Aminomethylation of Symmetric Dialkylthioureas with Formaldehyde and Amino Acids
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omethylation of Symmetric Dialkylthioureas with Formaldehyde and Amino Acids O. A. Mammeria, F. Hamouda, A. A. Sobinaa, S. M. Ramsha,*, V. S. Fundamenskya, V. V. Gurzhiyb, and E. S. Khrabrovaa a St.
Petersburg State Institute of Technology (Technical University), St. Petersburg, 190013 Russia b St. Petersburg State University, St. Petersburg, 199034 Russia *e-mail: [email protected] Received July 16, 2020; revised July 16, 2020; accepted July 29, 2020
Abstract—Condensation of 1,3-dialkylthiourea, formaldehyde, and terminal amino acids (C2, C3, or C4) taken in the 1 : 2 : 1 molar ratio has afforded the terminally substituted (3,5-dialkyl-4-thioxo-1,3,5-triazinan-1-yl)carboxylic acids. Keywords: aminomethylation, 1,3-dialkylthioureas, formaldehyde, ω-amino acids, terminally substituted (3,5-dialkyl-4-thioxo-1,3,5-triazinan-1-yl)carboxylic acids
DOI: 10.1134/S1070363220110043 Well-studied aminomethylation of unsubstituted thiourea with formaldehyde and С2–С4 terminal amino acids yields cyclic thioureas—terminally substituted (4-thioxo-1,3,5-triazinan-1-yl)carboxylic acids [1, 2]. These compounds are not formed from unsubstituted urea and the same aminomethylating agents, likely due to faster polycondensation of urea with formaldehyde catalyzed by amino acids, whereas symmetrical dialkylureas readily undergo the aminomethylation reaction with the formation of the corresponding terminally substituted (3,5dialkyl-4-oxo-1,3,5-triazinan-1-yl)carboxylic acids [3]. This study aimed to prepare the thio analogs of those compounds, namely (3,5-dialkyl-4-thioxo-1,3,5triazinan-1-yl)carboxylic acids, via the condensation of symmetrical dialkylthioureas with formaldehyde and С2–С4 terminal amino acids. The reaction was of practical interest in view of the preparation of prodrug forms [4]
of active pharmaceuticals containing the thiourea moiety –HNC(=S)NH–. It was found that, as in the case of the unsubstituted thiourea, 1,3-dimethylthiourea 1 and 1,3-diethylthiourea 2 readily reacted with the simplest amino acids (glycine, β-alanine, and γ-aminobutyric acid) in aqueous formaldehyde to give well-crystallized terminally substituted (3,5-dialkyl-4-thioxo-1,3,5-triazinan-1-yl)carboxylic acids 3a–c and 4a–4c in 76–93% yield (Scheme 1). Structure of the obtained compounds was confirmed by means of IR and NMR spectroscopy as well as mass spectrometry. The 1Н NMR spectra of compounds 3 and 4 contained a singlet of cyclic СH2 protons at 4.24–4.31 ppm and signals of the protons of the amino acid moieties and the N-alkyl groups of the respective intensity (Table 1). The signals of the carboxyl group protons were not observed, likely due to fast exchange with the protons
Scheme 1.
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of residual water in the solvent. The 13С NMR spectra contained the signals of the carbon atoms of the cyclic (66.2–68.8 ppm) and carboxylic (171.5–174.8 ppm) groups as well as the amino acid and N-alkyl moieties (Table 1). The IR spectra revealed the characteristic signals of the thioureia fragment at 1512–1530 cm–1 and the car
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