Cyclothiomethylation of primary amines with formaldehyde and hydrogen sulfide to nitrogen- and sulfur-containing heterocycles (review)

Published data and the authors' own experimental results on the synthesis of nitrogen- and sulfur-containing heterocycles based on the cyclothiomethylation of amines with formaldehyde and H₂S are reviewed. Features of the three-component condensation are discussed in relation to the nature and structure of the initial amines and also the reaction conditions.     

Reaction of ethyl acetoacetate with formaldehyde and primary amines

The condensation of ethyl acetoacetate with formaldehyde and primary amines in methanol at 65°C (Mannich reaction) gave up to 92% of hexahydropyrimidine derivatives containing ester and acetyl groups. Analogous reaction with aminopyridines stopped at the stage of formation of linear condensation products.     

The interaction of antitumor active vanadocene dichloride with sulfur-containing amino acids

Vanadocene dichloride (1) reacts with sulfur-containing amino acids, cysteine and methionine, giving new complexes with five- or six-membered chelate ring, but the structure of isolated compounds is affected by the pH value of the reaction mixture. Methionine reacts with aqueous 1 in the pH range of 3-8 affording chelate structure [Cp₂V(N,O-met)]Cl (4). Similar reaction with cysteine gives two different products depending on pH. In the acidic solution, the complex [Cp₂V(O,S-cys)]Cl (2) is present, whereas in neutral media the compound [Cp₂V(N,S-cys)] (3) could be identified. On inspection of spectroscopic measurements, particularly EPR and vibrational spectroscopy, it is evident that sulfur atom of amino acid is bonded directly to the vanadium atom of [Cp₂V]²⁺ moiety. For the purpose of comparison the complexes [Cp₂V(O,S-mpa)] (5) and [Cp₂V(N,S-csam)]⁺ (6a) with related chelating ligands, 3-mercaptopropionic acid (mpa) and cysteamine (csam), respectively, were prepared and spectroscopically characterized. The structure of the complex [Cp₂V(N,S-csam)]BPh₄ (6b) was also determined by X-ray diffraction analysis.     

Reductive methylation of primary and secondary amines and amino acids by aqueous formaldehyde and zinc

Amines can be methylated when treated with formaldehyde and zinc in aqueous medium. Selective mono- or dimethylation can be achieved by proper choice of pH, stoichiometry and reaction time. This method can also be applied for amino acids.     

2-Aminobenzimidazole in three-component cyclization reactions with formaldehyde and primary amines

Three-component condensation of 2-aminobenzimidazole and its N-substituted derivatives with formaldehyde and primary amines gave 1,2,3,4-tetrahydro[1,3,5]triazino[1,2-a]benzimidazoles. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 355–356, February, 2007.     

Solid-state interaction of trimethylammonioalkylferrocene iodides with primary amines

The syntheses of several aminoalkylferrocenes by the solid-state reactions of trimethylammoniomethylferrocene iodides and (S)-(–)-(1-trimethylammonio)ethylferrocene with primary amines are described. New ferrocenylalkylamines were synthesized: 1-(4-toluidino)ethylferrocene, 1-(2-pyridylamino)ethylferrocene, 2-pyridylaminomethylferrocene, and N,N-bis(ferrocenylmethyl)-2-pyridylamine.     

Reaction of γ-nitroketones and methyl 4-nitrobutanoates with formaldehyde and primary amines

5-Nitropentan-2-one reacts with methylamine and formaldehyde according to the Mannich reaction pattern to give 5-hexahydropyrimidinylcarbonyl-substituted 1-nitro-3,7-diazabicyclo[3.3.1]nonane in one experimental stage. When methyl 3-R-4-nitrobutanoates are used, the reaction stops after the formation of substituted 5-nitrohexahydropyrimidines in 40–98% yields. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1687–1693, July, 2005.     

The diene synthesis with sulfur-containing derivatives of acrylic acids

Reaction of aqueous solutions of salts of acrylic acids with thioepi chlorohydrin affords thietyl acrylates, which on hydrolysis give 3-hydroxythietane, and on oxidation with hydrogen peroxide give 3-hydroxythietane 1,1-dioxide. The diene synthesis was carried out with these acrylates, and also with acryloyl and methacryloyl isothiocyanates.The authors thanks M. I. Mironova for the IR spectra and the elemantal analyses.     

Cyclization of secondary aromatic amines with formaldehyde and cyclopentanone

Secondary aliphatic-aromatic and aromatic amines react with formaldehyde and cyclopentanone in the presence of perchloric acid to form cyclopenta[c]quinolinium salts in good yields. The yields of the cyclization conditions as a function of reagent ratio and reaction time and temperature were studied, and procedures for isolation and purification of the target compounds were developed.     

Multicomponent condensation of aliphatic amines with formaldehyde and hydrogen sulfide

Cyclothiomethylation of primary aliphatic amines with the reagent H₂S-CH₂O (2:3) in aqueous medium mainly gave substituted dithiazines; oxathiazines and dioxazines were obtained from butylamine and ethanolamine. Under the chosen reaction conditions, ethylenediamine was converted into 5-[2-(perhydro-1,3,5-dithiazin-5-yl)ethyl]perhydro-1,3,5-dithiazine or substituted thiazetidine and oxazetidine, depending on the order of mixing of the starting reagents.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 423–427, February, 2005.     

Reactions of proton transfer and exchange with the participation of OH,SH, and CH acids and amines

A comparison of proton exchange reactions between OH, SH, and CH acids and the NH groups of trialkylammonium ions showed that regardless of the nature of the acid XH, the mechanism of exchange includes transfer of a proton in the ion pair N-H⁺ ... X^– as the slow step. At the fast steps of proton exchange XH- N⁺H, i.e., molecular exchange with breaking of a hydrogen bond X-H ... N and transfer of a proton along these bonds, differences appear in the properties of XH acids. In the sequence from OH to SH and CH acids, the hydrogen bonds X-H ... N are weakened. As a result of this, in the same sequence the kinetic acidity (k₂) decreases but the rate of molecular exchange (k_H) increases. The ratio between the values of k₂ and k_H is inverted when the strong bonds O-H ... N (k₂/k_H 1) are replaced by weak bonds C-H ... N (k₂/k_H 1). It was also established that the kinetic stability of the anions increases as the oxygen atoms are replaced by sulfur in the series RCOO^– < RCOS^– < R₂PSS^– as a result of the more effective delocalization of the negative charge on the diffuse orbitals of sulfur.Translated from Teoreticheskaya i Éksperimental'naya Khimiya, Vol. 23, No. 4, pp. 471–475, July–August 1987.     

Study of the nature of the interaction of CH3CN with Lewis acids

The unperturbed ν⁰ (CN) stretching frequencies of CH₃CN in 18 complexes with Lewis acids are correlated with ν (CN) frequencies in cobalticyanides and with cation parameters which measure σ and π interactions. The results indicate that the nature of the interaction is predominantly of the σ donor—acceptor type wib no detectable π back-donation from the cation to the CN ligand.     

Rhenium(V) complexes with sulfur-containing amino acids

Rhenium(V) complexes with 2-amino-4-(methylthio)butanoic acid (methionine, Met) and 2-amino-3-sulfopropionic acid (cysteine, Cys) have been synthesized. Depending on the initial reagent ratio, the resulting complexes contain one or two ligand molecules. On heating the compounds with one amino acid molecule, two hydrogen halide molecules are removed at 128–132°C to form a molecular complex. The composition, structure, and thermal stability of the complexes have been studied by elemental analysis, conductometry, IR spectroscopy, NMR, and mass spectrometry.     

Effect of sulfur-containing phenols and amines on the decomposition of hydroperoxides

The effect of polyphenol sulfides (PPS) and dithiolthione, the sulfur-containing derivative of acetone anil, on the decomposition of cumyl andn-decyl hydroperoxides (DHP) studied. The decomposition of cumyl hydroperoxide (CHP) in the presence of PPS is a complex multistep autocatalytic process during which an efficient catalyst for CHP decomposition is formed from the initial PPS. The PPS catalyst for CHP decomposition is deactivated in the reaction with peroxy radicals. Kinetic characteristics of the reaction between polyphenol sulfides and CHP are determined. Dithiolthione catalytically decomposes CHP and reacts with n-decyl hydroperoxide DHP in the stoichiometric ratio