An Efficient Two-Step Protocol for the Isoprenylation of Xanthone at the C2 Position Starting from 1-Fluoroxanthone Derivative

Abstract

The S_NAr reaction of 1-fluoroxanthone derivatives with alkoxide of 1,1-dimethylallyl alcohol cleanly afforded the corresponding ethers, which have thus far been unavailable. The obtained ethers underwent the Claisen rearrangement at room temperature by treatment with silica gel in toluene. This two-step protocol provides expeditious and high-yield access to xanthones possessing isoprenyl or the related allylic side chain at the C2 position.

Key words

xanthone - isoprenylation - S_NAr reaction - Claisen rearrangement

• References and Notes


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• 11 Wang et al. pointed out the propargylation/half-reduction sequence was not capable of 1,1-dimethylallylation of C1-hydroxy group of xanthone derivative, see: Xu D, Nie Y, Liang X, Ji L, Hu S, You Q, Wang F, Ye H, Wang J. Nat. Prod. Commun. 2013; 8: 1101
• 12 In fact, our attempts to apply the Tsuji–Trost allylation to 1-hydroxyxanthone (4a) under various conditions with tert-butyl 1,1-dimethylallyl carbonate resulted in failure, as exemplified by Scheme 6.

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• 14 Silica gel-induced acceleration was also observed in the reactions of 2-(1,1-dimethylallyloxy)xanthone derivatives as illustrated in Scheme 7, which, incidentally, led to the selective isoprenylation at the C1 position. General aspects of the silica gel catalysis in the Claisen rearrangement of xanthone derivatives will be reported in due course.
• 15 Silica gel: Kanto Chemical Co. Inc. (63–210 mesh for chromatography), Florisil: FUJIFILM Wako Pure Chemical, Ltd. (100–200 mesh for chromatography), MS 4Å: FUJIFILM Wako Pure Chemical, Ltd, MS 13X: Kanto Chemical Co. Inc., neutral alumina: MP Biomedicals (Alumina N, Act-I for chromatography), Montmorillonite K10: Sigma-Aldrich Co. LLC.
• 16 Typical Procedure of the S_NAr Reaction/Claisen Rearrangement Sequence for the Synthesis of 5a A flame-dried two-necked round-bottomed flask was charged with NaH (60% dispersion in mineral oil, 160 mg, 4.0 mmol) and DMF (2.0 mL). Then, 1,1-dimethylallyl alcohol 2 (0.63 mL, 6.0 mmol) was added dropwise at 0 °C. After stirring for 30 min at 25 °C, the net concentration of the alkoxide was adjusted to 1.0 M by adding DMF (1.3 mL), ready to use for the S_NAr reactions. This solution of the alkoxide (1.0 M, 0.94 mL, 0.94 mmol) was added dropwise to a solution of fluoroxanthone 1a (100 mg, 468 μmol) in DMF (0.95 mL), and the stirring was continued for 1 h at 25 °C. The reaction was quenched with phosphate buffer (0.1 M, pH 7), and the products were extracted with Et₂O (3×). The combined extracts were washed with water, brine, dried over Na₂SO₄, and concentrated in vacuo. The residue was azeotropically dried with toluene and used for the next step without further purification. Silica gel (100 mg), placed in a two-necked round-bottomed flask, was dried in vacuo by heating it with a heating gun and then suspended in toluene (1.3 mL). To this suspension was added a solution of the above-stated crude material of ether 3a in toluene (1.0 mL) at 0 °C, and the mixture was stirred for 5 h at 25 °C. After removal of silica gel by filtration through a sintered glass filter, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, ­hexane/EtOAc = 9:1) to give xanthone 5a (124 mg, 95%) as yellow solids and a small amount of 1-hydroxyxanthone (4a, 2 mg). Mp 124.5–127.0 °C (yellow needles from hexane/EtOAc). ¹H NMR (400 MHz, CDCl₃): δ = 1.75 (s, 3 H), 1.77 (s, 3 H), 3.39 (d, 2 H, J = 7.2 Hz), 5.34 (br t, 1 H, J = 7.2 Hz), 6.87 (d, 1 H, J = 8.4 Hz), 7.37 (dd, 1 H, J = 8.0, 7.2 Hz), 7.44 (d, 1 H, J = 8.4 Hz), 7.47 (d, 1 H, J = 8.4 Hz), 7.72 (ddd, 1 H, J = 8.4, 7.2, 1.6 Hz), 8.27 (dd, 1 H, J = 8.0, 1.6 Hz), 12.91 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 17.8, 25.8, 26.9, 106.2, 108.5, 117.8, 120.5, 121.7, 122.9, 123.8, 126.0, 133.4, 135.4, 136.8, 154.5, 156.2, 159.0, 182.5. IR (ATR): 2962, 2902, 1607, 1574, 1472, 1458, 1440, 1424, 1374, 1306, 1277, 1237, 1220, 1202, 1154, 1119, 1056, 998, 918, 876, 851, 809, 790, 779, 753, 666, 636, 606, 576, 524, 481, 454, 426 cm^–1. HRMS (ESI-TOF): m/z calcd for C₁₈H₁₆O₃Na [M + Na]⁺: 303.0997; found: 303.0996. Anal. Calcd for C₁₈H₁₆O₃: C, 77.12; H, 5.75. Found: C, 77.11; H, 5.71.
• 17 See the Supporting Information for HOMOs of 3b and 3c, obtained by theoretical calculations (HF/6-311G(d,p)//B3LYP/6-31G (d)).
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• 19 DFT calculations performed at B3LYP/6-31G(d,p) level of theory suggested that the reaction of 3m is energetically more preferable than the reaction of 3l in 3.8 kcal/mol (ΔΔG ^‡). For details including the optimized TS structures and energies, see the Supporting Information.