Room‐Temperature Suzuki–Miyaura Coupling of Heteroaryl Chlorides and Tosylates

Abstract

Suzuki–Miyaura coupling of heteroaryls is an important method for the preparation of compound libraries for medicinal chemistry and materials research. Although many catalysts have been developed, none of them have been generally applicable to the coupling reactions of heteroaryl chlorides and tosylates at room temperature. We discovered that a catalyst combination of Pd(OAc)2 and XPhos (2‐dicyclohexylphosphanyl‐2′,4′,6′‐triisopropylbiphenyl) could efficiently catalyze these couplings. Besides the choice of catalyst, the use of hydroxide bases in an aqueous alcoholic solvent was essential for fast couplings. These conditions promoted fast release of active catalyst (XPhos)Pd0, and accelerated the transmetalation in the catalytic cycle. Most of the major families of heteroaryl chlorides (31 examples) and tosylates (17 examples) reached full conversion within minutes to hours at room temperature. The method could be easily scaled up for gram‐scale synthesis. Furthermore, we examined the relative reactivity of coupling partners in whole reactions. Electron‐rich heteroaryl chlorides and tosylates reacted more slowly than electron‐deficient ones, in the order of indole, pyrrole < furan, thiophene < pyridine and other six‐membered‐ring azines. For heteroarylboronic acids, the reactivity ranking was reversed: indole, pyrrole > furan, thiophene > pyridine. Similarly, electron‐deficient arylboronic acids were less reactive than electron‐neutral and electron‐rich ones. The reactivity trends from this study can help to choose appropriate coupling partners for Suzuki reactions.

Aziridine- and Azetidine-Pd Catalytic Combinations. Synthesis and Evaluation of the Ligand Ring Size Impact on Suzuki-Miyaura Reaction Issues

“…Catalysts 2017, 7, 27 2 of 9 based scaffolds as well as combinations of pyridines linked to flexible alkylamine arms or rigid cycloalkylamines such as piperidines have been successfully developed in recent years [17][18][19][20][21][22][23]. In this communication, we describe new ligands based on strained aza-heterocycles such as aziridines and azetidines.…”

“…Additionally, preformed and geometrically constrained catalytic systems appears as crucial features beneficial to a catalytic activity enhancement [8,17]. If phosphorus-based catalytic systems dominated this area during the last decades, nitrogen-containing ligands revealed recently useful and appear as a pertinent alternative.…”

“…If phosphorus-based catalytic systems dominated this area during the last decades, nitrogen-containing ligands revealed recently useful and appear as a pertinent alternative. In this context, ligands incorporating pyridyl-based scaffolds as well as combinations of pyridines linked to flexible alkylamine arms or rigid based scaffolds as well as combinations of pyridines linked to flexible alkylamine arms or rigid cycloalkylamines such as piperidines have been successfully developed in recent years [17][18][19][20][21][22][23]. In this communication, we describe new ligands based on strained aza-heterocycles such as aziridines and azetidines.…”

Synthesis of palladated magnetic nanoparticle (Pd@Fe3O4/AMOCAA) as an efficient and heterogeneous catalyst for promoting Suzuki and Sonogashira cross‐coupling reactions

“…In recent years, the reactions involving cross‐coupling carbon–carbon bond formation have drawn widespread interest due to their versatile implications in organic transformation, especially in the total synthesis of natural products, long‐chain organic molecules for organo‐electronic applications and the development of bioactive molecules …”

Einfache und doppelte metall‐ und reagensfreie anodische C‐C‐Kreuzkupplung von Phenolen mit Thiophenen

“…B. in pharmazeutischen Wirkstoffen, [5] Naturstoffen, [6] der Molekularelektronik [7] oder katalytisch aktiven Übergangsmetallkomplexen. [3,5,11,12,13] Diese Methoden weisen trotz hoher Selektivitätw esentliche Nachteile auf.V or der eigentlichen Kupplung ist eine Funktionalisierung von beiden Arylen durch Metallierungs-und/oder Halogenierungsreaktionen über mehrere Synthesestufen mit anspruchsvollen Reaktionsbedingungen notwendig. [3,5,11,12,13] Diese Methoden weisen trotz hoher Selektivitätw esentliche Nachteile auf.V or der eigentlichen Kupplung ist eine Funktionalisierung von beiden Arylen durch Metallierungs-und/oder Halogenierungsreaktionen über mehrere Synthesestufen mit anspruchsvollen Reaktionsbedingungen notwendig.…”