Construction and Function of Thiolate-Bridged Diiron NxHy Nitrogenase Model Complexes.

ConspectusBiological nitrogen fixation mediated by nitrogenases has garnered significant research interest due to its critical importance to the development of efficient catalysts for mild ammonia synthesis. Although the active center of the most studied FeMo-nitrogenases has been determined to be a complicated [Fe7S9MoC] hetero-multinuclear metal-sulfur cluster known as the FeMo-cofactor, the exact binding site and reduction pathway of N2 remain a subject of debate. Over the past decades, the majority of studies have focused on mononuclear molybdenum or iron centers as potential reaction sites. In stark contrast, cooperative activation of N2 through bi- or multimetallic centers has been largely overlooked and underexplored, despite the renewed interest sparked by recent biochemical and computational studies. Consequently, constructing bioinspired bi- or multinuclear metallic model complexes presents an intriguing yet challenging prospect. In this Account, we detail our long-standing research on the design and synthesis of novel thiolate-bridged diiron complexes as nitrogenase models and their application to chemical simulations of potential biological N2 reduction pathways.Inspired by the structural and electronic features of the potential diiron active center in the belt region of the FeMo-cofactor, we have designed and synthesized a series of new thiolate-bridged diiron nitrogenase model complexes, wherein iron centers with +2 or +3 oxidation states are coordinated by Cp* as carbon-based donors and thiolate ligands as sulfur donors. Through the synergistic interaction between the two iron centers, unstable diazene (NH═NH) species can be trapped to generate the first example of a [Fe2S2]-type complex bearing a cis-µ-η1:η1-NH═NH subunit. Significantly, this species can not only catalyze the reductive N-N bond cleavage of hydrazine to ammonia but also trigger a stepwise reduction sequence NH═NH → [NH2-NH]- → [NH]2-(+NH3) → [NH2]- → NH3. Furthermore, an unprecedented thiolate-bridged diiron µ-nitride featuring a bent Fe-N-Fe moiety was successfully isolated and structurally characterized. Importantly, this diiron µ-nitride can undergo successive proton-coupled electron transfer processes to efficiently release ammonia in the presence of separate protons and electrons and can even be directly hydrogenated using H2 as a combination of protons and electrons for high-yield ammonia formation. Based on combined experimental and computational studies, we proposed two distinct reductive transformation sequences on the diiron centers, which involve a series of crucial NxHy intermediates. Moreover, we also achieved catalytic N2 reduction to silylamines with [Fe2S2]-type complexes by ligand modulation.Our bioinspired diiron cooperative scaffold may provide a suitable model for probing the potential N2 stepwise reduction pathways from the molecular level. Different from the traditional alternating and distal pathways dominated by mononuclear iron or molybdenum complexes, our proposed alternating transformation route based on the diiron centers may not involve the N2H4 intermediate, and the convergence point of the alternating and terminal pathways is imide, not amide. Our research strategy could inform the design and development of new types of bioinspired catalysts for mild and efficient nitrogen reduction in the future.

Nickel-Catalyzed Carbonylative Negishi Cross-Coupling of Unactivated Secondary Alkyl Electrophiles with 1 atm CO Gas.

We describe a nickel-catalyzed carbonylative cross-coupling of unactivated secondary alkyl electrophiles with the organozinc reagent at atmospheric CO gas, thus allowing the expedient construction of unsymmetric dialkyl ketones with broad functional group tolerance. The leverage of a newly developed NN2-pincer type ligand enables the chemoselective three-component carbonylation by overcoming the competing Negishi coupling, the undesired ß-hydride elimination, and dehalogenation of alkyl iodides side pathways. Both alkyl iodides and alkyl tosylates are compatible in the single electron transfer involved mechanism.

Stepwise Reduction of Redox Noninnocent Nitrosobenzene to Aniline via a Rare Phenylhydroxylamino Intermediate on a Thiolate-Bridged Dicobalt Scaffold.

Nitrosobenzene (PhNO) and phenylhydroxylamine (PhNHOH) are of paramount importance because of their involvement as crucial intermediates in the biological metabolism and catalytic transformation of nitrobenzene (PhNO2) to aniline (PhNH2). However, a complete reductive transformation cycle of PhNO to PhNH2 via the PhNHOH intermediate has not been reported yet. In this context, we design and construct a new thiolate-bridged dicobalt scaffold that can accomplish coordination activation and reductive transformation of PhNO. Notably, an unprecedented reversible ligand-based redox sequence PhNO0 ↔ PhNO•- ↔ PhNO2- can be achieved on this well-defined {CoIII(µ-SPh)2CoIII} functional platform. Further detailed reactivity investigations demonstrate that the PhNO0 and PhNO•- complexes cannot react with the usual hydrogen and hydride donors to afford the corresponding phenylhydroxylamino (PhNHO-) species. However, the double reduced PhNO2- complex can readily undergo N-protonation with an uncommon weak proton donor PhSH to selectively yield a stable dicobalt PhNHO- bridged complex with a high pKa value of 13-16. Cyclic voltammetry shows that there are two successive reduction events at E1/2 = -0.075 V and Ep = -1.08 V for the PhNO0 complex, which allows us to determine both bond dissociation energy (BDEN-H) of 59-63 kcal·mol-1 and thermodynamic hydricity (ΔGH-) of 71-75 kcal·mol-1 of the PhNHO- complex. Both values indicate that the PhNO•- complex is not a potent hydrogen abstractor and the PhNO0 complex is not an efficient hydride acceptor. In the presence of BH3 as a combination of protons and electrons, facile N-O bond cleavage of the coordinated PhNHO- group can be realized to generate PhNH2 and a dicobalt hydroxide-bridged complex. Overall, we present the first stepwise reductive sequence, PhNO0 ↔ PhNO•- ↔ PhNO2- ↔ PhNHO- → PhNH2.

Palladium-Catalyzed Enantioselective Multicomponent Cross-Coupling of Trisubstituted Olefins.

The development of a catalytic method for stereogenic carbon center formation holds immense significance in organic synthesis. Transition-metal-catalyzed cross-coupling reaction has been regarded as a straightforward and efficient tool for stereoselectively forging C-C bond. Nevertheless, the creation of acyclic all-carbon quaternary-containing vicinal stereocenters remains notoriously challenging within the domain of cross-coupling chemistry despite their prominence in various bioactive small molecules. Herein, we describe a palladium-catalyzed asymmetric multicomponent cross-coupling of trisubstituted alkene with aryl diazonium salts and arylboronic acids to realize the formation of tertiary-quaternary carbon centers with high regio-, distereo-, and enantioselectivity. Specifically, the precise manipulation of the stereoconfiguration of trisubstituted alkenes enables the divergent stereoselective cross-coupling reaction, thus allowing for the facile construction of all four enantiomers. Harnessing the ligand-swap strategy involving a chiral bisoxazoline and an achiral fumarate individually accelerates the enantioselective migratory insertion and reductive elimination step in the cross-coupling process, as supported by density functional theory (DFT) calculations, thus obviating the requirement for a neighboring directing group within the internal olefin skeleton.

Asymmetric synthesis of atropisomeric arylpyrazoles via direct arylation of 5-aminopyrazoles with naphthoquinones.

Construction of axially chiral arylpyrazoles represents an attractive challenge due to the relatively low rotational barrier of biaryl structures containing five-membered heterocycles. This work describes the catalytic asymmetric construction of axially chiral arylpyrazoles using 5-aminopyrazoles and naphthoquinone derivatives. The chiral axis could be formed through a central-to-axial chirality relay step of the chiral phosphoric acid-catalyzed arylation reaction, which features excellent yields and enantioselectivities with a broad substrate scope under mild reaction conditions.

Nickel-catalyzed acylation of vinylpyridine with alkylzincs under 1 atm CO.

A nickel-catalyzed acylation of vinylpyridines with CO at atmospheric pressure is reported, allowing for an expedient approach to synthesize ß-acyl pyridine derivatives with high regio- and chemoselectivity. The electron-withdrawing property of pyridine plays pivotal roles in activating the alkenyl group, thereby facilitating this carbonylative process. In addition to vinylpyridines, other alkenylheterocycles such as thiazole and quinoline were also suitable for this method.

Novel trifluoromethyl ketone derivatives as oral cPLA2/COX-2 dual inhibitors for resolution of inflammation in rheumatoid arthritis.

Thirty-five trifluoromethyl hydrazones and seventeen trifluoromethyl oxime esters were designed and synthesized via molecular hybridization. All the target compounds were initially screened for in vitro anti-inflammatory activity by assessing their inhibitory effect on NO release in LPS-stimulated RAW264.7 cells, and the optimal compound was finally identified as 2-(3-Methoxyphenyl)-N'-((6Z,9Z,12Z,15Z)-1,1,1-trifluorohenicosa-6,9,12,15-tetraen-2-ylidene)acetohydrazide (F26, IC50 = 4.55 ± 0.92 µM) with no cytotoxicity. Moreover, F26 potently reduced the production of PGE2 in LPS-stimulated RAW264.7 cells compared to indomethacin. The interaction of F26 with COX-2 and cPLA2 was directly verified by the CETSA technique. F26 was found to modulate the phosphorylation levels of p38 MAPK and NF-κB p65, as well as the protein expression of IκB, cPLA2, COX-2, and iNOS in LPS-stimulated rat peritoneal macrophages. Additionally, F26 was observed to prevent the nuclear translocation of NF-κB p65 in LPS-stimulated rat peritoneal macrophages by immunofluorescence localization. Therefore, the aforementioned in vitro experiments demonstrated that F26 blocked the p38 MAPK and NF-κB pathways by binding to COX-2 and cPLA2. In the adjuvant-induced arthritis model, F26 demonstrated a significant effect in preventing arthritis symptoms and inflammatory status in rats, exerting an immunomodulatory role by regulating the homeostasis between Th17 and Treg through inhibition of the p38 MAPK/cPLA2/COX-2/PGE2 and NF-κB pathways. Encouragingly, F26 caused less acute ulcerogenicity in rats at a dose of 50 mg/kg compared to indomethacin. Overall, F26 is a promising candidate worthy of further investigation for treating inflammation and associated pain with lesser gastrointestinal irritation, as well as other symptoms in which cPLA2 and COX-2 are implicated in the pathophysiology.

Cobalt-Catalyzed Asymmetric Aza-Nozaki-Hiyama-Kishi (NHK) Reaction of α-Imino Esters with Alkenyl Halides.

Chromium-catalyzed enantioselective Nozaki-Hiyama-Kishi (NHK) reaction represents one of the most powerful approaches for the formation of chiral carbon-heteroatom bond. However, the construction of sterically encumbered tetrasubstituted stereocenter through NHK reaction still posts a significant challenge. Herein, we disclose a cobalt-catalyzed aza-NHK reaction of ketimine with alkenyl halide to provide a convenient synthetic approach for the manufacture of enantioenriched tetrasubstituted α-vinylic amino acid. This protocol exhibits excellent functional group tolerance with excellent 99 % ee in most cases. Additionally, this asymmetric reductive method is also applicable to the aldimine to access the trisubstituted stereogenic centers.

Cobalt-Catalyzed Enantioselective Reductive α-Chloro-Carbonyl Addition of Ketimine to Construct the ß-Tertiary Amino Acid Analogues.

ß-Tertiary amino acid derivatives constitute one of the most frequently occurring units in natural products and bioactive molecules. However, the efficient asymmetric synthesis of this motif still remains a significant challenge. Herein, we disclose a cobalt-catalyzed enantioselective reductive addition reaction of ketimine using α-chloro carbonyl compound as a radical precursor, providing expedient access to a diverse array of enantioenriched ß-quaternary amino acid analogues. This protocol exhibits outstanding enantioselectivity and broad substrate scope with excellent functional group tolerance. Preliminary mechanism studies rule out the possibility of Reformatsky-type addition and confirm the involvement of radical species in stereoselective addition process. The synthetic utility has been demonstrated through the rapid assembly of iterative amino acid units and oligopeptide, showcasing its versatile platform for late-stage modification of drug candidates.

Unusual Hydrogenation Reactivities of a Thiolate-Bridged Dicobalt µ-Nitride Featuring a Bent {CoIII-N-CoIII} Core.

Transition metal nitrides have received considerable attention owing to their crucial roles in nitrogen fixation and nitrogen atom transfer reactions. Compared to the early and middle transition metals, it is much more challenging to access late transition metal nitrides, especially cobalt in group 9. So far, only a handful of cobalt nitrides have been reported; consequently, their hydrogenation reactivity is largely unexplored. Herein, we present a structurally and spectroscopically well-characterized thiolate-bridged dicobalt µ-nitride [Cp*CoIII(µ-SAd)(µ-N)CoIIICp*] (2) featuring a bent {CoIII(µ-N)CoIII} core. Remarkably, complex 2 can realize not only direct hydrogenation of nitride to amide but also stepwise N-H bond formation from nitride to ammonia. Specifically, 2 can facilely activate dihydrogen (H2) at mild conditions to generate a dicobalt µ-amide [Cp*CoII(µ-SAd)(µ-NH2)CoIICp*] (4) via an unusual mechanism of two-electron oxidation of H2 as proposed by computational studies; in the presence of protons (H+) and electrons, nitride 2 can convert to dicobalt µ-imide [Cp*CoIII(µ-SAd)(µ-NH)CoIIICp*][BPh4] (3[BPh4]) and to CoIICoII µ-amide 4, and finally release ammonia. In contrast to 2, the only other structurally characterized dicobalt µ-nitride Na(THF)4{[(ketguan)CoIII(N3)]2(µ-N)} (ketguan = [(tBu2CN)C(NDipp)2]-, Dipp = 2,6-diisopropylphenyl) (e) that possesses a linear {CoIII(µ-N)CoIII} moiety cannot directly react with H2 or H+. Further in-depth electronic structure analyses shed light on how the varying geometries of the {CoIII(µ-N)CoIII} moieties in 2 and e, bent vs linear, impart their disparate reactivities.

DMAP-Catalyzed [4+3] Spiroannulation of Pyrazolone-Derived Morita-Baylis-Hillman Carbonates with N-(o-Chloromethyl)aryl Amides to Forge Spiro[pyrazolone-azepine] Scaffolds.

A novel DMAP-catalyzed [4+3] spiroannulation of pyrazolone-derived Morita-Baylis-Hillman carbonates with N-(o-chloromethyl)aryl amides was developed. This reaction led to the assembly of medicinally relevant pyrazolone and azepine nuclei into a structurally new spirocyclic scaffold, and a diverse array of spiro[pyrazolone-azepine] products were afforded in good to excellent yields (up to 93%) with a wide substrate scope (23 examples) under mild conditions. Moreover, a gram-scale reaction and product transformations were conducted, which further increased the diversity of products.

Squaramide-catalyzed asymmetric regioselective allylic alkylation of 4-aminopyrazolones with Morita-Baylis-Hillman carbonates.

An efficient squaramide-catalyzed asymmetric allylic alkylation of 4-aminopyrazolones with various MBH carbonates via different pathways has been described. This method provides access to a series of pyrazolone derivatives bearing a nitrogen-containing quaternary stereocenter in high yields with excellent enantioselectivities and regioselectivities under mild conditions. In addition, we utilized the target products to construct a range of bi-heterocyclic skeletons through [3 + 2] cycloadditions. These novel hybrid heterocycles would be promising candidates for drug-discovery programs and chemical biology.

Desymmetrization of Prochiral N-Pyrazolyl Maleimides via Organocatalyzed Asymmetric Michael Addition with Pyrazolones: Construction of Tri-N-Heterocyclic Scaffolds Bearing Both Central and Axial Chirality.

The desymmetrization of N-pyrazolyl maleimides was realized through an asymmetric Michael addition by using pyrazolones under mild conditions, leading to the formation of a tri-N-heterocyclic pyrazole-succinimide-pyrazolone assembly in high yields with excellent enantioselectivities (up to 99% yield, up to 99% ee). The use of a quinine-derived thiourea catalyst was essential for achieving stereocontrol of the vicinal quaternary-tertiary stereocenters together with the C-N chiral axis. Salient features of this protocol included a broad substrate scope, atom economy, mild conditions and simple operation. Moreover, a gram-scale experiment and derivatization of the product further illustrated the practicability and potential application value of this methodology.

Palladium-Catalyzed Stereoselective Construction of 1,3-Stereocenters Displaying Axial and Central Chirality via Asymmetric Alkylations.

The concurrent construction of 1,3-stereocenters remains a challenge. Herein, we report the development of stereoselective union of a point chiral center with allenyl axial chirality in 1,3-position by Pd-catalyzed asymmetric allenylic alkylation between racemic allenyl carbonates and indanone-derived ß-ketoesters. Various target products bearing a broad range of functional groups were afforded in high yield (up to 99%) with excellent enantioselectivities (up to 98% ee) and good diastereoselectivities (up to 13:1 dr).

Catalytic Asymmetric Diarylation of Internal Acyclic Styrenes and Enamides.

Enantioselective transformations of olefins are among the most important strategies for the asymmetric synthesis of organic compounds. Chemo-, diastereo-, and stereoselective control of reactions with internal acyclic alkenes for the construction of functionalized acyclic alkanes still remain a persistent challenge. Here, we report a palladium-catalyzed asymmetric regiodivergent Heck-type diarylation of internal acyclic alkenes. The 1,2-diarylation of two accessible acyclic alkenes, cinnamyl carbamates and enamides with diazonium salts and aromatic boronic acids, furnishes products containing vicinal stereogenic centers via the stereospecific formation of carbonyl coordination-assisted transient palladacycles. Moreover, the asymmetric migratory diarylation of enamides enables the formation of incontiguous stereocenters by an interrupted diastereoselective 1,3-chain-walking process. This protocol streamlines access to highly functionalized multisubstituted enantioenriched carbamates and amine derivatives which are embedded in the key biologically active motifs.

Carbonylative Cross-Coupling Reaction of Allylic Alcohols and Organoalanes with 1†atm CO Enabled by Nickel Catalysis.

A nickel-catalyzed three-component carbonylative cross-coupling reaction of allylic alcohols and organoalanes with CO at atmospheric pressure is reported, enabling the expedient formation of ß,γ-unsaturated ketones with broad scope. Particularly, the chemoselective allylic carbonylation of diols further highlights the practicability of this protocol. The leverage of organoalanes as both the coupling components and the activators for the alcohol functionalization is crucial for this method, thus no extraneous activators are required.

A Bioinspired Iron-Molybdenum µ-Nitrido Complex and Its Reactivity toward Ammonia Formation.

Multimetallic nitride species, especially those containing biologically related iron or molybdenum, are fundamentally important to understand the nitrogen reduction process catalysed by FeMo-nitrogenase. However, until now, there remains no report about the construction of structurally well-defined FeMo heteronuclear nitrido complex and its reactivity toward ammonia formation. Herein, a novel thiolate-bridged FeII MoVI complex featuring a bent Fe-N≡Mo fragment is synthesized and structurally characterized, which can be easily protonated to form a µ-imido complex. Subsequently, through the proton-coupled electron transfer (PCET) process, this imido species can smoothly convert into the µ-amido complex, which can further undergo reductive protonation to afford the FeMo complex containing an ammine ligand. Overall, we present the first well-defined {Fe(µ-S)2 Mo} platform that can give a panoramic picture for the late stage (N3- →NH2- →NH2- →NH3 ) of biological nitrogen reduction by the heterometallic cooperativity.

Nickel-Catalyzed Enantioselective Reductive Alkyl-Carbamoylation of Internal Alkenes.

Herein, we leverage the Ni-catalyzed enantioselective reductive dicarbofunctionalization of internal alkenes with alkyl iodides to enable the synthesis of chiral pyrrolidinones bearing vicinal stereogenic centers. The application of newly developed 1-Nap Quinim is critical for formation of two contiguous stereocenters in high yield, enantioselectivity, and diastereoselectivity. This catalytic system also improves both the yield and enantioselectivity in the synthesis of α,α-dialkylated γ-lactams. Computational studies reveal that the enantiodetermining step proceeds with a carbamoyl-NiI intermediate that is reduced by the Mn reductant prior to intramolecular migratory insertion. The presence of the t-butyl group of the Quinim ligand leads to an unfavorable distortion of the substrate in the TS that leads to the minor enantiomer. Calculations also support an improvement in enantioselectivity with 1-Nap Quinim compared to p-tol Quinim.

Catalytic Desymmetric Dicarbofunctionalization of Unactivated Alkenes.

The construction of multi-stereocenters by a transition metal-catalyzed cross-coupling reaction is a major challenge. The catalytic desymmetric functionalization of unactivated alkenes remains largely unexplored. Herein, we disclose -a desymmetric dicarbofunctionalization of 1,6-dienes via a nickel-catalyzed reductive cross-coupling reaction. The leverage of the underdeveloped chiral 8-Quinox enables the Ni-catalyzed desymmetric carbamoylalkylation of both unactivated mono- and disubstituted alkenes to form pyrrolidinone bearing two nonadjacent stereogenic centers in high enantio- and stereoselectivitives with broad functional-group tolerance. The synthetic application of pyrrolidinones allows the rapid access to complex chiral fused-heterocycles.

Generation of a Sulfinamide Species from Facile N-O Bond Cleavage of Nitrosobenzene by a Thiolate-Bridged Diiron Complex.

The activation of nitrosobenzene promoted by transition-metal complexes has gained considerable interest due to its significance for understanding biological processes and catalytic C-N bond formation processes. Despite intensive studies in the past decades, there are only limited cases where electron-rich metal centers were commonly employed to achieve the N-O or C-N bond cleavage of the coordinated nitrosobenzene. In this regard, it is significant and challenging to construct a suitable functional system for examining its unique reactivity toward reductive activation of nitrosoarene. Herein, we present a {Fe2S2} functional platform that can activate nitrosobenzene via an unprecedented iron-directed thiolate insertion into the N-O bond to selectively generate a well-defined diiron benzenesulfinamide complex. Furthermore, computational studies support a proposal that in this concerted four-electron reduction process of nitrosobenzene the iron center serves as an important electron shuttle. Notably, compared to the intact bridging nitrosoarene ligand, the benzenesulfinamide moiety has priority to convert into aniline in the presence of separate or combined protons and reductants, which may imply the formation of the sulfinamide species accelerates reduction process of nitrosoarene. The reaction pattern presented here represents a novel activation mode of nitrosobenzene realized by a thiolate-bridged diiron complex.