5-Substituted tetrazoles

Fetter and co-workers reacted the tetrazole-substituted pyrrolidinone 274 with cerium(rv) ammonium nitrate to generate the tricyclic spirocyclic ring system 275 in 60% yield (Equation 75) <1996T10169>. 

Cyclic versus non-cyclic replacements a. Cyclic replacements of non-cycllc functional groups e.g. phenol/Indole substitutions e.g.carboxylic acid/tetrazole substitutions ... 

Similar to these results, 2-alkyl-2H-tetrazoles substituted at the 5-position leads to deprotonation-silylation on the alpha position of the alkyl chain on the nitrogen.158... 

Kelley M, Groth-Watson A, Knoble D, et al. 1991. Induction of peroxisomal enzymes by a tetrazole-substituted 2-quinolinylmethoxy leukotriene D4 antagonist [abstract]. Toxicologist 11 184. 

Scheme8 Microwave-accelerated preparation and enzyme inhibition of a tetrazole-substituted C2-symmetric HIV-1 protease inhibitor...

As nitriles are generally readily available this is the main route to simple tetrazoles. More complicated ones are made by alkylation of the product of a cycloaddition. The tetrazole substitute for indomethacin that we mentioned in Chapter 43 is made by this approach. First, the nitrile is prepared from the indole. The 1,3-dipolar cycloaddition works well by the azide route we have just discussed, even though this nitrile will form an enoF rather easily. 

As the intermediate enamine reacts faster with imines than aldehydes, a one-pot three component coupling of the donor ketone, aldehyde and amine is possible. List and coworkers have achieved high ees in this reaction utilising L-proline (7.66) and some aliphatic aldehydes and aromatic aldehydes such as (7.136) in combination with p-anisidene (7.137). This catalyst system is also effective for the coupling of a-hydroxyketones. Use of the tetrazole-substituted proline (7.80) allows the reaction to be performed in dichloromethane rather than DMSO and high ees in the Mannich reaction between aliphatic ketones and imines derived from ethyl glyoxalate have been obtained imder these reaction conditions. 

Further elaboration of 4 can be accomplished to install assorted functional groups of relevance for proton-transfer relays (Figure 3.5). For example, hydrolysis provides the dicarboxylic acid-appended terpy 5 [32], reduction with borane and hydrolysis yields the aminomethyl-terpy 6 [33], addition of azide provides the tetrazole-substituted terpy 7 [32], and treatment with hydrazine yields 8 [34]. Compounds 5-7 have been utilized as ligands for studying luminescence in lanthanide complexes [32, 33], but to our knowledge, have not yet been described in the catalysis literature. 

In order to develop new antidiabetic agents, guanidine and tetrazole substituted amides of 6-fluoroquinolin-2-carboxamides 205, 206 and 207 have been obtained [138]. Compound 207 acts as fibroblast growth factor receptor 3 (FGFR ) inhibitor and can be used for treatment of multiple myeloma (Scheme 89) [139,140]. 

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