N-N(+) Bond-Forming Intramolecular Cyclization of O-Tosyloxy ß-Aminopropioamidoximes and Ion Exchange Reaction for the Synthesis of 2-Aminospiropyrazolilammonium Chlorides and Hexafluorophosphates.

Our research area is related to the spiropyrazolinium-containingcompounds, which are insufficiently studied compared with pyrazoline-containing compounds. Nitrogen-containing azoniaspiromolecules have also been well studied. In drug design and other areas, they are a priori important structures, since rigid spirocyclic scaffolds with the reduced conformational entropy are able to organize a closely spaced area. Azoniaspirostructures are currently of wide practical interest as ionic liquids, current sources (membranes), structure-directing agents in organocatalysis, and in the synthesis of ordered ceramics. Our goal was the synthesis of 2-aminospiropyrazolilammonium chlorides and hexafluorophosphates. Our methodology is based on the tosylation of ß-aminopropioamidoximes with six-membered N-heterocycles (piperidine, morpholine, thiomorpholine, and phenylpiperazine) at the ß-position. 2-Aminospiropyrazolilammonium chlorides and hexafluorophosphates were obtained by the reaction of double ion substitution in the reaction of toluenesulfonates of 2-aminospiropyrazolinium compounds with an ethereal solution of HCl in ethanol and with ammonium hexafluorophosphate in ethanol in quantitative yields of 55-97%. The physicochemical characteristics of the synthesized compounds and their IR and NMR spectra are presented. The obtained salts were additionally characterized by the single-crystal XRD analysis. The presence of both axial and equatorial conformations of spirocations in solids was confirmed. 2-Aminospiropyrazolilammonium chlorides and hexafluorophosphates have weak in vitro antimicrobial activity on Gram-positive and Gram-negative bacterial lines.

Crystal structure and antidiabetic activity of 2-aminospiropyrazolinium tosylates and the product of O-tosylation of ß-(benzimidazol-1-yl)propioamidoxime.

2-Amino-1,5-diazaspiro[4.5]dec-1-en-5-ium salts possess bioactivity tuned by the nature of the heteroatoms in the six-membered ring and the counter-ion. The molecular environment of these cations in solids provides an opportunity to establish the conformations and hydrogen-bonding patterns typical for this family. ß-Aminopropioamidoxime tosylation products [2-amino-1,5-diazaspiro[4.5]dec-1-en-5-ium tosylates and the product of the O-tosylation of ß-(benzimidazol-1-yl)propioamidoxime, namely, 2-amino-1,5-diazaspiro[4.5]dec-1-en-5-ium tosylate, C8H16N3+·C7H7O3S- (6), 2-amino-8-oxa-1,5-diazaspiro[4.5]dec-1-en-5-ium tosylate, C7H14N3O+·C7H7O3S- (7), the monohydrate of 7, C7H14N3O+·C7H7O3S-·H2O (7a), 2-amino-8-thia-1,5-diazaspiro[4.5]dec-1-en-5-ium tosylate, C7H14N3S+·C7H7O3S- (8), 2-amino-8-phenyl-1,5,8-triazaspiro[4.5]dec-1-en-5-ium tosylate, C13H19N4+·C7H7O3S- (9), and 3-(1H-benzimidazol-1-yl)-N'-(tosyloxy)propanimidamide, C17H18N4O3S (10)] were investigated using X-ray diffraction to study peculiarities of their molecular geometry and intermolecular interactions. In vitro antitubercular and antidiabetic screening of the ß-aminopropioamidoxime tosylation products was also carried out. It was revealed that this series of compounds does not have activity against drug-sensitive and multidrug-resistant M. tuberculosis strains, and exhibits high and moderate antidiabetic α-amylase and α-glucosidase activity. Using the hydrogen-bond propensity tool, we found that the inclination of counter-ions and atoms to act as acceptors of hydrogen bonds for the amino group decreases passing from tosylate O atoms to water molecules and the N atoms of five-membered rings. This fact is probably the reason for the formation in the solids of hydrogen-bonded tetramers consisting of two anions and two cations, and the rare occurrence of 2-aminospiropyrazolinium salt hydrates.

Reaction Products of ß-Aminopropioamidoximes Nitrobenzenesulfochlorination: Linear and Rearranged to Spiropyrazolinium Salts with Antidiabetic Activity.

Nitrobenzenesulfochlorination of ß-aminopropioamidoximes leads to a set of products depending on the structure of the initial interacting substances and reaction conditions. Amidoximes, functionalized at the terminal C atom with six-membered N-heterocycles (piperidine, morpholine, thiomorpholine and phenylpiperazine), as a result of the spontaneous intramolecular heterocyclization of the intermediate reaction product of an SN2 substitution of a hydrogen atom in the oxime group of the amidoxime fragment by a nitrobenzenesulfonyl group, produce spiropyrazolinium ortho- or para-nitrobenzenesulfonates. An exception is ortho-nitrobenzenesulfochlorination of ß-(thiomorpholin-1-yl)propioamidoxime, which is regioselective at room temperature, producing two spiropyrazolinium salts (ortho-nitrobezenesulfonate and chloride), and regiospecific at the boiling point of the solvent, when only chloride is formed. The para-Nitrobezenesulfochlorination of ß-(benzimidazol-1-yl)propioamidoxime, due to the reduced nucleophilicity of the aromatic ß-amine nitrogen atom, is regiospecific at both temperatures, and produces the O-para-nitrobenzenesulfochlorination product. The antidiabetic screening of the new nitrobezenesulfochlorination amidoximes found promising samples with in vitro α-glucosidase activity higher than the reference drug acarbose. 1H-NMR spectroscopy and X-ray analysis revealed the slow inversion of six-membered heterocycles, and experimentally confirmed the presence of an unfavorable stereoisomer with an axial N-N bond in the pyrazolinium heterocycle.

Redetermination of the structure of 2-amino-8-thia-1,5-di-aza-spiro-[4.5]dec-1-en-5-ium chloride monohydrate.

The reaction of ß-(thio-morpholin-1-yl)propio-amidoxime with tosyl chloride in CHCl3 in the presence of DIPEA when heated at 343 K for 8 h afforded the title hydrated salt, C7H14N3S+·Cl-·H2O, in 84% yield. This course of the tosyl-ation reaction differs from the result of tosyl-ation obtained for this substrate at room temperature, when only 2-amino-8-thia-1,5-di-aza-spiro-[4.5]dec-1-ene-5-ammonium tosyl-ate was isolated in 56% yield. The structure of the reaction product was established by physicochemical methods, spectroscopy, and X-ray diffraction. The single-crystal data demonstrated that the previously reported crystal structure of this compound [Kayukova et al. (2021). Chem. J. Kaz, 74, 21-31] had been refined in a wrong space group. In the extended structure, the chloride anions, water mol-ecules and amine groups of the cations form two-periodic hydrogen-bonded networks with the fes topology.

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.

The analysis of stability of biologically active compounds requires an accurate determination of their structure. We have found that 5-aryl-3-(2-aminoethyl)-1,2,4-oxadiazoles are generally unstable in the presence of acids and bases and are rearranged into the salts of spiropyrazolinium compounds. Hence, there is a significant probability that it is the rearranged products that should be attributed to biological activity and not the primarily screened 5-aryl-3-(2-aminoethyl)-1,2,4-oxadiazoles. A series of the 2-amino-8-oxa-1,5-diazaspiro[4.5]dec-1-en-5-ium (spiropyrazoline) benzoates and chloride was synthesized by Boulton-Katritzky rearrangement of 5-substituted phenyl-3-[2-(morpholin-1-yl)ethyl]-1,2,4-oxadiazoles and characterized using FT-IR and NMR spectroscopy and X-ray diffraction. Spiropyrazolylammonium chloride demonstrates in vitro antitubercular activity on DS (drug-sensitive) and MDR (multidrug-resistant) of MTB (M. tuberculosis) strains (1 and 2 µg/mL, accordingly) equal to the activity of the basic antitubercular drug rifampicin; spiropyrazoline benzoates exhibit an average antitubercular activity of 10-100 µg/mL on MTB strains. Molecular docking studies revealed a series of M. tuberculosis receptors with the energies of ligand-receptor complexes (-35.8--42.8 kcal/mol) close to the value of intermolecular pairwise interactions of the same cation in the crystal of spiropyrazolylammonium chloride (-35.3 kcal/mol). However, only in complex with transcriptional repressor EthR2, both stereoisomers of the cation realize similar intermolecular interactions.

Interaction of the O-Benzoyl-ß-aminopropioamidoximes with Lawesson's Reagent and Spectral Characterization of the Products.

Interaction of O-benzoyl-ß-aminopropioamidoximes [ß-amino group: pyperidin-1-yl; morpholin-1-yl; thiomorpholin-1-yl; 4-phenylpiperazin-1-yl; benzimidazol-1-yl] with Lawesson's reagent was done in tetrahydrofuran at heating to 70°C during 10 h. New O-thiobenzoyl-ß-aminopropioamidoximes were obtained with the outputs 57-96%; they were characterized with the help of physicochemical, IR, and NMR spectra.