A Tetrakis(tetrazolyl) Analogue of EDTA

Abstract

International audienceThe tetrazole moiety is usually established in situ with the corresponding inconveniences, such as reactant incompatibility, yield. In most of these cases, the tetrazole is formed in its nonprotected form. Subsequent protection is unattractive because of the promiscuous formation of two regioisomers. No particular protecting group has seen widespread use. The growing field of site-selective oxidation of unactivated hydrocarbons makes use of metal complexes based on multidentate ligands displaying nitrogen coordination sites. We have characterized an easily accessible, benzyl-protected synthon that allows the convergent introduction of the tetrazolylmethyl moiety and its smooth deprotection by catalytic hydrogenation. With the straightforward synthesis of the new hexadentate ligand EDTT, we have demonstrated the utility of this synthon for the fields of coordination, medicinal, and organocatalytic chemistry

A Synthon for the Convenient and Efficient Introduction of Tetrazolylmethyl Groups into Nucleophile‐Bearing Compounds

“…[13] We now wished to determine whether the use of BCE-protected synthon 5 would approach the remarkably efficient four-fold alkylation of ethylenediamine that we observed for 1 (Scheme 7). The driving force responsible for the almost quantitative yields of 2 was its precipitation in water even at 70°C.…”

“…The presence of lutidine did not seem to have an adverse effect on the base-sensitive BCE protective group. We then reexamined the deprotection conditions of benzylated 2 [13] to decide on the overall performance of the two strategies. Two flaws in the hydrogenative debenzylation of this particular compound can be identified: (1) The need for large amounts and a high quality/freshness of the Pd/C catalyst and (2) LCMS-monitoring to pinpoint the moment at which work-up should be launched.…”

“…We have therefore developed an alternative, highly convergent approach to introducing the tetrazolylmethyl group by using a regiochemically defined synthon bearing a benzyl protecting group and activated for nucleophilic attack (Scheme 3). [13] This strategy is analogous to many other strategies such as the grafting of tertbutyl-protected acetate groups onto nucleophile-bearing compounds. Synthon 1 [14] was thus applied to the straightforward synthesis of the tetrakis-tetrazolyl analogue of EDTA, namely EDTT.…”

“…[28] ) have served well to synthesize large quantities of synthon 1. The protocol for the synthesis of BCE derivative 5 is similar to that of the benzyl derivative 1 that we developed [13] based on the original report by Harvill et al [14] Economic β-aminopropionitrile is treated with chloroacetyl chloride to give solid Ncyanoethylchloroacetamide (4) in good yield (80 %, Scheme 5). Great care is crucial for the success of the next two steps: The transformation to the chloroimine intermediate (INT) by use of PCl 5 requires the removal of all HCl generated in the process.…”

“…Synthon 1 [14] was thus applied to the straightforward synthesis of the tetrakis-tetrazolyl analogue of EDTA, namely EDTT. [13] No ligand displaying multiple units of free tetrazoles has been synthesized by using a preprotected tetrazole synthon before. However, its synthesis was hampered in the last step by the requirement of large amounts of palladium/carbon to remove four units of the benzyl protecting group.…”