Study of the Effect of Substituents of ortho-Phenylenediamines in the Opening of Lactones and Lactams for Access to Benzimidazol-2-yl Alkanols and Benzimidazol-2-yl Alkylamines

Abstract

Benzimidazoles represent common chemical moieties in bioactive compounds. The synthesis of this heterocycle often involves a condensation of an ortho-phenylenediamine with a carboxylic acid derivative. The observed dialkylation of the starting ortho-phenylenediamine is avoided by opening of lactones or lactams. This strategy can directly yield 1H-benzimidazoles substituted at the 2-position by a functionalized chain. We present herein a study of the effect of different electron-withdrawing or electron-donating groups at the 4-position of ortho-phenylenediamines on the opening of lactones or lactams to synthesize benzimidazol-2-yl alkanols and benzimidazol-2-yl alkylamines.

Key words

2-benzimidazol-2-yl alkanols - 2-benzimidazol-2-yl alkylamines - ortho-phenylenediamines - lactones - lactams

• References and Notes

• 1 Pullagura MK. P, Avdhut KS, Raja S. Int. J. Pharm. Pharmaceut. Sci. 2016; 8: 22
• 2 Keri RS, Hiremathad A, Budagumpi S, Nagaraja BM. Chem. Biol. Drug Design 2015; 86: 19
• 3 Srestha N, Banerjee J, Srivastava S. IOSR J. Pharm. 2014; 4: 28
• 4 Elshihawy H, Helal MA, Said M, Hammad MA. Bioorg. Med. Chem. 2014; 22: 550
• 5 Alaqeel SI. J. Saudi Chem. Soc. 2017; 21: 229
• 6 Bastug G, Eviolitte C, Markó IE. Org. Lett. 2012; 14: 3502
• 7 Reppe W. Justus Liebigs Ann. Chem. 1955; 1208
• 8 Botta A. Justus Liebigs Ann. Chem. 1976; 336
• 9 Olhava EJ, Chesworth R, Kuntz K. WO/2012/075492, 2012
• 10 Keurulainen L, Vahermo M, Puente-Felipe M, Sandoval-Izquierdo E, Crespo-Fernández B, Guijarro-López L, Huertas-Valentín L, de las Heras-Dueña L, Leino TO, Siiskonen A, Ballell-Pages L, Sanz LM, Castañeda-Casado P, Jiménez-Díaz MB, Martínez-Martínez MS, Viera S, Kiuru P, Calderón F, Yli-Kauhaluoma J. J. Med. Chem. 2015; 58: 4573
• 11 Shelton KL, DeBord MA, Wagers PO, Southerland MR, Williams TM, Robishaw NK, Shriver LP, Tessier CA, Panzner MJ, Youngs WJ. Bioorg. Med. Chem. 2017; 25: 421
• 12 Indusegaram S, Katsifis AG, Ridley DD, Vonwiller SC. Aust. J. Chem. 2003; 56: 819
• 13 Woudenberg RC, Coughlin EB. Tetrahedron Lett. 2005; 46: 6311
• 14 Lee JE, Kwon TH, Gu SJ, Lee D.-H, Kim BM, Lee JY, Lee JK, Seo SH, Pae AN, Keum G, Cho YS, Min S.-J. Org. Biomol. Chem. 2014; 12: 5669
• 15 General Conditions A: A mixture of the corresponding ortho-phenylenediamine (1 equiv) and the corresponding lactone or lactam (4–6 equiv) in 4N HCl in a sealed tube was heated overnight (duration is reported in the manuscript). After cooling to room temperature, the pH was adjusted to pH 11 at 0 °C with sat. aq. K₂CO₃. The aqueous layer was extracted three times with EtOAc, the combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated in vacuo. The desired product was obtained by precipitation or by chromatography on silica gel [eluting with CH₂Cl₂–MeOH/ammonia, 9:1 (v/v)]. The final solid or oil obtained was dried over P₂O₅. Representative example 1a: Yield: 4.3 mmol (93%); white powder obtained from diethyl ether; mp 181–183 °C. ¹H NMR (300 MHz, DMSO-d₆ ): δ = 1.33 (s, 9 H, t-Bu), 1.90 (tt, ³ J = 6.0, 7.5 Hz, 2 H, CH₂), 2.83 (t, ³ J = 7.5 Hz, 2 H, CH₂-Ar), 3.49 (t, ³ J = 6.0 Hz, 2 H, CH₂-OH), 7.17–7.20 (m, 1 H, ArH), 7.35–7.40 (m, 2 H, ArH), 11.86 (br s, 1 H, NH). ¹³C NMR (75 MHz, DMSO-d₆ ): δ = 25.3 (CH₂), 30.8 (CH₂), 31.7 (t-Bu), 34.3 (Cq), 60.2 (CH₂-OH), 118.8 (3 CHAr), 143.8 (Cq), 154.9 (Cq). HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₁₄H₂₁N₂O: 233.1648; found: 233.1648. IR: 3117 (OH) cm^–1.
• 16 Rezaul Haque M, Rasmussen M. Tetrahedron 1997; 53: 6937
• 17 Venkatasubramanian N, Sabesan A. Can. J. Chem. 1969; 47: 3710
• 18 Shazhenov AA, Kadyrov CS, Kurbanov P. Chem. Heterocycl. Compd. 1972; 8: 580
• 19 Hoefnagel AJ, Hoefnagel MA, Wepster BM. J. Am. Chem. Soc. 1976; 98: 6194
• 20 Gross KC, Seybold PG. Int. J. Quantum Chem. 2000; 80: 1107
• 21 General Conditions B: Triphenylphosphine (2 equiv, 4.5 g, 17.1 mmol) was added in portions to a solution of 1a (1 equiv, 2 g, 8.6 mmol), phthalimide (2 equiv, 2.5 g, 17.1 mmol) and DIAD (2 equiv, 3.4 mL, 17.1 mmol) in diethyl ether (40 mL), and the mixture was stirred overnight at room temperature. The triphenylphosphine oxide precipitate was removed by filtration, and the filtrate was concentrated in vacuo. Diethyl ether was added to the residue and the additional precipitate was also removed by filtration. The filtrate was concentrated in vacuo, then ethanol (20 mL) and hydrazine monohydrate (12 equiv, 5 mL, 103 mmol) were added to the viscous residue. After heating at reflux overnight, the reaction mixture was cooled to room temperature and the solid phthalhydrazide was removed by filtration. The filtrate was concentrated in vacuo, and ethanol was added to the residue. The precipitate was again removed by filtration, the filtrate was concentrated in vacuo and the residue was purified by column chromatography over silica gel [eluting with CH₂Cl₂–CH₃OH/ammonia, 9:1 (v/v)]. The oil obtained was dried over P₂O₅. 2-(3-(5-(tert-Butyl)-1H-benzo[d]imidazol-2-yl)propyl)isoindoline-1,3-dione (4): Yellowish powder. ¹H NMR (300 MHz, DMSO-d₆ ): δ = 1.30 (s, 9 H, t-Bu), 2.09 (tt, ³ J = 6.8, 7.1 Hz, 2 H, CH₂), 2.82 (t, ³ J = 7.1 Hz, 2 H, CH₂-Ar), 3.67 (t, ³ J = 6.8 Hz, 2 H, CH₂-N), 7.13 (m, 1 H, ArH), 7.31 (m, 2 H, ArH), 7.82 (br s, 4 H, ArH), 11.97 (s, 1 H, NH). IR: 1705 (C=O) cm^–1. 3-(5-(tert-Butyl)-1H-benzo[d]imidazol-2-yl)propan-1-amine (2a): Yield: 0.4 mmol (overall yield 20%); brown oil. ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.32 (m, 9 H, t-Bu), 1.80 (tt, ³ J = 6.9, 7.6, 2 H, CH₂), 2.66 (t, ³ J = 6.9 Hz, 2 H, CH₂-NH₂), 2.82 (t, ³ J = 7.6 Hz, 2 H, CH₂-Ar), 3.16 (m, 2 H, NH₂), 7.18 (dd, ³ J = 8.4 Hz, ⁴ J = 1.6 Hz, 1 H, ArH), 7.34 (d, ³ J = 8.4, 1 H, ArH), 7.38 (d, ⁴ J = 1.6 Hz, 1 H, ArH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 26.0 (CH₂), 30.5 (CH₂), 31.7 (t-Bu), 34.3 (Cq), 40.7 (CH₂-NH₂), 118.8 (3 CHAr), 143.9 (Cq), 160.7 (Cq). HRMS (ESI⁺): m/z [M + H]⁺ calculated for C₁₄H₂₂N₃: 232.1808; found: 232.1801. IR: 3041 (NH) cm^–1.
• 22 Wright JB. Chem. Rev. 1951; 48: 397