Synthesis and Functionalization of 5‐Substituted Tetrazoles

Abstract

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.

Gold‐Catalyzed Synthesis of Tetrazoles from Alkynes by CC Bond Cleavage

“…Tetrazoles, which are important in medicinal chemistry and as energetic materials, have been obtained by 1,3-dipolar cycloaddition of azides with activated nitriles [28,29] and by cycloaddition of hydrazoic acid with the Ugi adducts generated in situ from carbonyl compounds, amines, and isonitriles. [30,31] This new reaction demonstrates that this new class of heterocyclic compounds can be prepared under relatively mild reaction conditions from readily available alkynes in a process in which gold(I) catalyzes the formation of alkenyl azides by nucleophilic attack onto the alkynes, as has been shown in the formation of carboxamides. [10] In addition, gold presumably provides the Brønsted acid required for the protodeauration and final formation of tetrazoles from the intermediate alkenyl azides under anhydrous, catalytic conditions.…”

Facile One-Pot Multicomponent Synthesis of Biaryl Tetrazoles through In Situ Formed Secondary Amides

“…To a stirred solution of benzo [1,3]dioxole-5-carbaldehyde 1a (0.005 mol), phenyldiamine 2a-2c (0.005 mol) and benzoyl chlorides 3a-3e (0.005 mol) were added and refluxed for 4 h at 70 °C. To this reaction mixture KOH (1 mmol), PCl 5 (0.001 mol) and NaN 3 (0.005 mol) were added and stirred for 6 h at 80 °C.…”

“…Tetrazoles are synthetic compounds with the highest nitrogen contents among the stable heterocycles 1 . They have long been recognized as carboxylic acid isosteres 2,3 and are important heterocycles in medicinal chemistry, owing to their increased stability towards metabolic degradation pathways 4 .…”

Synthesis and Physicochemical Characterization of the Process-Related Impurities of Olmesartan Medoxomil. Do 5-(Biphenyl-2-yl)-1-triphenylmethyltetrazole Intermediates in Sartan Syntheses Exist?

“…Alkylation of 5-phenyltetrazole with trityl chloride under alkaline conditions as well as with triphenylmethanol under acidic conditions should lead exclusively to the 5-phenyl-2-trityltetrazole [20,21]. Therefore, [2 1 -(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl bromide (2), the commercially available in kg scale intermediate to the syntheses of sartans, should be tritylated at the 2-position of tetrazole.…”