Encyclopedia Reagents in organic synthesis

Fully complementary bimetallic catalysis has been identified as an increasingly powerful tool for molecular transformations, which was largely inspired by early examples of sequential catalytic transformations. Thus, energy-efficient one-pot reactions involving different metal catalysts orchestrated in concert constitute an attractive alternative to multi-step protocols, with major recent progress through the elegant ligand design in heterobimetallic catalysis as well as sustainable photo-induced C-H transformations, among others. This review provides a critical assessment of the state of the art in heterobimetallic catalysis for sustainable organic syntheses (SOS), highlighting key advances and representative examples until summer 2017.

Heteromultimetallic catalysis for sustainable organic syntheses.

Palladium-catalyzed cross-coupling reactions have emerged as one of the most versatile tools in organic chemistry. Extensive efforts were made to adapt these reactions to aqueous media, not only for the purpose of environmental conservation but also to expand the scope, increase the efficiency and implement bio-compatible protocols. Among different palladium cross-coupling reactions, the Heck reaction turned out to be the most challenging in an aqueous environment. This led to various original developments in catalyst design. This review summarizes the different approaches pursued to perform Heck reactions in neat water as well as aqueous mixtures. Both, homogeneous and immobilized catalysts, including nanoparticles are presented herein.

Palladium-Catalyzed Heck Cross-Coupling Reactions in Water: A Comprehensive Review

Due to the low intrinsic acidity of amines, palladium-catalyzed C–N cross-coupling has been plagued continuously by the necessity to employ strong, inorganic, or insoluble bases. To surmount the many practical obstacles associated with these reagents, we utilized a commercially available dialkyl triarylmonophosphine-supported palladium catalyst that facilitates a broad range of C–N coupling reactions in the presence of weak, soluble bases. The mild and general reaction conditions show extraordinary tolerance for even highly base-sensitive functional groups. Additionally, insightful heteronuclear NMR studies using 15N-labeled amine complexes provide evidence for the key acidifying effect of the cationic palladium center.

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Breaking the Base Barrier: An Electron-Deficient Palladium Catalyst Enables the Use of a Common Soluble Base in C–N Coupling

Palladium-catalyzed amination reactions using soluble organic bases have provided a solution to the many issues associated with heterogeneous reaction conditions. Still, homogeneous C-N cross-coupling approaches cannot yet employ bases as weak and economical as trialkylamines. Furthermore, organic base-mediated methods have not been developed for Ni(0/II) catalysis, despite some advantages of such systems over those employing Pd-based catalysts. We designed a new air-stable and easily prepared Ni(II) precatalyst bearing an electron-deficient bidentate phosphine ligand that enables the cross-coupling of aryl triflates with aryl amines using triethylamine (TEA) as base. The method is tolerant of sterically congested coupling partners, as well as those bearing base- and nucleophile-sensitive functional groups. With the aid of density functional theory (DFT) calculations, we determined that the electron-deficient auxiliary ligands decrease both the pKa of the Ni-bound amine and the barrier to reductive elimination from the resultant Ni(II)-amido complex. Moreover, we determined that the preclusion of Lewis acid-base complexation between the Ni catalyst and the base, due to steric factors, is important for avoiding catalyst inhibition.

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The Quest for the Ideal Base: Rational Design of a Nickel Precatalyst Enables Mild, Homogeneous C-N Cross-Coupling.

Pd/PTABS: Catalyst for Room Temperature Amination of Heteroarenes.

Two new water-soluble phosphatriazene ligands have been synthesized as versatile ligands for complexation reactions with Pd(OAc)2 and utilized for catalyzing column-free Suzuki–Miyaura cross-coupling of various purine and pyrimidine halonucleosides in water. The water-solubility of the catalytic system simplified the isolation of the cross-coupled products to mere filtration, while the catalytically active solution in the filtrate was recycled eight times. A novel copper-free Sonogashira coupling protocol for the nucleosides has also been established via a one-pot synthesis of FV-100, a nucleoside-based drug in phase 3 clinical trials for herpes zoster or shingles treatment. Application of the Heck reaction was demonstrated by the synthesis of another antiviral drug: BVDU.

Novel water-soluble phosphatriazenes: versatile ligands for Suzuki–Miyaura, Sonogashira and Heck reactions of nucleosides

A mild, general, and highly efficient catalytic etherification protocol for chloroheteroarenes was developed using the Pd/PTABS catalytic system. The protocol is selective for the etherification of chloroheteroarenes using a large variety of electron-rich and electron-deficient phenol bearing synthons which include inter alia biologically and commercially important estrone, estradiol, tyrosine, and several other molecules. The mildness of the new protocol is expected to be beneficial for the synthesis of complex drugs and drug intermediates offering late-stage modification of bioactive compounds.

Pd/PTABS: Low Temperature Etherification of Chloroheteroarenes.

Phosphines have played an important role in the rapid rise of transition metal-catalysed processes and with the possibility of fine-tuning the electronic and steric properties of these ligands, several synthesis challenges have been overcome in the past decades leading to their application in academia and industry. Caged phosphines are one such class of phosphines with the phosphorus atom at the bridgehead of a cyclic cage and have exhibited excellent control of the steric and electronic properties leading to their applications as ligands in a vast number of catalytic processes. This review provides an overview of the origin of this area of research, as well as the developments that have taken place and how the unique properties of these ligand systems could help to fine-tune the reactivity. A critical analysis of the area reveals some lacunae that will also be highlighted to promote further developments in this area of research.

A comprehensive review of caged phosphines: synthesis, catalytic applications, and future perspectives

A highly efficient and mild protocol for the aminocarbonylation of a nucleoside is developed by employing palladium/(1,3,5-triaza-7-phosphaadamantan-1-ium-1-yl)butane-1-sulfonate (Pd/PTABS) as the catalytic system. The developed aminocarbonylation methodology employs CO gas at a relatively low temperature of 60 °C and is suitable for a wide range of amines, including (heteroaryl)benzylic, aliphatic acyclic, alicyclic and secondary amines. This protocol is also utilized for the synthesis of a sangivamycin precursor by carrying out the Pd-catalyzed amination and aminocarbonylation simultaneously. The utility of this protocol is further demonstrated by the synthesis of the drugs moclobemide and nikethamide.

Shatrughn Bhilare

Papers

Pd/PTABS: Catalyst for Room Temperature Amination of Heteroarenes.

Novel water-soluble phosphatriazenes: versatile ligands for Suzuki–Miyaura, Sonogashira and Heck reactions of nucleosides

Pd/PTABS: Low Temperature Etherification of Chloroheteroarenes.

A comprehensive review of caged phosphines: synthesis, catalytic applications, and future perspectives

Pd/PTABS: An Efficient Catalytic System for the Aminocarbonylation of a Sugar-Protected Nucleoside