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.

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.

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.

CAAC-IPr*: easily accessible, highly sterically-hindered cyclic (alkyl)(amino)carbenes.

IPr* (IPr* = 1,3-bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene) has emerged as a powerful highly hindered and sterically-flexible ligand platform for transition-metal catalysis. CAACs (CAAC = cyclic (al-kyl)(amino)carbenes) have gained major attention as strongly electron-rich carbon analogues of NHCs (NHC = N-heterocyclic carbene) with broad applications in both industry and academia. Herein, we report a merger of CAAC ligands with highly-hindered IPr*. The efficient synthesis, electronic characterization and application in model Cu-catalyzed hydroboration of alkynes is described. The ligands are strongly electron-rich, bulky and flexible around the N-Ar wingtip. The availability of various IPr* and CAAC templates offers a significant potential to expand the existing arsenal of NHC ligands to electron-rich bulky architectures with critical applications in metal stabilization and catalysis.

Well-Defined, Air- and Moisture-Stable Palladium-Imidazo[1,5-a]pyridin-3-ylidene Complexes: A Versatile Catalyst Platform for Cross-Coupling Reactions by L-Shaped NHC Ligands.

We describe the development of [(NHC)Pd(cinnamyl)Cl] complexes of ImPy (ImPy = imidazo[1,5-a]pyridin-3-ylidene) as a versatile class of precatalysts for cross-coupling reactions. These precatalysts feature fast activation to monoligated Pd(0) with 1:1 Pd to ligand ratio in a rigid imidazo[1,5-a]pyridin-3-ylidene template. Steric matching of the C5-substituent and N2-wingtip in the catalytic pocket of the catalyst framework led to the discovery of ImPyMesDipp as a highly reactive imidazo[1,5-a]pyridin-3-ylidene ligand for Pd-catalyzed cross-coupling of nitroarenes by challenging C-NO2 activation. Kinetic studies demonstrate fast activation and high reactivity of this class of well-defined ImPy-Pd catalysts. Structural studies provide full characteristics of this new class of imidazo[1,5-a]pyridin-3-ylidene ligands. Computational studies establish electronic properties of sterically-restricted imidazo[1,5-a]pyridin-3-ylidene ligands. Finally, a scalable synthesis of C5-substituted imidazo[1,5-a]pyridin-3-ylidene ligands through Ni-catalyzed Kumada cross-coupling is disclosed. The method obviates chromatographic purification at any of the steps, resulting in a facile and modular access to ImPy ligands. We anticipate that well-defined [Pd-ImPy] complexes will find broad utility in organic synthesis and catalysis for activation of unreactive bonds.

Pd-Catalyzed Double-Decarbonylative Aryl Sulfide Synthesis through Aryl Exchange between Amides and Thioesters.

We report the palladium-catalyzed double-decarbonylative synthesis of aryl thioethers by an aryl exchange reaction between amides and thioesters. In this method, amides serve as aryl donors and thioesters are sulfide donors, enabling the synthesis of valuable aryl sulfides. The use of Pd/Xantphos without any additives has been identified as the catalytic system promoting the aryl exchange by C(O)-N/C(O)-S cleavages. The method is amenable to a wide variety of amides and sulfides.

Suzuki-Miyaura Cross-Coupling of Esters by Selective O-C(O) Cleavage Mediated by Air- and Moisture-Stable [Pd(NHC)(µ-Cl)Cl]2 Precatalysts: Catalyst Evaluation and Mechanism.

The cross-coupling of aryl esters has emerged as a powerful platform for the functionalization of otherwise inert acyl C-O bonds in chemical synthesis and catalysis. Herein, we report a combined experimental and computational study on the acyl Suzuki-Miyaura cross-coupling of aryl esters mediated by well-defined, air- and moisture-stable Pd(II)-NHC precatalysts [Pd(NHC)(µ-Cl)Cl]2. We present a comprehensive evaluation of [Pd(NHC)(µ-Cl)Cl]2 precatalysts and compare them with the present state-of-the-art [(Pd(NHC)allyl] precatalysts bearing allyl-type throw-away ligands. Most importantly, the study reveals [Pd(NHC)(µ-Cl)Cl]2 as the most reactive precatalysts discovered to date in this reactivity manifold. The unique synthetic utility of this unconventional O-C(O) cross-coupling is highlighted in the late-stage functionalization of pharmaceuticals and sequential chemoselective cross-coupling, providing access to valuable ketone products by a catalytic mechanism involving Pd insertion into the aryl ester bond. Furthermore, we present a comprehensive study of the catalytic cycle by DFT methods. Considering the clear advantages of [Pd(NHC)(µ-Cl)Cl]2 precatalysts on several levels, including facile one-pot synthesis, superior atom-economic profile to all other Pd(II)-NHC catalysts, and versatile reactivity, these should be considered as the 'first-choice' catalysts for all routine applications in ester O-C(O) bond activation.

Total Flavonoids of Rhizoma Drynariae Restore the MMP/TIMP Balance in Models of Osteoarthritis by Inhibiting the Activation of the NF-κB and PI3K/AKT Pathways.

Total flavonoids of Rhizoma Drynariae (TFRD) have been shown to have beneficial effects on osteoarthritis (OA) clinically, but the mechanisms have not been elucidated. In this study, we investigated the effect of TFRD on articular cartilage in an OA rat model established by the Hulth method and in SW1353 chondrocytes induced by the proinflammatory factor interleukin-1ß (IL-1ß). The results showed that TFRD could alleviate the pathological changes in knee cartilage in OA model rats. In vivo, the qPCR analysis indicated that the mRNA levels of matrix metalloproteinases, MMP-1, MMP-3, and MMP-13, were decreased, while tissue inhibitor of matrix metalloproteinases- (TIMP-) 4 was increased in cartilage, and these changes could be partially prevented by TFRD. In vitro experiments showed that IL-1ß could significantly increase the expression of MMP-1, MMP-3, and MMP-13 and decrease the expression of TIMP-4 in SW1353 cells at the mRNA and protein levels. TFRD could increase the expression of MMP-3 and MMP-13 and decrease the expression of TIMP-4. Transfection of siRNA and addition of pathway inhibitors were used to clarify that inhibition of NF-κB and PI3K/AKT pathway decreased MMP-1, MMP-3, and MMP-13 and increased TIMP-4 expression. We also found that in IL-1ß-induced SW1353 cells, TFRD pretreatment had a modest inhibitory effect on p-AKT (Ser473) and reversed the increase of nuclear factor kappa-B (NF-κB) p65 in nuclear fraction and the decrease of inhibitor of NF-κB(IκB)-α in the cytosolic fraction. Further immunofluorescence confirmed that TFRD can inhibit IL-1ß-induced NF-κB p65 translocation to the nucleus to some extent. In conclusion, TFRD showed chondroprotective effects by restoring the MMP/TIMP balance in OA models by suppressing the activation of the NF-κB and PI3K/AKT pathways.

Early Diagnosis of Cerebral Ischemia Reperfusion Injury and Revelation of Its Regional Development by a H3R Receptor-Directed Probe.

In vivo imaging of cerebral hydrogen peroxide (H2O2) may facilitate early diagnosis of cerebral ischemia reperfusion injury (CIRI) and a revelation of its pathological progression. In this study, we report our rational design of a brain-targeting fluorescent probe using the basis of a pyridazinone scaffold. A structure-activity relationship study reveals that PCAB is the best candidate (Ki = 15.8 nM) for a histamine H3 receptor (H3R), which is highly expressed in neurons of the central nervous system. As a two-photon fluorescent probe, PCAB exhibits a fast, selective reaction toward both extra- and intracellular H2O2 in SH-SY5Y cells under oxygen glucose deprivation and resupply. In vivo fluorescent imaging of a middle cerebral artery occlusion mouse confirms that PCAB is an ultrasensitive probe with potent blood-brain barrier penetration, precise brain targeting, and fast detection of CIRI.

Bimetallic Cooperative Catalysis for Decarbonylative Heteroarylation of Carboxylic Acids via C-O/C-H Coupling.

Cooperative bimetallic catalysis is a fundamental approach in modern synthetic chemistry. We report bimetallic cooperative catalysis for the direct decarbonylative heteroarylation of ubiquitous carboxylic acids via acyl C-O/C-H coupling. This novel catalytic system exploits the cooperative action of a copper catalyst and a palladium catalyst in decarbonylation, which enables highly chemoselective synthesis of important heterobiaryl motifs through the coupling of carboxylic acids with heteroarenes in the absence of prefunctionalization or directing groups. This cooperative decarbonylative method uses common carboxylic acids and shows a remarkably broad substrate scope (>70 examples), including late-stage modification of pharmaceuticals and streamlined synthesis of bioactive agents. Extensive mechanistic and computational studies were conducted to gain insight into the mechanism of the reaction. The key step involves intersection of the two catalytic cycles via transmetallation of the copper-aryl species with the palladium(II) intermediate generated by oxidative addition/decarbonylation.

Decarbonylative Suzuki-Miyaura Cross-Coupling of Aroyl Chlorides.

Herein, we report a catalyst system for Pd-catalyzed decarbonylative Suzuki-Miyaura cross-coupling of aroyl chlorides with boronic acids to furnish biaryls. This strategy is suitable for a broad range of common aroyl chlorides and boronic acids. The synthetic utility is highlighted in the direct late-stage functionalization of pharmaceuticals and natural products capitalizing on the presence of carboxylic acid moiety. Extensive mechanistic and DFT studies provide key insight into the reaction mechanism and high decarbonylative cross-coupling selectivity.

[Pd(NHC)(µ-Cl)Cl]2: Versatile and Highly Reactive Complexes for Cross-Coupling Reactions that Avoid Formation of Inactive Pd(I) Off-Cycle Products.

The development of more reactive, general, easily accessible, and readily available Pd(II)-NHC precatalysts remains a key challenge in homogeneous catalysis. In this study, we establish air-stable NHC-Pd(II) chloro-dimers, [Pd(NHC)(µ-Cl)Cl]2, as the most reactive Pd(II)-NHC catalysts developed to date. Most crucially, compared with [Pd(NHC)(allyl)Cl] complexes, replacement of the allyl throw-away ligand with chloride allows for a more facile activation step, while effectively preventing the formation of off-cycle [Pd2(µ-allyl)(µ-Cl)(NHC)2] products. The utility is demonstrated via broad compatibility with amide cross-coupling, Suzuki cross-coupling, and the direct, late-stage functionalization of pharmaceuticals. Computational studies provide key insight into the NHC-Pd(II) chloro-dimer activation pathway. A facile synthesis of NHC-Pd(II) chloro-dimers in one-pot from NHC salts is reported. Considering the tremendous utility of Pd-catalyzed cross-coupling reactions and the overwhelming success of [Pd(NHC)(allyl)Cl] precatalysts, we believe that NHC-Pd(II) chloro-dimers, [Pd(NHC)(µ-Cl)Cl]2, should be considered as go-to precatalysts of choice in cross-coupling processes.

A Smart Fluorescent Probe for NO Detection and Application in Myocardial Fibrosis Imaging.

On the basis of the pyridazinone scaffold and photoinduced electron transfer (PET) mechanism, we designed a smart nitric oxide (NO) probe, PYSNO, with high sensitivity and selectivity. PYSNO exhibited a rapid response to both exogenous and endogenous NO. This probe can also be used in tracking and investigating NO generation in animal tissue. In the myocardial fibrosis model for mice, PYSNO exhibited a powerful imaging property in vivo as a result of unravelling the progressive relationship between the generation of myocardial NO and the occurrence of myocardial fibrosis.

Design and synthesis of tripeptidyl furylketones as selective inhibitors against the ß5 subunit of human 20S proteasome.

A series of tripeptidic proteasome inhibitors with furylketone as C-terminus were designed and synthesized. Biochemical evaluations against ß1, ß2 and ß5 subunits revealed that they acted selectively on ß5 subunit with IC50s against chymotrypsin-like (CT-L) activity in micromolar range. LC-MS/MS analysis of the ligand-20S proteasome mixture showed that the most potent compound 11m (IC50 = 0.18 µM) made no covalent modification on 20S proteasome. However, it was identified acting in a slowly reversible manner in wash-out assay and the reversibility was much lower than that of MG132, suggesting the possibility of these tripeptidic furylketones forming reversible covalent bonds with 20S proteasome. Several compounds were selected for anti-proliferative assay towards multiple cancer cell lines, and compound 11m displayed comparable potency to positive control (MG132) in all cell lines tested. Furthermore, the pharmacokinetic (PK) data in rats indicated 11m behaved similarly (Cmax, 2007 µg/L; AUC0-t, 680 µg/L·h; Vss, 0.66 L/kg) to the clinical used agent carfilzomib. All these data suggest 11m is a good lead compound to be developed to novel anti-tumor agent.

Palladium-Catalyzed Cross-Couplings by C-O Bond Activation.

Although palladium-catalyzed cross-coupling of aryl halides and reactive pseudohalides has revolutionized the way organic molecules are constructed today across various fields of chemistry, comparatively less progress has been made in the palladium-catalyzed cross-coupling of less reactive C-O electrophiles. This is despite the fact that the use of phenols and phenol derivatives as bench-stable cross-coupling partners has been well-recognized to bring about major advantages over aryl halides, such as (1) natural abundance of phenols, (2) avoidance of toxic halides, (3) orthogonal cross-coupling conditions, (4) prefunctionalization of phenolic substrates by electrophilic substitution or C-H functionalization, (5) ready availability of phenols from a different pool of precursors than aryl halides. In this review, we present an overview of recent advances made in the field of palladium-catalyzed cross-coupling of C-O electrophiles with a focus on (1) catalytic systems, (2) reaction type, and (3) class of C-O coupling partners. Although the field has been historically dominated by nickel catalysis, it is now evident that the use of more versatile, more functional group tolerant and highly active palladium catalysts supported by appropriately designed ancillary ligands enables the cross-coupling with improved substrate scope and generality, and likely represents a practical solution to the broadly applicable cross-coupling of various C-O bonds across diverse chemical disciplines. The review covers the period through June 2020.

Decarbonylative Phosphorylation of Carboxylic Acids via Redox-Neutral Palladium Catalysis.

We describe the direct synthesis of organophosphorus compounds from ubiquitous aryl and vinyl carboxylic acids via decarbonylative palladium catalysis. The catalytic system shows excellent scope and tolerates a wide range of functional groups (>50 examples). The utility of this powerful methodology is highlighted in the late-stage derivatization directly exploiting the presence of the prevalent carboxylic acid functional group. DFT studies provided insight into the origin of high bond activation selectivity and P(O)-H isomerization pathway.

[Pd(NHC)(acac)Cl]: Well-Defined, Air-Stable, and Readily Available Precatalysts for Suzuki and Buchwald-Hartwig Cross-coupling (Transamidation) of Amides and Esters by N-C/O-C Activation.

A general class of well-defined, air-stable, and readily available Pd(II)-NHC precatalysts (NHC = N-heterocyclic carbene) for Suzuki and Buchwald-Hartwig cross-coupling of amides (transamidation) and esters by selective N-C/O-C cleavage is reported. Since these precatalysts are highly active and the easiest to synthesize, the study clearly suggests that [Pd(NHC)(acac)Cl] should be routinely included during the development of new cross-coupling methods. An assay for in situ screening of NHC salts in this cross-coupling manifold is presented.

Palladium-catalyzed decarbonylative Suzuki-Miyaura cross-coupling of amides by carbon-nitrogen bond activation.

Palladium-catalyzed Suzuki-Miyaura cross-coupling or aryl halides is widely employed in the synthesis of many important molecules in synthetic chemistry, including pharmaceuticals, polymers and functional materials. Herein, we disclose the first palladium-catalyzed decarbonylative Suzuki-Miyaura cross-coupling of amides for the synthesis of biaryls through the selective activation of the N-C(O) bond of amides. This new method relies on the precise sequence engineering of the catalytic cycle, wherein decarbonylation occurs prior to the transmetallation step. The reaction is compatible with a wide range of boronic acids and amides, providing valuable biaryls in high yields (>60 examples). DFT studies support a mechanism involving oxidative addition, decarbonylation and transmetallation and provide insight into high N-C(O) bond activation selectivity. Most crucially, the reaction establishes the use of palladium catalysis in the biaryl Suzuki-Miyaura cross-coupling of the amide bond and should enable the design of a wide variety of cross-coupling methods in which palladium rivals the traditional biaryl synthesis from aryl halides and pseudohalides.