M. Reed, Alexandria D. M. Jeanneret
Nov 17, 2021
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Abstract
Significance: Tetrazoles are five-membered heterocycles that are used in medicinal chemistry as isosteres for various functional groups. For example, monosubstituted tetrazoles are used instead of carboxylic acids, whereas disubstituted tetrazoles are used as amine replacements. Despite the many synthetic routes available for the synthesis of 1,5disubstituted tetrazoles, synthetic options for 2,5disubstituted tetrazoles remain limited. A simple approach has been developed for the synthesis of a diverse array of 2,5-disubstituted tetrazoles through the alkylation of 5-substituted 1H-tetrazoles with diazotized primary amines. Furthermore, due to the limited commercial availability of 5-substituted 1H-tetrazoles, exploration of a one-pot multicomponent approach was initiated, as this would permit the use of more-abundant aryl or alkyl nitriles as reactants. This approach not only streamlines the synthesis of 2,5-disubstituted tetrazoles, but also eliminates the need to isolate potentially unstable 5-substituted 1H-tetrazoles. Additionally, as an azide source is required for the cycloaddition step, a one-pot approach provides a safer route, as any remaining azide can be quenched with the nitrite reagent used in the subsequent step. Comment: Initially, various nitrite reagents were tested and successfully used for the diazotization of 5-substitued 1H-tetrazoles, but 2,2-dimethylpropane-1,3-diyl dinitrite was selected, as it was the most atom-economical reagent. With this reagent, the scope of the reaction was explored, and it was found that not only tetrazoles bearing an unprotected hydroxyl group (e.g., 4a) were tolerated, but that amino alcohols also reacted smoothly (e.g., 4c). Furthermore, sterically hindered tritylamine gave the corresponding 2,5-disubstituted tetrazole 4b in a good yield. In the one-pot approach, a variety of aryl and alkyl nitriles were used, including the most-basic alkyl nitrile, acetonitrile, which gave the corresponding product 4e in a moderate yield. Moreover, the one-pot and the stepwise approaches gave similar yields (65 and 71%, respectively) of the desired tetrazole 4d, further highlighting the applicability of this method. HN