Nickel-Catalyzed Reductive [4 + 1] Sila-Cycloaddition of 1,3-Dienes with Dichlorosilanes.

Transition-metal-catalyzed sila-cycloaddition has been a promising tool for accessing silacarbocycle derivatives, but the approach has been limited to a selection of well-defined sila-synthons. Herein, we demonstrate the potential of chlorosilanes, which are industrial feedstock chemicals, for this type of reaction under reductive nickel catalysis. This work extends the scope of reductive coupling from carbocycle to silacarbocycle synthesis and from single C-Si bond formation to sila-cycloaddition reactions. The reaction proceeds under mild conditions and shows good substrate scope and functionality tolerance, and it offers new access to silacyclopent-3-enes and spiro silacarbocycles. The optical properties of several spiro dithienosiloles as well as structural variations of the products are demonstrated.

Reductive Cross-Coupling of Unreactive Electrophiles.

Transition-metal-catalyzed reductive coupling of electrophiles has emerged as a powerful tool for the construction of molecules. While major achievements have been made in the field of cross-couplings between organic halides and pseudohalides, an increasing number of reports demonstrates reactions involving more readily available, low-cost, and stable, but unreactive electrophiles. This account summarizes the recent results in our laboratory focusing on this topic. These findings typically include deoxygenative C-C coupling of alcohols, reductive alkylation of alkenyl acetates, reductive C-Si coupling of chlorosilanes, and reductive C-Ge coupling of chlorogermanes.The reductive deoxygenative coupling of alcohols with electrophiles is synthetically appealing, but the potential of this chemistry remains to be disclosed. Our initial study focused on the reaction of allylic alcohols and aryl bromides by the combination of nickel and Lewis acid catalysis. This method offers a selectivity that is opposite to that of the classic Tsuji-Trost reactions. Further investigation on the reaction of benzylic alcohols led to the foundation of a dynamic kinetic cross-coupling strategy with applications in the nickel-catalyzed reductive arylation of benzylic alcohols and cobalt-catalyzed enantiospecific reductive alkenylation of allylic alcohols. The titanium catalysis was later established to produce carbon radicals directly from unactivated tertiary alcohols via C-OH cleavage. The development of their coupling reactions with carbon fragments delivers new methods for the construction of all-carbon quaternary centers. These reactions have shown high selectivity for the functionalization of tertiary alcohols, leaving primary and secondary alcohols intact. Alkenyl acetates are inexpensive, stable, and environmentally friendly and are considered the most attractive alkenyl reagents. The development of reductive alkylation of alkenyl acetates with benzyl ammoniums and alkyl bromides offers mild approaches for the conversion of ketones into aliphatic alkenes.Extensive studies in this field have enabled us to extend the cross-electrophile coupling from carbon to silicon and germanium chemistry. These reactions harness the ready availability of chlorosilanes and chlorogermanes but suffer from the challenge of their low reactivity toward transition metals. Under reductive nickel catalysis, a broad range of alkenyl and aryl electrophiles couple well with vinyl- and hydrochlorosilanes. The use of alkyl halides as coupling partners led to the formation of functionalized alkylsilanes. The C-Ge coupling seems less substrate-dependent, and various common chlorogermanes couple well with aryl, alkenyl, and alkyl electrophiles. In general, functionalities such as Grignard-sensitive groups (e.g., acid, amide, alcohol, ketone, and ester), acid-sensitive groups (e.g., ketal and THP protection), alkyl fluoride and chloride, aryl bromide, alkyl tosylate and mesylate, silyl ether, and amine are tolerated. These methods provide new access to organosilicon and organogermanium compounds, some of which are challenging to obtain otherwise.

Nickel-Catalyzed Reductive Coupling of Chlorosilanes.

Organosilanes play essential roles in many important research areas. The use of readily available chlorosilanes to catalytically access these compounds is synthetically appealing but remains a long-standing challenge. Nickel-catalyzed reductive cross-coupling reaction has recently emerged as a promising protocol to arrive at this goal. This strategy allows the chlorosilanes to be coupled with various carbon electrophiles under mild conditions. These reactions afford organosilanes with improved molecular diversity, structural complexity, and functional group compatibility. This Concept article summarizes the recent advance on nickel-catalyzed reductive C-Si couplings of chlorosilanes.

Nickel-Catalyzed Cross-Electrophile 1,2-Silyl-Arylation of 1,3-Dienes with Chlorosilanes and Aryl Bromides.

Catalytic, three-component, cross-electrophile reactions have recently emerged as a promising tool for molecular diversification, but studies have focused mainly on the alkyl-carbonations of alkenes. Herein, the scope of this method has been extended to conjugated dienes and silicon chemistry through silylative difunctionalization of 1,3-dienes with chlorosilanes and aryl bromides. The reaction proceeds under mild conditions to afford 1,2-linear-silylated products, a selectivity that is different to those obtained from conventional methods via an intermediary of H(C)-η3 -π-allylmetal species. Preliminary mechanistic studies reveal that chlorosilane reacts with 1,3-diene first and then couples with aryl bromide.

Nickel-Catalyzed Reductive C(sp2 )-Si Coupling of Chlorohydrosilanes via Si-Cl Cleavage.

We report here a new method for the synthesis of organohydrosilanes from phenols and ketones. This method is established through reductive C-Si coupling of chlorohydrosilanes via unconventional Si-Cl cleavage. The reaction offers access to aryl- and alkenylhydrosilanes with a scope that is complementary to those of the established methods. Electron-rich, electron-poor, and ortho-/meta-/para-substituted (hetero)aryl electrophiles, as well as cyclic and acyclic alkenyl electrophiles, were coupled successfully. Functionalities, including Grignard-sensitive groups (e.g., primary amine, amide, phenol, ketone, ester, and free indole), acid-sensitive groups (e.g., ketal and THP protection), alkyl-Cl, pyridine, furan, thiophene, Ar-Bpin, and Ar-SiMe3 , were tolerated. Gram-scale reaction, incorporation of -Si(H)R2 into complex biologically active molecules, and derivatization of formed organohydrosilanes are demonstrated.

Reductive Alkylation of Alkenyl Acetates with Alkyl Bromides by Nickel Catalysis.

Catalytic alkylation of stable alkenyl C-O electrophiles is synthetically appealing, but studies to date have typically focused on the reactions with alkyl Grignard reagents. We report herein a cross-electrophile reaction of alkenyl acetates with alkyl bromides. This work has enabled a new method for the synthesis of aliphatic alkenes from alkenyl acetates to be established that can be used to add more structural complexity and molecular diversity with enhanced functionality tolerance. The method allows for a gram-scale reaction and modification of biologically active molecules, and it affords access to useful building blocks. Preliminary mechanistic studies reveal that the NiI species plays an essential role for the success of the coupling of these two reactivity-mismatched electrophiles.

Cobalt-Catalyzed Enantiospecific Dynamic Kinetic Cross-Electrophile Vinylation of Allylic Alcohols with Vinyl Triflates.

Asymmetric cross-electrophile coupling has emerged as a promising tool for producing chiral molecules; however, the potential of this chemistry with metals other than nickel remains unknown. Herein, we report a cobalt-catalyzed enantiospecific vinylation reaction of allylic alcohol with vinyl triflates. This work establishes a new method for the synthesis of enantioenriched 1,4-dienes. The reaction proceeds through a dynamic kinetic coupling approach, which not only allows for direct functionalization of allylic alcohols but also is essential to achieve high chemoselectivity. The use of cobalt enables the reactions to proceed with high enantiospecificity, which have failed to be realized by nickel catalysts.

Regiocontrolled Reductive Vinylation of Aliphatic 1,3-Dienes with Vinyl Triflates by Nickel Catalysis.

The regiocontrolled functionalization of 1,3-dienes has become a powerful tool for divergent synthesis, yet it remains a long-standing challenge for aliphatic substrates. Herein, we report a reductive approach for a branch-selective 1,2-hydrovinylation of aliphatic 1,3-dienes with R-X electrophiles, which represents a new selectivity pattern for diene functionalization. Simple butadiene, aromatic 1,3-dienes, and highly conjugated polyene were also tolerated. The combination of Ni(0) and the phosphine-nitrile ligand generally resulted in >20:1 regioselectivity with the retention of the geometry of the C3-C4 double bonds. This reaction proceeds with a broad substrate scope, and it allows for the conjugation of two biologically active units to form more complex polyene molecules, such as tetraene and pentaene as well as heptaene.

Nickel-Catalyzed Reductive C-Ge Coupling of Aryl/Alkenyl Electrophiles with Chlorogermanes.

Cross-electrophile coupling has emerged as a promising tool for molecular synthesis; however, current studies have focused mainly on forging C-C bonds. We report a cross-electrophile C-Ge coupling reaction and thereby demonstrate the possibility of constructing organogermanes from carbon electrophiles and chlorogermanes. The reaction proceeds under mild conditions and offers access to both aryl and alkenyl germanes. Electron-rich, electron-poor, and ortho-/meta-/para-substituted (hetero)aryl electrophiles, as well as cyclic and acyclic alkenyl electrophiles, were coupled. Gram-scale reaction, incorporation of the -GeR3 moiety into complex biologically active molecules, and derivatization of formed organogermanes are demonstrated.

Highly Enantioselective Cross-Electrophile Aryl-Alkenylation of Unactivated Alkenes.

Enantioselective cross-electrophile reactions remain a challenging subject in metal catalysis, and with respect to data, studies have mainly focused on stereoconvergent reactions of racemic alkyl electrophiles. Here, we report an enantioselective cross-electrophile aryl-alkenylation reaction of unactivated alkenes. This method provides access to a number of biologically important chiral molecules such as dihydrobenzofurans, indolines, and indanes. The incorporated alkenyl group is suitable for further reactions that can lead to an increase in molecular diversity and complexity. The reaction proceeds under mild conditions at room temperature, and an easily accessible chiral pyrox ligand is used to afford products with high enantioselectivity. The synthetic utility of this method is demonstrated by enabling the modification of complex molecules such as peptides, indometacin, and steroids.

Decryption of Active Constituents and Action Mechanism of the Traditional Uighur Prescription (BXXTR) Alleviating IMQ-Induced Psoriasis-Like Skin Inflammation in BALB/c Mice.

Bai Xuan Xia Ta Re Pian (BXXTR) is a traditional Uighur medicine ancient prescription in China widely used in the treatment of psoriasis, presenting a high curative rate and few side effects. Given that the active constituents and action mechanism still remain unclear, the aim of this study is to explore the potential active constituents and mechanism of antipsoriasis of BXXTR. Psoriasis-like lesions model in BALB/c mice was induced by Imiquimod (IMQ), including five treatment groups: control group, IMQ-treated group, IMQ-ACITRETIN group (Positive control group), IMQ-BXXTR low dose group, IMQ-BXXTR medium dose group and IMQ-BXXTR high dose group. The Psoriasis Area and Severity Index (PASI) score, skin and ear thickness, and histologic section were collected. The differentially expressed genes were determined by using RNAseq technology and the relevant pathways were analyzed by KEGG database. The ELISA kit and western blot assays were used to detect the related protein expression levels. In addition, the chemical constituents of BXXTR were determined by UPLC-TOF-MS analysis and the potential active constituents were predicted by SEA DOCK and Gene Ontology (GO). The data demonstrated that BXXTR significantly alleviated IMQ-induced psoriasis. RNA-seq analysis showed that BXXTR induced the expression levels of 31 genes; the KEGG analysis suggested that BXXTR could significantly change IL-17-related inflammatory pathways. The ELISA kit confirmed that the expression level of IL-17A protein was significantly reduced. 75 compounds of BXXTR were determined by UPLC-TOF-MS analysis, 11 of 75 compounds were identified as potential active compounds by similarity ensemble approach docking (SEA DOCK) and Gene Ontology (GO). BXXTR reduced the severity of skin lesions by inhibiting IL-17-related inflammatory pathways. The results indicated that BXXTR could suppress psoriasis inflammation by multiple-constituents-regulated multiple targets synergistically. Collectively, this study could provide important guidance for the elucidation of the active constituents and action mechanism of BXXTR for the treatment of psoriasis.

Copper-Catalyzed Tandem Aerobic Oxidative Cyclization for the Synthesis of Polysubstituted Quinolines via C(sp3)/C(sp2)-H Bond Functionalization.

One-pot Cu-catalyzed tandem aerobic oxidative cyclization for the synthesis of quinolines from 2-vinylanilines/2-arylanilines and 2-methylquinolines via C(sp3)-H/C(sp2)-H bond functionalization has been developed. Dioxygen as an ideal oxidant has been employed for this transformation. The substrates bearing various functional groups perform well in this process and generate the desired products in moderate to good yields.

tert-Butyl nitrite (TBN) as the N atom source for the synthesis of substituted cinnolines with 2-vinylanilines and a relevant mechanism was studied.

A green method to synthesize cinnolines by 6π electrocyclic reaction with alkenyl amines and TBN has been developed. TBN plays a dual role both as a nitrogen atom source and an oxidant in this procedure. Relevant mechanism experiments reveal that the reaction proceeds through electrocyclic reaction and with diazo hydroxide as a key intermediate.

Iodine-mediated thiolation of substituted naphthols/naphthylamines and arylsulfonyl hydrazides via C(sp2)-H bond functionalization.

A direct method has been developed for iodine-mediated thiolation of naphthols/naphthylamines and arylsulfonyl hydrazides through the formation of C-S bond and cleavage of S-N/S-O bonds. In this transformation, a range of valuable thioethers are easily achieved in moderate to good yields.

Nickel-Catalyzed Reductive Csp3-Ge Coupling of Alkyl Bromides with Chlorogermanes.

Reductive cross-coupling provides facile access to organogermanes, but it remains largely unexplored. Herein we report a nickel-catalyzed reductive Csp3-Ge coupling of alkyl bromides with chlorogermanes. This work has established a new method for producing alkylgermanes. The reaction proceeds under very mild conditions and tolerates various functionalities including ether, alcohol, alkene, nitrile, amine, ester, phosphonates, amides, ketone, and aldehyde. The application of this method to the modification of bioactive molecules is demonstrated.

Nickel-Catalyzed Cross-Electrophile C(sp3)-Si Coupling of Unactivated Alkyl Bromides with Vinyl Chlorosilanes.

Cross-electrophile C-Si coupling has emerged as a promising tool for the construction of organosilanes, but the potential of this method remains largely unexplored. Herein, we report a C(sp3)-Si coupling of unactivated alkyl bromides with vinyl chlorosilanes. The reaction proceeds under mild conditions, and it offers a new approach to alkylsilanes. Functionalities such as Grignard-sensitive groups (e.g., acid, amide, alcohol, ketone, and ester), acid-sensitive groups (e.g., ketal and THP protection), alkyl fluoride and chloride, aryl bromide, alkyl tosylate and mesylate, silyl ether, and amine were tolerated. Incorporation of the -Si(vinyl)R2 moiety into complex molecules and the immobilization of a glass surface by formed organosilanes were demonstrated.

Analyses and identification of the chemical constituents of the Uighur formulation Baixuan Xiatare using three-stage infrared spectroscopy.

OBJECTIVE: To identify, rapidly and accurately, the chemical composition of the traditional Uighur formulation Baixuan Xiatare (BXXTR-FU). METHODS: We investigated if application of three-stage infrared (IR) spectroscopy enabled identification of the main chemical constituents (and their origins) in BXXTR-FU. RESULTS: The characteristic peaks of herbal material(s) and BXXTR-FU were assigned. In Fourier transform-IR (FT-IR) spectroscopy of BXXTR-FU, peaks at 1616 and 1605 cm-1 of BXXTR-FU were considered to denote anthraquinones and their derivatives; 1066 cm-1 was regarded as the characteristic absorption peak of resin glycosides. In second-derivative IR (SD-IR) spectroscopy, the main carbonyl types of BXXTR-FU in the range 1743-1636 cm-1 were assigned: 1651 cm-1 belonged to the carbonyl stretching vibrations of flavonoids and chromones; 1717 cm-1 belonged to tannins; 1699 cm-1 belonged to carboxylic acids; 1636 cm-1 belonged to anthraquinones and their derivatives. SD-IR spectroscopy further confirmed that the characteristic absorption peaks at 1636, 1618 and 1603 cm-1 could be used as markers that BXXTR-FU contained anthraquinones and their derivatives. Synchronous 2D-IR correlation spectra of chemical groups further confirmed the results of FT-IR and SD-IR spectroscopy. CONCLUSION: Our study strongly supported the necessity and importance of three-stage IR spectroscopy owing to its rapid and accurate identification of herbal formulations.

Ni-catalyzed cross-electrophile coupling between vinyl/aryl and alkyl sulfonates: synthesis of cycloalkenes and modification of peptides.

We report here the coupling reactions between vinyl/aryl and alkyl C-O electrophiles that can be derived from chemical feedstocks and naturally occurring functional groups. This method provides an efficient approach to the synthesis of a wide range of functionalized, and/or secondary alkyl substituted cycloalkenes. These compounds are difficult to produce by conventional methods. The reaction proceeds with broad substrate scope, and tolerates various functional groups such as alcohol, aldehyde, ketone, ester, amide, alkene, alkyne, heterocycles, organotin and organosilicon compounds. The synthetic utility of this method has been demonstrated by providing facile access to important building blocks. We also demonstrated the possibility to apply this method for late-stage modification of peptides. A broad range of functionalized alkyl groups could be selectively introduced into tyrosine in peptides via C-C bond formation, which has been a challenge to the existing procedures.

Commonalities and characteristics of aqueous extracts from three Uighur medicines were analyzed by using three-stage infrared spectroscopy combined with ultra-performance liquid chromatography-time of flight-mass spectra.

OBJECTIVE: To establish a method to analyze the commonalities and characteristics of the aqueous extracts from three Uighur medicines. METHODS: In this study, a combination method of three-stage infrared spectroscopy and ultra-performance liquid chromatography-time of flight-mass spectra (UPLC-TOF-MS) method was used to analyze the commonalities and characteristics of the aqueous extracts from Hezi (Fructus Chebulae), Maohezi (Terminalia Belliricae Fructus) and Xiqingguo (Chebulae Fructus Immaturus). RESULTS: In Fourier transform-infrared spectroscopy spectra, all three samples showed the characteristic absorption peaks of tannins similarly. According to UPLC-TOF-MS data analysis, the difference of the position and intensity of the peaks at 1713- 1707 cm－1 in the three samples were related to the difference in the relative content of tannin and pentacyclic triterpenoids. In second derivative infrared spectroscopy spectra, further analysis of the differences in the infrared spectra of the three samples was performed by increasing the apparent resolution. In combination with UPLC-TOF-MS data, some features infrared absorption peaks were assigned. The absorption peaks at 1032-1030 cm－1 assigned to the stretching vibration of C-O-C (ether bond) groups of tannins; 1164-1163, 1063-1062, 1009- 1005, 904 cm－1 attributed to the stretching vibration of C-O (ether bond) and C-O-C groups of glycosidic compounds. 1385-1383 cm－1 attributed to the bending vibration of C-H (alkyl hydrogen) of methoxyl group of pentacyclic triterpenoids. Peak 835 cm－1 was assigned to the characteristic absorption peak of bending vibration of = C-H groups of pentacyclic triterpenoids. The two dimensional correlation infrared spectroscopy could further quickly distinguish three samples through the dynamic structural information of their chemical components and discrepancy of auto-peaks and cross- peaks intuitively in the range of 1720-419 cm－1. CONCLUSION: By comparing the intensity of the infrared characteristic absorption peaks, the main chemical components were assigned, which significantly enriched and perfected the data analysis of the infrared spectra of three Uighur Medicines. It provided a rationale for the identification of medicinal materials with complex and similar chemical components using the three-stage infrared spectroscopy and UPLC-TOF-MS.

I2-catalyzed synthesis of substituted imidazoles from vinyl azides and benzylamines.

A novel and efficient I2-catalyzed oxidative tandem cyclization of simple vinyl azides and benzylamines has been developed for the synthesis of substituted imidazoles. In this reaction, various substituted groups on vinyl azides and benzylamines proceed smoothly and the desired imidazoles are obtained in moderate to good yields.