Diaryl ether condensation reactions

Abstract

One aspect of the present invention relates to novel reaction conditions that allow the efficient synthesis of diaryl ethers from arenes bearing a leaving group and arenols under relatively mild conditions. Another aspect of the present invention relates to the dramatic effects of acidic activators on Ullmann-type couplings involving electron-poor and / or relatively insoluble substrates.

Description

BACKGROUND OF THE INVENTION The formation of diaryl ethers from arenols and aryl groups bearing a leaving group generally requires activated substrates. For aryloxide nucleophiles, the reaction is promoted by copper salts. For instance, Ullman (Ber. 37:853) observed in 1904 that the presence of metallic copper greatly facilitates the substitution of a halogen atom on an aromatic ring with a phenolic oxygen. This method for the synthesis of diaryl ethers, referred to in the contemporary art as the “Ullmann reaction” or “Ullmann condensation”, has become widely used in both academic and industrial chemistry. For a review, see Moroz et al. (1974) Russ. Chem. Rev. 43:679. The Ullmann reaction is typically carried out by heating the reactants at elevated temperatures, e.g., 150-300° C., in the presence of a copper salt, which in some cases is present in only a catalytic amount; Ullmann reactions are usually conducted in a solvent, however, in certain cases a solvent is not utilized (th...

AI Technical Summary

Benefits of technology

One aspect of the present invention relates to novel reaction conditions that allow the efficient synthesis of diaryl ethers from arenes bearing a leaving group and arenols under relatively mild conditions. Another aspect of the present invention relates to the discovery of the dramatic effects of aryl carboxylic acid additives on copper-catalyzed Ullmann-type couplings.

Problems solved by technology

The conditions used for the copper-mediated coupling of aryl halides and phenols according to the Ullmann reaction are usually harsh, requiring high temperatures and high-boiling, polar solvents (pyridine, collidine, DMF).

The yields of the reaction are substrate dependent and are usually low for transformations involving highly functionalized substrates.

Indeed, in the synthesis of pharmaceutical agents, many of the desirable substituents on the substrate aryl moieties may not be sufficiently stable, even when protected, for use in the Ullmann reaction of the prior art.

For instance, esters and anhydrides are not stable under the classical Ullmann reaction conditions.

Likewise, the conditions of the classical Ullmann reaction may be too harsh for use in a combinatorial approach to the synthesis of libraries of diaryl ethers and the like, particularly where labile groups are employed, for example, as linker groups or encoding tags (see: Ohlmeyer et al.

Another problem with the classical Ullmann reaction is that many of the solvents that are characteristically relied upon are extremely hazardous.

Disposal of reaction by-products, e.g., spent solvent, may accordingly pose significant obstacles, in terms of environmental safety and / or ultimate product cost, to reliance on the classical Ullmann reaction.

Recent efforts to develop Ullmann-type procedures which are applicable to more complex synthetic intermediates have met with only limited success (Evans et al.

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