Diaryl Ether and Diaryl Thioether Syntheses on Solid Supports via Copper (I)-Mediated Coupling

Abstract

An efficient method to synthesize diaryl ethers and thioethers on solid supports is described. Starting from immobilized phenols or arylhalides, coupling with an access of aryliodides/arylbromides or phenolic/thiophenolic substrates in solution was successful in the presence of CuCl and Cs(2)CO(3) as base. Coupling conditions known from solution-phase syntheses of diaryl ethers have been effectively modified and adapted to solid-phase synthesis. Optimized conditions enabled the coupling of sterically hindered and/or electronically deactivated aryl moieties. After coupling, a newly developed diversity-generating linker based on cinnamic acid allowed the diaryl ethers to be cleaved from the resin either via saponification/transesterification or via ozonolysis. Latter offers the possibility of generating several additional compounds by simple variation of the cleavage conditions. The target substances were generally isolated in good to excellent yields and high purities.

Synthesis of Natural Products on Solid Phases via Copper‐Mediated Coupling: Synthesis of the Aristogin Family, Spiraformin A, and Hernandial

“…[74] Moreover, in subsequent studies on non-triazene-linked aromatic systems, the copper-catalyzed transformations of halogenated phenyls as well as those with arylboronic acids were of special interest. [75] We found that phenols can be converted into diaryl ethers in excellent yields when reacted with solid-supported halogenated aryls, [76] under conditions similar to the syntheses first published by Song et al (Scheme 1). [77][78][79] Scheme 1.…”

“…Scheme 3 summarizes the previously published synthesis of the brominelinker and the subsequent attachment of carboxylic acids to give resin-bound esters. [76] Scheme 3. Linker syntheses and immobilization of the first aryl moiety.…”

“…The synthesis of Hernandial (5) was performed on resin 21b through coupling with 2-bromo-4,5-dimethoxybenzaldehyde under conditions pre-viously described by our group (Scheme 4). [76] The chosen linkage via a cinnamic ester yields resin-bound Hernandial precursor 25, which can be cleaved from the solid support by ozonolysis in 20 s. …”

Translation of microwave methodology to continuous flow for the efficient synthesis of diaryl ethers via a base-mediated SNAr reaction

“…1). Installation of the diaryl ether can, however, be synthetically challenging, and this is illustrated by the wide number of techniques developed, which include Ullmann ether synthesis [6], Pummerer-type rearrangements [7], Buchwald–Hartwig couplings [8], phenolic additions to amines [9], fluoride mediated couplings [10–11], and the use of solid supports [12]. …”

Comprehensive Survey of Chemical Libraries for Drug Discovery and Chemical Biology: 2008

“…In an effort to identify novel inhibitors of Bcl-2, scientists at Infinity Pharmaceuticals designed and prepared a 15,000-member pyridone library (Figure 9a/b), via discovery oriented synthesis (DOS). 182 The design of this library was based on the structure of the nicotinic agonist (−)-cytisine (130) and previous work describing the total synthesis of this natural product. In particular, the pyridone cyclization step, key transformation for the total synthesis of (−)-cytisine, was exploited for the diversity oriented synthesis of heterocycles 131a and 132a as well as their corresponding enantiomers 131b and 132b, respectively.…”