An Efficient Isoprenylation of Xanthones at the C1 Position by Utilizing Anion-Accelerated Aromatic Oxy-Cope Rearrangement

Dedicated to the departed Prof. Yoshiro Kobayashi

Abstract

An effective method for the installation of isoprenyl moiety at the C1 position of xanthone has been developed. Addition of isoprenyl Grignard reagent to 1-fluoroxanthone derivatives proceeded γ-selectively, and the obtained tertiary alcohols underwent aromatic oxy-Cope rearrangement and subsequent elimination of fluoride anion under mild conditions to give 1-isoprenylxanthones in high yields.

Key words

xanthone - isoprenylation - Grignard reaction - regioselective reaction - oxy-Cope rearrangement

• References and Notes

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• 12 1-Fluoroxanthone (1a) was prepared as shown in Scheme 4.
• 13 For the synthesis of compounds 2b–l, see Supporting Information.
• 14 The structures of 5, 3e, 3h, 3f, 3i, 3k and 2i were unambiguously determined by single-crystal X-ray analysis; CCDC 1010397 (5), 1010398 (3e), 1010399 (3h), 1010400 (3f), 1010401 (3i), 1010402 (3k) and 1410050 (2i).
• 15 We speculate the intermediacy of 15, generated via the photoenolization of 3a into 14 followed by the action of KHMDS. Studies to obtain mechanistic insights into the formation of by-products are undergoing (Figure 3).

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• 17 Typical Procedure for the Reaction of 2a: To a solution of 2a (285 mg, 1.00 mmol) in THF (10 mL) in a two-necked brown-glass flask was added KHMDS (0.5 M solution in toluene, 4.4 mL, 2.2 mmol) followed by a solution of 18-crown-6 (795 mg, 3.01 mmol) in THF (10 mL) at –78 °C. After carefully purging air with argon (3 ×), the reaction mixture was quickly warmed to 0 °C by replacing the dry ice/acetone bath with the ice-cold water bath, and the stirring was continued for 5 min. The reaction was quenched with sat. aq NH₄Cl solution, and the products were extracted with EtOAc (3 ×). The combined organic extracts were washed with brine and dried over Na₂SO₄. Removal of the solvents in vacuo and purification by column chromatography (silica gel, hexane–EtOAc, 20:1) gave 3a (225 mg, 85%) as a colorless oil and 4a (25 mg, 9%) as a colorless oil.
• 18 The reaction of alcohol 16 gave 17 (88%) and 18 (7%; Scheme 5).
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• 20 Experimental and computational studies to elucidate the reaction mechanism are in progress and will be reported elsewhere. Preliminary results show the rearrangement occurs in a concerted manner. Nevertheless, this formalism (depicted as A in Figure 2) is helpful to qualitative discussion on the substituent effect.
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• 23 The reaction of alcohol 19 gave 20 as the major product (Scheme 6).
• 24 The reaction of alcohol 22 gave 23 and 24 in a ratio of 89:11 (Scheme 7).