Transition-Metal-Free C-N Cross-Coupling Enabled by a Multifunctional Reagent.

We report the design and development of a transition-metal-free cross-coupling reaction of phenols and primary amines using a simple and readily available multifunctional reagent. The reactions work by induced proximity and electronic activation of both the nucleophile and the electrophile for net dehydrative C-N coupling reactions. Notably, the reactions do not involve the use of a transition metal for C-N bond formation, preactivation of the phenol electrophile, or exclusion of air or moisture. The mild conditions tolerate a broad range of functional groups and allow for this to be applied to the late-stage functionalization of complex substrates with a wide scope of coupling partners.

Reversible Homolysis of a Carbon-Carbon σ-Bond Enabled by Complexation-Induced Bond-Weakening.

A case study of catalytic carbon-carbon σ-bond homolysis is presented. The coordination of a redox-active Lewis acid catalyst reduces the bond-dissociation free energies of adjacent carbon-carbon σ-bonds, and this complexation-induced bond-weakening is used to effect reversible carbon-carbon bond homolysis. Stereochemical isomerization of 1,2-disubstituted cyclopropanes was investigated as a model reaction with a ruthenium (III/II) redox couple adopted for bond weakening. Results from our mechanistic investigation into the stereospecificity of the isomerization reaction are consistent with selective complexation-induced carbon-carbon bond homolysis. The ΔG‡ of catalyzed and uncatalyzed reactions were estimated to be 14.4 and 40.0 kcal/mol, respectively with the computational method, (U)PBE0-D3/def2-TZVPP-SMD(toluene)//(U)B3LYP-D3/def2-SVP. We report this work as the first catalytic example where the complexation-induced bond-weakening effect is quantified through transition state analysis.

A Multifunctional Reagent Designed for the Site-Selective Amination of Pyridines.

We report the development of a multifunctional reagent for the direct conversion of pyridines to Boc-protected 2-aminopyridines with exquisite site selectivity and chemoselectivity. The novel reagent was prepared on 200-g scale in a single step, reacts in the title reaction under mild conditions without precautions toward air or moisture, and is tolerant of nearly all common functionality. Experimental and in situ spectroscopic monitoring techniques provide detailed insights and unexpected findings for the unique reaction mechanism.

Regio- and Enantioselective Bromocyclization of Difluoroalkenes as a Strategy to Access Tetrasubstituted Difluoromethylene-Containing Stereocenters.

Difluoromethylene-containing compounds have attracted substantial research interest over the past decades for their ability to mimic biological functions of traditional functional groups while providing a wide variety of pharmacological benefits bestowed by the C-F bond. We report a novel strategy to access RCF2Br-containing heterocycles by regio- and enantioselective bromocyclization of difluoroalkenes enabled by chiral anion phase-transfer catalysis. The utility of this methodology was highlighted through a synthesis of an analogue of efavirenz, a drug used for treating HIV. Additionally, the synthetic versatility of the CF2Br intermediates was showcased through functionalization to a variety of enantioenriched α,α-difluoromethylene-containing products.

Strong Metal-Adsorbate Interactions Increase the Reactivity and Decrease the Orientational Order of OH-Functionalized N-Heterocyclic Carbene Monolayers.

Fundamental understanding of the correlation between the structure and reactivity of chemically addressable N-heterocyclic carbene (NHC) molecules on various surfaces is essential for the design of functional NHC-based self-assembled monolayers. In this work, we identified the ways by which the deposition of chemically addressable OH-NHCs on Au(111) or Pt(111) surfaces modified the anchoring geometry and chemical reactivity of surface-anchored NHCs. The properties of surface-anchored NHCs were probed by conducting X-ray photoelectron spectroscopy and polarized near-edge X-ray absorption fine structure measurements. While no preferred orientation was identified for OH-NHCs on Pt(111), the anchored molecules adopted a preferred flat-lying position on Au(111). Dehydrogenation and aromatization of the imidazoline ring along with partial hydroxyl oxidation were detected in OH-NHCs that were anchored on Au(111). The dehydrogenation and aromatization reactions were facilitated, along with partial decomposition, for OH-NHCs that were anchored on Pt(111). The spectroscopic results reveal that stronger metal-adsorbate interactions increase the reactivity of surface-anchored OH-NHCs while decreasing their molecular orientational order.

Site-dependent selectivity in oxidation reactions on single Pt nanoparticles.

Site-dependent selectivity in oxidation reactions on Pt nanoparticles was identified by conducting IR nanospectroscopy measurements while using allyl-functionalized N-heterocyclic carbenes (allyl-NHCs) as probe molecules. Following exposure to oxidizing conditions the allyl groups in NHCs that were located on the center of Pt nanoparticles were oxidized to hydroxyl while those located on the nanoparticle's periphery were oxidized into carboxylic acid. The superior reactivity on the periphery of the nanoparticles was correlated to higher density of low coordinated atoms on these surface sites.

Mechanism of Photoredox-Initiated C-C and C-N Bond Formation by Arylation of IPrAu(I)-CF3 and IPrAu(I)-Succinimide.

Herein, we report on the photoredox-initiated gold-mediated C(sp2)-CF3 and C(sp2)-N coupling reactions. By adopting gold as a platform for probing metallaphotoredox catalysis, we demonstrate that cationic gold(III) complexes are the key intermediates of the C-C and C-N coupling reactions. The high-valent gold(III) intermediates are accessed by virtue of photoredox catalysis through a radical chain process. In addition, the bond-forming step of the coupling reactions is the reductive elimination from cationic gold(III) intermediates, which is supported by isolation and crystallographic characterization of key Au(III) intermediates.

Reductive Cleavage of Secondary Sulfonamides: Converting Terminal Functional Groups into Versatile Synthetic Handles.

Sulfonamides are pervasive in pharmaceuticals and agrochemicals, yet they are typically considered as terminal functional groups rather than synthetic handles. To enable the general late-stage functionalization of secondary sulfonamides, we have developed a mild and general method to reductively cleave the N-S bonds of sulfonamides to generate sulfinates and amines, components which can further react in situ to access a variety of other medicinally relevant functional groups. The utility of this platform is highlighted by the selective manipulation of several complex bioactive molecules.

Flexible NO2 -Functionalized N-Heterocyclic Carbene Monolayers on Au (111) Surface.

The formation of flexible self-assembled monolayers (SAMs) in which an external trigger modifies the geometry of surface-anchored molecules is essential for the development of functional materials with tunable properties. In this work, it is demonstrated that NO2 -functionalized N-heterocyclic carbene molecules (NHCs), which were anchored on Au (111) surface, change their orientation from tilted into flat-lying position following trigger-induced reduction of their nitro groups. DFT calculations identified that the energetic driving force for reorientation was the lower steric hindrance and stronger interactions between the chemically reduced NHCs and the Au surface. The trigger-induced changes in the NHCs' anchoring geometry and chemical functionality modified the work function and the hydrophobicity of the NHC-decorated Au surface, demonstrating the impact of a chemically tunable NHC-based SAM on the properties of the metal surface.

Flexible NO2 -Functionalized N-Heterocyclic Carbene Monolayers on Au(111) Surface.

Invited for the cover of this issue are Elad Gross, F. Dean Toste, and co-workers at The Hebrew University and UC Berkeley. The image depicts the flexible anchoring geometry of addressable carbene molecules on Au surface, which upon exposure to reducing conditions changed their orientation from a standing into a flat-lying position. Read the full text of the article at 10.1002/chem.201903434.

Primary Ewing sarcoma of the kidney mimicking cystic papillary renal cell carcinoma in an older patient: A case report.

BACKGROUND: Ewing's sarcoma (ES) is a neuroectodermal tumor that typically occurs in the bones and soft tissues of children and young adults. Primary renal ES is rare; only a few cases and a small case series have been documented, and only four cases involved primary renal ES in older people (> 65 years old). CASE SUMMARY: Herein, we describe the radiological and pathological features of primary renal ES in an older person. A 76-year-old man complained of poor oral intake and was found to have a large cystic renal mass with indistinct margins on computed tomography. Ultrasound-guided biopsy revealed that the tumor contained small round blue cells. The patient underwent a right radical nephrectomy. The tumor cells showed diffuse membranous CD99, and nuclear friend leukemia integration 1 transcription factor and NK2 Homeobox 2. Fluorescence in situ hybridization revealed EWSR1 translocation. Postoperatively, 18F-fluorodeoxyglucose positron emission tomography revealed no evidence of metastasis. The patient was diagnosed with primary renal ES. Six months following the surgery, local recurrence and distant metastasis were observed. Primary renal ES is rare and often lethal in older individuals. The specific imaging findings are unknown, and treatment protocols have not been standardized. CONCLUSION: This case report describes the radiological and pathological features of primary renal ES in an older person.

CSF pulsations measured in Parkinson's disease patients using EPI-based fMRI data.

Introduction: Cerebrospinal fluid (CSF) flow is involved in brain waste clearance and may be impaired in neurodegenerative diseases such as Parkinson's disease. This study aims to investigate the relationship between the CSF pulsation and the development of dementia in Parkinson's disease (PD) patients using EPI-based fMRI. Methods: We measured CSF pulsation in the 4th ventricle of 17 healthy controls and 35 PD patients using a novel CSF pulsation index termed "CSFpulse" based on echo-planar imaging (EPI)-based fMRI. The PD patients were classified into a PD with dementia high-risk group (PDD-H, n = 19) and a low risk group (PDD-L, n = 16), depending on their development of dementia within 5 years after initial brain imaging. The size of the 4th ventricle was measured using intensity-based thresholding. Results: We found that CSF pulsation was significantly higher in PD patients than in healthy controls, and that PD patients with high risk of dementia (PDD-H) had the highest CSF pulsation. We also observed an enlargement of the 4th ventricle in PD patients compared to healthy controls. Conclusion: Our results suggest that CSF pulsation may be a potential biomarker for PD progression and cognitive decline, and that EPI-based fMRI can be a useful tool for studying CSF flow and brain function in PD.

Clinical Outcomes After Drug-Coated Balloon Treatment in Popliteal Artery Disease: K-POP Registry 12-Month Results.

BACKGROUND AND OBJECTIVES: The popliteal artery is generally regarded as a "no-stent zone." Limited data are available on the outcomes of drug-coated balloons (DCBs) for popliteal artery disease. This study aimed to evaluate the 12-month clinical outcomes among patients who received DCB treatment for atherosclerotic popliteal artery disease. METHODS: This prospective, multicenter registry study enrolled 100 patients from 7 Korean endovascular centers who underwent endovascular therapy using IN.PACT DCB (Medtronic) for symptomatic atherosclerotic popliteal artery disease. The primary endpoint was 12-month clinical primary patency and the secondary endpoint was clinically driven target lesion revascularization (TLR)-free rate. RESULTS: The mean age of the study cohort was 65.7±10.8 years, and 77% of enrolled patients were men. The mean lesion length was 93.7±53.7 mm, and total occlusions were present in 45% of patients. Technical success was achieved in all patients. Combined atherectomy was performed in 17% and provisional stenting was required in 11%. Out of the enrolled patients, 91 patients completed the 12-month follow-up. Clinical primary patency and TLR-free survival rates at 12 months were 76.0% and 87.2%, respectively. A multivariate Cox regression analysis identified female and longer lesion length as the significant independent predictors of loss of patency. CONCLUSIONS: DCB treatment yielded favorable 12-month clinical primary patency and TLR-free survival outcomes in patients with popliteal artery disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02698345.

Radiation-induced osteoradionecrosis of the ribs in a patient with breast cancer: A case report.

Osteoradionecrosis of the chest wall after radiation therapy for breast cancer is rare; however, it is one of the most severe complications of radiation treatment. Radiologically, osteoradionecrosis can manifest as a focal lucent area in bone, periostitis, sclerosis, and cortical irregularity of bones on X-ray or computed tomography; therefore, differentiation from bone metastasis can be challenging. Associated insufficiency fractures, ulceration, and skin necrosis may also occur. We encountered a patient with osteoradionecrosis in the left anterior ribs after radiation therapy for breast cancer. Chest computed tomography revealed cortical irregularity with severe sclerotic changes of the anterior arc of the left fist to the fourth ribs. The patient's skin on the left chest wall exhibited ulceration with purulent discharge. Ultrasonography of the left chest wall revealed diffuse skin thickening with hyperechoic changes in the subcutaneous fat layer of the left chest wall with calcifications. The patient underwent rib resection and chest wall reconstruction. Recognizing characteristic imaging features of osteoradionecrosis is important for radiologists to differentiate it from bone metastasis and plan appropriate treatment.

Deep learning-based amyloid PET positivity classification model in the Alzheimer's disease continuum by using 2-[18F]FDG PET.

BACKGROUND: Considering the limited accessibility of amyloid position emission tomography (PET) in patients with dementia, we proposed a deep learning (DL)-based amyloid PET positivity classification model from PET images with 2-deoxy-2-[fluorine-18]fluoro-D-glucose (2-[18F]FDG). METHODS: We used 2-[18F]FDG PET datasets from the Alzheimer's Disease Neuroimaging Initiative and Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer's disease for model development. Moreover, we used an independent dataset from another hospital. A 2.5-D deep learning architecture was constructed using 291 submodules and three axes images as the input. We conducted the voxel-wise analysis to assess the regions with substantial differences in glucose metabolism between the amyloid PET-positive and PET-negative participants. This facilitated an understanding of the deep model classification. In addition, we compared these regions with the classification probability from the submodules. RESULTS: There were 686 out of 1433 (47.9%) and 50 out of 100 (50%) amyloid PET-positive participants in the training and internal validation datasets and the external validation datasets, respectively. With 50 times iterations of model training and validation, the model achieved an AUC of 0.811 (95% confidence interval (CI) of 0.803-0.819) and 0.798 (95% CI, 0.789-0.807) on the internal and external validation datasets, respectively. The area under the curve (AUC) was 0.860 when tested with the model with the highest value (0.864) on the external validation dataset. Moreover, it had 75.0% accuracy, 76.0% sensitivity, 74.0% specificity, and 75.0% F1-score. We found an overlap between the regions within the default mode network, thus generating high classification values. CONCLUSION: The proposed model based on the 2-[18F]FDG PET imaging data and a DL framework might successfully classify amyloid PET positivity in clinical practice, without performing amyloid PET, which have limited accessibility.

Relationship between Visual Perception and Microstructural Change of the Superior Longitudinal Fasciculus in Patients with Brain Injury in the Right Hemisphere: A Preliminary Diffusion Tensor Tractography Study.

Right hemisphere brain damage often results in visual-spatial deficits. Because various microstructural changes of the superior longitudinal fasciculus (SLF) after a stroke in the right hemisphere affect visual perception, including neglect, the present study investigates the relationship between both microstructural change and lateralization of SLF and visual perception, using diffusion tensor imaging (DTI) in patients with lesions in the right hemisphere. Eight patients with strokes (five patients with intracranial hemorrhage, and three patients with infarction; mean age of 52.5 years) and 16 mean-age-matched healthy control subjects were involved in this study. The visual perception of all eight patients was assessed with the motor-free visual perception test (MVPT), and their SLFs were reconstructed using DTI. The results showed that there was a significant difference between the DTI parameters of the patients and the control subjects. Moreover, patients with microstructural damage to the right SLF showed impairment of visual perception. In patients with damage to both the dorsal and ventral pathways of the right SLF, spatial neglect was present. However, although a leftward SLF asymmetry was revealed in our patients, this lateralization did not show a relationship with visual perception. In conclusion, the microstructural changes of the right SLF play an important role in visual perception, and both pathways contribute to spatial neglect, but leftward lateralization of the right SFL activity after a stroke does not contribute to general visual perception.

Diffusion-Tensor-Tractography-Based Diagnosis for Injury of Corticospinal Tract in a Patient with Hemiplegia Following Traumatic Brain Injury.

This paper reports a mechanism for corticospinal tract injury in a patient with hemiplegia following traumatic brain injury (TBI) based on diffusion tensor tractography (DTT) finding. A 73-year-old male with TBI resulting from a fall, without medical history, was diagnosed as having left convexity epidural hematoma (EDH). He underwent craniotomy and suffered motor weakness on the right side of the body. Two weeks after onset, he was transferred to a rehabilitation department with an alerted level of consciousness. Four weeks after onset, his motor functions were grade 1 by the Medical Research Council's (MRC) standards in the right-side limbs and grade 4 in the left-side limbs. The result of DTT using the different regions of interest (ROIs) showed that most of the right corticospinal tract (CST) did not reach the cerebral cortex around where the EDH was located, and when the ROI was placed on upper pons, a disconnection of the CST was shown and a connection of the CST in ROI with the middle pons appeared. However, the right CST was connected to the cerebral cortex below the pons regardless of ROI. This study is the first report to use DTT to detect that the discontinuation of the left CST in the cerebral cortex and injury lesions below the lower pons and between the upper and lower pons are responsible for motor weakness in a patient.

Electrochemical deposition of N-heterocyclic carbene monolayers on metal surfaces.

N-heterocyclic carbenes (NHCs) have been widely utilized for the formation of self-assembled monolayers (SAMs) on various surfaces. The main methodologies for preparation of NHCs-based SAMs either requires inert atmosphere and strong base for deprotonation of imidazolium precursors or the use of specifically-synthesized precursors such as NHC(H)[HCO3] salts or NHC-CO2 adducts. Herein, we demonstrate an electrochemical approach for surface-anchoring of NHCs which overcomes the need for dry environment, addition of exogenous strong base or restricting synthetic steps. In the electrochemical deposition, water reduction reaction is used to generate high concentration of hydroxide ions in proximity to a metal electrode. Imidazolium cations were deprotonated by hydroxide ions, leading to carbenes formation that self-assembled on the electrode's surface. SAMs of NO2-functionalized NHCs and dimethyl-benzimidazole were electrochemically deposited on Au films. SAMs of NHCs were also electrochemically deposited on Pt, Pd and Ag films, demonstrating the wide metal scope of this deposition technique.

Characteristics of the Uncinate Fasciculus and Cingulum in Patients with Mild Cognitive Impairment: Diffusion Tensor Tractography Study.

Many studies have examined the relationship between cognition, and the cingulum and uncinate fasciculus (UF). In this study, diffusion tensor tractography (DTT) was used to investigate the correlation between fractional-anisotropy (FA) values and the number of fibers in the cingulum and UF in patients with and without cognitive impairment. The correlation between cognitive function, and the cingulum and UF was also investigated. Thirty patients (14 males, age = 70.68 ± 7.99 years) were divided into a control group (n = 14) and mild-cognitive-impairment (MCI) group (n = 16). The Seoul Neuropsychological Screening Battery (SNSB) and DTT were performed to assess cognition and bilateral tracts of the cingulum and UF. The relationship between SNSB values and the cingulum and UF was analyzed. The number of fibers in the right cingulum and right UF were significantly different between the two groups. The MCI group showed thinner tracts in both the cingulum and UF compared to the control group. A significant relationship was found between the number of fibers in the right UF and delayed memory recall. In conclusion, memory loss in MCI was associated with a decreased number of fibers in the right UF, while language and visuospatial function were related to the number of fibers in the right cingulum.