Ligand-Enabled Palladium-Catalyzed [3 + 2] Annulation of Aryl Iodides with Maleimides via C(sp3)-H Activation.

Palladium-catalyzed intermolecular [3 + 2] annulation reactions via C-H activation represent a powerful and charming tool for assembling cyclopentanes. Herein, we have developed a strategy for the palladium-catalyzed intermolecular alkene-relayed annulation reaction of aryl iodides and maleimides via C(sp3)-H activation for the construction of polycyclic structures. In contrast to directed-group-enabled intermolecular maleimide-relayed [3 + 2] annulation reactions, this protocol stands out for its utilization of aryl iodides as substrates. Notably, monoprotected amino acids played a crucial role as ligands in this reaction, which is rarely observed in C-H activation reactions initiated with organohalides.

Pd(0)-Catalyzed Intermolecular Methylene C(sp3)-H Silylation by Using N-Heterocyclic Carbene Ligands.

The direct functionalization of methylene C(sp3)-H bonds is one of the greatest challenges in transition metal-catalyzed C-H activation. Although Pd(0)-catalyzed intramolecular cyclization reactions of methylene C(sp3)-H bonds have been reported, intermolecular functionalization remains to be discovered. Herein, we report the first example of a Pd(0)-catalyzed intermolecular methylene C(sp3)-H functionalization reaction. By use of a N-heterocyclic carbene ligand, the methylene C(sp3)-H bonds of 1-(benzyloxy)-2-iodobenzenes are activated and disilylated with hexamethyldisilane, affording disilylated products.

Synthesis and evaluation of butylphthalide-scutellarein hybrids as multifunctional agents for the treatment of Alzheimer's disease.

A series of butylphthalide and scutellarein hybrids 3-(alkyl/alkenyl) hydroxyphthalide derivatives were designed, synthesized and evaluated as multifunctional agents against Alzheimer's disease. In vitro bioactivity assays indicated that most of the compounds displayed excellent antioxidant activity and moderate to good inhibition activities of self-induced Aß1-42 aggregation. Among them, compound 7c was demonstrated as a potential and balanced multifunctional candidate displaying the best inhibitory effects on self- and Cu2+-induced Aß1-42 aggregation (90.2 % and 35.4 %, respectively) and moderate activity for disaggregation of Aß1-42 aggregation (42.5 %). In addition, 7c also displayed excellent antioxidant (2.42 Trolox equivalents), metal ions chelating, oxidative stress alleviation, neuroprotective and anti-neuroinflammatory activities. Furthermore, in vivo study demonstrated that 7c could ameliorate the learning and memory impairment induced by sodium nitrite and Aß1-42 in the step-down passive avoidance test. These balanced multifunctional profiles supporting compound 7c as a novel potential candidate for the treatment of AD.

Synthesis of Naphthalimides through Tandem Pd(II)-Catalyzed C(sp3)-H Oxidation and Diels-Alder Reaction Using a Transient Directing Group Strategy.

Naphthalimides have found extensive applications in materials science and pharmaceuticals. It is still highly desirable to develop efficient methods for the synthesis of naphthalimides with structural diversity. In this work, we developed a new approach for the synthesis of naphthalimides via a tandem reaction of o-methylbenzaldehydes and maleimides. The tandem reaction involves Pd(II)-catalyzed benzylic C(sp3)-H oxidation using an amino acid as the transient directing group and Diels-Alder reaction. The subsequent dehydration forms naphthalimides. The reaction introduces the imide moiety and constructs a benzene ring simultaneously, allowing for easy access to a range of naphthalimides with a variety of substituents.

The comprehensive analysis of thalassemia alleles (CATSA) based on single-molecule real-time technology (SMRT) is a more powerful strategy in the diagnosis of thalassemia caused by rare variants.

Thalassemia is one of the most widely distributed monogenic disorders in the world and affects the largest number of people. It can manifest a wide spectrum of phenotypes from asymptomatic to fatal, which is associated with the degree of imbalance between α- and ß-globin chains. Therefore, individuals with different genotypes could present with a similar phenotype. Genetic analysis is always needed to make a correct diagnosis. However, routine genetic analysis of thalassemia used in the Chinese population identifies only 23 common variants, resulting in many cases undiagnosed or being misdiagnosed. In this study, we applied a long-read sequencing-based approach termed comprehensive analysis of thalassemia alleles (CATSA) to 30 subjects whose hematologic screening results could not be explained by the routine genetic test results. The identification of additional variants and the correction of genotypes allowed the interpretation of the clinical phenotype in 24 subjects, which have been confirmed to be correct by independent experiments. Moreover, we identified a novel 8.4-kb deletion containing the entire HBB and HBD genes as well as part of the HBBP1 gene, expanding the genotype spectrum of ß-thalassemia. CATSA showed a great advantage over other genetic tests in the diagnosis of thalassemia caused by rare variants.

Early Addition of Evolocumab to Statin Treatment in Patients with Acute Coronary Syndrome and Multivessel Disease Undergoing Percutaneous Coronary Intervention.

Background: Evolocumab has been demonstrated to significantly reduce ischemic cardiovascular events in patients with stable coronary heart disease. However, it is currently unclear whether this benefit extends to patients with acute coronary syndrome (ACS) and multivessel disease (MVD) undergoing percutaneous coronary intervention (PCI). The objective of this study was to assess the safety, efficacy and feasibility of the early addition of evolocumab to statin treatment for ACS patients with MVD undergoing PCI. Methods: The authors conducted a multicenter, retrospective cohort study involving 1199 ACS patients with MVD undergoing PCI and with elevated low-density lipoprotein cholesterol (LDL-C) levels. Patients were divided into an evolocumab group or a standard-of-care group based on evolocumab use or not. The 18-month primary efficacy endpoint was a composite of ischemic stroke, death from cardiac causes, recurrent myocardial infarction (MI), unplanned coronary revascularization or unstable angina requiring hospitalization. The principal secondary efficacy endpoint was a composite of ischemic stroke, death from cardiac causes or recurrent MI. Results: After propensity score matching, the addition of evolocumab to statin treatment lowered LDL-C levels by 42.62% compared with statin therapy alone at 18 months, from a mean baseline level of 3.37-0.75 mmol/L (p < 0.001). Relative to standard therapy, evolocumab added to statins was associated with significant reductions in the primary efficacy endpoint (8.3% vs. 13.3%; adjusted hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.39 to 0.91; p = 0.017) and the principal secondary efficacy endpoint (6.1% vs. 10.2%; adjusted HR, 0.61; 95% CI, 0.37 to 0.99; p = 0.048) after multivariable Cox regression adjustment. The treatment effect of evolocumab was consistent across all prespecified subgroups. There were no significant between-group differences in terms of adverse events. Conclusions: In ACS patients with MVD taken for PCI, early initiation of evolocumab along with statin treatment was associated with a significant reduction in LDL-C levels and a reduced risk of recurrent cardiovascular events. Clinical Trial Registration: Chinese Clinical Trials Registry, identifier ChiCTR2000035165. Date: 2 August 2020. URL: https://www.chictr.org.cn/.

Pd-Catalyzed Alkene-Relayed Intermolecular C-H Alkylation Using Aryl Halide Substrates.

Alkene-relayed C-H activation represents a novel strategy for functionalizing C-H bonds selectively. We developed a Pd-catalyzed annulation reaction of 2-iodobiphenyls with maleimides that act as a relay for C-H alkylation. The reaction features broad substrate scope and high efficiency, providing a straightforward method for the synthesis of succinimide-fused 9,10-dihydrophenanthrenes. The reaction using acenaphthylene as the relay has also been developed, which allows easy access to dibenzo[j,l]fluoranthenes.

Intermolecular Difunctionalization of C,C-Palladacycles Obtained by Pd(0)-Catalyzed C-H Activation.

C,C-Palladacycles are an important class of organometallic compounds in which palladium is σ-bonded to two carbon atoms. They have three notable features that make them attractive in organic synthesis and organometallic chemistry: (1) C,C-Palladacycles are reactive intermediates that can be accessed via Pd(0)-catalyzed C-H activation of organic halides. Compared to Pd(II)-catalyzed heteroatom-directed C-H activation, C-H activation catalyzed by Pd(0) has some distinct advantages. In this type of catalytic reaction, the halo groups of readily available organic halides act as traceless directing groups. Furthermore, this strategy avoids the use of stoichiometric external oxidants. (2) C,C-Palladacycles have differentiated reactivities from common open-chain Pd(II) species. In particular, C,C-palladacycles have high reactivity toward electrophiles including alkyl halides. This unique reactivity can be utilized to develop novel reactions. (3) C,C-Palladacycles have two C-Pd bonds, providing a unique platform for developing novel reactions.Although a number of reactions of C,C-palladacycles had been developed prior to our work, the scope was largely limited to intramolecular cyclization reactions. Although Catellani reactions are intermolecular reactions of C,C-palladacycles, only one of the C-Pd bonds is functionalized. Our laboratory has sought to develop intermolecular difunctionalization reactions of C,C-palladacycles that exploit their unique reactivity and open new possibilities in organic synthesis. Aiming to develop synthetically useful reactions, we primarily focus on ring-forming reactions. In this Account, we summarize our laboratory's efforts to exploit intermolecular difunctionalization reactions of C,C-palladacycles that are obtained through Pd(0)-catalyzed C-H activation. We have developed a wide array of new reactions that represent facile and efficient methods for the synthesis of cyclic organic compounds, including functional materials and drug molecules. A range of C,C-palladacycles have been studied, including C(aryl),C(aryl)-palladacycles from 2-halobiaryls, C(aryl),C(alkyl)-palladacycles from ortho-iodo-tert-butylbenzenes or ortho-iodoanisole derivatives, and those obtained by cascade reactions. C,C-Palladacycles have been found to react with a variety of oxidants to furnish Pd(IV) intermediates, such as alkyl halides, aryl halides, diazo compounds, and N,N-di-tert-butyldiaziridinone, ultimately affording various cyclic structures, including 5-10-membered rings, carbo- and azacycles, spirocycles, and fused rings. Furthermore, novel reactivity of C,C-palladacycles has been discovered. For example, we found that C,C-palladacycles have unusually high reactivity toward disilanes, which can be leveraged to disilylate a variety of C,C-palladacycles with very high efficiency. These results should provide inspiration to develop other C-Si bond-forming reactions in the future. We hope that this Account will stimulate further research into the rich chemistry of C,C-palladacycles, in particular reactions that find practical applications in the synthesis of bioactive and functional molecules and those that advance the state of the art in C-H functionalization.

Extracellular signal-regulated kinase in the basolateral amygdala is required for reconsolidation of heroin-associated memory.

Reconsolidation of heroin-associated memory is an independent memory process that occurs following retrieval, which is essential for the sustained capacity of an associative drug stimulus to precipitate heroin-seeking. Extracellular signal-regulated kinase (ERK) in the basolateral amygdala (BLA) mediates the reconsolidation of drug memory. In the present study, we utilized a rat model of drug craving and relapse to verify the hypothesis that the reconsolidation of heroin-associated memory requires ERK in an instrumental heroin-seeking behavior, focusing on the BLA brain region, which is crucial for synaptic plasticity and memory processes. We found that bilateral intra-BLA infusions of U0126 (1 µg/0.5 µl), an ERK inhibitor, immediately after retrieving heroin-associated memory significantly reduced cue-induced and drug-induced reinstatement and spontaneous recovery of heroin-seeking compared to the vehicle. Furthermore, this inhibitory effect was related to the characteristic of reconsolidation. Conversely, no effect was observed on the heroin-seeking behavior when the intra-BLA infusion of U0126 was administered 6 h after the heroin-associated memory retrieval or without memory retrieval. Together, these data suggest that disrupting the reconsolidation of heroin-associated memory via an ERK inhibitor may serve as a promising option for treating relapse in opiate addicts.

Disrupting reconsolidation by PKA inhibitor in BLA reduces heroin-seeking behavior.

Drug abuse is considered a maladaptive pathology of emotional memory and is associated with craving and relapse induced by drug-associated stimuli or drugs. Reconsolidation is an independent memory process with a strict time window followed by the reactivation of drug-associated stimulus depending on the basolateral amygdala (BLA). Pharmacology or behavior treatment that disrupts the reconsolidation can effectively attenuate drug-seeking in addicts. Here, we hypothesized that heroin-memory reconsolidation requires cAMP-dependent protein kinase A (PKA) of BLA based on the fundamental effect of PKA in synaptic plasticity and memory process. After 10 days of acquisition, the rats underwent 11 days of extinction training and then received the intra-BLA infusions of the PKA inhibitor Rp-cAMPS at different time windows with/without a reactivation session. The results show that PKA inhibitor treatment in the reconsolidation time window disrupts the reconsolidation and consequently reduces cue-induced reinstatement, heroin-induced reinstatement, and spontaneous recovery of heroin-seeking behavior in the rats. In contrast, there was no effect on cue-induced reinstatement in the intra-BLA infusion of PKA inhibitor 6 h after reactivation or without reactivation. These data suggest that PKA inhibition disrupts the reconsolidation of heroin-associated memory, reduces subsequent drug seeking, and prevents relapse, which is retrieval-dependent, time-limited, and BLA-dependent.

Early Initiation of Evolocumab Treatment in Chinese Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

PURPOSE: Evolocumab has been shown to improve cardiovascular outcomes in patients with stable atherosclerotic disease. Whether this benefit persists in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) remains undetermined. This study aimed to evaluate the efficacy and safety of the early initiation of evolocumab in Chinese patients with ACS undergoing PCI. METHODS: This retrospective cohort study involved 1564 consecutive patients who had been hospitalized with ACS and underwent PCI, and who had elevated LDL-C levels (≥1.8 mmol/L after receiving high-intensity statin therapy for ≥4 weeks; ≥2.3 mmol/L after receiving low- or moderate-intensity statin; or ≥3.2 mmol/L without statin therapy). Patients who received evolocumab (initiated in-hospital and after 18 months) were included in the evolocumab group (n = 414), and all other patients were included in the control group (n = 1150). The primary outcome at 18 months was a composite of ischemic stroke, cardiovascular death, myocardial infarction, hospitalization for unstable angina, or coronary revascularization. The evolocumab treatment effect on the primary outcome was assessed in all prespecified subgroups. FINDINGS: At 18 months, evolocumab combined with statins reduced LDL-C levels from baseline levels by 42.48% compared with statins alone. After multivariable adjustment, evolocumab combined with statins significantly reduced the primary outcome (8.2% vs 12.4%; adjusted hazard ratio, 0.65; 95% CI, 0.45-0.95; P = 0.025). In addition, evolocumab consistently reduced the primary outcome across the major subgroups. For the safety outcomes, no significant differences between the groups were observed in any adverse events. IMPLICATIONS: Among Chinese patients who underwent PCI for ACS, the early initiation of evolocumab combined with statin treatment effectively reduced LDL-C levels and lowered the incidence of recurrent ischemic cardiovascular events, with satisfactory tolerability and safety. Chinese Clinical Trial Registry identifier: ChiCTR2100049364.

Land use classification of open-pit mine based on multi-scale segmentation and random forest model.

The mining industry production is an important pillar industry in China, while its extensive production activities have led to several ecological and environmental problems. Earth observation technology using high-resolution satellite imagery can help us efficiently obtain information on surface elements, surveying and monitoring various land occupation issues arising from open-pit mining production activities. Conventional pixel-based interpretation methods for high-resolution remote sensing images are restricted by "salt and pepper" noise caused by environmental factors, making it difficult to meet increasing requirements for monitoring accuracy. With the Jingxiang phosphorus mining area in Jingmen Hubei Province as the studied area, this paper uses a multi-scale segmentation algorithm to extract large-scale main characteristic information using a layered mask method based on the hierarchical structure of the image object. The remaining characteristic elements were classified and extracted in combination with the random forest model and characteristic factors to obtain land occupation information related mining industry production, which was compared with the results of the Classification and Regression Tree model. 23 characteristic factors in three aspects were selected, including spectral, geometric and texture characteristics. The methods employed in this study achieved 86% and 0.78 respectively in overall extraction accuracy analysis and the Kappa coefficient analysis, compared to 79% and 0.68 using the conventional method.

Synthesis of Spiroindenyl-2-Oxindoles through Palladium-Catalyzed Spirocyclization of 2-Bromoarylamides and Vinyl Bromides.

An expeditious approach to the construction of spiroindenyl-2-oxindoles was developed via a palladium-catalyzed spirocyclization reaction of 2-bromoarylamides with vinyl bromides. The reaction formed spiropalladacycles as the intermediates via carbopalladation and the C-H functionalization of 2-bromoarylamides. The spiropalladacycles reacted with vinyl bromides to form spiroindenyl-2-oxindoles. A Heck process rather than vinylic C-H functionalization was involved in the reaction.

Synthesis of 9-Fluorenylidenes via Pd-Catalyzed C-H Vinylation with Vinyl Bromides.

A facile and efficient approach for the synthesis of 9-fluorenylidenes has been developed via the palladium-catalyzed cross-coupling of 2-iodobiphenyls and vinyl bromides. The reaction involves the C-H activation of 2-iodobiphenyls and dual C-C bond formations. A range of 9-fluorenylidene derivatives, including diphenyldibenzofulvenes, can be synthesized with the reaction.

Intermolecular C-H silylation through cascade carbopalladation and vinylic to aryl 1,4-palladium migration.

A palladium-catalyzed remote C-H silylation reaction has been developed through vinylic to aryl 1,4-palladium migration. By using alkyne-tethered aryl iodides as the starting materials and hexamethyldisilane as the silylating reagent, the reaction involves cascade intramolecular carbopalladation, 1,4-palladium migration, and silylation with hexamethyldisilane, and leads to the formation of exocyclic alkene-containing 5-silylisoquinolines as the final products.

Palladium-Catalyzed Intramolecular Cross-Coupling of Unactivated C(sp3)-H and C(sp2)-H Bonds.

Direct C-H/C-H coupling represents an appealing method for the construction of C-C bonds, and the cross-coupling of unactivated C(sp3)-H and C(sp2)-H bonds is challenging and remains to be investigated. We have developed the Pd-catalyzed intramolecular coupling of inert C(sp3)-H and C(sp2)-H bonds. The reaction proceeded by o-methyl oxime-directed aryl C(sp2)-H activation and subsequent alkyl C(sp3)-H cleavage, generating C(sp2),C(sp3)-palladacycles as the key intermediates. Dihydrobenzofurans and indanes were formed as the final products.

Pd-catalyzed cross-electrophile Coupling/C-H alkylation reaction enabled by a mediator generated via C(sp3)-H activation.

Transition-metal-catalyzed cross-electrophile C(sp2)-(sp3) coupling and C-H alkylation reactions represent two efficient methods for the incorporation of an alkyl group into aromatic rings. Herein, we report a Pd-catalyzed cascade cross-electrophile coupling and C-H alkylation reaction of 2-iodo-alkoxylarenes with alkyl chlorides. Methoxy and benzyloxy groups, which are ubiquitous functional groups and common protecting groups, were utilized as crucial mediators via primary or secondary C(sp3)-H activation. The reaction provides an innovative and convenient access for the synthesis of alkylated phenol derivatives, which are widely found in bioactive compounds and organic functional materials.

Palladium-Catalyzed anti-Carbosilylation of Alkynes to Access Isoquinolinone-Containing Exocyclic Vinylsilanes.

A Pd-catalyzed trans-selective carbosilylation reaction of alkynes has been developed. The trans-vinylpalladium species, generated through intramolecular syn-carbopalladation of alkynes and subsequent cis-trans isomerization, were captured by hexamethyldisilane to form multisubstituted vinylsilanes. This reaction provides a useful strategy for the stereoselective synthesis of isoquinolinone-containing exocyclic tetrasubstituted vinylsilanes.

Efficacy and Safety of Bivalirudin During Percutaneous Coronary Intervention in Chronic Total Occlusion: A Retrospective Study.

PURPOSE: Bivalirudin as a thrombin inhibitor is proven to have a low risk of bleeding during percutaneous coronary intervention (PCI). Some evidence indicates comparable effectiveness and safety between bivalirudin and unfractionated heparin (UFH). Although bivalirudin during PCI offers more clinical and safety benefits to patients with chronic total occlusion (CTO), mostly via radial access, this has not been confirmed. The objective of this study was to examine the efficacy and safety of bivalirudin during percutaneous coronary intervention (PCI) in patients with CTO. METHODS: This trial used a retrospective cohort study design. Medical information from 736 patients with CTO who underwent PCI with bivalirudin or UFH at the First Affiliated Hospital of Zhengzhou University from July 2019 to September 2020 was extracted and analyzed. The primary end point was the 30-day incidence of net adverse clinical events (NACEs), and the secondary end point was the major adverse cardiovascular events (MACEs), which were related to safety and efficacy, respectively. Other end points incorporated each component of the primary outcome, target vessel revascularization, and stent thrombosis. Clinical and procedural characteristics at baseline were adjusted by using a logistic regression model. FINDINGS: Overall, 71.5% of patients with CTO used the radial approach. Both groups exhibited nonsignificant differences in the majority of baseline characteristics. The bivalirudin group was associated with a significant reduction in NACEs (12.9% vs 21.5%; P = 0.002) and major bleeding (2.5% vs 8.0%; P = 0.001) versus the UFH group at the end of the 30-day follow-up. The incidence of MACEs, myocardial infarction, death, stroke, stent thrombosis, and target vessel revascularization did not differ significantly between the 2 groups. Moreover, the bivalirudin group also reported a lower incidence of NACEs in the prespecified subgroups. IMPLICATIONS: Bivalirudin exhibited comparative efficacy but superior safety compared with UFH among patients with CTO undergoing PCI. Chinese Clinical Trial Registry: ChiCTR2000034771.

Pd-Catalyzed ipso,meta-Dimethylation of ortho-Substituted Iodoarenes via a Base-Controlled C-H Activation Cascade with Dimethyl Carbonate as the Methyl Source.

A methyl group can have a profound impact on the pharmacological properties of organic molecules. Hence, developing methylation methods and methylating reagents is essential in medicinal chemistry. We report a palladium-catalyzed dimethylation reaction of ortho-substituted iodoarenes using dimethyl carbonate as a methyl source. In the presence of K2CO3 as a base, iodoarenes are dimethylated at the ipso- and meta-positions of the iodo group, which represents a novel strategy for meta-C-H methylation. With KOAc as the base, subsequent oxidative C(sp3)-H/C(sp3)-H coupling occurs; in this case, the overall transformation achieves triple C-H activation to form three new C-C bonds. These reactions allow expedient access to 2,6-dimethylated phenols, 2,3-dihydrobenzofurans, and indanes, which are ubiquitous structural motifs and essential synthetic intermediates of biologically and pharmacologically active compounds.