N-Substituted azoles

A mesoionic diazo-type structure can be invoked also in the case of N-substituted azoles of type 21-23, in which there is loss of proton from an enolizable group (such as OH or NHCOR) (Scheme 7). For these unconventional diazoazoles, the same considerations about the contributions of the different forms to the resonance hybrid are compatible. 

A simple calculation can serve to demonstrate this chemical variability (Figure 14). If one designates the substituents of the N-substituted azoles as X, Y, Z and the number of variations as n, then the total number N of azole derivatives possible can easily be calculated. If n = 200, which is certainly a very modest number of different X, Y, Z substituents, then this means that with imidazole and triazole as components, it is possible to make 5.4 million different compounds ... 

It is instructive to consider N-substituted azoles in reverse, i.e., the azole ring as the substituent linked to some other group. Hammett and Taft -constant values for azoles as substituents are given in Table 11. The values show that all A-azolyl groups are rather weak net resonance donors, imidazol-l-yl being the strongest. They are all rather strong inductive acceptors, with pyrazole considerably weaker in this respect than imidazole or the triazoles. 

Dalinger IL, nogiadov VM, Shevelev SA, Kuz min VS (1996) N-(Dilluoroamino)azoles - a new class of N-substituted azoles. Mendeleev Commun 6 13-15... 

In N-substituted pyrazole and other azoles, stereoelectronic conditions for the intramolecular 1,2 shifts of both and Csp -centered groups are unfavorable in 29 and 30. Therefore, all currently known examples of N,N-migration of such groups in this series of compounds are intermolecular. 

The azolide concept can be extended further to other TV-substituted azoles, such as N-sulfonyl- or TV-phosphorylazoles, for which an analogous gradation of reactivity is observed depending on the choice of the specific azole system. The reactions of these compounds are dealt with in Chapters 10 and 12, respectively. 

There are no reports concerning reactivity of substituents attached to ring heteroatoms. In fact, most 1,4-(oxa/thia)-2-azoles are unsubstituted at ring heteroatoms and the only data concerning dithia- or oxathiazolidine S,S-dioxides, or N-substituted derivatives is limited to their preparation and to the reactivity of the ring systems. 

When N-substituted pyrrole 37 and trithiazyl trichloride (NSCfis are heated at reflux in carbon tetrachloride, IH-pyrrolo[2,3-r 4,5-. V-Substituted pyrrolo[2,3-f]-l,2,5-thiadi-azole 38 is believed to be an intermediate in this reaction (Equation 2). The enamine character of the carbon-carbon double bond of 38 is presumed to be enhanced compared to pyrrole 37, rendering 38 more reactive toward (NSCfis. 

J(P1)2797>. A similar cycloaddition-rearrangement sequence accounted for the formation of oxazolo[4,5-r/ [l,2,3]tri-azoles 203 as side products from the reaction between triazolium imides 201 and N-substituted benzaldimines, leading to the imidazo[4,5-t/ [l,2,3]triazole 204 (Equation 23) (see Section 10.05.10.3). The oxazolotriazoles 203 were presumed to arise as a consequence of hydrolysis of the imine to the parent aldehydes under the reaction conditions <2003ARK110>. 

This section covers ligands containing the 1,2,3-triazole ring system. These include, in addition to the parent triazole, various N- and/or C-substituted triazoles, benzotri azole, and a number of 8-azapurines. The coordination chemistry of 5-thio-l,2,3,4-thiatriazole is selectively reviewed. All of these molecules, with the exception of the N-substituted triazoles, are capable of coordinating in anionic as well as neutral form. 1,2,3-Triazole, first prepared by von Pechmann in 1888 (215), is a weak acid (p/ a = 9.26) (88) and exists as a mixture of the tautomeric forms (structures la and lb). Benzotriazole (2), first correctly formulated... 

The intramolecular 1,3-dipolar cycloadditions of homochiral nitrilimines derived from methyl esters of glycine, L-alanine, L-phenylalanine, and (S)-2-phenylglycine produced enantiopure 2,3,3a,4,5,6-hexahydropyrrolo[3,4-c]pyrazoles in fair to good overall product yields.50 The thermal reaction of diphenylnitrilimine with N-substituted benzimidazoles (47) produced lV,AP-disubstituted o-phenylenediamines (51). The reaction involved two 1,3-dipolar cycloadditions with two nitrilimine moieties yielding adducts (48-50), followed by a ring opening of the azolic ring of (50) (Scheme 13).51... 

The azole N-oxides display enhanced reactivity and complementary regioactivation as compared to the parent azoles. They can undergo unique reactions making them highly versatile by regiocontrolled functionalization of 5-membered azaheterocycles, when functionalization is followed by removal of the N-oxide oxygen atom. O-Alkylation or acylation further activates both ring and lateral positions for subsequent transformations in one pot into substituted azoles. 

Azole N-oxides la-c-16a-c are structurally derived from N-substituted pyrrole, furan, thiophene, etc. by replacing one, two, or three ring carbon atoms with sp2 hybridized nitrogen atoms, one of which is attached to an oxygen atom. The azole N-oxides la-c-16a-c are shown in Scheme 1. The scheme also shows the possible azole N-oxide structures that have been reported. 

For 1,3-type azole N-oxides, only abstraction of a lateral proton at the 2-position gives an anion in which charge counterbalancing is possible as apparent from resonance structure 48. This explains why protons at this position are more acidic than lateral protons at the 4- and 5-positions of the N-oxide and more acidic than the lateral protons in the parent 3-substituted azole where charge counterbalancing is impossible (Scheme 10). 

Even weak nucleophiles may add at C3 or C5 of 1,2-type or at C2 of 1,3-type N-alkoxyazolium salts. Subsequent elimination of methanol leads to substituted azoles. The net result is replacement of hydrogen at the heteroaromatic nucleus with a nucleophile (Scheme 13 and 14). The entire sequence, including O-alkylation of the N-oxide, can be performed in one pot. 

The chemical variability of the 1-substituted azoles can already be recognized from the subgroups presented thus far, Including the N-tritylazoles and their analogues, the N-diphenylmethylazoles, the phenethylazoles and the azolyl-0,N-acetals. The only essential feature is the imidazole or 1,2,4-triazole ring. The quality of the fungicidal action and of the properties necessary for practical use are determined only by the selection of a suitable substituent R. 

The N-vinyl-azole class, in which the 1-N atom of the azole is directly bonded to an sp2-hybridized carbon of a substituted olefin, belongs to the relatively recently synthesized subgroup of bioactive azoles. Compounds of this nature can be obtained by condensation of aldehydes with triazolyl-pinacolone resulting in a mixture of the E and Z isomers of the corresponding a, f3 -unsaturated ketones. Borohy-dride reduction easily converts these ketones into the corresponding alcohols (9)(Figure 16). 

Systematic replacement of CH in pyrrole 1 (Chapter 2.3) by N leads to nine additional monocyclic heteroaromatic nitrogen systems 2-10 (Figure 1), which are known collectively as azoles. Annular tautomerism is an important feature of all azoles having an NH function. For example, the triazoles 4 and 6, the triazoles 5 and 7, and the tetrazoles 8 and 9 can equilibrate by proton transfer (see Section 2.4.5). N-Substituted derivatives cannot equilibrate. Tautomers of the parent ring systems of all the azoles except pentazole 10 are known TV-aryl derivatives of pentazole have been characterized . 

Simple complexes. Many examples are known of complexes between metal cations and both neutral azoles and azole anions. Azoles can form stable compounds in which metallic and metalloid atoms are linked to nitrogen. For example, pyrazoles and imidazoles N-substituted by B, Si, P, Ga, Ge, Sn, and Hg groups are made in this way. Overlap between the d-orbitals of the metal atom and the azole -orbitals is believed to increase the stability of many of these complexes. 

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