An Efficient Strategy for the Synthesis of Aryl Ethers

Abstract

An efficient strategy for the construction of aryl ethers using aryl fluorides and silyl ethers is described. This protocol uses a sub-stoichiometric amount of silicon-based reagent and proceeds under milder conditions than previously reported reactions of this type.The aryl ether moiety is found in a wide range of bioactive molecules 1,2 and materials. 3 Not surprisingly, efforts toward developing efficient and convenient protocols for the synthesis of aryl ethers has received considerable attention. 4 The Ullmann coupling has been used extensively for aryl ether synthesis, yet suffers from the requirement for high reaction temperatures and excess Cu salt. 5 Efforts to circumvent these limitations have been reported, 6,7 with the first example of a catalytic Ullmann coupling appearing in 1997. 7 Despite this considerable advance, high reaction temperatures were still required. In comparison, Cu-mediated cross couplings of aryl boronic acids can be run at room temperature, but require stoichiometric copper. 8 Pd-catalyzed cross-coupling of aryl bromides with phenoxides and alkoxides was introduced in 1999 independently by Hartwig and Buchwald. 9 These methods still required high temperatures, as well as pre-formation of the alkoxide or aryl oxide. Shortly thereafter, room-temperature coupling was achieved, but a limited substrate scope was described. 10 More recently, S N Ar reactions have been developed as a strategy for diaryl ether formation. For example, activated aryl fluorides have been coupled with aryl alcohols using excess KF·Al 2 O 3 and catalytic 18-crown-6, in refluxing acetonitrile. 11 Addition of phenols to benzynes generated from silylaryl triflates has also been reported. 12 An alternate strategy involves the coupling of silyl-protected aryl alcohols with aryl fluorides. A variety of reagents have been used to promote deprotection of the silyl group, including CsF, 13 TBAF, 14 phosphazenes 15 or proazaphosphatranes. 16 These protocols all use trialkylsilyl-protected aryl alcohols. As such, these reactions produce one equivalent of silicon by-product relative to the amount of aryl ether formed. A more efficient protocol would be to use readily available tetraaryloxysilanes, which would substantially reduce the amount of silicon by-product. In addition, the ability to generate aryl alkyl ethers using tetraalkoxysilanes would increase the generality of the methodology.We report herein that tetraphenoxysilane and tetraalkoxysilanes react readily with aryl fluorides in the presence of TBAF and that a sub-stoichiometric amount of silane, relative to the aryl fluoride, can indeed effect the transformation without compromising reaction outcome. Moreover, the reaction scope is broader and the reaction conditions are milder than those reported for related fluoride-promoted reactions. 13,14 Our study began with 2,4-dinitrofluorobenzene (1a), which was reacted with 0.3 equivalent of tetraphenoxysilane in acetone at 50 °C for 24 hours to generate phenyl ether 2a in 73% isolated yield (Table 1, entry 1). The c...

Selective Palladium-Catalyzed C–F Activation/Carbon–Carbon Bond Formation of Polyfluoroaryl Oxazolines

“…As a result, the activation energy for C–F activation decreased as the number of fluorine increased. The similar phenomena was observed by Crespo and Martinez, Love, , and Sandford . No C–F bond activation was observed for the reaction of monofluorophenyl oxazoline as substrate (Table , entry 14).…”

Palladium-Catalyzed Coupling of Polyfluorinated Arenes with Heteroarenes via C–F/C–H Activation

“…No C–F bond activation was observed for the reaction of 2-(2-fluorophenyl)pyridine as substrate. Several groups have reported that the activation of the C–F bond in less fluorinated arenes were much more difficult than those in pentafluorophenyl substrates. ,, Jones and co-workers reported that the strength of the metal–Ar F bond increases with the increasing of the electronegativity of the aryl group . Consequently, the energy for C–F activation decreased as the number of fluorine increased.…”