Palladium-Catalyzed Allylation of 2-Hydroxy-1,4-naphthoquinone: ­Application to the Preparation of Lapachol

Abstract

The Pd(PPh₃)₄-catalyzed reaction of 2-hydroxy-1,4-naphthoquinone (lawsone) with allyl alcohols and allyl esters offers an easy access to 3-allyl-2-hydroxy-1,4-naphthoquinones, compounds with interesting biological activity. The reaction finds application in the preparation of lapachol. Other 2-hydroxy-1,4-benzoquinones give allylation products in low yields.

Keywords

allylation - lawsone - palladium-catalyzed - lapachol

References and Notes

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General Procedure for the Allylation Reaction of Lawsone under Neat Conditions.
A mixture of lawsone (157 mg, 0.9 mmol), Pd(Ph₃P)₄ (50 mg, 0.045 mmol), AcOH (6 mg, 0.09 mmol, ca. 2 drops) and the proper allylating agent (alcohol or ester, 1.5 mmol) was thoroughly mixed and was put in an oven preheated at 100 °C. After 35 min the gummy material was subjected to column chromatography (silica gel, hexane-EtOAc, 5:1) to afford the allyl derivatives 8a-e.
Representative Data for Allylation Products. 2-Hydroxy-3-(3-phenylallyl)-1,4-naphthoquinone (8b): mp 168-170 °C (lit. [18] 170 °C). IR (KBr): ν = 3289, 1671, 1641 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 8.14 (1 H, d, J = 7.3 Hz), 8.09 (1 H, d, J = 7.3 Hz), 7.77 (1 H, t, J = 7.3 Hz), 7.69 (1 H, t, J = 7.3 Hz), 7.41 (1 H, s, OH), 7.35-7.17 (5 H, m), 6.57 (1 H, d, J = 15.9 Hz), 6.30 (1 H, dt, J ₁ = 15.9 Hz, J ₂ = 7.5 Hz), 3.52 (2 H, d, J = 7.5 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 184.3, 181.5, 153.1, 137.3, 135.0, 133.0, 132.0, 129.4, 128.4, 127.2, 126.9, 126.1, 125.4, 26.7. MS (EI): m/z (%) = 290 (94) [M⁺], 199 (81), 91 (100). Anal. Calcd for C₁₉H₁₄O₃: C, 78.61; H, 4.86. Found: C, 78.42; H, 4.89.

15

Preparation of Lapachol ( 4). A mixture of lawsone (6, 157 mg, 0.9 mmol), Pd(Ph₃P)₄ (50 mg, 0.045 mmol), 1-AdCOOH (16 mg, 0.09 mmol) and 3-methyl-2-buten-1-ol (7i, 4 mL) was refluxed for 1 h. After removal of excess butenol in vacuum, the residue was subjected to column chromatography (silica gel, hexane-EtOAc, 5:1) to afford lapachol(4) in 43% yield; mp 137-139 °C (lit. [16] 139-140 °C) and ¹H NMR data identical to those reported in the literature. [16]