Phase-Transfer Catalysts in the O-Alkylation of 2-Hydroxynaphthoquinones

Abstract

A mild procedure has been developed for the O-alkylation of 2-hydroxynaphthoquinones by using phase-transfer catalysts. Optimal yields were obtained when 18-crown-6 (10 mol%) and tetrabutylammonium iodide (10 mol% ) were used as cocatalysts in refluxing tetrahydrofuran containing potassium carbonate. Variability in the product yields (0-82%) was attributed to differences in the reactivity of the alkylating agent and to resonance stabilization of the 2-hydroxynaphthoquinone anion. Comparisons of the UV-visible spectra suggest that the degree of electron delocalization has a marked effect on the outcome of the reaction. Quinoid π-electrons were more delocalized in the absence of a stabilizing counteraction, resulting in lower yields. In the presence of tetrabutylammonium iodide, reduced levels of electron delocalization were detected, possibly as a result of ion pairing between the tetrabutylammonium cation and the C-2 oxygen anion. Enhanced reactivity correlates to a lower level of delocalization, and a combination of both catalysts is necessary to facilitate the O-alkylation.Natural and synthetic 1,4-naphthoquinones 1 are important modulators of cellular function, serving as agonists or antagonists of various biological processes, depending on the type of cell. Natural phylloquinones (for example, vitamin K 1 ) and menaquinones (for example, vitamin K 2 ) are redox-active catalysts that participate in the enzymatic conversion of glutamate into γ-carboxyglutamate in mammalian blood clotting. 2 Bacterial menaquinones are cofactors that undergo redox cycling in facilitating the biosynthesis of ATP under anaerobic conditions. 3 Many synthetic 1,4-naphthoquinones are important antioxidants, ubiquinone antagonists, or competitive inhibitors of DNA topoisomerases. Potential clinical applications of this heterogeneous class of compounds include the treatment of cardiovascular diseases, 4 skeletal diseases, 5 inflammation, 6 cancer, 7 or microbial infections. 8The 2-hydroxynaphthoquinones are a prominent family of biologically active quinones, 9 among which the antiparasitic agent atovaquone 10 is the most established in medicinal use. Alkoxy analogues of 2-hydroxynaphthoquinones are also being studied for a variety of potential applications. 11 With the exception of procedures that employ an excess of silver(I) oxide, 11b the preparation of 2-alkoxynaphthoquinones by direct S N 2 alkylation of the C-2 hydroxyl group typically produces low yields of the required products. This poor reactivity of the quinones is partly the result of suppression of the nucleophilicity of the oxygen anion as a result of electron delocalization. 12 Further complications are encountered when bases containing mono-or divalent metals are used in the reaction, as 2-hydroxynaphthoquinones are efficient chelators of cationic metals, forming complexes that are highly insoluble in most organic solvents (for example, complex 1; Scheme 1). 13 Scheme 1 O-Alkylation of 2-hydroxy-3-methyl-1,4-naphthoquinone (phthiocol) in the presence and absence of 18...