Diazines reaction with nucleophiles

All the halo-diazines, apart from 5-halo-pyrimidines, react readily with soft nucleophiles, such as amines, thiolates and malonate anions, with substitution of the halide. Even 5-bromopyrimidine can be brought into reaction with nucleophiles using microwave heating. All cases are more reactive than 2-halo-pyridines the relative reactivities can be summarised ... 

Unsaturated 5(4//)-oxazolones derived from aromatic and heterocyclic aldehydes including phthalic anhydride/ antipyrine/ " chromone/ indoles/ pyridines/" ° quinolines/" diazines/" benzoxazoles/" and benzimidazoles " " have been prepared. Reaction with nitrogen nucleophiles and subsequent cycliza-tion leads to the expected 5(477)-imidazolones. 

Other factors can influence the rate of quatemisation all the diazines react with iodomethane more slowly than does pyridine. Pyridazine, much more weakly basic (p/faH 2.3) than pyridine, reacts with iodomethane faster than the other diazines, a result which is ascribed to the a effect , i.e. the increased nucleophilicity is deemed to be due to electron repulsion between the two immediately adjacent nitrogen lone pairs. Reaction rates for iodomethane with pyridazine, pyrimidine and pyrazine are respectively 0.25,0.044 and 0.036, relative to the rate with pyridine. 

The reaction of nucleophilic radicals, under acidic conditions, with heterocycies containing an imine unit is by far the most important and synthetically useful radical substitution of heterocyclic compounds. Pyri-dines, quinolines, diazines, imidazoles, benzothiazoles and purines are amongst the systems that have been shown to react with a wide range of nucleophilic radicals, selectively at positions a and y to the nitrogen, with replacement of hydrogen. Acidic conditions are essential because A-protonation of the heterocycle... 

The diazines are very susceptible to nucleophilic addition pyrimidine, for example, is decomposed when heated with aqueous alkali by a process that involves hydroxide addition as a first step. It is converted into pyrazole by reaction with hot hydrazine. 

Tetrafluoropyrazine Reactions of tetrafluoropyrazine with nucleophiles occur readily (Fig. 8.16) and, of course, there are no issues regarding regioselectivity of the first nucleophilic substitution process due to the symmetry of this system. The reduced reactivity of tetrafluoropyrazine compared to the other perfluorinated diazines reflects the absence of highly activated sites para to ring nitrogen. 

Chloro-benzo-l Athia-2,4-diazine 161 (R = CF3) affords 1-amino adducts 162 upon reaction with piperidine and cyclohexylamine (Scheme 12) <2002UKZ44>, while treatment of 161 (R = CCl3, CF3, Ph) with malonate-type nucleophiles produces ylides represented as 163 (X = C02R, CN) (Scheme 12) <2002UKZ80>. 

Nucleophilic substitution of common nucleofuges such as halogenes is one of the most well-studied reactions in the chain-fluorinated diazine series. Analysis of the literature data shows that nearly 90 % examples of chain-fluorinated halodiazine reactions with N-, S-, and 0-nucleophiles refer to pyrimidine derivatives (Table 47). Only 2- and 4-fluoroalkyl-5-halopyrimidines have received almost no attention in these transformations. Data on nucleophilic substitution of halogens in chain-fluorinated diazines correlates with the accessibility of the corresponding substrates, and to a lesser extent - with their reactivity towards nucleophiles. 

The chemistry of diazines remains an area of intense interest, both academic and industrial, with applications in many areas, from biomedical to materials science and electronics. They are versatile, having very varied reactivity, giving many opportunities for manipulation of substituents. Nucleophilic substitutions, electrophilic substitution in oxy and amino derivatives, organometallic and transition metal-catalysed coupling reactions are all subjects of substantial research effort. There are obvious similarities in reactivity of the three diazine systems but also many interesting and practically important, often subtle, differences. 

The reaction of 1,2-diazinamines with electrophiles is well studied while the substitution of amines-imines by nucleophiles is a highly nonstandard process. Nevertheless, even in the latter class new examples appeared since CHEC-II(1996) <1996CHEC-II(6)1>. A new section dealing with the so-called f-amino effect was added since many examples on 1,2-diazines have appeared since the mid-1990s. 

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