LETTER
dimethoxyphenol (2; 1 g, 5.1 mmol) and dibenzylamine
Easy Access to ( )-Schefflone and Espintanol
919
(12) (a) Zúñiga, A. C.; Romero-Ortega, M.; Zárraga, J. G. A.
Synthesis 2005, 527. (b) Tomooka, C. S.; Liu, H.; Moore,
H. W. J. Org. Chem. 1996, 61, 6009. (c) Wadsworth, D. J.;
Losch, S. Tetrahedron 1994, 50, 8673. (d) Hocquemiller,
R.; Cortes, D.; Arango, G. J.; Myint, S. H.; Cave, A. J. Nat.
Prod. 1991, 54, 445. (e) Söderberg, B. C.; Fields, S. L. Org.
Prep. Proced. Int. 1996, 28, 221.
(13) 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
(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): d =
1.31 [d, J = 7.1 Hz, 6 H, CH(CH3)2], 3.50 [sept, J = 7.1 Hz,
1 H, CH(CH3)2], 3.62 (s, 4 H, 2 × CH2Ph), 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): d = 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.
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): d = 1.32 [d, J = 7.1 Hz, 6 H, CH(CH3)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): d =
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.
(8) Osyanin, V. A.; Klimochkin, Y. N. Chem. Heterocycl.
Compd. (Engl. Transl.) 2011, 47, 242.
(9) Kowalski, C. J.; Fields, K. W. J. Org. Chem. 1981, 46, 197.
(10) 6-Isopropyl-5,7-dimethoxy-3,3-dimethyl-2,3,4,9-
tetrahydro-1H-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): d = 1.11 [s, 6 H,
C(CH3)2], 1.28 [d, J = 7.1 Hz, 6 H, CH(CH3)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):
d = 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.
(14) Burnell, R. H.; Caron, S. Can. J. Chem. 1992, 70, 1446.
(15) 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):
d = 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): d = 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.
6-(1H-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): d = 1.31
[d, J = 7.1 Hz, 6 H, CH(CH3)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): d = 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.
(11) According to mass spectrometric data.
© Thieme Stuttgart · New York
Synlett 2012, 23, 917–919