[(NHC)Pd(OAc)2]: Highly Active Carboxylate Pd(II)-NHC (NHC = N-Heterocyclic Carbene) Precatalysts for Suzuki-Miyaura and Buchwald-Hartwig Cross-Coupling of Amides by N-C(O) Activation.

In the past eight years, the selective cross-coupling of amides by N-C(O) bond activation has emerged as a highly attractive manifold for the manipulation of traditionally unreactive amide bonds. In this Special Issue on Next-Generation Cross-Coupling Chemistry, we report the Suzuki-Miyaura and Buchwald-Hartwig cross-coupling of amides by selective N-C(O) cleavage catalyzed by bench-stable, well-defined carboxylate Pd(II)-NHC (NHC = N-heterocyclic carbene) catalysts {[(NHC)Pd(O2CR)2]}. This class of Pd(II)-NHCs promotes cross-coupling under exceedingly mild room-temperature conditions owing to the facile dissociation of the carboxylate ligands to form the active complex. These readily accessible Pd(II)-NHC precatalysts show excellent functional group tolerance and are compatible with a broad range of amide activating groups. Considering the mild conditions for the cross-coupling and the facile access to carboxylate Pd(II)-NHC complexes, we anticipate that this class of bench-stable complexes will find wide application in the activation of amide N-C(O) and related acyl X-C(O) bonds.

Pd-NHC (NHC = N-Heterocyclic Carbene)-Catalyzed B-Alkyl Suzuki Cross-Coupling of 2-Pyridyl Ammonium Salts by N-C Activation: Application to the Discovery of Agrochemical Molecular Hybrids.

2-Alkylpyridines are a privileged scaffold throughout the realm of organic synthesis and play a key role in natural products, pharmaceuticals, and agrochemicals. Herein, we report the first B-alkyl Suzuki cross-coupling of 2-pyridyl ammonium salts to access functionalized 2-alkylpyridines. The use of well-defined, operationally simple Pd-NHCs permits for an exceptionally broad scope of the challenging B-alkyl C-N cross-coupling with organoboranes containing ß-hydrogen, representing a novel method for the discovery of highly sought-after molecules for plant protection.

Indazolin-3-ylidenes (Indy*): easily accessible, sterically-hindered indazole-derived N-heterocyclic carbenes and their application in gold catalysis.

Sterically-hindered N-heterocyclic carbenes (NHCs) with functionalized N-wingtips are a pivotal class of ligands in organic synthesis. Herein, we report the first class of sterically-hindered N-heterocyclic carbenes based on the indazole framework. These ligands combine the strong σ-donation of the carbene center due to the carbene placement at the C3-indazole position with the sterically-hindered and flexible N-substitution with the versatile 2,6-bis(diphenylmethyl)aryl moiety that extends beyond the metal centre for the first time in non-classical N-heterocyclic carbenes. The ligands are readily accessible by the rare Cadogan indazole synthesis of sterically-hindered N-aryl-1-(2-nitrophenyl)methanimines. Steric and electronic characterization as well as catalytic studies in the synthesis of oxazolines are described. Considering the unique properties of indazole-derived carbenes, we anticipate that this class of compounds will find broad application in organic synthesis and catalysis.

Palladium-Catalyzed Decarbonylative Sonogashira Alkynylation of Carboxylic-Phosphoric Anhydrides.

We report the first palladium-catalyzed decarbonylative alkynylation of carboxylic-phosphoric anhydrides via highly selective C(O)-O bond cleavage. Carboxylic-phosphoric anhydrides are highly active carboxylic acid derivatives, which are generated through activating carboxylic acids using phosphates by esterification or direct dehydrogenative coupling with phosphites. Highly valuable internal alkynes have been generated by the present method, and the efficiency of this approach has been demonstrated through a wide substrate scope and excellent functional group tolerance.

Wingtip-Flexible N-Heterocyclic Carbenes: Unsymmetrical Connection between IMes and IPr.

IMes (IMes=1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) and IPr (IPr=1,3- bis(2,6-diisopropylphenyl)imidazol-2-ylidene) represent by far the most frequently used N-heterocyclic carbene ligands in homogeneous catalysis, however, despite numerous advantages, these ligands are limited by the lack of steric flexibility of catalytic pockets. We report a new class of unique unsymmetrical N-heterocyclic carbene ligands that are characterized by freely-rotatable N-aromatic wingtips in the imidazol-2-ylidene architecture. The combination of rotatable N-CH2 Ar bond with conformationally-fixed N-Ar linkage results in a highly modular ligand topology, entering the range of geometries inaccessible to IMes and IPr. These ligands are highly reactive in Cu(I)-catalyzed ß-hydroboration, an archetypal borylcupration process that has had a transformative impact on the synthesis of boron-containing compounds. The most reactive Cu(I)-NHC in this class has been commercialized in collaboration with MilliporeSigma to enable broad access of the synthetic chemistry community. The ligands gradually cover %Vbur geometries ranging from 37.3 % to 52.7 %, with the latter representing the largest %Vbur described for an IPr analogue, while retaining full flexibility of N-wingtip. Considering the modular access to novel geometrical space in N-heterocyclic carbene catalysis, we anticipate that this concept will enable new opportunities in organic synthesis, drug discovery and stabilization of reactive metal centers.

Amide N-C Bond Activation: A Graphical Overview of Acyl and Decarbonylative Coupling.

This Graphical Review provides an overview of amide bond activation achieved by selective oxidative addition of the N-C(O) acyl bond to transition metals and nucleophilic acyl addition, resulting in acyl and decarbonylative coupling together with key mechanistic details pertaining to amide bond distortion underlying this reactivity manifold.

Divergent Acyl and Decarbonylative Liebeskind-Srogl Cross-Coupling of Thioesters by Cu-Cofactor and Pd-NHC (NHC = N-Heterocyclic Carbene) Catalysis.

Transition-metal-catalyzed cross-coupling reactions of thioesters by selective acyl C(O)-S cleavage have emerged as a powerful platform for the preparation of complex molecules. Herein, we report divergent Liebeskind-Srogl cross-coupling of thioesters by Pd-NHC (NHC = N-heterocyclic carbene) catalysis. The reaction provides straightforward access to functionalized ketones by highly selective C(acyl)-S cleavage under mild conditions. Most crucially, the conditions enable direct functionalization of a range of complex pharmaceuticals decorated with a palette of sensitive functional groups, providing attractive products for medicinal chemistry programs. Furthermore, decarbonylative Liebeskind-Srogl cross-coupling by C(acyl)-S/C(aryl)-C(O) cleavage is reported. Cu metal cofactor directs the reaction pathway to acyl or decarbonylative pathway. This reactivity is applicable to complex pharmaceuticals. The reaction represents the mildest decarbonylative Suzuki cross-coupling discovered to date. The Cu-directed divergent acyl and decarbonylative cross-coupling of thioesters opens up chemical space in complex molecule synthesis.

IPr*Oxa - a new class of sterically-hindered, wingtip-flexible N,C-chelating oxazole-donor N-heterocyclic carbene ligands.

N-heterocyclic carbenes (NHCs) have emerged as a major direction in ancillary ligand development for stabilization of reactive metal centers in inorganic and organometallic chemistry. In particular, wingtip-flexible NHCs have attracted significant attention due to their unique ability to provide a sterically-demanding environment for transition metals in various oxidation states. Herein, we report a new class of sterically-hindered, wingtip-flexible NHC ligands that feature N,C-chelating oxazole donors. These ligands are readily accessible through a modular arylation of oxazole derivatives. We report their synthesis and complete structural and electronic characterization. The evaluation of steric, electron-donating and π-accepting properties and coordination chemistry to Ag(I), Pd(II) and Rh(I) is described. Preliminary studies of catalytic activity in Ag, Pd and Rh-catalyzed coupling and hydrosilylation reactions are presented. This study establishes the fluxional behavior of a freely-rotatable oxazole unit, wherein the oxazolyl ring adjusts to the steric and electronic environment of the metal center. Considering the tremendous impact of sterically-hindered NHCs and their potential to stabilize reactive metals by N-chelation, we expect that this class of NHC ligands will be of broad interest in inorganic and organometallic chemistry.

[IPr#-PEPPSI]: A Well-Defined, Highly Hindered and Broadly Applicable Pd(II)-NHC (NHC = N-Heterocyclic Carbene) Precatalyst for Cross-Coupling Reactions.

In this Special Issue, "Featured Papers in Organometallic Chemistry", we report on the synthesis and characterization of [IPr#-PEPPSI], a new, well-defined, highly hindered Pd(II)-NHC precatalyst for cross-coupling reactions. This catalyst was commercialized in collaboration with MilliporeSigma, Burlington, ON, Canada (no. 925489) to provide academic and industrial researchers with broad access to reaction screening and optimization. The broad activity of [IPr#-PEPPSI] in cross-coupling reactions in a range of bond activations with C-N, C-O, C-Cl, C-Br, C-S and C-H cleavage is presented. A comprehensive evaluation of the steric and electronic properties is provided. Easy access to the [IPr#-PEPPSI] class of precatalysts based on modular pyridine ligands, together with the steric impact of the IPr# peralkylation framework, will facilitate the implementation of well-defined, air- and moisture-stable Pd(II)-NHC precatalysts in chemistry research.

Esterification of Thioamides via Selective N-C(S) Cleavage under Mild Conditions.

Herein, we report an exceedingly mild method for the direct, transition-metal-free esterification of thioamides through the selective generation of tetrahedral intermediates. The method represents the first transition-metal-free approach to the thioamide to thionoester transformation in organic synthesis. This reactivity has been accomplished through N,N-Boc2-thioamides that engage in ground-state destabilization of the nN → π*C═S conjugation. The ground-state destabilization of "single-atom" bioisosteric thioamides will expand the arsenal of valuable amide bond functionalization reactions.

Suzuki-Miyaura Cross-Coupling of Amides by N-C Cleavage Mediated by Air-Stable, Well-Defined [Pd(NHC)(sulfide)Cl2] Catalysts: Reaction Development, Scope, and Mechanism.

The Suzuki-Miyaura cross-coupling of amides by selective N-C acyl bond cleavage represents a powerful tool for constructing biaryl ketones from historically inert amide bonds. These amide bond activation reactions hinge upon efficient oxidative addition of the N-C acyl bond to Pd(0). However, in contrast to the well-researched activation of aryl halides by C(sp2)-X oxidative addition, very few studies on the mechanism of C(acyl)-N bond oxidative addition and catalyst effect have been reported. Herein, we report a study on [Pd(NHC)(sulfide)Cl2] catalysts in amide N-C bond activation. These readily prepared, well-defined, air- and moisture-stable Pd(II)-NHC catalysts feature SMe2 (DMS = dimethylsulfide) or S(CH2CH2)2 (THT = tetrahydrothiophene) as ancillary ligands. The reaction development, kinetic studies, and reaction scope are presented. Extensive DFT studies were conducted to gain insight into the mechanism of C(acyl)-N bond oxidative addition and catalyst activation. We expect that [Pd(NHC)(sulfide)Cl2] precatalysts featuring sulfides as well-defined, readily accessible ancillary ligands will find application in C(acyl)-X bond activation in organic synthesis and catalysis.

ItOct (ItOctyl) - pushing the limits of ItBu: highly hindered electron-rich N-aliphatic N-heterocyclic carbenes.

ItBu (ItBu = 1,3-di-tert-butylimidazol-2-ylidene) represents the most important and most versatile N-alkyl N-heterocyclic carbene available in organic synthesis and catalysis. Herein, we report the synthesis, structural characterization and catalytic activity of ItOct (ItOctyl), C2-symmetric, higher homologues of ItBu. The new ligand class, including saturated imidazolin-2-ylidene analogues has been commercialized in collaboration with MilliporeSigma: ItOct, 929 298; SItOct, 929 492 to enable broad access of the academic and industrial researchers within the field of organic and inorganic synthesis. We demonstrate that replacement of the t-Bu side chain with t-Oct results in the highest steric volume of N-alkyl N-heterocyclic carbenes reported to date, while retaining the electronic properties inherent to N-aliphatic ligands, such as extremely strong σ-donation crucial to the reactivity of N-alkyl N-heterocyclic carbenes. An efficient large-scale synthesis of imidazolium ItOct and imidazolinium SItOct carbene precursors is presented. Coordination chemistry to Au(i), Cu(i), Ag(i) and Pd(ii) as well as beneficial effects on catalysis using Au(i), Cu(i), Ag(i) and Pd(ii) complexes are described. Considering the tremendous importance of ItBu in catalysis, synthesis and metal stabilization, we anticipate that the new class of ItOct ligands will find wide application in pushing the boundaries of new and existing approaches in organic and inorganic synthesis.

Hydration Reactions Catalyzed by Transition Metal-NHC (NHC = N-Heterocyclic Carbene) Complexes.

The catalytic addition of water to unsaturated C-C or C-N π bonds represent one of the most important and environmentally sustainable methods to form C-O bonds for the production of synthetic intermediates, medicinal agents and natural products. The traditional acid-catalyzed hydration of unsaturated compounds typically requires strong acids or toxic mercury salts, which limits practical applications and presents safety and environmental concerns. Today, transition-metal-catalyzed hydration supported by NHC (NHC = N-heterocyclic carbene) ligands has attracted major attention. By rational design of ligands, choice of metals and counterions as well as mechanistic studies and the development of heterogeneous systems, major progress has been achieved for a broad range of hydration processes. In particular, the combination of NHC ligands with gold shows excellent reactivity compared with other catalytic systems; however, other systems based on silver, ruthenium, osmium, platinum, rhodium and nickel have also been discovered. Ancillary NHC ligands provide stabilization of transition metals and ensure high catalytic activity in hydration owing to their unique electronic and steric properties. NHC-Au(I) complexes are particularly favored for hydration of unsaturated hydrocarbons due to soft and carbophilic properties of gold. In this review, we present a comprehensive overview of hydration reactions catalyzed by transition metal-NHC complexes and their applications in catalytic hydration of different classes of π-substrates with a focus on the role of NHC ligands, types of metals and counterions.

Suzuki-Miyaura Cross-Coupling of 2-Pyridyl Trimethylammonium Salts by N-C Activation Catalyzed by Air- and Moisture-Stable Pd-NHC Precatalysts: Application to the Discovery of Agrochemicals.

We report the first Suzuki-Miyaura cross-coupling of 2-pyridyl ammonium salts by highly selective N-C activation catalyzed by air- and moisture-stable Pd(II)-NHC (NHC = N-heterocyclic carbene) precatalysts. The use of well-defined and highly reactive [Pd(IPr)(3-CF3-An)Cl2] (An = aniline) or [Pd(IPr)(cin)Cl] (cin = cinnamyl) Pd(II)-NHC catalysts permits an exceptionally broad scope of the cross-coupling to furnish valuable biaryl and heterobiarylpyridines that are ubiquitous in medicinal chemistry and agrochemistry research. The overall process leverages the Chichibabin C-H amination of pyridines with N-C activation to enable an attractive strategy to the 2-pyridyl problem. The utility of the method to the discovery of potent agrochemicals is presented. Considering the importance of 2-pyridines and the versatility of N-C activation methods, we envision that this new C-H/N-C activation strategy will find broad application.

Decarbonylative Alkynylation of Aryl Anhydrides via Palladium Catalysis.

A robust palladium-catalyzed decarbonylative alkynylation of aryl anhydrides is reported. The catalytic system of Pd(OAc)2/XantPhos and DMAP as a nucleophilic additive has been identified as effective promoters for decarbonylative Sonogashira alkynylation. Recently, activated esters, amides, and carboxylic acids were applied as electrophiles in transition-metal-catalyzed decarbonylative alkynylation. The present process expands this reactivity to readily available aryl anhydrides as electrophilic reagents for decarbonylative alkynylation. It is worth noting that the reactivity of aryl anhydrides is higher than that of esters, amides, and carboxylic acids in decarbonylative alkynylation. Broad substrate scope and excellent functional group tolerance are presented, demonstrating that aryl anhydrides may serve as a general and practical class of electrophiles to achieve the synthesis of internal alkynes.

Hypervalent iodine-promoted twofold oxidative coupling of amines with amides and thioamides: chemoselective pathway to oxazoles and thiazoles.

Direct functionalization of the C(O)-N amide bond is one of the most high-profile research directions in the last few decades; however oxidative couplings involving amide bonds and functionalization of thioamide C(S)-N analogues remain an unsolved challenge. Herein, a novel hypervalent iodine-induced twofold oxidative coupling of amines with amides and thioamides has been established. The protocol accomplishes divergent C(O)-N and C(S)-N disconnection by the previously unknown Ar-O and Ar-S oxidative coupling and highly chemoselectively assembles the versatile yet synthetically challenging oxazoles and thiazoles. Employing amides instead of thioamides affords an alternative bond cleavage pattern, which is a result of the higher conjugation in thioamides. Mechanistic investigations indicate ureas and thioureas generated in the first oxidation as pivotal intermediates to realize the oxidative coupling. These findings open up new avenues for exploring oxidative amide and thioamide bond chemistry in various synthetic contexts.

Ag-NHC Complexes in the π-Activation of Alkynes.

Silver-NHC (NHC = N-heterocyclic carbene) complexes play a special role in the field of transition-metal complexes due to (1) their prominent biological activity, and (2) their critical role as transfer reagents for the synthesis of metal-NHC complexes by transmetalation. However, the application of silver-NHCs in catalysis is underdeveloped, particularly when compared to their group 11 counterparts, gold-NHCs (Au-NHC) and copper-NHCs (Cu-NHC). In this Special Issue on Featured Reviews in Organometallic Chemistry, we present a comprehensive overview of the application of silver-NHC complexes in the p-activation of alkynes. The functionalization of alkynes is one of the most important processes in chemistry, and it is at the bedrock of organic synthesis. Recent studies show the significant promise of silver-NHC complexes as unique and highly selective catalysts in this class of reactions. The review covers p-activation reactions catalyzed by Ag-NHCs since 2005 (the first example of p-activation in catalysis by Ag-NHCs) through December 2022. The review focuses on the structure of NHC ligands and p-functionalization methods, covering the following broadly defined topics: (1) intramolecular cyclizations; (2) CO2 fixation; and (3) hydrofunctionalization reactions. By discussing the role of Ag-NHC complexes in the p-functionalization of alkynes, the reader is provided with an overview of this important area of research and the role of Ag-NHCs to promote reactions that are beyond other group 11 metal-NHC complexes.

Carboxylic-Phosphoric Anhydrides as Direct Electrophiles for Decarbonylative Hirao Cross-Coupling of Carboxylic Acids: DFT Investigation of Mechanistic Pathway.

In this anniversary issue, we present a DFT study of the mechanism of decarbonylative Hirao cross-coupling of carboxylic-phosphoric anhydrides to afford aryl phosphonates. Traditionally, the direct activation of carboxylic acids to participate in decarbonylative couplings is performed in the presence of carboxylic acid anhydride activators. We discovered that direct dehydrogenative decarbonylative phosphorylation of benzoic acid can be performed in high yield via dehydrogenative and decarbonylative coupling in the presence of phosphite as dual activating and nucleophilic reagent, enabling direct decarbonylative phosphorylation. Control studies demonstrated that carboxylic-phosphoric anhydride (acyl phosphate) is an intermediate in this process. DFT studies were conducted to gain insight into this decarbonylative process and compare the selectivity of C-O and P-O bond activations. Considering the utility of ubiquitous carboxylic acids, this alternative activation pathway may find applications in decarbonylative coupling of carboxylic acids for the synthesis of valuable molecules in organic synthesis.

Diversification of Indoles and Pyrroles by Molecular Editing: New Frontiers in Heterocycle-to-Heterocycle Transmutation.

Skeletal editing via single-atom insertion reactions involving nitrogen heterocycles have been reported by two innovative and complementary methods for the conversion of pyrroles and indoles to pyridines, quinolines and quinazolines. The use of electrophilic carbonyl cation equivalents and in situ generated nitrenes enables molecular editing to transform heterocycles forming the foundation of best-selling pharmaceuticals. Considering the importance of heterocycles in medicinal chemistry, biology and natural products, these methods offer innovative approach to complex molecular structures by heterocycle diversification and peripheral editing.

L-Shaped Heterobidentate Imidazo[1,5-a]pyridin-3-ylidene (N,C)-Ligands for Oxidant-Free AuI /AuIII Catalysis.

In the last decade, major advances have been made in homogeneous gold catalysis. However, AuI /AuIII catalytic cycle remains much less explored due to the reluctance of AuI to undergo oxidative addition and the stability of the AuIII intermediate. Herein, we report activation of aryl halides at gold(I) enabled by NHC (NHC=N-heterocyclic carbene) ligands through the development of a new class of L-shaped heterobidentate ImPy (ImPy=imidazo[1,5-a]pyridin-3-ylidene) N,C ligands that feature hemilabile character of the amino group in combination with strong σ-donation of the carbene center in a rigid conformation, imposed by the ligand architecture. Detailed characterization and control studies reveal key ligand features for AuI /AuIII redox cycle, wherein the hemilabile nitrogen is placed at the coordinating position of a rigid framework. Given the tremendous significance of homogeneous gold catalysis, we anticipate that this ligand platform will find widespread application.