Pyrimidines electrophilic substitution

The reaction involves an electrophilic attack into the 5-position of the pyrimidine ring and thus only those pyrimidines that are activated toward electrophilic substitution by the presence of electron-donating substituents at the 2- and 4-positions undergo cyclization. 2,4,6-Triaminopyrimidine, 6-aminouracil, 6-amino-2-thiouracil, 4-amino-2,4 dimercaptopyrimidine, 2,4-diaminopyrimidin-6(l/I)-one, and various 4-amino-vV-alkyl and aryl pyriinidones have all been converted into pyrido[2,3-[Pg.160]

Electrophilic substitution at ring nitrogen atoms has been limited to protonation and iV-alkylation of the anion derived from a pyrido-pyrimidinone.i - Thus, the sodium salt of pyrido-[2,3-d]pyrimidine-2,4-(l//,3ir)-dione and dimethylsulfate yield the 1,3-dimethy] derivative (176). 

When 7r-deficient thiadiazoles are fused to an azine, electrophilic substitution is possible only in the presence of strongly electron-donating substituents (74BCJ2813) (Scheme 56). Some [l,3,4]thiadiazolo[3,2-a]pyrimidin-5-ones were brominated next to the oxo group (90DOK743). 

Figure 1.44 Nucleophilic addition at C-6 of the pyrimidine double bond can cause electrophilic substitution to occur at the C-5 position.

Due to the electronegativity of the two nitrogen atoms, pyrimidine is a deactivated, rc-electron-deficient heterocycle. Its chemical behavior is comparable to that of 1,3-dinitrobenzene or 3-nitropyridine. One or more electron-donating substituents on the pyrimidine ring is required for electrophilic substitution to occur. In contrast, nucleophilic displacement takes place on pyrimidine more readily than pyridine. The trend also translates to palladium chemistry 4-chloropyrimidine oxidatively adds to Pd(0) more readily than does 2-chloropyridine. 

Alkylation by electrophilic substitution applies to pyrimidines carrying at least two strongly electron-donating substituents and has been discussed in Section 8.02.5.3.6. 

Scheme 9 shows an example of selective electrophilic substitution at N-3 of [l,2,3]triazolo[4,5- pyrimidin-7-one reported by Ding et al., who showed that glycosylation can occur at the 4-position of diazido-2-deoxystreptamine derivative, if the alkyl halide is appropriately substituted at this position <2003AGE3409>. 

The nucleophilicity of the two nitrogen atoms in the pyrimidine ring of 5,7-dimethylpyrido[2,3- pyrimidine-2,4(177,37T)-dione toward electrophilic substitution has been found to be different. Thus, alkylation of its lithium salt with dimethyl sulfate gave the methylated products 139 and 140 in a 4.8 1 ratio. The ratio decreased to 2 1 in case of the sodium salt, whereas when the potassium salt was used, the main product was 140 <1996DOK33>. 

Pyrimido[4,5-c][l,2]thiazines have been synthesized by formation of 4-(alkanesulfonamido)pyrimidine bearing an electrophilic substitutent at C-5, and cyclization of an anion generated adjacent to the sulfonamide. The 5-sub-stituent can be a ketone (Equation 171) <2003W003/062246>, or a carboxylate or nitrile, in which case the product contains a carbonyl group at C-4 (Scheme 89) <2002W002/076463>. 

Reaction of 2-amino-3-phenylazo-5-methyl-6,7-dihydropyrazolo [ 1,5-a] -pyrimidine-7-one (209) with ACOH/H2SO4 gives the pyrazolo[l,5-a]-pyrimidine derivative 210 (77JHC155). This reaction can be looked at as electrophilic substitution of the arylazo function by the proton. Similarly, 4,5,6,7-tetrahydro-2-phenyl-3-phenylazo-5-oxopyrazolo[l,5-a] pyrimidine gives 4,5,6,7-tetrahydro-2-phenyl-5-oxopyrazolo[l,5-a]pyrimidine 212 by the action of acetic/hydrochloric acid (75T63). 

Electrophilic aromatic substitutions The chemistry of pyrimidine is similar to that of pyridine with the notable exception that the second nitrogen in the aromatic ring makes it less reactive towards electrophilic substitutions. For example, nitration can only be carried out when there are two ring-activating substituents present on the pyrimidine ring (e.g. 2,4-dihydroxypyrimidine or uracil). The most activated position towards electrophilic substitution is C-5. 

Electrophilic substitution reactions of thieno[3,2-cf pyridine occur at position 7 (equation 38). With dimethyl sulfate in an alkaline medium, thieno[3,2-cf pyrimidin-4-one (347) yields an N-methyl derivative. 

The C-3 atom of 4-oxo-4/f-pyrido[l,2-a]pyrimidines readily takes part in electrophilic substitutions. 4-Oxo-4//-pyrido[ 1,2-a]pyrimidines unsubstituted at position 3 may be transformed by nitrating agents to the 3-nitro derivatives37 42,52 96,1 16,293 and by halogenating agents to the 3-halo derivatives.18,34 108 253,255,294 Nitration of 2-benzyloxy-4-oxo-4H-pyrido-[ 1,2-a] pyrimidine was accompanied by debenzylation.116 Halogenation of the pyrido[l,2-a]pyrimidine (63 R = H) under forced conditions afforded the 2,3-dichloro derivatives.253,255... 

Electrophilic substitutions occur easily at position 3 of 4//-pyrido[l,2-a]pyrimidin-4-ones. 

The electrophilic substitution reactions of 1,3-dimethylpyrrolo[3,2-coupling yield 7-substituted products. However, nitration in acetic acid gives primarily attack at position 6. In some reactions 6,7-disubstitution is observed [95CHE(30)1077]. 

Formal replacement of a CH unit in pyridine 5.1 by a nitrogen atom leads to the series of three possible diazines, pyridazine 10.1, pyrimidine 10.2, and pyrazine 10.3. Like pyridine they are fully aromatic heterocycles. The effect of an additional nitrogen atom as compared to pyridine accentuates the essential features of pyridine chemistry. Electrophilic substitution is difficult in simple unactivated diazines because of both extensive protonation under strongly acidic conditions and the inherent lack of reactivity of the free base. Nucleophilic displacements are comparatively easier. 

As mentioned earlier, electrophilic substitution on unactivated pyrimidines is of little importance. But, as with pyridine, the pyrimidine nucleus can be activated towards electrophilic attack by employing N-oxides or pyrimidones, for the same reasons as were discussed in Chapter 5. 

Further studies of electrophilic substitution using the 2,3-dihydrothiazolo analogue (320) show that regioselective bromination can be effected in the 7-position (347) at low temperature. Chlorination with sulfuryl chloride, however, occurs exclusively in the 5-position. The 5-chloro derivative (348) can be further nitrated in the 7-position. By analogy, bromination of quinoline analogues (349) occurs in the azine ring, in the 5-position. The [3,2-a]pyrimidine analogue (350 R=H) similarly yields the 7-bromide. The activation by... 

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. 

This chapter is concerned with the electrophilic substitution of pyridaz-ine, pyrimidine, pyrazine, and their derivatives. Aspects of this topic have been reviewed previously [72AHC( 14)99 74AHC(16)1] and the general chemistry of the monocyclic azines has been surveyed in Comprehensive Organic Chemistry, Vol. 4 (1979) and Comprehensive Heterocyclic Chemistry, Vol. 3 (1984). 

With the introduction of electron-releasing substituents, as is the case with the biologically occurring pyrimidines, the tr electron deficiency is counteracted in such a manner that the system approximates an aromatic ring. The 2-, 4-, and 6-positions are now deactivated toward nucleophilic attack and electrophilic substitution is facilitated. 

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