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Synlett 2012(6): 917-919  
DOI: 10.1055/s-0031-1290611
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Easy Access to (±)-Schefflone and Espintanol

Dmitry V. Osipov, Vitaly A. Osyanin*, Yuri N. Klimochkin
Department of Organic Chemistry, Samara State Technical University, 244 Molodogvardeiskaya St., 443100 Samara, Russian Federation
Fax: +7(846)3322122; e-Mail: VOsyanin@mail.ru;
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Publication History

Received 6 December 2011
Publication Date:
15 March 2012 (online)

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Abstract

Oxidation of espintanol by silver oxide gives trimeric monoterpenoid (±)-schefflone via ortho-quinone methide intermediate. The heating of 6-[(dibenzylamino)methyl]-3-isopropyl-2,4-dimethoxyphenol also results in ortho-quinone methide intermediate which is trapped by 3-(dimethylamino)-5,5-dimethylcyclohex-2-en-1-one or benzotriazole.

Key words

(±)-schefflone - ortho-quinone methide - espintanol - trimerization - Diels-Alder reaction

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6-[(Dibenzylamino)methyl]-3-isopropyl-2,4-dimethoxyphenol (3): To a mixture of 3-isopropyl-2,4-dimethoxyphenol (2; 1 g, 5.1 mmol) and dibenzylamine (1.01 g, 5.1 mmol) in MeOH (10 mL) 30% aq formaldehyde (0.53 g, 5.3 mmol) was added and the solution was stirred at r.t. for 24 h. The solvent was evaporated under vacuum. Recrystallization of the residue from MeOH yielded the pure product. Yield: 1.82 g (88%); colorless crystals; mp 102-104 ˚C. IR (KBr): 3100-2400 (OH), 2984, 2951, 2926, 2870, 2833, 1477, 1449, 1396, 1323, 1238, 1130, 1103, 1069, 827, 746, 696 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.31 [d, J = 7.1 Hz, 6 H, CH(CH 3)2], 3.50 [sept, J = 7.1 Hz, 1 H, CH(CH3)2], 3.62 (s, 4 H, 2 × CH 2Ph), 3.69 (s, 2 H, CH2), 3.72 (s, 3 H, CH3O), 3.86 (s, 3 H, CH3O), 6.32 (s, 1 H, H-5), 7.25-7.40 (m, 10 H, 2 × Ph), 10.32 (br s, 1 H, OH). ¹³C NMR (100 MHz, CDCl3): δ = 21.4 [CH(CH3)2], 25.2 [CH(CH3)2], 56.4 (CH3O-2), 57.3 (CH2), 58.1 (CH2), 60.8 (CH3O-4), 107.8 (CH-5), 119.6 (C-3), 127.7, 128.7, 129.7 (CH-2′,3′,4′), 130.0 (C-6), 137.0 (C-1′), 144.7, 146.4 (C-1,2), 151.3 (C-4). Anal. Calcd for C26H31NO3 (405.53): C, 77.01; H, 7.71; N, 3.45. Found: C, 77.11; H, 7.67; N, 3.39.

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6-Isopropyl-5,7-dimethoxy-3,3-dimethyl-2,3,4,9-tetrahydro-1 H -xanthen-1-one (5): A mixture of 3-dimethylamino-5,5-dimethyl-2-cyclohexen-1-one (4; 0.1 g, 0.6 mmol) and 3 (0.25 g, 0.6 mmol) in DMF (2 mL) was refluxed for 4 h. The reaction mixture was poured into 5% AcOH (10 mL) to yield a solid product, which was filtered, washed with H2O, dried and recrystallized from EtOH. Yield: 0.13 g (64%); orange crystals; mp 155-157 ˚C. IR (KBr): 2959, 2924, 2851, 1647 (C=O), 1616, 1574, 1512, 1454, 1420, 1389, 1254, 1231, 1134, 1076, 1049, 1034, 854, 841 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.11 [s, 6 H, C(CH3)2], 1.28 [d, J = 7.1 Hz, 6 H, CH(CH 3)2], 2.32 (s, 2 H, CH2), 2.48 (s, 2 H, CH2), 3.45 (s, 2 H, 9-CH2), 3.47 [sept, J = 7.1 Hz, 1 H, CH(CH3)2], 3.76 (s, 3 H, CH3O), 3.83 (s, 3 H, CH3O), 6.36 (s, 1 H, 5-H). ¹³C NMR (100 MHz, CDCl3): δ = 21.2 [CH(CH3)2], 21.4 (CH2), 25.1 [CH(CH3)2], 28.5 (2 × CH3), 32.2 (C), 41.7 (CH2), 50.8 (CH2), 55.8 (4-CH3O), 61.8 (2-CH3O), 106.5 (8-CH), 108.3 (C), 119.0 (C), 128.0 (C), 137.7 (C), 146.6 (C), 155.0 (C), 164.9 (C), 198.1 (C=O). Anal. Calcd for C20H26O4 (330.42): C, 72.70; H, 7.93. Found: C, 72.79; H, 7.87.
6-(1 H -1,2,3-Benzotriazol-1-ylmethyl)-3-isopropyl-2,4-dimethoxyphenol (6): A mixture of benzotriazole (0.08 g, 0.67 mmol) and 3 (0.25 g, 0.6 mmol) in DMF (2 mL) was heated at 170 ˚C for 1 h under solvent-free conditions. The reaction mixture was diluted with EtOH (1 mL). The formed precipitate was filtered, washed with H2O and recrystallized from EtOH. Yield: 0.16 g (79%); colorless crystals; mp 178-179 ˚C. IR (KBr): 3300-3100 (OH), 2986, 2957, 2932, 2874, 2837, 1487, 1454, 1423, 1344, 1180, 1130, 1096, 1059, 1005, 750 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.31 [d, J = 7.1 Hz, 6 H, CH(CH 3)2], 3.31 [sept, J = 7.1 Hz, 1 H, CH(CH3)2], 3.63 (s, 3 H, CH3O), 3.74 (s, 3 H, CH3O), 5.80 (br s, 1 H, OH), 5.83 (s, 2 H, CH2), 6.51 (s, 1 H, 5-H), 7.33, 7.43 (t, J = 8.2 Hz, 2 H, 5′-H, 6′-H), 7.68, 8.03 (t, J = 8.2 Hz, 2 H, 4′-H, 7′H). ¹³C NMR (100 MHz, CDCl3): δ = 20.9 [CH(CH3)2], 26.1 [CH(CH3)2], 46.2 (CH2), 55.8 (4-CH3O), 62.1 (2-CH3O), 108.2 (CH), 110.4 (CH), 118.1 (C), 119.9 (CH), 123.9 (CH), 127.2 (CH), 130.3 (C), 133.0 (C), 141.0 (C), 145.4 (C), 146.1 (C), 152.8 (4-C). Anal. Calcd for C18H21N3O3 (327.38): C, 66.04; H, 6.47; N, 12.84. Found: C, 65.96; H, 6.52; N, 12.90.

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According to mass spectrometric data.

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3-Isopropyl-2,4-dimethoxy-6-methylphenol(espintanol) (7): A mixture of 3 (0.96 g, 2.37 mmol) and sodium cyanoborohydride (0.90 g, 14.29 mmol) in i-BuOH (10 mL) was stirred at reflux under argon atmosphere for 4 h. The cooled reaction mixture was quenched with 2 N HCl (10 mL), poured into H2O (20 mL) and extracted with CH2Cl2 (3 × 10 mL). The organic layer was separated, washed with sat. NaHCO3 (10 mL), H2O (5 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (15 g) eluting with CCl4. Yield: 0.45 g (91%); colorless oil. IR (KBr): 3500-3350 (OH), 2988, 2955, 2938, 2874, 2835, 1489, 1458, 1416, 1358, 1211, 1188, 1130, 1067, 1009, 833 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.32 [d, J = 7.1 Hz, 6 H, CH(CH 3)2], 2.23 (s, 3 H, CH3), 3.32 [sept, J = 7.1 Hz, 1 H, CH(CH3)2], 3.74 (s, 3 H, CH3O), 3.75 (s, 3 H, CH3O), 5.43 (br s, 1 H, OH), 6.45 (s, 1 H, 5-H). ¹³C NMR (100 MHz, CDCl3): δ = 15.8 (CH3), 21.3 [CH(CH3)2], 25.9 [CH(CH3)2], 55.9 (4-CH3O), 61.9 (2-CH3O), 110.1 (5-C), 121.4 (3-C), 126.9 (6-C), 141.2 (1-C), 144.9 (2-C), 152.1 (4-C). MS (70 eV): m/z (%) = 210 (66) [M]+, 195 (100) [M - CH3]+, 180 (28) [M - 2 × CH3]+, 147 (11), 139 (17), 91 (13) [C7H7]+. Anal. Calcd for C12H18O3 (210.27): C, 68.54; H, 8.63. Found: C, 68.60; H, 8.57.

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4′,6′,7-Triisopropyl-3′,4a′,5′,6,7′,8-hexamethoxy-3,4,9′,9a′-tetrahydrospiro[chromene-2,1′-xanthen]-2′(4a′ H )-one [(±)-Schefflone] (1): To a solution of espintanol (7; 69 mg, 0.33 mmol) in anhyd CHCl3 (2 mL), silver oxide (125 mg, 0.54 mmol) was added and the mixture was stirred at reflux for 2 h. The solution was filtered and evaporated under vacuum. Recrystallization of the residue from MeOH yielded the pure product. Yield: 52 mg (76%); colorless crystals; mp 215-217 ˚C. IR (KBr): 2994, 2959, 2932, 2872, 2839, 1695 (C=O), 1618, 1481, 1456, 1423, 1341, 1273, 1240, 1130 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.09 (d, J = 7.1 Hz, 3 H, CH3), 1.27-1.33 (m, 15 H, 5 × CH3), 2.12 (ddd, J = 14.2, 11.0, 5.0 Hz, 1 H), 2.51 (ddd, J = 16.0, 10.6, 5.6 Hz, 1 H), 2.55 (dd, J = 16.0, 12.4 Hz, 1 H), 2.69 (ddd, J = 16.5, 5.0, 4.6 Hz, 1 H), 2.77 (ddd, J = 14.2, 10.1, 5.0 Hz, 1 H), 2.90 (dd, J = 12.4, 5.0 Hz, 1 H), 3.04 [sept, J = 7.1 Hz, 1 H, CH(CH3)2], 3.25 (dd, J = 16.0, 5.0 Hz, 1 H), 3.40 (s, 3 H, CH3O), 3.47 [sept, J = 7.1 Hz, 1 H, CH(CH3)2], 3.53 [sept, J = 7.1 Hz, 1 H, CH(CH3)2], 3.67 (s, 3 H, CH3O), 3.72 (s, 6 H, 2 × CH3O), 3.87 (s, 3 H, CH3O), 3.92 (s, 3 H, CH3O), 6.28 (s, 1 H, ArH), 6.33 (s, 1 H, ArH). ¹³C NMR (100 MHz, CDCl3): δ = 20.4 (CH3), 21.3 (CH3), 21.4 (3 × CH3), 21.5 (CH3), 22.0 (CH2), 25.2 (2 × CH), 26.1 (CH2), 27.6 (CH), 28.8 (CH2), 43.3 (CH), 49.6 (CH3O), 56.0 (2 × CH3O), 59.0 (CH3O), 61.2 (CH3O), 61.4 (CH3O), 81.2 (C), 102.4 (C), 105.9 (CH), 106.6 (CH), 118.4 (C), 121.1 (C), 128.9 (C), 129.0 (C), 140.6 (C), 141.2 (C), 146.4 (C), 146.4 (C), 148.1 (C), 148.6 (C), 151.9 (C), 152.9 (C), 194.1 (C=O). MS (70 eV): m/z (%) = 624 (<1) [M]+, 593 (3) [M - CH3O]+, 416 (21) [C24H32O6]+, 208 (48) [C12H16O3]+, 193 (62) [C12H16O3 - CH3]+, 178 (32) [C12H16O3 - 2 × CH3]+, 165 (54) [C12H16O3 - C3H7]+, 136 (60), 43 (100) [C3H7]+. Anal. Calcd for C36H48O9 (624.76): C, 69.21; H, 7.74. Found: C, 69.17; H, 7.79.