Organosilicon compounds act as a nucleophile upon activation by an appropriate base and behave in a manner similar to main-group organometallic reagents. In the last decades, structurally divergent ...organosilicon reagents are available and have become more employed for synthetic transformation with the aid of transition-metal complexes, because organosilicon compounds are in general superior to other organometallic compounds in view of stability, solubility, nontoxicity, and easy-handling. Particularly, cross-coupling of organosilicon reagents with organic halides or pseudohalides has been considered to be a useful tool for constructing the carbon frameworks of various target molecules such as pharmaceuticals and π-conjugated functional materials. Perfluoroalkylsilicon compounds such as CF3SiEt3 have found use as reagents for the metal-catalyzed introduction of perfluoroalkyl groups into many substrates. In addition, functionalized organosilicon reagents are readily accessible by catalytic approach starting with appropriate hydrocarbons such as alkenes, alkynes, alkanes, and arenes. This article reviews recent advances in transition-metal-catalyzed transformations of organosilicon reagents according to the type of synthetic transformation and metal catalyst.
Organic synthesis based on straightforward transformations is essential for environmentally benign manufacturing for the invention of novel pharmaceuticals, agrochemicals, and organoelectronic ...materials in order to ultimately realize a sustainable society. Metal-catalyzed C–H bond-cleaving functionalization has become a promising method for achieving the above goal. For site-selective C–H bond cleavage, so-called directing groups, i.e., ligands attached to substrates, are employed. Commonly utilized directing groups are carbonyls, imines, carboxyls, amides, and pyridyls, which σ-donate electron pairs to metals. On the other hand, unsaturated substrates such as alkenes and alkynes, which participate largely as reactants in organic synthesis, are prepared readily by a wide variety of synthetic transformations and are also employed as reactants in organometallic chemistry. Moreover, such unsaturated groups form complexes with some metals by ligation of their p orbitals via donation and back-donation. However, the use of unsaturated bonds as directing groups has not been studied extensively. We have been involved in the development of methods for the cleavage of C–H bonds by means of transition-metal catalysts to achieve new carbon–carbon bond-forming reactions and incidentally came to focus on the alkynoxy group (−OCC−), which shows a ketene-like resonance structure. We expected the alkynoxy group to interact electrophilically with a low-valent transition-metal complex in order to cleave adjacent C–H bonds. In this Account, we summarize our recent achievements on C–H activation based on interactions of palladium with the alkynoxy group in alkynyl aryl ethers. The alkynoxy group plays two roles in the transformation: as a directing group for adjacent C–H bond activation and as an acceptor for the carbon and hydrogen fragments. A typical example is palladium-catalyzed ortho-C–H bond activation in alkynoxyarenes followed by sequential insertion/annulation with internal alkynes and the alkynoxy group to produce 2-methylidene-2H-1-benzopyrans. Mechanistic studies have shown that the presence of both oxygen and alkynyl moieties is essential for selective ortho-C–H bond activation and subsequent annulation. In addition to internal alkynes, norbornene, allenes, isocyanates, and ketenes produce the corresponding oxacycles. It is worthy of note that benzoxadinones formed by the reaction with isocyanates exhibit solid-state luminescence. In addition, 2-methylphenyl alkynyl ethers and 2-alkynoxybiaryls undergo intramolecular annulation at the benzylic γ-position and aryl δ-position via C–H bond activation to give benzofurans and dibenzopyrans, respectively. The disclosed methods allow us to construct useful π-conjugated systems in a straightforward manner.
Organo(trialkyl)silanes have several advantages, including high stability, low toxicity, good solubility, easy handling, and ready availability compared with heteroatom‐substituted silanes. However, ...methods for the cross‐coupling of organo(trialkyl)silanes are limited, most probably because of their exceeding robustness. Thus, a practical method for the cross‐coupling of organo(trialkyl)silanes has been a long‐standing challenging research target. This article discusses how aryl(trialkyl)silanes can be used in cross‐coupling reactions. A pioneering example is CuII catalytic conditions with the use of electron‐accepting aryl‐ or heteroaryl(triethyl)silanes and aryl iodides. The reaction forms biaryls or teraryls. This design concept can be extended to Pd/CuII‐catalyzed cross‐coupling polymerization reactions between such silanes and aryl bromides or chlorides and to CuI‐catalyzed alkylation using alkyl halides.
In plain Si‐ght! This concept article focuses on transition‐metal‐catalyzed cross‐coupling reactions using organo(trialkyl)silanes. Mainly, we discuss methods for the practical activation of robust carbon–trialkylsilyl bonds and our recent developments in aryl–aryl and aryl–alkyl bond‐forming cross‐coupling reactions of aryl(trialkyl)silanes with aryl or alkyl halides. n‐Hex=n‐hexyl, Ts=tosyl.
Local ablative techniques-percutaneous ethanol injection, microwave coagulation therapy and radiofrequency ablation （RFA）-have been developed to treat unresectable hepatocellular carcinoma （HCC）. The ...success rate of percutaneous ablation therapy for HCC depends on correct targeting of the tumor via an imaging technique. However, probe insertion often is not completely accurate for small HCC nodules, which are poorly def ined on conventional B-mode ultrasound （US） alone. Thus, multiple sessions of ablation therapy are frequently required in diffi cult cases. By means of two breakthroughs in US technology, harmonic imaging and the development of second-generation contrast agents, dynamic contrast-enhanced harmonic US imaging with an intravenous contrast agent can depict tumor vascularity sensitively and accurately, and is able to evaluate small hypervascular HCCs even when B-mode US cannot adequately characterize the tumors. Therefore, dynamic contrast-enhanced US can facilitate RFA electrode placement in hypervascular HCC, which is poorly depicted by B-mode US. The use of dynamic contrast-enhanced US guidance in ablation therapy for liver cancer is an effi cient approach. Here, we present an overview of the current status of dynamic contrast-enhanced US-guided ablation therapy, and summarize the current indications and outcomes of reported clinical use in comparison with that of other modalities.
Percutaneous radiofrequency ablation (RFA), a generally accepted alternative therapy for patients with liver metastases, is a minimally invasive approach with a favorable safety profile and a lower ...rate of major complications. The use of RFA or combined RFA plus resection can produce total tumor clearance in patients with unresectable liver metastases. However, the relatively high rate of local tumor progression has prevented the widespread use of RFA. Furthermore, its efficacy is controversial because there have been no comparisons for its effect on overall survival compared with standard options such as systemic chemotherapy. Meanwhile, immunotherapy has become a major research focus for oncology based on the recent successes reported for immune checkpoint inhibitors for melanoma, non-small cell lung cancer, gastric cancer, and other cancers. Immune checkpoints negatively regulate T cell function, and inhibition prevents the blockade of the immune system by cancer cells to prevent their destruction. Unfortunately, only some patients (< 25%) respond to immuno-oncology drugs, whereas other patients acquire resistance. However, RFA can induce massive necrotic cell death which might activate immunity and the presentation of cryptic antigens to induce tumor-specific T cell response. Because RFA can induce the rapid release of large amounts of tumor antigens, it can potentially stimulate transient immune responses to much tumor antigens. Combination therapies have induced synergistic enhancement of anticancer immune response in preclinical studies, indicating great promise for the future of oncologic treatment.
Key Points
• Only some patients respond to immuno-oncology drugs.
• RFA causes the release of large amounts of cellular debris, a source of tumor antigens that elicit immune responses against tumors.
• Combination RFA for liver metastases and immune checkpoint inhibitor therapies might synergistically enhance antitumor immunity.
The ultrasound (US) imaging technology, including contrast-enhanced US (CEUS) and fusion imaging, has experienced radical improvement, and advancement in technology thus overcoming the problem of ...poor conspicuous hepatocellular carcinoma (HCC). On CEUS, the presence or absence of enhancement distinguishes the viable portion from the ablative necrotic portion. Using volume data of computed tomography (CT) or magnetic resonance imaging (MRI), fusion imaging enhances the three-dimensional relationship between the liver vasculature and HCC. Therefore, CT/MR-US fusion imaging provides synchronous images of CT/MRI with real-time US, and US-US fusion imaging provides synchronous US images before and after ablation. Moreover, US-US overlay fusion can visualize the ablative margin because it focuses the tumor image onto the ablation zone. Consequently, CEUS and fusion imaging are helpful to identify HCC with little conspicuity, and with more confidence, we can perform ablation therapy. CEUS/fusion imaging guidance has improved the clinical effectiveness of ablation therapy in patients with poor conspicuous HCCs. Therefore; this manuscript reviews the status of CEUS/fusion imaging guidance in ablation therapy of poor conspicuous HCC.
Although transcatheter arterial chemoembolization (TACE) is the standard of care for intermediate-stage hepatocellular carcinoma (HCC), this is a largely heterogeneous disease that includes a ...subgroup of patients who do not benefit from TACE. The treatment strategy for this subgroup of patients currently remains an unmet need in clinical practice. Here, we performed a proof-of-concept study that lenvatinib may be a more favorable treatment option over TACE as an initial treatment in intermediate-stage HCC patients with large or multinodular tumours exceeding the up-to-seven criteria. This proof-of-concept study included 642 consecutive patients with HCC initially treated with lenvatinib or conventional TACE (cTACE) between January 2006 and December 2018. Of these patients, 176 who received lenvatinib or cTACE as an initial treatment and met the eligibility criteria (unresectable, beyond the up-to-seven criteria, no prior TACE/systemic therapy, no vascular invasion, no extrahepatic spread and Child-Pugh A liver function) were selected for the study. Propensity score matching was used to adjust for patient demographics. After propensity-score matching, the outcome of 30 patients prospectively treated with lenvatinib (14 in clinical trials, one in an early access program and 15 in real world settings) and 60 patients treated with cTACE as the initial treatment was compared. The change of albumin-bilirubin (ALBI) score from baseline to the end of treatment were -2.61 to -2.61 for 30 patients in the lenvatinib group (
= 0.254) and -2.66 to -2.09 in the cTACE group (
< 0.01), respectively. The lenvatinib group showed a significantly higher objective response rate (73.3% vs. 33.3%;
< 0.001) and significantly longer median progression-free survival than the cTACE group (16.0 vs. 3.0 months;
< 0.001). Overall survival was significantly longer in the lenvatinib group than in the cTACE group (37.9 vs. 21.3 months; hazard ratio: 0.48,
< 0.01). In patients with large or multinodular intermediate-stage HCC exceeding the up-to-seven criteria with Child-Pugh A liver function, who usually do not benefit from TACE, lenvatinib provides a more favorable outcome than TACE.
Aryl(triethyl)silanes are found to undergo cross‐coupling with iodoarenes in the presence of catalytic amounts of CuBr2 and Ph‐Davephos, as well as cesium fluoride as a stoichiometric base. Because ...the silicon reagents are readily accessible through catalytic C−H silylation of aromatic substrates, the net transformation allows coupling of aromatic hydrocarbons with iodoarenes via triethylsilylation.
Simple aryl(triethyl)silanes are demonstrated to undergo cross‐coupling with iodoarenes to form biaryls and teraryls. The reaction is characterized by a diverse substrate scope, including 4,7‐bis(triethylsilyl)‐5,6‐difluorobenzothiadiazole and thiophene derivatives, and the use of CuBr2 as a crucial catalyst. The employed aryl(triethyl)silanes are accessible by Ir‐catalyzed C−H silylation.
Facile synthesis of various benzonaphthofurans was achieved by intramolecular hydroarylation of 1,4‐disilyl‐2‐aryloxy‐1,3‐enynes followed by cycloaddition with arynes or alkenes and finally ...desilylaromatization. The three‐step transformation can be operated sequentially in one‐pot, providing with a range of furanoacenes easily and highly effectively.
Furanoacenes: Facile synthesis of various benzonaphthofurans was achieved from 1,4‐disilyl‐2‐aryloxy‐1,3‐enynes by hydroarylation, cycloaddition with arynes or alkenes, and desilylated aromatization. These three reactions could be operated sequentially in one‐pot, being highly effective and providing a range of furanoacene products easily.
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