Jiří Hanusek

Synthesis of Substituted 2-Benzoylaminothiobenzamides and Their Ring Closure to Substituted 2-Phenylquinazoline-4-thiones

Acylation of 2-aminothiobenzamide or 2-methylaminothiobenzamide with substituted benzoyl chlorides has been used to synthesise the corresponding 2-benzoyl-aminothiobenzamides whose subsequent sodium methoxide-catalysed ring closure gives the corresponding quinazoline-4-thiones. These compounds were characterised by means of their 1H- and 13C-NMR spectra. The preferred tautomeric form of selected compounds has been discussed on the basis of their 13C-NMR, IR and Raman spectra. It has been found that in the given medium 1-methyl-quinazoline-4-thiones undergo a replacement of the sulphur substituent by oxygen giving 1-methyl-quinazoline-4-ones. In strong acid media, 2-benzoylaminothiobenzamide is cyclised through its sulphur atom to give 2-phenylbenzo[d-1,3]thiazin-4-one.

Influence of substitution on kinetics and mechanism of ring transformation of substituted S-[1-phenylpyrrolidin-2-on-3-yl]isothiuronium salts.

Twelve new substituted S-(1-phenylpyrrolidin-2-on-3-yl)isothiuronium bromides and twelve corresponding 2-imino-5-(2-phenylaminoethyl)thiazolidin-4-ones have been prepared and characterised. Kinetics and mechanism of transformation reaction of S-[1-(4-methoxyphenyl)pyrrolidin-2-on-3-yl]isothiuronium bromide and its N,N-dimethyl derivative 5a into corresponding substituted thiazolidin-4-ones 2a and 6a have been studied in aqueous solutions of amine buffers (pH 8.1-11.5) and sodium hydroxide solutions (0.005-0.5 mol l(-1)) at 25 degrees C and at I= 1 mol l(-1) under pseudo-first-order reaction conditions. The kinetics observed show that the transformation reaction is subject to general acid-base, and hydroxide ion catalyses. Acid catalysis does not operate in the transformation of 1a; the rate-limiting step of the base-catalysed transformation is the decomposition of bicyclic tetrahedral intermediate In(+/-) and the Brønsted dependence is non-linear (pK(a) approximately 9.8). In the case of derivative 5a both base and acid catalyses make themselves felt. In the base catalysis, the rate-limiting step consists of the decomposition of bicyclic intermediate In, and the Brønsted dependence is linear (beta = 0.9; pK(a) > 11.5). The acid-catalysed transformation of 5a also proceeds via the intermediate In, and the reaction is controlled by diffusion (alpha approximately equal to 0). With compound 5a in triethylamine and butylamine buffers, the general base catalysis changes into specific base catalysis. The effect of substitution in aromatic moiety of compounds 1a-h and 3a-h on the course of the transformation reaction has been studied in solutions of sodium hydroxide (0.005-0.5 mol l(-1)) at 25 degrees C by the stopped-flow method. The electron-acceptor substituents 4-NO(2) and 4-CN do not obey the Hammett correlation, which is due to a suppression of cross-conjugation in the ring-closure step of the transformation reaction.

Kinetics and mechanism of ring transformation of S-1-(4- methoxyphenyl)pyrrolidin-2-on-3-yl isothiuronium bromide to 2- methylimino-5-2-(4-methoxyphenylamino)ethyl thiazolidin-4-one

The kinetics and mechanism of transformation reaction of S-[1-(4- methoxyphenyl)pyrrolidin-2-one-3-yl]-N-methyl-isothiuronium bromide into 2-methylimino-5-[2-(4-methoxyphenylamino) ethyl)]thiazolidin-4-one have been studied in aqueous solutions of amine buffers (pH 8.1-11.5) and sodium hydroxide solutions (0.005-0.5 mol l-1) at 25 degrees C and at I = 1 mol l-1 at pseudo-first-order reaction conditions. The kinetics observed shows that the transformation reaction is subject to general base, general acid, and hydroxide-ion catalyses. The rate-limiting step of transformation is the splitting-off a proton from the tetrahedral intermediate In. The value of pKa for S-[1-(4-methoxyphenyl)- pyrrolidin-2-one-3-yl]-N-methylisothiuronium bromide has been determined from the kinetic data (pKa = 8.75 +/- 0.10) and by potentiometric titration (pKa = 8.90 +/- 0.05). With increasing pKa value of the acid buffer component, the value of Brønsted coefficient beta gradually decreases from about 0.7 to almost zero. The value of pKa approximately 10 for the intermediate to base-catalysed transformation has been found from this dependence. In the N-methylpyrrolidine and triethylamine buffers, the rate-limiting step of transformation is changed into ring opening of In-, and the general-base-catalysed reaction changes into a specific-base-catalysed one.

New substituted mono-and bis(imidazolyl)pyridines and their application in nitroaldolisation reaction

New chiral nitrogen ligands based on the substituted mono-and bis(imidazolyl)pyridines have been prepared and characterised. Their complexes with cupric acetate were used as catalysts in the nitroaldolisation reaction. In the case of optically pure complexes of mono(imidazolyl)pyridine, the isolated products were 2-nitro-1-(2-nitrophenyl)ethanols or 2-nitro-1-(4-nitrophenyl)ethanols in overall yields of 49–93 % and with the maximum enantiomeric excess of 15.6 %. The complexes of bis(imidazolyl)pyridine also catalyse the nitroaldol reaction, the yields being 64–90 %, but with zero enantioselective excess.

Mechanism of the sulfurisation of phosphines and phosphites using 3-amino-1,2,4-dithiazole-5-thione (xanthane hydride)

Contrary to a previous report, the sulfurisation of phosphorus(III) derivatives by 3-amino-1,2,4-dithiazole-5-thione (xanthane hydride) does not yield carbon disulfide and cyanamide as the additional reaction products. The reaction of xanthane hydride with triphenyl phosphine or trimethyl phosphite yields triphenyl phosphine sulfide or trimethyl thiophosphate, respectively, and thiocarbamoyl isothiocyanate which has been trapped with nucleophiles. The reaction pathway involves initial nucleophilic attack of the phosphorus at sulfur next to the thiocarbonyl group of xanthane hydride followed by decomposition of the phosphonium intermediate formed to products. The Hammett rho-values for the sulfurisation of substituted triphenyl phosphines and triphenyl phosphites in acetonitrile are approximately -1.0. The entropies of activation are very negative (-114+/-15 J mol-1 K-1) with little dependence on solvent which is consistent with a bimolecular association step leading to the transition state. The negative values of DeltaS(not equal) and rho values indicate that the rate limiting step of the sulfurisation reaction is formation of the phosphonium ion intermediate which has an early transition state with little covalent bond formation. The site of nucleophilic attack has been also confirmed using computational calculations.

Kinetics and mechanism of base-catalysed degradations of substituted aryl-N-hydroxycarbamates, their N-methyl and N-phenyl analogues.

The kinetics and mechanism of the degradation reactions of substituted phenyl N-hydroxycarbamates and their N-methyl and N-phenyl analogues have been studied at pseudo-first-order reaction conditions in aqueous buffers and sodium hydroxide solutions at 20 [degree]C and 60 [degree]C and at I= 1 mol[middle dot]l(-1). The dependence of log k(obs) on pH for phenyl N-hydroxycarbamates at pH < 9 and pH > 13 is linear with the unit slope; at pH 10-12 log k(obs) is pH independent. The Bronsted coefficient [small beta](lg) is about -1 (pH 7-13) and -1.53 (pH > 13) indicating that the degradation reaction of phenyl N-hydroxycarbamates follows an E1cB mechanism giving the corresponding phenol/phenolate and HO-N[double bond, length as m-dash]C[double bond, length as m-dash]O. The latter species undergoes further decomposition to give carbonate, nitrogen and ammonia as final products. In contrast to the phenyl N-hydroxycarbamates the N-methyl derivatives at pH 7-9 undergo degradation to the corresponding phenol/phenolate, carbonate and methylamine via a concerted mechanism ([small beta](lg) is about -0.75). The only exception is 4-nitrophenyl N-hydroxy-N-methylcarbamate in which the predominant break down pathway proceeds via the Smiles rearrangement to give sodium N-methyl-(4-nitrophenoxy)carbamate. At pH > 9 the reaction of N-hydroxy-N-methylcarbamates is kinetically complex: the dependence of absorbance on time is not exponential and it proceeds as a consecutive two-step reaction. N-Hydroxy-N-phenylcarbamate under the same conditions undergoes degradation to phenol, carbonate, aniline and azoxybenzene.

Kinetics and Mechanism of the Base-Catalyzed Rearrangement and Hydrolysis of Ezetimibe

The pH-rate profile of the pseudo-first-order rate constants for the rearrangement and hydrolysis of Ezetimibe giving (2R,3R,6S)-N,6-bis(4-fluorophenyl)-2-(4-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran-3-carboxamide (2) as the main product at pH of less than 12.5 and the mixture of 2 and 5-(4-fluorophenyl)-5-hydroxy-2-[(4-fluorophenylamino)-(4-hydroxyphenyl)methyl]-pentanoic acid (3) at pH of more than 12.5 in aqueous tertiary amine buffers and in sodium hydroxide solutions at ionic strength I = 0.1 mol L(-1) (KCl) and at 39 °C is reported. No buffer catalysis was observed and only specific base catalysis is involved. The pH-rate profile is more complex than the pH-rate profiles for the hydrolysis of simple β-lactams and it contains several breaks. Up to pH 9, the log k(obs) linearly increases with pH, but between pH 9 and 11 a distinct break downwards occurs and the values of log k(obs) slightly decrease with increasing pH of the medium. At pH of approximately 13, another break upwards occurs that corresponds to the formation of compound 3 that is slowly converted to (2R,3R,6S)-6-(4-fluorophenyl)-2-(4-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran-3-carboxylic acid (4). The kinetics of base-catalyzed hydrolysis of structurally similar azetidinone is also discussed.

(3RS)-S-[1-(3-Chloro-phen-yl)-2-oxopyr-rolidin-3-yl]-N,N'-dimethyl-thio-uronium bromide.

The title molecule, C13H17ClN3OS+·Br−, consists of benzene and pyrrolidine rings and an S–C(NHCH3)2 group. The central C—N bond lengths in the S–C(NHCH3)2 fragment indicate partial double-bond character. Molecules are interconnected into chains by N—H⋯Br hydrogen bonds and the chains are linked into pairs by weak C—H⋯Br hydrogen bonds.

(3RS)-S-[1-(3-Chloro­phen­yl)-2-oxopyr­roli­din-3-yl]thio­uronium bromide

In the title molecular salt, C11H13ClN3OS+·Br−, the C—N bond lengths in the –S–C(NH2)2 fragment indicate partial double-bond character of these bonds. The constituent ions are connected by N—H⋯Br bridges into Z-shaped chains. The supramolecular architecture of the structure can be described by being composed of these chains interlocked by additional C—H⋯Br short contacts. An intramolecular N—H⋯O=C bridge, as well as weak C—H⋯O hydrogen bonds, are also present in the structure.

[3 + 2]-Cycloaddition reaction of sydnones with alkynes

This review covers all known examples of [3 + 2]-cycloaddition between sydnones and both terminal as well as internal alkynes/cycloalkynes taken from literature since its discovery by Huisgen in 1962 up to the current date. Except enumeration of synthetic applications it also covers mechanistic studies, catalysis, effects of substituents and reaction conditions influencing reaction rate and regioselectivity.