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Pd PEPPSI-IPr-Mediated Reactions in Metal-Coated Capillaries Under MACOS: The Synthesis of Indoles by Sequential Aryl Amination/ Heck Coupling
Abstract
A method has been devised for the microwave-assisted, continuous-flow preparation of indole alkaloids by a two-step aryl amination/cross-coupling sequence of bromoalkenes and 2-bromoanilines. This process requires both the presence of a metal-lined flow tube (a 1180 micron capillary) and the Pd PEPPSI-IPr catalyst; without either, the catalyst or the film, there is zero turnover of this catalytic process. A silver film has been shown to provide some conversion (48-62 %), but optimal results (quantitative) across a variety of bromoalkenes and bromoanilines were achieved by using a highly porous palladium film. Possible roles for the Pd film are considered, as is the interplay of the catalyst and the film.
... [18] The palladium film-coated capillary reactor was also applied to indole synthesis under MW-assisted continuousflow conditions. [26] When solutions of a 2-bromoaniline derivative, a 1-substituted 1-bromoethene, and NaOtBu in toluene were flowed together with homogeneous Pd PEPPSI-IPr as an additional co-catalyst [27] into the palladium filmcoated reactor under MW irradiation, the corresponding 2substituted indoles were obtained in good yield through Scheme 5. MW-assisted continuous-flow Suzuki-Miyaura reaction using SiC tube reactor. [21] Scheme 6. MW-assisted continuous-flow Mizoroki-Heck reaction catalyzed by Pd(OAc) 2 . ...
... Indole synthesis via sequential MW-assisted continuous-flow amination/intramolecular Mizoroki-Heck reaction through the combined use of a Pd thin film-coated reactor and additional homogeneous Pd PEPPSI-IPr. [26] Scheme 11. MW-assisted continuous-flow Suzuki-Miyaura reaction catalyzed by Pd/Al 2 O 3 packed in a gold-coated U-shaped capillary reactor. ...
... [34] The advantage of this system is that palladium species are hardly leached from the Pd/silica-monolith during the reaction (< 100 ppb, ICP-AES), and the catalyst could be used for six runs without any deactivation. [32] Although Organ et al. demonstrated a the palladium film coated on the inner wall of a capillary reactor could effectively catalyze cross-coupling reactions under MW-assisted continuous-flow conditions as aforementioned, [17,18,26] they realized that there were three problems: 1) the flow was highly laminar; 2) the film could be detached due to differential thermal expansion at the metal-capillary interface; and 3) the metal film is heated more effectively than the reaction solution due to the electrical current generated by subjecting an electrically conducting metal to an oscillating magnetic field, such as MW irradiation. [35] Thus, they selected a MWtransparent silica macrosphere as the catalyst support; since the spherical shape with monodisperse distribution would promote turbulent flow, the differential thermal expansion at the metal-capillary interface would not cause the leaching of palladium nanoparticles, and the use of MW-transparent Scheme 12. MW-assisted continuous-flow Suzuki-Miyaura reaction catalyzed by Pd EnCat with simultaneous air cooling. ...
Microwave‐assisted continuous‐flow reactions have attracted significant interest from synthetic organic chemists, especially process chemists from practical points of view, due to a less complicated shift to large‐scale synthesis based on simple and continuous access to products with low energy requirements. In this personal account, we focused on the Suzuki‐Miyaura and Mizoroki‐Heck reactions, both of which are significantly important cross‐coupling reactions for the synthesis of various functional materials. Microwave power is effective for heating. Typical homogeneous palladium catalysts, such as PdCl2(PPh3)2, Pd(PPh3)4, and Pd(OAc)2, as well as heterogeneous palladium catalysts, such as Pd‐film, Pd/Al2O3, Pd/SiO2, and Pd supported on polymers, can be used for these reactions. Recent progress on the microwave‐assisted continuous‐flow Suzuki‐Miyaura and Mizoroki‐Heck reactions is demonstrated based on the classification of homogeneous and heterogeneous palladium catalysts.
... Some representative examples including the modification of NHC carbene ligands [8] , dimetallic bis -carbene-based [9] , trimetallic tris -carbene-derived [10] , solid phase-supported [11] , benzimidazole-derived amide [12] , bulky arly-substitued [13] , ring-expanded [14] tetraaryl-functionalized (sterically encumbered) [15] and acenaphtyl-derived [16] species have been reported. Even microwave-assisted flow processes were published using PEPPSI catalysts [17] . However, the impact of different type of carbene ligands on the catalytic activity of the PEPPSI-complexes is less investigated so far. ...
A series of bicyclic alkylamino carbenes (BICAAC) (where N-aryl = dipp, mes, 2,6-dimethyl-4-(dimethylamino)phenyl, 5a-d) and their novel air- and moisture-resistant pyridine (pyridine, 4-dimethylaminopyridine) containing palladium Pd(II) complexes (6a-e) were synthetized and characterized. As novel examples of the PEPPSI (“pyridine enhanced precatalyst preparation stabilization and initiation”)-Pd compounds, the reported complexes have shown high activity in Mizoroki–Heck coupling reaction even at as low as 100 ppm loading (TON up to 10000). Kinetic studies revealed that reactions carried out in the presence of elemental mercury resulted decrease in activity. It indicates that the coupling reaction may have both molecular and Pd(0)-mediated catalytic paths.
... Shore et al. [61] have devised a method for the preparation of indole alkaloids by a two-step aryl amination/cross-coupling sequence of bromoalkenes and 2-bromoanilines by microwave-assistance. This process requires both the presence of a metal-lined flow tube and the Pd PEPPSI-IPr (PEPPSI: pyridine, enhanced, precatalyst, preparation, stabilization, and initiation) catalyst. ...
Usually, in organic and organometallic synthesis an external conventional heat source is applied to carry out a chemical reaction at high temperature. Nonetheless, these conventional heating systems have some disadvantages as the heterogeneous heating causing a low reproducibility of the results and extended reaction times. A promising alternative is the use of microwave (MW) and ultrasound (US) energy. The use of these techniques has led to considerable advantages as better homogeneity in temperature and very short reaction time. By virtue of the effects mentioned above, the MW and US irradiation constitutes a convenient way to accelerate and improve a great number of organic and organometallic reactions. In this paper, we have compiled an overview developed during the last decade in the synthesis of such catalysts and organic transformations assisted by both techniques mentioned above.
... Currently, the most popular methods employ transition-metal catalysts such as Pd, Fe, Cu, Ni and Zn, [97] with Pd being the most popular candidate9899100. The development of Pd-catalyzed carbon–carbon bond-forming reactions has improved the " state-of-the-art " of organic synthesis [101,102] with versatile applications exemplified by various cross-coupling reactions103104105106 such as Suzuki [107], Heck [108,109], Stille110111112113, Negishi114115116, Hiyama [117], Kumada [118,119] and Sonogashira [120] cross-coupling reactions. ...
... Currently, the most popular methods employ transition-metal catalysts such as Pd, Fe, Cu, Ni and Zn, [97] with Pd being the most popular candidate [98][99][100]. The development of Pd-catalyzed carbon-carbon bond-forming reactions has improved the "state-of-the-art" of organic synthesis [101,102] with versatile applications exemplified by various cross-coupling reactions [103][104][105][106] such as Suzuki [107], Heck [108,109], Stille [110][111][112][113], Negishi [114][115][116], Hiyama [117], Kumada [118,119] and Sonogashira [120] cross-coupling reactions. ...
Continuous-flow technology represents a paradigm shift in the manufacture of specialty chemicals and pharmaceuticals. In many such syntheses, catalysis by N-heterocyclic carbenes plays an important role due to the stability, activity, and broad synthetic utility of these species. This chapter explores the “sweet-spot” in the combination of catalysis by N-heterocyclic carbenes and flow-chemistry technology. The chapter opens with a description of the fundamentals of flow technology and then relates the functions of flow reactors to the specifics of N-heterocyclic carbene based catalysis. The chapter provides an overview of up-to-date literature on catalysis by carbenes in flow reactors.
Advances in Organic Synthesis is a book series devoted to the latest advances in synthetic approaches towards challenging structures. The series presents comprehensive reviews written by eminent authorities on different synthetic approaches to selected target molecules and new methods developed to achieve specific synthetic transformations or optimal product yields. Advances in Organic Synthesis is essential for all organic chemists in academia and the industry who wish to keep abreast of rapid and important developments in the field.
Contents of this volume include these 6 reviews:
- Multicomponent synthesis of heterocycles by microwave irradiation
- Stereoselective procedures for the synthesis of olefines
- Advanced microwave assisted organic synthesis method in organic chemistry
- Five and six-membered n-heterocycle rings from diaminomaleonitrile
- Peptidomimetics: current and future perspectives on hiv protease inhibitors
- A review on synthesis, chemistry, and medicinal properties of benzothiazines and their related scaffolds
A series of bicyclic alkylamino carbenes (BICAAC) (where N-aryl = dipp, mes, 2,6-dimethyl-4-(dimethylamino)phenyl, 5a-d) and their novel air- and moisture-resistant pyridine (pyridine, 4 dimethylaminopyridine) containing palladium PEPPSI-type Pd(II) complexes (6a-e) were synthetized and characterized. The new palladium complexes have shown high activity in Mizoroki–Heck coupling reaction even at as low as 100 ppm loading (TON up to 10000). Kinetic studies revealed that reactions carried out in the presence of elemental mercury resulted in decrease in activity. It indicates that the coupling reaction may have both molecular and Pd(0)-mediated catalytic paths.
We report herein the synthesis of four new Pd-PEPPSI complexes with backbone-modified N-heterocyclic carbene (NHC) ligands and their application as catalysts in the α-alkylation of ketones with primary alcohols using a borrowing hydrogen process and tandem Suzuki-Miyaura coupling/α-alkylation reactions. Among the synthesized Pd-PEPPSI complexes, complex 2c having 4-methoxyphenyl groups at the 4,5-positions and 4-methoxybenzyl substituents on the N-atoms of imidazole exhibited the highest catalytic activity in the α-alkylation of ketones with primary alcohols (18 examples) with yields reaching up to 95%. Additionally, complex 2c was demonstrated to be an effective catalyst for the tandem Suzuki-Miyaura-coupling/α-alkylation of ketones to give biaryl ketones with high yields. The heterogeneous nature of the present catalytic system was verified by mercury poisoning and hot filtration experiments. Moreover, the formation of NHC-stabilized Pd(0) nanoparticles during the α-alkylation reactions was identified by advanced analytical techniques.
Pharmaceutical and fine chemical products are typically synthesised batchwise which is an anomaly since batch processes have a series of practical and economical disadvantages. On the contrary, flow continuous processes present a series of advantages leading to new ways to synthesise chemical products. Flow processes - * enable control reaction parameters more precisely (temperature, residence time, amount of reagents and solvent etc.), leading to better reproducibility, safer and more reliable processes * can be performed more advantageously using immobilized reagents or catalysts * improve the selectivity and productivity of the process and possibly even the stability of the catalyst * offer opportunities for heat exchange and energy conservation as well as an easy separation and recycling of the reactants and products by adequate process design * achieve multistep syntheses by assembling a line of reactors with minimum or no purification in between two reaction steps * can be assured by facile automation * scale-up can be easily conducted by number-up With all the new research activity in manufacturing chemical products, this comprehensive book is very timely, as it summarises the latest trends in organic synthesis. It gives an insight into flow continuous processes, outlining the basic concepts and explaining the terminology of, and systems approach to, process design dealing with both homogeneous and heterogeneous catalysis and mini- or micro-reactors. The book contains case studies, extensive bibliographies and reference lists in each chapter to enable the reader to grasp the contents and to go on to more detailed texts on specific subjects if desired. The book is written by both organic chemists and engineers giving a multidisciplinary vision of the new tools and methodologies in this field. It is essential reading for organic chemists (in industry or academia) working alongside chemical engineers or who want to undertake chemical engineering projects. It will also be of interest for chemical engineers to see how basic engineering concepts are applied in modern organic chemistry.
With the aim of developing a facile and efficient method to access structurally intriguing and valuable functionalized (hetero)aryls, two unsymmetrical Pd-PEPPSI-type NHC complexes (PEPPSI, pyridine-enhanced precatalyst preparation, stabilization, and initiation; NHC, N-heterocyclic carbene) were designed and synthesized to catalyze the direct arylation of heteroarenes with (hetero)aryl bromides. The results demonstrated that the utilization of this "unsymmetrical"strategy led to much higher efficiency in comparison to the commonly used C2-symmetric Pd-PEPPSI-type NHC complexes. Furthermore, a broad range of heteroaromatics and (hetero)aryl bromide partners with a wide variety of functional groups were all amenable to the developed protocol even at as low as 0.05 mol % catalyst loading and under aerobic conditions. More importantly, along with our study, we also found that the present protocol could provide expedient access to the gram-scale synthesis of the muscle relaxant drug dantrolene and conjugated mesopolymers.
This chapter presents examples of and advocates for the adoption of tunable solid-state (semiconductor) oscillator single-mode microwave flow reactors toward laboratory and larger-scale synthetic chemistry applications. Tunable solid-state oscillator single-mode microwave flow reactors are more versatile heaters that impart both better process control and energy efficiency than conventional magnetron oscillator flow reactors when operated in single-mode or multimode.
To explore high efficiency of the Buchwald-Hartwig amination with wide substrates scope, a type of easily prepared and air stable palladium precatalysts bearing rigid hindered N-heterocyclic carbenes (NHCs) were synthesized and characterized. A simple and efficient protocol for amination of (hetero)aryl chlorides with amines was described, which revealed that the sterically encumbered NHCs ligands is crucial to promote the transformation. It is highlight that the most challenging reactions could be performed between less reactive five-membered heteroaryl chlorides with heteroanilines. This methodology provides a rapid and straightforward access to a wide range of arylated amines with excellent functional groups tolerance. Remarkably, the powerful synthetic utility of the palladium precatalyst was further extended to the synthesis of pharmaceuticals.
Continuous flow chemistry has improved efficiency in the Heumann indole process. 3-Substituted indoles were prepared by three flow steps performed in succession in better overall yield and shorter reaction times relative to their batch counterparts. Novel 3-alkyl and 3-methoxyindoles were synthesized from their corresponding amino ketone and ester precursors by flow sequences featuring base-free alkylation with methyl bromoacetate in DMF, saponification, and cyclization with acetic anhydride and Et3N.
Microwave heating in chemical reactions was first reported in 1986. There have since been many reports employing microwave heating in organic chemistry, where microwave heating has afforded higher yields of products in shorter time periods. However, such reactions are challenging to scale in batch due to the limited penetration depth of microwaves as well as the wave propagation dependence on cavity size. Continuous flow has addressed both these issues, enabling scalability of microwave processes. As such, a host of reports employing microwave flow chemistry have emerged, employing various microwave heating and reactor configurations in the context of either custom‐built or commercial apparatus. The focus of this review is to present the benefits of microwave heating in the context of continuous flow and to characterize the different types of microwave flow apparatus by their design (oscillator, cavity type and reactor vessel). We advocate the adoption of tunable, steady‐state oscillator single‐mode microwave flow reactors which are more versatile heaters, impart better process control and energy efficiency toward laboratory and larger‐scale synthetic chemistry applications. We present the benefits of microwave (MW) heating in the context of continuous flow and characterize different types of MW flow apparatus by their design. Various MW flow reactors and reaction examples (including our own) are presented on g/h to 100’s g/h scale. We advocate for tunable, steady‐state oscillator single‐mode MW flow reactors which are more versatile heaters, impart better process control and energy efficiency toward laboratory and larger‐scale synthetic chemistry applications.
We report herein a highly efficient Pd-catalyzed amination by “bulky-yet-flexible” Pd-PEPPSI-IPentAn complexes. The relationship between the N-heterocyclic carbenes (NHCs) structure and catalytic properties was discussed. Sterically hindered (hetero)aryl chlorides and a variety of aliphatic and aromatic amines can be applied in this cross-coupling, which smoothly proceeded to provide desired products. The operationally simple protocol highlights the rapid access to CAr-N bond formation under mild conditions without the exclusion of air and moisture.
This chapter discusses the applications of 2-(hetero) arylindoles in the treatment of infectious diseases, central nervous system complications, cardiovascular diseases, metabolic diseases, inflammatory diseases and oncology diseases. 5-HT2a Antagonists have been evaluated as potential therapy for chronic schizophrenia. A series of 2-aryl hydroxyindole carboxylic acids revealed the therapeutic potential for targeting the oncogenic Src homology 2 domain containing protein tyrosine SHP2 phosphatase. SERMs are unnatural ligands of the estrogen receptor and show tissue-selectivity in regulating the receptor activities, and thus have the potential to effectively treat estrogen-related disorders while avoiding the adverse side-effects of the natural hormones. Three main strategies exist for the C-2 arylation of indoles. All these approaches rely on the use of transition metals as catalysts, and vary depending on the level of pre-functionalization on the substrate starting materials.
Propargylamine and its derivatives are important skeletal structure for synthesis of many nitrogen containing active biological and pharmaceutical compounds. They are classically prepared from aldehyde, amine and alkyne (A3 coupling) which proved to be an exciting method since water is the only by-product with the desired compound. Three component coupling strategies are very attractive research domain in organic chemistry during the past two decades for the synthesis of highly functionalized organic molecules. Molecular diversity in three component reactions ends up with several methods for drug discovery process towards the synthesis of structurally tailored heterocyclic compounds. These one pot transformation processes do involve simultaneous addition of reactants, reagents and catalyst. The reactions are generally carried out by employing several transition metal catalysts. Nanoparticles have shown their potential as catalysts in several fields of chemical research in modern era. Now, they have taken entry in multicomponent reaction system for playing the role of a catalyst. This review highlights a library of metal nanoparticles which have been used in recent years for synthesis of propargylamine and its derivatives via A3 coupling reactions.
Heterogeneous chemical reactions that produce precipitates are generally considered to be poor choices for adaptation to a flowed format. Among various complexities associated with working with slurries, sampling from a moving slurry is perhaps the most challenging task as the flow-paths inside the sampling device quickly become clogged by the heterogeneous reaction matrices. We report here a new sampling strategy using a multi-configuration sampling valve that was found to be an effective alternative to conventional sampling methods. When a model reaction that produces crystalline solid byproducts was performed using a traditional two-configuration valve, the flow-paths inside the sampling valve quickly clogged and the process had to be shut down. Using the new multi-configuration sampling protocol, we could maintain clear flow-paths inside the valve for extended periods of operation. With this technology in hand, we could obtain reproducible data from sampling operations and build a sampling mechanism capable of monitoring flowed chemical reactions that contain particulates at the outset, or produce them over time.
Flow chemistry involves the use of channels or tubing to conduct a reaction in a continuous stream rather than in a flask. Flow equipment provides chemists with unique control over reaction parameters enhancing reactivity or in some cases enabling new reactions. This relatively young technology has received a remarkable amount of attention in the past decade with many reports on what can be done in flow. Until recently, however, the question, “Should we do this in flow?” has merely been an afterthought. This review introduces readers to the basic principles and fundamentals of flow chemistry and critically discusses recent flow chemistry accounts.
Metal complexes bearing N-heterocyclic carbene (NHC) ligands are typically considered the system of choice for homogeneous catalysis with well-defined molecular active species due to their stable metal–ligand framework. A detailed study involving 19 different Pd-NHC complexes with imidazolium, benzimidazolium, and triazolium ligands has been carried out in the present work and revealed a new mode of operation of metal-NHC systems. The catalytic activity of the studied Pd-NHC systems is predominantly determined by the cleavage of the metal–NHC bond, while the catalyst performance is strongly affected by the stabilization of in situ formed metal clusters. In the present study, the formation of Pd nanoparticles was observed from a broad range of metal complexes with NHC ligands under standard Mizoroki–Heck reaction conditions. A mechanistic analysis revealed two different pathways to connect Pd-NHC complexes to “cocktail”-type catalysis: (i) reductive elimination from a Pd(II) intermediate and the release of NHC-containing byproducts and (ii) dissociation of NHC ligands from Pd intermediates. Metal-NHC systems are ubiquitously applied in modern organic synthesis and catalysis, while the new mode of operation revealed in the present study guides catalyst design and opens a variety of novel opportunities. As shown by experimental studies and theoretical calculations, metal clusters and nanoparticles can be readily formed from M-NHC complexes after formation of new M–C or M–H bonds followed by C–NHC or H–NHC coupling. Thus, a combination of a classical molecular mode of operation and a novel cocktail-type mode of operation, described in the present study, may be anticipated as an intrinsic feature of M-NHC catalytic systems.
Five novel trinuclear N-heterocyclic carbene-palladium(ii) complexes 5a-e were conveniently synthesized through one-pot reactions of imidazolium salts, tridentate N-heterocycles {tris(4-(pyridin-4-yl)phenyl)amine or tris(4-(pyridin-3-yl)phenyl)amine} and palladium chloride in one step. All of the new complexes have been fully characterized by elemental analysis, ¹H, ¹³C NMR, and IR spectra. Among them, the molecular structures of complex 5d have been determined by X-ray single-crystal diffraction. Moreover, the obtained trinuclear palladium(ii) complexes were the effective catalyst precursors for the Suzuki-Miyaura coupling of aryl as well as benzyl chlorides with arylboronic acids. Under the optimal reaction conditions, the expected biaryl products were obtained in good to almost quantitative yields.
A variety of functionalised biaryls were synthesised on the 20–30 mmol scale by using Knochel type organozinc reagents (organozinc reagents prepared from aryl halides, Zn powder and LiCl) catalysed by PEPPSI (a pyridine enhanced palladium catalyst). The protocol enabled the Negishi reactions to proceed in a smooth, rapid and mild way to give the corresponding products in excellent yields (80 ∼ 96%). Sensitive functional groups, such as CN and COOEt groups, were tolerated in the coupling reaction.
The synthesis of a triethoxysilyl functionalised Pd-PEPPSI-IPr complex prepared via azide-alkyne cycloaddition is described. The complex was immobilised onto silica gel and applied as a heterogeneous catalyst in the Negishi reaction. The catalyst was active in both batch and continuous flow operation and was particularly effective for the coupling of heteroaryl chlorides. Long-term continuous flow experiments demonstrated good catalyst activity over fifteen hours.
A series of mono- and dendritic trimetallic PEPPSI-type (pyridine-enhanced precatalyst preparation stabilization and initiation) complexes bearing N-heterocyclic carbene (NHC) ligands containing a protected amine in the form of an ethylphthalimido group have been synthesized. These discrete prototypes of complexes covalently bound to suitable supports have been studied in the Mizoroki–Heck coupling of aryl iodides under mild conditions, including sets of experiments to assess the lifetime of the active species. The palladated dendrons are more efficient and robust catalysts than their monometallic counterparts.
Microreactor technology applied in continuous flow processing is an essential feature in making organic synthesis more economical and environmentally friendly. On the other hand, microwave-assisted chemistry is a key technique that has made a significant contribution to the thermal control of synthetic reactions in the early 90's by speeding up reaction times from days to merely minutes. The combination of both techniques into the same synthetic platform sets the stage for changing forever the way synthetic chemistry is being conducted by providing fast, reliable and labor-free means of synthesizing chemical compounds. Flow reactors and microwave irradiation theory are analyzed separately in the first part, focusing mainly on the microwave heating and special microwave effects. The second part of this review summarizes several successful applications of microwave-assisted, continuous flow microreactor technology from recent synthetic organic chemistry literature; a snapshot of the state of the art of this technique is also shown at the end.
A continuous flow system complete with inline analytics is described. Sampling from a high pressure reactor and automated delivery mechanisms are detailed. The ability of the system to maintain critical process parameters (CPP) throughout a reaction process is demonstrated. Setup performance was evaluated using the Claisen rearrangement of allyl phenyl ether (1).
A series of new structurally and electronically diversified palladium complexes derived from seven less sterically crowded 2-(4,5-dimethyl-1H-imidazol-2-yl) phenol/2-(4,5-diethyl-1H-imidazol-2-yl) phenol ligands and fourteen 2-(4,5-diphenyl-1H-imidazol-2-yl) phenols/2-(1H-phenanthro[9,10-d]imidazol-2-yl) phenols bearing varying degrees of higher steric bulk have been prepared and characterized. While single crystals grown from precipitated products of complexation reactions confirmed the bis-ligand Pd(N^O)2 coordination, few crystals obtained from reaction filtrates involving the 2-(4,5-diphenyl-1H-imidazol-2-yl) phenols provided evidence for formation of N^O^C chelation species achieved by cyclometallation. Results from structural analyses and catalytic outcomes generally indicate that desirable variables on the ligand frameworks for obtaining superior catalyst activities either provides hemilabile or sterically strained chelation characters, which would both favour generation of monodentate coordination species at the catalysis temperature. In particular, correlation was observed between tendency for cyclometallation in the palladium complexes and poor Suzuki–Miyaura catalytic prospects. Based on hopeful activity obtained for the complex bearing 4-bromo-2-(4,5-dimethyl-1H-imidazol-2-yl) phenol, it was also concluded that sterically bulky ligand is not a necessity for high coupling efficiency, while presence of potentially cyclometallating substituent moieties in the vicinity of the palladium centre may in fact destroy catalytic prospects.
The development of new strategies for synthesis of medium-sized S-heterocycles has remained a highly attractive but challenging proposition. An overview of the application of microwave irradiation in sulfur-containing seven-membered heterocyclic compounds synthesis is presented, focusing on the developments in the past 5–10 years. This contribution covers the literature concerning the total synthesis of S-heterocycles. The literature data are summarized based on the size of cycles.
Chemical intensification aims to enhance chemical processes by employing harsh reaction conditions, such as high temperatures, high pressures, solvent effects, high concentration of the reactants, handling of hazardous compounds and novel chemical transformations. The process design intensification field is directed toward the complete production design aspect of chemical manufacturing. It intends to simplify and integrate the different reaction and purification steps of a chemical reaction sequence in a single streamlined and continuous-flow process. Although the concept is relatively new, novel process windows have had already a significant impact on flow chemistry applications, as well as on the process engineering aspect. This chapter discusses each aspect of novel process windows and provides several literature examples. It concludes by providing two verified in-house laboratory experiments.
Aromatic heterocycles are ubiquitous in nature and throughout the pharmaceutical and agrochemical industries. A vast array of research has been dedicated to investigating their synthesis and to developing new and more efficient synthetic routes. This chapter discusses the synthesis of aromatic heterocycles where a key palladium- or copper-catalyzed aryl halide (or equivalent) amination, etherification or thioetherification process is employed. Annulative routes utilizing anilines and related compounds with alkynes (Larock type) are also considered. The discussion is structured predominantly around the type of bond being formed (C-N, C-O, or C-S) and is classified further by heterocycle type. Intramolecular and intermolecular C-X bond formations as well as tandem catalytic processes leading to aromatic heterocycle products are discussed.
The palladium-catalyzed assembly of the functionalized pyrrole nucleus on a benzenoid scaffold is a widley used synthetic tool for the preparation of indole derivatives. This construction can be categorized into four main types: (1) cyclization of alkynes; (2) cyclization of alkenes; (3) cyclization via C-vinyl reactions; and (4) cyclization via N − arylation or N − vinylation reactions. The first approach is the most versatile in terms of range of the added functional groups and of the bonds that can be created in the construction of the pyrrole ring. This method is based on the utilization of precursors containing nitrogen nucleophiles and carbon-carbon triple bonds. The nitrogen nucleophile and alkyne moiety may be part of the same molecule or belong to two different molecules. Some of the most general cyclizations of indoles are summarized. Alkene-based cyclizations to give indoles are also summarized. Cyclization to indoles via arene vinylation has limited synthetic scope. Indoles can be prepared via cyclizations proceeding through N-arylation and N-vinylation reactions based on pioneering work. In general, only synthetic procedures where palladium catalysis is involved in the pryrrole ring construction event are discussed in this chapter.Keywords:Indoles;Palladium catalysts;Pyrroles;Cyclization;Vinylation;Alkenes;Alkynes;Copper;Catalysts;Substituted indoles;Mechanisms;Method comparisons;Experimental procedures
A new reaction setup using a gold-based catalytic microcapillary reactor was developed. In order to immobilize the gold nanoparticles onto the fused silica inner wall, two different linkers were used: (3-aminopropyl)triethoxysilane (APTES) and (3-mercaptopropyl)triethoxysilane (MPTES). Three different types of gold nanoparticles: (i) Turkevich gold nanoparticles (Citrate-Au), (ii) polyvinylpyrrolidone stabilized gold nanoparticles (PVP-Au) and (iii) polyvinylalcohol stabilized gold nanoparticles (PVA-Au) were synthesized to be anchored on the microcapillary internal surface. The catalytic efficiency of these new microsystems has been investigated for oxidation as a function of the nature of the linkers and/or the type of gold nanoparticles. The oxidation of benzyl alcohol in the presence of H2O2 was used to evaluate the catalytic performance of these microreactors. Under the reaction conditions (80 degrees C, resident time = 639 s), the Citrate-Au nanoparticles leaked out slightly from the capillary reactor, whereas high conversions (>90%) and high selectivity to benzoic acid were achieved with PVP-Au and PVA-Au nanoparticles. A catalytic microreactor based on MPTES/PVP-Au functionalization proved to be the most effective for this reaction.
A continuous-flow microwave reactor with a unique pressure control device is described. The reactor has been designed to withstand extremely high pressure without the involvement of a conventional backpressure-creating device that commonly results in carryover and cross-contamination problems. The reactor efficiency has been evaluated by product conversions using two model reactions, namely, the Claisen rearrangement and the synthesis of benzimidazole.
In the not too distant future many industrially important chemicals (including pharmaceuticals) will probably be manufactured using continuous flow technology. For a significant number of synthetic steps involved in these protocols transition metal (mostly palladium)-catalyzed carbon–carbon or carbon–heteroatom bond forming reactions (“cross-coupling chemistry”) will play an important role. Designing a process for continuous cross-coupling chemistry involves either the use of a homogeneous or of a heterogeneous (immobilized) catalyst/ligand system. In the latter case, the catalyst/ligand system is typically in the form of a packed-bed reactor, through which the reaction mixture is pumped, employing an appropriate temperature regime and residence time. Although this approach has been widely popular during the past 15 years, there is growing evidence that suggests that the use of immobilized transition metal catalysts for performing cross-coupling chemistry in continuous flow is, in fact, not very practical. As demonstrated in this review, significant leaching of the transition metal out of the packed-bed catalyst will almost inevitably occur, leading to decreased catalyst activity and contamination of the product with transition metal. This is a consequence of the well-known fact that the reaction mechanism for these kinds of transformations is (quasi)homogeneous and involves the transformation of a Pd0 species into a (soluble) PdII species. Using an immobilized catalyst in a batch protocol the transient leaching of palladium will not be immediately obvious, as, after completion of the catalytic cycle, Pd0 will typically redeposit onto the support. In contrast, in continuous flow mode, the palladium metal will progressively be “chromatographed” through the packed-bed catalyst until, ultimately, all palladium will be removed from the support. This effect typically will become only evident when long run experiments are performed. The preferred alternative, in particular for larger scale experiments, is to use a homogeneous (pre)catalyst in combination with an appropriate catalyst recycling technology.
The development of new strategies for synthesis of medium-sized heterocycles has remained a highly attractive but challenging proposition. An overview of the application of microwave irradiation in the synthesis of nitrogen-containing seven- and higher membered heterocyclic compounds is presented, focusing on the developments in the past 5–10 years. This contribution covers the literature concerning the total synthesis of N-heterocycles. The literature data are summarized based on the size of cycles.
A flow procedure for the metalation of functionalized heterocycles (pyridines, pyrimidines, thiophenes, and thiazoles) and various acrylates using the strong, non-nucleophilic base TMPMgCl⋅LiCl is reported. The flow conditions allow the magnesiations to be performed under more convenient conditions than the comparable batch reactions, which often require cryogenic temperatures and long reaction times. Moreover, the flow reactions are directly scalable without further optimization. Metalation under flow conditions also allows magnesiations that did not produce the desired products under batch conditions, such as the magnesiation of sensitive acrylic derivatives. The magnesiated species are subsequently quenched with various electrophiles, thereby introducing a broad range of functionalities.
Es wird eine Durchflussmethode für die Metallierung funktionalisierter Heterocyclen (Pyridine, Pyrimidine, Thiophene und Thiazole) und verschiedener Acrylate unter Verwendung der starken, nichtnukleophilen Base TMPMgCl⋅LiCl beschrieben. Die Flussbedingungen ermöglichen Magnesierungen unter zweckmäßigeren Bedingungen als die entsprechenden Kolbenreaktionen, die oft tiefe Temperaturen und lange Reaktionszeiten benötigen. Ferner sind die Durchflussreaktionen ohne weitere Optimierung skalierbar und erlauben Metallierungen, die nicht das gewünschte Produkt im Reaktionskolben ergeben, wie die Magnesierung empfindlicher Acrylderivate. Die Magnesiumspezies reagieren im Anschluss mit verschiedenen Elektrophilen, wodurch vielfältige Funktionalitäten eingeführt werden.
Laboratory scaled flow‐through processes have seen an explosive development over the past decade and have become an enabling technology for improving synthetic efficiency through automation and process optimization. Practically, flow devices are a crucial link between bench chemists and process engineers. The present review focuses on two unique aspects of modern flow chemistry where substantial advantages over the corresponding batch processes have become evident. Flow chemistry being one out of several enabling technologies can ideally be combined with other enabling technologies such as energy input. This may be achieved in form of heat to create supercritical conditions. Here, indirect methods such as microwave irradiation and inductive heating have seen widespread applications. Also radiation can efficiently be used to carry out photochemical reactions in a highly practical and scalable manner. A second unique aspect of flow chemistry compared to batch chemistry is associated with the option to carry out multistep synthesis by designing a flow set‐up composed of several flow reactors. Besides their role as chemical reactors these can act as elements for purification or solvent switch.
A series of mononuclear N,N-heterocyclic carbene (NNHC) complexes of PdII with mixed ligands of 1,3-dibenzylbenzimidazoly-2-ylidene and solvate (dimethyl sulfoxide, CH3CN, N,N-dimethylformamide, and pyridine) or PPh3 were prepared and characterized by X-ray single-crystal diffraction analysis. They are more active in the Suzuki–Miyaura coupling of selected aryl bromides than their N,S-heterocyclic carbene (NSHC) analogues.
A new metal-free method for the rapid and productive preparation of indoles has been developed. This process is based on sterically congested hypervalent iodine compounds of the family of Koser reagents, and iodosobenzene in combination with 2,4,5-tris-isopropylbenzene sulfonic acid provides the highest yields and fastest reaction times. This reagent alone promotes the chemoselective oxidative cyclization of 2-amino styrenes to indoles in high yields under mild conditions. Convenient route to indole: A fast, productive, and operationally simple indole synthesis was developed.
Eine neue Methode unter metallfreien Bedingungen zur schnellen und produktiven Synthese von Indolen wurde entwickelt. Dieser Prozess beruht auf einer voluminösen Iodverbindung der Familie der Koser-Reagentien, wobei die Kombination aus Iodosobenzol und 2,4,5-Tris(isopropyl)benzolsulfonsäure die höchsten Ausbeuten und kürzesten Reaktionszeiten gewährleistet. Dieses Reagens vermittelt die chemoselektive oxidative Cyclisierung von 2-Vinylanilinen zu Indolen in hohen Ausbeuten und unter milden Reaktionsbedingungen.
Six dinuclear N-heterocyclic carbene (NHC) palladium complexes, [PdCl2(IMes)]2(μ-dppe) (), [PdCl2(IPr)]2(μ-dppe) (), [PdCl2(IMes)]2(μ-dppb) (), [PdCl2(IPr)]2(μ-dppb) (), [PdCl2(IMes)]2(μ-dpph) (), and [PdCl2(IPr)]2(μ-dpph) () [IMes = N,N'-bis-(2,4,6-trimethylphenyl)imidazol-2-ylidene; IPr = N,N'-bis-(2,6-di(iso-propyl)phenyl)imidazol-2-ylidene; dppe = 1,2-bis(diphenylphosphino)ethane, dppb = 1,4-bis(diphenylphosphino)butane; and dpph = 1,6-bis(diphenylphosphino)hexane], have been synthesized through bridge-cleavage reactions of chloro-bridged dimeric compounds, [Pd(μ-Cl)(Cl)(NHC)]2, with the corresponding diphosphine ligands. The obtained compounds were fully characterized by (1)H NMR, (13)C NMR and (31)P NMR spectroscopy, FT-IR, elemental analysis and single-crystal X-ray crystallography. Moreover, further explorations of the catalytic potential of the dinuclear carbene palladium complexes as catalysts for the Pd-catalyzed transformations have been performed under microwave irradiation conditions, and the complexes exhibited moderate to good catalytic activity in the Hiyama coupling reaction of trimethoxyphenylsilane with aryl chlorides.
A new approach was described for the synthesis of substituted 2-carboxyindole using 3-(2-aminophenyl)-2-bromo-acrylates through a CuI-catalyzed intramolecular coupling. The reactions were mild, rapid and with good to excellent yields. Crown Copyright
Imines have been reduced to amines in high yield, and with excellent chemoselectivity, by catalytic hydrogenation in a continuous flow-reactor, utilising an electrochemically-generated hydrogen source to produce a mixed hydrogen-liquid flow stream.
The ability of metal powders to couple to microwave radiation at 2450 MHz has been used to accelerated a range of solid-state reactions. Although metal objects cause extensive arcing within a microwave cavity, metal powders couple in a more conventional manner with the microwave radiation and experience high heating rates. This property has been utilised for the synthesis of metal chalcogenides and metal cluster compounds of the Group 5 and 6 elements.
Palladium on porous glass is a useful heterogeneous catalyst for liquid
phase organic coupling reactions which can be carried out in the presence
of air, without the need for solubilizing and activating ligands.
A series of synthetic transformations were successfully and safely scaled up to multigram quantities using focused microwave irradiation with a continuous flow reaction cell that was developed in-house and which can be easily adapted to commercially available instrumentation. The representative reactions that were investigated included aromatic nucleophilic substitution (SNAr), esterification, and the Suzuki cross-coupling reaction. In general, the product yields were equivalent to or greater than those run under conventional thermal heating conditions.
A laboratory-scale continuous microwave reactor (CMR) has been developed and used to conduct organic syntheses routinely, rapidly, and safely in a range of solvents, under pressures up to 1400 kPa and at temperatures up to 200 degrees C. Advantages and applications of the CMR are discussed, along with the rationale for the design. Reactions carried out with the CMR included nucleophilic substitution, addition, esterification, transesterification, acetalization, amidation, base- and acid-catalyzed hydrolysis, isomerization, decarboxylation, and elimination. Name reactions included the Michael addition, Hofmann degradation, Williamson ether synthesis, and the Mannich, Finkelstein, Baylis-Hillman, and Knoevenagel reactions.
Die offene Flamme konnte erst gezielt als Heizquelle für Reaktionsgefäße in der Synthesechemie verwendet werden, nachdem Robert Bunsen 1855 den nach ihm benannten Brenner erfunden hatte. Der Bunsen-Brenner wurde später durch den Heizpilz, das Ölbad und die Heizplatte als Wärmequellen für chemische Reaktionen abgelöst. In den vergangenen Jahren ist das Erhitzen und Beschleunigen chemischer Reaktionen durch Mikrowellenenergie populär geworden. Diese Heiztechnik hat sich von einer Laborkuriosität zu einer etablierten Methode entwickelt, die an Universitäten und in der Industrie stark genutzt wird. Die effiziente Verringerung der Reaktionszeiten (von Tagen und Stunden auf Minuten und Sekunden) ist nur einer der vielen Vorteile des schnellen Erhitzens mit Mikrowellen (“microwave flash heating”). Dieser Aufsatz gibt einen Überblick über neuere Anwendungen des kontrollierten Mikrowellenerhitzens in der modernen organischen Synthese und diskutiert einige grundlegende Vorgänge.
This review article describes how microreactors are being applied to synthetic organic chemistry within the pharmaceutical industry and how microreactors may improve the efficiency of the drug discovery process. This article explores how miniaturization may revolutionize chemical synthesis and demonstrates that products are generated in higher yield and purity compared to the equivalent bulk reactions, in much shorter periods of time.
Palladium-catalyzed allylic substitution and cross-coupling reactions have been combined into a sequential procedure to provide a range of disubstituted olefin products starting from two-, three-, and four-carbon common olefin templates. Diverse application of this template strategy is demonstrated in a variety of model studies and in a parallel synthesis (combinatorial) approach to prepare an allylic amine molecular library. An approach toward the preparation of astaxanthin beta-D-diglucoside, an interesting antioxidant whose total synthesis has yet to be reported, using the olefin-template approach is also discussed.
Rapid, direct transition metal-catalyzed C-P(III) cross-coupling reactions were performed by microwave dielectric heating, employing diphenylphosphine and aryl halides/triflates as substrates. Depending on the specific aryl halide/triflate precursor, the highest yields were obtained utilizing heterogeneous or homogeneous Pd or Ni catalysts in DMF or NMP in the presence of KOAc or DABCO as a base. [reaction: see text]
Although fire is now rarely used in synthetic chemistry, it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied to a reaction vessel in a focused manner. The Bunsen burner was later superseded by the isomantle, oil bath, or hot plate as a source for applying heat to a chemical reaction. In the past few years, heating and driving chemical reactions by microwave energy has been an increasingly popular theme in the scientific community. This nonclassical heating technique is slowly moving from a laboratory curiosity to an established technique that is heavily used in both academia and industry. The efficiency of "microwave flash heating" in dramatically reducing reaction times (from days and hours to minutes and seconds) is just one of the many advantages. This Review highlights recent applications of controlled microwave heating in modern organic synthesis, and discusses some of the underlying phenomena and issues involved.
An automated system for loading samples into a microcoil NMR probe has been developed using segmented flow analysis. This approach enhanced 2-fold the throughput of the published direct injection and flow injection methods, improved sample utilization 3-fold, and was applicable to high-field NMR facilities with long transfer lines between the sample handler and NMR magnet. Sample volumes of 2 microL (10-30 mM, approximately 10 microg) were drawn from a 96-well microtiter plate by a sample handler, then pumped to a 0.5-microL microcoil NMR probe as a queue of closely spaced "plugs" separated by an immiscible fluorocarbon fluid. Individual sample plugs were detected by their NMR signal and automatically positioned for stopped-flow data acquisition. The sample in the NMR coil could be changed within 35 s by advancing the queue. The fluorocarbon liquid wetted the wall of the Teflon transfer line, preventing the DMSO samples from contacting the capillary wall and thus reducing sample losses to below 5% after passage through the 3-m transfer line. With a wash plug of solvent between samples, sample-to-sample carryover was <1%. Significantly, the samples did not disperse into the carrier liquid during loading or during acquisitions of several days for trace analysis. For automated high-throughput analysis using a 16-second acquisition time, spectra were recorded at a rate of 1.5 min/sample and total deuterated solvent consumption was <0.5 mL (1 US dollar) per 96-well plate.
Glycosylation reactions are performed rapidly over a wide range of conditions as an example of microreactor-based method optimization and process development in organic chemistry.
A novel approach for the synthesis of the important indole ring is described. Indoles are obtained from o-bromoanilines and alkenyl halides in a Pd-catalyzed cascade process that involves an alkenyl amination followed by an intramolecular Heck reaction. The overall process represents the first example of the participation of alkenyl amination reactions in Pd-catalyzed cascade reactions. Initially, the relative reactivity of aryl and alkenyl bromides and chlorides towards Pd-catalyzed amination was investigated. Competition experiments were carried out in the presence of primary and secondary amines, and these revealed the reactivity order alkenyl bromides > aryl bromides > alkenyl chlorides > aryl chlorides, as well as very high chemoselectivity; the more reactive halide was always favored. Thereafter, optimized reaction conditions for the sequential alkenyl amination/Heck cyclization to give indoles were investigated with the model reaction of o-bromoaniline with alpha-bromostyrene. An extensive screening of ligands, bases, and reaction conditions revealed that the [Pd2(dba)3]/DavePhos, NaOtBu, toluene combination at 100 degrees C were the optimized reaction conditions to carry out the cascade process (dba=dibenzylideneacetone, DavePhos=2-dicyclohexylphosphino-2'-N,N-dimethylaminobiphenyl). The reaction proceeds with aryl, alkyl, and functionalized substitutents in both starting reactants. The cyclization was also studied with N-substituted o-bromoanilines (which would give rise to N-substituted indoles); however, in this case, indole formation occurred only with 1-substituted-2-bromoalkenes. Finally, the application of this methodology to o-chloroanilines required further optimization. Although the catalyst based on DavePhos failed to promote the cascade process, a catalytic combination based on [Pd2(dba)3]/X-Phos promoted the formation of the indole ring also from the less reactive chloroanilines.
A capillary-based flow system has been developed for conducting microscale organic synthesis with the aid of microwave irradiation. The capillary internal diameter investigated ranged from 200 to 1200 mum, while the flow rate was varied between 2 and 40 muL/min, which corresponds to the sample being irradiated approximately 4 min. Other parameters investigated include reaction concentration and power setting of the microwave. Excellent conversion was observed in a variety of cross coupling and ring-closing metathesis (RCM) reactions employing metal catalysts and in nucleophilic aromatic substitution and Wittig reactions that do not employ metals. Reactions that have solids in them do not seem to pose a significant concern for the method, such as blocked channels. It was shown that capillaries coated internally with thin films of Pd metal show tremendous rate accelerations and that the thin films themselves are capable of catalyzing Suzuki-Miyaura reactions with no exogenous catalyst added. Importantly, it has been demonstrated that reagents in separate syringes can be coinjected into the capillary, mix, and react with none of the laminar flow problems that plague microreactor (lab on a chip) technology. This paves the way to use microwave-assisted, flow capillary synthesis as a powerful and efficient means to replace "one-at-a-time" microwave synthesis to provide libraries of compounds in a scale suitable for biological screening purposes.
A new simple procedure for microwave-assisted organic synthesis under continuous flow processing has been developed for use in a monomodal microwave synthesizer with direct temperature control using the instrument's in-built IR sensor. This design makes optimum use of the standing wave cavity to improve the energy efficiency of microwave-assisted flow reactions.
A number of oligomeric alkynes underwent [2 + 2 + 2] intramolecular trimerization to afford arenes under metal-free conditions using focussed microwave heating.
A continuous flow, microwave-assisted, parallel-capillary microreactor has been developed. Libraries of drug candidates were prepared on the milligram scale with this reactor by injecting plugs of reagents from separate syringes into common reaction capillaries, thereby producing discrete compounds in excellent yield and purity. Microwave irradiation provides the necessary energy that existing room-temperature microreactor technology lacks for higher activation barrier transformations, producing the required amounts of desired compounds in minutes or less.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
The synthesis of NHC-PdCl(2)-3-chloropyridine (NHC=N-heterocyclic carbene) complexes from readily available starting materials in air is described. The 2,6-diisopropylphenyl derivative was found to be highly catalytically active in alkyl-alkyl Suzuki and Negishi cross-coupling reactions. The synthesis, ease-of-use, and activity of this complex are substantial improvements over in situ catalyst generation and all current Pd-NHC complexes. The utilization of complex 4 led to the development of a reliable, easily employed Suzuki-Miyama protocol. Employing various reaction conditions allowed a large array of hindered biaryl and drug-like heteroaromatic compounds to be synthesized without difficulty.
We have developed the first user-friendly Negishi protocol capable of routinely cross-coupling all combinations of alkyl and aryl centers. The use of an easily synthesized, air stable, highly active, well-defined precatalyst PEPPSI-IPr (1; PEPPSI=pyridine-enhanced precatalyst preparation, stabilization and initiation; IPr=diisopropylphenylimidazolium derivative) substantially increases the scope, reliability, and ease-of-use of the Negishi reaction. All organohalides and routinely used pseudohalides were excellent coupling partners, with the use of chlorides, bromides, iodides, triflates, tosylates, and mesylates resulting in high yield of the coupled product. Furthermore, all reactions were performed by using general laboratory techniques, with no glove-box necessary as the precatalyst was weighed and stored in air. Utilization of this methodology allowed for the easy synthesis of an assortment of sterically encumbered biaryls and druglike heteroaromatics, demonstrating the value of the PEPPSI-IPr system. Furthermore, this is also the first time Pd-NHC (NHC=N-heterocyclic carbene) methodology has surpassed the related phosphine-ligated Negishi processes both in activity and use.
An easily employed, highly versatile Kumada-Tamao-Corriu (KTC) protocol utilizing the PEPPSI (Pyridine, Enhanced, Precatalyst, Preparation, Stabilization and Initiation) precatalysts 1 and 2 is detailed. The ease-of-use of these catalysts and the synthesis of a wide range of hindered biaryls, large coupling partners and drug-like heterocycles, in high yield, makes the PEPPSI-KTC protocol very attractive. The high reactivity of the PEPPSI system allowed a tetra-ortho-substituted heterocycle, 11 to be synthesized at room temperature for the first time using any protocol. The PEPPSI protocols also tolerated the Boc protecting group and phenols required no protection in modified conditions. A relatively large scale (10 g) reaction was also performed with no loss in performance. Furthermore, PEPPSI-IPr, 1, was compared to previously reported highly active phosphine ligands 42, 43, and 44 and was shown to result in significantly better yields under identical conditions. Finally, we demonstrated that the PEPPSI catalyst system is very adept at performing sequential KTC coupling reactions, analogous to multicomponent reactions, which allow complex polyaryl and polyheteroaryl architectures to be produced in one single operation.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
- Stadler
Indole and its derivatives
- Joule
- Shore