Synthesis of hydroxamic acid derivatives of 1,3,5-substituted-1,2,4-triazoles.

December 26, 2023

• Title:

  Synthesis of hydroxamic acid derivatives of 1,3,5-substituted-1,2,4-triazoles. Reagents and conditions: (i) KSCN, con. HCl, anhydrous  EtOH, reflux, 5 h; (ii) Et3N, acetone, reflux, 2 h; (iii) a. 10% NaOH, MeOH, reflux, 2 h; b. 10% HCl; (iv) ethyl 3-bromopropionate, K2CO3, acetone, reflux,  3 h; (v) a. 2 mol L−1 NH2OH/MeOH, KOH, r.t., 1 h; b. glacial acetic acid; (vi) TFA/methylanisole, 0 °C–r.t., 24 h; (vii) a. 10% NaOH, MeOH, reflux, 2 h;  b. 10% HCl; c. oxalyl dichloride, dry DCM, r.t., 3 h; (viii) N-methylhydroxylamine hydrochloride, Et3N, dry DCM, r.t., 2 h.

• Image Source:

  Discovery of potential anti-inflammatory drugs: Diaryl-1,2,4-triazoles bearing N-hydroxyurea moiety as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase

• Mark:

  Scheme 1

• Associated context:

  The synthetic route of target compounds 8a–j and 10a–o is  shown in Scheme 1. Using commercially available para-position substituted phenylhydrazine hydrochloride as initial  material, the critical intermediates 6a–j were synthesized as described in our previous report. The thiols bearing 1,2,4-  triazole were readily converted into the corresponding esters 7a–o by treatment with ethyl 3-bromopropionate in good  yields. The target hydroxamic acid derivatives 8a–j could be  directly prepared by mixing 7a–o with hydroxylamine metha-nol solution in the presence of KOH at room temperature.  Nevertheless, it was difficult to obtain N-methyl hydroxamic  acid derivatives 10a–o by the above-mentioned procedures, pre-  sumably owing to the steric hindrance of methyl. Thus, the  esters 7a–o were converted to more active acyl chloride 9a–j,  then by reaction with N-methyl hydroxylamine hydrochloride  in the presence of Et3N to give the desired N-methylhydroxa-  mic acid compounds 10a–e. The target compounds bearing  p-NH2SO2 moiety at N-1 phenyl ring were obtained by depro-  tection of tert-butyl in CF3COOH–PhOCH3 solution.