2.4.6- trisubstituted pyrimidines

Many pyrimidine derivatives have been prepared via the Pinner procedure. Amidines react with 1,3-dicarbonyl compounds to form 2, 4, 6-trisubstituted pyrimidines. ... 

A wide range of 2,4,6-trisubstituted pyrimidines were quatemized by Curd et al. during the Antricyde project, and the results are given in Table III, Apart from the possible steric effect of the anilino group,... 

Fig. 19 Synthesis and cyclative cleavage of 2,4,6-trisubstituted pyrimidines using microwave-assisted solid-phase protocol. Reagents and conditions a DMF, camphorsul-phonic acid, MW 80 °C, 30 min, open vessel b EtONa, EtOH/THF (4/1), MW 130 °C, to min, closed vessel. Y = O, NEt2 R = Me, i-Pr R = Et R" = H, alkyl, cycloalkyl, aryl, benzyl R" = H, Me, Et...

Reaction of amidoximes with dicarbonyl compounds in the presence of Ru3(CO)i2 afforded pyrimidine derivatives" . Reaction of oximes of type RCH=CMeC(=NOH)Me with R NCN also leads to pyrimidines" . a-Halo- and dihaloketoximes and Grignard reagents undergo dimerization to 2,4,6-trisubstituted pyrimidines" " For example. 

After carbonylative alkynylation of aryl iodides 34 with terminal alkynes 4 and in the presence of carbon monoxide under ambient pressure the subsequent addition of an amidinium salt 32 gives rise to the formation of 2,4,6-trisubstituted pyrimidines 33 in the sense of a four-component reaction (Scheme 25) [143]. 

Scheme 48 Cl-cyclocondensation three-component synthesis of 2,4,6-trisubstituted pyrimidines 89...

Likewise, upon CIR of electron-deficient (hetero)aryl halides 11 and (hetero)aryl propargyl alcohols 12, and subsequent addition of amidinium salts 32, 2,4,6-trisubstituted pyrimidines 89 can be obtained in a consecutive three-component reaction in good yields (Scheme 48) [241]. Interestingly, in all cases the aromatic products 89 are found and not the expected dihydropyrimidines, regardless whether the reaction has been performed under an anaerobic or an aerobic atmosphere. Therefore, it can be assumed that the presence of the transition metal catalysts is beneficial for a terminal aromatizing dehydrogenation. 

In a standard method, 1,3-diketones are cyclocondensed with amidines, ureas, thioureas and guanidines giving 4,6-di- and 2,4,6-trisubstituted pyrimidines 4, 2-pyrimidones 5, 2-thiopyrimidones 6 and 2-aminopyrimidines 7 respectively Pinner synthesis) [140] ... 

The high selectivity in sequential nucleophilic substitution in perfluorodiazines made them attractive scaffolds for the synthesis of a diverse array of polysubstituted diazines. These approaches were recently developed by Stanford group. Thus, tetra-fluoropyritnidine may be used as a scaffold for the synthesis of a range of 2,4,6-trisubstituted pyrimidine derivatives upon sequential displacement of the fluorine atoms attached to the strongly activated 4-, 6- and 2-positions (Table 9) [158]. The first two substitutions proceed in very mild conditioned (0 °C or room temperature). The last nucleophilic substitution of fluorine at 2-position proceeds in harsh conditions and needs MW heating. 

Pyridine can become involved in nucleophilic substitution when very reactive triflates are being synthesized. One approach to minimize this disadvantage is to replace it with ster-ically hindered bases, such as 2,6-di-r-butyl-4-methylpyridine, 2,4,6-trisubstituted pyrimidines, or nonnucleophilic aliphatic amines (usually N,(V-diisobutyl-2,4-dimethyl-3-pentylamine). No salt formation appears to take place under these conditions. The triflic anhydride seems to be the direct triflating agent and the base only neutralizes the triflic acid formed. Numerous alkyl triflates have been prepared in the literature by the above method. Some recent examples of triflates prepared from alcohols are illustrated in eqs 2 and 3. As an exception, 2,6-dinitrobenzyl alcohol does not react with Tf20 although similar sulfonyl esters could be prepared. ... 

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