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A robust synthesis of 1,2,4-triazoles is disclosed with a particular focus on developing methodology capable of delivering gram quantities and minimising hazardous waste.Heterocycles are well known as potential isosteres to replace carboxylic acids, esters and amides in the design of orally bioavailable drug candidates. 1 As part of our research it became necessary to design a range of trisubstituted 1,2,4-triazoles wherein the triazole 4-nitrogen is linked to a piperidine or tropane (Figure 1). From a medicinal chemistry perspective this is an attractive motif and a practical synthesis was required. For expedience we were keen that the methodology would enable us to readily vary the alkyl/aryl substituents R and R¢. 2 A recent publication has prompted us to disclose our results in this area of heterocycle synthesis. 3 Figure 1 Targets of interest.Initially attempts to construct the 3,5-dimethyl substituted triazole 2 were made in one step from the corresponding thioamide 1 and acetic hydrazide (Scheme 1). Although precedented in the literature, 4 in our hands we found the reaction to be low yielding and product isolation non-trivial; we suspected the problem to be associated with the quality of the thioamide used in the reaction. Disappointingly, this route presented significant difficulties on scaling due to the use of Lawesson's 5 or Belleau's 6 reagent in formation of the thioamide and disposal of mercuric residues.After a review of the literature we were intrigued at the publications that used the iminoyl chloride as a precursor for reaction with an acyl hydrazide and subsequent cyclisation to the 1,2,4-triazole. 7 In particular the work of Atkinson and Polya was of interest with the one-pot preparation of triazole 4 using conditions that appeared simple to perform. 8 We also felt the reported low yield was open to optimization (Scheme 2).For our initial attempt we focused on the equatorially substituted tropane 5 and used identical conditions to those described by Atkinson and Polya. We were delighted to find complete consumption of the starting material and formation of a new compound, however, the mass spectrum indicated that we had only formed the intermediate N-acyl amidrazone 6. Various conditions were examined to complete the cyclisation and the optimum conditions were determined to be heating under reflux in toluene with addition of a catalytic quantity (typically 5 mol%) of p-toluenesulfonic acid to furnish 7 in a satisfactory yield of 59% (Scheme 3).It is reasonable to postulate that the low yield reported by Atkinson and Polya is due to incomplete cyclisation of the corresponding intermediate to the 1,2,4-triazole. N-Acyl amidrazone 6 is stable to an aqueous work up, and washing out the phosphorous oxychloride residues appeared to make the cyclisation proceed with greater consistency, however, due to the polar nature of the N-acyl amidrazone care is needed with the wash if undertaken. From an analysis of the literature it would appear that cyclisation of amidrazones typically requires forcing cond...

A functionalisation of 1,3-diones using hypervalent iodine has been developed that is useful in the preparation of libraries of heterocyclic compounds.The use of high throughput chemistry has been shown to be an important development in the discovery of drugs in the modern pharmaceutical industry. 1 It fulfils the need to generate large chemical libraries which have utility both for the generation of lead candidates in the drug design process and for the optimisation of structure-activity relationships within a series of compounds. In particular the efficient construction of heterocyclic scaffolds such as oxadiazoles in a combinatorial paradigm has been a focus of interest. 2 The reactions used in high throughput synthesis need to be robust and applicable to a variety of substrates. This enables the introduction of diversity into the library so that compounds prepared possess a range of structural features. Herein we describe the application of hypervalent iodine reagents to the functionalisation of 1,3-diones and their use in heterocycle formation. 3 A recent publication in this area of chemistry has prompted us to disclose our results on the use of iodosylbenzene. 4,5 As part of our research it became necessary to prepare a range of pyrazoles 1 with an oxygen linker at the 4-position of the template. It was a goal that the chemistry should be designed for the simple variation of commercially available building blocks 2, 3 and 4 to enable the introduction of diversity. For synthetic expedience we were keen that both dione functionalisation and heterocycle formation be performed in a single reaction well ( Figure 1). Figure 1 Retrosynthesis of 4-alkoxy pyrazoles.Initial attempts to functionalise the dione were made using diazotransfer reagents to prepare a diazodiketone for transition metal mediated insertion chemsitry. 6 This is well precedented in the literature, however, rhodium or copper mediated intermolecular OH insertion reactions are capricious. They often require a large excess of the alcohol and optimisation of metal ligands and reaction conditions. 7 In our hands this approach was low yielding and therefore of limited general utility in the preparation of libraries of functionalised diones for heterocycle synthesis.We were intrigued at the number of publications that used hypervalent iodine for the functionalisation of carbonyl compounds and the potentially simple reaction conditions, which were amenable to high throughput synthesis. A publication by Moriarty was particularly interesting in which a simple dione 5 was functionalised using iodosylbenzene. 8 A small number of nucleophiles were considered including azide and methanesulfonate that were used as reactants in stoichiometric ratios. Alcohols were also investigated and coupled into the dione in reasonable yield, however, the alcohol was used as solvent. Obviously the use of alcohols as solvent would be severely limiting in our work and it was imperative to reduce the alcohol to a stoichiometric level as had been demonstrated for azidotrimethylsi...

Triazole derivatives R 0280A Practical Synthesis of Piperidine-/Tropane-Substituted 1,2,4-Triazoles. -The range of substituents is limited by their compatibility with the use of the chlorination conditions rather than by any steric considerations. -(PRICE*, D. A.; GAYTON, S.; SELBY, M. D.; AHMAN, J.; HAYCOCK-LEWANDOWSKI, S.; Synlett 2005, 7, 1133-1134; Sandwich Lab., Pfizer Global Res. Dev., Sandwich, Kent CT13 9NJ, UK; Eng.) -C. Herrmann 42-145