The present invention relates to improved methods for preparing aryl ethers which are useful intermediates and end products in pharmaceutical and agricultural applications.
It has been recently reported that aryl bromides react with simple primary and secondary amines in the presence of a palladium catalyst, supporting ligands and Na(OtBu) (base) to form the corresponding arylamine in good yields. See, Guram et al. Angew. Chem. 34(12):1348 (1995).
Despite the recent successes with palladium-catalyzed cross-coupling reactions of Ar--X (X=Br) with amines, comparable coupling of aryl halides with alcohols remains elusive, and this in spite of its obvious utility in organic synthesis. Aryl ethers, including oxygen heterocycles, are prominent in a large number of pharmacologically important molecules and are found in numerous secondary metabolites.
Existing methods for the conversion of Ar--X to aryl ethers often require harsh or restrictive reaction conditions and/or the presence of activating groups on the arene ring. For example, the Cu(I)-catalyzed syntheses of aryl and vinyl ethers commonly require large amounts of freshly prepared sodium alkoxides and/or large excess of the corresponding alcohol in order to achieve reasonable yields from the corresponding aryl halides and vinyl halides. See, Keegstra et al. Tetrahedron 48(17):3633 (1992).
Cramer and Coulson also reported limited success with the Ni(II)-catalyzed synthesis of diphenyl ether using sodium phenolate at reaction temperatures greater than 200.degree. C. See, J. Org. Chem. 40(16):2267 (1975). Christau and Desmurs describe the nickel-catalyzed reactions of alcohols with aryl bromides in the presence of a base. Good yields (ca. 80%) were reported only for reactions with primary alcohols with 7 mol % nickel catalyst at 125.degree. C . Ind. Chem Libr. 7:240 (1995). Christau and Desmurs also reported that synthesis of aryl ethers was possible only for primary and secondary alcohols. Houghton and Voyle reported the Rh(IIl)-catalyzed cyclization of 3-(2-fluorophenyl)propanols to chromans activated by .pi.-bonding to the metal center; however, the reaction required very high rhodium catalyst loading (17 mol %). See, J. Chem. Soc. Perkin Trans. I, 925 (1984).
Ether formation has been reported as a minor side product in the palladium-catalyzed carbonylation reactions of highly activated aromatic compound such as .alpha.-substituted quinolines. Because of the highly reactive nature of the .alpha.-site, it is possible that the reaction proceeds by direct nucleophilic substitution, without promotion or catalysis by the palladium metal center. See, Cacchi et al. Tet. Lett. 27(33):3931 (1986).
Thus there remains a need for an effective method of preparing a wide range of aryl ethers under mild conditions and in high yields. There is a further need for an efficient catalytic system with high efficiencies and turnover number for the synthesis of aryl ethers. In addition, there still remains a need for an effective method for the arylation of tertiary alkoxides.
USPTO Backgrounds
USPTO Backgrounds