One-Pot, Three-Component Synthesis of Novel Pyrroloacridinones via Intramolecular ipso Dearomatization–Intramolecular Aza-Michael Addition Sequence

Abstract

A one-pot, three-component synthesis of novel pyrroloacridinones from a set of alkoxy arenes and 2,6-dialkylphenols, isobutyric aldehyde, and 2-aminobenzonitrile is described. We have demonstrated the efficacy of the combination of intramolecular electrophilic ipso dearomatization of suitable aromatic compounds leading to spiro-substituted cyclohexa-2,5-dienones and intramolecular aza-Michael addition for the preparation of complex aza-heterocyclic systems.

Key words

intramolecular ipso dearomatization - spiro-substituted cyclohexa-2,5-dienone - intramolecular aza-Michael addition - domino reaction - cyclization

• References and Notes


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• 6 Typical Experimental Procedure for the Synthesis of 5a A mixture of 1-methoxynaphthalene (1a, 316 mg, 2.0 mmol), isobutyric aldehyde (2, 216 mg, 3.0 mmol), and 2-aminobenzonitrile (3, 236 mg, 2.0 mmol) was added dropwise to stirred concentrated sulfuric acid (92%, 1 mL, 17 mmol) at 5–7 °C. The reaction mixture was stirred at r.t. for 25 min and poured into a mixture of ice (25 g) and aq NH₃ (7 mL). The product was extracted with CH₂Cl₂ (3 × 15 mL), and the combined organic layers were washed with H₂O, dried over anhydrous Na₂SO₄, and filtered. After the solvent was removed, the crude mixture was purified by column chromatography on silica gel (hexane–EtOAc, 4:1 to 2:1) to give pure 5a (516 mg, 82%).
• 7 Data for 5a Pale yellow solid; R_f = 0.63 (hexane–EtOAc, 2:1); mp 267–269 °C. IR (film): ν = 3364, 3066, 3026, 2964, 2867, 1674, 1610 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.42 (s, 3 H, CH₃C¹³), 1.47 (s, 3 H, CH₃C¹³), 2.05 (d, 1 H, J = 13.1 Hz, H-14^B), 2.10 (d, 1 H, J = 13.1 Hz, H-14^A), 2.79 (dd, 1 Н, J = 18.0, 3.0 Hz, H-6^B), 3.02 (dd, 1 Н, J = 18.0, 3.0 Hz, H-6^A), 3.96 (t, 1 H, J = 3.0 Hz, H-6a), 4.32 (br s, 1 H, NH), 6.41 (br d, 1 H, J = 8.3 Hz, H-8), 6.72 (ddd, 1 H, J = 7.9, 7.1, 1.2 Hz, H-10), 7.06–7.10 (m, 2 H, H-1 and H-9), 7.29 (td, 1 H, J = 7.6, 1.0 Hz, H-3), 7.41 (td, 1 H, J = 7.6, 1.4 Hz, H-2), 7.92 (dd, 1 H, J = 7.9, 1.5 Hz, H-11), 8.03 (dd, 1 H, J = 7.8, 1.4 Hz, H-4) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 29.29 (CH₃C¹³), 32.46 (CH₃C¹³), 40.53, 48.41 (C-6, C-14), 56.30 (C-14a), 58.45 (C-6a), 72.87 (C-13), 114.75 (C-8), 115.62 (C-11a), 118.32 (C-10), 126.85, 127.00, 127.31 and 127.90 (C-1, C-4, C-9, and C-11), 131.08 (C-4a), 131.81 and 134.17 (C-2, C-3), 143.59 and 147.00 (C-7a and C-14b), 166.59 (C-11b), 195.23 (С-5). MS (EI): m/z (%) = 316 [M]⁺ (78), 316 [M – Me]⁺ (100). Anal. Calcd for C₂₁H₂₀N₂O: C, 79.72; H, 6.37; N, 8.85. Found: C, 79.42; H, 6.43; N, 8.64.
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• 10 Crystallographic data for compound 4i, 5h, 5i′, and 5j' have been deposited with the Cambridge Crystallographic Data Centre [CCDC no 988501 (4i), CCDC no 988502 (5h), CCDC no 988503 (5i'), CCDC no 988504 (5j')]. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. See Supporting Information for details.
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