ABSTRACT
Two protocols for the combinatorial synthesis of 5-(dialkylamino)tetrazoles were developed. The best success rate (67%) was shown by the method that used primary and secondary amines, 2,2,2-trifluoroethylthiocarbamate, and sodium azide as the starting reagents. The key steps included the formation of unsymmetrical thiourea, subsequent alkylation with 1,3-propane sultone and cyclization with azide anion. A 559-member aminotetrazole library was synthesized by this approach; the overall readily accessible (REAL) chemical space covered by the method exceeded 7 million feasible compounds.
Subject(s)
Tetrazoles/chemical synthesis , Alkylation , Amines/chemistry , Azides/chemistry , Catalysis , Cyclization , Molecular Structure , Sodium Azide/chemistry , Temperature , Thiocarbamates/chemistry , Thiophenes/chemistry , Thiourea/chemistryABSTRACT
A 1,2,4-triazole motif is present in numerous commercialized and investigational bioactive molecules. Despite its importance for medicinal chemistry, there is a lack of convenient combinatorial approaches toward this molecular core. Herein, we present a synthetic strategy suitable for the quick preparation of a library of structurally diverse 1,2,4-triazoles in a one-pot setting. The key steps include the formation of thioureas followed by S-alkylation using 1,3-propane sultone and consecutive ring closure leading to the desired 1,2,4-triazoles. Parallel synthesis yields thousands of 1,2,4-triazoles in a cost- and time-efficient manner from commercially available chemicals.
Subject(s)
Small Molecule Libraries/chemical synthesis , Triazoles/chemical synthesis , Alkylation , Molecular Structure , Temperature , Thiophenes/chemistry , Thiourea/chemical synthesis , Time FactorsABSTRACT
One-pot synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from carboxylic acids and nitriles was optimized to parallel chemistry. The method was validated on a 141 member library; the desired products were recovered with a high success rate and in moderate yields. Practical application of the approach was demonstrated in the synthesis of bioactive compound pifexole and agonists of free fatty acid receptor 1. A library of 4â¯948â¯100 synthesizable drug-like 3,5-disubstituted 1,2,4-oxadiazoles was enumerated based on the method and available validated reagents.
Subject(s)
Carboxylic Acids/chemistry , Nitriles/chemistry , Oxadiazoles/chemistry , Humans , Oximes/chemical synthesis , Receptors, G-Protein-Coupled/agonists , Structure-Activity RelationshipABSTRACT
A one-pot parallel synthesis of N(1)-aryl-N(2)-alkyl-substituted oxamides with 2,2,2-trifluoroethyl chlorooxoacetate was developed. The synthesis of a library of 45 oxamides revealed higher efficiency of this reagent over the known ethyl chlorooxoacetate. The reagent was successfully used to prepare the known oxamide-containing HIV entry inhibitors.