A highly active and efficient catalyst system derived from a palladium precatalyst and monophosphine ligands 1 or 2 for the Suzuki-Miyaura cross-coupling reaction of heteroaryl boronic acids and esters has been developed. This method allows for the preparation of a wide variety of heterobiaryls in good to excellent yields and displays a high level of activity for the coupling of heteroaryl chlorides as well as hindered aryl and heteroaryl halides. Specific factors that govern the efficacy of the transformation for certain heterocyclic motifs were also investigated.
Unprecedented activity: Catalysts derived from Pd and bulky dialkylphosphinobiaryl ligands are shown to be highly stable and active in Suzuki–Miyaura reactions of heteroaryl halides and heteroaryl boronic acids/esters (e.g., 3‐ or 4‐pyridine, indole, and N‐protected pyrrole derivatives). Furthermore, this catalyst system is not inhibited by the presence of highly basic aminopyridines or aminopyrimidines.
The Suzuki-Miyaura cross-coupling of unprotected, nitrogen-rich heterocycles using precatalysts P1 or P2 is reported. The procedure allows for the reaction of variously substituted indazole, benzimidazole, pyrazole, indole, oxindole and azaindole halides under mild conditions in good to excellent yields. Additionally, the mechanism behind the inhibitory effect of unprotected azoles on Pd-catalyzed cross-coupling reactions is described based on evidence gained through experimental, crystallographic, and theoretical investigations.
Aryl boronic acids and esters are versatile reagents for organic synthesis that are utilized in the preparation of various carbon-oxygen, carbon-nitrogen, and carbon-carbon bonds. [1] In addition, the use of organoboranes for crosscoupling processes is particularly attractive owing to their high stability and low toxicity. However, boronic acids and esters usually are prepared via intermediate alkyl and aryllithium compounds or Grignard reagents, processes that are not compatible with numerous functional groups. [2] Furthermore, the use of aryl iodides or bromides is often necessary, while the more readily available aryl chlorides [3] are often unsuitable precursors.In recent years, the development of a variety of transitionmetal-catalyzed processes has allowed for the preparation of aryl boronate esters under milder conditions.[4] In particular, numerous palladium-catalyzed methods have emerged for the conversion of aryl iodides, bromides, and triflates to the corresponding pinacol or catechol boronate esters.[5] However, only two reports [6] can be found in which unactivated aryl chlorides are suitable coupling partners, and these methods have several disadvantages: 1) High quantities of palladium catalysts (5-6 mol %) are required for many substrates. 2) Long reaction times (24-48 h) are necessary. 3) Limited substrate scope and functional-group tolerance (e.g. few or no examples with ortho substituents, phenols, and anilines) is exhibited. Herein, we report an active catalyst composed of Pd and dialkylphosphinobiphenyl ligands 1 or 2 that efficiently converts aryl chlorides to pinacol boronate esters and allows, for the first time, the direct "one-pot" synthesis of symmetrical and unsymmetrical biaryl compounds from two aryl chlorides. In addition, computational studies are presented that provide insight into the efficacy of biaryl monophosphine ligands in the palladium-catalyzed borylation process.We began by optimizing the reaction parameters. We found that a variety of dialkylphosphinobiphenyl ligands could be employed to afford highly active catalysts for the borylation of 4-n-butylchlorobenzene (Table 1). In each instance, the desired aryl boronate ester was obtained in good or excellent yield. The optimum system, based upon [Pd 2 dba 3 ] and XPhos (1), allowed for the use of relatively low quantities of catalyst and provided a quantitative yield of product in just two hours (Table 1, entry 6). We found KOAc to be the optimum base, although a variety of inorganic bases could be utilized. However, the use of K 3 PO 4 or fluoride bases, despite resulting in full conversion of the aryl chloride, also led to the formation of approximately 15-20 % of the homocoupling product 4,4'-n-butylbiphenyl.To illustrate the activity of the catalyst, the borylation of an electron-rich aryl chloride, 4-chloroanisole, was examined (Scheme 1). The best previous result for the transformation of this substrate combination required 5 mol % [Pd(dba) 2 ] and a 24-h reaction time to obtain a 86 % yield of the pinacol boronate est...
A highly efficient method for the palladium-catalyzed borylation of aryl halides with an inexpensive and atom-economical boron source, pinacol borane, has been developed. This system allows for the conversion of aryl and heteroaryl iodides, bromides and several chlorides, containing a variety of functional groups, to the corresponding pinacol boronate esters. In addition to the increase in substrate scope, this is the first general method where relatively low quantities of catalyst and short reaction times can be employed.The utility of aryl boronic acids and esters throughout organic synthesis is seen by their use as key intermediates in the preparation of a wide range of synthetic targets. 1 Despite their versatility, standard methods for the preparation of these compounds can be harsh and, hence, be incompatible with a variety of functional groups. 2 However, various techniques have recently emerged that provide access to aryl boronate esters under milder reaction conditions. 3 In particular, palladium-based systems for the conversion of aryl halides to the corresponding carbon-boron bonds have proved to be a powerful synthetic tool. Recently, we reported a highly active catalyst for transforming aryl chlorides into aryl pinacol-derived boronate esters. 4 However, this system required the use of an expensive boron source, bis(pinacolato)diboron. 5 In addition, the reactions of sterically hindered aryl chlorides were less efficient as they required higher quantities of Pd as well as an increase in the number of equivalents of the expensive boron reagent.In order to address these issues, we sought to develop a system where pinacol borane, a cheaper and more atom-economical boron source, could be employed in the borylation of aryl halides and concurrently to produce a method applicable to sterically hindered substrates. Although several systems have been developed for the borylation of aryl halides with pinacol borane, these methods have several limitations. 6 In general, aryl iodides and bromides are necessary, while the cheaper and more readily available aryl chlorides are unsuitable substrates. 7 We are aware of only one report in which aryl chlorides are efficiently transformed to the corresponding boronate esters when using pinacol borane as the boron source. 8 However, this method had a limited substrate scope as only para-substituted electron-rich aryl chlorides were efficiently converted to the desired products. In addition, all Pd-catalyzed borylation methods employing pinacol borane rely upon high quantities of palladium catalyst (>3.0 mol%) in order to efficiently process the aryl halides. Herein, we report a highly active catalyst system based upon PdCl 2 (CH 3 CN) 2 and SPhos (1) as the supporting ligand for the borylation of aryl and heteroaryl iodides and bromides with pinacol borane. This method not only allows for the use of lower amounts of Pd catalyst with shorter reaction times but also proved general for the borylation of a range of aryl, heteroaryl and vinyl chlorides.sbuchwal@mit.e...
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