Applications of trichloroisocyanuric acid and triphenylphosphine in the synthesis of azole derivatives

Abstract

Triphenylphosphine (PPh3) and trichloroisocyanuric acid (TCCA) are two reagents that are commonly used in organic synthesis. When combined, they can form a highly effective and versatile reagent that can be used in a wide range of organic reactions. This combination is particularly useful in the synthesis of various organic compounds such as ketones, aldehydes, and carboxylic acid derivatives. In this work, the applications of this reagent system in the synthesis of azole derivatives, including imidazolones, 2,5-disubstituted 1,3,4-oxadiazoles, 5‑aminosubstituted 2‑methoxy-1,3,4-oxadiazoles, 1,3,4-oxadiazol-2(3H)‑ones and urazoles. In the first study, N-acylcyanamides were synthesized via a convenient ultrasound-assisted one-pot reaction starting from readily available carboxylic acids and sodium cyanamide. TCCA and PPh3 were used to activate the reaction, which converted a range of carboxylic acids into N-acylcyanamides with good to excellent yields in a short time at room temperature without the need for additional base. The method deployed also enables rapid access to substituted imidazolone derivatives through a three-component coupling reaction of carboxylic acid, sodium cyanamide, and L-amino acid methyl esters. In the second study, the synthesis of 2,5-disubstituted 1,3,4-oxadiazoles was developed by using mechanochemical synthesis as an environmentally friendly alternative to traditional solvent-based methods. In the presence of TCCA and PPh3, N-acylbenzotriazoles condense with acylhydrazides leading to oxadiazoles derivatives in good to excellent yields within minutes. This approach eliminates the requirement for strictly anhydrous conditions, external heating, and long reaction times, as well as tedious multistep procedures. In the third part study, TCCA and PPh3 were used as reagents in the cyclization reaction of thiosemicarbazates to prepare 5-aminosubstituted 2-methoxy-1,3,4-oxadiazoles. Upon alkylation, oxadiazoles can be converted into two different classes of azoles, including 1,3,4-oxadiazol-2(3H)‑ones and urazoles, depending on the reaction time and temperature, and the excess of alkyl halides used. This operationally simple protocol provides efficient access to a diverse set of isomeric azoles using minimum synthetic steps and easily accessible oxadiazole key precursors.