1.3- Azoles nucleophilic substitution

If the fV-aryl group is strongly activated, then it can be removed in nucleophilic substitution reactions in which the azole anion acts as leaving group. Thus l-t2,4-dinitrophenyl)pyrazole reacts with N2H4 or NaOMe. 

Imidazole is a n-electron-excessive heterocycle. Electrophilic substitution normally occurs at C(4) or C(5), whereas nucleophilic substitution takes place at C(2). The order of reactivity for electrophilic substitution for azoles is ... 

Alkylthio groups are sometimes replaced in nucleophilic substitutions, but such reactions are difficult in most neutral azoles. Thus, 3-alkylthio-l,2,4-thiadiazoles resist the action of aniline at 100°C, ammonia at 120°C, molten urea and ammonium acetate. However, hydrazine attacks... 

Conversely, nucleophilic substitution (which we have seen in earlier chapters on 1,3-azoles and pyridines) does occur in these systems, especially when the carbon atom concerned is between two heteroatoms, as in the displacement reactions of oxadiazole 8.12 and tetrazole 8.13. 

The ease of nucleophilic substitution in the azine ring is increased after fusion with the azole. Substitution is also possible in the azole ring, especially in the fused isothiazole systems. 

So far little information is available on electrophilic substitution reactions these are mainly expected to occur in the azine ring when activated by electron-releasing substituents. Nucleophilic substitution reactions, however, occur readily in either ring. The N—S bond may be cleaved by nucleophilic attack at sulfur and this may be the preferential reaction path in some cases. The N—S bond may also be cleaved as a result of proton abstraction from the azole ring. 

Abstract Synthesis methods of various C- and /V-nitroderivativcs of five-membered azoles - pyrazoles, imidazoles, 1,2,3-triazoles, 1,2,4-triazoles, oxazoles, oxadiazoles, isoxazoles, thiazoles, thiadiazoles, isothiazoles, selenazoles and tetrazoles - are summarized and critically discussed. The special attention focuses on the nitration reaction of azoles with nitric acid or sulfuric-nitric acid mixture, one of the main synthetic routes to nitroazoles. The nitration reactions with such nitrating agents as acetylnitrate, nitric acid/trifluoroacetic anhydride, nitrogen dioxide, nitrogen tetrox-ide, nitronium tetrafluoroborate, V-nitropicolinium tetrafluoroborate are reported. General information on the theory of electrophilic nitration of aromatic compounds is included in the chapter covering synthetic methods. The kinetics and mechanisms of nitration of five-membered azoles are considered. The nitroazole preparation from different cyclic systems or from aminoazoles or based on heterocyclization is the subject of wide speculation. The particular section is devoted to the chemistry of extraordinary class of nitroazoles - polynitroazoles. Vicarious nucleophilic substitution (VNS) reaction in nitroazoles is reviewed in detail. 

Table I). Among these are (1) nucleophilic substitution reactions, (2) use of pyrylium salts, (3) generation of the azole nucleus in the last synthetic step, (4) condensation reactions, and (5) miscellaneous reactions. 

Nucleophilic substitution reactions of 5-chlorop5Tazoles 48 with amines and thiols under mild conditions provided 5-alkyl amino and thioether pyrazoles 49 as selective COX-2 inhibitors <03TL7629>. 4-Chloromethylpyrazoles 50 reacted readily with amides, carbamates, urea, azoles, alcohols, and thiols under neutral conditions to give substituted benzylic products 51 in moderate yields <03H(60)167>. 

Semi-empirical LCAO calculations for all azoles, introducing cr-electrons, indicate that charges are weak except those on NH nitrogen atoms, and that the cr-dipolar moments are close to those of lone pairs. It is therefore inappropriate to take cr-polarity into account in the approximations used in 7r-calculations for these heterocycles. A number of other quantum mechanical calculations have been applied to reactions of imidazoles (80AHC 27)241), while the nucleophilic substitution reactions at C-2 of benzimidazoles, and diazo coupling at C-2 of uncondensed imidazoles have been discussed from theoretical points of view. 

Vicarious nucleophilic substitution of hydrogen in nitro-substituted azoles and benzoazoles 02KGS435. 

An example of nucleophilic substitution involving a quaternary ammonium salt such as [A-(l,3-benzodithiol-2-ylidene)]-A-methylbenzaminium iodide 321 and 5-aminopyr-azol-3-one 51 was described by Sprague and Heikes (79S297) (Scheme 88). The reaction required heating in dry DMF at 120 °C with anhydrous sodium carbonate but iminobenzothiadiazolepyrazol-3-one 322 was obtained in only 34% yield. 

Various benzimidazole derivatives can be fused between the C-2 and N-1 positions in order to build novel heterocyclic ring systems. For example, the reaction of 2-cyanomethylbenzimidazole 73 with hydrazonoyl halides 74 in the presence of triethylamine led to the formation of pyrrolo[l,2-a]benzimid-azoles 76 (Scheme 16) [60]. It has been suggested that the reaction starts with the nucleophilic substitution of the halogen by the benzimidazole carban-ion to give intermediate 75, which upon cyclization via elimination of water gives the desired cyclic pyrrolobenzimidazoles 76. On the other hand, the reaction of hydrazonoyl chlorides 77 with 2-cyanomethylbenzimidazole 73 in sodium ethoxide afforded pyrazole-3-carboxylate 80, which upon treatment under triethylamine yielded the pyrazolopyrrolobenzimidazole 81. The product was also obtained by the direct reaction of 2-cyanomethylbenzimidazole 73 with hydrazonoyl chlorides 77 in the presence of triethylamine. 

The converse of electrophilic substitution following the flve-membered pattern, is that nucleophilic substitution of halogen follows the pyridine pattern i.e. it is much faster at the 2-position of 1,3-azoles and at the 3-position of 1,2-azoles, than at other ring positions. Resonance contributors to the intermediates for such substitutions make the reason for this plain the imine nitrogen can act as an electron sink for the attack, only at these positions. 

Reaction of 1 -chloro-3-nitrotriazole 42c with potassium salts of 3-bromo and 3-nitro-l,2,4-triazoies yields the NH-azole as the main product, with 5-10% of 1,5-bistriazoles, which are formed as a result of nucleophilic substitution of hydrogen in the position 5 of (V-chlorotriazole (Scheme 42). 

Azoles (imidazoles, benzotriazole, and 3,5-dimethylpyrazoles) are very good nucleofuges. C-Nucleophilic substitution of one of the two dimethylpyrazolyl, benzotriazolyl, or imidazolyl moieties with 1-methylquinaldinium and... 

Donskaya OV, Dolgushin GV, Lopyrev VA (2002) Vicarious nucleophilic substitution of hydrogen in nitro-substituted pyrroles, azoles, and benzannelated systems based on them. Chem Heterocycl Comp 38 371-384... 

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