Selective alkylation of 1,2,4-triazole

Using MW irradiation under solvent-free conditions, it was possible to obtain regio-specific benzylation in position 1 of 1,2,4-triazole whereas only the 1,4-dialkylated product was obtained in poor yields under the action of conventional heating [114] (Eq. 64). 

This observation may be explained by the increased efficiency of the first benzyla-tion (Sn2 reaction between two neutral reagents proceeding via a dipolar TS) under microwave conditions. 

As an extension towards azolic fungicides, phenacylation was next examined. Under the action of microwave irradiation, exclusive reaction in position 1 (or equivalent 2) occurred whereas mixtures of N1 N4 and N14 products were obtained by A under the same conditions [115] (Eq. (65) and Tab. 3.26). 

As kinetic control was ensured, this clear microwave effect could possibly be due to a difference in polarity of the transition states, with apparently a more polar TS being formed when n attack by the nitrogen atom in position 2 is concerned. Theoretical calculations are in progress at the present time to try to confirm this assumption. 

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Selective alkylation of 1,2,4-triazole in position 1 is of primary interest for the synthesis of biologically active molecules such as fungicides (fluconazole, flutriafole,... 

Abendaim D, Diez-Barra E, de la Hoz A, Loupy A, Sanchez-Migallon A (1994) Selective alkylations of 1,2,4-triazole and benzotriazole in the absence of solvent. Heterocycles 38 793-802... 

Loupy et al. [70] have studied the effect of solvent on the selectivity of the alkylation of 1,2,4-triazole 62 by 2,2, 4 -trichloroacetophenone 63 (Scheme 4.31) under MW and conventional heating. The reactions were all performed at 140 °C. 

Abstract In this chapter, selected results obtained so far on Fe(II) spin crossover compounds of 1,2,4-triazole, isoxazole and tetrazole derivatives are summarized and analysed. These materials include the only compounds known to have Fe(II)N6 spin crossover chromophores consisting of six chemically identical heterocyclic ligands. Particular attention is paid to the coordination modes for substituted 1,2,4-triazole derivatives towards Fe(II) resulting in polynuclear and mononuclear compounds exhibiting Fe(II) spin transitions. Furthermore, the physical properties of mononuclear Fe(II) isoxazole and 1-alkyl-tetrazole compounds are discussed in relation to their structures. It will also be shown that the use of a,p- and a,C0-bis(tetrazol-l-yl)alkane type ligands allowed a novel strategy towards obtaining polynuclear Fe(II) spin crossover materials. 

The examples in Table 9.1 demonstrate scale-up by two orders of magnitude for solvent-free reactions. Hundreds of grams of product were obtained on the larger scale, with little difference in the final percentage yield or reaction conditions. The phenyla-cylation of 1,2,4-triazole (entry 2) was not only amenable to scale-up by a factor of 90, but enhanced selectivity to the N — 1 product occurred under microwave irradiation. Classical heating affords a mixture of N — 1 and N — 4 alkylated products as well as quaternary salts80. 

Pyridones were studied for N- and C-alkylation reactions by de la Hoz et al. [100] as already mentioned for 1,2,4 triazoles, the selectivity of the alkylation is highly dependent on the activation technique (microwave or conventional heating). 

Reaction of Af-alkyl-1,2,4-triazoles 122 with an alkyl radical generated from the corresponding carboxylic acid afforded the triazole ring 123 alkylated selectively in the 5-position <01TL7353>. 

Anastrozole is an aromatase inhibitor that is used to treat breast cancer by decreasing the amount of estrogen synthesized by the human body. The synthesis of anastrozole entails a selective bromination and alkylation reaction with 1,2,4-triazole. 

Direct alkylation with classical heating gave a mixture of 1- and 4-alkylated triazoles together with quaternary salts resulting from alkylations at both the 1 and 4 positions. Interestingly, it has been shown that benzylation and phenacylation occurred selectively at position 1 without any base under the action of irradiation and under solvent-free conditions (Scheme 10.94) [183]. The reaction with (2,4-dichloro)phenacyl chloride was studied in particular depth (Chapter 4). This reaction has been scaled-up to more than 100 g by use of a Synthewave 1000 oven. 

Recently Yi et al. also utilized 2-perfluoroaIkylethyl azides as 1,3-dipoles in the 1,3-dipolar cycloaddition to phenyl- or butylacetylenes [48]. As a result in the presence of copper(I) salt the corresponding l-fluoroalkyl-4-substituted 1,2,3-triazoles were obtained in about 60 % yield. Note that in this case only anti- isomers were obtained l-fluoroalkyl-4-aryl- or l-fluoroalkyl-4-butyl-l,2,3-triazoles. The authors do not explain the high selectivity of the process, although it may be attributed to the steric effect of the bulky substituents (aryl, butyl). Yi et al. note the relatively high efficiency of the fluoroalkyl 1,4-disubstituted-1,2,3-triazoles as catalysts of aldol condensation which may be easily recovered and reused [48]. Read et al. [49] virtually simultaneously with [48] published the results of their proper exploration of the copper salts catalyzed 1,3-dipolar cycloaddition of fiuo-rinated alkyl azides to acetylenes. This research extended the methodology... 

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