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The demand for molecules of increasing complexity creates a strong need for new chemical tools. In particular, the synthesis of polyarene molecules bearing multiple substituents is challenging as no direct methods allow for the selectively introduction of non-identical substituents. In this respect, chemoselective reactions play a crucial role as they represent a straightforward method, suppressing the need for unnecessary additional synthetic steps and thus lowering the formation of possible by-products. In this light, the site-selective cross coupling reaction of di- and tri-halogenated arenes to form complex molecular scaffolds recently attract the attention of several research groups and novel selective methods were developed.
Despite remarkable advances, some of the most commonly used coupling reactions still suffer from a lack of selective methods in this area. In the past decade, various chemoselective strategies were developed based on the use of non-covalent interactions. In these strategies, non-covalent supramolecular interactions between the substrate and the catalyst are introduced to stir the selectively of the reaction by influencing one or more determining steps in the reaction mechanism. In a recent article published in JACS, Phipps and coworkers (DOI: 10.1021/jacs.0c11056) report a new site-selective method for cross coupling reactions using a catalytic toolkit made of two ligands (sulfonated SPhos and XPhos) and a series of bases with different cations of increasing size (Li, Na, K, Rb, Cs). The method was successfully applied to the Suzuki-Miyaura coupling and the Buchwald-Hartwig reaction, providing a direct and highly selective method for the synthesis of multi-substituted arene molecules.
Initial studies for the Suzuki-Miyaura reaction and preparation on scale
During initial studies, the authors evaluated the chemoselectivity observed in the Suzuki-Miyaura reactions of di-chloroarenes using 0.5 equivalent of boronic acid and a toolkit of two sulfonated ligands and carbonate bases. For the four tested dichlorinated isomer substrates, a high selectivity in favor of the activation of the proximal chloride (2-position) was observed using sSPhos (a 3’-sulfonated Sphos ligand) and a base with a large cation (Rb2CO3 or Cs2CO3) for the 2,3- and 2,5 substrates. For the 2,4-dichlorinated substrate, sXphos (a 4’-sulphonated Xphos ligand) performed with higher selectivity. For all tested substrates, control experiments using Sphos or Xphos as ligand showed no selectivity, confirming that there is no particular bias under the applied reactions conditions toward one specific isomer.
Interestingly, upon applying the new method on preparative scale using 1.5 equivalents of boronic acid, only small amounts of dicoupled products were observed and moderate to high yields of the monocoupled products were obtained (between 20%-80%), indicating a strong control over the formation of the dicoupled by-product. Also, two aryl- and heteroarylboronic acids were successfully used on scale in high yields.
Applying the method to the Buchwald-Hartwig coupling
The novel site-selective method was then applied to the Buchwald-Hartwig coupling. In this case, the reaction conditions needed to be adapted (temperature, solvent) but the use of a similar ligand/cation combination as for the Suzuki-Miyaura coupling also resulted in a very high site-selectivity for the coupling of 2,5-dichloro substrates to the corresponding meta-substituted aniline. However, low conversions were observed for the 2,3-dichloroarenes and 2,4-dichloroarenes, even upon complete screening of the toolkit. For the reaction of the 2,4-dichlorinated isomer, it was discovered that switching to a phosphate base was crucial for promoting the reactivity with this substrate and acceptable conversions were obtained using K3PO4 as base. Three different aniline substrates could be successfully coupled on the ortho-position with high isomeric purity (>20:1) and in high yields.
Successful application of the method to trichlorinated substrates
Next, the ligand/base toolkit approach was tested in the site-selective cross-coupling of trichlorinated isomers. This reaction represents a real challenge as non-selective standard protocols would only generate highly complex mixtures of products. For the 2,3,4-trichlorinated substrate, the ligand/cation combination that was effective for the coupling of the 2,4-dichlorinated substrate gave similar results, resulting in a selective coupling on the ortho-position. For this substrate, several boronic acids could efficiently be used to give similar selectivity, showing the robustness of the method. In a similar approach, the chemoselective method was applied to a 2,4,5-trichlorinated substrate using the optimal conditions used for the Suzuki-Miyraura coupling used for the 2,5 dichlorinated substrate, also providing the monocoupled product in meta-position with very high selectivity (also using three different boronic acids). For the 2,3,5-trichlorinated isomer, the full toolkit was screened, which also resulted in the successful selective synthesis of the meta-coupled product using sSphos and large metal cations. Importantly for all the tested trichlorinated substrates, control experiments using Sphos or Xphos confirmed the directional effect of the sulfonated ligand and cation.
Interestingly, a sequential synthetic method was explored by performing consecutive selective couplings starting from a trichlorinated substrate. By means of two successive site-selective coupling reactions and a standard Suzuki coupling method, the trichlorinated substrate could be converted into a single regioisomer bearing three different arene substituents (see scheme below). The same sequential coupling method was applied to a 2,3,4,5-tetrachlorinated isomer resulting in a successful selective disubstitution on the ortho-and meta-position. However, in this case the Cl3- and Cl4 positions could not react further, probably due to geometrical and steric reasons, showing the limitations of the method. Finally, the authors explore the possibility to introduce the directing sulfonate group directly in the substrate itself, which results also in high selectivity.
This new method for the site-selective coupling reaction highlights that fine-tuning of electrostatic interactions can lead to a very precise control of the selectivity. In this method, the sulfonated group on the ligand has a crucial role, interacting indirectly with the substrate via the cation to stir the selectivity of the reaction. In this new synthetic method, the chloride at the meta-position reacts first followed by the reaction at the ortho-position after which the para-position can be functionalized using a standard catalyst. The author observed that less reactive are the para-position and the meta-position, when blocked by a substituent in ortho-position, and this for geometrical reasons. This paper shows that the fine-tuning of electrostatic interactions can be used as a new tool to reach precise selectivity with high control for the synthesis of complex polyarene molecules.
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Article: “Systematic Variation of Ligand and Cation Parameters Enables Site-Selective C−C and C−N Cross-Coupling of Multiply Chlorinated Arenes through Substrate−Ligand Electrostatic Interactions”
By: William A. Golding, Hendrik L. Schmitt, and Robert J. Phipps
J. Am. Chem. Soc. 2020, 142, 21891−21898