Rapid Boulton–Katritzky rearrangement of 5-aryl-3-[2-(piperidin-1-yl)ethyl]-1,2,4-oxadiazoles upon exposure to water and HCl

Boulton-Katritzky Rearrangement of 5-Substituted Phenyl-3-[2-(morpholin-1-yl)ethyl]-1,2,4-oxadiazoles as a Synthetic Path to Spiropyrazoline Benzoates and Chloride with Antitubercular Properties

“…Nevertheless, for cations in 5c – e and 6 with similar conformations, the mean atomic deviation doesn′t exceed 0.5Å ( Figure 2 b). The positive charge on quaternary ammonium atom causes elongation of N(1)-N(2) and N(1)-C(1) bonds as it was previously demonstrated for 5-aryl-3-[2-(piperidin-1-yl)ethyl]-1,2,4-oxadiazoles [ 9 ], 2-amino-8-thia-1-aza-5-azoniaspiro[4.5]dec-1-ene [ 7 ], 1-( tert -butyl)-4,5-dihydro-1 H -pyrazol-1-ium [ 19 ] and 1,1,3-trimethyl-Δ 2 -pyrazolinium [ 20 ] analogs.…”

“…As we have proved in this article, 1,2,4-oxadiazoles 4a – e are recorded spectroscopically (FT-IR and NMR spectral data), and they are the initial ones during hydrolysis to pyrazolinium compounds. The Boulton–Katritsky rearrangement mechanism 4a – e → 5a – e , and 4a – e → 6 can be represented as a sequence of protonation, proton transfer and nucleophilic attack steps, representing hydrolysis during the reaction of 1,2,4-oxadiazoles 4a – e with water and wet HCl in the same way as we indicated for piperidine derivatives [ 9 ].…”

“…A monocarboxylate can only be an acceptor of 2–4 H-bonds. Thus, in the absence of water molecules, the cations and anions form simple H-bonded chains ( Figure 4 ) [ 9 ]. In 5d , these chains are further connected through halogen C-Br..O interactions ( Figure 4 a).…”

“…In some works, we found spiropyrazolinium compounds with a quaternary nitrogen atom, which is common for two heterocycles. When studying the stability of 3-(2-aminoethyl)-5-aryl-1,2,4-oxadiazoles having six-membered cyclic tertiary 2-amino groups towards hydrolysis, we found that they were capable of rearranging to spiropyrazoline benzoates or chlorides [ 7 , 8 , 9 ].…”

“…Furthermore, at targeted exposure on 3-[2-(piperidin-1-yl)ethyl]-5-aryl-1,2,4-oxadiazoles with: ( i ) water, ( ii) water in DMF or ( iii ) ethereal HCl they underwent rearrangement with the formation 2-amino-1,5-diazaspiro[4.5]dec-1-en-5-ium benzoates or chlorides ( Scheme 2 ). In the latter case, along with the formation of spiropyrazolinium chloride hydrate from 3-[2-(piperidin-1-yl)ethyl]-5-(3-chloro-phenyl)-1,2,4-oxadiazole hydrochlorides of starting 1,2,4-oxadiazoles were obtained as secondary products [ 9 ].…”