Azoles, acidity

Title Substituted Azole Acid Derivatives Useful as Antidiabetic and Antiobesity Agents and Method... 

Invention Significance Azole acid derivatives have been prepared... 

A general review (61 references) of the nucleophiUc and electrophilic reactions of tervalent phosphorus acid derivatives has appeared. The kinetics of the reaction of diisopropyl tetrazolylphosphonite (146 R = Mc2CH) with r-BuOH in dry THF have been studied in the presence of various acids, bases, and salts that catalyse the process. Ammonium azolide salts were found to be considerably more efficient catalysts than the corresponding azole acids or tertiary amine bases. For instance, the relative rates obtained with lV,lV-diisopropylethylammonium tetrazolide, N,N-diisopropylethylamine, and tetrazole were 104, 28 and 1, respectively. ... 

Synthesis and biological evaluation of azole acid analogs as novel, potent dual PPAR alpha/gamma activators... 

An interesting application is the preparation of 1 2 3 4-tetrahydrocarb azole (VI), which is formed when phenylhydrazine is added to a boiling aolutiai of cyclohexanone in acetic acid the plienylhydrazone (V) Intermediately produced undergoes ring closure directly ... 

Bis(azol-2-5l)stilbenes (2(i]ll such as (4) have been prepared. 4,4 -Dihydrazinostilbene-2,2 -disulfonic acid, obtained from the diamino compound, on treatment with 2 moles of oximinoacetophenone and subsequent ring closure, leads to the formation of (4) [23743-28 ]. Such compounds are used chiefly as washing powder additives for the brightening of cotton fabrics, and exhibit excellent light- and hypochlorite-stabiUty. 

Table 36 summarizes the known annular tautomerism data for azoles. The tautomeric preferences of substituted pyrazoles and imidazoles can be rationalized in terms of the differential substituent effect on the acidity of the two NFI groups in the conjugate acid, e.g. in (138 EWS = electron-withdrawing substituent) the 2-NFI is more acidic than 1-NFI and hence for the neutral form the 3-substituted pyrazole is the more stable. 

Orientation in azole rings containing three or four heteroatoms Effect of azole ring structure and of substituents Proton acids on neutral azoles basicity of azoles Proton acids on azole anions acidity of azoles Metal ions... 

In this initial section the reactivities of the major types of azole aromatic rings are briefly considered in comparison with those which would be expected on the basis of electronic theory, and the reactions of these heteroaromatic systems are compared among themselves and with similar reactions of aliphatic and benzenoid compounds. Later in this chapter all the reactions are reconsidered in more detail. It is postulated that the reactions of azoles can only be rationalized and understood with reference to the complex tautomeric and acid-base equilibria shown by these systems. Tautomeric equilibria are discussed in Chapter 4.01. Acid-base equilibria are considered in Section 4.02.1.3 of the present chapter. 

Proton acids on neutral azoles, basicity of azoles... 

Amination at an azole ring nitrogen is known for Af-unsubstituted azoles. Thus 4,5-diphenyl-1,2,3-triazole with hydroxylamine-O-sulfonic acid gives approximately equal amounts of the 1- (104) and 2-amino derivatives (105) (74AHC(16)33). Pyrazole affords (106) and indazole gives comparable amounts of the 1- and 2-amino derivatives. 

Alkyl radicals produced by oxidative decarboxylation of carboxylic acids are nucleophilic and attack protonated azoles at the most electron-deficient sites. Thus imidazole and 1-alkylimidazoles are alkylated exclusively at the 2-position (80AHC(27)241). Similarly, thiazoles are attacked in acidic media by methyl and propyl radicals to give 2-substituted derivatives in moderate yields, with smaller amounts of 5-substitution. These reactions have been reviewed (74AHC(i6)123) the mechanism involves an intermediate cr-complex. 

Primary amino groups attached to azole rings react normally with nitrous acid to give diazonium compounds via primary nitroso compounds. However, the azole series shows two special characteristics the primary nitroso compounds can be stable enough to be isolated, and diazo anhydrides are formed easily from azoles containing ring NH groups. 

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 general discussion (Section 4.02.1.4.1) on reactivity and orientation in azoles should be consulted as some of the conclusions reported therein are germane to this discussion. Pyrazole is less reactive towards electrophiles than pyrrole. As a neutral molecule it reacts as readily as benzene and, as an anion, as readily as phenol (diazo coupling, nitrosation, etc.). Pyrazole cations, formed in strong acidic media, show a pronounced deactivation (nitration, sulfonation, Friedel-Crafts reactions, etc.). For the same reasons quaternary pyrazolium salts normally do not react with electrophiles. 

Table 7 Reactivities of Some Azoles and Other Five-membered Heterocyeles in Acid-catalyzed Deuteriodeprotonation <74jcs(P2)399>...

Compound (122) is also obtained by decarboxylative ring-opening of l,2-benzisoxazole-3-carboxylic acid. It has also been concluded that the reaction involves an intermediateless, concerted loss of carbon dioxide via a transition state in which the negative charge is spread over the carboxyl group and the isox azole ring. 

Azocrown ethers pyrazoles, 5, 228 Azo dyes, 1, 328-331 colour and constitution, 1, 342 heterocyclic, 1, 325-326 Azo-hydrazone tautomerism, 1, 331, 334 Azoles acetic acids decarboxylation, 5, 92 acetoxymercurio reactions, 5, 107 acetyl... 

A wide variety of a-tnfluoromethyl a-amino acids are readily available from the reaction of 5-fluoro-4-tnfluoromethyl-l,3 azoles with allylic alcohols [138, 139] a-Tnfluoromethyl-subsumted a-amino acids show anubactenal and antihy pertensive activity Some are highly specific enzyme inhibitors (suicide inhibitors) and may be important as bioregulators [140] Furthermore, they are interesting candidates for peptide modification... 

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