N-Substituted 1,2,3-triazoles

Reactions of salts of 1,2,3-triazole with electrophiles provide an easy access to 1,2,3-triazol-jV-yl derivatives although, usually mixtures of N-l and N-2 substituted triazoles are obtained that have to be separated (see Section 5.01.5). Another simple method for synthesis of such derivatives is addition of 1,2,3-triazole to carbon-carbon multiple bonds (Section 5.01.5). N-l Substituted 1,2,3-triazoles can be selectively prepared by 1,3-dipolar cycloaddition of acetylene or (trimethylsilyl)acetylene to alkyl or aryl azides (Section 5.01.9). 

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Vercek and co-workers described an effective approach to some 3-cyano-4-amino[l,2,3]triazolo[l,5-tf]pyrazines starting from the N-substituted triazole derivatives 396 <2002H(56)353>. This compound when treated either with acetic acid or triethylamine gave rise to the ring-closed products 397 in acceptable yield (55-66%). 

Halogenation usually proceeds through the A-halotriazoles, as described in Section 4.02.5.3. The bromination of N-substituted triazoles by NBS in CHCI3 is also believed to involve A-bromo-triazolium intermediates <75BSF647>. 

N-substituted triazoles on treatment with sulfur give the thione <66MI 402-01, 70JCS(C)2403>, but the corresponding oxidation and amination reactions appear not to be known. 

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 C-5 position of 1,2,3 N-substituted triazoles is the most acidic one and can regioselectively be deprotonated with lithiated bases (Scheme 33) [83]. 

For N-hydroxy-1,2,4-triazole, the zwitterionic structure 128 was suggested [89AX(C)782,96CHEC-II(4)127]. Whereas N -substituted 3-hydroxy-1,2,5-triazoles prefer the hydroxy form 129, 2-hydroxy-1,3,4-triazoles exist as 0X0 forms 130 (Scheme 49) [76AHC(S1), pp. 380,383,388,389],... 

Table 20-1. N-Substituted imidazoles and triazoles prepared by transfer reactions of azolides A—F with tertiary alcohols of the triphenylmethanol type and analogues.

Liu et al. elaborated an efficient synthetic route to [l,2,4][5,l-A][l,3,5]thiadiazine-7-ones 122 <2000M953, 2000JFC111> starting from 3-mercapto[l,2,4]triazoles 121. These compounds were treated with N-substituted A-chloromethylcarbamoyl choride in dimethylformamide (DMF) solution at room temperature for 1-2 h to give the ring-closed products in high yield (>80%) (Scheme 22). 

With N-1-substituted -triazoles, 1,3-disubstituted triazolium salts... 

The direct lithiation of a 2-substituted 1,2,3-triazole has not been reported. Halogen-metal exchange of 4,5-dibromotriazole with n-butyllithium at — 80 °C occurs smoothly and the subsequent reaction of the lithium intermediate (244) with various electrophiles except aldehydes gives the 4-bromo-5-substituted triazoles (245) (Scheme 46). The corresponding 1-substituted 4,5-dibromo-1,2,3-triazole undergoes a similar reaction at the 5-position . 

Heating of 1,2,3-triazolium-l-aminide 168 with acrylonitrile in dry acetone at reflux yielded a mixture of pyrrolo[2,3-similar reactions with different N-substituted maleimides produced only one product in each case. Table 6 summarizes the results of these reactions <2001J(P1)1778>. 

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>. 

Synthesis A also may lead to N-substituted TPs. 4-Alkyl-ATs and 5-alkylamino-1,2,4-triazoles are cyclized by 3-ketocarboxylic esters (and equivalents) forming 3- and 4-alky 1-oxo-TPs, respectively [67JCS(C)503 70GEP1946315 87T2497]. Similar reactions with 1,3-diketones afford the following 1,3,4-triazolo[ 1,5-a]pyrimidinium salts 3-methyl (74KGS565),... 

The triazole ring can be synthesized by reaction between a suitable pyridine (or piperideine) and an azide. Thus 5-nitro-2-pyridone (or N-substituted pyridones) and sodium azide give a 5-oxotriazolo[4,5-b]pyridine (94)182-184 whereas the enamine 95 reacts with p-nitrophenyl azide to give the hexahydro-l//-triazolo[4,5-c]pyridine 96.185,186... 

Thiation of N-substituted 1,2,4-triazole has been also achieved (93ZOR1896). 

The 1,3-dipolar cycloaddition of azides to acetylenic amides is particularly difficult under conventional thermal conditions and extended reaction times of 14 h to 1 week have been reported32,33. Katritzky reported a microwave-mediated solvent-free variant ofthis procedure to give N-substituted C-carbamoyl- 1,2,3-triazoles in good to excellent yields in only 30 min (Scheme 3.19)34. 

The 4-chloro-substituted triazole 1-oxide 470 could be chlorinated and brominated at the 5-position affording 471 or 472 in excellent yield (1987ACSA(B)724). Even the 3-phenyl compound 470 (R=Ph) reacted regioselectively in the triazole ring confirming the activation conveyed by the N-oxide functionality (Scheme 137). 

The hydroxytriazole 1-oxides 500 and 502 when treated with methyl iodide were methylated predominantly at the N-oxygen affording mesoionic anhydro l-methoxy-3-methyl-4-hydroxy- or 5-hydroxy-l,2,3-triazolium hydroxide 501 or 503 (Scheme 146) (1987ACSA(B)724). In both cases methylation at the C-hydroxy group took place to a minor extent giving rise to methoxy-substituted triazole 1-oxides 499 or 503, respectively. Under similar conditions 3-methyl 4-hydroxy-5-chloro-l,2,3-triazole 1-oxide 505 produced a 2 1 mixture of the C-methoxy and the N-methoxy derivatives 504 and 506. The mesoionic triazoles 501, 503, and 506 were dealkylated upon heating with 1-M sodium methoxide, reforming the hydroxy-substituted N-oxides 500, 502, and 505, respectively. 

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 ... 

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 . 

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