Diels-Alder Reaction of 2-Nitro Glycals: A New Route to the Synthesis of Benzopyrans

Abstract

Synthesis of different benzopyrans was achieved by Diels-Alder reaction of 2-nitro glycals with Danishefky’s diene, hydrolysis of the enol ether moiety, and subsequent elimination of the nitro and methoxy group.

2-nitro glycals - Diels-Alder reaction - chromans - benzopyrans - benzannulated dihydropyrans - C-glycosides

References

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General experimental procedure for 6, 9, 10 and 12: A solution of 2-nitro glycal (1 mmol) and Danishefky’s diene (1.1 mmol) in dry toluene (2 mL) was refluxed under argon for 36 h. The reaction mixture was allowed to cool and the toluene was removed under reduced pressure. Then a mixture of THF-10% H₂SO₄ in H₂O (2:1) was added and stirred at room temperature for 30 min. The product was isolated by extractive workup followed by filtration by column chromatography. The hydrolyzed product was dissolved in 1 M NaOCH₃ in methanol (2 mL) and heated at 50 °C for 1.5 h. Methanol was evaporated followed by neutralization with saturated aq NH₄Cl solution and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous MgSO₄. Evaporation of the solvent yielded the benzannulated pyrans.
For compound 5: A mixture of hydrolyzed products 3 and 4 and DBN (3 equiv) in toluene (2 mL) was refluxed for 24 h. The reaction mixture was neutralized with aq NH₄Cl after removal of the toluene followed by extraction with ethyl acetate. The organic layer was washed with dilute HCl, water, brine and dried over anhydrous MgSO₄. Evaporation of the solvent and purification by column chromatography yielded the product 5 in 68% yield.
Some selected data:
5: [α]_D ²⁰ = -39.1 (c 1, CHCl₃); ¹H NMR (250 MHz): δ 2.86 (br s, 1 H), 3.45-3.55 (m, 2 H), 3.59 (dd, J = 1.99, 7.82 Hz, 1 H), 3.93 (d, J = 10.8 Hz, 1 H), 4.09 (d, J = 10.8 Hz, 1 H), 4.19 (br s, 1 H), 4.25 (d, J = 11.46 Hz, 1 H), 4.44 (d, J = 11.46 Hz, 1 H), 4.43-4.54 (m, 3 H), 5.37 (br s, 1 H), 6.81-6.85 (m, 2 H), 6.93-6.97 (m, 2 H), 7.18-7.35 (m, 15 H). ¹³C NMR (62.9 MHz): δ 69.7, 70.4, 71.2, 73.3, 73.9, 80.3, 81.1, 115.4, 127.6, 127.7, 127.9, 128.2, 128.3, 129.1, 130.5, 137.5, 137.8, 156.1. MALDI: m/z 507 (M + Na⁺). Calcd: C, 76.80; H, 6.66. Found: C, 76.55; H, 6.39.
6: [α]_D ²⁰ = +6.3 (c 1, CHCl₃); ¹H NMR (250 MHz): δ 3.71-3.83 (m, 2 H), 4.14 (dd, J = 2.2 Hz, 3.2 Hz, 1 H), 4.34 (td, J = 1.4 Hz, 5.9 Hz, 1 H), 4.44 (d, J= 11.9 Hz, 1 H), 4.53 (d, J = 11.9 Hz, 1 H), 4.57-4.86 (m, 5 H), 5.14 (br s, 1 H), 6.29 (d, J = 2.4 Hz, 1 H), 6.39 (dd, J = 2.5 Hz, 8.3 Hz, 1 H), 7.20-7.40 (m, 16 H). ¹³C NMR (62.9 MHz): δ 69.1, 70.1, 71.8, 73.1, 73.5, 74.0, 75.8, 103.1, 108.6, 114.0, 127.7, 127.8, 128.1, 128.3, 128.4, 129.3, 137.7, 138.1, 153.9, 156.7. MALDI: m/z 505 (M + Na⁺⁾. Calcd: C, 77.16; H, 6.27. Found: C, 76.82; H, 6.57.
9: [α]_D ²⁰ = +26.7 (c 1, CHCl₃); ¹H NMR (250 MHz): δ 3.7-3.89 (m, 2 H), 4.04 (t, J = 6.1 Hz, 1 H), 4.29-4.35 (m, 1 H), 4.58-4.80 (m, 7 H), 5.4 (br s, 1 H), 6.34 (d, J = 2.43 Hz, 1 H), 6.4 (dd, J = 2.44 Hz, 8.34 Hz, 1 H), 7.1 (d, J = 8.38 Hz, 1 H), 7.23-7.37 (m, 15 H). ¹³C NMR (62.9 MHz): δ 69.0, 71.2, 73.1, 73.5, 73.6, 76.1, 77.01, 103.3, 109, 113.9, 127.7, 127.9, 128.0, 128.5, 130.2, 137.8, 138.2, 154.6, 156.7. MALDI: m/z 505(M + Na⁺).
10: [α]_D ²⁰ = +30.1 (c 1, CHCl₃); ¹H NMR (250 MHz): δ 3.53-3.92 (m, 6 H), 4.35-4.92(m, 17 H), 5.18 (br s, 1 H), 5.34 (d, J = 3.6 Hz, 1 H), 6.37 (d, J = 2.18 Hz, 1 H), 6.42 (dd, J = 2.32 Hz, 8.24 Hz, 1 H), 7.12 (dd, J = 3.26 Hz, 7.06 Hz, 1 H), 7.24-7.30 (m, 30 H). ¹³C NMR (62.9 MHz): δ 68.4, 69.0, 69.4, 70.9, 72.9, 73.3, 73.4, 74.5, 75.0, 75.5, 76.9, 80.0, 81.7, 96.1, 103.7, 109.1, 112.7, 127.6, 127.7, 127.8, 127.9, 128.3, 128.4, 131.1, 137.9, 138.0, 138.1, 138.3, 138.8, 154.9, 156.9. MALDI: m/z 937 (M + Na⁺).
12: [α]_D ²⁰ = -27.1 (c 1, CHCl₃); ¹H NMR (250 MHz): δ 1.46 (d, J = 6.48 Hz, 3 H), 3.69 (dd, J = 6.83 Hz, 8.08 Hz, 1 H), 4.11-4.19 (m, 1 H), 4.65-4.88 (m, 6 H), 6.27 (d, J = 2.48 Hz, 1 H), 6.40 (dd, J = 2.51 Hz, 8.39 Hz, 1 H), 7.15 (dd, J = 0.64 Hz, 8.41 Hz, 1 H), 7.23-7.36 (m, 10 H). ¹³C NMR (62.9 MHz): δ 17.9, 71.5, 73.7, 74.4, 77.3, 79.1, 102.9, 109.0, 114.7, 127.7, 127.87, 127.89, 127.9, 128.5, 129.8, 137.8, 138.2, 155.0, 156.5. Cald: C, 76.57; H, 6.43. Found: C, 76.25; H, 6.32.
15: [α]_D ²⁰ = +53.6 (c 0.5, CHCl₃); ¹H NMR (600 MHz): δ 2.02, 2.12 (2 s, 6 H), 2.25-2.33 (m, 1 H), 2.4-2.5 (m, 1 H), 2.9 (t, J = 6.7 Hz, 1 H), 3.77 (s, 3 H), 4.2-4.35 (m, 3 H), 5.08-5.17 (m, 3 H), 5.8-5.9 (m, 1 H), 6.46 (d, J = 1 Hz, 1 H), 6.53 (dd, J = 2.5 Hz, 8.4 Hz, 1 H), 6.98 (d, J = 8.5 Hz, 1 H). ¹³C NMR (150.8 MHz): δ 20.8, 21.0, 38.4, 41.5, 55.3, 63.3, 68.0, 69.9, 101.2, 108.5, 118.0, 130.5, 134.8, 153.5, 159.4, 170.4, 170.7. Calcd: C, 64.66; H, 6.63. Found: C, 64.95; H, 7.0.
17: [α]_D ²⁰ = +29.6 (c 1, CHCl₃); ¹H NMR (250 MHz): δ 1.98, 2.0, 2.1 (3 s, 9H), 2.77 (d, J = 6.9 Hz, 2 H), 3.75 (s, 3 H), 4.07 (dd, J = 6.8 Hz, 11.8 Hz, 1 H), 4.23 (dd, J = 4.6 Hz, 11.8 Hz, 1 H), 5.13-5.26 (m, 2 H), 6.92-7.2 (m, 4 H). ¹³C NMR (62.9 MHz): δ 20.6, 20.7, 21.0, 36.2, 62.2, 70.6, 72.0, 121.6, 130.2, 133.6, 149.6, 169.3, 170.0, 170.4.

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