[(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.

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.

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.

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.

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.

Classes of Amides that Undergo Selective N-C Amide Bond Activation: The Emergence of Ground-State Destabilization.

Ground-state destabilization of the N-C(O) linkage represents a powerful tool to functionalize the historically inert amide bond. This burgeoning reaction manifold relies on the availability of amide bond precursors that participate in weakening of the nN → π*C=O conjugation through N-C twisting, N pyramidalization, and nN electronic delocalization. Since 2015, acyl N-C amide bond activation through ground-state destabilization of the amide bond has been achieved by transition-metal-catalyzed oxidative addition of the N-C(O) bond, generation of acyl radicals, and transition-metal-free acyl addition. This Perspective summarizes contributions of our laboratory in the development of new ground-state-destabilized amide precursors enabled by twist and electronic activation of the amide bond and synthetic utility of ground-state-destabilized amides in cross-coupling reactions and acyl addition reactions. The use of ground-state-destabilized amides as electrophiles enables a plethora of previously unknown transformations of the amide bond, such as acyl coupling, decarbonylative coupling, radical coupling, and transition-metal-free coupling to forge new C-C, C-N, C-O, C-S, C-P, and C-B bonds. Structural studies of activated amides and catalytic systems developed in the past decade enable the view of the amide bond to change from the "traditionally inert" to "readily modifiable" functional group with a continuum of reactivity dictated by ground-state destabilization.

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.

Acyclic Twisted Amides.

In this contribution, we provide a comprehensive overview of acyclic twisted amides, covering the literature since 1993 (the year of the first recognized report on acyclic twisted amides) through June 2020. The review focuses on classes of acyclic twisted amides and their key structural properties, such as amide bond twist and nitrogen pyramidalization, which are primarily responsible for disrupting nN to π*C═O conjugation. Through discussing acyclic twisted amides in comparison with the classic bridged lactams and conformationally restricted cyclic fused amides, the reader is provided with an overview of amidic distortion that results in novel conformational features of acyclic amides that can be exploited in various fields of chemistry ranging from organic synthesis and polymers to biochemistry and structural chemistry and the current position of acyclic twisted amides in modern chemistry.

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.

[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.

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.

Synthesis of Natural Products by C-H Functionalization of Heterocycless.

Total synthesis is considered by many as the finest combination of art and science. During the last decades, several concepts were proposed for achieving the perfect vision of total synthesis, such as atom economy, step economy, or redox economy. In this context, C-H functionalization represents the most powerful platform that has emerged in the last years, empowering rapid synthesis of complex natural products and enabling diversification of bioactive scaffolds based on natural product architectures. In this review, we present an overview of the recent strategies towards the total synthesis of heterocyclic natural products enabled by C-H functionalization. Heterocycles represent the most common motifs in drug discovery and marketed drugs. The implementation of C-H functionalization of heterocycles enables novel tactics in the construction of core architectures, but also changes the logic design of retrosynthetic strategies and permits access to natural product scaffolds with novel and enhanced biological activities.

Buchwald-Hartwig Amination of Coordinating Heterocycles Enabled by Large-but-Flexible Pd-BIAN-NHC Catalysts.

A new class of large-but-flexible Pd-BIAN-NHC catalysts (BIAN=acenaphthoimidazolylidene, NHC=N-heterocyclic carbene) has been rationally designed to enable the challenging Buchwald-Hartwig amination of coordinating heterocycles. This robust class of BIAN-NHC catalysts permits cross-coupling under practical aerobic conditions of a variety of heterocycles with aryl, alkyl, and heteroarylamines, including historically challenging oxazoles and thiazoles as well as electron-deficient heterocycles containing multiple heteroatoms with BIAN-INon (N,N'-bis(2,6-di(4-heptyl)phenyl)-7H-acenaphtho[1,2-d]imidazol-8-ylidene) as the most effective ligand. Studies on the ligand structure and electronic properties of the carbene center are reported. The study should facilitate the discovery of even more active catalyst systems based on the unique BIAN-NHC scaffold.

Suzuki-Miyaura Cross-Coupling of Aryl Fluorosulfonates Mediated by Air- and Moisture-stable [Pd(NHC)(µ-Cl)Cl]2 Precatalysts: Broad Platform for C-O Cross-Coupling of Stable Phenolic Electrophiles.

A highly efficient protocol for the Suzuki-Miyaura cross-coupling of aryl fluorosulfonates by selective -OF cleavage using well-defined, air- and moisture-stable NHC-Pd(II) chloro dimers is presented. The reaction proceeds in excellent yields and with broad functional group tolerance using 0.10-0.20 mol % of [Pd] in the presence of mild K3PO4 base under aqueous conditions. A variety of sensitive functional groups are tolerated in this operationally trivial protocol for C-O bond activation. Selectivity studies and gram scale cross-coupling are presented. The method advances well-defined and highly reactive Pd(II)-NHCs to the cross-coupling of readily available, orthogonal, and bench-stable fluorosulfonates as aryl halide surrogates.

Transamidation of thioamides with nucleophilic amines: thioamide N-C(S) activation by ground-state-destabilization.

Thioamides are 'single-atom' isosteres of amide bonds that have found broad applications in organic synthesis, biochemistry and drug discovery. In this New Talent themed issue, we present a general strategy for activation of N-C(S) thioamide bonds by ground-state-destabilization. This concept is outlined in the context of a full study on transamidation of thioamides with nucleophilic amines, and relies on (1) site-selective N-activation of the thioamide bond to decrease resonance and (2) highly chemoselective nucleophilic acyl addition to the thioamide CS bond. The follow-up collapse of the tetrahedral intermediate is favored by the electronic properties of the amine leaving group. The ground-state-destabilization concept of thioamides enables weakening of the N-C(S) bond and rationally modifies the properties of valuable thioamide isosteres for the development of new methods in organic synthesis. We fully expect that in analogy to the burgeoning field of destabilized amides introduced by our group in 2015, the thioamide bond ground-state-destabilization activation concept will find broad applications in various facets of chemical science, including metal-free, metal-catalyzed and metal-promoted reaction pathways.

N-Heterocyclic Carbene Complexes in C-H Activation Reactions.

In this contribution, we provide a comprehensive overview of C-H activation methods promoted by NHC-transition metal complexes, covering the literature since 2002 (the year of the first report on metal-NHC-catalyzed C-H activation) through June 2019, focusing on both NHC ligands and C-H activation methods. This review covers C-H activation reactions catalyzed by group 8 to 11 NHC-metal complexes. Through discussing the role of NHC ligands in promoting challenging C-H activation methods, the reader is provided with an overview of this important area and its crucial role in forging carbon-carbon and carbon-heteroatom bonds by directly engaging ubiquitous C-H bonds.

Sequential Iron-Catalyzed C(sp2)-C(sp3) Cross-Coupling of Chlorobenzamides/Chemoselective Amide Reduction and Reductive Deuteration to Benzylic Alcohols.

Benzylic alcohols are among the most important intermediates in organic synthesis. Recently, the use of abundant metals has attracted significant attention due to the issues with the scarcity of platinum group metals. Herein, we report a sequential method for the synthesis of benzylic alcohols by a merger of iron catalyzed cross-coupling and highly chemoselective reduction of benzamides promoted by sodium dispersion in the presence of alcoholic donors. The method has been further extended to the synthesis of deuterated benzylic alcohols. The iron-catalyzed Kumada cross-coupling exploits the high stability of benzamide bonds, enabling challenging C(sp2)-C(sp3) cross-coupling with alkyl Grignard reagents that are prone to dimerization and ß-hydride elimination. The subsequent sodium dispersion promoted reduction of carboxamides proceeds with full chemoselectivity for the C-N bond cleavage of the carbinolamine intermediate. The method provides access to valuable benzylic alcohols, including deuterium-labelled benzylic alcohols, which are widely used as synthetic intermediates and pharmacokinetic probes in organic synthesis and medicinal chemistry. The combination of two benign metals by complementary reaction mechanisms enables to exploit underexplored avenues for organic synthesis.

Chemoselective Transamidation of Thioamides by Transition-Metal-Free N-C(S) Transacylation.

Thioamides represent highly valuable isosteric in the strictest sense "single-atom substitution" analogues of amides that have found broad applications in chemistry and biology. A long-standing challenge is the direct transamidation of thioamides, a process which would convert one thioamide bond (R-C(S)-NR1 R2 ) into another (R-C(S)-NR3 N4 ). Herein, we report the first general method for the direct transamidation of thioamides by highly chemoselective N-C(S) transacylation. The method relies on site-selective N-tert-butoxycarbonyl activation of 2° and 1° thioamides, resulting in ground-state-destabilization of thioamides, thus enabling to rationally manipulate nucleophilic addition to the thioamide bond. This method showcases a remarkably broad scope including late-stage functionalization (>100 examples). We further present extensive DFT studies that provide insight into the chemoselectivity and provide guidelines for the development of transamidation methods of the thioamide bond.

Highly Chemoselective Transamidation of Unactivated Tertiary Amides by Electrophilic N-C(O) Activation by Amide-to-Acyl Iodide Re-routing.

The challenging transamidation of unactivated tertiary amides has been accomplished via cooperative acid/iodide catalysis. Most crucially, the method provides a novel manifold to re-route the reactivity of unactivated N,N-dialkyl amides through reactive acyl iodide intermediates, thus reverting the classical order of reactivity of carboxylic acid derivatives. This method provides a direct route to amide-to-amide bond interconversion with excellent chemoselectivity using equivalent amounts of amines. The combination of acid and iodide has been identified as the essential factor to activate the amide C-N bond through electrophilic catalytic activation, enabling the production of new desired transamidated products with wide substrate scope of both unactivated amides and amines, including late-stage functionalization of complex APIs (>80 examples). We anticipate that this powerful activation mode of unactivated amide bonds will find broad-ranging applications in chemical synthesis.