Samarium diiodide/samarium-mediated direct deoxygenative hydroborylation of ketones with hydroborane esters.

A direct deoxygenative hydroborylation of ketones with hydroborane ester promoted by a combination of samarium diiodide, samarium and nickel has been developed. In this method, secondary alkyl borate esters are synthesized from unactivated ketones with hydroborane esters in one step. A broad substrate scope and excellent selectivity toward CO cleavage has been demonstrated. This approach represents a general method for the construction of versatile secondary alkyl borate esters from unactivated ketones.

IPr*Thia - wingtip-flexible, sterically hindered, modular, N,C/S,C-chelating thiazole-donor N-heterocyclic carbene ligands.

N-Heterocyclic carbenes (NHCs) represent a pivotal class of ligands in coordination chemistry owing to their unique electronic properties. In particular, hemilabile N-heterocyclic carbenes have garnered significant attention over the past decade due to their capacity to transiently coordinate to metals and open coordination sites. However, hemilabile NHC ligands have been predominantly limited to N, O and P donors, while NHC ligands bearing versatile S-donors have been severely underdeveloped. Herein, we report wingtip-flexible, sterically hindered NHC ligands that feature N,C/S,C-chelating thiazole donors in combination with the powerful IPr* (IPr* = (2,6-bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene) scaffold. These ligands are prepared using a highly modular SNAr arylation of thiazole derivatives. Full structural and electronic characterization is reported. The ligands feature a high barrier to rotation around the N-thiazole axis (10 kcal mol-1). The ligands are evaluated for their steric, electron-donating and π-accepting properties as well as coordination chemistry to Ag(I), Pd(II), Rh(I) and Se. Preliminary studies on Ag, Pd and Rh catalysis are presented. The efficiency of the approach is highlighted by preparing a library of unsymmetrical imidazolium precursors. The mono-IPr* wingtip provides a highly hindered yet sterically flexible environment adjusting to metal centers, while the N-thiazolyl wingtip displays a fluxional behavior that interchanges from the hard/soft N,C to soft/soft S,C coordination. Considering the importance of hemilabile N-heterocyclic carbene ligands in metal stabilization in inorganic and organometallic chemistry, we expect that this class of ligands will be of broad interest.

Gold-catalysed amine synthesis by reductive hydroamination of alkynes with nitroarenes.

Amines are the most pivotal class of organic motifs in pharmaceutical compounds. Here we provide a blueprint for a general synthesis of amines by catalyst differentiation enabled by triple Au-H/Au+/Au-H relay catalysis. The parent catalyst is differentiated into a set of catalytically active species to enable triple cascade catalysis, where each catalytic species is specifically tuned for one catalytic cycle. This strategy enables the synthesis of biorelevant amine motifs by reductive hydroamination of alkynes with nitroarenes. Using this triple cascade approach, we have achieved exceptional functional group tolerance, enabling the use of bulk chemical feedstocks as coupling partners for the amination of both simple and complex alkynes (>100 examples), including those derived from pharmaceuticals, peptides and natural products (>30 examples). The isolation and full crystallographic characterization of gold hydride and hydride-bridged gold complexes has garnered insights into the catalyst differentiation process of fundamental organometallic gold hydride complexes.

IPr*F - Highly Hindered, Fluorinated N-Heterocyclic Carbenes.

The introduction of fluorine atom has attracted considerable interest in molecular design owing to the high electronegativity and the resulting polarization of carbon-fluorine bonds. Simultaneously, sterically-hindered N-heterocyclic carbenes (NHCs) have received major interest due to high stabilization of the reactive metal centers, which has paved the way for the synthesis of stable and reactive organometallic compounds with broad applications in main group chemistry, inorganic synthesis and transition-metal-catalysis. Herein, we report the first class of sterically-hindered, fluorinated N-heterocyclic carbenes. These ligands feature variable fluorine substitution at the N-aromatic wingtip, permitting to rationally vary steric and electronic characteristics of the carbene center imparted by the fluorine atom. An efficient, one-pot synthesis of fluorinated IPr*F ligands is presented, enabling broad access of academic and industrial researchers to the fluorinated ligands. The evaluation of steric, electron-donating and π-accepting properties as well as coordination chemistry to Au(I), Rh(I) and Se is presented. Considering the unique properties of carbon-fluorine bonds, we anticipate that this novel class of fluorinated carbene ligands will find widespread application in stabilizing reactive metal centers.

Tuning the steric hindrance of alkylamines: a predictive model of steric editing of planar amines.

Amines are one of the most prevalent functional groups in chemistry. Perhaps even more importantly, amines represent one of the most ubiquitous moieties within the realm of bioactive natural products and life-saving pharmaceuticals. The archetypal geometrical property of amines is their sp3 hybridization with the lone pair of nitrogen occupying the apex of the pyramid. Herein, we present a blueprint for quantifying the properties of extremely sterically hindered alkylamines. These amines reach planarity around the nitrogen atom due to the excessive steric hindrance, which results in a conformational re-modeling of the amine moiety. Crucially, the steric properties of amines are characterized by the %V Bur index, which we show is a general predictive parameter for evaluating the properties of sterically hindered amines. Computational studies on the acidic nature and the reactivity of organometallic Au and Pd complexes are outlined. Density functional theory calculations permit for predictive catalysis, ordering the mapping of extremely hindered tertiary amines by employing artificial intelligence via machine learning. Overall, the study outlines the correlation between the unusual geometry and the key thermodynamic and kinetic properties of extremely hindered alkylamines. The steric hindrance, as quantified by %V Bur, is the crucial factor influencing the observed trends and the space required to accommodate sterically hindered tertiary amines.

[(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.

Deoxygenative alkynylation of amides via CO bond cleavage.

A novel deoxygenative alkynylation of amides promoted by a synergistic action of a divalent rare-earth element and a transition metal has been developed. In this method, α-alkynyl substituted amines are synthesized from unactivated amides and alkynes in a single transformation. Broad substrate scope and excellent selectivity for CO cleavage has been demonstrated. This approach represents a general method for the construction of versatile α-alkynyl substituted amines from unactivated amide 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.

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.

[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.

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.