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Flow processing offers many opportunities to optimize reactions in a rapid and automated manner, yet often requires relatively large quantities of input materials. To combat this, the use of a flexible slug flow reactor, equipped with two analytical instruments, for low‐volume optimization experiments are reported. A Buchwald–Hartwig amination toward the drug olanzapine, with 6 independent optimizable variables, is optimized using three different automated approaches: self‐optimization, design of experiments, and kinetic modeling. These approaches are complementary and provide differing information on the reaction: pareto optimal operating points, response surface models, and mechanistic models, respectively. The results are achieved using <10% of the material that would be required for standard flow operation. Finally, a chemometric model is built utilizing automated data handling and three subsequent validation experiments demonstrate good agreement between the slug flow reactor and a standard (larger scale) flow reactor. [ABSTRACT FROM AUTHOR]

A continuous flow microwave system based on a transmission line short-circuited waveguide reactor concept is described. The continuous flow reactor is capable of operating in a genuine high-temperature/high-pressure process window (310°C/60 bar), applying a microwave transparent and chemical resistant cylindrical γ-Al2O3 tube as reaction zone. The system can be operated in an extremely energy efficient manner, utilizing 0.6–6 kW microwave power (2.45 GHz). The application of the reactor for processing four chemical transformations in a high-temperature/high-pressure regime with a throughout of 3.5–6.0 l/h is demonstrated.

A series of five known symmetric organocatalytic reactions at elevated temperatures are re-evaluated to detect the existence of specific or nonthermal microwave effects. The results obtained either with microwave irradiation or with microwave irradiation with simultaneous cooling might be reproduced by conventional heating at the same reaction temperature and time in an oil bath, though no evidence was found for specific or nonthermal effects.

Microwave-assisted organic synthesis in nonpolar solvents is investigated utilizing cylinders of sintered silicon carbide SiC, a chemically inert and strongly microwave absorbing material, as passive heating elements PHEs. Microwave energy is absorbed due to this heating, which subsequently transfer the generated thermal energy through conduction phenomena to the reaction mixture.

Research has been conducted on 2(1H)-pyrazinones. The study of the inter- and intramolecular hetero-Diels-Alder reactions carried out under controlled microwave irradiation in a series of functionalized 2(1H)-pyrazinones is presented.

Research has been conducted on the 4-alkyl- and 4-aryl-dihydropyrimidones. The structural features, electronic absorption and circular dichroism spectra of these dihydropyrimidones have been investigated and the use of the semispherical, ab initio and density functional theory methods is described.

Research has been conducted on the aryliminopropadienethiones. The generation of these compounds via the flash vacuum thermolysis of isoxazolones and their characterization via mass spectrometry and matrix isolation IR spectroscopy, chemical trapping and DFT calculations is described.

Research has been conducted on the nitrile ylides and their 1,5-electrocyclizations. The results of ab initio and density function calculations are presented.

Research was conducted to examine the pericyclic versus pseudopericyclic 1,5-electrocyclization of iminodiazomethanes using ab initio calculations and the density functional theory method. The ring closure reactions of (e)- and Z-iminodiazomethane (E)-, (Z), vinyldiazomethane and formyldiazomethane to 1H-1,2,3-triazole, 3H-pyrazole and 1,2,3-oxadiazole, respectively, were analyzed. Results provide evidence for a pseudopericyclic molecular orbital topology involving an in-plane attack of the imine lone pair on the terminal nitrogen of the diazo functionality.

Research was conducted to study the construction of the erythrinane skeleton using a triple cascade sequence approach. Mass spectra were determined at an ionizing voltage of 70 eV while the starting sulfoxide was consumed immediately upon the addition of the Pummerer promoter. Results indicated the inherent instability of the 2-aminofuran ring system. They also showed that the resulting cycloadduct was transformed to several types of arylnaphthalene lignans.

Studies made by Biginelli in 1893 showed how dihydropyrimidines of type 4 were synthesized through a simple one-pot condensation reaction of ethyl acetoacetate, benzaldehyde and urea. In this study, the mechanism of the three-component Biginelli dihydropyrimidine synthesis was reinvestigated using H and C nuclear magnetic resonance spectroscopy. NMR spectroscopy results show that there is no evidence that the first step in the Biginelli reaction is an acid-catalyzed aldol reaction of ethyl acetoacetate and benzaldehyde which leads to a carbenium ion intermediate.

A novel method for the synthesis of conformationally restricted polycyclic dihydropyrimidines (DHPs) was developed based on the utilization of omicron-alkenylaryl-tethered DHP-fused mesomeric betaines. The synthetic process was characterized by the intramolecular 1,3-dipolar cycloaddition reaction of the mesomeric betaine which led to the formation of the target compounds. The cycloaddition reaction was characterized by a reqioselective two-step annulation sequence which induced the formation of a rigid, polycyclic DHPs.

The Diels-Alder reaction of 2-amino-5(alkylthio)-substituted isobenzofurans was analyzed to characterize the influence of the amine on intramolecular cycloaddition. Analysis of the Pummerer-induced cyclization-cycloaddition reaction sequence involving 2-amino-substituted isobenzofurans indicated the efficiency of the tandem-amido-Pummerer-Diels-Alder reaction sequence in the generating vinylogous C-acyliminium ions. Furthermore, the activation barrier of the reaction sequence was reduced by amide incorporation which lowered the transition state energies.

Several thieno[2,3-c]furans and furo[3,4-b]indoles with polyheterocyclic ring systems were synthesized by utilizing tandem Pummerer-Diels-Alder reaction sequence. The sequence utilizes alpha-thioisobenzofurans as key intermediates in the cascade process which forms 4+2-cycloadducts when combined with a specific dienophile. The tandem-cascade process exhibited intramolecular variation on the thiophene series during the subsequent reactions.

A new synthetic route to the phenylnaphthyl skeleton of 1-arylnaphthalene lignans is introduced. The procedure involves the Pummerer cyclization of o-benzoyl-substituted sulfoxide precursors followed by the Diels-Alder cycloaddition of the alpha-thio isobenzofuran intermediate with added dienophiles. It has been applied to the preparation of taiwanin C and E as well as justicidin E.

Matrix photolysis and flash vacuum pyrolysis (FVP) from four different precursors yields acetylketene. The infrared spectra of the conformers produced are identified by matrix isolation of the infrared spectroscopy. The acetylketene conformers are found to have equal energy and a rotational barrier of ca. 39 kilojoules per mole.

A study was made on the preparative and mechanistic aspects of the formation of simple mono- and bifunctionalized trioxabicyclononadienes. The methods entailed the addition of nucleophiles to alpha-oxoketene 5 following a multistep reaction sequence. The results indicated the viability of the methods which permit the synthesis of several varieties of mono- and bifunctionalized derivatives as opposed to previous approaches which showed limited synthetic value.

Dipivaloylketene dimerization in several polar and nonpolar media leads to the formation of the (2 + 4) dimer while in dimethyl sulfoxide pyridine or tributylphosphine, dimerization takes place at the C=O bond leading to the formation of a dioxinone. The latter dimerization reaction is a new type of alpha-oxo ketene dimerization. Cycloaddition reactions of dipivaloylketene with a number of compounds reveal that dipivaloylketene undergoes both (2 + 4) and (2 + 2) addition the general aspects of which are discussed.

Oxidative functionalization of alkenes is a versatile strategy for the preparation of many oxygen-containing scaffolds, such as epoxides, diols, or carbonylcontaining compounds. In addition to conventional chemical methods, which rely on the utilization of stoichiometric amounts of oxidizing reagents, some electrochemical procedures have been developed to achieve these transformations. Typical electrochemical procedures employ tailored and often complex redox mediators to achieve the target transformation. Herein we present a modular approach for the synthesis of epoxides, diols, and aldehydes from a single set of reaction components. With sodium bromide as an inexpensive electrocatalyst and water as the oxygen donor, the outcome of the reaction (epoxide, 1,2-diol, or aldehyde) can be selected by simply tuning the electrolysis conditions. This convenient platform has been accomplished by developing a selective one-pot three-step bromide-electrocatalyzed epoxidation/ring opening/carboncarbon cleavage sequence. Its modularity permits the selection of the desired product, as the sequential reaction can be ended when the target compound has been formed. Themethod has been applied to a diversely functionalized terminal and non-terminal olefins. [ABSTRACT FROM AUTHOR]