6-Aminopyrimidine, reaction with

Finally, Katritzky et al.sii have measured first-order rate coefficients for deuteration of pyrimidines by deuterated sulphuric acid (Table 152), and all pD and —D0 values given in the Table refer, as in the earlier work, to a temperature of 20 °C. For 2-aminopyrimidine, reaction clearly occurs on the free base and comparison of the data with the earlier work on anilines and by making a number of assumptions, conjugate acid at higher acidities is apparent and this follows the previously established pattern. This work yielded a value of 0.55 for [Pg.236]

The resin-bound reagents thus obtained were reacted with a variety of nucleophiles to give different heterocycles (Scheme 13). So, reaction with hydrazine or hydroxylamine gave respectively pyrazoles and isoxazoles in excellent yields (94-99%, 34 examples) and excellent purities (> 95%). Reaction with guanidines afforded 2-aminopyrimidines. 

Ring B of pyrimido[l,6-tf]pyrimidines has been most frequently synthesized from [3+3] atom fragments. The 6-aminopyrimidin-2-one derivative, cytidine 211, on reaction with acrylic acid under thermal conditions gave the pyrimido[l,6- ]pyrimidin-4,6-dione 212 <1996MI301> while reaction with 3-chloropropionaldehyde under base catalysis resulted in the pyrimido[l,6- ]pyrimidine-6-one 213 (Scheme 33) <1996MI501, 1996BAP209>. 

Aminopyrimidines react with DMAD in the presence of a catalytic amount of a strong acid to give pyrrolo[3,4-f]pyridines in a cycloaddition reaction (Equation 66) <2001SL57>. In the absence of the acid catalyst, aminopyridines are produced in the reaction. 

The reaction of 4,6-dichloro-5-aminopyrimidine 396 with phenyl isothiocyanate in the presence of triethylamine afforded directly 7-substituted aminothiazolo[5,4-4]pyrimidines 397 in a modest yield (Equation 61). Better yields... 

The analogous reaction to that described in Equation (42) using paraformaldehyde in equimolar amount to dimedone (instead of a large excess) was irradiated for 3 min to yield pyrimido[4,5- ]quinoline-4,6-dione 591 via formation of intermediate adduct 590 <2006TL27>. The 5-aryl-5,6,7,8,9,10-hexahydropyrimido[4,5-/ ]quinolines 592 were also prepared by the cyclocondensation reaction of 6-aminopyrimidine 460 with dimedone and 4-sub-stituted benzaldehydes by boiling in absolute ethanol for 30 min <1998JHC231>. 

A compound that includes an aminopyrimidine ring as well as the quaternary salt present in thiamine shows preferential inhibition of absorption of that co-factor by coccidia parasites over uptake by vertebrates. The compound is thus used in poultry where coccidiosis is an economically important disease. Condensation of ethoxymethylenemalononitrile (42-1) with the amidine (42-2) leads to the aminopyrimidine (42-4), probably via the intermediate addition-elimination intermediate (42-3). The nitrile group is then reduced to the methylamino derivative (42-5) by means of hthium aluminum hydride. Exhaustive methylation, for example by reaction with formaldehyde and formic acid, followed by methyl iodide leads to the quaternary methiodide (42-6). The quaternary salt is then displaced by bromine, and the resulting benzyhc-like cylic halide (42-7) is displaced by 2-picoline (42-8). There is thus obtained amprolium (42-9) [43]. 

Aryl-l, 2,4-triazolo[l, 5-a]pyrimidines (17) were prepared by oxidative cyclization, by the action of lead tetraacetate (LTA), of 2-pyrimidylary-lamidines (16), first prepared by the reaction of 2-aminopyrimidines (15) with aryl cyanides in the presence of A1C13 (90SC2617) (Scheme 6). 

Most derivatives of this ring system are prepared from 2-aminopyrimidines. Ethoxy-methylenemalonic ester (220) is a versatile synthon which can be reacted with 2-aminopyrimidines to give pyrimido[l,2-a]pyrimidine precursors. Reaction of 2-aminopyrimidine (219) with this ester gives the aminomethylenemalonic ester (221), which can be thermally cyclized to the heterocyclic ester (222). The enamine analogous to (221) which is derived from 2-amino-4,6-dimethylpyrimidine cannot be cyclized under these conditions. Presumably this cyclization fails due to steric hindrance of the methyl groups (72JMC1203). 

The heteroaromatic betaine (110) is formed in the reaction of 4,6-dimethyl-2-methyl-aminopyrimidine (234) with carbon suboxide (73JOC3485). 

Chlorinated pyrimidines themselves are often accessible from the corresponding pyrimidones by reaction with phosphorus oxychloride. (Again, see Chapter 5 for an explanation of this sort of reaction.) For instance, aminopyrimidine 10.24 can be synthesised by the classical sequence depicted below. 

Azine approach. The fused pyrimidines can be synthesized in the same way as the pyridines, e.g. by the cyclization of vicinal aminothiocyanates (70JCS(C)2478>. Another useful method for aminoazines is the reaction with chlorocarbonylsulfenyl chloride, e.g. with the aminopyrimidine (440) (73LA1018). The reaction can be rationalized by initial acylation of the amino group which is then cyclized with formation of the 2(3//)-one (441). Another case is the reaction of the 6-aminouracil (442) with thionyl chloride (69JOC3285). The reaction is rationalized as an initial electrophilic substitution at the 5-position of the activated pyrimidine. Subsequently the chlorosulfinyl derivative (443) is cyclized to a thiazoline S-oxide which loses water to yield the thiazole. 

The treatment of 4,6-dichloro-5-aminopyrimidine 1198 with indoline 1197 gave 4-chloro-6-(2,3-dihydro-l//-indol-l-yl)-5-pyrimidinamine 1199 in 79% yield (Scheme 230) <2005JC0813>. Subsequent oxidation of the indoline moiety to the corresponding indole was achieved with DDQ in refluxing benzene to yield the indole-substituted pyrimidine 1200, the key compound in the cyclization reactions with various aldehydes and ketones leading to a novel heterocyclic scaffold consisting of indole-fused pteridines. 

Using a carboxamide group as a source of an amino group by applying Hoffman type reactions, it has been possible to prepare several purines. Thus 4-aminopyrimidine-5-carboxamide and alkaline hypochlorite gave, a 60% yield of 8-oxo-7,8-dihydropurine (302) (62CB956), and the same authors achieved a Curtius reaction with a 4-aminopyrimidine-5-carbohydrazide and nitrous acid (Scheme 113). 

Reaction of 2-aminopyrimidines 1525 with a-bromocarbonyl compounds 1526 affords imidazo[l,2- ]pyrimidinium salts 1528, which undergo a ring-opening process in the presence of hydrazine to yield 2-aminoimidazoles 1529 in good yields (Scheme 395) <20060L5781>. 

Analogous condensation with guanidine gave 2-aminopyrimidines (e.g. 28 a) reaction with benzamidine gave 2-phenylpyrimidines (e.g. 28b). 

Annulation of aminomethyl and ring-nitrogen functions with ethyl acetimi-date hydrochloride gives a good yield of a dihydroimidazo compound [3736]. Glyddylaldehyde reacts with guanine derivatives to give the linear tricyclic pr uct [3066]. 6-Aminopyrimidine-2,4-diones are converted into purines by reaction with diethyl azodicarboxylate [2914]. The chemistry of a-halo-aldehydes and -ketones has been reviewed [B-4S, 2348]. 

Hie cyclic anhydride (80.4) reacts with trimethylsilyi azide under anhydrous conditions to give a mixture of I,3-oxazine-2,6-dione isomers, which was used without further purification to synthesis several extended purines. Reaction with formamidine acetate in DMF in effect replaced the furandione ring by a pyrimidinone. Cyanamide produced a new fiued 2-aminopyrimidin-4-one [in (80.5, R = NH )], while urea led to a pyrimidinedione. Isatoic anhydride similarly yields 2-aminoquinazolin-4-one on treatment with cyanamide-DMF. 

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