1-Alkyl-5-((di)alkylamino) Tetrazoles: Building Blocks for Peptide Surrogates

Abstract

An approach to the synthesis of 1-alkyl-5-((di)alkylamino)tetrazoles by nucleophilic substitution in 1-alkyl-5-sulfonyltetrazoles with anions generated from the primary or secondary amines was developed. Tolerance of the method to the presence of some functional groups (i.e., protected amine) in both components of the reaction was demonstrated. Obtained tetrazoles are promising building blocks for the design of peptide surrogates, in particular, for replacement approaches of alkyl urea derivatives.

Butadiene sulfone as ‘volatile’, recyclable dipolar, aprotic solvent for conducting substitution and cycloaddition reactions

“…Tetrazoles have a broad range of applications. They are found in number of pharmaceutical compounds, they can be surrogates for peptides [11] and carboxylic acids [12], and they have been used to tag drug receptor proteins [13]. In addition, tetrazole ligands have also been used for fabricating coordination polymers [14,15].…”

One-Pot Parallel Synthesis of 5-(Dialkylamino)tetrazoles

“…Whereas 5-substituted tetrazoles are well-known bioisosteres of carboxylic acid function, 1,5-disubstituted derivatives can be used to mimic the cis configuration of the amide bond, , which is higher in energy to the commonly found trans configuration (Figure A). Recently, the 1-alkyl-5-(alkylamino)­tetrazole motif was envisioned as a potential replacement of the alkyl urea moiety, which is present in the structures of dozens therapeutics. , 1,5-Disubstituted tetrazoles are represented by a series of approved cephalosporin antibiotics (e.g., cefmetazole, , ceforanide , ) and antiplatelet therapeutic cilostazol , (Figure B). Therefore, access to the diverse library based on an N-substituted 1-alkyl-5-aminotetrazole scaffold 1 became the prime objective of the current work.…”

“…One of the options to obtain 1-substituted 5-aminotetrazoles is nucleophilic substitution at the carbon atom of a tetrazole bearing a good leaving group, for example amination of 5sulfonyltetrazoles 2 (Scheme 1A). 20 Alternative methods include the reaction of NaN 3 with aminoiminomethanesulfonic acids 3a, 29 α-chloroformamidines 3b, 30 (benzotriazolyl)carboximidamides 3c, 31 thioureas 4, 32 and substituted cyanamides 5, 33,34 the reaction of primary amines with highly reactive cyanogen azide (6), 35 and diazotization of aminoguanidines 7. 36 Because the aforementioned reagents are not readily accessible and some of them are difficult to handle, they are not suitable for combinatorial synthesis.…”

The Synthesis of 5-Substituted 1H-Tetrazoles in Molten Tetrabutylammonium Bromide

“…[8][9][10] The 1,3-dipolar cycloaddition of nitriles and azides is a reliable method for the synthesis of 5-substitued 1H-tetrazoles and extensive work has been reported. Many of the approaches involve the use of noble metal catalysts that are only removed or recovered with difficulty, troublesome solvents or hazardous substances.…”

“…During the past several decades, tetrazole derivatives have gained wide attention in the field of enantioselective catalysts, [1][2][3] host-guest complexes, 4 energetic materials [5][6][7] and peptide surrogates. [8][9][10] The 1,3-dipolar cycloaddition of nitriles and azides is a reliable method for the synthesis of 5-substitued 1H-tetrazoles and extensive work has been reported. Many of the approaches involve the use of noble metal catalysts that are only removed or recovered with difficulty, troublesome solvents or hazardous substances.…”