Login In
2017 Volume 33 Issue 8
2017, 75(8): 733-743
doi: 10.6023/A17040170
Abstract:
As a grand research area closely related to human civilization and living, the activation and transformation of dinitrogen (nitrogen fixation) under mild conditions used to be a central research theme worldwide in the 1970's~1990's. Nitrogen fixation is the process by which atmospheric nitrogen is directly converted to a bioavailable form. This basic chemical reaction process is essential to sustaining all life on this planet. However, due to great challenging of the nature of this research, slow progress and worldwide change of academic culture, the number of researchers engaged in this fundamental research area has been drastically reduced. Nevertheless, there is no doubt that realizing activation and transformation of dinitrogen under mild conditions is a grand scientific problem that people need to solve, required by sustainable development of human society. It is thus one of the most important missions of scientists, especially chemists. Three types of N-containing products can be obtained through direct transformation of dinitrogen. The most popular one is the formation of ammonia NH3 and NxHy. The industrial Haber-Bosch process, which requires harsh reaction conditions such as high temperature and pressure and uses at least 1%~2% of the annual primary energy supply in the world, is still the main method to produce ammonia from molecular dinitrogen and dihydrogen gases. Inspired by the investigation of nitrogenase and the discovery of the first molecular nitrogen complex in 1965, chemists have paid more attention to achieving the reduction of dinitrogen to ammonia with transition metal complexes either as regents or as catalysts. Reports on the other two types of products, the N-E (E=P, Si) bonding compounds, and the N-C bonding compounds, are very rare. Compared with ammonia, nitrogen-containing organic compounds such as amines, amides, imides, amino acids and aza-heterocycles are also high-value products. This review mainly summarizes the progress in the field of direct transformation of molecular nitrogen to nitrogen-containing organic compounds by using transition metal complexes, as well as the elucidation of transformation mechanisms. The N-containing organic compounds thus formed include amines, amides, imides, nitriles, diazenes, azines, carbodiimides, isocyanates and heterocycles. Although some progress has been achieved, examples are still very much limited, efficiency is generally very low. Transition metal complex-catalyzed reaction process is in great demand. Synergetic strategy is considered to be one of the efficient ways to realize transition metal complex-catalyzed direct transformation of molecular nitrogen to nitrogen-containing organic compounds under mild conditions. The formation of N-E (E=P, Si) bonding compounds and the reduction of dinitrogen to ammonia and other partially reduced or protonated products of dinitrogen are not covered here.
As a grand research area closely related to human civilization and living, the activation and transformation of dinitrogen (nitrogen fixation) under mild conditions used to be a central research theme worldwide in the 1970's~1990's. Nitrogen fixation is the process by which atmospheric nitrogen is directly converted to a bioavailable form. This basic chemical reaction process is essential to sustaining all life on this planet. However, due to great challenging of the nature of this research, slow progress and worldwide change of academic culture, the number of researchers engaged in this fundamental research area has been drastically reduced. Nevertheless, there is no doubt that realizing activation and transformation of dinitrogen under mild conditions is a grand scientific problem that people need to solve, required by sustainable development of human society. It is thus one of the most important missions of scientists, especially chemists. Three types of N-containing products can be obtained through direct transformation of dinitrogen. The most popular one is the formation of ammonia NH3 and NxHy. The industrial Haber-Bosch process, which requires harsh reaction conditions such as high temperature and pressure and uses at least 1%~2% of the annual primary energy supply in the world, is still the main method to produce ammonia from molecular dinitrogen and dihydrogen gases. Inspired by the investigation of nitrogenase and the discovery of the first molecular nitrogen complex in 1965, chemists have paid more attention to achieving the reduction of dinitrogen to ammonia with transition metal complexes either as regents or as catalysts. Reports on the other two types of products, the N-E (E=P, Si) bonding compounds, and the N-C bonding compounds, are very rare. Compared with ammonia, nitrogen-containing organic compounds such as amines, amides, imides, amino acids and aza-heterocycles are also high-value products. This review mainly summarizes the progress in the field of direct transformation of molecular nitrogen to nitrogen-containing organic compounds by using transition metal complexes, as well as the elucidation of transformation mechanisms. The N-containing organic compounds thus formed include amines, amides, imides, nitriles, diazenes, azines, carbodiimides, isocyanates and heterocycles. Although some progress has been achieved, examples are still very much limited, efficiency is generally very low. Transition metal complex-catalyzed reaction process is in great demand. Synergetic strategy is considered to be one of the efficient ways to realize transition metal complex-catalyzed direct transformation of molecular nitrogen to nitrogen-containing organic compounds under mild conditions. The formation of N-E (E=P, Si) bonding compounds and the reduction of dinitrogen to ammonia and other partially reduced or protonated products of dinitrogen are not covered here.
2017, 75(8): 744-769
doi: 10.6023/A17050202
Abstract:
With a significantly high Hansch's hydrophobicity parameter (π=1.44), electron-withdrawing trifluoromethylthio group (CF3S-) has been considered as one of the most lipophilic substituents and privileged fragments that are able to improve drug molecules' pharmacokinetic and physicochemical properties such as lipophilicity and metabolic stability. It is well-known that incorporation of the trifluoromethylthio group into small molecules greatly enhances its ability to cross lipid membranes and in vivo absorpotion rate. In addition, the high electronegativity of the trifluoromethylthio group significantly improves the small molecule's stablity in acidic environments. Not surprisingly, the trifluoromethylthio group has been of special attention not only from the academia but also from pharmaceutical and agrochemical industry for their use in isostere-based drug design. Development of highly efficient methods for the introduction of the trifluoromethylthio group into small molecules, thereafter, has become a subject of recent focus in the field of organic chemistry. In the early 1960s, a few methods for the formation of trifluoromethylthioethers were reported, which typically involved halogen exchange of the trichloromethyl-substituted compounds and trifluoromethylation of thiolated substrates. However, the conditions of these methods were harsh and incompatible with many common functional groups. Since 2008, new reagents and methods that were able to efficiently incorporate the trifluoromethylthio group under mild conditions have emerged, that pave the way for the facile introduction of trifluoromethylthio group into site-specific positions of the target molecules. In this review, we will first briefly introduce the indirect strategies for trifluoromethylthiolation including halogen exchange and trifluoromethylation of thiolated substrates, and then focus on the direct trifluoromethylthiolation strategies including the transition metal-catalyzed trifluoromethylthiolation reactions, electrophilic trifluoromethylthiolation reactions with electrophilic trifluoromethylthiolating reagents and radical trifluoromethylthiolations. These methods represent the most straightforward and promising approaches for the incorporation of the trifluoromethylthio group into small molecules. At the end, we will discuss the remaining problems and challenges in this particular field.
With a significantly high Hansch's hydrophobicity parameter (π=1.44), electron-withdrawing trifluoromethylthio group (CF3S-) has been considered as one of the most lipophilic substituents and privileged fragments that are able to improve drug molecules' pharmacokinetic and physicochemical properties such as lipophilicity and metabolic stability. It is well-known that incorporation of the trifluoromethylthio group into small molecules greatly enhances its ability to cross lipid membranes and in vivo absorpotion rate. In addition, the high electronegativity of the trifluoromethylthio group significantly improves the small molecule's stablity in acidic environments. Not surprisingly, the trifluoromethylthio group has been of special attention not only from the academia but also from pharmaceutical and agrochemical industry for their use in isostere-based drug design. Development of highly efficient methods for the introduction of the trifluoromethylthio group into small molecules, thereafter, has become a subject of recent focus in the field of organic chemistry. In the early 1960s, a few methods for the formation of trifluoromethylthioethers were reported, which typically involved halogen exchange of the trichloromethyl-substituted compounds and trifluoromethylation of thiolated substrates. However, the conditions of these methods were harsh and incompatible with many common functional groups. Since 2008, new reagents and methods that were able to efficiently incorporate the trifluoromethylthio group under mild conditions have emerged, that pave the way for the facile introduction of trifluoromethylthio group into site-specific positions of the target molecules. In this review, we will first briefly introduce the indirect strategies for trifluoromethylthiolation including halogen exchange and trifluoromethylation of thiolated substrates, and then focus on the direct trifluoromethylthiolation strategies including the transition metal-catalyzed trifluoromethylthiolation reactions, electrophilic trifluoromethylthiolation reactions with electrophilic trifluoromethylthiolating reagents and radical trifluoromethylthiolations. These methods represent the most straightforward and promising approaches for the incorporation of the trifluoromethylthio group into small molecules. At the end, we will discuss the remaining problems and challenges in this particular field.
2017, 75(8): 770-782
doi: 10.6023/A17050194
Abstract:
The controlled drug delivery systems, due to their precise control of drug release in spatiotemporal level triggered by specific stimulating factors and advantages such as higher utilization ratio of drug, less side-effects to normal tissues and so forth, provide a new strategy for the precise treatment of many serious diseases, especially tumors. The materials that constitute the controlled drug delivery systems are called "smart materials" and they can respond to the stimuli of some internal (pH, redox, enzymes, etc.) or external (temperature, electrical/magnetic, ultrasonic and optica l, etc.) environments. Before and after the response to the specific stimulus, the composition or conformational of smart materials will be changed, damaging the original balance of the delivery systems and releasing the drug from the delivery systems. Amongst them, the photo-controlled drug delivery systems, which display drug release controlled by light, demonstrated extensive potential applications, and received wide attention from researchers. In recent years, photo-controlled drug delivery systems based on different photo-responsive groups have been designed and developed for precise photo-controlled release of drugs. Herein, in this review, we introduced four photo-responsive groups including photocleavage groups, photoisomerization groups, photo-induced rearrangement groups and photocrosslinking groups, and their different photo-responsive mechanisms. Firstly, the photocleavage groups represented by O-nitrobenzyl are able to absorb the energy of the photons, inducing the cleavage of some specific covalent bonds. Secondly, azobenzenes, as a kind of photoisomerization groups, are able to convert reversibly between the apolar trans form and the polar cis form upon different light irradiation. Thirdly, 2-diazo-1, 2-naphthoquinone as the representative of the photo-induced rearrangement groups will absorb specific photon energy, carrying out Wolff rearrangement reaction. Finally, coumarin is a promising category photocrosslinking groups that can undergo[2+2] cycloaddition reactions under light irradiation. The research progress of photo-controlled drug delivery systems based on different photo-responsive mechanisms were mainly reviewed. Additionally, the existing problems and the future research perspectives of photo-controlled drug delivery systems were proposed.
The controlled drug delivery systems, due to their precise control of drug release in spatiotemporal level triggered by specific stimulating factors and advantages such as higher utilization ratio of drug, less side-effects to normal tissues and so forth, provide a new strategy for the precise treatment of many serious diseases, especially tumors. The materials that constitute the controlled drug delivery systems are called "smart materials" and they can respond to the stimuli of some internal (pH, redox, enzymes, etc.) or external (temperature, electrical/magnetic, ultrasonic and optica l, etc.) environments. Before and after the response to the specific stimulus, the composition or conformational of smart materials will be changed, damaging the original balance of the delivery systems and releasing the drug from the delivery systems. Amongst them, the photo-controlled drug delivery systems, which display drug release controlled by light, demonstrated extensive potential applications, and received wide attention from researchers. In recent years, photo-controlled drug delivery systems based on different photo-responsive groups have been designed and developed for precise photo-controlled release of drugs. Herein, in this review, we introduced four photo-responsive groups including photocleavage groups, photoisomerization groups, photo-induced rearrangement groups and photocrosslinking groups, and their different photo-responsive mechanisms. Firstly, the photocleavage groups represented by O-nitrobenzyl are able to absorb the energy of the photons, inducing the cleavage of some specific covalent bonds. Secondly, azobenzenes, as a kind of photoisomerization groups, are able to convert reversibly between the apolar trans form and the polar cis form upon different light irradiation. Thirdly, 2-diazo-1, 2-naphthoquinone as the representative of the photo-induced rearrangement groups will absorb specific photon energy, carrying out Wolff rearrangement reaction. Finally, coumarin is a promising category photocrosslinking groups that can undergo[2+2] cycloaddition reactions under light irradiation. The research progress of photo-controlled drug delivery systems based on different photo-responsive mechanisms were mainly reviewed. Additionally, the existing problems and the future research perspectives of photo-controlled drug delivery systems were proposed.
2017, 75(8): 783-787
doi: 10.6023/A17040146
Abstract:
D-A cyclopropanes have emerged as versatile synthons for construction of carbocycles and heterocycles via a [3 +2] annulation reactions, and have been used in the total synthesis of natural products. Recently, it has been witnessed tremendous progress within the area of transformation of 2-monosubstituted-cyclopropane-1, 1-diesters. However, cyclopropane-1, 1-diesters with full substitution at the donor site have not been well explored. C2, C3-fused indolines are widely existed in a plenty of natural products and biologically active compounds, and have been the synthetic targets for decades. Among the various approaches to access these important structural motifs, the cyclopentannulation of indoles with Donor-Acceptor (D-A) cyclopropanes, represents a concise, economical and effective method. Previously, we have developed a highly diastereo-and enantioselective BOX/Cu(Ⅱ) catalyzed C2, C3-cyclopentannulation of indoles with 2-monosubstituted-cyclopropane-1, 1-diesters, a facile access to a series of enantioenriched cyclopenta-fused indoline products. As our further studies, Lewis acid catalyzed [3+2] annulation of indoles with 1, 1, 2, 2-tetrasubstituted D-A cyclopropanes was reported in this paper. This annulation method of C3-substituted indoles with quaternary donor site D-A cyclopropanes yielded C2, C3-fused indolines, bearing three quaternary stereocentres on the newly built cyclopentane ring without the formation of the common Friedel-Crafts byproducts. The ester groups on cyclopropane, ligand, and protection group of indole have great influence on both yield and dr selectivity. Thus, the reaction between indole (1b, -NMe) and cyclopropane 2 (CO2R2=CO2CH2CF3) can give the highest yield and the best dr in the presence of 10 mol% BOX/Cu(SbF6)2 in DCM, which is prepared in situ. Under the optimal conditions, the[3+2] annulation reacts smoothly with a wide range of substituted indole derivatives and D-A cyclopropanes, giving the desired products in up to 91% yield with up to >20/1 diastereoselectivity. The relative configuration of the products is determined by X-ray crystallographic analysis of the major diastereoisomer of 3b. The general experimental procedure for the [3+2] annulations is shown below:A mixture of CuBr2(0.02 mmol), AgSbF6 (0.04 mmol), and bisoxazoline (L, 0.024 mmol) in DCM (1 mL) was stirred at room temperature for 3 h under the atmosphere of nitrogen. Then, the mixture was cooled to 0℃ for 20 min and the cyclopropane 1(0.2 mmol) and the indole derivative 2 (0.4 mmol) in 1 mL DCM were added to the mixture of catalyst via a syringe. After the reaction was complete (monitored by TLC), the reaction was filtered through a glass funnel with thin layer (20 mm) of silica gel (100~200 mesh) and eluted with DCM (approx 100 mL). The filtrate was concentrated under reduced pressure. After the determination of the diatereoselectivity by 1H NMR, the residue was purified by flash chromatography to afford the product 3.
D-A cyclopropanes have emerged as versatile synthons for construction of carbocycles and heterocycles via a [3 +2] annulation reactions, and have been used in the total synthesis of natural products. Recently, it has been witnessed tremendous progress within the area of transformation of 2-monosubstituted-cyclopropane-1, 1-diesters. However, cyclopropane-1, 1-diesters with full substitution at the donor site have not been well explored. C2, C3-fused indolines are widely existed in a plenty of natural products and biologically active compounds, and have been the synthetic targets for decades. Among the various approaches to access these important structural motifs, the cyclopentannulation of indoles with Donor-Acceptor (D-A) cyclopropanes, represents a concise, economical and effective method. Previously, we have developed a highly diastereo-and enantioselective BOX/Cu(Ⅱ) catalyzed C2, C3-cyclopentannulation of indoles with 2-monosubstituted-cyclopropane-1, 1-diesters, a facile access to a series of enantioenriched cyclopenta-fused indoline products. As our further studies, Lewis acid catalyzed [3+2] annulation of indoles with 1, 1, 2, 2-tetrasubstituted D-A cyclopropanes was reported in this paper. This annulation method of C3-substituted indoles with quaternary donor site D-A cyclopropanes yielded C2, C3-fused indolines, bearing three quaternary stereocentres on the newly built cyclopentane ring without the formation of the common Friedel-Crafts byproducts. The ester groups on cyclopropane, ligand, and protection group of indole have great influence on both yield and dr selectivity. Thus, the reaction between indole (1b, -NMe) and cyclopropane 2 (CO2R2=CO2CH2CF3) can give the highest yield and the best dr in the presence of 10 mol% BOX/Cu(SbF6)2 in DCM, which is prepared in situ. Under the optimal conditions, the[3+2] annulation reacts smoothly with a wide range of substituted indole derivatives and D-A cyclopropanes, giving the desired products in up to 91% yield with up to >20/1 diastereoselectivity. The relative configuration of the products is determined by X-ray crystallographic analysis of the major diastereoisomer of 3b. The general experimental procedure for the [3+2] annulations is shown below:A mixture of CuBr2(0.02 mmol), AgSbF6 (0.04 mmol), and bisoxazoline (L, 0.024 mmol) in DCM (1 mL) was stirred at room temperature for 3 h under the atmosphere of nitrogen. Then, the mixture was cooled to 0℃ for 20 min and the cyclopropane 1(0.2 mmol) and the indole derivative 2 (0.4 mmol) in 1 mL DCM were added to the mixture of catalyst via a syringe. After the reaction was complete (monitored by TLC), the reaction was filtered through a glass funnel with thin layer (20 mm) of silica gel (100~200 mesh) and eluted with DCM (approx 100 mL). The filtrate was concentrated under reduced pressure. After the determination of the diatereoselectivity by 1H NMR, the residue was purified by flash chromatography to afford the product 3.
2017, 75(8): 788-793
doi: 10.6023/A17050199
Abstract:
Lignin is a potential resources of aromatic compound that can be obtained from renewable biomass. There are many ongoing research efforts to utilize lignin as a sustainable alternative to petroleum derived aromatic compounds. Because of the complex three-dimensional structure, the depolymerization of lignin into monomer molecule became a core challenge for the utilization of lignin. The β-O-4 structure is the most abundant linkage in lignin. Owing to its abundance, the β-O-4 structure has been representatively studied in many aspects of scientific research on lignin degradation. Among the different reported strategies for the cleavage of β-O-4 ether bonds, C-C bond cleavage is one of the most important approaches to depolymerizing lignin. In this study, we accomplished the oxidative C-C bond cleavage of the β-O-4 structure by the catalysis of NH4VO3 using the pre-oxidized 2-phenoxy-1-phenylethanone (1a) as a model compound of lignin. In the DMSO-HOAc solvent system, benzoic acid and phenol were produced in a moderate condition, the yeild of benzoic acid and phenol were 82.1% and 88.1%, respectively. The reaction process was investigated via 1H NMR and X-ray photoelectron spectra (XPS) characterizations and the possible reaction pathway was further proposed. As the results shown, two possible reaction routes existed in this catalytic system. Pathway one:the 2-hydroxyacetophenone and phenol formed after the C-O bond cleavage of 1a in the acidic system, then, the intermediate 2-hydroxyacetophenone was converted to benzoic via the cleavage of C-C bond. Pathway two:benzoic acid and phenol yielded by the C-C bond of 1a cleaved directly over the catalyst. In addition, the catalyst characterization results confirmed that the oxovanadium(V) directly catalyzed the depolymerization of the β-O-4 structure and generated oxovanadium(Ⅳ), then oxovanadium(Ⅳ) was oxidized by O2 and finish the catalytic cycle. All reactions were carried out by the following general procedure. This reaction was carried out in glass tube and heated by oil bath. 0.5 mmol of 1a was added into 2 mL of DMSO-HOAc (V:V=3:1) with 30 mol% NH4VO3 (17.5 mg) under an oxygen atmosphere (101 kPa, in balloon). The reactor was heated to 100℃ with a powerful stirring. After 8 h, the reaction was cooled to room temperature, then 5 mL of ethyl acetate was added into the mixtures. Ash black precipitate was removed by filtration and the liquid mixture was detected by GC.
Lignin is a potential resources of aromatic compound that can be obtained from renewable biomass. There are many ongoing research efforts to utilize lignin as a sustainable alternative to petroleum derived aromatic compounds. Because of the complex three-dimensional structure, the depolymerization of lignin into monomer molecule became a core challenge for the utilization of lignin. The β-O-4 structure is the most abundant linkage in lignin. Owing to its abundance, the β-O-4 structure has been representatively studied in many aspects of scientific research on lignin degradation. Among the different reported strategies for the cleavage of β-O-4 ether bonds, C-C bond cleavage is one of the most important approaches to depolymerizing lignin. In this study, we accomplished the oxidative C-C bond cleavage of the β-O-4 structure by the catalysis of NH4VO3 using the pre-oxidized 2-phenoxy-1-phenylethanone (1a) as a model compound of lignin. In the DMSO-HOAc solvent system, benzoic acid and phenol were produced in a moderate condition, the yeild of benzoic acid and phenol were 82.1% and 88.1%, respectively. The reaction process was investigated via 1H NMR and X-ray photoelectron spectra (XPS) characterizations and the possible reaction pathway was further proposed. As the results shown, two possible reaction routes existed in this catalytic system. Pathway one:the 2-hydroxyacetophenone and phenol formed after the C-O bond cleavage of 1a in the acidic system, then, the intermediate 2-hydroxyacetophenone was converted to benzoic via the cleavage of C-C bond. Pathway two:benzoic acid and phenol yielded by the C-C bond of 1a cleaved directly over the catalyst. In addition, the catalyst characterization results confirmed that the oxovanadium(V) directly catalyzed the depolymerization of the β-O-4 structure and generated oxovanadium(Ⅳ), then oxovanadium(Ⅳ) was oxidized by O2 and finish the catalytic cycle. All reactions were carried out by the following general procedure. This reaction was carried out in glass tube and heated by oil bath. 0.5 mmol of 1a was added into 2 mL of DMSO-HOAc (V:V=3:1) with 30 mol% NH4VO3 (17.5 mg) under an oxygen atmosphere (101 kPa, in balloon). The reactor was heated to 100℃ with a powerful stirring. After 8 h, the reaction was cooled to room temperature, then 5 mL of ethyl acetate was added into the mixtures. Ash black precipitate was removed by filtration and the liquid mixture was detected by GC.
2017, 75(8): 794-797
doi: 10.6023/A17040144
Abstract:
To date, copper catalysis has become an attractive approach to access multifunctional alkylborons through borylative coupling processes, many important protocols such as carboboration, stannylboration and aminoboration were developed. Among these methods, however, there is no report involving enantioselective aminoboration of simple styrene substrates, which can generate a class of useful chiral compounds. In this work, an enantioselective Cu-catalyzed aminoboration of styrenes by using a chiral sulfoxide-phosphine (SOP) ligand was developed, chiral β-aminoalkylboranes were obtained in satisfied yields and ee values, and these products can be readily converted to a class of valuable β-hydroxylalkylamines. A general procedure for the aminoboration of styrenes is as following:in glove box, CuCl (0.02 mmol), chiral sulfoxide phosphine L1 (0.022 mmol) and 2.0 mL of dried tetrahydrofuran were added into a flame-dried tube, the resolved solution was stirred for 30 min at room temperature, then bis(pinacolato)diboron (B2pin2) (0.3 mmol), t-BuOLi (0.6 mmol) and styrene (0.2 mmol) were added. The tube was taken out of the glove box and cooled to 0℃. Electrophilic amination reagent, O-benzoyl-N, N-dibenzylhydroxylamine (2a, 0.3 mmol), was dissolved in 1.0 mL of ethyl acetate and added to the mixture, the resolved mixture was stirred at 0℃ for 24 h. The crude product was filtered through a celite pad, concentrated and oxidized by NaBO3·4H2O. The mixture was extracted three times with ethyl acetate, concentrated and purified with silica gel chromatography to give the desired β-hydroxylalkylamines, the enantioselective excess of products were determined by chiral HPLC analysis. Broad substrate scope which related to steric and electronic effect were compatible in this catalysis under the standard conditions. To demonstrate the utility of this method, a gram scale experiment was performed and the desired product was obtained in 92% isolated yield and 90% ee. The benzyl group of products can be readily removed via a Pd/C-catalyzed hydrogenation process and the corresponding product with a free amino group in excellent yield (95%).
To date, copper catalysis has become an attractive approach to access multifunctional alkylborons through borylative coupling processes, many important protocols such as carboboration, stannylboration and aminoboration were developed. Among these methods, however, there is no report involving enantioselective aminoboration of simple styrene substrates, which can generate a class of useful chiral compounds. In this work, an enantioselective Cu-catalyzed aminoboration of styrenes by using a chiral sulfoxide-phosphine (SOP) ligand was developed, chiral β-aminoalkylboranes were obtained in satisfied yields and ee values, and these products can be readily converted to a class of valuable β-hydroxylalkylamines. A general procedure for the aminoboration of styrenes is as following:in glove box, CuCl (0.02 mmol), chiral sulfoxide phosphine L1 (0.022 mmol) and 2.0 mL of dried tetrahydrofuran were added into a flame-dried tube, the resolved solution was stirred for 30 min at room temperature, then bis(pinacolato)diboron (B2pin2) (0.3 mmol), t-BuOLi (0.6 mmol) and styrene (0.2 mmol) were added. The tube was taken out of the glove box and cooled to 0℃. Electrophilic amination reagent, O-benzoyl-N, N-dibenzylhydroxylamine (2a, 0.3 mmol), was dissolved in 1.0 mL of ethyl acetate and added to the mixture, the resolved mixture was stirred at 0℃ for 24 h. The crude product was filtered through a celite pad, concentrated and oxidized by NaBO3·4H2O. The mixture was extracted three times with ethyl acetate, concentrated and purified with silica gel chromatography to give the desired β-hydroxylalkylamines, the enantioselective excess of products were determined by chiral HPLC analysis. Broad substrate scope which related to steric and electronic effect were compatible in this catalysis under the standard conditions. To demonstrate the utility of this method, a gram scale experiment was performed and the desired product was obtained in 92% isolated yield and 90% ee. The benzyl group of products can be readily removed via a Pd/C-catalyzed hydrogenation process and the corresponding product with a free amino group in excellent yield (95%).
Asymmetric Formal Synthesis of Cortistatins via a Gold-Catalyzed Semi-Pinacol Rearrangement Strategy
2017, 75(8): 798-807
doi: 10.6023/A17040190
Abstract:
Over the past decade, Gold complexes have emerged as efficient and mild catalysts for the transformation of substrates possessing alkyne functionality into a range of useful scaffolds. These powerful methods have enabled the development of novel approaches for the total synthesis of biologically active natural products by gold catalysis. In this case, we found that the intramolecular nucleophilic addition of a hydroxyl group to a carbon-carbon triple bond, which activated by a gold catalyst, followed by further useful transformation has proven to be an excellent method for rapid construction of structural diversity of molecular scaffolds. The cortistatins are a family of 11 steroidal alkaloids which exhibit significant biological activities. The intriguing biological properties and their low natural abundance have elevated cortistatins to be a typical target for both partial and total synthesis. Up to now, more than a dozen research groups have published approaches directed toward the synthesis of cortistatins, including one semi-synthesis, five total syntheses and five formal syntheses, as well as a number of synthetic studies about the pentacyclic core and some illuminating model studies. One of the biggest challenges for the synthesis of cortistatins is how to construct the unprecedented oxabicyclo [3.2.1]octane ring system which lies within a complex tetracarbocyclic skeleton. In our previous work, we have developed a gold-catalyzed semi-pinacol rearrangement strategy to diastereoselective synthesis of the oxabicyclo [3.2.1]octane ring system. The wide substrate scope as well as the high diastereoselectivity have made us to apply this method into the asymmetric formal synthesis of Cortistatins. Herein, full details about our efforts towards the formal synthesis of cortistatins were described by employing our developed gold-catalyzed cascade reaction to oxabicyclo[3.2.1]octane ring systems. This route is featured with a novel gold-catalyzed cascade reaction involving intramolecular nucleophilic addition of hydroxyl group to the carbon-carbon triple bond, followed by an oxonium ion initiated semi-pinacol-type 1, 2-migration to construct the key oxabicyclo [3.2.1]octane skeleton.
Over the past decade, Gold complexes have emerged as efficient and mild catalysts for the transformation of substrates possessing alkyne functionality into a range of useful scaffolds. These powerful methods have enabled the development of novel approaches for the total synthesis of biologically active natural products by gold catalysis. In this case, we found that the intramolecular nucleophilic addition of a hydroxyl group to a carbon-carbon triple bond, which activated by a gold catalyst, followed by further useful transformation has proven to be an excellent method for rapid construction of structural diversity of molecular scaffolds. The cortistatins are a family of 11 steroidal alkaloids which exhibit significant biological activities. The intriguing biological properties and their low natural abundance have elevated cortistatins to be a typical target for both partial and total synthesis. Up to now, more than a dozen research groups have published approaches directed toward the synthesis of cortistatins, including one semi-synthesis, five total syntheses and five formal syntheses, as well as a number of synthetic studies about the pentacyclic core and some illuminating model studies. One of the biggest challenges for the synthesis of cortistatins is how to construct the unprecedented oxabicyclo [3.2.1]octane ring system which lies within a complex tetracarbocyclic skeleton. In our previous work, we have developed a gold-catalyzed semi-pinacol rearrangement strategy to diastereoselective synthesis of the oxabicyclo [3.2.1]octane ring system. The wide substrate scope as well as the high diastereoselectivity have made us to apply this method into the asymmetric formal synthesis of Cortistatins. Herein, full details about our efforts towards the formal synthesis of cortistatins were described by employing our developed gold-catalyzed cascade reaction to oxabicyclo[3.2.1]octane ring systems. This route is featured with a novel gold-catalyzed cascade reaction involving intramolecular nucleophilic addition of hydroxyl group to the carbon-carbon triple bond, followed by an oxonium ion initiated semi-pinacol-type 1, 2-migration to construct the key oxabicyclo [3.2.1]octane skeleton.
2017, 75(8): 808-818
doi: 10.6023/A17030114
Abstract:
In this work, we demonstrate the microwave-assisted synthesis of naphthalene diimide-based polymers via three-component polymerization (TCP) of diynes, dialdehydes and dibenzylamine, and the applications of such polymers as cathode interfacial layers for polymer solar cells. The TCP of diynes (1a~1c), dialdehydes (2a~2b) and dibenzylamine catalyzed by InCl3 could be performed smoothly under microwave irradiation in very short reaction time, yielding soluble polymers P1~P4 with high molecular weights. The chemical structures of these resulting polymers were confirmed by nuclear magnetic resonance spectroscopy. The thermal stability, photophysical and electrochemical properties of the resulting polymers were also investigated. Besides, the effects of chemical environment of amine groups on the resulting polymers' electrode modification capability and self-doping behavior were explored by conducting scanning Kelvin probe microscopy and electron paramagnetic resonance (EPR) spectroscopy studies, respectively. It was found that the chemical environment variation of amine groups, including the decreasing electron density of the nitrogen atoms in alkylamine and the enhancing steric hindrance around the nitrogen atoms from substituent groups, can substantially influence the electrode modification capability and self-doping behavior of the resulting polymers. Moreover, quantum chemistry calculation was also conducted to qualitatively illuminate the essential distinction in chemical environment of different amine groups. It was found that the negative atomic dipole moment corrected Hirshfeld (ADCH) charge of nitrogen atoms in side chains was significantly larger than the ADCH charges of nitrogen atoms in main chains. Among all the resulting polymers, P1 can be easily dissolved in alcohol due to its amino functionalized side chain groups and thus was utilized as the cathode interlayer for polymer solar cells. The device with P1 as the cathode interlayer and PTB7-Th:PC71BM as the photoactive layer exhibits a high power conversion efficiency of 9.34%, which is much better than that of the control device without such cathode interlayer. All these results provide a guideline for the material design of amino-functionalized polymers for the optoelectronic devices. And it was also shown that the multicomponent polymerization (MCP) is an effective strategy for the synthesis of functional polymers, and may trigger broad research interests in developing effective polymerization approaches toward multi-functional polymer materials.
In this work, we demonstrate the microwave-assisted synthesis of naphthalene diimide-based polymers via three-component polymerization (TCP) of diynes, dialdehydes and dibenzylamine, and the applications of such polymers as cathode interfacial layers for polymer solar cells. The TCP of diynes (1a~1c), dialdehydes (2a~2b) and dibenzylamine catalyzed by InCl3 could be performed smoothly under microwave irradiation in very short reaction time, yielding soluble polymers P1~P4 with high molecular weights. The chemical structures of these resulting polymers were confirmed by nuclear magnetic resonance spectroscopy. The thermal stability, photophysical and electrochemical properties of the resulting polymers were also investigated. Besides, the effects of chemical environment of amine groups on the resulting polymers' electrode modification capability and self-doping behavior were explored by conducting scanning Kelvin probe microscopy and electron paramagnetic resonance (EPR) spectroscopy studies, respectively. It was found that the chemical environment variation of amine groups, including the decreasing electron density of the nitrogen atoms in alkylamine and the enhancing steric hindrance around the nitrogen atoms from substituent groups, can substantially influence the electrode modification capability and self-doping behavior of the resulting polymers. Moreover, quantum chemistry calculation was also conducted to qualitatively illuminate the essential distinction in chemical environment of different amine groups. It was found that the negative atomic dipole moment corrected Hirshfeld (ADCH) charge of nitrogen atoms in side chains was significantly larger than the ADCH charges of nitrogen atoms in main chains. Among all the resulting polymers, P1 can be easily dissolved in alcohol due to its amino functionalized side chain groups and thus was utilized as the cathode interlayer for polymer solar cells. The device with P1 as the cathode interlayer and PTB7-Th:PC71BM as the photoactive layer exhibits a high power conversion efficiency of 9.34%, which is much better than that of the control device without such cathode interlayer. All these results provide a guideline for the material design of amino-functionalized polymers for the optoelectronic devices. And it was also shown that the multicomponent polymerization (MCP) is an effective strategy for the synthesis of functional polymers, and may trigger broad research interests in developing effective polymerization approaches toward multi-functional polymer materials.
2017, 75(8): 819-823
doi: 10.6023/A17040142
Abstract:
Although in recent years the frustrated Lewis pairs (FLPs) reactivity towards small molecule activation has been widely concerned, the reports on the FLPs derived from aromatic amines are few. This paper describes a new method of an one-pot hydroamination/reduction reaction of terminal alkynes with aromatic amines catalyzed by the B(C6F5)3/aromatic ammonium chloride systems with a hydridosilane as a source of the hydride. We consider that the active intermediate[Ar2NH2]+[H-B(C6F5)3]-which formed by the aromatic ammonium chloride/B(C6F5)3 reaction with silanes plays a very important role on the formation and reduction of the mediate product imines. The hydroamination reaction is firstly induced by the trace amount amines produced by the dissociation of the borohydride aromatic amine salt, which then reacts with the alkynes and forms the imines. Then the borohydride intermediate[Ar2NH2]+[H-B(C6F5)3]- reduces the imines to amines. It has been proved that the borohydride intermediate[Ar2NH2]+[H-B(C6F5)3]-could successfully reduce the corresponding imines to amines in an in-situ reaction condition. However it has been found that the usually most active mono-substituted hydridosilane, such as PhSiH3 shows the poorest reactivity in this case. And the less active trisubstituted silanes such as Et3SiH or Ph3SiH exhibit the highest reactivity. To explain this abnormal phenomenon the different reaction speeds of the cascade hydroamination/reduction reaction and the dissociation of the borohydride aromatic amine salt should be concerned. Since the dissociation of[Ar2NH2]+[H-B(C6F5)3]-to H2 is comparably quicker than the hydroamination reaction. By reacting with the less active trisubstituted silanes could not only slow down the formation and dissociation of[Ar2NH2]+[H-B(C6F5)3]-, but could also let the hydroamination and reduction steps proceeded completely. Moreover by slowly adding the diluted hydrosilanes to the reaction systems could also improve the reaction. The reaction yield is affected by the substituent on the terminal alkynes, too. The alkynes with the electron withdrawn group show comparably higher reactivity than with the electron donating ones.
Although in recent years the frustrated Lewis pairs (FLPs) reactivity towards small molecule activation has been widely concerned, the reports on the FLPs derived from aromatic amines are few. This paper describes a new method of an one-pot hydroamination/reduction reaction of terminal alkynes with aromatic amines catalyzed by the B(C6F5)3/aromatic ammonium chloride systems with a hydridosilane as a source of the hydride. We consider that the active intermediate[Ar2NH2]+[H-B(C6F5)3]-which formed by the aromatic ammonium chloride/B(C6F5)3 reaction with silanes plays a very important role on the formation and reduction of the mediate product imines. The hydroamination reaction is firstly induced by the trace amount amines produced by the dissociation of the borohydride aromatic amine salt, which then reacts with the alkynes and forms the imines. Then the borohydride intermediate[Ar2NH2]+[H-B(C6F5)3]- reduces the imines to amines. It has been proved that the borohydride intermediate[Ar2NH2]+[H-B(C6F5)3]-could successfully reduce the corresponding imines to amines in an in-situ reaction condition. However it has been found that the usually most active mono-substituted hydridosilane, such as PhSiH3 shows the poorest reactivity in this case. And the less active trisubstituted silanes such as Et3SiH or Ph3SiH exhibit the highest reactivity. To explain this abnormal phenomenon the different reaction speeds of the cascade hydroamination/reduction reaction and the dissociation of the borohydride aromatic amine salt should be concerned. Since the dissociation of[Ar2NH2]+[H-B(C6F5)3]-to H2 is comparably quicker than the hydroamination reaction. By reacting with the less active trisubstituted silanes could not only slow down the formation and dissociation of[Ar2NH2]+[H-B(C6F5)3]-, but could also let the hydroamination and reduction steps proceeded completely. Moreover by slowly adding the diluted hydrosilanes to the reaction systems could also improve the reaction. The reaction yield is affected by the substituent on the terminal alkynes, too. The alkynes with the electron withdrawn group show comparably higher reactivity than with the electron donating ones.
2017, 75(8): 824-830
doi: 10.6023/A17040141
Abstract:
Stereoselective hydroboration reaction of alkynes has been considered as one of the most important organic reaction. To date a handful of metal-catalyzed systems have been demonstrated to achieve trans-hydroboration of alkynes. This paper describes the first non-metal-catalyzed systems which could stereoselectively hydroborate the terminal alkynes in a trans-configuration. The Lewis acid B(C6F5)3 and ammonium chloride have been used as the reaction substrates, and phenylsilane as the hydride source. The hydroboration reaction could be performed in a one-pot procedure by mixing of B(C6F5)3, ammonium chloride and silane together in an equivalent amount. But this one-pot reaction is not so nice since there is always mixed with the ammonium hydroborate[R2NH2]+[H-B(C6F5)3]- intermediates products. A series of ammonium hydroborates prepared from the corresponding primary, secondary, tertiary and quaternary amine hydrochlorides have been isolated, and used in the directly hydroboration with terminal alkynes. To our surprise the ammonium hydroborate[R2NH2]+[H-B(C6F5)3]- could not react with the alkynes alone. When using[R2NH2]+[H-B(C6F5)3]- to react with alkynes, trace amount of catalytic Lewis acid B(C6F5)3 is necessary to firstly activate the carbon-carbon triple bonds and form the crucial zwitterionic σ-complexes. The mechanism study has shown that different from the typical Lewis acid/Lewis base FLPs system reacted with alkynes, in this B(C6F5)3/ammonium chloride system the ammonium chloride plays an important role on the stereoselective control of the reaction. The week interaction between the Cl ion and B(C6F5)3 in the σ-complexes has not only slowed down the unfavorite 1, 1-carboboration reaction, but also stabilized the σ-complexes which has offer the chance for the nucleophilic reagent to attack the reaction center in a cis-or trans-mode. In our experiment the bulky ion[H-B(C6F5)3]-could only attach the active alkynes from the trans-side and form the Z-hydroboration product. This work demonstrates that the combination of the ammonium halides with the Lewis acid B(C6F5)3 could act as a novel "frustrated Lewis pair" to activate alkynes, and will enable the development of even more sophisticated FLP and related catalyzed reactions.
Stereoselective hydroboration reaction of alkynes has been considered as one of the most important organic reaction. To date a handful of metal-catalyzed systems have been demonstrated to achieve trans-hydroboration of alkynes. This paper describes the first non-metal-catalyzed systems which could stereoselectively hydroborate the terminal alkynes in a trans-configuration. The Lewis acid B(C6F5)3 and ammonium chloride have been used as the reaction substrates, and phenylsilane as the hydride source. The hydroboration reaction could be performed in a one-pot procedure by mixing of B(C6F5)3, ammonium chloride and silane together in an equivalent amount. But this one-pot reaction is not so nice since there is always mixed with the ammonium hydroborate[R2NH2]+[H-B(C6F5)3]- intermediates products. A series of ammonium hydroborates prepared from the corresponding primary, secondary, tertiary and quaternary amine hydrochlorides have been isolated, and used in the directly hydroboration with terminal alkynes. To our surprise the ammonium hydroborate[R2NH2]+[H-B(C6F5)3]- could not react with the alkynes alone. When using[R2NH2]+[H-B(C6F5)3]- to react with alkynes, trace amount of catalytic Lewis acid B(C6F5)3 is necessary to firstly activate the carbon-carbon triple bonds and form the crucial zwitterionic σ-complexes. The mechanism study has shown that different from the typical Lewis acid/Lewis base FLPs system reacted with alkynes, in this B(C6F5)3/ammonium chloride system the ammonium chloride plays an important role on the stereoselective control of the reaction. The week interaction between the Cl ion and B(C6F5)3 in the σ-complexes has not only slowed down the unfavorite 1, 1-carboboration reaction, but also stabilized the σ-complexes which has offer the chance for the nucleophilic reagent to attack the reaction center in a cis-or trans-mode. In our experiment the bulky ion[H-B(C6F5)3]-could only attach the active alkynes from the trans-side and form the Z-hydroboration product. This work demonstrates that the combination of the ammonium halides with the Lewis acid B(C6F5)3 could act as a novel "frustrated Lewis pair" to activate alkynes, and will enable the development of even more sophisticated FLP and related catalyzed reactions.
