Stephen L. Buchwald

Biaryl Phosphane Ligands in Palladium‐Catalyzed Amination

Palladium-catalyzed amination reactions of aryl halides have undergone rapid development in the last 12 years, largely driven by the implementation of new classes of ligands. Biaryl phosphanes have proven to provide especially active catalysts in this context. This Review discusses the application of these catalysts in C-N cross-coupling reactions in the synthesis of heterocycles and pharmaceuticals, in materials science, and in natural product synthesis.

Dialkylbiaryl Phosphines in Pd-Catalyzed Amination: A User’s Guide

Dialkylbiaryl phosphines are a valuable class of ligand for Pd-catalyzed amination reactions and have been applied in a range of contexts. This review attempts to aid the reader in the selection of the best choice of reaction conditions and ligand of this class for the most commonly encountered and practically important substrate combinations.

Practical Palladium Catalysts for C-N and C-O Bond Formation

The development of new palladium catalysts for the arylation of amines and alcohols with aryl halides and sulfonates is reviewed. Initial systems as well as mechanistic issues are discussed briefly, while subsequent generations of catalysts are described in greater detail. For these later generations of catalysts, substrate scope and limitations are also discussed. The review is organized by substrate class. Modifications and improvements in technical aspects of reaction development are described where appropriate. In addition, applications of this technology toward natural product synthesis, new synthetic methodology, and medicinal chemistry are chronicled. This review is organized in a manner that is designed to be useful to the synthetic organic chemist.

Palladium-catalyzed amination of aryl halides and sulfonates

Abstract In this review, the progress made in the palladium-catalyzed amination of aryl halides and sulfonates is described with particular attention given to applications in synthetic organic chemistry.

CH Functionalization/CN Bond Formation: Copper‐Catalyzed Synthesis of Benzimidazoles from Amidines

An immense effort has been made to develop efficient strategies for the direct functionalization of C H bonds using transition-metal catalysis. For the most part, ruthenium-, rhodium-, and palladium-based catalysts have been applied to effect either C C or C Het (Het= heteroatom) bond formation by replacement of a C H bond. Few examples have been described that employ copper as catalysts, which is particular attractive due to its low cost and low toxicity. Herein, we disclose a new Cu(OAc)2catalyzed synthesis of benzimidazoles from amidines through a C H functionalization/C N bond-forming process that uses oxygen as the oxidant and generates water as the only direct waste product. Recently, we reported that carbazoles could be formed by intramolecular C H bond functionalization. We were eager to extend our approach to the synthesis of other classes of heterocycles, such as benzimidazoles, which are of considerable importance in medicinal chemistry. Brain0s palladiumcatalyzed N-arylation of (ortho-bromophenyl)amidines to give benzimidazoles inspired us to use amidines as our starting materials. The cyclization of amidines by oxidative means had been reported earlier. However, the use of stoichiometric amounts of reagents, such as Pb(OAc)4 [9] and iodine(III) compounds, and a rather narrow functionalgroup scope—only examples with Me, Cl, and Br substituents were reported—are major disadvantages. NaOCl is known to promote the cyclization as well via N-chlorinated amidines. Although the low cost of NaOCl is an appealing feature, low to moderate yields were obtained for amidines bearing functional groups, and as mentioned in one report, chlorinated side products might be anticipated when this method is applied. Altogether, these drawbacks prompted us to reinvestigate this transformation. We started our study by examining the conversion of Nphenylbenzamidine (1) into 2-phenylbenzimidazole (2). After an initial screen of palladium and copper catalysts, solvents, and reaction temperatures, we found that the use of 15 mol% Cu(OAc)2 in DMSO at 100 8C under an oxygen atmosphere produced 2 after 18 h in 19% yield with a low conversion of 1 (Table 1, entry 1). Using 5 equivalents of pyridine or triethylamine as a basic additive, the conversion was enhanced, but

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

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 analogues proceed at room temperature or 40 °C in short reaction times to give the desired products in excellent yields.

Diamine Ligands in Copper-Catalyzed Reactions

The utility of copper-mediated cross-coupling reactions has been significantly increased by the development of mild reaction conditions and the ability to employ catalytic amounts of copper. The use of diamine-based ligands has been important in these advances and in this review we discuss these systems, including the choice of reaction conditions and applications in the synthesis of pharmaceuticals, natural products and designed materials.

A Highly Active Catalyst for Pd-Catalyzed Amination Reactions: Cross-Coupling Reactions Using Aryl Mesylates and the Highly Selective Monoarylation of Primary Amines Using Aryl Chlorides

A catalyst system based on a new biarylmonophosphine ligand (BrettPhos) that shows excellent reactivity for C-N cross-coupling reactions is reported. This catalyst system enables the use of aryl mesylates as a coupling partner in C-N bond-forming reactions. Additionally, the use of BrettPhos permits the highly selective monoarylation of an array of primary aliphatic amines and anilines at low catalyst loadings and with fast reaction times, including the first monoarylation of methylamine. Lastly, oxidative addition complexes of BrettPhos are included, which provide insight into the origin of reactivity for this system.

Copper‐Catalyzed Trifluoromethylation of Unactivated Olefins

The inclusion of fluorinated functional groups in small molecules has had a profound impact on the pharmaceutical, material, and agrochemical industries.[1, 2] In particular, the trifluoromethyl (CF3) substituent has emerged as an important functional group for the modulation of the physical properties in new pharmaceutical candidates as it has excellent metabolic stability, lipophilicity, and is electron-withdrawing in nature.[3] Myriad of fluorinated biologically active pharmaceutical compounds have been identified,[4] with an estimated 20% of drugs on the market containing fluorine.[1] On this basis, there has been a recent surge in the number of reports describing the formation of carbon–trifluoromethyl (C–CF3) bonds, demonstrating the continuing need for the development of efficient methods to incorporate these groups.

An efficient copper-catalyzed coupling of aryl halides with imidazoles

Abstract Copper-catalyzed N-arylation of imidazoles can be accomplished using (CuOTf) 2 ·benzene as a copper source and Cs 2 CO 3 as a base in xylenes at 110–125 °C. Addition of 1,10-phenanthroline (phen) and trans,trans -dibenzylideneacetone (dba) was crucial to the success of the process. The products, N -arylimidazoles, were isolated in high yields.