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

Abstract

International audienceAn activated synthon for the efficient introduction of a protected tetrazolylmethyl group into nucleophile-bearing compounds is presented. The β-cyanoethyl protecting group allows for very effective deprotection under mild basic conditions. The synthon can be prepared by a two-step procedure (42 %) starting from cheap starting material and can alkylate piperidine in 91 % yield. Even quadruple alkylation to form a protected version of the hexadentate ligand EDTT gives decent yields. Simultaneous removal of the four protecting groups furnishes the lithium salt of a formally zwitterionic ligand in 75 % yield. Finally, the synthon's performance has been assessed by comparison with its benzyl-protected counterpart and was found to be equally efficient in the alkylation of simple amines but superior in deprotection. For substrates bearing basic amine sites, the β-cyanoethyl group is largely preferable

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“…The reason for the high amounts of catalyst is attributed to the presence of the tertiary amine groups, 21 and our own experiences appear to indicate that bidentate chelating motifs may also reduce the catalytic power of palladium on carbon. 15,16 and subsequent purification of 9 by chromatography on a reversed-phase cartridge led to final yields of 60À78%. Complex 1 was synthesized by reacting ligand 9 with Fe-(BF 4 ) 2 3 6H 2 O under argon.…”

“…We used our very recently established strategy of introducing the tetrazole in the form of a preformed, preprotected synthon rather than establishing the azole in situ as is widely practiced in the literature (see refs and , references therein, and refs and ). This gave very satisfactory results (Scheme ), in contrast to those reported for a comparable synthetic target .…”

“…This gave very satisfactory results (Scheme ), in contrast to those reported for a comparable synthetic target . We apply benzylated tetrazolylmethyl chloride , ( 7 , Scheme ) here for the introduction of two pendent arms by double alkylation of formylated 1,4,7-triazacyclonane ( 6 ) that can be obtained reliably from the N/N/N orthoacetal 5 by acidic hydrolysis if great care is applied. Key intermediate 8 is purified to homogeneity by silica gel chromatography to give satisfactory yields (62–78%).…”

“…While hydrolysis of the formamide group of 8 is straightforward (95%), the removal of the two benzyl groups by catalytic hydrogenation requires amounts of palladium on carbon exceeding the weight of the introduced starting material (3.5 equiv w/w) but then succeeds efficiently in the course of 48 h at 1 atm of hydrogen. The reason for the high amounts of catalyst is attributed to the presence of the tertiary amine groups, and our own experiences appear to indicate that bidentate chelating motifs may also reduce the catalytic power of palladium on carbon. , We eventually ran the reaction at the gram scale, and subsequent purification of 9 by chromatography on a reversed-phase cartridge led to final yields of 60–78%.…”

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“…4) was synthesized in a highly convergent manner using a preprotected synthon. 60 The general utility of this synthon was also demonstrated at the example of the synthesis of a new hexadentate ligand (EDTT), tetrakis(tetrazolyl)-ethylenediamine, an EDTA isostere. 61 A protocol consisting of intra-muscular injection into anesthesized mice followed by electroporation permitted us to internalize an unknown proportion of the injected chelate into muscle cells.…”