Iron/NHC-Catalyzed Regio- and Stereoselective 1,6-Additions of Aliphatic Grignard Reagents to α,β,γ,δ-Unsaturated Carbonyl Compounds: Asymmetric Variants with Chiral NHCs.

Although conjugate addition to an α,β‐unsaturated carbonyl compound is a well‐established method in synthetic organic chemistry, controlling regioselectivity, olefin geometry, and positional isomerism in analogous 1,6‐addition chemistry, which provides a powerful approach for constructing molecular complexity, remains a key challenge. Herein, we report the iron‐catalyzed regio‐, stereo‐, and enantioselective 1,6‐additions of aliphatic Grignard reagents to α,β,γ,δ‐unsaturated carbonyl compounds. The incorporation of an N ‐heterocyclic carbene (NHC) ligand effectively suppresses undesired β‐hydride elimination, thereby enabling the highly cis ‐selective installation of the aliphatic group. Remarkably, the use of a rigid tetracyclic chiral NHC ligand afforded the corresponding adducts with enantioselectivities of up to 99%. The developed reaction shows broad substrate scope, accommodating various aliphatic Grignard reagents and unsaturated carbonyl compounds, thereby providing direct access to optically active 1,6‐adducts bearing cis ‐configured olefins. Mechanistic investigations, including deuterium‐labeling experiments, support the involvement of magnesium enolates and an iron–NHC catalytic cycle. The developed transformation provides a powerful strategy for the remote functionalization of extended conjugated carbonyl frameworks.

ConspectusAsymmetric transition-metal catalysis stands as a cornerstone in the construction of molecules with stereogenic centers, profoundly impacting modern organic synthesis. Over the past decades, catalytic asymmetric synthesis has witnessed remarkable advancements, largely driven by the development of sophisticated chiral ligands. While chiral phosphorus ligands have experienced rapid growth and widespread application, chiral N-heterocyclic carbene (NHC) ligands remain underexplored, primarily due to the inherent challenges in designing and synthesizing suitable chiral frameworks. Given the unique topology and modular steric environment of NHCs, the development of novel NHC ligands holds significant promise.In our pursuit of broadly applicable and privileged catalysts with innovative structural motifs, we have developed a family of induced-fit chiral NHC ligands based on the privileged chiral fragment strategy using a C2-symmetric chiral aniline. These ligands are characterized by their ease of structural modification, bulky yet flexible nature, and versatile utility in asymmetric metal catalysis. Notably, they can be synthesized on a large scale from inexpensive starting materials without the need for column chromatography, offering a modular and straightforward preparation method that facilitates further exploration of their applications in asymmetric reactions. In this Account, we summarize recent progress in our group regarding the diverse and unique applications of these induced-fit NHC ligands in Pd-, Ni-, and Cu-catalyzed asymmetric reactions, encompassing reaction types, substrate scope, stereocontrol steps, and mechanistic insights. Our work is categorized into five sections based on reaction types: asymmetric cross-coupling reactions, asymmetric functionalization of alkenes, asymmetric hydrogen transfer reactions, asymmetric C-H functionalization reactions, and asymmetric nucleophilic addition reactions. These studies demonstrate the broad utility of the ligands in asymmetric catalysis, with their bulky yet flexible nature enabling adaptive stereocontrol across diverse elementary steps and challenging transformations.We anticipate that this Account will not only broaden the application of this class of chiral ligands but also inspire the design of new chiral NHC ligands for transition-metal-catalyzed asymmetric reactions. We believe that continued efforts focused on bulky yet flexible NHC ligands will offer practical solutions to critical challenges in chemical synthesis, further advancing the field of asymmetric catalysis.

The cyclopentane scaffold has attracted much attention due to its ubiquity in numerous bioactive natural products such as prostaglandins and polyquinanes. However, despite a plethora of available procedures to access this motif, a lack of methods that rival the generality of the Diels-Alder reaction for the synthesis of six-membered rings represents an important gap. Thus, the development of protocols providing efficient access to functionalized chiral cyclopentanes from simple and readily accessible starting materials is highly desirable. In this respect, the tremendous advances in the development of nickel-catalyzed carbon-carbon bond-forming reactions, combined with the unique properties of N-heterocyclic carbenes have led to the development of new approaches to five-membered carbocyclic rings. These include nickel-catalyzed reductive couplings and reductive [3+2] cycloadditions. These strategies are attractive, as functionalized five-membered carbocyclic rings can be accessed from two simple pi-components without any changes in atom connectivity. Despite the recent development of numerous chiral N-heterocyclic carbenes and their successful application in various transition metal-catalyzed reactions, applications in asymmetric nickel catalysis remain scarce. This thesis describes the development of efficient enantioselective nickel-catalyzed methodologies for the formation of five-membered carbocycles from readily accessible and inexpensive starting materials, enabled by two novel chiral N-heterocyclic carbene ligands. First, the development of an intermolecular enantioselective nickel-catalyzed reductive [3+2] cycloaddition of unsaturated aromatic esters and internal alkynes for the synthesis of cyclopentenones is described. For this scalable methodology, a bulky chiral C1-symmetric N-heterocyclic carbene ligand was shown to facilitate the efficient asymmetric synthesis of cyclopentenones from a wide range of mesityl enoates and internal alkynes under mild conditions. Unsymmetrically substituted alkynes were incorporated in a regioselective fashion and the cyclopentenones were synthesized in high yields and enantioselectivity. As a second methodology for the construction of chiral cyclopentane scaffolds, an intermolecular diastereoselective and enantioselective nickel-catalyzed reductive three-component coupling of various aryl aldehydes, norbornene derivatives and silanes is described, which gives access to synthetically valuable silyl-protected indan-1-ols via an aromatic C(sp2)-H functionalization. A bulky chiral C2-symmetric N-heterocyclic carbene ligand possessing a 1,2-(dinaphthalen-1-yl)ethylene diamine scaffold provided the silylated indan-1-ols under mild and scalable conditions, as a single diastereoisomer, in high enantioselectivity and good regioselectivity in the case of meta-substituted aryl aldehydes.

The Kundig group has developed Herrmann-Enders type bulky chiral N-heterocyclic carbene (NHC) ligand precursors during the last couple of years. The aim of this thesis is to study the intrinsic properties of these carbene ligands and to broaden their scope in the field of asymmetric catalysis. The structural properties of the NHCs had been studied by employing their corresponding NHC-BH3 adducts. Crystal structures of the NHC-BH3 complexes showed the importance of allylic strain in the arrangement of the ligands' substituents in space. Our interest in the electron donating ability of the NHCs motivated us to synthesize cis-Ir(CO)2Cl(NHC) type of complexes. Such complexes gave us the opportunity to compare the electron donating ability of the NHC ligands developed in our research group with the literature known NHC ligands. The chiral NHC ligands were tested in the asymmetric gold catalysis and ruthenium catalyzed asymmetric hydrogenation of prochiral ketones.

This chapter aims to provide an overview of the most successful families of chiral N-heterocyclic carbene (NHC) ligands used in asymmetric catalysis since 2011. Over the past decade, the structures of chiral NHCs have gained in diversity, and new families of very efficient ligands have emerged, particularly bulky chiral monodentate NHCs. On the other hand, chiral NHC ligands, which had previously proven their usefulness, were used to remove bottlenecks in homogeneous catalysis. Both directions are explored and illustrated in this chapter. New trends and challenges in ligand design are also discussed.

Quantum chemical calculations at B3LYP/aug-cc-pVTZ level about singlet N-heterocyclic carbene (NHC) ligands, imidazol-2-ylidene, imidazol-4-ylidene, pyrazol-3-ylidene and pyrazol-4-ylidene, and their protonated analogues show that they are considerably aromatic except for pyrazol-3-ylidene. This result is experimentally verified by approximately five thousand NHC transition metal complexes retrieved from the Cambridge Structural Database (CSD). CSD search discloses that NHCs can participate in π-stacking interactions, albeit scarce. Geometry-based HOMA and electronic aromaticity index FLU rather than NICS provide a satisfactory description of the bonding situations in NHC ligands. Singlet state of the normal NHC has electron-deficient aromaticity as compared to those of the abnormal and remote NHCs. Depending on the transition from the singlet to triplet state, NHCs become electron-deficient ligands except for remote NHC. Computational studies regarding electronic nature of free NHC ligands show that the π-electronic population of the formally vacant pπ orbital on the carbene atoms in abnormal and remote NHC is occurred as a result of the aromaticity of NHCs, not as a result of the direct electron donation from LP-orbitals of N atoms to carbene atom according to putative push-pull effect used in understanding the electronic stabilization of normal NHC. Increase in the aromaticity raises σ-donating ability of both imidazol- and pyrazol-based NHC ligands. Free abnormal and remote NHC ligands have higher σ-donation ability than normal NHC ligands. The lack of σ-donating ability of normal NHC is compensated by its relatively high π-accepting ability, whereas π-back donation abilities of abnormal and remote NHCs are prohibited by their almost fully occupied π-orbitals. Aromaticities of the triplet NHC ligands are higher than that of the lowest-lying triplet state of benzene. Increase in the aromaticity of NHC ligands decreases van der Waals shortening in TM-NHC bonds mainly due to diminishing dative character of these bonds.

Chiral N-heterocyclic carbene ligands with additional chelating group(s) applied to homogeneous metal-mediated asymmetric catalysis

Four novel stable Hoveyda-Grubbs-type catalysts containing N,N'-dineopentyl- and N,N'-dicyclohexyl-substituted N-heterocyclic carbene (NHC) ligands with syn and anti phenyl groups on the ring backbone were synthesized and fully characterized. The catalytic potential of these complexes was investigated in metathesis reactions of both standard and renewable substrates. Compared to the Hoveyda-Grubbs second generation catalyst (HGII), all of the new catalysts showed high performances in most of the examined metathesis transformations. In particular, N,N'-dicyclohexyl catalysts gave improved results in the challenging ring-closing metathesis (RCM) reaction to form tetrasubstituted olefins, while catalysts with neopentyl N-groups were found to be more active and Z-selective in cross-metathesis (CM) reactions. Modest enantioselectivities in the asymmetric ring-closing metathesis (ARCM) of achiral trienes with different steric hindrance were observed in the presence of catalysts bearing chiral C2-symmetric NHC ligands.

We report on novel synthetic approaches to molybdenum imido alkylidene N‐heterocyclic carbene (NHC) complexes including the first NHC alkylidene complexes featuring pentafluorophenyl‐substituted imido ligands, highly basic 6‐Mes (6‐Mes = 1,3‐dimesityl‐3,4,5,6‐tetrahydropyrimidin‐2‐ylidene) NHC ligands and the preparation of the first representatives of cationic 14‐electron Mo imido alkylidene NHC catalysts bearing sterically demanding anionic terphenoxide ligands. Also, the Mo imido alkylidene and alkylidyne NHC bisalkoxide complexes [Mo(NR)(CHCMe2Ph)(NHC)(OR′)2], [Mo(NH‐C6F5)(CCMe2Ph)(aIMes){OCMe(CF3)2}2] (aIMes = 1,3‐dimesitylimidazol‐5‐ylidene, an abnormally C5‐bound imidazolylidene) and [Mo(NH‐2‐CF3‐C6H4)(CCMe2Ph)(6‐Mes){OCMe(CF3)2}2] are presented. Anionic Mo amido alkylidyne complexes have been found to form preferentially in the presence of sterically demanding NHC and alkoxide ligands. The first Mo imido alkylidene NHC complexes containing the strongly basic 6‐Mes ligand, namely [Mo(N‐C6F5)(CHCMe2Ph)(6‐Mes)(Br)2], [Mo(N‐2‐CF3‐C6H4)(CHCMe2Ph)(6‐Mes)(Br)2] and [Mo(N‐2,6‐Me2‐C6H3)(CHCMe2Ph)(6‐Mes)(Br)2], were synthesized from the corresponding Mo imido dibromo alkylidene‐DME complexes (DME = 1,2‐dimethoxyethane) and transformed into their cationic monobromo or monoalkoxide derivatives. Finally, we developed the high yield synthesis of Mo imido alkylidene NHC dichloro complexes via direct protonation of [Mo(N‐Adamantyl)2(CH2CMe2Ph)2] with HCl followed by stabilization with NHCs.

(Imido)vanadium(V)−alkyl, alkylidene complexes containing an N-heterocyclic carbene (NHC) ligand, V(CHSiMe3)(NR)(CH2SiMe3)(NHC) [R = 1-adamantyl (Ad) or 2,6-Me2C6H3 (Ar), NHC = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene], have been prepared from the trialkyl analogues, V(NR)(CH2SiMe3)3, by α-hydrogen elimination in C6D6 in the presence of NHC. The V−C(NHC) bond distance [2.172(2) A] in V(CHSiMe3)(NAd)(CH2SiMe3)(NHC) is much longer than the V−C(alkylidene) [1.829 A] and the V−C(alkyl) [2.069 A] distances, indicating that NHC plays an important role in the stabilization of the high-oxidation-state vanadium(V)−alkylidene as a neutral carbene ligand.

We report the synthesis and characterization of a newseries ofimidazopyridine-based N-heterocyclic carbene (NHC)ligands, including three unique binding modes: less atom-stabilized(C5-bound), remote normal (C7-bound), and remote mesoionic (C8-bound)configurations. These distinct ligands were incorporated into palladium­(II)complexes of both mixed phosphine/NHC and PEPPSI-type structures toinvestigate the ligands’ electron-donating properties and theircatalytic properties. Spectroscopic and computational analyses revealedthat the C7-bound remote NHC ligand exhibits the highest electron-donatingability, with a unique balance of σ-donating and π-acceptingcharacteristics that significantly enhance catalytic performance.The catalytic efficiency of the C7-bound NHC ligand, as demonstratedin the Mizoroki–Heck coupling of aryl chlorides, achieved near-quantitativeyields and displayed rapid activation. This study underscores thepotential of imidazopyridine-based NHC ligands for advancing catalystdesign, especially for applications demanding high electron densityand stability. These findings open new avenues to explore remote NHCligands for challenging catalytic transformations, paving the wayto improved reaction efficiency in synthetic organic chemistry.

The asymmetric functionalization of C-H bond is a particularly valuable approach for the production of enantioenriched chiral organic compounds. Chiral N-heterocyclic carbene (NHC) ligands have become ubiquitous in enantioselective transition-metal catalysis. Conversely, the use of chiral NHC ligands in metal-catalyzed asymmetric C-H bond functionalization is still at an early stage. This minireview highlights all the developments and the new advances in this rapidly evolving research area.

Methods for the selective functionalization of otherwise inert C–H bonds have been recognized as a transformative tool in synthetic organic chemistry, with applications ranging from the synthesis of complex bioactive compounds to material sciences. In particular, 3d metal catalysts have emerged in recent years as inexpensive, earth-abundant and less toxic alternatives to their heavier counterparts. However, full selectivity control in base metal-catalyzed C–H activation continues to be challenging. In this context, the development of novel 3d transition metal catalysts enabling chemo- and stereo-selective C–H functionalizations should be investigated. Within this thesis, we became interested in the development of a user-friendly and broadly applicable protocol for synthetically useful cobalt-catalyzed C–H amidations with ample substrate scope. Furthermore, while the enantioselective functionalization of C–H bonds remains largely dominated by noble transition metal catalysts such as palladium, rhodium and iridium, we developed an unprecedented enantioselective iron-catalyzed C–H alkylation by alkene hydroarylation. The design of novel chiral N-heterocyclic carbene (NHC) ligands proved to be crucial to achieve high enantioselectivities. Furthermore, detailed mechanistic studies were conducted to unravel the nature and mode of action of the in situ generated catalyst. Recently, nickel-catalyzed hydroarylation-type C–H activation has emerged as a cost-efficient alternative to expensive rhodium catalysis. However, the intramolecular hydroarylations of unactivated alkenes remain strongly limited by the requirement of pyrophoric organoaluminium additives, significantly compromising their functional group tolerance and synthetic utility. This observation prompted us to investigate the asymmetric cyclization of N-homoallylimidazoles under aluminium-free conditions. Interestingly, the endo product was selectively obtained, which in sharp contrast to previously reported methods. Mechanistic studies were then conducted in order to delineate the unique reactivity of the developed catalytic system.

N-Heterocyclic carbenes (NHCs) are the ligands of choice in a large variety of transformations entailing different transition metals. However, the number and variety of chiral NHCs suitable as stereo-controlling ligands in asymmetric catalysis remains limited. Herein we highlight the introduction of a modular NHC ligand family, consisting of a chiral version of the widely used IPr ligand. These chiral NHC ligands were applied in the nickel-catalyzed enantioselective C-H functionalization of N-heterocycles. Nickel-NHC catalysis unlocked the stereoselective C-H annulation of 2- and 4-pyridones, delivering fused bicyclic compounds found in many biologically active compounds. Applying a bulky, yet flexible ligand scaffold enabled the highly enantioselective C-H functionalization of pyridones under mild conditions. The introduction of a bulky chiral SIPr analogue enabled the nickel-catalyzed enantioselective C-H functionalization of indoles, yielding valuable tetrahydropyridoindoles. Additionally, pyrrolopyridines, pyrrolopyrimidines and pyrroles were efficiently functionalized, delivering chiral annulated azoles.

The combination of simple cobalt salts and N-heterocyclic carbene (NHC) ligands has been highly effective in C-H functionalization, hydroarylation and cross-coupling catalysis, though displaying a strong dependence on the identity of the NHC ligand. In addition, reactions effective with NHC ligands are often ineffective with phosphine ligands, further motivating the evaluation of the fundamental electronic structure and bonding differences in well-defined distorted tetrahedral Co(ii) complexes. Magnetic circular dichroism (MCD) studies indicate that Co(ii)-bisphosphines have larger ligand fields than Co(ii)-NHC complexes. Theoretical density functional theory (DFT) calculations were performed on an expanded set of L2CoCl2 complexes (L2 = NHC, bisphosphine and diamine) to study the electronic structure and relative ligation properties of NHCs compared to bisphosphine and diamine ligands. Mayer bond order and charge decomposition analyses indicate that NHC ligands are slightly stronger donor ligands than bisphosphines but also result in a weakening of Co-Cl bonds in a trans-like influence. From MCD and DFT studies, changing the NHC N-substituent has a larger effect on the ligand field of Co(ii)-NHC complexes than saturating the backbone. Overall, these studies provide detailed insight into the electronic structure and bonding effects in Co(ii) complexes with ligand types commonly explored in catalysis.