Acid/azole complex

Example 5 Hayakawa and Noyori group in their studies on new activators for phosphoroamidite coupling reactions have applied the most effective member of the group of acid/azole complexes AT-(phenyl)imidazolium tri-flate (N-PhIMT) in the efficient synthesis of biologically important compounds [20j]. A noteworthy example is synthesis of cytidine-5 -monophos-pho-AT-acetylneuraminic acid. This compound is a source of sialic acid in the sialyltransferase-catalysed biosynthesis of sialyl oligosaccharides [25]. 

Acid salts of imidazole- and benzimidazole-related compounds have been evaluated as alternative promoters to the various activators developed for the condensation of a nucleoside phosphoramidite and a nucleoside. The acid/azole complexes were developed to circumvent some of the disadvantages most commonly encountered in both solution- and solid-phases. Azolium promoters were shown to achieve high yielding coupling reactions even with nucleosides of low reactivity. Hayakawa has also reviewed and broadened the recent phosphoramidite methodologies by describing the versatility of allyl and allyloxycar-... 

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. 

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. 

Pinacolone, o-(diphenylphosphino)benzoyl-coordination chemistry, 2, 401 Ping-pong reactions copper(II) complexes, 5, 717 Piperidine, /V-hydroxy-metal complexes, 2, 797 P a values azole ligands, 2, 77 Plant roots amino acids, 2, 962 carboxylic adds, 2,962 Plants... 

Another very instructive case concerns the alleged initiation of a cationic polymerisation by a charge-transfer complex formed by the compound chloranil (2,3,5,6-tetrachloroquinone) with the monomer N-vinyl-carb-azole. It was shown (Natsuume et al., 1969 1970) that this compound is not an initiator, but that the polymerisations were caused by a hydrolysis product, 2-hydroxy-3,5,6-trichloroquinone, which is a strong acid. One has learnt from this finding to be extremely suspicious of any claims for charge-transfer catalysis and to test one s suspicions by appropriate experiments involving progressive purification of the putative catalyst. 

Worth mentioning are some relevant studies on the prototropic exchanges of azoles in excited states involving the formation of hydrogen-bonded complexes [(7a) - (7b)] via Si (85JPC399) in complexes with acetic or via Ti in complexes with benzoic acid (83JA6790), or intramolecular complexes, as in the case of 2-(2 -hydroxy-5 -methylphenyl)benzotriazole (82JCP4978). 

Most fundamental work on the vibrational spectra of azoles appeared in the period 1960-1980. Examples of more recent work include (i) a complete assignment of the gas-phase IR spectrum of indazole (93JCS(F1)4005) (ii) IR spectral data were used to determine the enthalpies of 0—H. . . N and N—H. . . O bonds in complexes of formic acid and 3,5-dimethylpyrazole (87MI301-01) (iii) the vibrational assignment of the Raman spectrum of polycrystalline pyrazole (92MI301-01) based on 3-21G calculations. 

Azoles containing an acidic NH-group, e.g. 3,5-dimethylpyrazole, react with various alcohols in the presence of a catalytic amount of ruthenium-, rhodium-, and iridium-trialkylphosphite complexes to afford the corresponding A-alkyl derivatives with excellent yields (92CL575). Regioselective A-alkylation was achieved using alkenes and sulfuric acid (89JHC3). 

The pKa values of azoles cr-bound to transition metals have been extensively studied for a variety of reasons. The acidity of a proton on a heterocycle bound to a transition metal is very sensitive to the electronic properties of the metal ion and numerous studies of these complexes... 

The acid-base properties of 4-nitroso-5-aminopyrazoles 50 have been studied. In particular, protonation sites have been determined where salts 51 are formed [66], The effects produced on II, 13C, and 15N chemical shifts by protonation and by hydrogen-bonding solvents on five azoles (imidazole, 4,5-dimethylimidazole, pyra-zole, 3,5-dimethyl-pyrazole, and 4,5-dihydro-3-methyl-2//-benz[g]indazole) have been determined experimentally. Phase effects on the 13C chemical shifts of the C-4 atom of pyrazole were discussed, based both on empirical models and on GIAO calculations of absolute shieldings in different complexes. The special case of the chemical shifts of pyrazoles in the solid state, where they form multiple N-H N hydrogen bonds, was also studied theoretically [88],... 

Amongst the N,S-azole ligands [8,13], benzo-2,l,3-thiadiazol deserves a special mention. The controversial question about the possibility of one particular kind of coordination within the complexes formed from benzo-2,l,3-thiadiazol, one in which only one atom of the heterocycle, either N or S, was able to participate [8,13], was solved by x-ray structure studies in favor of the N-coordination 489 [882], However, the examples of the kinds of coordination presented by the sulfur atom in the thiophene cycle (Sec. 2.2.4.5) do not exclude the possibility of M — S binding, particularly when using softer (i.e., Pt, Pd) Pearson acids. 

The transmetallation of lithiated heterocycles has been described as a method to provide NHC complexes, and other Fischer-type carbene complexes [161]. The method proceeds via the alkylation of an alkylimidazole with BuLi to generate the lithiated azole, which can transmetallate to the metal complex. Further reaction with an acid or an alkylating agent would provide the desired NHC - M complex (Scheme 47). 

The most widespread and convenient method for the preparation of nitrobenzazoles is the reaction of nitration. Electrophilic substitution of azoles is a complex reaction in which the experimental conditions can modify the product orientation. The ability of azoles to electrophilic substitution is determined by the activity of reagents, the basicity of substrates, and the acidity of medium. This caused some uncertainty in interpreting the results and complicated comparison of the reactivity of various azoles among them. The situation has changed after Katritzky and Johnson [7] had reported the criteria allowing, with a sufficient degree of reliance, the establishment in what form (base or conjugative acid) the compound reacts. The information on the mechanism of nitration of azoles is basically borrowed from the extensive literature on the nitration of aromatic and heteroaromatic compounds [8] therefore, it does not make sense to discuss this point in the review. 

Values of molar Kerr constants and dipole moments of nitrogen azoles and their complexes with phenols have been obtained. " These complexes are formed by an intermolecular hydrogen bond between the pyridine-type nitrogen of the azole and the phenolic proton. " The use of dipole moments in conformational studies has shown that A-aryl- and C-aryl- and A-furyl- and C-furyl imidazoles (and benzimidazoles) are nonplanar, but l-(a-furyl)-4,5-diphenylimidazoles do have a planar bicyclic fragment. The dipole moments and conformations of azolides (A-acylazoles) have been studied. In the 1-arylimidazoles the dipole is toward the aryl group. In 4,5-di-t-butylimidazole the molecule is essentially planar, but the C-4—C-5 bond is slightly stretched. Among other imidazole derivatives which have been studied by X-ray are histidine hydrochloride, 4-acetyl-amino - 2 - bromo - 5 - isopropyl -1 - methylimidazole, 4- acetyl - 5 - methyl - 2 -phenylimidazole, and imidazole-4-acetic acid hydrochloride. 

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