidines synthesis

An 8000-member library of trisamino- and aminooxy-l,3,5-triazines has been prepared by use of highly effective, microwave-assisted nucleophilic substitution of polypropylene (PP) or cellulose membrane-bound monochlorotriazines. The key step relied on the microwave-promoted substitution of the chlorine atom in monochlorotriazines (Scheme 12.7) [35]. Whereas the conventional procedure required relatively harsh conditions such as 80 °C for 5 h or very long reaction times (4 days), all substitution reactions were found to proceed within 6 min, with both amines and solutions of cesium salts of phenols, and use of microwave irradiation in a domestic oven under atmospheric reaction conditions. The reactions were conducted by applying a SPOT-synthesis technique [36] on 18 x 26 cm cellulose membranes leading to a spatially addressed parallel assembly of the desired triazines after cleavage with TFA vapor. This concept was later also extended to other halogenated heterocycles, such as 2,4,6-trichloropyrimidine, 4,6-dichloro-5-nitropyrimidine, and 2,6,8-trichloro-7-methylpurine, and applied to the synthesis of macrocyclic peptidomimetics [37]. 

Solid-phase synthesis of dihydropteridinones has been achieved from 4,6-dichloro-5-nitropyrimidine <00TL8177>. A series of ethyl 7-aminopteridine-6-carboxylate derivatives has been prepared in one step from the reaction of vicinal diamines as 13-dialky 1-5,6-diamino-2-thiouracils with diethyl ( )-2,3-dicyanobutenedioate <99JHC1317>. The relative binding affinities to human dihydrofolate reductase of new 2,4-diaminopteridine derivatives... 

Intermolecular N-C-C transfragment replacement occurs less widely than the N-C-N replacement. A synthesis of alkyl(aryl)pyrimidines has been published that was based on the replacement of the N-C-C fragment of the pyrimidine ring by an identical sequence of atoms derived from a ketone in the presence of ammonia [94H(38)249]. Heating a solution of 3-methyl-5-nitropyrimidin-4(3//)-one (120) in acetonitrile with cyclohexanone and ammonia gas in a sealed tube at 100°C for 3 hours gave tetrahy-... 

ANTA (114) readily forms a stable anion on reaction with bases like sodium ethoxide and this anion has been used as a nucleophile for the synthesis of many ANTA derivatives. Laval and co-workers synthesizedDANTNP (116) (calculated VOD 8120 m/s, = 1.84 g/cm, m.p. > 330 °C) from the reaction of 4,6-dichloro-5-nitropyrimidine (115) with two equivalents of ANTA (114) in the presence of sodium ethoxide. Agrawal and co-workers studied the thermal and explosive properties of both ANTA and DANTNP and suggested their use for applications in propellant/explosive formulations where insensitivity coupled with thermal stability is of prime importance. The activation energies of ANTA and DANTNP indicate that DANTNP is more thermally stable than ANTA. 

Pagoria and co-workers synthesized a number of thermally stable explosives from the reaction of the sodium salt of ANTA with chloro-substituted arylenes and A-heterocycles. These include the synthesis of (117) from picryl ehloride, PRAN (118) from 2-chloro-3,5-dinitropyridine, IHNX (119) from 2,4-dichloro-5-nitropyrimidine, (120) from 1,5-dichloro-2,4-dinitrobenzene, and (121) from 4-chloro-6-(3-nitro-l,2,4-triazolyl)-5-nitropyrimidine. Coburn and co-workers " reported the synthesis of the tetrazine (122) and the triazine (123) from the reaction of the sodium salt of ANTA with 3,6-dichlorotetrazine and cyanuric chloride respectively. 

Nair and Baugh have described the synthesis of isoFA (462) (Scheme 3.92) [202]. Arylation of (457) with 2-amino-6-chloro-4-hydroxy-5-nitropyrimidine in refluxing aqueous ethanol gave (458). Reduction of (458) with sodium... 

Stepwise pyrazine ring-formation using 5-nitropyrimidine was applied to the synthesis of 4a-hydroxytetrahydrobiopterin (95), which is an interesting intermediate in the metabolism of aromatic amino acids (see Sect. 5.2). As illustrated in Scheme 18, the 5-aminopyrimidine 97 prepared from chloroni-tropyrimidine 96 by nucleophilic substitution followed by catalytic hydrogenation was oxidized under acidic conditions to o-quinone derivative 98. 

The synthesis of N-alkylated dihydropteridinones 34 started with a displacement reaction of 4,6-dichloro-5-nitropyrimidine with a fluorous amino-ester (Scheme 23) [53]. The compounds formed 35 were then reacted with secondary amines to yield 36. The reduction of the nitro group of 36 was conducted by hydrogenation using Pd on charcoal as a catalyst. The cyclization reactions of 37 were promoted by microwave irradiation. The N-alkylation reaction of the cyclized products 38 with benzyl halides gave monobenzylated... 

Another important synthesis involves the reductive cyclization of 4-ethoxyalkylidinehydrazino-5-nitropyrimidines of type (372), which are obtained readily by reaction of 4-hydrazino-5-nitro-pyrimidines (371) with ortho esters. Catalytic reduction of the nitro group in (372) affords the 5-aminopyrimidine intermediate (373), which cyclizes in situ to the dihydro product (374). This may be oxidized without isolation to give the fully aromatic product (375). These reactions are shown in... 

Solid-phase syntheses of pyrimidines continue to appear at a rapid pace. Solid-phase syntheses of olomoucine from 4,6-dichloro-2-(methylthio)-5-nitropyrimidine <02TL8071> and of 2,6-disubstituted 4(3//)-quinazolinones from 2,4-dichloro-6-hydroxyquinazoline <02TL2971> have been developed. 2-(Arylamino)quinazolinones 83 were accessed by a traceless parallel solid-phase route from 2-nitrobenzamides 82 <02JOC5831>. A solid-phase synthesis of quinazolin-4(3W)-ones with 3-point diversity relied on the use of immobilized arylguanidines <02TL5579>. 

The action of hydrazine or hydroxylamine on certain other nitropyrimidine systems leads to 4-nitropyrazoles and 4-nitrooxazoles [549], When 1,5-disubstituted 4-nitro-6-pyridazinone derivatives are heated in an alkaline medium the derivatives of 4-nitropyrazole are formed with high yields. 1-Substituted 4-nitropyrazole-5-carboxyiic acids [550, 551] or 1-substituted 4-nitropyrazoles [552-554] can be obtained, depending on the conditions. Another promising method of synthesis has been opened up for the production of 4-nitropyrazole derivatives. 4-Nitropyrazole is obtained with a high yield in the reaction of 3,5-dinitro-2-pyridone with hydrazine [555] (Scheme 99). 

Several condensed 5-nitropyrimidine derivatives have also been prepared from appropriate nitro-containing precursors. 2-Nitromethylene hexahydro-azepine (127) forms an adduct with benzoyl isothiocyanate which, during recrystallization from acetic acid, cyclizes to the pyrimido[3,4-a] azepine 128 (Scheme 25).119 This seems to be the only example of the use of a type 2 synthon for the synthesis of a 5-nitropyrimidine. 

Other reactive chlorine compounds used in the synthesis of carbodiimides include 2,4-dichloro-5-nitropyrimidine, ° 1-chlorobenzothiazole, 2-chlorobenzothiazole, 2-chloro-... 

Usually, the pyrimidine ring used in the Traube synthesis carries two amino groups in the 4-and 5-position. I lowevcr, the condensation reaction can also be performed with other precursor molecules. The most common ones are 5-nitropyrimidin-4-amines and 5-nitrosopyrimidin-4-amines, as well as 5-azopyrimidin-4-amines. 

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. 

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... 

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