Combined Alkylating Agents as a Resolution for Highly Selective N-Alkylation of 2-Hydroxybenzaldehyde Acylhydrazones

Abstract

Although 2-hydroxybenzaldehyde acylhydrazones, such as salicylaldehyde acylhydrazones, are intriguing bioactive molecules, few of their N-alkylated derivatives are known, and only methyl analogues have been reported previously. We achieved selective N-alkylation of 2-hydroxybenzaldehyde acylhydrazones, as their Fe(III) complexes, by using combinations of alkylating agents (for example, an alkyl bromide and a dialkyl sulfate). Fifteen substrates were examined, and 45 new 2-hydroxybenzaldehyde acyl(alkyl)hydrazones were synthesized in moderate to good yields. In all cases, the target products were obtained exclusively, and no O-alkylation byproducts were produced. The method provides an efficient way of preparing 2-hydroxybenzaldehyde acyl(alkyl)hydrazones.

Key words

alkylation - regioselectivity - medicinal chemistry - salicylaldehyde acylalkylhydrazones - hydrazones

• References and Notes

• 1 dos Santos JM. Filho, Pinheiro SM. Green Chem. 2017; 19: 2212
• 2 Lima PC, Lima LM, da Silva KC. M, Léda PH. O, de Miranda AL. P, Fraga CA. M, Barreiro EJ. Eur. J. Med. Chem. 2000; 35: 187
• 3 Jacques SA, Kuhn I, Koniev O, Schuber F, Lund FE, Wagner A, Muller-Steffner H, Kellenberger E. J. Med. Chem. 2015; 58: 3582
• 4 Palanimuthu D, Wu Z, Jansson PJ, Braidy N, Bernhardt PV, Richardson DR, Kalinowski DS. Dalton Trans. 2018; 47: 7190
• 5 Georgakis ND, Karagiannopoulos DA, Thireou TN, Eliopoulos EE, Labrou NE, Tsoungas PG, Koutsilieris MN, Clonis YD. Chem. Biol. Drug Des. 2017; 90: 900
• 6 Taha M, Arbin M, Ahmat N, Imran S, Rahim F. Bioorg. Chem. 2018; 77: 47
• 7 Hrušková K, Potůčková E, Opálka L, Hergeselová T, Hašková P, Kovaŕíková P, Šimůnek T, Vávrova K. Chem. Res. Toxicol. 2018; 31: 435
• 8 Gou Y, Zhang Y, Zhang Z, Wang J, Zhou Z, Liang H, Yang F. Mol. Pharmaceutics 2017; 14: 1861
• 9 Cindrić M, Bjelopetrović A, Pavlović G, Damjanović V, Lovrić J, Matković-Calogović D, Vrdoljak V. New J. Chem. 2017; 41: 2425
• 10 D’Acunto CW, Kaplánek R, Gbelcová H, Kejík Z, Bríza T, Vasina L, Havlík M, Ruml T, Král V. Eur. J. Med. Chem. 2018; 150: 140
• 11 Chimmalagi GH, Kendur U, Patil SM, Gudasi KB, Frampton CS, Budri MB, Mangannavar CV, Muchchandi IS. Appl. Organomet. Chem. 2018; 32: e4337
• 12 Fekri R, Salehi M, Asadi A, Kubicki M. Appl. Organomet. Chem. 2018; 32: e4019
• 13 Pereira SL, Kummerle AE, Fraga CA. M, Barreiro EJ, Sudo RT, Zapata-Sudo G. Fundam. Clin. Pharmacol. 2014; 28: 29
• 14 Silva AG, Zapata-Sudo G, Kummerle AE, Fraga CA. M, Barreiro EJ, Sudo RT. Bioorg. Med. Chem. 2005; 13: 3431
• 15 Kümmerle AE, Raimundo JM, Leal CM, da Silva GS, Balliano TL, Pereira MA, de Simone CA, Sudo RT, Zapata-Sudo G, Fraga CA. M, Barreiro EJ. Eur. J. Med. Chem. 2009; 44: 4004
• 16 Wang L.-M, Jenkinson K, Wheatley AE. H, Kuwata K, Saito S, Naka H. ACS Sustainable Chem. Eng. 2018; 6: 15419
• 17 Polidano K, Allen BD. W, Williams JM. J, Morrill LC. ACS Catal. 2018; 8: 6440
• 18 Ray PC, Pawar YD, Singare DT, Deshpande TN, Singh GP. Org. Process Res. Dev. 2018; 22: 520
• 19 Kümmerle AE, Schmitt M, Cardozo SV. S, Lugnier C, Villa P, Lopes AB, Romeiro NC, Justiniano H, Martins MA, Fraga CA. M, Bourguignon J.-J, Barreiro EJ. J. Med. Chem. 2012; 55: 7525
• 20 Li Z, Wu L, Zhang T, Huang Z, Qiu G, Zhou Z, Jin L. Dalton Trans. 2014; 43: 7554
• 21 2-Hydroxybenzaldehyde Acyl(benzyl)hydrazones (1a–15a); General Procedure K₂CO₃ (0.55 g, 4.0 mmol), BnCl (0.36 mL, 3.2 mmol), and BnBr (0.05 mL, 0.8 mmol) were added to a solution of the Fe(III) complex of the appropriate hydroxybenzaldehyde acylhydrazone (prepared from 4.0 mmol of the hydrazone) in THF (10 mL). The black mixture was refluxed for 8–16 h before removal of the solid by hot filtration. The mother solution was concentrated, and the product was harvested by crystallization from MeOH. N-Benzyl-N′-[ (2-hydroxyphenyl)methylene]benzohydrazide (1a) White solid; yield: 1.04 g (79%); mp 132–133 °C. IR (KBr): 3448 (m), 3058 (vs), 1666 (vs), 1616 (s), 1600 (s) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.76 (s, 1 H), 8.12 (s, 1 H), 7.67 (d, J = 7.2 Hz, 2 H), 7.57–7.50 (m, 3 H), 7.41–7.37 (m, 4 H), 7.30–7.25 (m, 2 H), 7.17 (t, J = 8.0 Hz, 1 H), 6.75 (t, J = 8.0 Hz, 2 H), 5.45 (s, 2 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.9, 156.7, 141.1, 135.8, 135.5, 131.5, 130.6, 129.3, 128.7, 128.7, 128.4, 127.7, 127.0, 119.8, 119.6, 116.6, 44.4. Anal. Calcd for C₂₁H₁₈N₂O₂: C, 76.34; H, 5.49; N, 8.48. Found: C, 76.33; H, 5.63; N, 8.36. N-Ethyl-N′-[ (2-hydroxyphenyl)methylene]benzohydrazide (1b) Prepared by following the general procedure, but using EtBr and Et₂SO₄ in a 5:1 ratio, to give a white solid; yield: 850 mg (79%); mp 108–110 °C. IR (KBr): 3425 (m), 2982 (vs), 1654 (vs), 1518 (s), 1604 (s) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.87 (s, 1 H), 8.26 (s, 1 H), 7.62–7.34 (m, 6 H), 7.20 (m, 1 H), 6.83 (t, J = 8.0 Hz, 1 H), 6.78 (d, J = 8.0 Hz, 1 H), 4.18 (q, J = 7.2 Hz, 2 H), 1.21 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.1, 156.8, 141.4, 136.1, 131.4, 130.4, 129.7, 128.4, 119.8, 119.6, 116.6, 35.7, 11.2. Anal. Calcd for C₁₆H₁₆N₂O₂: C, 71.62; H, 6.01; N, 10.44. Found: C, 71.43; H, 6.00; N, 10.39. N-Butyl-N′-[ (2-hydroxyphenyl)methylene]benzohydrazide (1c) Prepared by following the general procedure, but using BuBr and Bu₂SO₄ in a 5:1 ratio, to give a white solid; yield: 770 mg (65%); mp 99–100 °C. IR (KBr): 3174 (m), 2954 (vs), 1658 (vs), 1626 (s), 1601 (s). ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.83 (s, 1 H), 8.24 (s, 1 H), 7.52–7.40 (m, 6 H), 7.20 (t, J = 7.6 Hz, 1 H), 6.83 (t, J = 7.6 Hz, 1 H), 6.78 (d, J = 8.4 Hz, 1 H), 4.15 (t, J = 7.2 Hz, 2 H), 1.62 (m, 2 H), 1.40 (m, 2 H), 0.96 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.5, 156.8, 141.3, 136.2, 131.4, 130.3, 129.7, 128.4, 128.2, 119.7, 119.6, 116.6, 27.6, 20.0, 14.1. Anal. Calcd for C₁₈H₂₀N₂O₂: C, 72.95; H, 6.80; N, 9.45. Found: C, 73.07; H, 6.99; N, 9.02.
• 22 Christie JJ, Lewis ES, Casserly EF. J. Org. Chem. 1983; 48: 2531