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.

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.

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.

Discovery of novel NSAID hybrids as cPLA2/COX-2 dual inhibitors alleviating rheumatoid arthritis via inhibiting p38 MAPK pathway.

A series of NSAIDs hybrid molecules were synthesized and characterized, and their ability to inhibit NO release in LPS-induced RAW264.7 macrophages was evaluated. Most of the compounds showed significant anti-inflammatory activity in vitro, of which (2E,6Z,9Z,12Z,15Z)-1,1,1-trifluorohenicosa-2,6,9,12,15-pentaen-2-yl 2-(4-benzoylphenyl) propanoate (VI-60) was the most optimal (IC50 = 3.85 ± 0.25 µΜ) and had no cytotoxicity. In addition, VI-60 notably reduced the production of PGE2 in LPS-stimulated RAW264.7 cells compared to ketoprofen. Futhur more, VI-60 significantly inhibited the expression of iNOS, cPLA2, and COX-2 and the phosphorylation of p38 MAPK in LPS-stimulated RAW264.7 cells. The binding of VI-60 to cPLA2 and COX-2 was directly verified by the CETSA technique. In vivo studies illustrated that VI-60 exerted an excellent therapeutic effect on adjuvant-induced arthritis in rats by regulating the balance between Th17 and Treg through inhibiting the p38 MAPK/cPLA2/COX-2/PGE2 pathway. Encouragingly, VI-60 showed a lower ulcerative potential in rats at a dose of 50 mg/kg compared to ketoprofen. In conclusion, the hybrid molecules of NSAIDs and trifluoromethyl enols are promising candidates worthy of further investigation for the treatment of inflammation, pain, and other symptoms in which cPLA2 and COX-2 play a role in their etiology.

Modular α-tertiary amino ester synthesis through cobalt-catalysed asymmetric aza-Barbier reaction.

Unnatural chiral α-tertiary amino acids containing two different carbon-based substituents at the α-carbon centre are widespread in biologically active molecules. This sterically rigid scaffold is becoming a growing research interest in drug discovery. However, a robust protocol for chiral α-tertiary amino acid synthesis remains scarce due to the challenge of stereoselectively constructing sterically encumbered tetrasubstituted stereogenic carbon centres. Herein we report a cobalt-catalysed enantioselective aza-Barbier reaction of ketimines with various unactivated alkyl halides, including alkyl iodides, alkyl bromides and alkyl chlorides, enabling the formation of chiral α-tertiary amino esters with a high level of enantioselectivity and excellent functional group tolerance. Primary, secondary and tertiary organoelectrophiles are all tolerated in this asymmetric reductive addition protocol, which provides a complementary method for the well-exploited enantioselective nucleophilic addition with moisture- and air-sensitive organometallic reagents. Moreover, the three-component transformation of α-ketoester, amine and alkyl halide represents a formal asymmetric deoxygenative alkylamination of the carbonyl group.

Nickel-catalyzed acylzincation of allenes with organozincs and CO.

Transition metal-catalyzed carbonylative reaction with CO gas are among the central task in organic synthesis, enabling the construction of highly valuable carbonyl compound. Here, we show an earth-abundant nickel-catalyzed three-component tandem acylzincation/cyclization sequence of allene and alkylzinc reagent with 1 atm of CO under mild conditions. This protocol is featured by broad functional group tolerance with high reaction selectivity, providing a rapid and convenient synthetic method for the construction of diverse fully substituted benzotropone derivatives. Mechanistic studies reveal that the installation of a cyano group tethered to allene moiety enables the high regio- and stereoselectivity of this acylzincation of allene, allowing the selective formation of three consecutive C-C bonds in a highly efficient manner.

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.

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.

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.

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).

Merging Alkene Isomerization Enables Difunctionalization of Cyclic Enamines toward Ring-Fused Aminal Synthesis.

Here we report a Pd-catalyzed isomerization of alicyclic allyl amine to achieve the unprecedented α,ß-difunctionalization of synthetically inaccessible trisubstituted cyclic enamine. The dual role of in situ formed enamine intermediate allows for the intermolecular formal [4 + 2] reaction with acrylamide or isatoic anhydride to simultaneously construct the C-C bond and C-N bond, thus realizing the expedient construction of [4.3.0]-aminal with excellent diastereoselectivity and high atom economy.

Nickel-Catalyzed Aminocarbonylation of Aryl Iodides with 1 atm CO.

Reported here is a nickel-catalyzed aminocarbonylation of aromatic iodides with (hetero)aryl anilines and alkyl amines under atmospheric CO pressure. The reaction features with broad substrate scope with excellent functional group tolerance, providing an expedient method for the construction of amide analogues. Notably, amino alcohols can be selectively transformed into the corresponding amides successfully without interfering the hydroxyl group under the current standard conditions.

Ni-catalyzed carbamoylation of unactivated alkenes for stereoselective construction of six-membered lactams.

Nitrogen-based heterocycles have aroused widespread interest due to their reoccurrence in many pharmaceuticals. Amongst these motifs, the enantioenriched lactams are the ubiquitous scaffolds found in myriad biologically active natural products and drugs. Recently, the transition metal-catalyzed asymmetric carbamoylation has been widely employed as a straightforward arsenal for chiral lactam architecture synthesis, including ß-lactam and γ-lactam. However, despite the extensive efforts, there still remains no protocol to accomplish the related δ-lactam synthesis. In this manuscript, the Ni-catalyzed enantioselective carbamoylation of unactivated alkenes by the leverage of reductive dicarbofunctionalization strategy allows for the expedient access to two types of mostly common six-membered lactams: 3,4-dihydroquinolinones and 2-piperidinone in high yield and enantioselectivity. This protocol features with good functional group tolerance, as well as broad substrate scope. The newly developed chiral 8-Quinox skeleton ligand is the key parameter for this transformation, which significantly enhances the reactivity and enantioselectivity.

Asymmetric [3+2] spiroannulation of pyrazolone-derived Morita-Baylis-Hillman carbonates with alkynyl ketones: facile access to spiro[cyclopentadiene-pyrazolone] scaffolds.

A tertiary amine-catalyzed asymmetric [3+2] spiroannulation reaction of pyrazolone-derived Morita-Baylis-Hillman carbonates with alkynyl ketones was achieved under mild conditions. This protocol offers a facile approach to chiral spiro[cyclopentadiene-pyrazolone] scaffolds in good to high yields (up to 92%) with good degrees of enantiocontrol (up to 98% ee). In addition, scale-up reaction and transformation of the products were performed to show the synthetic utility of this protocol.

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.

Palladium(II)-catalyzed enantioselective intermolecular oxidative diarylation of internal enamides.

The construction of vicinal stereogenic centers via the simultaneous formation of two C-C bonds across alkenes under oxidative conditions is a stubborn challenge. Herein, we report a Pd(II)-catalyzed highly enantioselective intermolecular oxidative 1,2-diarylation reaction of internal enamides with aryl boronic acids, enabling the expedient construction of two vicinal stereocenters with excellent diastereo-, and enantioselectivities.

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.

A thiolate-bridged ruthenium-molybdenum complex featuring terminal nitrido and bridging amido ligands derived from the N-H and N-N bond cleavage of hydrazine.

Biomimetic di- or multimetallic complexes featuring NxHy species in a sulfur-rich coordination sphere have attracted considerable attention in modelling the possible scenarios of biological nitrogen fixation by nitrogenases. Although the active site of nitrogenases is a complex heterometallic sulfur cluster, the feasibility of NxHy species on different metal sites is scarcely investigated. Herein, we report an unprecedented thiolate-bridged ruthenium-molybdenum complex featuring bridging amido and terminal nitrido ligands obtained by cleaving the N-N and N-H bonds of hydrazine. Remarkably, this RuMo complex is also capable of catalyzing the reduction of hydrazine to ammonia. Overall, this rare activation pattern of hydrazine on a thiolate-bridged RuMo platform provides new insight into the heterometallic cooperativity in nitrogenase.