Ligand‐Free Copper‐Catalyzed Negishi Coupling of Alkyl‐, Aryl‐, and Alkynylzinc Reagents with Heteroaryl Iodides

Reported herein is an unprecedented ligand‐free copper‐catalyzed cross‐coupling of alkyl‐, aryl‐, and alkynylzinc reagents with heteroaryl iodides. The reaction proceeds at room temperature for the coupling of primary, secondary, and tertiary alkylzinc reagents with heteroaryl iodides without rearrangement. An elevated temperature (100 °C) is required for aryl–heteroaryl and alkynyl–heteroaryl couplings.     

Basic Alumina‐Supported Synthesis of Aryl‐Heteroarylmethanes via Palladium Catalyzed Cross‐Coupling under Microwave Irradiation

A basic alumina‐supported microwave assisted simple methodology has been developed for the synthesis of aryl‐heteroaryl methanes (benzylated quinolones) via transition metal catalyzed cross‐coupling reaction of halo substituted polynuclear oxa‐aza quinolones with benzyl indium, an organometallic reagent easily derived from commercially available benzyl bromide.     

Efficient Synthesis of Unsymmetrical Heteroaryl Ethers by a Transition Metal‐Free C?O Cross‐Coupling Reaction of Activated and Unactivated Heteroaryl Chlorides with Alcohols and Phenols

By optimizing the reaction conditions via a careful screening of the bases and solvents, we developed an efficient transition metal‐free method for C? O cross‐coupling of activated and unactivated heteroaryl chlorides with primary and secondary alcohols and phenols, providing a simple, efficient, and practical method for synthesis of the useful unsymmetrical heteroaryl alkyl and heteroaryl aryl ethers.     

Cobalt‐Catalyzed Intermolecular C(sp2)O Cross‐Coupling

Cobalt(II)‐catalyzed C(sp²)?O cross‐coupling between aryl/heteroaryl alcohols and vinyl/aryl halides in the presence of Cu^I has been achieved under ligand‐free conditions. In this reaction, copper plays a significant role in transmetalation rather than being directly involved in the C?O coupling. This unique Co/Cu‐dual catalyst system provides an easy access to a library of aryl–vinyl, heteroaryl–styryl, aryl–aryl, and heteroaryl–heteroaryl ethers in the absence of any ligand or additive.     

A General Palladium‐Catalyzed Hiyama Cross‐Coupling Reaction of Aryl and Heteroaryl Chlorides

A general palladium‐catalyzed Hiyama cross‐coupling reaction of aryl and heteroaryl chlorides with aryl and heteroaryl trialkoxysilanes by a Pd(OAc)₂/ L2 catalytic system is presented. A newly developed water addition protocol can dramatically improve the product yields. The conjugation of the Pd/ L2 system and the water addition protocol can efficiently catalyze a broad range of electron‐rich, ‐neutral, ‐deficient, and sterically hindered aryl chlorides and heteroaryl chlorides with excellent yields within three hours and the catalyst loading can be down to 0.05 mol % Pd for the first time. Hiyama coupling of heteroaryl chlorides with heteroaryl silanes is also reported for the first time. The reaction can be easily scaled up 200 times (100 mmol) without any degasification and purification of reactants; this facilitates the practical application in routine synthesis.     

A Robust and Broadly Applicable Cobalt‐Catalyzed Cross‐Coupling of Functionalized Bench‐Stable Organozinc Pivalates with Unsaturated Halides

We report a robust and broadly applicable CoCl₂‐catalyzed cross‐coupling between functionalized aryl and heteroaryl zinc pivalates and various electron‐poor aryl and heteroaryl halides (X=Cl, Br, I). Couplings with (E)‐ or (Z)‐bromo‐ or iodo‐alkenes proceed with retention of configuration. Also, alkynyl bromides react with arylzinc pivalates providing arylated alkynes.     

Recent progress in coupling of two heteroarenes

The biheteroaryl structural motif is prevalent in polymers, advanced materials, liquid crystals, ligands, molecules of medicinal interest, and natural products. Many types of synthetic transformations have been known for the construction of heteroaryl–heteroaryl linkages. Coupling reactions provide one of the most efficient ways to achieve these biheterocyclic structures. In this review, four types of coupling reactions are discussed: 1) transition‐metal‐catalyzed coupling reactions of heteroaryl halides or surrogates with heteroarylmetals; 2) direct inter‐ and intramolecular heteroarylations of C? H bonds of heteroarenes with heteroaryl halides or pseudohalides; 3) oxidative C? H/C? H homo‐ and cross‐couplings of two unpreactivated heteroarenes; and 4) transition‐metal‐catalyzed decarboxylative cross‐coupling reactions between haloheteroarenes or heteroarenes and heteroarenecarboxylic acids. The general purpose of this review is to give an exhaustive and clear picture in heteroaryl–heteroaryl bond formation as well as its application in the synthesis of natural products, pharmaceuticals, catalyst ligands, and materials.     

Sulfur(IV)-Mediated Unsymmetrical Heterocycle Cross-Couplings

Despite the tremendous utilities of metal-mediated cross-couplings in modern organic chemistry, coupling reactions involving nitrogenous heteroarenes remain a challenging undertaking – coordination of Lewis basic atoms into metal centers often necessitate elevated temperature, high catalyst loading, etc. Herein, we report a sulfur (IV) mediated cross-coupling amendable for the efficient synthesis of heteroaromatic substrates. Addition of heteroaryl nucleophiles to a simple, readily-accessible alkyl sulfinyl (IV) chloride allows formation of a trigonal bipyramidal sulfurane intermediate. Reductive elimination therefrom provides bis-heteroaryl products in a practical and efficient fashion.     

Phosphonium Salts as Pseudohalides: Regioselective Nickel‐Catalyzed Cross‐Coupling of Complex Pyridines and Diazines

Heterobiaryls are important pharmacophores that are challenging to prepare by traditional cross‐coupling methods. An alternative approach is presented where pyridines and diazines are converted into heteroaryl phosphonium salts and coupled with aryl boronic acids. Nickel catalysts are unique for selective heteroaryl transfer, and the reaction has a broad substrate scope that includes complex pharmaceuticals. Phosphonium ions also display orthogonal reactivity in cross‐couplings compared to halides, enabling chemoselective palladium‐ and nickel‐catalyzed coupling sequences.     

An Efficient Low‐Temperature Stille–Migita Cross‐Coupling Reaction for Heteroaromatic Compounds by Pd–PEPPSI–IPent

The reactivity of Pd–PEPPSI (Pyridine, Enhanced, Precatalyst, Preparation, Stabilization, and Initiation) precatalysts in the Stille–Migita cross‐coupling reaction between heteroaryl stannanes and aryl or heteroaryl halides was evaluated. In general, Pd–PEPPSI–IPent (IPent=diisopentylphenylimidazolium derivative) demonstrated high efficiency over a variety of challenging aryl or heteroaryl halides with thiophene‐, furan‐, pyrrole‐, and thiazole‐based organostannanes when compared with Pd–PEPPSI–IPr (IPr=diisopropylphenylimidazolium derivative). The transformations proceeded at appreciably lower temperatures (30–80 °C) than triarylphosphine‐based Pd catalysts, improving the scope of this useful carbon–carbon bond‐forming process.     

Transition‐Metal‐Free BF3‐Mediated Oxidative and Non‐Oxidative Cross‐Coupling of Pyridines

We report a BF₃‐mediated direct alkynylation of pyridines at C(2) by using a variety of alkynyllithium reagents (oxidative cross‐coupling). Moreover, we have developed a novel transition‐metal‐free cross‐coupling method between alkylmagnesium reagents and 4‐substituted pyridines, such as isonicotinonitrile and 4‐chloropyridine, by employing BF₃?OEt₂ as a promoter. The combination of these methods enabled us to efficiently prepare a range of di‐, tri‐, and tetrasubstituted pyridines.     

Synthesis of All‐Carbon Disubstituted Bicyclo[1.1.1]pentanes by Iron‐Catalyzed Kumada Cross‐Coupling

1,3‐Disubstituted bicyclo[1.1.1]pentanes (BCPs) are important motifs in drug design as surrogates for p‐substituted arenes and alkynes. Access to all‐carbon disubstituted BCPs via cross‐coupling has to date been limited to use of the BCP as the organometallic component, which restricts scope due to the harsh conditions typically required for the synthesis of metallated BCPs. Here we report a general method to access 1,3‐C‐disubstituted BCPs from 1‐iodo‐bicyclo[1.1.1]pentanes (iodo‐BCPs) by direct iron‐catalyzed cross‐coupling with aryl and heteroaryl Grignard reagents. This chemistry represents the first general use of iodo‐BCPs as electrophiles in cross‐coupling, and the first Kumada coupling of tertiary iodides. Benefiting from short reaction times, mild conditions, and broad scope of the coupling partners, it enables the synthesis of a wide range of 1,3‐C‐disubstituted BCPs including various drug analogues.     

Palladium‐catalyzed Suzuki–Miyaura coupling with aryl and heteroaryl bromides using N,N,N′,N′‐tetra(diphenylphosphinomethyl)‐1,2‐ethylenediamine

An easily prepared tetraphosphine N,N,N′,N′‐tetra(diphenylphosphinomethyl)‐1,2‐ethylenediamine (1) combined with PdCl₂ affords an efficient catalytic system for Suzuki cross‐coupling of aryl and heteroaryl bromides. A high turnover number of 750 000 is obtained with the catalyst loading as low as 1 ppm. This catalyst system exhibits good stability and longevity. In this study, a broad scope of substrates is investigated and satisfactory yields are obtained. Copyright © 2012 John Wiley & Sons, Ltd.     

Nano palladium supported on high‐surface‐area metal–organic framework MIL‐101: an efficient catalyst for Sonogashira coupling of aryl and heteroaryl bromides with alkynes

Palladium nanoparticle‐incorporated metal–organic framework MIL‐101 (Pd/MIL‐101) was successfully synthesized and characterized using X‐ray diffraction, nitrogen physisorption, X‐ray photoelectron, UV–visible and infrared spectroscopies, and transmission electron microscopy. The characterization techniques confirmed high porosity and high surface area of MIL‐101 and high stability of nano‐size palladium particles. Pd/MIL‐101 nanocomposite was investigated for the Sonogashira cross‐coupling reaction of aryl and heteroaryl bromides with various alkynes under copper‐free conditions. The reusability of the catalyst was tested for up to four cycles without any significant loss in catalytic activity. Copyright © 2015 John Wiley & Sons, Ltd.     

Catalytic Ester and Amide to Amine Interconversion: Nickel‐Catalyzed Decarbonylative Amination of Esters and Amides by C−O and C−C Bond Activation

An efficient nickel‐catalyzed decarbonylative amination reaction of aryl and heteroaryl esters has been achieved for the first time. The new amination protocol allows the direct interconversion of esters and amides into the corresponding amines and represents a good alternative to classical rearrangements as well as cross coupling reactions.     

Synthesis of 2‐Aryl‐ and 2‐Heteroaryl‐3,5‐dimethoxy‐1,4‐benzoquinones Involving Pd‐Catalyzed Cross‐Coupling of (2,3,4,6‐Tetramethoxyphenyl)boronic Acid

A series of 2‐aryl‐ and 2‐heteroaryl‐substituted 3,5‐dimethoxy‐1,4‐benzoquinones (compounds 27 – 36 ) have been synthesized by cross‐coupling of (2,3,4,6‐tetramethoxyphenyl)boronic acid ( 2 ) with aromatic bromides or iodides in the presence of [Pd⁰(Ph₃)₄] and Na₂CO₃, followed by AgO‐promoted oxidation of the resulting biaryl compounds 17 – 26 .     

The Selective Cross‐Coupling of Secondary Alkyl Zinc Reagents to Five‐Membered‐Ring Heterocycles Using Pd‐PEPPSI‐IHeptCl

The ability to cross‐couple secondary alkyl centers is fraught with a number of problems, including difficult reductive elimination, which often leads to β‐hydride elimination. Whereas catalysts have been reported that provide decent selectivity for the expected (non‐rearranged) cross‐coupled product with aryl or heteroaryl oxidative‐addition partners, none have shown reliable selectivity with five‐membered‐ring heterocycles. In this report, a new, rationally designed catalyst, Pd‐PEPPSI‐IHept^Cl, is demonstrated to be effective in selective cross‐coupling reactions with secondary alkyl reagents across an impressive variety of furans, thiophenes, and benzo‐fused derivatives (e.g., indoles, benzofurans), in most instances producing clean products with minimal, if any, migratory insertion for the first time.     

tBuLi‐Mediated One‐Pot Direct Highly Selective Cross‐Coupling of Two Distinct Aryl Bromides

A Pd‐catalyzed direct cross‐coupling of two distinct aryl bromides mediated by tBuLi is described. The use of [Pd‐PEPPSI‐IPr] or [Pd‐PEPPSI‐IPent] as catalyst allows for the efficient one‐pot synthesis of unsymmetrical biaryls at room temperature. The key for this selective cross‐coupling is the use of an ortho‐substituted bromide that undergoes lithium–halogen exchange preferentially.     

Synthesis of heterobiaryls via Suzuki‐Miyaura coupling reaction of potassium aryltrifluoroborates with heteroaryl halides in aqueous systems

A variety of heterobiaryl compounds have been synthesized by the Suzuki‐Miyaura coupling reactions of heteroaryl halides with potassium aryltrifluoroborates. Pd (OAc)₂ was found to be highly efficient for the Suzuki‐Miyaura coupling reactions of various heteroaryl halides with potassium aryltrifluoroborates in aqueous systems, delivering the corresponding heterobiaryl compounds in good to excellent yields.     

Cross‐Coupling Reaction of Saccharide‐Based Alkenyl Boronic Acids with Aryl Halides: The Synthesis of Bergenin

A convenient synthetic pathway enabling D ‐glucal and D ‐galactal pinacol boronates to be prepared in good isolated yields was achieved. Both pinacol boronates were tested in a series of cross‐coupling reactions under Suzuki–Miyaura cross‐coupling conditions to obtain the corresponding aryl, heteroaryl, and alkenyl derivatives in high isolated yields. This methodology was applied to the formal synthesis of the glucopyranoside moiety of papulacandin D and the first total synthesis of bergenin.