Rapid One-Pot Microwave-Assisted Synthesis of a Hexadentate Chelating Agent

Abstract

A rapid one-pot microwave-assisted synthesis of a hexadentate chelating ligand prepared from (1α,3α,5α)-1,3,5-cyclohexanetriamine and 3-methyl-2-pyridinecarboxaldehyde is reported.

Key words

microwave synthesis - hexadentate ligand - condensation - reduction - pyridines

References

• Reviews on microwave-assisted organic synthesis include:
• 1a Kuhnert N. Angew. Chem. Int. Ed.  2002,  41:  1863 
• 1b Hayes BL. Microwave Synthesis, Chemistry at the Speed of Light   CEM Corporation; Matthews: 2002. 
• 1c Lidstrom P. Tierney J. Wathey B. Westman J. Tetrahedron  2001,  57:  9225 
• 1d Loupy A. Petit A. Hamelin J. Texier-Boullet F. Jacquault P. Mathe D. Synthesis  1998,  1213 
• 1e Galema SA. Chem. Soc. Rev.  1997,  26:  233 
• 1f Caddick S. Tetrahedron  1995,  51:  10403 
• 1g Strauss CR. Trainor RW. Aust. J. Chem.  1995,  48:  1665 
• Selected references on imine formation under microwave conditions include:
• 2a Vanden Eynde JJ. Fromont D. Bull. Soc. Chim. Belg.  1997,  106:  393 
• 2b Ridha T. Hassine BB. Genêt JP. C. R. Acad. Sci. Paris, Ser. IIc, Chem.  2000,  3:  35 
• 2c Yang H. Sun W.-H. Li Z. Wang L. Synth. Commun.  2002,  32:  2395 
• 2d Alkhathlan HZ. Synth. Commun.  2004,  34:  71 
• 3 Ma D. Lu F. Overstreet T. Milenic DE. Brechbiel MW. Nucl. Med. Biol.  2002,  29:  91 
• 9 Bowen T. Planalp RP. Brechbiel MW. Bioorg. Med. Chem. Lett.  1996,  6:  807 

4

All microwave reactions were performed in single-neck round bottom flasks fitted with a cold water condenser. Microwave heating was performed in a CEM Discover Focused Microwave System producing continuous irradiation at 2450 MHz (CEM Corporation, Matthews, NC, USA). Reaction mixtures were stirred with a magnetic stir bar during irradiation. The temperature and irradiation power were monitored during the course of the reaction. After the completed irradiation, the reaction flask was cooled with high pressure argon until the temperature had fallen below 30 °C, unless noted. ¹H NMR spectra were recorded at 500 or 600 MHz, and signals are given in ppm; J values are given in Hertz. IR spectra of liquids were recorded as thin films on NaCl plates, and IR spectra of solids were recorded as KBr pellets. Mass spectra were determined by electrospray (ES). UV spectra were recorded in MeOH solution at 200-400 nm. Column chromatography was carried out using Merck 60 silica gel. TLC was performed on Merck 60 F₂₅₄ silica gel glass plates. Elemental analyses were performed by Atlantic Microlabs (Norcross, GA). Melting points are uncorrected. Unless stated, all solvents and reagents were purchased from commercial sources and used without further purification.

5

(1α,3α,5α)-1,3,5-Cyclohexanetriamine was prepared by passing a solution of the trihydrobromide [9] (17.6 g, 47.3 mmol) in a mixture of MeOH (40.0 mL) and deionized H₂O (20.0 mL) through a column of AG1-X8 ion exchange resin (200 g, 5 × 40 cm bed volume, hydroxide form, 200-400 mesh, Bio-Rad Laboratories) eluted with MeOH. Product containing fractions (ninhydrin detection) were concentrated, and the residue was coevaporated with EtOH (2 × 50 mL) and MeCN (2 × 50 mL), then dried in vacuo at r.t. to give 1 (6.1 g, 100%), as a white solid; mp 58-60 °C (uncorrected). ¹H NMR (500 MHz, DMSO-d ₆): δ = 0.61-0.68 (q, 3 H, J = 11.6 Hz), 1.27 (br s, 6 H), 1.75-1.77 (d, 3 H, J = 11.3 Hz), 2.46-2.52 (m, 3 H + DMSO). MS (ES): m/z = 130 [M + 1]. Anal. Calcd for C₆H₁₅N₃·0.35MeCN·0.1MeOH·0.1EtOH·1.7H₂O: C, 46.19; H, 11.32; N, 25.78. Found: C, 46.25; H, 11.31; N, 25.75.

6

3-Methyl-2-pyridinecarboxaldehyde was prepared according to the procedure described in ref. [3]

7

The E/Z geometry of 3 was not investigated since 3 was not isolated.

8

Preparation of 4: A solution of 1 (540 mg, 4.18 mmol) and 2 (2.53 g, 20.9 mmol) in EtOH (20.0 mL) was irradiated at 78 °C/10 W for 1.0 h. The mixture was cooled to 35 °C, and NaBH₄ (590 mg, 7.50 mmol) was added. The reaction mixture was irradiated at 50 °C/10 W for 0.5 h, then cooled to 25 °C. The reaction mixture was concentrated to dryness. The residue was dissolved in CH₂Cl₂ (100 mL) and washed with a solution of 5% aq NaHCO₃-brine (1:1, 100 mL). The organic layer was dried (MgSO₄), filtered, and concentrated to give crude 4 (2.69 g). The crude material was purified on a short pad of silica gel eluted with 1:1 MeOH-EtOAc (removes impurities less polar than 4), followed by elution with 25:25:1 MeOH-EtOAc-concd NH₄OH to give a viscous oil. The oil was dissolved in EtOAc (75.0 mL), dried (MgSO₄), filtered, and concentrated. The solid residue was dissolved in Et₂O (2 mL) and evaporated over a stream of argon to give 4 (580 mg, 31%), as a white solid: mp
80-84 °C (uncorrected). IR (KBr): 3320, 2920, 2840, 1575, 1445, 1420, 1335, 1225, 1221, 1140, 1095, 775, 740 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 1.19-1.25 (q, 3 H, J = 11.5 Hz), 2.32 (s, 9 H), 2.36 (m, 6 H), 2.72-2.76 (tt, 3 H, J = 11.3, 3.7 Hz), 3.95 (s, 6 H), 7.07 (dd, 3 H, J = 7.5, 4.8 Hz), 7.42 (d, 3 H, J = 7.5 Hz), 8.39 (d, 3 H, J = 4.5 Hz). MS (ES): m/z = 445 [M + 1], 223 [M + 2/2]. UV (c = 0.04 g/L, MeOH): 208 nm (log ε 4.2689), 265 nm (log ε 4.0468). Anal. Calcd for C₂₇H₃₆N₆·0.82H₂O: C, 70.59; H, 8.26; N, 18.29. Found: C, 70.57; H, 8.29; N, 18.40. A control experiment was performed to prepare 4 from 1 and 2 using conventional thermal heating and using otherwise identical conditions of time, temperature and work-up conditions as was used in the microwave reaction. This control experiment resulted in less than one-third the yield of isolated 4 (10%) in comparison with the microwave-assisted reaction.