One-Pot Dehydrazinative β-Glycosylation in Aqueous Media: Synthesis of Benzoxazinone C-Nucleosides

Abstract

An expeditious mineral-catalyzed cycloisomerization of salicylaldehyde 4-arylsemicarbazones under solvent-free microwave irradiation yields 4-hydrazino-2H-benz[e]-1,3-oxazin-2-ones, which conveniently undergo dehydrazinative β-glycosylation ­directly with unprotected d-ribose in aqueous media to afford high yields of 4-β-d-ribofuranosyl-2H-benz[e]-1,3-oxazin-2-ones in a one-pot procedure.

Key words

aqueous media - benzoxazinone C-nucleosides - microwaves - β-glycosylation - mineral-catalyzed

References and Notes

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26

General Procedure ⁸ for the Synthesis of 3-Aryl-4-hydrazino-3,4-dihydro-2 H -benz[ e ]-1,3-oxazin-2-ones 2: To a solution of 1 (3.0 mmol) in a small amount of CH₂Cl₂ (10 mL) was added montmorillonite K-10 clay (0.3 g). After thoroughly mixing and drying under reduced pressure, the contents were taken in a 20-mL vial and subjected to MW irradiation in a CEM Discover Focused Microwave Synthesis System at 90 °C for 6-10 min. After completion of the reaction as indicated by TLC (hexane-EtOAc, 8:2), the product was extracted with CH₂Cl₂ (3 × 25 mL), the extract was filtered and the filtrate was evaporated under reduced pressure to leave the crude product, which was recrystallized from EtOH to obtain an analytically pure sample of 2 as yellowish needles.
Characterization Data for Representative Compounds
Compound 2a: yellowish needles; mp 208-210 °C. IR (KBr): 3367, 3011, 1715, 1605, 1584, 1453 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.08 (br s, 3 H, exchanges with D₂O), 6.81 (d, J = 9.1 Hz, 1 H, H-4), 7.32-7.98 (m, 8 H, ArH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 78.1, 112.9, 115.1, 118.3, 120.0, 124.5, 127.8, 129.1, 130.2, 152.4, 162.8, 174.2. MS: m/z = 289 [M⁺]. Anal. Calcd for C₁₄H₁₂ClN₃O₂: C, 58.04; H, 4.17; N, 14.50. Found: C, 57.71; H, 3.96; N, 14.68.
Compound 2e: yellowish needles; mp 213-215 °C. IR (KBr): 3372, 3015, 1717, 1605, 1585, 1455 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.16 (br s, 3 H, exchanges with D₂O), 6.87 (d, J = 9.1 Hz, 1 H, H-4), 7.35-8.15 (m, 6 H, ArH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 78.6, 112.6, 115.5, 118.8, 120.5, 124.8, 127.6, 129.7, 130.4, 152.8, 162.9, 174.5. MS: m/z = 357 [M⁺]. Anal. Calcd for C₁₄H₁₀Cl₃N₃O₂: C, 46.89; H, 2.81; N, 11.72. Found: C, 47.01; H, 2.73; N, 11.99.
Compound 2j: yellowish needles; mp 188-189 °C. IR (KBr): 3366, 3009, 1717, 1603, 1585, 1454 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.08 (br s, 3 H, exchanges with D₂O), 3.73 (s, 3 H, OMe), 6.85 (d, J = 9.0 Hz, 1 H, H-4), 7.29-8.01 (m, 6 H, ArH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 54.4, 78.5, 112.5, 114.9, 118.3, 120.0, 124.4, 127.4, 129.4, 130.5, 152.2, 162.5, 174.6. MS: m/z = 353 [M⁺]. Anal. Calcd for C₁₅H₁₃Cl₂N₃O₃: C, 50.87; H, 3.70; N, 11.86. Found: C, 50.97; H, 3.51; N, 11.61.

28

General Procedure for the Synthesis of 3-Aryl-4-β- d-ribofuranosyl-3,4-dihydro-2H -benz[ e ]-1,3-oxazin-2-ones 3: To a suspension of 4-hydrazinobenzoxazinone 2 (2.0 mmol) in H₂O (15 mL) was added KOH (0.17 g, 3 mmol). After stirring the reaction mixture for 1 h at 75 °C, d-ribose (0.3 g, 2.0 mmol) was added to it and the reaction mixture was further stirred for 4-5 h at 90 °C. After completion of the reaction as indicated by TLC (hexane-EtOAc, 9:1), glacial AcOH (1.0 mL) was added and the product was extracted with CH₂Cl₂ (3 × 20 mL). The extract was filtered and the filtrate was evaporated under reduced pressure to leave the crude product, which was recrystallized from EtOH to obtain an analytically pure sample of 3 as a yellowish powder.
Characterization Data for Representative Compounds:
Compound 3a: yellowish powder; mp 236-238 °C; [α]_D ²⁷ +46.3 (c = 1.5, MeOH). IR (KBr): 3390, 3015, 1692, 1604, 1581, 1455 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.51 (ddd, J = 3.5, 5.3, 11.6 Hz, 1 H, H_a-5′), 3.63 (ddd, J = 3.5, 5.7, 11.6 Hz, 1 H, H_b-5′), 4.01 (ddd, J = 3.5, 3.5, 4.2 Hz, 1 H, H-4′), 4.38 (dd, J = 5.6, 6.4 Hz, 1 H, H-1′), 4.51 (ddd, J = 4.6, 5.6, 6.8 Hz, 1 H, H-2′), 4.64 (ddd, J = 4.6, 5.2, 6.8 Hz, 1 H, H-3′), 5.16 (dd, J = 5.3, 5.7 Hz, 1 H, OH-5′), 5.29 (d, J = 5.2 Hz, 1 H, OH-3′), 5.58 (d, J = 5.6 Hz, 1 H, OH-2′), 6.54 (d, J = 6.4 Hz, 1 H, H-4), 7.21-7.79 (m, 8 H, ArH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 37.8, 62.5, 72.7, 73.3, 76.4, 78.3, 83.4, 113.4, 114.9, 119.0, 120.5, 122.9, 130.3, 130.9, 151.9, 166.3, 174.7. MS (FAB, NBA): m/z = 392 [MH⁺]. Anal. Calcd for C₁₉H₁₈ClNO₆: C, 58.24; H, 4.63; N, 3.57. Found: C, 58.53; H, 4.39; N, 3.85.
Compound 3e: yellowish powder; mp 247-250 °C; [α]_D ²⁷ +52.5 (c = 1.6, MeOH). IR (KBr): 3395, 3018, 1695, 1601, 1581, 1457 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.49 (ddd, J = 3.7, 5.4, 11.6 Hz, 1 H, H_a-5′), 3.68 (ddd, J = 3.7, 5.8, 11.6 Hz, 1 H, H_b-5′), 4.09 (ddd, J = 3.7, 3.7, 4.1 Hz, 1 H, H-4′), 4.45 (dd, J = 5.5, 6.4 Hz, 1 H, H-1′), 4.59 (ddd, J = 4.5, 5.5, 6.9 Hz, 1 H, H-2′), 4.71 (ddd, J = 4.1, 5.1, 6.9 Hz, 1 H, H-3′), 5.15 (dd, J = 5.4, 5.8 Hz, 1 H, OH-5′), 5.30 (d, J = 5.1 Hz, 1 H, OH-3′), 5.61 (d, J = 5.5 Hz, 1 H, OH-2′), 6.59 (d, J = 6.4 Hz, 1 H, H-4), 7.32-7.81 (m, 6 H, ArH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 38.2, 62.4, 72.6, 73.9, 76.8, 78.5, 83.5, 113.7, 114.9, 119.6, 120.5, 122.9, 130.8, 131.5, 152.2, 166.5, 174.7. MS (FAB, NBA): m/z = 460 [MH⁺]. Anal. Calcd for C₁₉H₁₆Cl₃NO₆: C, 49.53; H, 3.50; N, 3.04. Found: C, 49.79; H, 3.61; N, 2.87.
Compound 3j: yellowish powder; mp 212-215 °C; [α]_D ²⁷ +48.3 (c = 1.5, MeOH). IR (KBr): 3394, 3016, 1694, 1601, 1585, 1457 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.51 (ddd, J = 3.4, 5.2, 11.7 Hz, 1 H, H_a-5′), 3.66 (ddd, J = 3.4, 5.7, 11.7 Hz, 1 H, H_b-5′), 4.05 (ddd, J = 3.3, 3.4, 4.3 Hz, 1 H, H-4′), 3.80 (s, 3 H, OMe), 4.39 (dd, J = 5.8, 6.3 Hz, 1 H, H-1′), 4.50 (ddd, J = 4.8, 5.6, 6.7 Hz, 1 H, H-2′), 4.65 (ddd, J = 4.3, 5.3, 6.8 Hz, 1 H, H-3′), 5.19 (dd, J = 5.2, 5.7 Hz, 1 H, OH-5′), 5.31 (d, J = 5.3 Hz, 1 H, OH-3′), 5.59 (d, J = 5.6 Hz, 1 H, OH-2′), 6.53 (d, J = 6.3 Hz, 1 H, H-4), 7.19-7.87 (m, 6 H, ArH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 37.6, 54.6, 62.5, 72.7, 73.6, 76.7, 78.5, 83.7, 113.6, 114.8, 119.2, 120.3, 122.8, 130.3, 131.7, 151.7, 166.4, 174.8. MS (FAB, NBA): m/z = 456 [MH⁺]. Anal. Calcd for C₂₀H₁₉Cl₂NO₇: C, 52.65; H, 4.20; N, 3.07. Found: C, 52.73; H, 4.09; N, 3.19.