Azoles halogenations

In azole chemistry the total effect of the several heteroatoms in one ring approximates the superposition of their separate effects. It is found that pyrazole, imidazole and isoxazole undergo nitration and sulfonation about as readily as nitrobenzene thiazole and isothiazole react less readily ica. equal to m-dinitrobenzene), and oxadiazoles, thiadiazoles, triazoles, etc. with great difficulty. In each case, halogenation is easier than the corresponding nitration or sulfonation. Strong electron-donor substituents help the reaction. 

Nitro groups on azole rings are often smoothly displaced by nucleophiles even more readily than are halogen atoms in the corresponding position. Thus 2,4,5-trinitroimidazole (450) is converted by HCl successively into (451) and (452) (80AHC(27)24l). 

Metalloid azoles frequently show expected properties, especially if not too many heteroatoms are present. Thus Grignard reagents prepared from halogen-azoles (see Section 4.02.3.9.3) show normal reactions, as in Scheme 60. 2-Lithioimidazoles react normally, e.g. with acetaldehyde (Scheme 61) (70AHC(12)103) 5-lithioisothiazoles (see Scheme 62) (72AHC(14)1) and 2-lithiothiazoles undergo many of the expected reactions. 

Electrophilic substitution occurs readily in Af-phenyl groups, e.g. 1-phenyI-pyrazoIes, -imidazoles and -pyrazolinones are all nitrated and halogenated at the para position. The aryl group is attacked preferentially when the reactions are carried out in strongly acidic media, where the azole ring is protonated. 

The mechanisms of the electrophilic substitutions in the isoxazole nucleus have not yet been studied. They should not differ fundamentally from those usually accepted for the substitution of aromatic systems but the structural specificity of the isoxazole ring might give rise to some peculiarities, as recently specially discussed.One important point is that isoxazole shows a clearcut tendency to form coordination compounds. Just as pyridine and other azoles, isoxazoles coordinate with halogens and the salts of heavy metals, for example of cadmium,mercury,zinc. Such coordination... 

Substitution on the carbon atoms of the azole rings has the expected effect electron-withdrawing substituents such as nitro or halogen increase the reactivity of the azolides, whereas alkyl substituents lead to a decrease in transacylation rates. 101... 

One of the most frequently studied transition metal catalyzed transformations of azoles and indole is their participation in cross-coupling reactions. Due to the abundance of examples in this field we only present some representative examples of the different reaction classes. In this chapter reactions where a halogenated azole is used to introduce the five membered ring onto the palladium in the oxidative addition and processes,... 

Treatment of tetrazolium salts (154) with mercuric acetate gives the bistetrazolium mercury salts (155) which represent essentially a metal-carbene trapping of the tetrazolium ylide species. Replacement of the mercury atom of (155) is readily achieved with halogens to give the 5-halotetrazolium compounds (156) (93CB1149). These electrophilic reactions at the tetrazole C-5 arise from the lability of the 5-CH proton and they show the necessity of generating carbanionic character at C-5 before electrophilic attack can occur on this strongly ir-deficient azole. 

Replacement of halogen substituents on the azole moiety by amines and hydrazines can also be effected. For example, the compound (165) reacts with amines and amidines to yield the derivatives (166) <75KFZ10>. 

In the 2-oxo derivative (189), which has no vacant C-position in the azole ring, both halogenation and nitration occur at C-6 in the six-membered ring C-6 is a pyridine meta-position and is para to the azole nitrogen (76HCA1593). 

Franssen MCR, van Boven HG, van der Plas HC (1987) Enzymatic halogenation of pyr-azoles and pyridine derivates. J Heteroatom Chem 24 1313-1316... 

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