Stable Axially Chiral Cyclohexylidenes from Catalytic Asymmetric Knoevenagel Condensation.

Axially chiral cycloalkylidenes are interesting but less developed axially chiral molecules. Here, a bispidine-based chiral amine catalytic system was developed to promote efficiently the asymmetric Knoevenagel condensation of N-protected oxindoles and benzofuranones with 4-substituted cyclohexanones. A variety of alkylidenecycloalkanes with stable axial chirality were obtained in good yields and fairly good er (enantiomeric ratio). Based on the absolute configuration determination of product and DFT calculations, a possible mechanism of stereoselective induction was proposed.

Iron-Catalyzed Asymmetric α-Alkylation of 2-Acylimidazoles via Dehydrogenative Radical Cross-Coupling with Alkanes.

The direct α-alkylation of acyclic carbonyls with nonactivated hydrocarbons through C(sp3 )-H functionalization is both extremely promising and notably challenging, especially when attempting to achieve enantioselectivity using iron-based catalysts. We have identified a robust chiral iron complex for the oxidative cross-coupling of 2-acylimidazoles with benzylic and allylic hydrocarbons, as well as nonactivated alkanes. The readily available and tunable N,N'-dioxide catalysts of iron in connection with oxidants exhibit precise asymmetric induction (up to 99 % ee) with good compatibility in moderate to good yields (up to 88 % yield). This protocol provides an elegant and straightforward access to optically active acyclic carbonyl derivatives starting from simple alkanes without prefunctionalization. Density functional theory (DFT) calculations and control experiments were made to gain insight into the nature of C-C bond formation and the origin of enantioselectivity. We propose a radical-radical cross-coupling process enabled by the immediate interconversion between chiral ferric species and ferrous species.

Asymmetric Epoxidation of Alkenes Catalyzed by a Cobalt Complex.

Asymmetric epoxidation of alkenes catalyzed by nonheme chiral Mn-O and Fe-O catalysts has been well established, but chiral Co-O catalysts for the purpose remain virtually undeveloped due to the oxo wall. Herein is first reported a chiral cobalt complex to realize the enantioselective epoxidation of cyclic and acyclic trisubstituted alkenes by using PhIO as the oxidant in acetone, wherein the tetra-oxygen-based chiral N,N'-dioxide with sterically hindered amide subunits plays a crucial role in supporting the formation of the Co-O intermediate and enantioselective electrophilic oxygen transfer. Mechanistic studies, including HRMS measurements, UV-vis absorption spectroscopy, magnetic susceptibility, as well as DFT calculations, were carried out, confirming the formation of Co-O species as a quartet Co(III)-oxyl tautomer. The mechanism and the origin of enantioselectivity were also elucidated based on control experiments, nonlinear effects, kinetic studies, and DFT calculations.

Enantioselective anti-Dihalogenation of Electron-Deficient Olefin: A Triplet Halo-Radical Pylon Intermediate.

The textbook alkene halogenation reaction establishes straightforward access to vicinal dihaloalkanes. However, a robust catalytic method for dihalogenizing electron-deficient olefins in an enantioselective manner is still under development, and its mechanism remains controversial. Herein, we disclose efficient regio-, anti-diastereo-, and enantioselective dibromination, bromochlorination, and dichlorination reactions of enones catalyzed by a chiral N,N'-dioxide/Yb(OTf)3 complex. With the combination of electrophilic halogen and halide salts as halogenating agents, an array of homo- and heterodihalogenated derivatives is achieved in moderate to good enantioselectivities. Moreover, DFT calculations reveal that a novel triplet halo-radical pylon intermediate is probable in accounting for the exclusive regio- and anti-diastereoselectivity.

Catalytic Enantioselective Nucleophilic Addition to Arynes by a New Quaternary Guanidinium Salt-Based Phase-Transfer Catalyst.

Owing to the mild generation methods, arynes have been widely used in synthetic chemistry. However, achieving asymmetric organocatalytic reactions with arynes remains a formidable and infrequent challenge, primarily because these neutral and transient species tend to spontaneously quench. To address this issue, a solid-liquid phase-transfer strategy is devised in which the generation speed of arynes could be controlled by the in situ generated fluoride-based chiral phase-transfer catalyst. In this study, we present a catalytic enantioselective nucleophilic addition reaction involving arynes, utilizing an amino amide-based guanidinium salt QG•X. Furthermore, we demonstrate the broad compatibility of this reaction with various arynes and cyclic/acyclic ß-keto amides, leading to the creation of diverse α-aryl quaternary stereocenters with good stereoselectivity. Mechanistic investigations have uncovered the potential involvement of a chiral intramolecular cationic-anionic pair and HF during the ion exchange between QG•X and CsF for nucleophile activation and aryne generation. Additionally, DFT calculations suggested that the observed high levels of enantioselectivity can be attributed to steric repulsion and the cumulative noncovalent interactions between the catalysts and substrates.

Nickel-Catalyzed Enantioselective Reductive Arylation and Heteroarylation of Aldimines via an Elementary 1,4-Addition.

Nickel catalysts of chiral pyrox ligands promoted enantioselective reductive arylation and heteroarylation of aldimines, using directly (hetero)aryl halides and sulfonates. The catalytic arylation can also be conducted with crude aldimines generated from condensation of aldehydes and azaaryl amines. Mechanistically, density functional theory (DFT) calculations and experiments pointed to an elementary step of 1,4-addition of aryl nickel(I) complexes to N-azaaryl aldimines.

Direct Amination of α-Triaryl Alcohols via Vanadium Catalysis.

α-Triaryl amines have been used as pharmaceuticals and pharmaceutical intermediates for antifungal and anticancer applications. Current methods to synthesize such compounds require at least two steps, and no direct amination of tertiary alcohols has been reported. Herein, we disclose efficient catalytic conditions for the direct amination of α-triaryl alcohols to access α-triaryl amines. VO(OiPr)3, a commercially available reagent, has been identified as an effective catalyst for the direct amination of several α-triaryl alcohols. This process is scalable, as demonstrated by a gram-scale synthesis, and the reaction still works at as low as a 0.01 mol % catalyst loading with the turnover number reaching 3900. Moreover, commercial pharmaceuticals including clotrimazole and flutrimazole have been successfully prepared rapidly and efficiently using this newly developed method.

Nickel-Catalyzed Enantioselective Reductive Conjugate Arylation and Heteroarylation via an Elementary Mechanism of 1,4-Addition.

A nickel complex of isoquinox promoted enantioselective conjugate arylation and heteroarylation of enones using aryl and heteroaryl halides directly. The reaction was successfully applied to stereoselective syntheses of ar-turmerone, chiral fragments of (+)-tolterodine and AZD5672. Mechanistically, experiments and calculations supported that an arylnickel(I) complex inserted to enones via an elementary 1,4-addition.

Rhomboidal Pt(II) metallacycle-based NIR-II theranostic nanoprobe for tumor diagnosis and image-guided therapy.

Fluorescent theranostics probes at the second near-IR region (NIR-II; 1.0-1.7 µm) are in high demand for precise theranostics that minimize autofluorescence, reduce photon scattering, and improve the penetration depth. Herein, we designed and synthesized an NIR-II theranostic nanoprobe 1 that incorporates a Pt(II) metallacycle 2 and an organic molecular dye 3 into DSPE-mPEG5000 (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-5000]). This design endows 1 with good photostability and passive targeting ability. Our studies show that 1 accurately diagnoses cancer with high resolution and selectively delivers the Pt(II) metallacycle to tumor regions via an enhanced permeability and retention effect. In vivo studies reveal that 1 efficiently inhibits the growth of tumor with minimal side effects. At the same time, improved fluorescent imaging quality and signal-to-noise ratios are shown due to the long emission wavelengths. These studies demonstrate that 1 is a potential theranostic platform for tumor diagnosis and treatment in the NIR-II region.

Asymmetric Catalytic (2+1) Cycloaddition of Thioketones to Synthesize Tetrasubstituted Thiiranes.

Herein, we report the first example of enantioselective (2+1) cycloaddition of thioketones with α-diazo pyrazoleamides for the direct synthesis of tetrasubstituted thiiranes. In the presence of chiral N,N'-dioxide/cobalt(ΙΙ) complexes (2-5 mol%), excellent efficiency (up to 99 % yield within 15 mins) and high stereoselectivity (up to >19 : 1 dr and 97 % ee) are available. Elaborations of thiiranes via desulfuration have also been conducted to deliver tetrasubstituted olefins. Density functional theory calculations reveal that the reaction initiates from a doublet state cobalt(ΙΙ) carbenoid, which is followed by a quartet cobalt(ΙΙ)-bound thiocarbonyl ylide pathway. This work provides a route for the selective construction of tetrasubstituted thiiranes and olefins that are otherwise difficult to access.

Enantioselective Synthesis of Nitriles Containing a Quaternary Carbon Center by Michael Reactions of Silyl Ketene Imines with 1-Acrylpyrazoles.

The enantioselective construction of quaternary carbon centers is a marked challenge in asymmetric catalysis research. It is extremely difficult when a chiral catalyst can not distinguish the facial selectivity of the substrate through bond interactions. Here we realized an enantioselective Michael reaction of silyl ketene imines to 1-acrylpyrazoles using a chiral N,N'-dioxide-Co(II) complex. The protocol is highly efficient for the construction of nitrile-, aryl-, and dialkyl-bearing carbon centers and has been successful applied in the divergent synthesis of pharmaceuticals and natural products. The through-space dispersion interactions between unbound silyl ketene imines and the 1-acrylpyrazole-bonded catalyst play a key role in facilitating the reactivity and the enantioselectivity of this process.

Enantioselective Formal Vinylogous N-H Insertion of Secondary Aliphatic Amines Catalyzed by a High-Spin Cobalt(II) Complex.

Vinylcarbene insertion into the nitrogen-hydrogen (N-H) bond of amines allows direct access to α,ß-unsaturated γ-amino acid derivatives, meeting a marked challenge in the control of regio- and enantioselectivities. Here, we report a highly γ-selective and enantioselective insertion into N-H bonds of aliphatic or aromatic secondary amines with vinyl substituted α-diazo pyrazoleamides using a high-spin chiral N,N'-dioxide/cobalt(II) complex catalyst. The method affords a wide variety of valuable optically active Z- and E-type vinyl γ-amino amides. Calculation reveals a spin state change from the quartet cobalt(II) complex to a doublet Co(II)-carbene species for facile Z-selective and enantioselective nucleophilic addition.

Iron-Catalyzed Enantioselective Radical Carboazidation and Diazidation of α,ß-Unsaturated Carbonyl Compounds.

Azidation of alkenes is an efficient protocol to synthesize organic azides which are important structural motifs in organic synthesis. Enantioselective radical azidation, as a useful strategy to install a C-N3 bond, remains challenging due to the inherently instability and unique structure of radicals. Here, we disclose an efficient enantioselective radical carboazidation and diazidation of α,ß-unsaturated ketones and amides catalyzed by chiral N,N'-dioxide/Fe(OTf)2 complexes. An array of substituted alkenes was transformed to the corresponding α-azido carbonyl derivatives in good to excellent enantioselectivities, benefiting the preparation of chiral α-amino ketones, vicinal amino alcohols, and vicinal diamines. Control experiments and mechanistic studies proved the radical pathway in the reaction process. The DFT calculations showed that the azido transferred to the radical intermediate via an intramolecular five-membered transition state with the internal nitrogen of the Fe-N3 species.

Catalytic Asymmetric Homologation of Ketones with α-Alkyl α-Diazo Esters.

The homologation of ketones with diazo compounds is a useful strategy to synthesize one-carbon chain-extended acyclic ketones or ring-expanded cyclic ketones. However, the asymmetric homologation of acyclic ketones with α-diazo esters remains a challenge due to the lower reactivity and complicated selectivity. Herein, we report the enantioselective catalytic homologation of acetophenone and related derivatives with α-alkyl α-diazo esters utilizing a chiral scandium(III) N,N'-dioxide as the Lewis acid catalyst. This reaction supplies a highly chemo-, regio-, and enantioselective pathway for the synthesis of optically active ß-keto esters with an all-carbon quaternary center through highly selective alkyl-group migration of the ketones. Moreover, the ring expansion of cyclic ketones was accomplished under slightly modified conditions, affording a series of enantioenriched cyclic ß-keto esters. Density functional theory calculations have been carried out to elucidate the reaction pathway and possible working models that can explain the observed regio- and enantioselectivity.

Enantioselective Intermolecular Heck and Reductive Heck Reactions of Aryl Triflates, Mesylates, and Tosylates Catalyzed by Nickel.

Nickel-catalyzed intermolecular Heck reaction of cycloalkenes proceeds well with aryl triflates, mesylates and tosylates in excellent enantiomeric ratios. The asymmetric reductive Heck reaction also works with a 2-cyclopentenone ketal, which is equivalent to conjugate arylation of the enone itself.

Computational Study on the Fate of Oxidative Directing Groups in Ru(II), Rh(III), and Pd(II) Catalyzed C-H Functionalization.

Activation of C-H bonds assisted by a directing group is indispensable in organic synthesis. Among them, utilizing oxidative directing groups that can serve as an internal oxidant to drive the Mn/Mn+2 catalytic cycle has recently become a promising strategy. A survey of published reactions involving N-alkoxyamides or N-acyloxyamides reveals that not all N-O bonds act as an internal oxidant. We have therefore systematically investigated the effect of the oxidative groups on a model reaction catalyzed by Ru(II), Rh(III), and Pd(II) complexes. DFT calculations show that N-methoxy and N-acyloxy groups oxidize Ru(II) to Ru(IV) and Rh(III) to Rh(V), but cannot oxidize a cyclo-Pd(II) intermediate to Pd(IV). The stability of the metal imido intermediate 7-M (M = Ru, Rh, and Pd) controls whether the oxidation occurs or not. N-Acyloxy groups show a more pronounced selectivity than N-methoxy to oxidize Ru(II) and Rh(III) species, while no distinctive effect is observed for Pd(II).

Asymmetric Reductive and Alkynylative Heck Bicyclization of Enynes to Access Conformationally Restricted Aza[3.1.0]bicycles.

Conformationally restricted azabicycles are becoming increasingly important in medicinal research. Asymmetric Heck bicyclization of enynes proceeds to give medicinally useful aza[3.1.0] and aza[4.1.0] bicycles with excellent enantioselectivity. The key organopalladium species after bicyclization can be trapped by silanes and terminal alkynes.

Arylation of Axially Chiral Phosphorothioate Salts by Dinuclear PdI Catalysis.

S-aryl phosphorothioates are privileged motifs in pharmaceuticals, agrochemicals, and catalysts; yet, the challenge of devising a straightforward synthetic route to enantioenriched S-aryl phosphorothioates has remained unsolved to date. We demonstrate herein the first direct C-SP(=O)(OR')(OR'') coupling of diverse and chiral phosphorothioate salts with aryl iodides, enabled by an air- and moisture-stable PdI dimer. Our mechanistic and computational data suggest distinct dinuclear PdI catalysis to be operative, which allows for operationally simple couplings with broad scope and full retention of stereochemistry.

Investigation of (Me4 N)SCF3 as a Stable, Solid and Safe Reservoir for S=CF2 as a Surrogate for Thiophosgene.

While thiophosgene finds widespread usage on a multi-ton scale, its fluorinated counterpart S=CF2 is essentially unexplored in synthesis. Using experimental reactivity tests, ReactIR and computational techniques, we herein showcase that the solid (Me4 N)SCF3 functions as a safe reservoir for S=CF2 . A key feature is that the reactive electrophile is not simply released over time, but instead is liberated under activation with a protic nucleophile. The reactivity of S=CF2 is mild, allowing large-scale and late-stage synthetic applications without special reaction control. The mechanism was fully elucidated, including a rationalization of the role of the Me4 N cation and the origins of selectivity.

Divergent Reactivity of Stannane and Silane in the Trifluoromethylation of PdII : Cyclic Transition State versus Difluorocarbene Release.

The transmetalation is a key elementary step in cross-coupling reactions. Yet, the precise nature of its mechanism and transition state geometry are frequently elusive. This report discloses our study of the transmetalation of [PdII ]-F complexes with the silane- and stannane-based trifluoromethylation agents, R3 SiCF3 and R3 SnCF3 . A divergent reactivity was uncovered, with the stannane showing selective R-group transfer, and the silane selective CF3 -group transfer. Using a combined experimental and computational approach, we uncovered a hitherto unrecognized transmetalation mechanism with the widely employed R3 SiCF3 reagent, explaining its unique activity in metal-catalyzed trifluoromethylations. While the stannane reacts via a cyclic, 4-membered transition state, the silane undergoes a fundamentally different pathway and releases a difluorocarbene in the transmetalation event. Molecular dynamics studies clearly reinforced the liberation of a free CF2 carbene, which reacts with [PdII ]-F to ultimately generate [PdII ]-CF3.