C. Oliver Kappe

Biologically active dihydropyrimidones of the Biginelli-type : a literature survey

In 1893, the synthesis of functionalized 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) via three-component condensation reaction of an aromatic aldehyde, urea and ethyl acetoacetate was reported for the first time by P. Biginelli. In the past decades, such Biginelli-type dihydropyrimidones have received a considerable amount of attention due to the interesting pharmacological properties associated with this heterocyclic scaffold. In this review, we highlight recent developments in this area, with a focus on the DHPMs recently developed as calcium channel modulators, alpha(1a) adrenoceptor-selective antagonists and compounds that target the mitotic machinery.

Microwave dielectric heating in synthetic organic chemistry

First described more than two decades ago, microwave-assisted organic synthesis has matured from a laboratory curiosity to an established technique that today is heavily used in both academia and industry. One of the most valuable advantages of using controlled microwave dielectric heating for chemical synthesis is the dramatic reduction in reaction times: from days and hours to minutes and seconds. As will be explained in this tutorial review, there are many more good reasons why organic chemists are nowadays incorporating dedicated microwave reactors into their daily work routine.

Continuous‐Flow Technology—A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients

In the past few years, continuous-flow reactors with channel dimensions in the micro- or millimeter region have found widespread application in organic synthesis. The characteristic properties of these reactors are their exceptionally fast heat and mass transfer. In microstructured devices of this type, virtually instantaneous mixing can be achieved for all but the fastest reactions. Similarly, the accumulation of heat, formation of hot spots, and dangers of thermal runaways can be prevented. As a result of the small reactor volumes, the overall safety of the process is significantly improved, even when harsh reaction conditions are used. Thus, microreactor technology offers a unique way to perform ultrafast, exothermic reactions, and allows the execution of reactions which proceed via highly unstable or even explosive intermediates. This Review discusses recent literature examples of continuous-flow organic synthesis where hazardous reactions or extreme process windows have been employed, with a focus on applications of relevance to the preparation of pharmaceuticals.

Conformational analysis of 4-aryl-dihydropyrimidine calcium channel modulators. A comparison of ab initio, semiempirical and X-ray crystallographic studies

Abstract The conformational features of 4-aryl-dihydropyrimidine calcium channel modulators were investigated by computational and X-ray crystallographic studies. The geometries of dihydropyrimidines 8–11 were fully optimized using ab initio (HF/3-21G) and semiempirical (AM1, AM1/MM, PM3, PM3/MM) methods, and rotational barriers for important functional groups determined. All computational treatments predict the lowest energy conformation to be identical with the recently proposed receptor-bound geometry.

Controlled microwave heating in modern organic synthesis: highlights from the 2004-2008 literature.

Direct and rapid heating by microwave irradiation in combination with sealed vessel processing in many cases enables reactions to be carried out in a fraction of the time generally required using conventional conditions. This makes microwave chemistry an ideal tool for rapid reaction scouting and optimization of conditions, allowing very rapid progress through hypotheses–experiment–results iterations. The speed at which multiple variations of reaction conditions can be performed allows a morning discussion of “What should we try?” to become an after-lunch discussion of “What were the results” Not surprisingly, therefore, many scientists both in academia and industry have turned to microwave synthesis as a front-line methodology for their projects. In this review, more than 220 published examples of microwave-assisted synthetic organic transformations from the 2004 to 2008 literature are discussed. An additional ca. 500 reaction schemes are presented in the Electronic Supplementary Material, providing the reader with an overall number of ca. 930 references in this fast-moving and exciting field.

Synthetic applications of furan Diels-Alder chemistry

3. Introduction Bimolecular Diels-Alder Reactions of Furans 2.1. Scope and limitations 2.1.1. Alkenes 2.1.2. Alkynes 2.1.3. Allenes 2.2. Reactive g-bonds 2.3. Catalysts and high pressure 2.4. Asymmetric Diels-Alder reactions 2.5. Total synthesis Intramolecular Diels-Alder Reactions of Furans 3.1. Scope and limitations 3.1.1. Nature of the diene 3.1.1.1. Fused furans 3.1.1.2. Vinyl furans 3.1.2. Nature of the dienophile 3.1.2.1. Alkenes 3.1.2.2. Alkynes 3.1.2.3. Ailenes 3.1.2.4. Benzynes 3.2. Mechanistic considerations 3.2.1. Substituent/structural effects 3.2.2 Catalysts 3.2.3. High-pressure reactions 3.3. Applications 3.3.1. Methodology 3.3.2. Asymmetric synthesis 3.3.3 Synthetic targets

Microwave Effects in Organic Synthesis: Myth or Reality?

on the use ofmicrowaveirradiationto“accelerate”organicchemicaltrans-formations, there has been considerable speculation anddiscussion of this effect. Much of the debate has centeredaround the question whether the observed effects can in allinstances be rationalized by purely thermal/kinetic phenom-ena (thermal microwave effects) arising from the rapidheating and high bulk reaction temperatures attained withmicrowave dielectric heating, or whether some effects areconnected to so-called specific or nonthermal microwaveeffects.

Continuous flow organic synthesis under high-temperature/pressure conditions.

Microreactor technology and continuous flow processing in general are key features in making organic synthesis both more economical and environmentally friendly. When preformed under a high-temperature/pressure process intensification regime many transformations originally not considered suitable for flow synthesis owing to long reaction times can be converted into high-speed flow chemistry protocols that can operate at production-scale quantities. This Focus Review summarizes the state of the art in high-temperature/pressure microreactor technology and provides a survey of successful applications of this technique from the recent synthetic organic chemistry literature.

High-speed combinatorial synthesis utilizing microwave irradiation

Recent advances in microwave-assisted combinatorial chemistry include high-speed solid-phase and polymer-supported organic synthesis, rapid parallel synthesis of compound libraries, and library generation by automated sequential microwave irradiation. In addition, new instrumentation for high-throughput microwave-assisted synthesis continues to be developed at a steady pace. The impressive speed combined with the unmatched control over reaction parameters justifies the growing interest in this application of microwave heating.

A critical assessment of the greenness and energy efficiency of microwave-assisted organic synthesis

The question “why should microwave chemistry be green?” is evaluated in the context of the twelve principles of green chemistry, with a focus on the 6th principle: design for energy efficiency. A significant number of publications on microwave-assisted organic transformations during the past 25 years describe this non-classical heating technology as being “green”, assuming that microwave dielectric heating is more energy efficient than classical conductive heat transfer methods. In this Perspective article, we critically assess the energy efficiency of microwave-assisted transformations in the context of scaling-up this technology to production quantities.