C–C Chemokines Released by Lipopolysaccharide (LPS)-stimulated Human Macrophages Suppress HIV-1 Infection in Both Macrophages and T Cells

Human immunodeficiency virus-1 (HIV-1) expression in monocyte-derived macrophages (MDM) infected in vitro is known to be inhibited by lipopolysaccharide (LPS). However, the mechanisms are incompletely understood. We show here that HIV-1 suppression is mediated by soluble factors released by MDM stimulated with physiologically significant concentrations of LPS. LPS-conditioned supernatants from MDM inhibited HIV-1 replication in both MDM and T cells. Depletion of C–C chemokines (RANTES, MIP-1α, and MIP-1β) neutralized the ability of LPS-conditioned supernatants to inhibit HIV-1 replication in MDM. A combination of recombinant C–C chemokines blocked HIV-1 infection as effectively as LPS. Here, we report an inhibitory effect of C–C chemokines on HIV replication in primary macrophages. Our results raise the possibility that monocytes may play a dual role in HIV infection: while representing a reservoir for the virus, they may contribute to the containment of the infection by releasing factors that suppress HIV replication not only in monocytes but also in T lymphocytes.     

1,2-Difunctionalizations of alkynes entailing concomitant C–C and C–N bond-forming carboamination reactions

Vicinal carboamination of alkynes is a highly reliable and efficient practical strategy for the quick preparation of valuable and diverse amine derivatives starting from simple synthons. The last decade has witnessed numerous practical methods employing transition-metal-based/metal-free carboamination approaches using alkynes for the synthesis of these N-bearing entities. Driven by the renaissance of transition metal catalysis, intermolecular and intramolecular carboamination of alkynes comprising concomitant C–N and C–C bond formation has been studied extensively. In contrast to metal catalysis, though analogous metal-free approaches have been relatively less explored in the literature, they serve as alternatives to these expensive approaches. Despite this significant progress, reviews documenting such examples are sporadic; as a result, most reports of this type remained scattered throughout the literature, thereby hampering further developments in this escalating field. In this review, different conceptual approaches will be discussed and examples from the literature will be presented. Further, the reader will get insight into the mechanisms of different transformations.

The 1,2-difunctionalization of alkynes happening through concomitant C–C and C–N bond formation strategies have provide an unified access to diversely functionalized N-bearing heterocycles.     

Solvent-free and room temperature microwave-assisted direct C7 allylation of indolines via sequential C–H and C–C activation

A Ru or Rh-catalyzed efficient and atom-economic C7 allylation of indolines with vinylcyclopropanes was developed via sequential C–H and C–C activation. A wide range of substrates were well tolerated to afford the corresponding allylated indolines in high yields and E/Z selectivities under microwave irradiation. The obtained allylated indolines could further undergo transformations to afford various value-added chemicals. Importantly, this reaction proceeded at room temperature under solvent-free conditions.

A Ru or Rh-catalyzed direct C7 allylation of indolines with vinylcyclopropanes via sequential C–H/C–C activation under microwave irradiation has been disclosed.

The development of sustainable methodologies is attractive for access to complex molecular architectures in organic chemistry.¹ In recent years, various non-conventional techniques, such as microwave irradiation, sonochemistry, mechanical grinding and photochemistry, have achieved remarkable success.² In particular, microwaves have shown unique advantages with regards to reaction times, energy efficiency, temperature, and reaction media.³ On the other hand, transition-metal-catalyzed activation of C–H⁴ and C–C⁵ bonds has been considered as an ideal method for the formation of C–C and C–X bonds. Nevertheless, transition-metal-catalyzed C–H or C–C bond activation under the above non-conventional techniques remains to be explored. It is thus highly imperative to develop a practical strategy in combination of C–H or C–C activation and microwave irradiation.⁶Recently, there have significant advances in C–H activation technology by merging C–H functionalization with challenging C–C cleavage strategies.⁷ Since the pioneering work by Bergman and co-workers⁸ on the sequential C–H and C–C bond activation, many research groups, including Dong,⁹ Ackermann,¹⁰ Li,¹¹ Cramer,¹² and others¹³ have contributed to C–H/C–C activation. In this content, certain small strained rings are often utilized as an effective synthons to undergo ring-opening reactions driven by strain-release energy.¹⁴ Very recently, VCPs (vinylcyclopanes) have been reported as allyl reagents to access various (hetero)aromatic derivatives through sequential C–H and C–C activation (Scheme 1a–d).¹⁵Open in a separate windowScheme 1Sequential C–H/C–C activations using VCPs.As a continuation of our interest in chelation-directed reactions and novel methods for C–H functionalization,¹⁶ we herein report a Ru or Rh-catalyzed C-7 allylation of indolines under microwave irradiation using VCPs as the allylating agents (Scheme 1e). This transformation possesses great synthetic potential from the viewpoint of green and sustainable chemistry. Notable features of our protocol include (1) C–H/C–C activation with VCPs by microwave irradiation, (2) broad substrate scope with good regio- and E/Z selectivities, (3) high atom economy, and (4) high efficiency (2 h) at room temperature under solvent-free conditions.We initiated our investigation by choosing indoline 1a and VCP 2a as model substrates under microwave irradiation conditions (

Human Macrophage–derived Chemokine (MDC), a Novel Chemoattractant for Monocytes, Monocyte-derived Dendritic Cells, and Natural Killer Cells

A cDNA encoding a novel human chemokine was isolated by random sequencing of cDNA clones from human monocyte-derived macrophages. This protein has been termed macrophagederived chemokine (MDC) because it appears to be synthesized specifically by cells of the macrophage lineage. MDC has the four-cysteine motif and other highly conserved residues characteristic of CC chemokines, but it shares <35% identity with any of the known chemokines. Recombinant MDC was expressed in Chinese hamster ovary cells and purified by heparin– Sepharose chromatography. NH₂-terminal sequencing and mass spectrophotometry were used to verify the NH₂ terminus and molecular mass of recombinant MDC (8,081 dalton). In microchamber migration assays, monocyte-derived dendritic cells and IL-2–activated natural killer cells migrated to MDC in a dose-dependent manner, with a maximal chemotactic response at 1 ng/ml. Freshly isolated monocytes also migrated toward MDC, but with a peak response at 100 ng/ml MDC. Northern analyses indicated MDC is highly expressed in macrophages and in monocyte-derived dendritic cells, but not in monocytes, natural killer cells, or several cell lines of epithelial, endothelial, or fibroblast origin. High expression was also detected in normal thymus and less expression in lung and spleen. Unlike most other CC chemokines, MDC is encoded on human chromosome 16. MDC is thus a unique member of the CC chemokine family that may play a fundamental role in the function of dendritic cells, natural killer cells, and monocytes.     

C反应蛋白和脂多糖致单核细胞核因子-κB活化的时间效应

目的：观察C反应蛋白（CRP）和脂多糖（LPS）刺激人外周血单核细胞核因子-kB（NF—kB）活化及白细胞介素-6（IL-6）表达，探讨CRP／NF—kB在动脉粥样硬化（AS）致病机制中的作用。方法：密度梯度离心法分离人外周血单核细胞，免疫细胞化学观察CRP和LPS致单核细胞NF—kB p65活化的时间效应，ELISA法观察IL-6产生的时间效应。结果：CRP和LPS刺激单核细胞NF—kB活化呈时间依赖性，开始活化的时间在刺激后30min，高峰分别在2h与1h；CRP和LPS刺激单核细胞合成IL-6呈时间依赖性，开始合成的时间分别在刺激后4h与2h，高峰在24h，其合成出现在核因子-kB活化后。结论：CRP和LPS激活单核细胞NF—kB信号途径，并诱导IL-6产生。     

One-pot facile and mild construction of densely functionalized pyrimidines in water via consecutive C–C and C–S bonds formation

Fused pyrimidines composed of alternating heteroatoms and a pyrimidine moiety were synthesized efficiently using readily available starting material 4-hydroxycoumarin, aromatic aldehydes, and urea/thiourea at room temperature. Acid, metal salts, and surfactants were screened for their influence on catalytic activity in three-component reactions and sodium lauryl sulphate (SLS) was used as the best catalyst with different concentrations. Screening results of catalyst loading from our investigation showed that good to excellent yields were obtained with 10 mol%. Our method efficiently synthesized heterocycles and avoided the use of hazardous solvents and conventional organic solvents. Our procedure which involves a surfactant is operationally simple, environmentally benign, has excellent yields, short reaction times, and synthetically is as efficient as conventional procedures using organic solvents.

Fused pyrimidines composed of alternating heteroatoms and a pyrimidine moiety were synthesized efficiently using readily available starting material 4-hydroxycoumarin, aromatic aldehydes, and urea/thiourea at room temperature.     

B(C6F5)3 catalyzed direct nucleophilic substitution of benzylic alcohols: an effective method of constructing C–O,C–S and C–C bonds from benzylic alcohols

An efficient and general method of nucleophilic substitution of benzylic alcohols catalyzed by non-metallic Lewis acid B(C₆F₅)₃ was developed. The reaction could be carried out under mild conditions and more than 35 examples of ethers, thioethers and triarylmethanes were constructed in high yields. Some bioactive organic molecules were synthesized directly using the methods.

An efficient and general method of nucleophilic substitution of benzylic alcohols catalyzed by non-metallic Lewis acid B(C₆F₅)₃ was developed.

Alcohols are ideal building blocks for high-value chemicals because of their high stability, low toxicity and wide availability.¹ However, due to the poor leaving ability of the hydroxyl group, in most cases, alcohol substitution requires hydroxyl preactivation or the use of excess Brønsted acids or stoichiometric amounts of Lewis acids. In 2005, the OH-activation for nucleophilic substitution was considered a central issue by the ACS Green Chemistry Institute² because the direct catalytic nucleophilic substitutions of alcohols are highly desirable in constructing high-value organic compounds such as ethers, thioethers and a variety of bioactive molecules. Furthermore, the reaction produces only H₂O as a byproduct, which meets the requirements of green chemistry and atom-economy.³In recent years, the direct catalytic nucleophilic substitution of alcohol has been explored, however, many urgent, difficult problems are still waiting to be solved. The catalytic nucleophilic substitutions of π-activated alcohols such as allylic/propargyl alcohols have been developed as well as the double bond or triple bond of the substrates being able to coordinate to the metal catalysts (Au, Bi, In, Al, Fe etc.), stabilizing the carbocations.⁴ In contrast, for benzylic alcohols, the catalytic substitution reactions are much less explored.⁵ Furthermore, harsh conditions and excess nucleophiles are two major defects in the existing reports, and for different nucleophiles, varied catalysts are always required. Therefore, a mild, green, efficient and general method of benzylic alcohol nucleophilic substitution is highly desirable (Scheme 1).Open in a separate windowScheme 1The difference between traditional method and catalytic method.In recent years, B(C₆F₅)₃ as a non-metallic Lewis acid has drawn notable attention because of its strong Lewis acidity, high-stability and environmental friendliness.⁶ Furthermore, the borane hydrate is also a strong Brønsted acid.⁷ And these inspired us that the borane may offer another chance to realize the direct substitution reaction of benzylic alcohols such as etherification, thioetherification and arylation (Scheme 2).Open in a separate windowScheme 2Catalytic substitution of alcohols.For the etherification of alcohols, the difficulty is that how to realize the high selectivity between cross-etherification and homo-etherification. Initially we chose diphenylmethanol 1a and BnOH as the model alcohol compounds. The reaction was carried out with 10 mol% B(C₆F₅)₃ in toluene at 60 °C (8 was formed between B(C₆F₅)₃ and THF. When the catalyst loading was decreased to 5 mol%, the yield had no erosion (entry 6), and a further decrease led to a longer reaction time and a slight lower yield (entry 7). Longer time was needed when the reaction was carried out at room temperature.Optimization conditions^a

Recent trends in the direct oxyphosphorylation of C–C multiple bonds

Due to the wide importance of β-phosphorylated ketones as key building-blocks in the fabrication of various pharmaceutically active organophosphorus compounds, finding new and truly efficient methods for their preparation from simple, low-cost and ubiquitous feedstock materials within a single click is an interesting subject in organic synthesis. Recently, oxyfunctionalization of carbon–carbon multiple bonds has arisen as a straightforward and versatile tool for the synthesis of complex organic molecules from the simple and easily accessible alkenes/alkynes via a single operation. In this context, oxyphosphorylation of alkenes/alkynes with P(O)–H compounds has attracted considerable attention as a unique procedure for the construction of β-phosphorylated ketones. In this review, we outline the recent advances and developments in this fast-growing research field with particular emphasis on the mechanistic aspects of reaction.

Due to the wide importance of β-phosphorylated ketones as key building-blocks in the fabrication of various pharmaceutically active organophosphorus compounds, finding new and truly efficient methods for their preparation.     

Differential Induction of Apoptosis by Fas–Fas Ligand Interactions in Human Monocytes and Macrophages

Human monocytes undergo spontaneous apoptosis upon culture in vitro; removal of serum from the media dramatically increases the rate of this process. Monocyte apoptosis can be significantly abrogated by the addition of growth factors or proinflammatory mediators. We have evaluated the role of the endogenous Fas–Fas ligand (FasL) interaction in the induction of this spontaneous apoptosis and found that a Fas–immunoglobulin (Ig) fusion protein, an antagonistic anti-Fas monoclonal antibody and a rabbit anti-FasL antibody all greatly reduced the onset of apoptosis. The results indicate that spontaneous death of monocytes is mediated via an autocrine or paracrine pathway. Treatment of the cells with growth factors or cytokines that prevented spontaneous apoptosis had no major effects on the expression of Fas or FasL. Additionally, monocyte-derived macrophages were found to express both Fas and FasL but did not undergo spontaneous apoptosis and were not sensitive to stimulation by an agonistic anti-Fas IgM. These results indicate that protective mechanisms in these cells exist at a site downstream of the receptor–ligand interaction.     

Catalysis with magnetically retrievable and recyclable nanoparticles layered with Pd(0) for C–C/C–O coupling in water

Nanoparticles layered with palladium(0) were prepared from nano-sized magnetic Fe₃O₄ by coating it with silica and then reacting sequentially with phenylselenyl chloride under an N₂ atmosphere and palladium(ii) chloride in water. The resulting Fe₃O₄@SiO₂@SePh@Pd(0) NPs are magnetically retrievable and the first example of NPs in which the outermost layer of Pd(0) is mainly held by selenium. The weight percentage of Pd in the NPs was found to be 1.96 by ICP-AES. The NPs were authenticated via TEM, SEM-EDX, XPS, and powder XRD and found to be efficient as catalysts for the C–O and C–C (Suzuki–Miyaura) coupling reactions of ArBr/Cl in water. The oxidation state of Pd in the NPs having size distribution from ∼12 to 18 nm was inferred as zero by XPS. They can be recycled more than seven times. The main features of the proposed protocols are their mild reaction conditions, simplicity, and efficiency as the catalyst can be separated easily from the reaction mixture by an external magnet and reused for a new reaction cycle. The optimum loading (in mol% of Pd) was found to be 0.1–1.0 and 0.01–1.0 for O-arylation and Suzuki–Miyaura coupling, respectively. For ArCl, the required amount of NPs was more as compared to that needed for ArBr. The nature of catalysis is largely heterogeneous.

Fe₃O₄@SiO₂@SePh@Pd(0) (Pd, 1.96%) as the first example of NPs having a Pd(0) layer held by selenium can execute C–C/C–O coupling in 2–6 h (80 °C).     

Synthesis of benzoxazoles via an iron-catalyzed domino C–N/C–O cross-coupling reaction

An eco-friendly and efficient method has been developed for the synthesis of 2-arylbenzoxazoles via a domino iron-catalyzed C–N/C–O cross-coupling reaction. Some of the issues typically encountered during the synthesis of 2-arylbenzoxazoles in the presence of palladium and copper catalysts, including poor substrate scope and long reaction times have been addressed using this newly developed iron-catalyzed method.

The synthesis of benzoxazoles via an iron-catalyzed cascade C–N and C–O coupling is described.

2-Arylbenzoxazoles are an important class of structures in natural products, and pharmaceuticals and has shown a wide range of biological activities, such as antitumor, antiviral, and antimicrobial activities.¹ In particular, they show a marvellous efficacy in the treatment of duchenne muscular dystrophy (DMD) which is one of the most common of the muscular dystrophies that is caused by a mutation in the gene DMD, located in humans on the X chromosome (Xp21).² So the synthesis of 2-arylbenzoxazoles has been intensively studied for use in organic and medicinal chemistry over the past few years.Numerous methods have been reported to synthesise this motif, one of the common methods is transition-metal-catalyzed (like Pd,³ Ni,⁴ Cu,⁵ Mn⁶etc.) cross-coupling from pre-existing benzoxazoles with aryl halide or arylboronic acid. And another method is the classic one employing a cyclocondensation approach between an aminophenol and either a carboxylic acid⁷ or benzaldehyde⁸ (Scheme 1, path a). In 2004, Frank Glorius'' group reported a domino copper-catalyzed C–N and C–O cross-coupling for the conversion of primary amides into benzoxazoles⁹ (Scheme 1, path b) which is a new reaction type for the synthesis of benzoxazoles. Bunch et al. apply this domino reaction in the synthesis of planar heterocycles in 2014.¹⁰ In addition the cyclization of o-halobenzenamides to benzoxazoles has been reported several times.^11,12 Nevertheless, some limitations in the reported methods need to be overcome, such as the use of palladium complexes and narrow substrate range.Open in a separate windowScheme 1Classic method of benzoxazole formation.In the last few years, there has been a significant increase in the number of reports pertaining to the development of iron-catalyzed reactions in organic synthesis, where iron has shown several significant advantages over other metals, such as being more abundant, commercially inexpensive, environmentally friendly and drug safety.¹³ Compared with palladium and copper, the use of iron is particularly suitable for reactions involving the preparation of therapeutic agents for human consumption. With this in mind, it was envisaged that an new method should be developed for the synthesis of benzoxazoles via an iron-catalyzed domino C–N/C–O cross-coupling reaction.The reaction of benzamide (1a) with 1-bromo-2-iodobenzene was used as model transformation to identify the optimum reaction conditions by screening a variety of different iron salts, bases, ligands and solvents (l-proline provided no product (14 high-purity Fe₂O₃ (99.999%) and K₂CO₃ (99.999%) were applied in the reaction ( EntryIron saltLigandBaseSolvent Y ^b (%)1FeCl₃DMEDAKO^tBuPhMeTrace2FeCl₂·4H₂ODMEDAKO^tBuPhMeTrace3FeSO₄·7H₂ODMEDAKO^tBuPhMe04Fe(acac)₃DMEDAKO^tBuPhMe05Fe₂O₃DMEDAKO^tBuPhMe156Fe₃O₄DMEDAKO^tBuPhMe07Fe₃O₄(nano)DMEDAKO^tBuPhMe108Fe₂O₃(nano)DMEDAKO^tBuPhMe09Fe₂(SO₄)₃DMEDAKO^tBuPhMe010Fe(NO₃)₃·9H₂ODMEDAKO^tBuPhMe011Fe₂O₃DMEDALiO^tBuPhMe012Fe₂O₃DMEDANa₂CO₃PhMe013Fe₂O₃DMEDANaOAcPhMe014Fe₂O₃DMEDAKOHPhMe015Fe₂O₃DMEDAK₂CO₃ (24 h)PhMe3716Fe₂O₃DMEDAK₂CO₃ (48 h)PhMe8717Fe₂O₃PhenK₂CO₃PhMeTrace18Fe₂O₃ l-ProlineK₂CO₃PhMe019Fe₂O₃DpyK₂CO₃PhMe020Fe₂O₃DMEDAK₂CO₃DMSO021Fe₂O₃DMEDAK₂CO₃DMF022Fe₂O₃DMEDAK₂CO₃PhMe₂023—DMEDAK₂CO₃PhMe024Fe₂O₃DMEDAK₂CO₃PhMe86^c25Fe₂O₃DMEDAK₂CO₃PhMe58^dOpen in a separate window^aReaction conditions: benzamides (0.5 mmol), 1-bromo-2-iodobenzene (1.5 eq.), iron salt (20% mol), base (1 eq.), ligand (20%) were added to a solvent (2 mL) and react at 110 °C for 48 h under N₂.^bIsolated yield based on 1a after silica gel chromatography.^cFe₂O₃ and K₂CO₃ were applied in purity of 99.999% from alfa.^dwith Fe₂O₃ in a dosage of 10 mmol%.At last, the dosage of Fe₂O₃ was reduce to 10 mmol%, but only 58% yield was obtained (Scheme 2.Open in a separate windowScheme 2The pathway of the reaction.With the optimized reaction conditions in hand, we proceeded to investigate the substrate scope of the reaction using a variety of different 1,2-dihalobenzene substrates and aryl formamide ( Open in a separate window^aReaction conditions: 1a (0.5 mmol), o-dihalo substrate (1.5 eq.), Fe₂O₃ (20% mol), K₂CO₃ (1 eq.), DMEDA (20%) were added to PhMe (2 mL) and react at 110 °C for 48 h under N₂.Based on the results observed in the current study and Goldberg reaction,¹⁵ we have proposed a reaction mechanism for this transformation, which is shown in Scheme 3. The initial transmetalation of benzamide with Fe₂O₃L_n in the presence of K₂CO₃ would give rise to the iron(iii) species A. Complex A would then undergo an oxidative addition reaction with 1-bromo-2-iodobenzene to give the iron(v) species B, which would undergo a reductive elimination reaction to give iron(iii) species C with the concomitant formation of a C–N bond. Followed the tautomerism of intermediate C to D, the intermediate iron(iii) species E was formed in the presence of K₂CO₃, which would undergo another oxidative addition reaction to afford iron(v) species F. Compound 3a would then be obtained via a reductive elimination reaction from iron(v) species F.Open in a separate windowScheme 3Possible catalytic cycle.In summary, we have demonstrated that the cheap and environmental friendly catalyst system composed of Fe₂O₃ and ligand DMEDA is highly effective for the synthesis of 2-arylbenzoxazoles. The new catalyzed system can be effective for both C–N coupling and C–O coupling.     

Reactions of triosmium and triruthenium clusters with 2-ethynylpyridine: new modes for alkyne C–C bond coupling and C–H bond activation

The reaction of the trimetallic clusters [H₂Os₃(CO)₁₀] and [Ru₃(CO)₁₀L₂] (L = CO, MeCN) with 2-ethynylpyridine has been investigated. Treatment of [H₂Os₃(CO)₁₀] with excess 2-ethynylpyridine affords [HOs₃(CO)₁₀(μ-C₅H₄NCH=CH)] (1), [HOs₃(CO)₉(μ₃-C₅H₄NC CH₂)] (2), [HOs₃(CO)₉(μ₃-C₅H₄NC CCO₂)] (3), and [HOs₃(CO)₁₀(μ-CH CHC₅H₄N)] (4) formed through either the direct addition of the Os–H bond across the C C bond or acetylenic C–H bond activation of the 2-ethynylpyridine substrate. In contrast, the dominant pathway for the reaction between [Ru₃(CO)₁₂] and 2-ethynylpyridine is C–C bond coupling of the alkyne moiety to furnish the triruthenium clusters [Ru₃(CO)₇(μ-CO){μ₃-C₅H₄NC CHC(C₅H₄N) CH}] (5) and [Ru₃(CO)₇(μ-CO){μ₃-C₅H₄NCCHC(C₅H₄N)CHCHC(C₅H₄N)}] (6). Cluster 5 contains a metalated 2-pyridyl-substituted diene while 6 exhibits a metalated 2-pyridyl-substituted triene moiety. The functionalized pyridyl ligands in 5 and 6 derive via the formal C–C bond coupling of two and three 2-ethynylpyridine molecules, respectively, and 5 and 6 provide evidence for facile alkyne insertion at ruthenium clusters. The solid-state structures of 1–3, 5, and 6 have been determined by single-crystal X-ray diffraction analyses, and the bonding in the product clusters has been investigated by DFT. In the case of 1, the computational results reveal a rare thermodynamic preference for a terminal hydride ligand as opposed to a hydride-bridged Os–Os bond (3c,2e Os–Os–H bond).

The reactivity of 2-ethynylpyridine at low-valent triosmium and triruthenium centers has been investigated.     

Role of C,S, Se and P donor ligands in copper(i) mediated C–N and C–Si bond formation reactions

The first comparative study of C, S, Se and P donor ligands-supported copper(i) complexes for C–N and C–Si bond formation reactions are described. The syntheses and characterization of eight mononuclear copper(i) chalcogenone complexes, two polynuclear copper(i) chalcogenone complexes and one tetranuclear copper(i) phosphine complex are reported. All these new complexes were characterized by CHN analysis, FT-IR, UV-vis, multinuclear NMR and single crystal X-ray diffraction techniques. The single crystal X-ray structures of these complexes depict the existence of a wide range of coordination environments for the copper(i) center. This is the first comparative study of metal–phosphine, metal–NHC and metal–imidazolin-2-chalcogenones in C–N and C–Si bond formation reactions. Among all the catalysts, mononuclear copper(i) thione, mononuclear copper(i) N-heterocyclic carbene and tetranuclear copper(i) phosphine are exceedingly active towards the synthesis of 1,2,3-triazoles as well as for the cross-dehydrogenative coupling of alkynes with silanes. The cross-dehydrogenative coupling of terminal alkynes with silanes represents the first report of a catalytic process mediated by metal–imidazolin-2-chalcogenones.

The first comparative study of C, S, Se and P donor ligands-supported copper(i) complexes for C–N and C–Si bond formation reactions.     

Iodine-catalyzed synthesis of benzoxazoles using catechols,ammonium acetate,and alkenes/alkynes/ketones via C–C and C–O bond cleavage

An efficient metal-free synthesis strategy of benzoxazoles was developed via coupling catechols, ammonium acetate, and alkenes/alkynes/ketones. The developed methodology represents an operationally simple, one-pot and large-scale procedure for the preparation of benzoxazole derivatives using molecular iodine as the catalyst.

A metal-free one-pot multi-component method for the efficient synthesis of 2-aryl benzoxazoles via coupling of catechols, ammonium acetate and alkenes/alkynes/ketones using an I₂–DMSO catalyst system is illustrated.     

Domino C–C/C–O bond formation: palladium-catalyzed regioselective synthesis of 7-iodobenzo[b]furans using 1,2,3-triiodobenzenes and benzylketones

A facile and efficient synthesis of 7-iodobenzo[b]furan derivatives via a highly regioselective tandem α-arylation/intramolecular O-arylation of 5-substituted-1,2,3-triiodobenzenes and benzylketones is described. Remarkably, the α-arylation coupling reactions initiate exclusively at the least sterically-hindered position of the triiodoarene, which results in a highly chemoselective transformation. The highest yields were observed in reactions between electron-poor 1,2,3-triiodoarenes and electron-rich benzylketones, yet the optimized reaction conditions were found to be tolerant to a wide range of different functional groups. This unprecedent synthesis of 7-iodobenzo[b]furans from 1,2,3-triiodobenzenes is scalable, general in scope, and provides easy access to valuable precursors for other chemical transformations.

A facile and unprecedented synthesis of 7-iodobenzo[b]furans via a highly regioselective tandem α-arylation/intramolecular O-arylation is reported that is efficient, scalable and creates versatile precursors for further chemical manipulation.     

About the selectivity and reactivity of active nickel electrodes in C–C coupling reactions

Active anodes which are operating in highly stable protic media such as 1,1,1,3,3,3-hexafluoroisopropanol are rare. Nickel forms, within this unique solvent, a non-sacrificial active anode at constant current conditions, which is superior to the reported powerful molybdenum system. The reactivity for dehydrogenative coupling reactions of this novel active anode increases when the electrolyte is not stirred during electrolysis. Besides the aryl–aryl coupling, a dehydrogenative arylation reaction of benzylic nitriles was found while stirring the mixture providing quick access to synthetically useful building blocks.

Active anodes which are operating in highly stable protic media such as 1,1,1,3,3,3-hexafluoroisopropanol are rare.

Organic electro-synthesis evolved most recently as one of the major research areas in the toolbox of organic chemists.^1–5 The development of new chemistry and reactivity requires innovative approaches, such as material science aspects, to advance this purely synthetic habit. Usually, platinum and carbon allotropes perform best in anodic conversions. In particular, boron-doped diamond (BDD) facilitates anodic coupling reactions due to the inert behaviour and clean electron transfer,^6–8 exploiting inherent reactivity of substrates, such as phenols, arenes, anilines and various heterocycles and leading to high yields of the desired coupling products.^9–13 In particular, solvent control enables distinct selectivity, wherein protic media, such as 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), outperform others.^14,15 To improve the morphology and allowing other design options instead of the limited geometries of BDD, together with a less costly anode material, we investigated different transition metals and their alloys with regards to their applicability in electrochemical conversions. Leaded bronze enabled the selective and high yielding dehalogenation reaction of cyclopropanes.^16–20 These electrocatalytically active metal electrodes represent elegant alternatives to commonly applied materials which turned out to be unstable. Since the electro-catalytic species (mediator) remains immobilized at the electrode surface, the electrolyte is not contaminated which significantly facilitates work-up and down-stream processing (Fig. 1).Open in a separate windowFig. 1Schematic representation of an active anode within dehydrogenative electrolysis.Combining this elegant approach with the high performance of HFIP based electrolytes resulted in an active and non-sacrificial molybdenum anode, which accomplished a variety of dehydrodimerization and oxidative cyclization reactions.^21–23 Obviously, these results represent only a starting point and much more common and abundant metals are favoured. Nickel is advantageous due to its inexpensive nature as well as many geometries being commercially available due to battery applications. Noteworthy, nickel seems to play an outstanding role as active anode in oxidations within alkaline media and anhydrous HF.^24–29 In addition, nickel phosphides and other nickel salt coatings have been described as electrocatalytically active systems.^30–35During this work we observed a distinct influence of mechanical stirring on the formation of either homo- or cross-coupling products, which we attribute to the interaction of the vortex motion and the electrode double layer as described by Huang et al.³⁶ In the absence of stirring, local substrate concentration is high and facilitates dimerization, whereas cross-coupling is enhanced due to charge distribution in stirred electrolytes.In our previous study,²³ 4-fluoroveratrole (1a) turned out to be a challenging substrate at the active molybdenum anode, since the corresponding biaryl 2a was only obtained in 12% isolated and 21% GC yield, respectively (ref. 23 for a full collection), such as nickel, were barely superior and the yield of 2a was only slightly increased (†) we determined the amount of trace metals. The amount of 62 ± 5 ppm of nickel in solution (equals corrosion of 0.19 nmol C⁻¹) was at least one order of magnitude lower compared to our previously reported protocol employing molybdenum as active anode material (740 ± 10 ppm),²³ based on the higher mechanical stability of nickel or the lower solubility of nickel species on the surface. We therefore continued to use nickel and tried to optimize the condition. Various electrolysis parameters were investigated (see ESI, Section 9^†), but interestingly the previous conditions²³ matched the best. The applied charge was kept at 3.0 F per mole 2a. The substrate concentration was optimal at 0.2 M, and at room temperature the highest yield was detected by GC (for calibration details see ESI, Sections 7 and 8^†). Similar to the molybdenum system, the use of additives like water or methanol resulted in diminished yield or complete failure.³⁷ Other common alloys, such as Monel or Hastelloy, as well as several geometries^25,27,38 were not able to outperform the simple nickel electrode making this protocol even more practical (see ESI, Sections 1 and 3^†).Effect of stirring onto the dehydrogenative coupling of 4-fluoroveratrole (1a) at different anodes

Pd-catalyzed C–C and C–N cross-coupling reactions in 2-aminothieno[3,2-d]pyrimidin-4(3H)-one series for antiplasmodial pharmacomodulation

In 2015, we identified gamhepathiopine (M1), a 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one antiplasmodial hit targeting all development stages of the human malarial parasite P. falciparum. However, this hit compound suffers from sensitivity to hepatic oxidative metabolism. Herein, we describe the synthesis of 33 new compounds in the 2-aminothieno[3,2-d]pyrimidin-4(3H)-one series modulated at position 6 of this scaffold. The modulations were performed using three palladium-catalyzed cross coupling reactions, namely Suzuki–Miyaura, Sonogashira, and Buchwald–Hartwig. For the latter, we developed the reaction conditions. Then, we evaluated the synthesized compounds for their antiplasmodial activity on the K₁P. falciparum strain and their cytotoxicity on the human HepG2 cell line. Although we did not obtain a compound better than M1 in terms of the antiplasmodial activity, we identified compound 1g bearing a piperidine at position 6 of the thieno[3,2-d]pyrimidin-4(3H)-one ring with an improved cytotoxicity and metabolic stability. 1g is an interesting new starting point for further pharmacomodulation studies. This study also provides valuable antiplasmodial SAR data regarding the nature of the ring at position 6, the possible substituent on this ring, and the introduction of a spacer between this ring and the thienopyrimidinone moiety.

Pharmacomodulation at position 6 of a thienopyrimidinone antiplasmodial hit using palladium-catalyzed cross-coupling reactions afforded 33 new compounds, among which a new hit was found with enhanced metabolic stability.     

Direct phosphorylation of benzylic C–H bonds under transition metal-free conditions forming sp3C–P bonds

Direct phosphorylation of benzylic C–H bonds was achieved in a biphasic system under transition metal-free conditions. A selective radical/radical sp³C–H/P(O)–H cross coupling was proposed, and various substituted toluenes were applicable. The transformation provided a promising method for constructing sp³C–P bonds.

Direct phosphorylation of benzylic C–H bonds with secondary phosphine oxides was first realized. The reaction was performed in organo/aqueous biphasic system and under transition metal-free conditions, proceeding via the cross dehydrogenative coupling.

To construct C–P bonds is of great significance in modern organic synthesis,¹ because organophosphorus compounds play varied roles in medical,^2,3 materials,⁴ and synthetic chemistry fields.⁵ Traditionally, the C–P bonds were formed from P–Cl species via nucleophilic substitutions with organometallic reagents,⁶ P–OR species via Michaelis–Arbusov reactions,⁷ or P–H species via the alkylation in the present of a base or a transition metal.⁸Over the past decades, cross dehydrogenative coupling reactions (CDC reactions) have become a powerful and atom-economic methodology for constructing chemical bonds.⁹ By using this strategy, C–H bonds can couple with Z–H bonds without prefunctionalization and thus short-cut the synthetic procedures (Scheme 1a).Open in a separate windowScheme 1Cross dehydrogenative coupling reactions and direct phosphorylation of benzylic C–H bonds.A similar construction of C–P bonds via CDC was also realized.^10,11 Among these methods, the phosphorylation of sp³C–H having an adjacent N or O atom, or the carbonyl group was well-developed.¹¹ Relatively, the formation of benzylic sp³C–P bond was less reported,^11w which was mainly limited to the sp³C–H of xanthene or 8-methylquinoline (Scheme 1b).¹² In these reported processes, transition metal catalysts or photo-, electro-catalysts were usually involved,^11v and an excess of P(O)–H compounds was usually employed.^11,13 To the best of our knowledge, the phosphorylation of non-active benzylic C–H bonds has scarcely been reported.Considering both benzylic and phosphorus radicals could be generated by oxidation,¹⁴ which might subsequently couple, the phosphorylation of benzylic sp³C–H bonds would be achieved (Scheme 1c). Herein, we disclosed the construction of benzylic C–P bonds from toluene and P–H species. The reaction was carried out under transition metal-free reaction conditions,¹⁵ and exhibited high regio-selectivity. The aromatic C–H remained intact during the reaction.We began our investigation by exploring the reaction of toluene 1a and diphenylphosphine oxide 2a in the presence of an oxidant (16 Other persulfates could also be used as an oxidant albeit with decreasing yields ( EntryOxidantToluene/water (v/v)Additive3a yield^b (%)3a/4^c1K₂S₂O₈1 : 0—Trace—2K₂S₂O₈1 : 1—1216 : 843K₂S₂O₈1 : 1SDS3726 : 744Na₂S₂O₈1 : 1SDS3127 : 735(NH₄)₂S₂O₈1 : 1SDS2723 : 776Oxone1 : 1SDSNone—7—1 : 1SDSNone—8—1 : 1—None—9K₂S₂O₈1 : 1SDBS4136 : 6410K₂S₂O₈1 : 2SDBS4628 : 7211K₂S₂O₈1 : 3SDBS3524 : 7612^dK₂S₂O₈1 : 2SDBS4632 : 6813^eK₂S₂O₈1 : 2SDBS2621 : 7914^fK₂S₂O₈1 : 2SDBS2926 : 7415^gK₂S₂O₈1 : 2SDBS4838 : 6216^g,hK₂S₂O₈1 : 2SDBS0—Open in a separate window^aReaction condition: 1a (1 mL), 2a (0.2 mmol), oxidant (2 equiv.), additive (1 equiv.) and H₂O, 120 °C, 3 h. under N₂.^bGC yields using n-dodecane as an internal standard.^cThe ratio of 3a/4 was determined by GC analysis.^d50 mol% SDBS was used.^e20 mol% SDBS was used.^fAt 100 °C.^g1 (0.8 mL) and H₂O (1.6 mL), 3 equiv. K₂S₂O₈ was used, 120 °C for 15 min.^h3 equiv. TEMPO was added.Based on the above results, we can easily find that a serious amount of 1,2-diphenylethane 4 was formed. These results suggest that the homocoupling rate of 1a was very quick. Thus, the choice of the phase transfer reagent and oxidant is the key to cross-coupling of toluene and diphenylphosphine oxide in this biphasic solvent system.Excessive P–H species were usually employed in reported CDC reactions to form C–P bonds, because of their facile oxidation.¹³ In our procedure, toluene was excessive, thus the yields were calculated based on 2a. The yields looked like low, which did not indicate the poorer conversion rate of P–H species. With the optimized conditions in hand, the substrate scope of the CDC reactions was explored ( Open in a separate window^aReaction conditions: 1 (0.8 mL), 2 (0.2 mmol), K₂S₂O₈ (3 equiv.), SDBS (50%) and H₂O (1.6 mL), 120 °C, under N₂, the reactions were monitored by TLC and/or GC until 2 work out.^b1 mmol scale, 30 min.^c130 °C.^d100 °C.In addition to toluene, o-xylene, m-xylene, p-xylene, mesitylene, and 1,2,4,5-tetramethylbenzene all coupled with 2a to give the expected 3b–f in moderate yields. Methoxy substituted toluene gave relatively lower yields of 3g and 3h. para-Halo substituted toluene exhibited good reactivity, furnishing the coupling products 3i and 3j in moderate yields. Comparing to toluene, a decreasing order of reactivity was observed for ethyl benzene (3l, 30% yield), isobutyl benzene (3m, 27% yield), isopropyl benzene (3n, <10% yield), and diphenyl methane (3o, trace). The order was probably controlled by the steric hindrance around the benzylic carbon. 1-Methylnaphthalene and 2-methylnaphthalene also gave low yields (3p and 3q). However, 2-methylquinoline served well and coupled with 2a, affording the product 3r in 49% yield, which could be ascribed to the activation of the nitrogen atom. Besides of 2a, diaryl phosphine oxides having methyl, F, and Cl substituents could also be employed as the substrate, producing 3s–3u in moderate yields under similar reaction conditions.Although the mechanism of the direct phosphorylation of benzyl C–H bond in aqueous solution is not quite clear, some aspects could be grasped based on experimental results. Firstly, the desired product 3a was not detected when the 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added, implying that a radical pathway might be possible in this reaction (entry 16). Secondly, the reaction only occurred in aqueous phase, and relied on the presence of PTC (phase transfer catalyst), as seen in that 3a was difficultly formed in entries 1 and 2 of 17We supposed 1 is converted to benzyl radical 5 by SO₄⁻ radical that is generated via hemolytic cleavage of potassium persulfates.¹⁸ Meanwhile, phosphorus radical 6 is similarly formed from 2. Because potassium persulfate was water soluble, both 1 and 2 had to be transferred into aqueous solution to react with potassium persulfates.¹⁹ This proposal is also in accord with the experimental results that no products of sp²C–H phosphorylation are detected, which are the main products in the previous radical systems.²⁰ Finally, cross couplings between 5 and 6 produce 3 (Scheme 2).Open in a separate windowScheme 2Proposed mechanism for the direct phosphorylation of benzylic C–H bonds under transition metal-free reaction conditions.     

C–C and C–H coupling reactions by Fe3O4/KCC-1/APTPOSS supported palladium-salen-bridged ionic networks as a reusable catalyst

This study investigates the potential application of an efficient, easily recoverable and reusable magnetically separable Fe₃O₄/KCC-1/APTPOSS nanoparticle-supported salen/Pd(ii) catalyst for C–C and C–H cross-couplings. The Fe₃O₄/KCC-1/APTPOSS/salen/Pd(ii) MNPs were thoroughly characterized by using TEM, FE-SEM, TGA, XRD, VSM, FT-IR, ICP-MS, and BET. This observation was exploited in the direct and selective chemical reaction of 2-acetyl-benzaldehyde with cyclopentadiene for the synthesis of pentafulvene. The recycled catalyst has been analyzed by ICP-MS showing only minor changes in the morphology after the reaction, thus confirming the robustness of the catalyst.

This study investigates the potential application of an efficient, easily recoverable and reusable magnetically separable Fe₃O₄/KCC-1/APTPOSS nanoparticle-supported salen/Pd(ii) catalyst for C–C and C–H cross-couplings.     

Transition-metal-catalyzed remote C–H functionalization of thioethers

In the last decade, transition-metal-catalyzed direct C–H bond functionalization has been recognized as one of most efficient approaches for the derivatization of thioethers. Within this category, both mono- and bidentate-directing group strategies achieved the remote C(sp²)–H and C(sp³)–H functionalization of thioethers, respectively. This review systematically introduces the major advances and their mechanisms in the field of transition-metal-catalyzed remote C–H functionalization of thioethers from 2010 to 2021.

This minireview systematically introduces the major advances and their mechanisms in the field of transition-metal-catalyzed remote C–H functionalization of thioethers.