Diazines nucleophiles

Chlorophthalazine is quite reactive to many basic nucleophiles but reacts sluggishly with aqueous or alcoholic alkali. In contrast, it is very rapidly hydrolyzed by warm, concentrated hydrochloric acid as are its diazine isomers. In hydrolysis with very dilute acid or with water, it forms some phthalazinone but mostly the self-con-densation product which hydrolyses to give 2-(l -phthalazinyl)-phthalazin-l-one (70% yield). Such self-condensations in diazanaph-thalenes and in monocyclic azines are always acid-catalyzed (Sections II, C and III,B). With methanolic methoxide, 1-chlorophthalazine (65°, few mins), its 7-methoxy analog (20°), and 1,6- and 1,7-dichlorophthalazines (20°) readily undergo mono-substitution. 

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. 

JAP(K)48664. 4-Diazo-5-thiocarbamoylimidazole at pH 5 intramolecu-larly cyclized with the more nucleophilic sulfur to give the imidazo-thia-diazine 228 instead of the imidazotriazine-4-thione 229, which was expected by analogy with the 4-diazoimidazole-5-carboxamide (73KGS1292) (Scheme 65). 

As described in detail in CHEC-II(1996) <1996CHEC-II(6)1 > N-acylation of 1,2-diazines is often used to make the nucleus more susceptible for nucleophilic attack (see Section 8.01.5.4.4). Intramolecular reactions on nitrogen... 

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. 

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. 

Adducts of diazines were obtained by Zoltewicz as deeply colored solutions upon addition to KNH2 or NaNH2 in liquid ammonia.89 The H-NMR spectra (Table X) show that in the presence of an excess of amide ion diazines are completely converted to adducts, whereas with less than the equimolecular amount of the nucleophile, signals of both free diazines and the corresponding adducts, but no signal averaging, are observed. The adduct solutions are stable for days at -70°C, but the spectra change irreversibly at room temperature. No isolation of the diazine adducts has been reported. 

Reactions of powerful alkyllithiums with halo pyridines, quinolines, and diazines may lead to nucleophilic substitution (by addition-elimination or hetaryne mechanisms), ring opening, halogen-scrambling, and coupling reactions, which compete with the desired DoM process. 

The reactivity of 1,8-naphthyridine (27) is greater than expected.61,79 Here, unlike the diazines, the two heteroatoms with their unshared electron pairs are in separate rings. After correction for the two kinetically equivalent reactive sites, the rate constant for 27 is nearly the same as that for pyridine and four times larger than that for quinoline. These results are surprising, especially when it is remembered that the diaza substrate is substantially less basic than the comparison compounds. Correcting for the diminished nucleophilicity expected to be associated with the lower basicity of 27 serves to make the reactivity comparisons even more striking.61... 

The extensive kinetic data available for quaternization of substituted pyridines and derivatives, such as benzologs and diazines, under a uniform set of conditions make possible the calculation of substituent rate factors that are of considerable value in dealing with new substrates. When a heteroaromatic molecule has two or more nucleophilic annular positions that can react, often it is possible to estimate, in some cases very accurately, the ratio of quaternized products using these rate factors. 

Diazines are considerably more reactive toward nucleophiles than pyridines and as the number of ring nitrogens increases the propensity for nucleophilic addition reactions increases still more. Many 1,2,4-triazines give addition products with various nucleophiles which are formally dihydrotriazines. 

Reactivity increases in the diazines as compared with pyridines. 3-Chloropyridazine (910) and 2-chloropyrazine, for example, undergo the usual nucleophilic replacements (cf. Section 3.2.3.10.6.ii) rather more readily than does 2-chloropyridine. 2-, 4- and 6-Halogen atoms in pyrimidines are easily displaced. The reactivity of halogens in pyridazine 1-oxides toward nucleophilic substitution is in the sequence 5 > 3 > 6 > 4. 

Diazines other than diketopiperazines can also be prepared on insoluble supports (Table 15.31 see also Figure 3.13 [382]). Most strategies are based on intramolecular nucleophilic substitutions or acylations. Several examples of the solid-phase preparation of quinoxalinones have been reported. In most cases, the compounds have been prepared from support-bound 2-fluoronitrobenzenes according to the strategies outlined in Figure 15.18. Alternatively, a-amino acid esters bound to polystyrene as IV-benzyl derivatives can be N-arylated with 2-fluoronitrobenzene. Reduction of the resulting 2-nitroaniline leads to the formation of quinoxalinones [383]. 1,4-Diazines have been chemically modified by N- or C-alkylation on insoluble supports (Entries 9 and 10, Table 15.31). 

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