Abstract Copper‐catalyzed S N 2' substitution reactions of chiral propargyl compounds provides an efficient synthetic method for chiral allenes that have widespread applications in pharmaceuticals and artificial functional materials. However, compared with the S N 2' reaction catalyzed by palladium, ruthenium, and other noble metals, the development of S N 2' reaction catalyzed by copper is relatively delayed due to its sensitivity to steric hindrance. Herein we reported a highly selective copper‐catalyzed S N 2' substitution reaction through the use of weakly nucleophilic zinc reagents. A wide variety of polyfluoroaryl allenes bearing an assortment of functional groups (36 examples) are compatible with this catalysis system. It is worth noting that chiral polyfluoroaryl allenes can also be efficiently constructed from chiral propargyl esters via this S N 2' reaction. A series of mechanism verification experiments and DFT calculations also provide a basis for the reaction mechanism and the stereo‐model of chiral transfer. Moreover, the preparation of other valuable polyfluoroarene containing compounds from polyfluoroaryl allenes also proves the synthetic utility of this methodology.

Quaternary stereocenters are prevalent in natural products and bioactive molecules, where they influence the molecular structure, conformation, and function by enhancing the fraction of sp3 character. The enantioselective construction of such structures via cross-coupling remains a long-standing challenge, owing to the steric demands of forging C(sp3)-C(sp3) bonds and the limited accessibility of suitable tertiary carbon coupling partners. Here, we report a palladium-catalyzed asymmetric decyanative allylation (ADCNA) platform of C(sp3)-C(sp3) cross-coupling that transforms stable and readily available tertiary nitriles into enantioenriched acyclic and cyclic compounds bearing quaternary centers. This process proceeds via the selective addition of in situ-formed allyl zinc reagent to the cyano group, followed by retro-Thorpe-type C-CN bond cleavage and asymmetric allylation, guided by newly developed chiral ligands. The method exhibits a broad substrate scope across three classes of tertiary nitriles─malononitriles, α-cyano indolinones, and α-cyano lactones─offering high yields and excellent enantioselectivities under mild conditions. This research establishes a conceptually distinct retrosynthetic paradigm, from prochiral or racemic quaternary carbons to enantioenriched quaternary centers, enabled by chemoselective C-C bond cleavage and stereoselective C-C bond formation. The synthetic utility of this strategy is demonstrated by the downstream synthesis of a monoamine reuptake inhibitor and a CNGA2 channel blocker as well as synthetic intermediates of natural products physovenine and physostigmine.

Cobalt-catalyzed alkylation of α-trifluoromethyl alkenes with α-chloro esters has been developed. This reaction provides an efficient approach for the synthesis of gem-difluoroalkenes featuring a broad substrate scope and good yields under mild conditions. The practical applicability has been shown by the gram-scale synthesis and subsequent derivatization of the products. Furthermore, the preliminary mechanistic studies demonstrated that cobalt promotes the generation of alkyl zinc reagents from zinc powder and α-chloro esters, which attack the α-trifluoromethyl alkenes and ultimately yield the target products.

The highly strained bicyclic hydrocarbon bicyclo[1.1.1]propellane has emerged as a versatile scaffold in synthetic organic and medicinal chemistry due to the remarkable structural reactivity of its central bond between the two bridgehead carbons. Over the past decade, many research groups have harnessed this strain-release reactivity to advance an efficient synthetic approach for constructing bicyclo[1.1.1]pentane (BCP) scaffolds. This review presents a comprehensive overview of the most recent advancements in the functionalization of bicyclo[1.1.1]propellane using commercially accessible organometallic reagents (RMX). Organo-lithium, magnesium, zinc, and boron reagents have demonstrated excellent ring-opening reactivity under mild and sustainable conditions, furnishing highly functionalized 1,3-disubstituted BCP derivatives and related amine scaffolds in excellent yields, with broad functional group tolerance, eco-friendly, and low-toxicity reagents. These organometallic-reagent-mediated strain-release functionalization methods are expected to have noteworthy synthetic utility, mostly in medicinal and pharmaceutical chemistry.

Reductive elimination of dialkyl Ni(II) species for the enantioselective construction of a C(sp3)-C(sp3) bond represents a fundamental challenge due to the low oxidative ability of the Ni(II) ion. Here we report that a Ni(0) complex can perform as a π-Lewis base to activate the 2,4-dienoic carboxylate salts formed in situ with zinc reagents, such as dimethylzinc, and undergo vinylogous addition to carbonyls α-regioselectively and stereoselectively. After transmetalation with another organometallic reagent, the resultant alkyl allylic nickel(II) species readily undertake reductive elimination to finally forge two C(sp3)-C(sp3) bonds, even with switchable diastereodivergence and α,β- or α,δ-regiodivergence via ligand or substrate control. A self-assembled dinuclear Zn cage framework is believed to enhance the latter process through an intriguing outer-sphere π-acidic activation mode.

Swinhoeisterols A-C are 13(14→8),14(8→7)-diabeo-steroids possessing an intriguing 6/6/5/7 tetracyclic core framework and potent inhibitory activity against the histone acetyltransferase p300. Herein we report their divergent total syntheses from readily available (S)-Wieland-Miescher ketone. A tandem Negishi/Heck cross-coupling of a chloroenol triflate was developed to install the labile methylenecyclopentene motif using a silyl-tethered homoallylic zinc reagent that was carefully designed to suppress undesired [Pd]-H insertion. Furthermore, a Baran reductive olefin coupling of a diene, a rarely used radical donor, with a tethered acrylonitrile group allowed for the simultaneous construction of the seven-membered ring and two contiguous stereocenters, including a quaternary carbon center.

We report a modular three-component annulation among propargyl zinc reagents, unsaturated 1,3-dicarbonyls, and electrophiles to enable rapid construction of highly substituted cyclopentenes. In addition to optimization studies, a range of substrates were investigated. These products can be readily diversified to highlight their synthetic utility.

A cobalt-catalyzed desulfonylative cross-coupling of glycosyl sulfones with organozinc reagents toward the stereoselective synthesis of C-glycosides is reported. The new C-glycoside synthesis proceeds under mild reaction conditions and exhibits tolerance to a range of functional groups. Diverse alkynylated, arylated, and alkenylated products are formed with high efficiency and excellent diastereoselectivity. Mechanistic studies indicate a radical pathway.

The advancement of robust synthetic methodologies for generating fluorinated quaternary carbon chiral centers is highly sought after in the fields of organic and medicinal chemistry. This study successfully provides such compounds through cobalt-catalyzed asymmetric Negishi coupling reactions of α-bromo-α-fluoro ketones with aryl/alkenyl zinc reagents. The adjustment of chiral unsymmetric N,N,N-tridentate (CUT) ligands played a key role in improving reactivity and selectivity in the cobalt catalysis, preventing the formation of hydrodebromination byproducts, and accommodating sterically hindered substrates and heterocycles. Control and kinetic experiments reveal that transmetalation serves as the rate-limiting step, a mechanistic characteristic that sets the newly developed asymmetric cobalt-catalyzed cross-couplings apart from previous methodologies.

A novel Zn-mediated preparation of propiolonitriles using electrophilic cyanation of alkynyl bromides with N-cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS) has been achieved here. The zinc dust was firstly used to activate the C(sp)–Br bond in the presence of tetrabutylammonium iodide (TBAI) to form an alkynyl zinc reagent in situ, which would undergo a nucleophilic addition with NCTS at the cyano group to afford an imine. Finally the propiolonitrile product was obtained after the elimination of the zinc complex. According to this new protocol, various phenylpropiolonitriles have been prepared from alkynyl bromides in moderate to excellent yields (51–95%), and could also be generated from the combination of inactive alkynyl chlorides with tetrabutylammonium bromide (TBAB) in lower yields (23–70%).

Zn(NTf2)2 in combination with N-iodosuccinimide provides a powerful promoter system, capable of activating 4, 6-O-di-tert-butylsilylene-thiogalactoamine and 4, 6-O-benzylidene-2-thiogalactoazide donors. The activation protocol is successfully applied to a wide range of alcohol acceptors, rendering excellent yields of α-galactosamines and α-galactosazides. This method features simple operation and the use of air-stable and commercially available zinc reagents.

Aryl triflates make up a class of aryl electrophiles that are available in a single step from the corresponding phenol. Despite the known reactivity of nickel complexes for aryl C-O bond activation of phenol derivatives, nickel-catalyzed cross-electrophile coupling using aryl triflates has proven challenging. Herein, we report a method to form C(sp2)-C(sp3) bonds by coupling aryl triflates with alkyl bromides and chlorides using phenanthroline (phen) or pyridine-2,6-bis(N-cyanocarboxamidine) (PyBCamCN)-ligated nickel catalysts. The scope of the reaction is demonstrated with 38 examples (61 ± 14% average yield). Mechanistic studies provide a rationale for the conditions used and a roadmap for further applications of cross-electrophile coupling. First, the rate of alkyl radical generation is controlled by maintaining the majority of alkyl halide as the alkyl chloride, which is unreactive, and utilizing a dynamic halide exchange process to adjust the concentration of reactive alkyl bromide or iodide. Second, the challenge of using electron-rich aryl triflates appears to be due to off-cycle transmetalation to form unproductive aryl zinc reagents. The optimal PyBCamCN ligand together with LiCl avoids this deleterious transmetalation step.

Abstract The reaction of the ferrocene derivative Fe(ƞ 5-C5H4CO2H)(ƞ 5-C5H4CH=CH2) (=fcCO2H) (1) with the zinc reagents [Zn(OAc)2]·xH2O (OAc = acetate; 2a, x = 0; 2b, x = 2) or ZnEt2 (3) in non-aqueous solvents toluene or tetrahydrofuran resulted in the formation of the cluster [Zn4O(fcCO2)6] (4). The structure of 4 in the solid state has been determined by single-crystal X-ray diffraction analysis. Cluster 4 crystallizes in the triclinic space group P 1 ‾ $\overline{1}$ . In 4, the cluster core is set-up by four zinc(II) ions which are forming the vertices of a tetrahedron with a μ 4-oxygen atom in its center. Six μ-fcCO2 units bridge the edges of the tetrahedron. IR spectroscopy confirms with ∆ν CO2 = 91 cm−1 (∆ν CO2 = ν CO2,asym − ν CO2,sym) the μ-bridging character of the fcCO2 entities. Cyclic voltammetry studies showed a reversible redox event at E°′ = 245 mV versus FcH/FcH+ (FcH = Fe(ƞ 5-C5H5)2) for 4 with the six fcCO2 redox events superimposed. High-resolution ESI-TOF measurements verified the identity of 4.

In the purification process of zinc hydrometallurgy, the spectra of copper and cobalt seriously overlap in the whole band and are interfered with by the spectra of zinc and nickel, which seriously affects the detection results of copper and cobalt in zinc solutions. Aiming to address the problems of low resolution, serious overlap, and narrow characteristic wavelengths, a novel spectrophotometric method for the robust detection of trace copper and cobalt is proposed. First, the Haar, Db4, Coif3, and Sym3 wavelets are used to carry out the second-order continuous wavelet transform on the spectral signals of copper and cobalt, which improves the resolution of copper and cobalt and eliminates the background interference caused by matrix zinc signals and reagents. Then, the information ratio and separation degree are defined as optimization indexes, a multi-objective optimization model is established with the wavelet decomposition scale as a variable, and the non-inferior solution of multi-objective optimization is solved by the state transition algorithm. Finally, the optimal second-derivative spectra combined with the fine zero-crossing technique are used to establish calibration curves at zero-crossing points for the simultaneous detection of copper and cobalt. The experimental results show that the detection performance of the proposed method is far superior to the partial least squares and Kalman filtering methods. The RMSEPs of copper and cobalt are 0.098 and 0.063, the correlation coefficients are 0.9953 and 0.9971, and the average relative errors of copper and cobalt are 3.77% and 2.85%, making this method suitable for the simultaneous detection of trace copper and cobalt in high-concentration zinc solutions.

(-)-Pleurotin (1) and (+)-dihydropleurotinic acid (2) are benzoquinone meroterpenoids isolated from fungal sources with powerful antitumor and antibiotic activities. Concise asymmetric total syntheses of the stereochemically pure (+)-dihydropleurotinic acid (2) and (-)-pleurotin (1) from the chiral pool (R)-Roche ester-derived vinyl bromide 7 have been achieved in 12 and 13 longest linear steps, respectively. The key transformations feature a Michael addition/alkylation cascade reaction to forge three contiguous stereocenters matched with the natural products, a PtO2-catalyzed stereoselective reduction of olefin to generate the correct stereocenter at C3, a palladium-catalyzed Negishi cross-coupling between triflate and zinc reagent to introduce the redox-sensitive para-quinone moiety, and a hydroboration/copper-catalyzed carboxylation sequence to incorporate the vital carboxyl group. Thus, the highly efficient and scalable preparation of pleurotin's pentacyclic skeleton enables the late-stage diversification, affording otherwise unavailable pleurotin analogs with significantly improved antiproliferative activities against the thioredoxin reductase (TrxR) overexpressed human breast cancer cell lines relative to the natural product pleurotin (1).

Organoboronic acids, some of the most common and widely used organoboron compounds, have not yet been used in the cobalt-catalyzed cross coupling reactions, despite cobalt demonstrating good reactivity with zinc reagents, Grignard reagents, and metal organoborates that are formed by n-butyl lithium or alkaline metal alkoxide salts and organoboron esters. Herein, a highly efficient and practical cobalt-catalyzed coupling reaction of aryl/alkenyl boronic acids and alkynyl chloride under mild reaction conditions is reported. The advantages of the organoboronic acids, along with a broad functional group compatibility and the reaction's tolerance to moisture and air, enable this reaction to be a synthetically useful protocol for the construction of a C(sp2)-C(sp) bond. Lastly, the synthesis of two natural products and a key intermediate of roxadustat was effectively accomplished using the methodology to construct the critical alkynyl-aryl bond.

Abstract This short review article demonstrates recent techniques for the typical conversion of adamantyl C(sp 3 )−Br bond to various C−C, C−N, and C−X bonds enabled by multiple conditions and reagents with the use of organometallic reagents. This work mainly focuses on developing a mild and convenient system for the selective preparation of substituted adamantyl zinc and magnesium reagents (Ad‐MX) bearing different functional groups on the adamantyl framework. The adamantane scaffolds were selectively functionalized using a various of catalytic methods, most likely organometallic‐Zn, Mg reagent‐mediated Negishi cross‐coupling reactions, acylation, arylation, thiolation, 1,2/1,4‐addition, alkynylation, amination, halogenation, and allylation, etc. Over the years adamantyl derivatives have been broadly studied in various medicinal applications, drug development, supramolecular chemistry, material science, and nanotechnologies, etc.

The construction of quaternary carbon centers via C-C coupling protocols remains challenging. The coupling of tertiary C(sp3) with secondary or tertiary C(sp3) counterparts has been hindered by pronounced steric clashes and many side reactions. Herein, we have successfully developed a type of bisphosphine ligand iron complex-catalyzed coupling reactions of tertiary alkyl halides with secondary alkyl zinc reagents and efficiently realized the coupling reaction between tertiary C(sp3) and secondary C(sp3) with high selectivity for the initial instance, which provided an efficient method for the construction of quaternary carbon centers with high steric hindrance. The combination of an iron catalyst and directing group of the substrate makes the great challenging transformation possible.

Seven asymmetric zinc benzamidinate complexes featuring or lacking side-arm functionalities were synthesized. Using equimolar zinc reagent produced distinct dinuclear motifs [(C6H5-C = NC6H5)ZnEt]2 (R = tBu, 1; (CH2)2OMe, 2; (CH2)2NMe2, 3). Half the zinc reagent yielded dinuclear [(C6H5-C = NC6H5)2Zn]2 (R = tBu, 4) or mononuclear zinc bis(chelate) complexes (R = (CH2)2OMe, 5; (CH2)2NMe2, 6; CH2Py, 7). Molecular structures of 1-4 and 7 were determined via single-crystal X-ray diffraction. Altering benzamidinate substituents modifies both coordination modes and catalytic activities in ring-opening polymerization of L-lactide. Specifically, complex 7 exhibits enhanced catalytic activity at 25 °C using 100 equivalents of L-lactide with a turnover frequency of 1820 h-1.

We developed a Pd-catalyzed decarboxylative cross-coupling of zinc polyfluorobenzoates, which were used as precursors for producing zinc reagents in situ, with aryl bromides and nonaflates, providing a mild and efficient pathway for the synthesis of polyfluorinated biaryls. This protocol exhibits a broad substrate scope and excellent functional tolerance. Moreover, the versatility of this approach was demonstrated by the straightforward late-stage modification of drugs, biologically active molecules, and pesticides, indicating its potential significance in drug discovery.