1.3.5- Trisubstituted 1,2,4-triazoles

Table 20 Cycloaddition reaction of in s/ fu-generated nitrilimines with nitriles to give 1,3,5-trisubstituted 1,2,4-triazole derivatives (Equation 37)...

Cyclization of the aminomethylhydrazone derivative 167 in the presence of base gave the 1,3,5-trisubstituted 1,2,4-triazole 168 in 50% yield a mechanism for the formation of triazole 168 also accounts for the formation of accompanying di- and tricyclic by-products (Equation 53) <1997S1461>. 

Hydrazonyl chlorides have been employed in the synthesis of 1,2,4-triazoles. Intermolecular cyclization of hydrazonyl chlorides 166 with nitriles catalyzed by ytterbium(I) triflate afforded a series of 1,3,5-trisubstituted-1,2,4-triazoles 167 in good yields <05SC1435>. Dipolar cycloadditions between hydrazonyl chlorides 168 and nitriles in aqueous sodium bicarbonate in the presence of a surfactant provided mild conditions for the syndesis of l-aryl-5-substituted-... 

As a mechanistic rationale, LEwis-acid mediated nitrile N-alkylation (11 —> 12) could be the primary step the nitrilium ion 12 undergoes cyclization via the hydrazone moiety to afford 1,3,5-trisubstituted 1,2,4-triazoles 13. 

Acyl hydrazides are useful precursors for the synthesis of 1,2,4-triazoles. Reaction of acyl hydrazides 149 with imidoylbenzotriazoles 148 in the presence of catalytic amounts of acetic acid under microwave irradiation afforded 3,4,5-trisubstituted triazoles 150 <06JOC9051>. Treatment of A-substituted acetamides with oxalyl chloride generated imidoyl chlorides, which reacted readily with aryl hydrazides to give 3-aryl-5-methyl-4-substituted[ 1,2,4]triazoles <06SC2217>. 5-Methyl triazoles could be further functionalized through a-lithiation and subsequent reaction with electrophiles. ( )-A -(Ethoxymethylene)hydrazinecarboxylic acid methyl ester 152 was applied to the one-pot synthesis of 4-substituted-2,4-dihydro-3//-1,2,4-triazolin-3-ones 153 from readily available primary alkyl and aryl amines 151 <06TL6743>. An efficient synthesis of substituted 1,2,4-triazoles involved condensation of benzoylhydrazides with thioamides under microwave irradiation <06JCR293>. 

This sequence could be further extended to the synthesis of 1,4,5-triaryl-l,2,3-triazoles 44—46 (Scheme 7.16) by assembling the 5-iodotriazole and immediately employing Pd(0)-catalyzed cross-coupling with an appropriate arylboronic acid. This simple stepwise construction obviates purification of any intermediates and simultaneously provides complete control over the placement of substituents around the 1,2,3-triazole core, allowing facile access to all regioisomeric permutations of trisubstituted triazoles 44—46. Similar regiocontrolled synthesis would not be possible via thermal or ruthenium-catalyzed reaction due to the steric and electronic similarity of the aryl substituents (phenyl, tolyl, and p-methoxyphenyl). 

More recently, there has been a growing interest in the use of well-defined copper(I) catalysts as precursors of catalytic active species in water. An updated account of these developments is presented in this chapter, including transformations with terminal and internal alkynes that lead to the preparation of 1,4-disubstituted and 1,4,5-trisubstituted triazoles, respectively. 

Scheme 15.7 S5mtbesis of 5-iodo-l, 4-trisubstituted triazoles catalyzed by Cul-TTTA.

Preparation of Heterocycles. BSA has been used in the solid-phase synthesis of 1,2,3-triazoles via trimethylsilyl-directed 1,3-dipolar cycloaddition reactions of 1-trimethylsilylacetylenes with organic azides (eq 48). When resin 56 was allowed to react with trimethylsilylpropynoic acid in the presence of BSA, high regioselectivity was observed and the trisubstituted triazole 57a was obtained in near quantitative yield that is greater than 98% purity. 

Watt JA, Gannon CT, Loft KJ, Dinev Z, Wilhams SJ (2008) CUck Preparation of carbohydrate 1-benzotriazoles, 1,4-disubstituted, and 1,4,5-trisubstituted triazoles and their utility as glycosyl donors. Aust J Chem 61 837-846... 

Abstract Although the synthesis of 1,4- or 1,5-disubstituted 1,2,3-triazoles has been popularized by the recent developments of metal-catalyzed 3-1-2 cycloaddition of organic azides and terminal alkynes, the preparation of 1,4,5-trisubstituted triazoles is less popular. The focus of this chapter is the synthesis of these heterocycles, using condensation reactions and rearrangements, selective preparation of trisubstituted triazoles from disubstituted precursors, and formal [3-1-2] cycloaddition reactions involving internal alkynes. 

Keywords Alkynes, Azides, C-H activation. Condensation, Cycloadditions, Diazo compounds, 1,4,5-Trisubstituted triazoles. 

Synthesis of 1,4,5-Trisubstituted Triazoles from 1,4-Disubstituted Triazoles... 207... 

This example outlines the need for the development of efficient synthetic methods to prepare 1,4,5-trisubstituted triazoles in a selective manner. 

One of the useful synthetic pathway for the preparation of 1,4,5-trisubstituted triazoles involves condensation of azides (ahphatic, aromatic, etc.) with active... 

Scheme 1 Main 1,4,5-trisubstituted triazoles prepared from the corresponding active methylene compounds and azides...

Several syntheses of 1,4,5-trisubstituted triazoles from diazo compounds have been reported [1]. Thus, compoimd 26, prepared in 79% yield from 25, reacts with primary aliphatic or aromatic amines 27 in refluxing 1,2-dichloroethane with catalytic titanium (IV) chloride to give trisubstituted triazoles 28 in good yield (Scheme 9) [42],... 

Furthermore, Au(l) catalyzed addition of triazoles to nonactivated alkynes has been reported to deliver mixture of N1 and N2 isomers, N2 being the major one [84]. This general lack of selectivity clearly outlines that the clean synthesis of 1,4,5-trisubstituted triazoles by 77-alkylation is not possible. 

A similar strategy has been used for the preparation of chiral triazolium precursors [85], protease inhibitors [86] C5-iodinated [87] or phosphorylated [88] 1,4,5-trisubstituted triazoles (Scheme 34)... 

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