Heteroaromatic-substituted pyrimidines

The third quite unique approach to the title system is a [1,3]-dipolar cycloaddition between a substituted pyrimidine 482 and an arylnitrilimine <1994LA1005>. In this reaction, the C=N bond of the heteroaromatic pyrimidine ring fulfills the role of the dipoloarophile. A [l,3]-dipolar cycloaddition has been applied to prepare 483 <2003PS1101, 2004PS601>. 

Nucleophilic substitution reactions (SnAt) are among the most common transformations of pyrimidines. Direct displacements of a variety of leaving groups have been reported, such as the reactions of 23 with heteroaromatic nucleophiles which produced 2-substituted pyrimidines 24 <99JCS(P1)1325>. 

This reaction exemplified the difference between the reactivity of polychloropyrimidines with heteroaromatic and that with aliphatic nucleophiles, which predominantly yield 4-substituted pyrimidines. For example, a series of trichloropyrimidines 25 reacted with various Grignard, lithium, sodium, and tMolate reagents (R2M) to produce mainly 26, along with occasional, minor amounts of the competitive products 27 <99SC1503>. 

The pyridine family of heteroaromatic nitrogen compounds is reactive toward nucleophilic substitution at the C(2) and C(4) positions. The nitrogen atom serves to activate the ring toward nucleophilic attack by stabilizing the addition intermediate. This kind of substitution reaction is especially important in the chemistry of pyrimidines. 

Thus, the unsubstituted starting compound 69 was treated with resorcinol in the presence of trifluoroacetic acid (TFA) to yield 70. Then, reaction of 69 with the cyclic a,/3-unsaturated ketone in the presence of lithium hydride gave the 7-substituted heteroaromatic compound 71, and ethyl cyanoacetate afforded the cross-conjugated product 72, whereas reaction with pyrimidine-2,4,6-trione in the presence of triethylamine yielded the addition product 73. Indole also been reacted with 69, and heating of the dichloromethane solution for 90 min in the presence of TFA yielded the addition product 74 in excellent yield (95%) <1998ZOR450> (Scheme 12). 

N-Arylations of amines have also been realized with support-bound heteroaromatic halides (Entries 9-11, Table 10.4). Several examples of the synthesis of substituted 1,3,5-triazines [83-85], purines [78,85-93], and pyrimidines [77,85,94—96] have been reported. The reactivity of these arylating agents depends strongly on their precise substitution pattern, and generally increases with decreasing electron density of the het-eroarene. Illustrative examples are given in Table 10.4. The arylation of amines with simultaneous cleavage of the product from the support is discussed in Section 3.8. 

It should be noted that for N-substituted dihydropyridines and pyrimidines, an alternative aromatization is observed. It includes the elimination of a substituent from the nitrogen atom [246, 247, 288, 289] (Schemes 3.88, 3.89). Heteroaromatized derivatives of pyrimidine, in addition, can be obtained as a... 

Biological pyrimidines, tautomerism and electronic structure of, 18, 199 Bipyridines, 35, 281 Boron-substituted heteroaromatic compounds, 46, 143 Bridgehead nitrogen saturated bicyclic 6/5 ring-fused systems with, 49, 193... 

Because the transmissions of the former and the latter effects through the benzene and pyrimidine systems are different (Section IV,C), the contributions of the inductive and mesomeric effects of the substituents to the electronic effects of the respectively substituted phenyl and pyrimidinyl groups have also been assumed to be different. The transmissions of electronic effects of substituents through heteroaromatic systems are numerically expressed by means of the transmission factors Vi and Vr (Section IV,B). The products Viflphff (Y) and VR Ph RlY) can therefore serve as numerical characteristics of the contributions of the inductive and mesomeric effects of the substituent Y to the electronic effects of a substituted heteroaromatic group. Thus, for substituted pyrimidinyl groups, Eqs. (38) and (39) take the form ... 

At one time the idea of recording a mass spectrum of a nucleic acid would have been considered utopic and futuristic. Nucleic acids are practically nonvolatile and usually possess a molecular weight of several million atomic mass units (amu) (fi) often expressed in daltons up to 10 daltons where 1 dalton = 1.67 X 10 g. They possess their own mass spectra. In general they are esters of phosphoric acid and polyols, such as the sugars ribose and 2 -deoxyribose, which are themselves substituted with heteroaromatic purine or pyrimidine bases. Consequently, fragment ions characteristic of all these structural elements can be found in the mass spectra of nucleic acids. 

The SNAr reactions of heteroarenes can be realized in a similar manner, as in the series of arenes [71, 82]. These nucleophilic reactions are analogous to electrochemical Sn transformations of arenes [22, 24, 25]. Terrier and co-workers considered an opportunity for electrochemical methoxylation of 4,6-dinitrobenzofuroxan by action of the methoxide ion via the SnAt mechanism [21]. The intermediate o -complex formed was oxidized successfully into the corresponding substitution product. Analogously, the formation of heteroaromatic amines has been suggested to occur via intermediacy of the corresponding amino adducts, as exemplified by the oxidation of the o -complex derived fi om the reaction of pyrimidine with NH2 (Scheme 26) [3, 102-104]. 

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