Alkyl-1,2-Azoles

Protons on alkyl groups at the 1,3-azole 2-positions are sufficiently acidic for strong base deprotonation, and are more acidic than methyl groups at other positions even the assistance of an ojXho-re sited carboxylate is usually insufficient to overcome the intrinsic tendency for 2-methyl-lithiation, though an adjacent tertiary amide can do this. The side-chain metallated derivatives can be utilised in reactions with electrophiles. The presence of a 5-nitro group allows much milder, base-catalysed condensations to occur. 

A -Acylation also increases the acidity of 2-methyl groups, allowing acylation via a non-isolable enamide.  

A-Alkoxycarbonyl 1,3-azolium salts, generated in situ by reaction with chloro-formates, will react with allylstannanes, or allylsilanes by addition of the 

Azolium salts are readily attacked by nucleophiles, for example with hydroxide, addition at C-2 is followed by ring opening.  

Neat exploitations of this process, include the synthesis of medium-sized heterocycles as products of a three stage sequence involving addition of hydroxide to w-iodoalkyl thiazolium salts, ring-opening and then reclosure by intramolecular S-alkylation, illustrated below for the formation of an eight-membered ring, and the introduction of sulfur to the imidazole 2-position using phenyl chlorothionofor-mate.  

5- methylisoxazole can be deprotonated at the methyl without ring degradation. Conversion to A-oxide ° activates adjacent methyl groups, for example subsequent reaction with trimethylsilyl iodide permits side-chain iodination.  

On subjection of 3-methyl-5-phenylisothiazole or 3-methyl-5-phenylisoxazole to lithiation conditions, competitive side-chain and C-4 deprotonation is observed, except when lithium j-propyl(cyclohexyl)amide (LICA) is used - this allows exclusive side-chain Uthiation.  

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The reactions of most of known Nu (tertiary amines, N-alkylated azoles, etc.) with BENA proceed through the pathway (a). This interpretation is additionally confirmed by the fact that the reaction of N-methylimidazole with unsymmet-rical BENA (434a) produces exclusively trimethylsilyl salt (512"), whereas the pathway (b) would afford salt (512 ). 

It can be assumed that the azoles are deprotonated by the interfacial exchange mechanism, but it is noteworthy that it has been suggested that the rate of alkylation of indole under liquiddiquid two-phase conditions decreases with an increase in the concentration of the sodium hydroxide [8]. The choice of catalyst appears to have little effect on the reaction rate or on the overall yields of alkylated azole. Benzyltriethylammonium chloride, Aliquat, and tetra-n-butylammonium hydrogen sulphate or bromide have all been used at ca. 1-10% molar equivalents (relative to the concentration of the azole) for alkylation reactions, but N-arylation of indole with an activated aryl halide requires a stoichiometric amount of the catalyst [8]. 

All this applies in particular to the copper (l)-catalyzed coupling of azides and terminal acetylenes to form exclusively 1,4-disubstituted 1,3-triazole linkages, according to example (b) in Scheme 15.1. From the biological standpoint, the topological and electronic features shared by 1,2,3-triazoles and amide bonds are particularly important, since the latter are ubiquitous connectors in Natiue. From the synthetic point of view, it is important to note that alkyl azoles can give 1,4- and 1,5-disubstituted, or syn- and anti-1,2,3-triazoles (Scheme 15.2). 

TABLE in-104. 4-ALKYTHI AZOLES WITH ONE FUNCTION ON THE ALKYL GROUP... 

In general, substituent frequencies in azoles are consistent with those characteristic of the same substituents in other classes of compounds. Some characteristic trends are found, and these have been used to measure electronic effects. Thus, for example, the frequencies of v C—0] in 3-, 4- and 5-alkoxycarbonylisoxazoles (cf. 100) are respectively 9-12, 2-8 and 17-18 cm higher than those of the corresponding alkyl benzoates, indicating the... 

Alkyl halides and related compounds azoles without a free NHgroup Alkyl halides and related compounds compounds with a free NH group... 

Azole iV-oxides, iV-imides and iV-ylides are formally betaines derived from iV-hydroxy-, iV-amino- and iV-alkyl-azolium compounds. Whereas iV-oxides (Section 4.02.3.12.6) are usually stable as such, in most cases theiV-imides (Section 4.02.3.12.5) andiV-ylides (Section 4.02.3.12.3) are found as salts which deprotonate readily only if the exocyclic nitrogen or carbon atom carries strongly electron-withdrawing groups. 

Similar ambiguities arise in the reactions of azole anions. At least as regards alkylation reactions in the 1,2,3-triazole series (79), the product appears to depend on the reagent used. In the 1,2,4-triazole series (80) a single product is formed, whereas tetrazole (81) gives mixtures. 

Alkyl halides and related compounds azoles without a free NHgroup... 

For both azole and benzazole rings the introduction of further heteroatoms into the ring affects the ease of quaternization. In series with the same number and orientation of heteroatoms, rate constants increase in the order X = 0requires stronger reagents and conditions methyl fluorosulfonate is sometimes used (78AHC(22)71). The 1-or 2-substituted 1,2,3-triazoles are difficult to alkylate, but methyl fluorosulfonate succeeds (7IACS2087). 

Pyrazoles and imidazoles with free NH groups are readily alkylated, e.g. by Mel or Me2S04. A useful procedure is to use the alkyl salt of the azole in liquid ammonia (80AHC(27)241). However, alkylation can also occur under neutral conditions, particularly with imidazoles. 

Although in general azoles do not undergo Friedel-Crafts type alkylation or acylation, several isolated reactions of this general type are known. 3-Phenylsydnone (120) undergoes Friedel-Crafts acetylation and Vilsmeier formylation at the 4-position, and the 5-alkylation of thiazoles by carbonium ions is known. 

In contrast to pyridine chemistry, the range of nucleophilic alkylations that can be effected on neutral azoles is quite limited. Lithium reagents can add at the 5-position of 1,2,4-oxadiazoles (Scheme 16) (70CJC2006). Benzazoles are attacked by organometallic compounds at the C=N a-position unless it is blocked. 

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. 

Pyrazole and indazole anions, in a manner similar to other azole anions, show the expected inversion of reactivity when compared with the cations. They are more reactive towards electrophiles, both at the nitrogen and carbon atoms, and less reactive towards nucleophiles than the corresponding neutral molecules. For practical purposes most of the N -alkylated pyrazoles and indazoles are prepared from the corresponding anions. 

Tire and NMR parameters of some 1-alkyl-4-benzimidazolyl-2-idene- (type 72) and l-alkyl-4-(5-methylpyrazolyl-3-idene)-l,4-dihydro pyridines (type 73) were discussed in 89CC1086 and 91JOC4223. Comparison of the shifts for DMSO-dg and CDCI3 solutions with data reported for quaternary pyridinium compounds as well as anionic species in the azole series and data obtained for mesoionic betaines of the azinium azolate class left no doubt that these heterofulvalenes have a betaine character and, therefore, the NMR signals correspond to their dipolar resonance form. 

Products of cyclization of 5-aminoethylene benzotriazole derivatives with eliminated prototropy of the azole ring can be alkylated on the nitrogen atom of the pyridone and then hydrolyzed to the corresponding acids (76JAP(K)1, 89FA619). The prepared compounds 167-169 and their salts were tested against bacteria (no data) (76JAP(K)1). 

A characteristic feature of picolines and many azoles is the well-known ability of methyl (and corresponding methylene) groups to undergo condensation of the aldol, crotonic, and Michael type. This is especially pronounced in the quaternary salts of these heterocycles where it occurs under comparatively mild conditions. Such condensations are not unknown for alkylisoxazoles. Lampe and Smolinska were the first to describe the condensation of the quaternary alkyl iodides of 3,5-dimethyl- (96) and 3-methyl-5-phenylisoxazole with... 

Abbreviations aapy, 2-acetamidopyridine Aik, alkyl AN, acetoniuile Ar, aryl Bu, butyl cod, 1,5-cyclooctadiene COE, cyclooctene COT, cyclooctatetraene Cp, cyclopentadienyl Cp , penta-methylcyclopentadienyl Cy, cyclohexyl DME, 1,2-dimethoxyethane DME, dimethylformamide DMSO, dimethyl sulfoxide dmpe, dimethylphosphinoethane dppe, diphenylphosphinoethane dppm, diphenylphosphinomethane dppp, diphenylphosphinopropane Et, ethyl Ec, feirocenyl ind, inda-zolyl Me, methyl Mes, mesitylene nb, norbomene orbicyclo[2.2.1]heptene nbd, 2,5-norbomadiene OTf, uiflate Ph, phenyl PPN, bis(triphenylphosphoranylidene)ammonium Pi , propyl py, pyridine pz, pyrazolate pz, substituted pyi azolate pz , 3,5-dimethylpyrazolate quin, quinolin-8-olate solv, solvent tfb, teti afluorobenzobaiTelene THE, tetrahydrofuran THT, tetrahydrothiophene tmeda, teti amethylethylenediamine Tol, tolyl Tp, HB(C3H3N2)3 Tp , HB(3,5-Me2C3HN2)3 Tp, substituted hydrotiis(pyrazol-l-yl)borate Ts, tosyl tz, 1,2,4-triazolate Vin, vinyl. 

From the point of view of reactivity, there is little difference between 2-amino-selenazoles and aryl- or alkyl-2-aminoselen azoles, except that the A -arvl derivatives are generally less basic and that their salts are more easily hydrolyzed. 

B enzam ido -4-ary l(alkyl) selen azole s, nitration in 5-position. 241 2-Benzamido-4-p-nitrophenylselenazole, nitration, 243... 

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... 

In the reactions considered here the N-acyl group functions as a readily cleavable protecting group in facilitating exclusive alkylation at normally unfavored positions in the azole moiety.[1]... 

Carbene complexes have also been prepared by transmetallation reactions. Lithiated azoles react with gold chloride compounds and after protonation or alkylation the corresponding dihydro-azol-ylidene compounds, e.g., (381) or (382), are obtained.22 9-2264 Silver salts of benz-imidazol have also been used to obtain carbene derivatives.2265 Mononuclear gold(I) carbene complexes also form when trimeric gold(I) imidazolyl reacts with ethyl chlorocarbonate or ethyl idodate.2266,2267 The treatment of gold halide complexes with 2-lithiated pyridine followed by protonation or alkylation also yields carbene complexes such as (383).2268 Some of these carbene complexes show luminescent properties.2269-2271... 

Quatemized azines and azoles have also been investigated as potential phase-transfer catalysts. 1-Alkyl-2- and 4-dialkylaminopyridinium salts [38, 39] have... 

The greater acidities of the heteroaromatic azoles (pKa ca. 15), compared with simple acyclic and non-aromatic cyclic amines, is reflected in the ease with which the systems are /V-alkylated and /V-acylated. 

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