A One-Pot Diastereoselective Synthesis of 2-[Aryl(hydroxy)methyl]-6-methyl-2H-furo[3,2-c]pyran-3,4-diones: Crystallographic Evidence for the Furanone Ring Closure

Abstract

Novel furopyran-3,4-dione-fused heterocycles have been obtained by a one-pot reaction of α-brominated dehydroacetic acid and benzaldehydes under organobase conditions. The prepared 2-[aryl(hydroxy)methyl]-6-methyl-2H-furo[3,2-c]pyran-3,4-diones were fully characterized by 2D NMR spectroscopy and supported by single-crystal X-ray analysis to unequivocally prove the furan-3-one five-membered ring-closure mechanism instead of the dihydroflavanon-3-ol six-membered cyclization which has recently been proposed in the literature.

Keywords

furan-3-ones - pyran-2-ones - dehydroacetic acid - synthesis - organobase - 2D NMRspectroscopy - single-crystal X-ray diffraction

• References and Notes

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• 9 Synthesis of 3-Bromoacetyl-4-hydroxy-6-methyl-2H-pyran-2-one (2) A solution of bromine (0.27 mL, 5 mmol) in AcOH (10 mL) was added portionwise to a solution of DHA (1, 0.84 g, 5 mmol) in AcOH (20 mL). After heating to reflux for 2 h, the reaction mixture was poured into H₂O (100 mL) and ice (50 g). The solid obtained was filtered off and recrystallized from a 1:1 mixture of hexane–CHCl₃ to afford compound 2. Analytical Data for Compd 2 C₈H₇BrO₄ (yellow crystals, MW = 247.04 g/mol, 0.75 g, 61%; mp 118–119 °C [111–114 °C]⁷). ¹H NMR (300.13 MHz, CDCl₃): δ = 2.31 (s, 3 H, 6-CH₃), 4.71 (s, 2 H, CH₂Br), 6.03 (s, 1 H, H-5), 15.51 (s, 1 H, OH) ppm. ¹³C NMR (75.47 MHz, CDCl₃): δ = 20.8 (6-CH₃), 35.2 (CH₂Br), 99.4 (C-3), 101.3 (C-5), 160.6 (C-6), 170.1 (C-2), 180.9 (C-4), 197.2 (C-3) ppm. ESI⁺-MS: m/z = 271 (⁸¹Br, 18) [M + Na]⁺, 269 (⁷⁹Br, 20) [M + Na]⁺, 249 (⁸¹Br, 90) [M + H]⁺, 247 (⁷⁹Br, 95) [M + H]⁺, 167 (100) [M – Br]⁺. Anal. Calcd (%) for C₈H₇BrO₄: C, 38.89; H, 2.86. Found: C, 39.10; H, 2.80.
• 10 Synthesis of 2-[Aryl(hydroxy)methyl]-6-methyl-2H-furo[3,2-c]pyran-3,4-diones 3a–j A suspension of the appropriate benzaldehyde (1 mmol), 3-(bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one (2, 0.25 g, 1 mmol), and Et₃N (0.2 mL, 1.5 mmol) was stirred in EtOH (3 mL) at ambient temperature for 15 min. The powder formed was collected by filtration, washed with H₂O and then allowed to dry. The crude compounds thus obtained were recrystallized from EtOH to give pure compounds 3a–j. Representative Analytical Data
  2-[Hydroxy(phenyl)methyl]-6-methyl-2H-furo[3,2-c]pyran-3,4-dione (3a) C₁₅H₁₂O₅ (violet solid, MW = 272.26 g/mol, 0.25 g, 92%; mp 160 °C). ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 2.34 (s, 3 H, 6-CH₃), 5.16 (dd, J = 1.5, 3.7 Hz, 1 H, H-1′), 5.20 (d, J = 1.5 Hz, 1 H, H-2), 5.99 (d, J = 3.7 Hz, 1 H, 1′-OH), 6.69 (s, 1 H, H-7), 7.20–7.41 (m, 5 H, H-2′′3 ′′,4′′,5′′,6′′) ppm. ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 20.7 (6-CH₃), 70.9 (C-1′), 91.4 (C-2), 96.8 (C-7), 99.7 (C-9), 126.2 (C-2′′,6′′), 127.4 (C-4′′), 128.0 (C-3′′,5′′), 140.9 (C-1′′), 155.4 (C-4), 174.1 (C-6), 188.3 (C-8), 192.8 (C-3) ppm. ESI⁺-HRMS: m/z calcd for [C₁₅H₁₂O₅ + Na]⁺: 295.0582; found: 295.0588. Crystal Data for Compound 3a (C₁₅H₁₂O₅)₂·H₂O, M = 562.51, triclinic, space group P 1, Z = 1, a = 7.1249(5) Å, b = 8.0504(6) Å, c = 12.2442(10) Å, α = 107.237(4)°, β = 96.608(5)°, γ = 102.845(4)°, V = 641.51(9) ų, μ(Mo-Kα) = 0.112 mm^–1, D _c = 1.456 g cm^–3, red block, crystal size of 0.20 × 0.12 × 0.10 mm³. Of a total of 4402 reflections collected, 2331 were independent (R _int = 0.0292). Final R1 = 0.0391 [I > 2σ(I)] and wR2 = 0.0966 (all data). Data completeness to θ = 25.24°, 98.8%; CCDC 1050452. 2-[Hydroxy(3-nitrophenyl)methyl]-6-methyl-2H-furo[3,2-c]pyran-3,4-dione (3b) C₁₅H₁₁NO₇ (pale violet solid, MW = 317.25 g/mol, 0.29 g, 91%; mp 208 °C). ¹H NMR (??? MHz, DMSO-d ₆): δ = 2.35 (s, 3 H, 6-CH₃), 5.35–5.36 (m, 2 H, H-1′, H-2), 6.37 (d, J = 6.4 Hz, 1 H, 1′-OH), 6.70 (s, 1 H, H-7), 7.69 (dd, J = 7.8, 7.9 Hz, 1 H, H-5′′), 7.98 (d, J = 7.8 Hz, 1 H, H-6′′) 8.19 (dd, J = 1.7, 7.9 Hz, 1 H, H-4′′), 8.36 (d, J = 1.7 Hz, 1 H, H-2′′) ppm. ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 20.7 (6-CH₃), 69.8 (C-1′), 90.7 (C-2), 96.7 (C-7), 99.7 (C-9), 121.1 (C-2′′), 122.5 (C-4′′), 129.7 (C-5′′), 133.1 (C-6′′), 143.4 (C-1′′), 147.7 (C-3′′), 155.4 (C-4), 174.3 (C-6), 188.2 (C-8), 192.2 (C-3) ppm. ESI⁺-HRMS: m/z calcd for [C₁₅H₁₁NO₇ + Na]⁺: 340.0433; found: 340.0439. 2-[Hydroxy(2-hydroxyphenyl)methyl]-6-methyl-2H-furo[3,2-c]pyran-3,4-dione (3c) C₁₅H₁₂O₆ (grey solid, MW = 288.25 g/mol, 0.27 g, 94%; mp 185 °C). ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 2.34 (s, 3 H, 6-CH₃), 5.11 (d, J = 1.5 Hz, 1 H, H-2), 5.38 (dd, J = 1.5, 4.8 Hz, 1 H, H-1′), 5.76 (d, J = 4.8 Hz, 1 H, 1′-OH), 6.66 (s, 1 H, H-7), 6.81–6.88 (m, 2 H, H-3′′, H-5′′), 7.09–7.17 (m, 1 H, H-4′′), 7.40 (dd, J = 7.7, 1.1 Hz, 1 H, H-6′′), 9.81 (s, 1 H, 2′′-OH) ppm. ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 20.7 (6-CH₃), 66.2 (C-1′), 89.8 (C-2), 96.8 (C-7), 99.8 (C-9), 114.6 (C-3′′), 118.8 (C-5′′), 126.9 (C-6′′), 127.4 (C-1′′), 128.2 (C-4′′), 153.2 (C-2′′), 155.5 (C-4), 173.9 (C-6), 188.4 (C-8), 193.3 (C-3) ppm. ESI⁺-HRMS: m/z calcd for [C₁₅H₁₂O₆ + Na]⁺: 311.0532; found: 311.0541. 2-[Hydroxy(3-hydroxyphenyl)methyl]-6-methyl-2H-furo[3,2-c]pyran-3,4-dione (3d) C₁₅H₁₂O₆ (pale violet solid, MW = 288.25 g/mol, 0.26 g, 90%; mp 205–206 °C). ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 2.35 (s, 3 H, 6-CH₃), 5.07 (dd, J = 1.3, 5.4 Hz, 1 H, H-1′), 5.15 (d, J = 1.3 Hz, 1 H, H-2), 5.91 (d, J = 5.4 Hz, 1 H, 1′-OH), 6.68 (s, 1 H, H-7), 6.70–6.71 (m, 1 H, H-4′′), 6.87–6.90 (m, 2 H, H-2′′, H-6′′), 7.13–7.19 (m, 1 H, H-5′′), 9.41 (s, 1 H, 3′′-OH) ppm. ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 20.7 (6-CH₃), 70.8 (C-1′), 91.5 (C-2), 96.7 (C-7), 99.7 (C-9), 113.3 (C-2′′), 114.3 (C-4′′), 116.7 (C-6′′), 129.1 (C-5′′), 142.5 (C-1′′), 155.4 (C-3′′), 157.2 (C-4), 174.1 (C-6), 188.3 (C-8), 192.9 (C-3) ppm. ESI⁺-HRMS: m/z calcd for [C₁₅H₁₂O₆ + Na]⁺: 311.0532; found: 311.0535. 2-[Hydroxy(4-chlorophenyl)methyl]-6-methyl-2H-furo[3,2-c]pyran-3,4-dione (3e) C₁₅H₁₁ClO₅ (pale yellow solid, MW = 306.69 g/mol, 0.28 g, 91%; mp 268 °C). ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 2.34 (s, 3 H, 6-CH₃), 5.17–5.20 (m, 2 H, H-1′, H-2), 6.10 (d, J = 5.5 Hz, 1 H, 1′-OH), 6.67 (s, 1 H, H-7), 7.44 and 7.52 (2 d, J = 8.5 Hz, 2 × 2 H, H-2′′,3′′, H-5′′,6′′) ppm. ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 20.7 (6-CH₃), 70.2 (C-1′), 91.1 (C-2), 96.7 (C-7), 99.8 (C-9), 128.1 and 128.2 (C-2′′,3′′ and C-5′′,6′′), 132.1 (C-4′′), 140.0 (C-1′′), 155.4 (C-4), 174.2 (C-6), 188.3 (C-8), 192.6 (C-3) ppm. ESI⁺-HRMS: m/z calcd for [C₁₅H₁₁ClO₅ + Na]⁺: 329.0193; found: 329.0192. 2-[Hydroxy(o-tolyl)methyl]-6-methyl-2H-furo[3,2-c]pyran-3,4-dione (3f) C₁₆H₁₄O₅ (red violet solid, MW = 286.27 g/mol, 0.25 g, 87%; mp 207 °C). ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 2.35 and 2.36 (2 s, 6 H, 2′′-CH₃, 6-CH₃), 5.12 (d, J = 1.0 Hz, 1 H, H-2), 5.33 (dd, J = 1.0, 5.3 Hz, 1 H, H-1′), 5.87 (d, J = 5.3 Hz, 1 H, 1′-OH), 6.72 (s, 1 H, H-7), 7.16–7.30 (m, 3 H, H-3′′, H-4′′, H-5′′), 77.56 (dd, J = 7.5, 5.3 Hz, 1 H, H-6′′) ppm. ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 18.5 (2′′-CH₃), 20.6 (6-CH₃), 67.8 (C-1′), 89.7 (C-2), 96.6 (C-7), 99.6 (C-9), 125.5 (C-5′′), 126.9 (C-6′′), 127.2 (C-3′′), 130.0 (C-4′′), 133.7 (C-2′′), 138.6 (C-1′′), 155.3 (C-4), 174.1 (C-6), 188.3 (C-8), 192.9 (C-3) ppm. ESI⁺-HRMS: m/z calcd for [C₁₆H₁₄O₅ + Na]⁺: 309.0793; found: 309.0777. 2-[Hydroxy(4-methoxyphenyl)methyl]-6-methyl-2H-furo[3,2-c]pyran-3,4-dione (3g) C₁₆H₁₄O₆ (pale brown solid, MW = 302.27 g/mol, 0.27 g, 89%; mp 195 °C). ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 2.35 (s, 3 H, 6-CH ₃), 3.76 (s, 3 H, 4′′-OCH₃), 5.11 (dd, J = 1.5, 5.2 Hz, 1 H, H-1′), 5.13 (d, J = 1.5 Hz, 1 H, H-2), 5.89 (d, J = 5.2 Hz, 1 H, 1′-OH), 6.89 (s, 1 H, H-7), 6.94 (d, J = 8.7 Hz, 2 H, H-3′′,5′′), 7.39 (d, J = 8.7 Hz, 2 H, H-2′′,6′′) ppm. ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 20.7 (6-CH₃), 55.1 (4′′-OCH₃), 70.6 (C-1′), 91.6 (C-2), 96.8 (C-7), 99.8 (C-9), 113.4 (C-3′′,5′′), 127.5 (C-2′′,6′′), 132.9 (C-1′′), 155.4 (C-4), 158.6 (C-4′′), 174.0 (C-6), 188.2 (C-8), 192.8 (C-3) ppm. ESI⁺-HRMS: m/z calcd for [C₁₆H₁₄O₆ + Na]⁺: 325.0688; found: 325.0721.
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