Azoles Pyrroles

In 1972, van Leusen, Hoogenboom and Siderius introduced the utility of TosMIC for the synthesis of azoles (pyrroles, oxazoles, imidazoles, thiazoles, etc.) by delivering a C-N-C fragment to polarized double bonds. In addition to the synthesis of 5-phenyloxazole, they also described reaction of TosMIC with /7-nitro- and /7-chloro-benzaldehyde (3) to provide analogous oxazoles 4 in 91% and 57% yield, respectively. Reaction of TosMIC with acid chlorides, anhydrides, or esters leads to oxazoles in which the tosyl group is retained. For example, reaction of acetic anhydride and TosMIC furnish oxazole 5 in 73% yield. ... 

The diazotization of heteroaromatic amines is basically analogous to that of aromatic amines. Among the five-membered systems the amino-azoles (pyrroles, diazoles, triazoles, tetrazoles, oxazoles, isooxazoles, thia-, selena-, and dithiazoles) have all been diazotized. In general, diazotization in dilute mineral acid is possible, but diazotization in concentrated sulfuric acid (nitrosylsulfuric acid, see Sec. 2.2) or in organic solvents using an ester of nitrous acid (ethyl or isopentyl nitrite) is often preferable. Amino derivatives of aromatic heterocycles without ring nitrogen (furan and thiophene) can also be diazotized. 

Due to the biological significance of some azoles (pyrrole, indole, imidazole, benzimidazole) and the consequences of acid-base equilibria in their functions, a continuous interest in the behavior in water is to be expected. To quote a significant approach, imidazole is being used to determine the intra- and extracellular acidity by H-NMR (82MI4 86UP13). 

As an excellent complement to the Pd-catalyzed methodology that has been utilized in a number of applications, in general experimentally simple and inexpensive catalyst system for the N-arylation of a wide variety of azoles (pyrrole, indoles, 7-azaindole, carbazole) has been developed (Equation 37) <2001JA7727>. In particular, it was shown that the combination of air stable Cul and racemic ( )-l,2-cyclohexanediamine 186a in the presence of K3PO4 is an extremely efficient and general catalyst system for the N-arylation of a number of azoles. Competitive C-arylation under these conditions is not observed. 

Vinylation of various azoles (pyrrole, indole, carbazole, and their derivatives) with vinyl bromides catalyzed by palladium/phosphine complexes results in the A -vinylazoles in 30-99% yields (Equation 49) <20020L623>. This reaction with cis- and /ra r-P-bromostyrenes is stereospecific giving the respective products with full retention of configuration. 

A study of the intermolecular vinylation of azoles (pyrrole, carbazole, and indoles) and phenothiazines was published by I. P. Beletskaya and co-workers.116 This vinylation is catalyzed by Pd(f-Bu)3P and utilizes the lithium amide of various azoles. Various vinyl bromides efficiently undergo the cross-coupling with full retention of their configuration (E or Z). 

C-arylations of azoles proceed smoothly when N-protected azoles (pyrrole, indole, and imidazole) are used. N-free pyrrole, imidazole, and indole are poor substrates for C-arylation. However, Sezen and Sames reported an interesting effect of MgO as an additive [10], 2-Phenylpyrrole was obtained cleanly in 86% yield by the reaction of unprotected pyrrole with iodobenzene in the presence of MgO (1.2 equiv.). No N-arylation occurred. MgO seems to be bound to nitrogen strongly, and not only protects the nitrogen, but also increases the nucleophilicity of heteroarene nucleus. 

Bromocyclopropylcarboxamides undergo a highly diastereoselective 5 reaction with azoles, pyrroles, indoles, benzimidazoles, pyrazoles, and benzotriazoles in the presence of KOH and 18-crown-6 ether, giving A-cyclopropyl aromatic heterocycles in yields between 48 and 85%. " The transicis ratio in the crude product ranged from 0 72 28 to 95 5 but was increased to a dr of 95 5-100 0 in a base-assisted epimerization in a f-BuOK-18-crown-6 mixture. 

A large group of heterocyclic aromatic compounds are related to pyrrole by replacement of one of the ring carbons p to nitrogen by a second heteroatom Com pounds of this type are called azoles... 

For the NH azoles (Table 3), the two tautomeric forms are usually rapidly equilibrating on the NMR timescale (except for triazole in HMPT). The iV-methyl azoles (Table 4) are fixed chemical shifts are shifted downfield by adjacent nitrogen atoms, but more by a pyridine-like nitrogen than by a pyrrole-like iV-methyl group. 

Electron donation from pyrrole-like nitrogen, or to a lesser extent from analogous sulft or oxygen atoms, helps electrophilic attack at azole carbon atoms, but as the number c heteroatoms in the ring increases, the tendency toward electrophilic attack at both C an N decreases rapidly. 

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 also indicates that the rate enhancements for a 3- and 5-methyl group vary significantly among 1,2-azoles. The difference between the increments in log units for a 3-and 5-methyl group, which should vary directly with bond fixation in the ground state, is larger for isoxazole (1.4) than for pyrazole (0.7) and for isothiazole (0.2). This indicates that the aromaticity increases in the same order and contributes the first quantitative evidence that the 1,2-azoles follow the same aromaticity order as furan < pyrrole < thiophene. 

Azole) lAzine) (4- Pyridol) (l-8enxo [b] pyrrole) (8enzo [b] pyridine)... 

We have looked at the five-membered aromatic heterocycles pyrrole, furan and thiophene in Section 11.5. Introduction of a second heteroatom creates azoles. This name immediately suggests that nitrogen is one of the heteroatoms. As soon as we consider valencies, we discover that in order to draw a five-membered aromatic heterocycle with two heteroatoms, it must contain nitrogen A neutral oxygen or sulfm atom can have only two bonds, and we cannot, therefore, have more than one of these atoms in any aromatic heterocycle. On the other hand, there is potential for having as many nitrogens as we like in an aromatic ring. 

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