Tetrazole 5-substituted

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]. 

Action of HSO3CI on 2-substituted thiazoles affords the 5-chlorosulfonyl derivatives (337, 338). Addition of 6-phenylthiazolo[2,3-e]tetra2ole to oleum opens the tetrazole ring to form 2-azido-4-phenyI-thiazolyl-5-sulfonic acid, isolated as its salt (339). 5-Chloro-sulphonyl derivative is obtained similarly by action of HSO,Cl. 

Annular tautomerism (e.g. 133 134) involves the movement of a proton between two annular nitrogen atoms. For unsubstituted imidazole (133 R = H) and pyrazole (135 R = H) the two tautomers are identical, but this does not apply to substituted derivatives. For triazoles and tetrazoles, even the unsubstituted parent compounds show two distinct tautomers. Flowever, interconversion occurs readily and such tautomers cannot be separated. Sometimes one tautomeric form predominates. Thus the mesomerism of the benzene ring is greater in (136) than in (137), and UV spectral comparisons show that benzotriazole exists predominantly as (136). 

For both azole and benzazole rings the introduction of further heteroatoms into the ring affects the ease of quaternization. In series with the same number and orientation of heteroatoms, rate constants increase in the order X = 0requires stronger reagents and conditions methyl fluorosulfonate is sometimes used (78AHC(22)71). The 1-or 2-substituted 1,2,3-triazoles are difficult to alkylate, but methyl fluorosulfonate succeeds (7IACS2087). 

Substituted tetrazoles readily exchange the 5-hydrogen for deuterium in aqueous solution. A major rate-enhancing effect is observed with copper(II) or zinc ions due to complexation with the heterocycle. The rate of base-induced proton-deuterium exchange of 1-methyltetrazole is 10 times faster than 2-methyltetrazole (77AHC(2l)323). 

The reaction is illustrated by the intramolecular cycloaddition of the nitrilimine (374) with the alkenic double bond separated from the dipole by three methylene units. The nitrilimine (374) was generated photochemically from the corresponding tetrazole (373) and the pyrrolidino[l,2-6]pyrazoline (375) was obtained in high yield 82JOC4256). Applications of a variety of these reactions will be found in Chapter 4.36. Other aspects of intramolecular 1,3-dipolar cycloadditions leading to complex, fused systems, especially when the 1,3-dipole and the dipolarophile are substituted into a benzene ring in the ortho positions, have been described (76AG(E)123). 

Other amino substituted isoxazoles undergo ring-opening reactions on treatment with base. Thus the amidine derivative (249) gave the triazole (250) (64TL149), while the triazene (251) on reaction with ammonia gave the tetrazole (252) (64X461). 

Tetrazolate, 5-(3-chlorobenzyldimethylammonium)-structures, 5, 796 Tetrazolate, 5-cyclopropyl-rearrangement, 5, 810 Tetrazolate, 5-(p-substituted)phenyl-alkylation, 5, 818 Tetrazolates anions... 

UV spectra, 5, 798 synthesis, 5, 833 thermolysis, 5, 812 Tetrazole, 5-amino-2-methyl-methylation, 5, 818 Tetrazole, 2-aryl-5-substituted quatemization, 5, 815 Tetrazole, 5-aryl-acidity, 5, 816... 

Tetrazole, l-(p-substituted phenyl)-antimicrobial activity, 5, 835 Tetrazole, 5-thio-rearrangements, 5, 823 Tetrazole, 2-thioacyl-reactions, 5, 109 Tetrazole, 5-(o-tolyl)-tautomerism, 5, 804 Tetrazole, 5-(p-tolyl)-dipole moments, 5, 795 tautomerism, 5, 804 Tetrazole, 5-(trimethylsilylamino)-synthesis, 5, 832 Tefrazolecarbaldehydes reactions, 5, 820 Tetrazole-5-carbaldehydes reactions, 5, 820 Tetrazolecarbonitriles reactions, 5, 820 Tetrazole carbonyl compounds reactions, 5, 820 Tetrazolecarboxylic acid, 5-aryl-acidity, 5, 816... 

Azides have been shown to react with itniniutn salts to give addition products. The same product is obtained if the iminium salt is treated with azide ion or if the enamine is treated with hydrazoic acid 14). The yields of the products were all very high (85-95 %). The interest in this reaction centers on the fact that the azides react with isonitriles to give substituted tetrazoles (83) 44). 

Cyanothiophenes have been converted to amidines, and thienyl-substituted tetrazoles have been prepared from them for pharmacological evaluation. ... 

Tautomeric Equilibrium Constants Kt = [ll/]/[21/] OF Substituted Tetrazoles 27 in DMSO Estimated from NMR Studies... 

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