CC BY-NC-ND 4.0 · SynOpen 2020; 04(02): 38-43
DOI: 10.1055/s-0040-1707519
letter
This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/) (2020) The Author(s)

Convenient Synthesis of 2-Thioimidazolone/Menadione Conjugates via a Two-Step Sequence Starting with Direct Amination of Menadione

Chemistry Department of Lomonosov Moscow State University, 119991, Moscow, Russian Federation   Email: dmh200949@gmail.com
,
Olga O. Krasnovskaya
,
Nikolai V. Zyk
,
› Author Affiliations
This work was supported by the Russian Foundation for Basic Research (project no. 19-33-90103).
Further Information

Publication History

Received: 09 April 2020

Accepted after revision: 21 April 2020

Publication Date:
20 May 2020 (online)


Abstract

A convenient route to conjugates of 2-thiohydantoins and menadione with linkers of various chemical nature through a two-stage reaction sequence (direct amination of the menadione with a functional amine followed by modification of a functional group) is presented. Optimal conditions for the direct amination of menadione using alkyl amines with substituents such as azide, alkyne, hydroxyl, amine, halogen, and carboxyl have been developed. Further modification of selected functionalities using CuAAC or esterification reactions with 2-thio­hydantoines has been performed.

Supporting Information

 
  • References and Notes

  • 1 Gaál A, Orgován G, Mihucz VG, Pape I, Ingerle D, Streli C, Szoboszlai N. J. Trace Elem. Med. Biol. 2018; 47: 79
  • 2 Dabrowiak JC. Metals in Medicine . Wiley; Weinheim: 2009: 49-249
  • 3 Xin C, Xiaolan Z, Jinghong C, Qianqian Y, Li Y, Dacai X, Peiquan Z, Xuejun W, Jinbao L. Eur. J. Pharmacol. 2017; 815: 147
  • 4 Zeeshan M, Murugadas A, Ghaskadbi S, Rajendran RB, Akbarsha MA. Comp. Biochem. Physiol., Part C: Toxicol. Pharmacol. 2016; 185: 1
  • 5 Qin Q.-P, Meng T, Tan M.-X, Liu Y.-C, Luo X.-J, Zou B.-Q, Liang H. Eur. J. Med. Chem. 2018; 143: 1597
  • 6 Hernandes MS, Britto LR. Curr. Neuropharmacol. 2012; 10: 321
  • 7 Fatfat M, Merhi RA, Rahal O, Stoyanovsky DA, Zaki A, Haidar H, Kagan VE, Gali-Muhtasib H, Machaca K. BMC Cancer 2014; 14: 527
  • 8 Kremer ML. Phys. Chem. Chem. Phys. 1999; 1: 3595
  • 9 Sangeetha S, Murali M. Int. J. Biol. Macromol. (Part B) 2018; 107: 2501
  • 10 Martinez-Bulit P, Garza-Ortíz A, Mijangos E, Barrón-Sosa L, Sánchez-Bartéz F, Gracia-Mora I, Flores-Parra A, Contreras R, Reedijk J, Barba-Behrens N. J. Inorg. Biochem. 2015; 142: 1
  • 11 Beloglazkina EK, Krasnovskaya OO, Guk DA, Tafeenko VA, Moiseeva AA, Zyk NV, Majouga AG. Polyhedron 2018; 148: 129
  • 12 Tishchenko K, Beloglazkina E, Proskurnin M, Malinnikov V, Guk D, Muratova M, Krasnovskaya O, Udina A, Skvortsov D, Shafikov RR, Ivanenkov Y, Aladinskiy V, Sorokin I, Gromov O, Majouga A, Zyk N. J. Inorg. Biochem. 2017; 175: 190
  • 13 Majouga AG, Zvereva MI, Rubtsova MP, Skvortsov DA, Mironov AV, Azhibek DM, Krasnovskaya OO, Gerasimov VM, Udina AV, Vorozhtsov NI, Beloglazkina EK, Agron L, Mikhina LV, Tretyakova AV, Zyk NV, Zefirov NS, Kabanov AV, Dontsova OA. J. Med. Chem. 2014; 57: 6252
  • 14 Ren F, Logeman BL, Zhang X, Liu Y, Thiele DJ, Yuan P. Nat. Commun. 2019; 10: 1386
  • 15 Guk DA, Krasnovskaya OO, Dashkova NS, Skvortsov DA, Rubtsova MP, Dyadchenko VP, Yudina ES, Kosarev MA, Soldatov AV, Shapovalov VV, Semkina AS, Vlasova KY, Pergushov VI, Shafikov RR, Moiseeva AA, Andreeva AV, Melnikov MY, Zyk NV, Majouga AG, Beloglazkina EK. Dalton Trans. 2018; 17357
  • 16 Binder RG, Benson ME, Flath RA. Phytochemistry 1989; 28: 2799
  • 17 Nivinskas H, Stasskevicciene S, Sarlauskas J, Koder RL, Miller A.-F, Ceenas N. Arch. Biochem. Biophys. 2002; 403: 249
  • 18 Schepetkin IA, Karpenko AS, Khlebnikov AI, Shibinska MO, Levandovskiy IA, Kirpotina LN, Danilenko NV, Quinn MT. Eur. J. Med. Chem. 2019; 183: 111719
  • 19 Chadar D, Camilles M, Patil R, Khan A, Weyhermüller T, Salunke-Gawali S. J. Mol. Struct. 2015; 1086: 179
  • 20 Hiramoto M. Yakugaku Zasshi (J. Pharm. Soc. Jpn.) 1942; 62: 464
  • 21 Sharma U, Katoch D, Sood S, Kumar N, Singh B, Thakur A, Gulati A. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2013; 52: 1431
  • 22 Ohta S, Hinata Y, Yamashita M, Kawasaki I, Jinda Y, Horie S. Chem. Pharm. Bull. 1994; 42: 1730
  • 23 Schepetkin IA, Karpenko AS, Khlebnikov AI, Shibinska MO, Levandovskiy IA, Kirpotina LN, Danilenko NV, Quinn MT. Eur. J. Med. Chem. 2019; 183: 111719
  • 24 Wang M, Zhang C, Sun L.-P, Ding C, Zhang A. J. Org. Chem. 2014; 79: 4553
  • 25 Jing L, Wu G, Hao X, Olotu FA, Kang D, Chen CH, Lee K.-H, Soliman ME. S, Liu X, Song Y, Zhan P. Eur. J. Med. Chem. 2019; 183: 111696
  • 26 Vire JC, Patriarche GJ, Christian GD. Pharmazie 1980; 35: 209
  • 27 Brandao C, Rocha MissiasF. C, Arantes LM, Soares LF, Roy KK, Doerksen RJ, Braga de Oliveira A, Pereira GR. Eur. J. Med. Chem. 2018; 145: 191
  • 28 da Cruz EH, Hussene CM, Dias GG, Diogo EB, de Melo IM, Rodrigues BL, da Silva MG, Valenca WO, Camara CA, de Oliveira RN, de Paiva YG, Goulart MO, Cavalcanti BC, Pessoa C, da Silva Júnior EN. Bioorg. Med. Chem. 2014; 22: 1608
  • 29 Bahia SB. B. B, Reis WJ, Jardim GA. M, Souto FT, de Simone CA, Gatto CC, Menna-Barreto RF. S, de Castro SL, Cavalcanti BC, Pessoa C, Araujo MH, da Silva Júnior EN. MedChemComm 2016; 7: 1555
  • 30 Prasad CV, Nayak VL, Ramakrishna S, Mallavadhani UV. Chem. Biol. Drug Des. 2018; 91: 220
  • 31 Gholampour M, Ranjbar S, Edraki N, Mohabbati M, Firuzi O, Khoshneviszadeh M. Bioorg. Chem. 2019; 88: 102967
  • 32 Direct Amination of Menadione; General Procedure: To a stirred solution of menadione (100 mg, 0.6 mmol) in EtOH (10 mL), primary amine (1.2 mmol) was added in one portion. After 12 hours of stirring in the dark, the reaction mixture became dark red. The alcohol was evaporated under reduced pressure, and the residue was dissolved in a mixture of DCM/MeOH (30:1) and purified by silica gel column chromatography, eluting with the same solvent system. All products were isolated in the form of bright-red oils that crystallized with difficulty. Crystallization occurred when oils were left standing, giving red powders.
  • 33 2-Methyl-3-(prop-2-yn-1-ylamino)naphthalene-1,4-dione (1): From menadione and propargylamine (66 mg, 1.2 mmol), 1 was obtained as a bright-orange powder. Yield after purification by column chromatography: 105 mg (80%); mp 156 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 7.92 (d, J = 6.85 Hz, 2 H, Ar), 7.77 (t, J = 7.34 Hz, 1 H, Ar-CO), 7.69 (t, J = 7.34 Hz, 1 H, Ar-CO), 6.93 (t, J = 6.85 Hz, 1 H, NH), 4.28 (d, J = 6.85 Hz, 2 H, CH2), 3.25 (s, 1 H, C≡CH), 2.15 (s, 3 H, CH3). 13C NMR (100.67 MHz, DMSO-d 6): δ = 182.2 (CO), 181.9 (CO), 146.0 (C-NH), 134.5 (Ar), 132.4 (Ar), 130.3 (Ar), 125.7 (Ar), 113.3 (C-CH3), 82.0 (-C≡), 74.6 (≡CH), 33.9 (CH2), 10.19 (CH3). HRMS: m/z [M + H]+ calcd 226.0863; found. 226.0865. UV/Vis: λ (ε, Lmol–1cm–1): 457 (1587) nm.2-((2-Hydroxyethyl)amino)-3-methylnaphthalene-1,4-dione (2): From menadione and ethanolamine (73 mg, 1.2 mmol), 2 was obtained as a deep-violet powder. Yield after purification by column chromatography: 98 mg (73%); mp 98 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 7.90 (ddd, J = 7.58, 4.4, 1.17 Hz, 2 H, Ar), 7.76 (td, J = 7.58, 1.27 Hz, 1 H, Ar-CO), 7.66 (t, J = 7.58 Hz, 1 H, Ar-CO), 6.49 (t, J = 5.67, 1 H, NH), 4.90 (t, J = 5.09 Hz, 1 H, OH), 3.58 (m, 4 H, 2 × CH2), 2.09 (s, 3 H, CH3). 13C NMR (100.67 MHz, DMSO-d 6): δ = 182.5 (CO), 182.3 (CO), 147.3 (C-NH), 134.8 (Ar), 133.2 (Ar), 132.5 (Ar), 130.6 (Ar), 126.0 (Ar), 125.8 (Ar), 111.2 (C-CH3), 60.9 (CH2-NH), 47.2 (CH2-OH), 11.2 (CH3). HRMS: [M + H]+ calcd 232.0968; found: 232.0969. UV/Vis: λ (ε, Lmol–1 cm–1): 472 (2240) nm.2-((2-Azidoethyl)amino)-3-methylnaphthalene-1,4-dione (3): From menadione and 2-azidoethylamine (103 mg, 1.2 mmol), 3 was obtained as a bright-red powder. Yield after purification by column chromatography: 122 mg (82%); mp 100 °C (dec.). 1H NMR (400 MHz, DMSO-d 6): δ = 7.92 (d, J = 7.70 Hz, 2 H, Ar), 7.78 (td, J = 7.47, 1.38 Hz, 1 H, Ar-CO), 7.69 (t, J = 7.47 Hz, 1 H, Ar-CO), 6.68 (t, J = 6.69, 1 H, NH), 3.75 (q, J = 6.17 Hz, 2 H, NH-CH2), 3.53 (t, J = 5.78 Hz, 2 H, CH2-N3), 2.06 (s, 3 H, CH3). 13C NMR (100.67 MHz, CDCl3): δ = 183.6 (CO), 182.1 (CO), 145.7 (C-NH), 135.6 (Ar), 134.3 (Ar), 133.6 (Ar), 132.0 (Ar), 126.5 (Ar), 126.3 (Ar), 114.0 (C-CH3), 51.5 (CH2-NH), 44.2 (CH2-N), 11.2 (CH3). HRMS: m/z [M + H]+ calcd 257.1033; found: 257.1036. UV/Vis: λ (ε, Lmol–1cm–1): 467 (2797) nm
  • 34 Click Reactions in CH2Cl2/H2O; General Procedure: To a solution of alkyne (0.33 mmol) in CH2Cl2 (7.5 mL), CuSO4·5H2O (8 mg, 0.033 mmol) dissolved in distilled water (200 μL), followed by sodium ascorbate (14 mg, 0.066 mmol) in distilled water (200 μL) were added under an argon atmosphere. The mixture was stirred for 30 minutes and the azide (0.33 mmol) in CH2Cl2 (2.5 mL) was added to the dark-brown solution. The reaction mixture was then stirred overnight under argon. The reaction mixture was evaporated under reduced pressure and the solid residue was purified by silica gel column chromatography, eluting with CH2Cl2/MeOH (40:1).
  • 35 (Z)-2-Methyl-3-(((1-(2-(5-oxo-4-(pyridin-2-ylmethylene)-2-thioxoimidazolidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-amino)naphthalene-1,4-dione (11): To 2-methyl-3-(prop-2-yn-1-ylamino)naphthalene-1,4-dione (1; 150 mg, 0.67 mmol) in CH2Cl2 (7.5 mL), CuSO4·5H2O (17 mg) dissolved in distilled water (200 μL), followed by sodium ascorbate (28 mg) in distilled water (200 μL) were added under an argon atmosphere. The mixture was stirred for 30 minutes and 5-(Z)-3-(2-azidoethyl)-2-(methylthio)-5-(pyridine-2-ylmethylene)-1H-imidazol-4H-one (193 mg, 0.67 mmol) in CH2Cl2 (2.5 mL) was added to the dark-brown solution and the reaction mixture was stirred overnight under argon. The pink precipitate was filtered off, dried in air and purified by silica gel column chromatography, eluting with CH2Cl2/MeOH (40:1). Yield after purification by column chromatography: 299 mg (87%); mp 212 °C. 1H NMR (400 MHz, CDCl3): δ = 8.71 (d, J = 8.1 Hz, 1 H, Нα-Ру), 8.63 (d, J = 3.91 Hz, 1 H, Нγ-Ру), 8.05 (s, 1 H, H-triazole), 7.88 (m, 2 H, Ar), 7.75 (td, J = 7.52, 1.1 Hz, 1 H, Ar), 7.66 (m, 1 H, Ar), 7.34 (m, 1 H, Нβ-Ру), 7.04 (t, J = 6.72 Hz, 1 H, Нβ′-Ру), 6.69 (s, 1 H, -CH=), 4.78 (d, J = 6.6 Hz, 2 H, NH-CH2-), 4.60 (t, J = 6.6 Hz, 2 H, -CH2-CH2-), 3.95 (t, J = 5.3 Hz, 2 H, -CH2-CH2-), 2.58 (s, 3 H, SCH3), 2.07 (s, 3 H, CH3). 13C NMR (100.67 MHz, CDCl3): δ = 168.7 (CO), 167.7 (CO), 149.9 (CON), 146.2 (C-SCH3), 146.0 (Cα′-Py), 139.9 (Cα-Py), 136.6 (C-NH), 134.4 (Cγ-Py), 132.6 (CH=C<), 132.2 (CH-Ar), 130.3 (CH-Ar), 126.5 (C-Ar), 125.7 (C-Ar), 125.5 (-CH=), 123.6 (C-triazole), 123.4 (C-triazole), 121.8 (Cβ-Py), 112.1 (C-CH3), 50.3 (N-CH2-CH2-), 47.5 (NH-CH2-), 41.4 (N-CH2-CH2-), 12.9 (SCH3), 10.4 (CH3). HRMS: m/z [M + H]+ calcd 514.1656; found: 514.1664.
  • 36 (Z)-2-((3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)ethyl 2-(5-Oxo-4-(pyridin-2-ylmethylene)-2-thioxoimidazolidin-1-yl)acetate (13): To a stirred solution of (Z)-2-(5-oxo-4-(pyridin-2-ylmethylene)-2-thioxoimidazolidin-1-yl)acetic acid (50 mg, 0.2 mmol) in anhydrous CH2Cl2 (20 mL) were added DMAP (12 mg, 0.1 mmol) and EDC·HCl (44 mg, 0.23 mmol). After stirring for 20 minutes, a solution of 2 (60 mg, 0.26 mmol) in CH2Cl2 (3 mL) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the solid residue was purified by silica gel column chromatography, eluting with CH2Cl2/MeOH (40:1). Yield after purification by column chromatography: 60 mg (67%); mp 196 °C. 1H NMR (400 MHz, CDCl3): δ = 8.65 (d, J = 3.96 Hz, 1 H, Hα′-Py), 8.03 (dd, J = 7.70, 0.95 Hz, 1 H, CH-Ar), 7.92 (dd, J = 7.63, 1.03 Hz, 1 H, CH-Ar), 7.73 (td, J = 7.70, 1.76 Hz, 1 H, CH′-Ar), 7.63 (td, J = 7.56, 1.32 Hz, 1 H, CH-Ar′′), 7.53 (m, 1 H, Hβ-Py), 7.38 (d, J = 7.92 Hz, 1 H, Hβ′-Py), 7.24 (m, 1 H, Hγ-Py), 6.56 (s, 1 H, -CH=), 5.72 (br. s, 1 H, NH), 4.69 (s, 2 H, CH2COO), 4.37 (t, J = 5.21 Hz, 2 H, NH-CH2-), 3.83 (q, J = 5.67 Hz, 1 H, -CH2CH2-), 2.18 (s, 3 H, CH3). 13C NMR (100.67 MHz, CDCl3): δ = 183.5 (CO), 182.1 (CO), 176.9 (CS), 173.5 (COO), 166.6 (CON), 163.3 (αC-Py), 153.4 (α′C-Py), 149.7 (>C=CH), 145.9 (CH-NH), 137.1 (γC-Py), 134.1 (βC-Py), 131.9 (CH-Ar), 130.4 (C-Ar), 130.0 (C-Ar), 126.5 (CH-Ar), 126.1 (CH-Ar), 125.9 (CH-Ar), 123.1 (β′C-Py), 114.0 (-CH=), 108.9 (CH-CH3), 64.7 (CH2-CH2-COO), 44.0 (COO-CH2-NH), 41.7 (CH2-CH2-COO), 11.1 (CH3). HRMS: m/z [M + H]+ calcd 477.1227; found: 477.1223.