PhPAd‐DalPhos: Ligand‐Enabled,Nickel‐Catalyzed Cross‐Coupling of (Hetero)aryl Electrophiles with Bulky Primary Alkylamines

The base metal‐catalyzed C?N cross‐coupling of bulky α,α,α‐trisubstituted primary alkylamines with (hetero)aryl electrophiles represents a challenging and under‐developed class of transformations that is of significant potential utility, including in the synthesis of lipophilic active pharmaceutical ingredients. Herein, we report that a new, air‐stable Ni(II) pre‐catalyst incorporating the optimized ancillary ligand PhPAd‐DalPhos enables such transformations of (hetero)aryl chloride, bromide, and tosylate electrophiles to be carried out for the first time with substrate scope rivalling that achieved using state‐of‐the‐art Pd catalysts, including room temperature cross‐couplings of (hetero)aryl chlorides that are unprecedented for any catalyst (Pd, Ni, or other).     

Nickel‐Catalyzed Cross‐Coupling of Sulfonamides With (Hetero)aryl Chlorides

The development of Ni‐catalyzed C?N cross‐couplings of sulfonamides with (hetero)aryl chlorides is reported. These transformations, which were previously achievable only with Pd catalysis, are enabled by use of air‐stable ( L )NiCl(o‐tol) pre‐catalysts (L= PhPAd‐DalPhos and PAd2‐DalPhos ), without photocatalysis. The collective scope of (pseudo)halide electrophiles (X=Cl, Br, I, OTs, and OC(O)NEt₂) demonstrated herein is unprecedented for any reported catalyst system for sulfonamide C?N cross‐coupling (Pd, Cu, Ni, or other). Preliminary competition experiments and relevant coordination chemistry studies are also presented.     

PAd2‐DalPhos Enables the Nickel‐Catalyzed C−N Cross‐Coupling of Primary Heteroarylamines and (Hetero)aryl Chlorides

Base‐metal catalysts capable of enabling the assembly of heteroatom‐dense molecules by cross‐coupling of primary heteroarylamines and (hetero)aryl chlorides, while sought‐after given the ubiquity of unsymmetrical di(hetero)arylamino fragments in pharmacophores, are unknown. Herein, we disclose the new “double cage” bisphosphine PAd2‐DalPhos ( L2 ). The derived air‐stable Ni^II pre‐catalyst C2 functions well at low loadings in challenging test C?N cross‐couplings with established substrates, and facilitates the first Ni‐catalyzed C?N cross‐couplings of primary five‐ or six‐membered ring heteroarylamines and activated (hetero)aryl chlorides, with synthetically useful scope that is competitive with Pd catalysis.     

Nickel‐Catalyzed Monoarylation of Ammonia

Structurally diverse (hetero)aryl chloride, bromide, and tosylate electrophiles were employed in the Ni‐catalyzed monoarylation of ammonia, including chemoselective transformations. The employed JosiPhos/[Ni(cod)₂] catalyst system enables the use of commercially available stock solutions of ammonia, or the use of ammonia gas in these reactions, thereby demonstrating the versatility and potential scalability of the reported protocol. Proof‐of‐principle experiments established that air‐stable [(JosiPhos)NiCl₂] precatalysts can be employed successfully in such transformations.     

Nickel‐Catalyzed N‐Arylation of Primary Amides and Lactams with Activated (Hetero)aryl Electrophiles

The first nickel‐catalyzed N‐arylation of amides with (hetero)aryl (pseudo)halides is reported, enabled by use of the air‐stable pre‐catalyst (PAd‐DalPhos)Ni(o‐tolyl)Cl ( C1 ). A range of structurally diverse primary amides and lactams were cross‐coupled successfully with activated (hetero)aryl chloride, bromide, triflate, tosylate, mesylate, and sulfamate electrophiles.     

BippyPhos: A Single Ligand With Unprecedented Scope in the Buchwald–Hartwig Amination of (Hetero)aryl Chlorides

Over the past two decades, considerable attention has been given to the development of new ligands for the palladium‐catalyzed arylation of amines and related NH‐containing substrates (i.e., Buchwald–Hartwig amination). The generation of structurally diverse ligands, by research groups in both academia and industry, has facilitated the accommodation of sterically and electronically divergent substrates including ammonia, hydrazine, amines, amides, and NH heterocycles. Despite these achievements, problems with catalyst generality persist and access to multiple ligands is necessary to accommodate all of these NH‐containing substrates. In our quest to address this significant limitation we identified the BippyPhos/[Pd(cinnamyl)Cl]₂ catalyst system as being capable of catalyzing the amination of a variety of functionalized (hetero)aryl chlorides, as well as bromides and tosylates, at moderate to low catalyst loadings. The successful transformations described herein include primary and secondary amines, NH heterocycles, amides, ammonia and hydrazine, thus demonstrating the largest scope in the NH‐containing coupling partner reported for a single Pd/ligand catalyst system. We also established BippyPhos/[Pd(cinnamyl)Cl]₂ as exhibiting the broadest demonstrated substrate scope for metal‐catalyzed cross‐coupling of (hetero)aryl chlorides with NH indoles. Furthermore, the remarkable ability of BippyPhos/[Pd(cinnamyl)Cl]₂ to catalyze both the selective monoarylation of ammonia and the N‐arylation of indoles was exploited in the development of a new one‐pot, two‐step synthesis of N‐aryl heterocycles from ammonia, ortho‐alkynylhalo(hetero)arenes and (hetero) aryl halides through tandem N‐arylation/hydroamination reactions. Although the scope in the NH‐containing coupling partner is broad, BippyPhos/[Pd(cinnamyl)Cl]₂ also displays a marked selectivity profile that was exploited in the chemoselective monoarylation of substrates featuring two chemically distinct NH‐containing moieties.     

Selective Monoarylation of Primary Amines Using the Pd‐PEPPSI‐IPentCl Precatalyst

A single set of reaction conditions for the palladium‐catalyzed amination of a wide variety of (hetero)aryl halides using primary alkyl amines has been developed. By combining the exceptionally high reactivity of the Pd‐PEPPSI‐IPent^Cl catalyst (PEPPSI=pyridine enhanced precatalyst preparation, stabilization, and initiation) with the soluble and nonaggressive sodium salt of BHT (BHT=2,6‐di‐tert‐butyl‐hydroxytoluene), both six‐ and five‐membered (hetero)aryl halides undergo efficient and selective amination.     

Cross‐Coupling between Hydrazine and Aryl Halides with Hydroxide Base at Low Loadings of Palladium by Rate‐Determining Deprotonation of Bound Hydrazine

Reported here is the Pd‐catalyzed C–N coupling of hydrazine with (hetero)aryl chlorides and bromides to form aryl hydrazines with catalyst loadings as low as 100 ppm of Pd and KOH as base. Mechanistic studies revealed two catalyst resting states: an arylpalladium(II) hydroxide and arylpalladium(II) chloride. These compounds are present in two interconnected catalytic cycles and react with hydrazine and base or hydrazine alone to give the product. The selectivity of the hydroxide complex with hydrazine to form aryl over diaryl hydrazine was lower than that of the chloride complex, as well as the catalytic reaction. In contrast, the selectivity of the chloride complex closely matched that of the catalytic reaction, indicating that the aryl hydrazine is derived from this complex. Kinetic studies showed that the coupling process occurs by rate‐limiting deprotonation of a hydrazine‐bound arylpalladium(II) chloride complex to give an arylpalladium(II) hydrazido complex.     

Selected Copper‐Based Reactions for C−N,C−O,C−S,and C−C Bond Formation

Metal‐catalyzed cross‐coupling reactions belong to the most important transformations in organic synthesis. Copper catalysis has received great attention owing to the low toxicity and low cost of copper. However, traditional Ullmann‐type couplings suffer from limited substrate scopes and harsh reaction conditions. The introduction of several bidentate ligands, such as amino acids, diamines, 1,3‐diketones, and oxalic diamides, over the past two decades has totally changed this situation as these ligands enable the copper‐catalyzed coupling of aryl halides and nucleophiles at both low reaction temperatures and catalyst loadings. The reaction scope has also been greatly expanded, rendering this copper‐based cross‐coupling attractive for both academia and industry. In this Review, we have summarized the latest progress in the development of useful reaction conditions for the coupling of (hetero)aryl halides with different nucleophiles. Additionally, recent advances in copper‐catalyzed coupling reactions with aryl boronates and the copper‐based trifluoromethylation of aromatic electrophiles will be discussed.     

Heterogeneous Versus Homogeneous Palladium Catalysts for Ligandless Mizoroki–Heck Reactions: A Comparison of Batch/Microwave and Continuous‐Flow Processing

Mizoroki–Heck couplings of aryl iodides and bromides with butyl acrylate were investigated as model systems to perform transition‐metal‐catalyzed transformations in continuous‐flow mode. As a suitable ligandless catalyst system for the Mizoroki–Heck couplings both heterogeneous and homogeneous Pd catalysts (Pd/C and Pd acetate) were considered. In batch mode, full conversion with excellent selectivity for coupling was achieved applying high‐temperature microwave conditions with Pd levels as low as 10^?3 mol %. In continuous‐flow mode with Pd/C as a catalyst, significant Pd leaching from the heterogeneous catalyst was observed as these Mizoroki–Heck couplings proceed by a homogeneous mechanism involving soluble Pd colloids/nanoparticles. By applying low levels of Pd acetate as homogeneous Pd precatalyst, successful continuous‐flow Mizoroki–Heck transformations were performed in a high‐temperature/pressure flow reactor. For both aryl iodides and bromides, high isolated product yields of the cinnamic esters were obtained. Mechanistic issues involving the Pd‐catalyzed Mizoroki–Heck reactions are discussed.     

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.     

Supramolecular photocatalyst of Palladium (II) Encapsulated within Dendrimer on TiO2 nanoparticles for Photo‐induced Suzuki‐Miyaura and Sonogashira Cross‐Coupling reactions

In this study, synthesis, characterization and catalytic performance of a novel supramolecular photocatalytic system including palladium (II) encapsulated within amine‐terminated poly (triazine‐triamine) dendrimer modified TiO₂ nanoparticles (Pd (II) [PTATAD] @ TiO₂) is presented. The obtained nanodendritic catalyst was characterized by FT‐IR, ICP‐AES, XPS, EDS, TEM, TGA and UV‐DRS. The as‐prepared nanodendritic catalyst was shown to be highly active, selective, and recyclable for the Suzuki–Miyaura and Sonogashira cross‐coupling of a wide range of aryl halides including electron‐rich and electron‐poor and even aryl chlorides, affording the corresponding biaryl compounds in good to excellent yields under visible light irradiation. This study shows that visible light irradiation can drive the cross‐coupling reactions on the Pd (II) [PTATAD] @ TiO₂ under mild reaction conditions (27–30 °C) and no additional additives such as cocatalysts or phosphine ligands. So, we propose that the improved photoactivity predominantly benefits from the synergistic effects of Pd (II) amine‐terminated poly (triazine‐triamine) dendrimer on TiO₂ nanoparticles that cause efficient separation and photogenerated electron–hole pairs and photoredox capability of nanocatalyst which all of these advantages due to the tuning of band gap of catalyst in the visible light region.     

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 Enaminone‐Pd(II) Complexes and Their Application in Catalysing Aqueous Suzuki‐Miyaura Cross Coupling Reaction

A series of Pd(II)‐enaminone complexes, termed Pd(eao)₂, have been synthesized and characterized. The investigation on the catalytic activities of these new Pd(II)‐reagents has proved that the Pd(eao)₂‐ 1 possesses excellent catalytic activity for the Suzuki‐ Miyaura cross coupling reactions of aryl bromides/chlorides with aryl/vinyl boronic acids in the environmentally benign media of aqueous PEG400 at low loading (5 mol‰). The superiority of this Pd(II)‐reagent to those commercial Pd(II) and Pd(0) catalysts in catalyzing the reactions has been confirmed by parallel experiments. What's more, Pd(eao)₂‐ 2 has been found as a practical catalyst for the homo‐coupling reactions of aryl boronic acids.     

Reductive Cross‐Coupling Reactions between Two Electrophiles

Reductive cross‐electrophile coupling reactions have recently been developed to a versatile and sustainable synthetic tool for selective C?C bond formation. The employment of cheap and abundant electrophiles avoids the pre‐formation and handling of organometallic reagents. In situ reductive coupling is effected in the presence of a transition‐metal catalyst (Ni, Co, Pd, Fe) and a suitable metallic reductant (Mn, Zn, Mg). This Concept article assesses the current state of the art and summarizes recent protocols with various combinations of alkyl, alkenyl, allyl, and aryl reagents and highlights key mechanistic studies.     

Pd‐PEPPSI‐IPent‐SiO2: A Supported Catalyst for Challenging Negishi Coupling Reactions in Flow

A silica‐supported precatalyst, Pd‐PEPPSI‐IPent‐SiO₂, has been prepared and evaluated for its proficiency in the Negishi cross‐coupling of hindered and electronically deactivated coupling partners. The precatalyst Pd‐PEPPSI‐IPent loaded onto packed bed columns shows high catalytic activity for the room‐temperature coupling of deactivated/hindered biaryl partners. Also for the first time, the flowed Csp³–Csp² coupling of secondary alkylzinc reagents to (hetero)aromatics has been achieved with high selectivity with Pd‐PEPPSI‐IPent‐SiO₂. These couplings required residence times as short as 3 minutes to effect completion of these challenging transformations with excellent selectivity for the nonrearranged product.     

Pd‐Catalyzed Csp2H Functionalization of Heteroarenes via Isocyanide Insertion: Concise Synthesis of Di‐(Hetero)Aryl Ketones and Di‐(Hetero)Aryl Alkylamines

We report herein an efficient Pd‐catalyzed direct C?H bond functionalization of heteroarenes via an isocyanide insertion strategy for the synthesis of di‐(hetero)aryl ketones and di‐(hetero)aryl alkylamines. The methodology involves a three component reaction between an azole, a haloarene and an isocyanide resulting in the formation of an imine, which in turn is either hydrolyzed or reduced to get the desired product.     

Cross‐Coupling of Organolithium with Ethers or Aryl Ammonium Salts by C−O or C−N Bond Cleavage

Various aryl‐, alkenyl‐, and/or alkyllithium species reacted smoothly with aryl and/or benzyl ethers with cleavage of the inert C?O bond to afford cross‐coupled products, catalyzed by commercially available [Ni(cod)₂] (cod=1,5‐cyclooctadiene) catalysts with N‐heterocyclic carbene (NHC) ligands. Furthermore, the coupling reaction between the aryllithium compounds and aryl ammonium salts proceeded under mild conditions with C?N bond cleavage in the presence of a [Pd(PPh₃)₂Cl₂] catalyst. These methods enable selective sequential functionalizations of arenes having both C?N and C?O bonds in one pot.     

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.