Microwave-Assisted Tandem Reactions towards a New Synthesis of Cyclohepta[b]chromene-9,11-diones

Abstract

A microwave-assisted new synthesis of functionalized cyclohepta[b]chromene-9,11-diones has been described for the first time. The key step involves the reaction of (E)-3-bromo-2-styrylchromones with 1-(prop-1-en-2-yl)pyrrolidine and provides benzo[1,3]cyclopropa[1,2-b]chromene-4,5-diones by a tandem 1,6-conjugate addition/ Michael-initiated ring-closure/imine hydrolysis sequence. The second step involves an acid-catalyzed cyclopropane ring-expansion reaction of these polycyclic compounds to afford the expected cyclohepta[b]chromene-9,11-diones.

Key words

(E)-3-bromo-2-styrylchromones - conjugate additions - microwave irradiation - tandem reactions - oxygen polycycles - cyclopropane ring-expansion

• References and Notes

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• 17 General Procedure for the Synthesis of Benzo[1,3]cyclopropa[1,2-b]chromene-4,5-diones 2a–c Pyrrolidine (8.3 μL, 0.099 mmol) was added to a solution of the appropriate (E)-3-bromo-2-styrylchromone 1a–c (0.066 mmol) in acetone (1 mL) in a closed vessel. The mixture was heated at 100 °C under microwave irradiation (monomode apparatus) for 20 min. Then, the solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative TLC using CH₂Cl₂ as eluent to give the desired products 2a–c as an inseparable mixture of diastereomers: 2a (13.9 mg, 69%), 2b (15.7 mg, 71%), and 2c (11.4 mg, 51%). rel-(2S,4aR,4bR)- and rel-(2R,4aR,4bR)-2-Phenyl-2,3,4a,4b-tetrahydro-1H-benzo[1,3]cyclopropa[1,2-b]chromene-4,5-dione (2a) White solid. ¹H NMR (500.13 MHz, CDCl₃): aliphatic region: d₁ : δ = 2.46–2.58 (m, 3 H, H_b-1 and H-3), 2.53 (d, J = 4.9 Hz, 1 H, H-4a), 2.83 (d, J = 4.9 Hz, 1 H, H-4b), 2.91 (ddd, J = 1.7, 6.2, 15.1 Hz, 1 H, H_a-1), 3.41–3.48 (m, 1 H, H-2) ppm; d₂: δ = 2.41–2.47 (m, 1 H, H-3), 2.59 (d, J = 4.6 Hz, 1 H, H-4a), 2.69–2.77 (m, 3 H, H-1 and H-3), 2.97–3.04 (m, 1 H, H-2), 3.10 (d, J = 4.6 Hz, 1 H, H-4b) ppm; aromatic region: d₁ and d₂ : δ = 6.98–7.00 (m, 2 H, H-9), 7.07–7.14 (m, 2 H, H-7), 7.22–7.27 (m, 4 H, H-2′,6′), 7.28–7.32 (m, 2 H, H-4′), 7.36–7.40 (m, 4 H, H-3′,5′), 7.51–7.55 (m, 2 H, H-8), 7.88 and 7.89 (2 dd, J = 1.7, 7.9 Hz, 2 H, H-6) ppm. ¹³C NMR (125.77 MHz, CDCl₃): δ = 31.5 (C-4a of d₂), 31.8 (C-4a of d₁), 33.9 (C-1 of d₂), 34.1 (C-4b of d₂), 34.5 (C-2 of d₂), 38.6 (C-1 of d₁), 40.9 (C-2 of d₁), 41.6 (C-4b of d₁), 42.8 (C-3 of d₁), 44.6 (C-3 of d₂), 67.7 (C-10a of d₂), 70.0 (C-10a of d₁), 117.8 (C-5a of d₂), 117.87 and 117.88 (C-9), 118.4 (C-5a of d₁), 122.69 and 122.73 (C-7), 126.6 and 126.7 (C-2′,6′), 127.1 and 127.3 (C-6), 127.48 and 127.52 (C-4′), 129.07 and 129.11 (C-3′,5′), 136.3 and 136.4 (C-8), 141.6 and 141.9 (C-1′), 156.3 and 156.4 (C-9a), 185.9 and 186.3 (C-5), 201.8 (C-4 of d₂), 203.0 (C-4 of d₁) ppm. MS (EI): m/z (%) = 305 (14) [M^•+ + H]⁺, 304 (100) [M^•+], 276 (32), 275 (11), 261 (28), 247 (21), 200 (20), 199 (17), 187 (26), 186 (73), 185 (14), 172 (75), 171 (54), 159 (41), 158 (39), 144 (49), 121 (35). HRMS (EI): m/z calcd for C₂₀H₁₆O₃: 304.1099; found: 304.1101.
• 18 General Procedure for the Synthesis of Cyclohepta[b]chromene-9,11-diones 3a–c The appropriate benzo[1,3]cyclopropa[1,2-b]chromene-4,5-dione 2a–c (0.045 mmol) was refluxed in glacial acetic acid (1 mL) with a drop of sulfuric acid for 2 h. After this period, the reaction mixture was poured into ice and water. Then, this aqueous mixture was extracted with EtOAc (2 × 10 mL), and the obtained residue was purified by preparative TLC using a (9:1) mixture of CH₂Cl₂–EtOAc as eluent. Two fractions were obtained: 7-aryl-6,7,8,10-tetrahydrocyclohepta[b]chromene-9,11-diones 3a–c (higher R_f value) in 55–73% yield and 6-aryl-2-(2-hydroxyphenyl)-6,7-dihydrobenzofuran-4(5H)-ones 6a–c in 16–20% yield. 7-Phenyl-6,7,8,10-tetrahydrocyclohepta[b]chromene-9,11-dione (3a) Yield 8.4 mg (61%); white solid; mp 134–136 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 2.88–3.00 (m, 2 H, H-8), 3.21 (d, J = 6.9 Hz, 2 H, H-6), 3.63–3.72 (m, 1 H, H-7), 3.86 and 3.92 (ABq, J _AB = 17.2 Hz, 2 H, H-10), 7.26–7.36 (m, 5 H, H-2′,3′,4′,5′,6′), 7.36–7.45 (m, 2 H, H-2 and H-4), 7.67 (td, J = 1.6, 7.8 Hz, 1 H, H-3), 8.25 (dd, J = 1.6, 7.9 Hz, 1 H, H-1) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ = 38.0 (C-10), 39.4 (C-6), 41.1 (C-7), 49.1 (C-8), 115.4 (C-10a), 117.8 (C-4), 122.6 (C-11a), 125.3 (C-2), 126.2 (C-1), 126.5 (C-2′,6′), 127.4 (C-4′), 129.1 (C-3′,5′), 133.7 (C-3), 143.3 (C-1′), 155.9 (C-4a), 164.1 (C-5a), 176.2 (C-11), 207.2 (C-9) ppm. ESI-MS: m/z (%) = 305 (4) [M + H]⁺, 327 (100) [M + Na]⁺, 631 (16) [2M + Na]⁺. HRMS (EI): m/z calcd for C₂₀H₁₆O₃: 304.1099; found: 304.1105. 2-(2-Hydroxyphenyl)-6-phenyl-6,7-dihydrobenzofuran-4(5H)-one (6a) Yield 2.7 mg (20%); white solid; mp 269–272 °C. ¹H NMR (500.13 MHz, DMSO-d ₆): δ = 2.57 (dd, J = 3.9, 16.2 Hz, 1 H, H-5), 2.91 (dd, J = 12.4, 16.2 Hz, 1 H, H-5), 3.25 (d, J = 8.0 Hz, 2 H, H-7), 3.62–3.68 (m, 1 H, H-6), 6.90 (ddd, J = 1.1, 7.3, 7.8 Hz, 1 H, H-5′), 6.98 (dd, J = 1.1; 8.2 Hz, 1 H, H-3′), 7.08 (s, 1 H, H-3), 7.18 (ddd, J = 1.7, 7.3, 8.2 Hz, 1 H, H-4′), 7.27 (tt, J = 1.3; 7.3 Hz, H-4′′), 7.34–7.38 (m, 2 H, H-3′′,5′′), 7.42–7.44 (m, 2 H, H-2′′,6′′), 7.68 (dd, J = 1.7, 7.8 Hz, 1 H, H-6′), 10.37 (s, 1 H, 2′-OH) ppm. ¹³C NMR (125.77 MHz, DMSO-d ₆): δ = 30.3 (C-7), 40.3 (C-6), 44.5 (C-5), 104.5 (C-3), 116.1 (C-3′), 116.2 (C-1′), 119.3 (C-5′), 122.1 (C-3a), 125.2 (C-6′), 126.8 (C-4′′), 127.1 (C-2′′,6′′), 128.6 (C-3′′,5′′), 128.9 (C-4′), 143.1 (C-1′′), 150.9 (C-2), 153.8 (C-2′), 165.3 (C-7a), 192.6 (C-4) ppm. MS (EI): m/z (%) = 305 (10) [M^•+ + H]⁺, 304 (64) [M^•+], 200 (87), 173 (12), 172 (100), 171 (33), 121 (76). HRMS (EI): m/z calcd for C₂₀H₁₆O₃: 304.1099; found: 304.1096.
• 19 Hewitt RJ, Harvey JE. J. Org. Chem. 2010; 75: 955
• 20 General Procedure for the Synthesis of Dimers 13 and 14 A solution of (E)-3-bromo-2-styrylchromone 1a (50 mg, 0.15 mmol) in acetone (5 mL) at r.t. was irradiated with a 500 W halogen lamp for 16 h. After this period, the solvent was evaporated to dryness, and the obtained residue was purified by preparative TLC using CH₂Cl₂ as eluent. Mixture of two Diastereomers d_M and d_m (64:36) of (E)-8a-Bromo-2-(3-bromo-4-oxo-4H-chromen-2-yl)-1-phenyl-2a-styryl-1,2,2a,8a-tetrahydro-8H-cyclobuta[b]chromen-8-one (13) Yield 17.5 mg (18%); white solid. ¹H NMR (500.13 MHz, CDCl₃): d_M-13: δ = 4.72 (d, J = 12.4 Hz, 1 H, H-1), 5.20 (d, J = 12.4 Hz, 1 H, H-2), 6.75 (d, J = 15.8 Hz, 1 H, H-α), 7.16 (d, J = 15.8 Hz, 1 H, H-β), 7.52 (dd, J = 0.6, 8.5 Hz, 1 H, H-8′′), 7.66–7.73 (m, 2 H, H-5 and H-7′′), 7.86 (dd, J = 1.6, 7.9 Hz, H-7), 8.15 (dd, J = 1.4, 8.0 Hz, 1 H, H-5′′) ppm; d_m-13 δ = 5.16 (d, J = 11.1 Hz, 1 H, H-1), 5.27 (d, J = 11.1 Hz, 1 H, H-2), 6.76 and 6.80 (ABq, J _AB = 15.9 Hz, 2 H, H-α and H-β), 7.05 (dd, J = 0.6, 8.4 Hz, 1 H, H-4), 7.59 (ddd, J = 1.8, 7.2, 8.4 Hz, 1 H, H-5), 7.63–7.66 (m, 1 H, H-7′′), 8.06 (dd, J = 1.7, 7.9 Hz, 1 H, H-7), 8.26 (dd, J = 1.5, 8.0 Hz, 1 H, H-5′′) ppm; d_M- and d_m-13: δ = 7.16–7.47 (m, 26 H, H-4-d_M, H-6, H-2′,3′,4′,5′,6′, H-6′′, H-8′′, H-2′′′,3′′′,4′′′,5′′′,6′′′) ppm. ¹³C NMR (125.77 MHz, CDCl₃): d_M-13: δ = 48.2 (C-2), 49.2 (C-1), 64.5 (C-8a), 85.3 (C-2a), 111.3 (C-3′′), 117.4 (C-8′′), 119.6 (C-4), 119.9 (C-7a), 121.9 (C-4′′a), 123.5 (C-α), 123.7 (C-6), 126.1 (C-6′′), 126.6 (C-5′′), 126.8 (C-2′′′,6′′′), 127.31 (C-2′,6′), 128.15 and 128.4 (C-4′,4′′′), 128.17 (C-7), 128.66 (C-3′′′,5′′′), 128.9 (C-3′,5′), 133.0 (C-β), 133.4 (C-1′), 134.22 (C-7′′), 135.7 (C-1′′′), 137.5 (C-5), 155.2 (C-8′′a), 156.8 (C-3a), 158.68 (C-2′′), 172.0 (C-4′′), 184.6 (C-8) ppm; d_m-13: δ = 47.3 (C-1), 51.7 (C-2), 69.6 (C-8a), 88.9 (C-2a), 112.4 (C-3′′), 117.8 (C-8′′), 118.20 (C-7a), 118.23 (C-4), 122.1 (C-4′′a), 123.0 (C-6), 126.0 (C-6′′), 126.4 (C-α), 126.5 (C-5′′), 127.1 (C-2′′′,6′′′), 127.27 and 127.4 (C-4′,4′′′), 127.6 (C-2′,6′), 128.6 and 128.69 (C-3′,5′,3′′′,5′′′), 128.8 (C-7), 133.6 (C-β), 134.17 (C-7′′), 135.5 (C-1′′′), 136.1 (C-1′), 137.4 (C-5), 155.5 (C-8′′a), 158.74 (C-2′′), 159.8 (C-3a), 172.4 (C-4′′), 185.4 (C-8) ppm. 2,2′-(3,4-Diphenylcyclobutane-1,2-diyl)bis(3-bromo-4H-chromen-4-one) (14) Yield 15.9 mg (16%); white solid; mp 280–282 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 4.95 (dd, J = 7.4, 10.2 Hz, 2 H, H-3′′,4′′), 5.29 (dd, J = 7.4, 10.2 Hz, 2 H, H-1′′,2′′), 7.07 (t, J = 7.3 Hz, 2 H, H-4′′′,4′′′′), 7.19 (t, J = 7.6 Hz, 4 H, H-3′′′,5′′′,3′′′′,5′′′′), 7.31–7.40 (m, 8 H, H-6,6′,8,8′,2′′′,6′′′,2′′′′,6′′′′), 7.64 (ddd, J = 1.6, 7.3, 8.6 Hz, 2 H, H-7,7′), 8.13 (dd, J = 1.6, 8.0 Hz, 2 H, H-5,5′) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ = 43.3 (C-3′′,4′′), 45.9 (C-1′′,2′′), 111.3 (C-3,3′), 117.3 (C-8,8′), 121.6 (C-10,10′), 125.8 (C-6,6′), 126.4 (C-5,5′), 126.9 (C-2′′′,6′′′,2′′′′,6′′′′), 127.4 (C-4′′′,4′′′′), 128.7 (C-3′′′,5′′′,3′′′′,5′′′′), 134.0 (C-7,7′), 137.3 (C-1′′′,1′′′′), 154.9 (C-9,9′), 163.3 (C-2,2′), 172.0 (C-4,4′) ppm. ESI-MS: m/z (%) = 653 (⁷⁹Br, 43) [M + H]⁺, 655 (⁸¹Br, 83) [M + H]⁺, 675 (⁷⁹Br, 53) [M + Na]⁺, 677 (⁸¹Br, 100) [M + Na]⁺, 691 (⁷⁹Br, 17) [M + K]⁺, 693 (⁸¹Br, 32) [M + K]⁺. ESI-HRMS: m/z calcd for [C₃₄H₂₂ ⁷⁹Br₂O₄ + H]⁺: 652.9963; found: 652.9955.