Alkylation of 5-Substituted 1H-Tetrazoles via the Diazotization of Aliphatic Amines

Abstract

A new alkylation reaction of monosubstituted tetrazoles via the diazotization of aliphatic amines is reported. This method enables preferential formation of 2,5-disubstituted tetrazoles. A one-pot 1,3-dipolar cycloaddition/diazotization sequence starting from widely available nitriles is also described. Azide residues are quenched in the second step with the nitrite reagent, thus limiting the intrinsic risk associated with trimethylsilyl azide. The reaction conditions were compatible with several functional groups, including thiocyanates, which afford preferentially disubstituted 2-alkyl-5-(substituted-thio)­tetrazoles.

Coupling of N‐Tosylhydrazones with Tetrazoles: A Regioselective Synthesis of 2,5‐Disubstituted‐2H‐Tetrazoles

“…Resonances for this CH carbon appear between 62.7–64.3 ppm for 2,5‐ 9 and are shifted to 57.9–59.1 ppm in 1,5‐disubstituted tetrazoles 10 . These data are in good correlation with literature values: CH protons around 5.96–6.60 ppm in the 1 H NMR and CH carbons between 57.5–63.6 ppm in the 13 C NMR spectra of 2,5‐disubstituted tetrazoles [14c–e,41] . Regioisomers 9 and 10 showed quite different 13 C NMR spectral data for C‐5 of the tetrazole ring.…”

Understanding the regioselectivity of 5-substituted 1H-tetrazoles alkylation

“…On the contrary, when the reaction was performed with 1-phenylethan-1-amine, the selectivity decreased, despite the increase of the steric hindrance of the electrophile. In addition, as previously observed, 13 even when starting with an enantiomerically enriched secondary amine, 2,5-Tz 46 was isolated as a racemic mixture, supporting the involvement of a carbocation intermediate. A carbocation intermediate is also likely to be involved in the alkylation of tetrazoles with allylic and propargyl amines which give a lower selectivity compared to the corresponding alkyl amines (see 12 and 28 ).…”

“…A number of solvents performed well, with dinitrite N1, affording product 1a in Z55% yield and with isomer ratios Z70 : 30 (entries 1, 2, 4, 6, 7). Only polar solvents produced 1a in low yields (entries [9][10][11][12][13][14]. The isomer ratios were also slightly impacted when using polar solvents, and were typically above 60 : 40, without exceeding 70 : 30.…”

“…Scheme 2 Alkylation of 1H-Tz using the strategy of diazotisation of amines. 13 Table 1 Optimization of the reaction conditions for the diazotisation of benzylamine to perform the alkylation of 5-( 4…”

“…12 We have recently reported the alkylation of 1H-Tz using the amine diazotisation process we have developed to performed esterification reactions. 13,14 We recognized that the similarity of pKa in between a carboxylic acid and 1H-Tz could be exploited to form the transient alkyl diazonium intermediate which subsequently underwent the alkylation yielding a mixture of the two isomers of the corresponding disubstituted tetrazole, with 2,5-Tz as the major isomer (Scheme 2).…”