Expeditious Synthesis of Novel β-Lactam-Substituted Polycyclic Fused Chromeno Pyrrole Derivatives from MBH Carbonates by Intramolecular [3+2]-Cycloaddition Reaction

Abstract

A facile synthesis of tri- and tetracyclic fused chromeno pyrrole derivatives has been accomplished by intramolecular cycloaddition reaction of azomethine ylides generated from cyclic/acyclic secondary amino acids with O-allylated salicylaldehydes obtained from Morita–Baylis–Hillman carbonates of β-lactam aldehyde. The stereochemistry of the cycloadducts was confirmed on the basis of single crystal X-ray diffraction data.

Key words

1,3-dipolar cycloaddition - β-lactams - drug development - pyrroles

• References and Notes

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• 19 To a solution of the β-lactam-derived Baylis–Hillman alcohol 1a or 1b (1 equiv) in anhydrous CH₂Cl₂ (20 mL), kept at 0 °C, was added Boc₂O (1.5 equiv) and DMAP (10 mol%). The solution was stirred for 2 h. Upon completion of the reaction, the crude mixture was purified by column chromatography immediately (hexane–EtOAc). Compound 3a: Yield: 83%; colorless solid; mp 96–98 °C; IR (KBr): 1680, 1715, 1719 cm^–1; ¹H NMR (300 MHz, CDCl₃): δ = 1.37 (s, 9 H), 3.79 (s,3 H), 3.80 (s, 3 H), 4.37–4.38 (t, J = 1.8, 2.1 Hz, 1 H), 4.51–4.52 (d, J = 2.1 Hz, 1 H), 6.12–6.14 (d, J = 4.8 Hz, 2 H), 6.47 (s, 1 H), 6.90–6.93 (d, J = 7.2 Hz, 2 H), 7.18–7.46 (m, 5 H), 7.47–7.49 (t, J = 2.4, 4.5 Hz, 2 H); ¹³C NMR (75 MHz, CDCl₃): δ = 27.5, 52.4, 54.4, 55.4, 60.8, 69.1, 83.2, 114.5, 118.9, 127.2, 127.5, 128.9, 130.2, 134.7, 136.4, 151.8, 156.4, 164.6, 165.3.
• 20 To a solution of salicylaldehyde 4a or 4b (1.0 equiv), Cs₂CO₃ (2.0 equiv) in MeCN (25 mL) under a nitrogen atmosphere, was added Boc-protected Baylis–Hillman adduct 3a or 3b (1.0 equiv). After stirring at room temperature, the reaction mixture was filtered over Celite and the organic layer was evaporated, diluted with CH₂Cl₂ (3 × 10 mL) and washed with water followed by brine. The organic layer was separated, dried, and the product was purified by column chromatography (hexane–EtOAc, 7:3). Compound 5a: Yield: 72%; pale-brown solid; mp 106–108 °C; IR (KBr): 1684, 1713, 1718 cm^–1; ¹H NMR (300 MHz, CDCl₃): δ = 3.79 (s, 3 H), 3.83 (s, 3 H), 4.31–4.32 (d, J = 2.4 Hz, 1 H), 4.93 (s, 2 H), 4.95–4.96 (d, J = 2.4 Hz, 1 H), 6.84–7.51 (m, 13 H), 7.75–7.78 (d, J = 1.5 Hz, 1 H), 10.18 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 52.7, 55.5, 57.9, 61.9, 62.6, 112.9, 114.6, 118.1, 121.6, 125.1, 127.3, 128.3, 128.7, 129.2, 130.8, 131.0, 133.4, 135.8, 145.2, 156.6, 160.2, 163.6, 165.5, 188.9; MS: m/z = 471.56 [M]^+.
• 21 Synthesis of Angularly Fused Chromeno[4,3-b]pyrrolidine/pyrrolizidine/thiazolidine Derivatives; General Procedure: A solution of β-lactam-substituted O-allyl salicylaldehyde derivative 5a or 5b (1 mmol) and sarcosine (7) or proline (10) or thiazolidine-4-carboxylic acid (13) (1.2 mmol) in acetonitrile (10 mL) was heated at reflux until completion of the reaction (reaction monitored by TLC). The solvent was removed under vacuum and the crude product was subjected to column chromatography on silica gel (100–200 mesh; petroleum ether–ethyl acetate, 7:3).
• 22 Representative spectral data of the products. Compound 8b: Yield: 85%; colorless solid; mp 161–163 °C; IR (KBr): 1701, 1714 cm^–1; ¹H NMR (300 MHz, CDCl₃): δ = 2.45 (s, 3 H), 2.52–2.58 (t, J = 9.3 Hz, 1 H), 2.76 (s, 3 H), 2.79–2.84 (m, 1 H), 2.90–2.96 (t, J = 8.1, 9.0 Hz, 1 H), 3.63 (s, 1 H), 3.82 (s, 3 H), 4.09–4.13 (d, J = 10.2 Hz, 1 H), 4.22–4.23 (d, J = 1.8 Hz, 1 H), 4.40–4.43 (d, J = 10.2 Hz, 1 H), 4.55–4.57 (d, J = 2.1 Hz, 1 H), 6.81–6.84 (d, J = 8.1 Hz, 1 H), 6.91–6.96 (m, 3 H), 7.15–7.18 (m, 1 H), 7.20–7.24 (m, 3 H), 7.25–7.26 (m, 2 H), 7.29–7.35 (m, 2 H), 7.40–7.43 (m, 2 H); ¹³C NMR (75 MHz, CDCl₃): δ = 39.5, 41.3, 51.8, 54.6, 55.5, 57.0, 59.5, 65.0, 69.6, 114.8, 116.9, 119.3, 119.8, 120.6, 128.0, 128.1, 128.8, 129.1, 129.7, 131.3, 134.4, 154.0, 156.8, 164.4, 170.9; MS: m/z = 514.62 [M]⁺. Anal. Calcd for C₃₀H₃₀N₂O₆: C, 70.02; H, 5.88; N, 5.44. Found: C, 70.06; H, 5.83; N, 5.40. Compound 11b: Yield: 79%; colorless solid; mp 186–187 °C; IR (KBr): 1689, 1718 cm^–1; ¹H NMR (300 MHz, CDCl₃): δ = 1.06–1.19 (m, 1 H), 1.80–1.95 (m, 2 H), 1.99–2.04 (m, 1 H), 2.89–2.97 (m, 1 H), 3.12–3.16 (m, 1 H), 3.18–3.23 (m, 1 H), 3.70 (s, 3 H), 3.82 (s, 3 H), 4.21–4.24 (d, J = 10.8 Hz, 1 H), 4.31–4.34 (d, J = 10.5 Hz, 1 H), 4.10 (s, 1 H), 4.35 (s, 1 H), 4.68–4.69 (t, J = 2.4, 2.1 Hz, 1 H), 6.81–6.84 (d, J = 7.8 Hz, 1 H), 6.90–6.95 (m, 3 H), 7.13–7.19 (m, 2 H), 7.30–7.36 (m, 5 H), 7.39–7.43 (m, 2 H); ¹³C NMR (75 MHz, CDCl₃): δ = 28.3, 33.5, 49.4, 52.8, 54.2, 55.4, 55.5, 56.7, 58.4, 63.0, 64.86, 65.3, 114.7, 117.0, 119.2, 121.2, 122.8, 127.8, 128.2, 128.8, 129.2, 129.3, 129.5, 133.8, 152.7, 156.6, 164.4, 172.6; MS: m/z = 540.66 [M]⁺. Anal. Calcd for C₃₂H₃₂N₂O₆: C, 71.09; H, 5.97; N, 5.18. Found: C, 71.16; H, 5.92; N, 5.22. Compound 14a: Yield: 81%; colorless solid; mp 177–179 °C; IR (KBr): 1692, 1717 cm^–1; ¹H NMR (300 MHz, CDCl₃): δ = 2.42–2.48 (d, J = 6.0 Hz, 1 H), 2.87–2.93 (dd, J = 7.8 Hz, 1 H), 3.22–3.24 (t, J = 2.7, 3.9 Hz, 1 H), 3.65–3.72 (m, 1 H), 3.69 (s, 3 H), 3.82 (s, 3 H), 4.21–4.22 (d, J = 1.8 Hz, 1 H), 4.37–4.40 (d, J = 10.81 Hz, 1 H), 4.52–4.56 (d, J = 11.4 Hz, 1 H), 4.65–4.67 (t, J = 2.7, 2.4 Hz, 1 H), 6.83–6.85 (d, J = 8.1 Hz, 1 H), 6.93–6.98 (m, 3 H), 7.14–7.22 (m, 2 H), 7.32–7.44 (m, 7 H); ¹³C NMR (75 MHz, CDCl₃): δ = 39.5, 48.9, 51.6, 52.9, 55.5, 56.3, 57.7, 58.2, 58.6, 65.8, 66.0, 114.9, 116.9, 119.5, 120.3, 121.1, 127.9, 128.3, 128.9, 129.4, 129.5, 130.4, 133.5, 153.7, 156.9, 164.5, 172.5; MS: m/z = 542.67 [M]⁺; Anal. Calcd for C₃₁H₃₀N₂O₅S: C, 68.61; H, 5.57; N, 5.16. Found: C, 68.69; H, 5.52; N, 5.11.
• 23 The structure of compound 9a was confirmed by single-crystal X-ray data. These data have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-929940. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.