A New Palladium Precatalyst Allows for the Fast Suzuki−Miyaura Coupling Reactions of Unstable Polyfluorophenyl and 2-Heteroaryl Boronic Acids

Abstract

Boronic acids which quickly deboronate under basic conditions, such as polyfluorophenylboronic acid and five-membered 2-heteroaromatic boronic acids, are especially challenging coupling partners for Suzuki-Miyaura reactions. Nevertheless, being able to use these substrates is highly desirable for a number of applications. Having found that monodentate biarylphosphine ligands can promote these coupling processes, we developed a precatalyst that forms the catalytically active species under conditions where boronic acid decomposition is slow. With this precatalyst, Suzuki-Miyaura reactions of a wide range of (hetero)aryl chlorides, bromides, and triflates with polyfluorophenyl, 2-furan, 2-thiophene and 2-pyrroleboronic acids and their analogs proceed at room temperature or 40 °C in short reaction times to give the desired products in excellent yields.The Suzuki-Miyaura cross-coupling (SMC) reaction is arguably the most important and widely used method for the construction of sp 2 -sp 2 carbon-carbon bonds.1 However, since SMCs are typically performed at elevated temperatures and require several hours reaction time, the scope of usable boronic acids is limited to those that do not significantly decompose under standard conditions. Consequently, the SMCs of quickly deboronating2 2,6-difluorophenylboronic acid (1) and analog 2 as well as the SMCs of five-membered 2-heterocyclic boronic acids 3-8 (Chart 1) are problematic.3 , 4 , 5 , 6 Being able to couple these boronic acids with functionalized aryl and heteroaryl substrates would be of great interest for the synthesis of pharmaceutical and agrochemical candidates, natural products, and materials.One viable solution to this problem is the masking of the boronic acids as MIDA boronates, 7 cyclic triolborates,8 or trifluoroborate salts9 , 10 which slowly hydrolyze11 to the free boronic acid under the reaction conditions. The ratio of the concentration of catalyst and the boronic acid is relatively high and, as a result, transmetalation is favored over protodeboronation. Nevertheless, these surrogates are typically prepared from the free boronic acids, and often, high palladium loadings and/or long reaction times are required for Herein, we report the fast and efficient SMC of the free boronic acids 1-8 at room temperature or 40 °C in short reaction times of 30 minutes to 2 hours. Key to the success was the development of a new precatalyst that generates the catalytically active LPd(0) species quickly under mild conditions under which the deboronation of the boronic acid is significantly slowed down.In the course of mechanistic investigations, we prepared complex SPhosPdPhCl (9) that results from oxidative addition of SPhosPd(0) with chlorobenzene,14 and treated it with 1 in the presence of aqueous K 3 PO 4 (Scheme 1). Rapid formation of product 10 demonstrated that transmetalation and reductive elimination occur with 1 at room temperature.15Using 2 mol% of 9 as precatalyst, 4-chloroanisole was coupled with 1 to give the desired product in 93% yield in less than ...

Protodeboronation of Heteroaromatic, Vinyl, and Cyclopropyl Boronic Acids: pH–Rate Profiles, Autocatalysis, and Disproportionation

“…In 2010 Buchwald used calorimetry to measure protodeboronation kinetics of a series of substituted 2,6-difluorophenyl boronic acids in a biphasic basic aqueous medium (aq K3PO4/THF).12 Perrin extended this study, including other electronegative 2,6-disubstituents, Cl, Br, and CF3,17k which led to the proposal of a new, i.e., non-Kuivila type, mechanism involving specificbasemediated protolysis (k3) of the boronate anion ([ArB-(OH)3]−). The process was reported to only occur with boronic acids bearing a substituent at both ortho-positions (i.e., 2,6-disubstitution).17k Despite the core role of heteroaromatic boronic acids in synthesis and discovery, and the propensity for many to undergo protodeboronation, during storage17i and in coupling, 8,12 there is a near-complete absence of the kinetic data requisite for their behavior to be compared and contrasted. Thus, while it is known empirically, or anecdotally, that certain heteroaromatic boronic acids are much more prone to protodeboronation than others, 1,8,11b it is not clear whether overall they behave similarly to substituted phenylboronic acids, i.e., displaying the simple acid-and base-catalyzed pH relationships (k1, k2) identified by Kuivila, or whether there are more complex pH dependencies for some classes of heteroaromatic boronic acids, for example involving heterocycle basicity, or other pathways, such as the specific-base-mediated protolysis (k3) identified by Perrin.17k Indeed, it is not even clear for an individual class of heteroaromatic boronic acid whether extremes of pH (low or high) are to be avoided, or are beneficial, in terms of stability.…”

Ice Flow of the Antarctic Ice Sheet

“…which are unstable in many reactions (42)(43)(44)(45), also underwent this process to form the corresponding product from trans-hydroheteroarylation of diphenylacetylene. Reaction of a heteroaryl boronic acid with an internal alkyne possessing alkyl substituents also formed the product of hydroheteroarylation.…”

Synthesis of [1,2-a]-fused tricyclic dihydroquinolines by palladium-catalyzed intramolecular C–N cross-coupling of polarized heterocyclic enamines

“…4), introduced by Buchwald's group. 43 Three molar per cents of this precatalyst in the presence of common base (Cs2CO3) in tBuOH at 80 °C provided quantitative conversion of 9b to 11b in 7 h ( All the palladium sources, ligands and bases used in the cross-couplings were commercial (Aldrich, Acros, Strem) and stored under argon in a desiccator. Dry solvents were used commercial (Aldrich, Acros) and stored under argon using Sure/Seal™ or AcroSeal™ technology.…”