Synthesis and Functionalization of 5-Substituted Tetrazoles

Tetrazoles are synthetic heterocycles with numerous applications in organic chemistry, coordination chemistry, the photographic industry, explosives, and, in particular, medicinal chemistry. In organic chemistry, 5-substituted tetrazoles are used as advantageous intermediates in the synthesis of other heterocycles and as activators in oligonucleotide synthesis. In drug design, 5-monosubstituted tetrazoles are the most important tetrazole derivatives because they represent non-classical bioisosteres of carboxylic acids, with similar acidities but higher lipophilicities and metabolic resistance. In this review we focus on the preparation and further functionalization of these heterocycles. Firstly, the role of 5-substituted tetrazoles in medicinal chemistry is described, including examples of their effects on pharmacokinetics, pharmacodynamics, and metabolism of the associated drugs. Then, the main synthetic approaches to 5-substituted tetrazoles consisting of methods based on acidic media/proton catalysis, Lewis acids, and organometallic or organosilicon azides are presented, from the early procedures to the most recent ones, with special attention paid to the reaction mechanisms. Functionalization of 5-substituted tetrazoles is a challenging task because it usually leads to the formation of two isomers, 1,5- and 2,5-disubstituted tetrazoles, in various ratios. In this overview, reactions with high or unusual regioselectivities are described, with comments on the possible mechanisms. Microwave-assisted approaches to the synthesis and functionalization of 5-substituted tetrazoles are also included.