l-Phenylalanine Triflate as Organocatalyst for Divergent ­Approaches to Trisubstituted Hexahydroimidazo[1,2-a]pyridine and 1,4-Diazepane Derivatives

Abstract

The convergent synthesis of two biologically significant classes of trisubstituted hexahydroimidazo[1,2-a]pyridine and 1,4-diazepane derivatives from readily available aromatic aldehydes, ketones, and ethane-1,2-diamine is reported. This protocol is promoted by the highly effective l-phenylalanine triflate catalyst through intermolecular annulation, and tolerates a variety of functional groups with excellent yields.

Key words

multicomponent reactions - nitrogen heterocycles - imidazopyridines - diazepanes - organocatalysis - phenylalanine triflate

• References and Notes

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• 13 Trisubstituted hexahydroimidazo[1,2-a] pyridines 4a–r; General ProcedureThe appropriate aldehyde (1.0 mmol), ketone (2.5 mmol), H₂N(CH₂)₂NH₂ (1.0 mmol), and MeOH (5.0 mL) were mixed with LPAT (10 mol%), and the mixture was refluxed for 24 h. The solvent was evaporated and the residue was crystallized.5,7,8a-Triphenyl-1,2,3,7,8,8a-hexahydroimidazo[1,2-a]pyridine (4a)White solid; yield: 320.5 mg (91%); mp 133.5–134.5 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.68–7.61 (m, 4 H), 7.39–7.16 (m, 11 H), 4.97 (s, 1 H), 3.62–3.56 (m, 1 H), 3.18–3.05 (m, 2 H), 3.00–2.94 (m, 2 H), 2.45 (dd, J = 12.4, 5.6 Hz, 1 H), 2.17 (s, 1 H), 1.87 (t, J = 12.4 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 145.7, 145.4, 144.9, 139.7, 128.4, 128.3, 127.9, 127.4, 127.2, 126.2, 125.9, 107.5, 80.8, 52.5, 44.4, 41.8, 39.4. MS (ESI): m/z = 353.2 [M + 1]⁺.7-(3,4-Dimethylphenyl)-5,8a-diphenyl-1,2,3,7,8,8a-hexahydroimidazo[1,2-a]pyridine (4c)Pale-yellow solid; yield: 353.6 mg (93%); mp 122.8–123.6 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.64 (dd, J = 16.0, 7.2 Hz, 4 H), 7.38–7.27 (m, 6 H), 7.05–6.96 (m, 3 H), 4.96 (s, 1 H), 3.61–3.55 (m, 1 H), 3.17–3.04 (m, 2 H), 3.00–2.89 (m, 2 H), 2.42 (dd, J = 12.0, 5.6 Hz, 1 H), 2.24 (s, 3 H), 2.23 (s, 3 H), 2.13 (s, 1 H), 1.86 (t, J = 12.4 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 145.4, 145.0, 142.8, 139.7, 136.5, 134.4, 129.7, 128.8, 128.4, 128.2, 127.8, 127.4, 127.2, 126.0, 124.8, 108.1, 80.8, 52.5, 44.4, 41.7, 39.0, 20.1, 19.6. MS (ESI): m/z = 381.2 [M + 1]⁺. HRMS-ESI: m/z calcd for C₂₇H₂₉N₂: 381.2325; found: 381.2345.
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• 16 1,4-Diazepane 6a–h; General Procedure Aromatic aldehyde (1.0 mmol), ethyl acetoacetate (1.2 mmol), H₂N(CH₂)₂NH₂ (1.0 mmol), and toluene (5.0 mL) were mixed with LPAT (10 mol%), and the mixture was refluxed for 24 h. The solvent was evaporated under reduced pressure to afford the crude compound, which was purified by flash chromatography (silica gel).Ethyl (2Z)-(7-Phenyl-1,4-diazepan-5-ylidene)acetate (6a)Yellow oil; yield: 161.2 mg (62%). ¹H NMR (400 MHz, CDCl₃): δ = 8.90 (br s, 1 H), 7.35–7.24 (m, 5 H), 4.45 (s, 1 H), 4.09 (q, J = 7.2 Hz, 2 H), 3.75 (d, J = 10.0 Hz, 1 H), 3.62–3.55 (m, 1 H), 3.42–3.35 (m, 1 H), 3.16 (dd, J = 12.8, 4.4 Hz, 1 H), 2.98–2.82 (m, 2 H), 2.34 (d, J = 14.4 Hz, 1 H), 1.93 (br s, 1 H), 1.25 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.6, 165.4, 145.0, 128.8, 127.7, 126.4, 82.5, 62.8, 58.7, 51.0, 46.5, 46.2, 14.9. MS (ESI): m/z = 261.0 [M + 1]⁺.
• 17 CCDC 1422263 contains the supplementary crystallographic data for compound 4a. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.