Nitroxides: applications in synthesis and in polymer chemistry

This Review describes the application of nitroxides to synthesis and polymer chemistry. The synthesis and physical properties of nitroxides are discussed first. The largest section focuses on their application as stoichiometric and catalytic oxidants in organic synthesis. The oxidation of alcohols and carbanions, as well as oxidative C-C bond-forming reactions are presented along with other typical oxidative transformations. A section is also dedicated to the extensive use of nitroxides as trapping reagents for C-centered radicals in radical chemistry. Alkoxyamines derived from nitroxides are shown to be highly useful precursors of C-centered radicals in synthesis and also in polymer chemistry. The last section discusses the basics of nitroxide-mediated radical polymerization (NMP) and also highlights new developments in the synthesis of complex polymer architectures.     

The combined use of microwaves and ultrasound: improved tools in process chemistry and organic synthesis

Microwave heating and ultrasonic waves are among the most simple, inexpensive, and valuable tools in applied chemistry. Besides saving energy, these green techniques promote faster and more selective transformations. Could they be combined to enhance their effects still further? As they are of a basically different nature (quantum and non‐quantum fields), each must be fine‐tuned by its specific parameters; a combined device will often be subject to additional hazard limitations. However, recent developments evidence that such a combination is certainly possible and safe, ranging from simple modifications to flow systems that are well suited for automation and scaling‐up. By using selected examples, this concept article gives an overview of apparatus currently available for simultaneous or tandem irradiation and explains how it can be utilized in organic synthesis and analysis.     

The microwave-to-flow paradigm: translating high-temperature batch microwave chemistry to scalable continuous-flow processes

The popularity of dedicated microwave reactors in many academic and industrial laboratories has produced a plethora of synthetic protocols that are based on this enabling technology. In the majority of examples, transformations that require several hours when performed using conventional heating under reflux conditions reach completion in a few minutes or even seconds in sealed-vessel, autoclave-type, microwave reactors. However, one severe drawback of microwave chemistry is the difficulty in scaling this technology to a production-scale level. This Concept article demonstrates that this limitation can be overcome by translating batch microwave chemistry to scalable continuous-flow processes. For this purpose, conventionally heated micro- or mesofluidic flow devices fitted with a back-pressure regulator are employed, in which the high temperatures and pressures attainable in a sealed-vessel microwave chemistry batch experiment can be mimicked.     

Diastereoselective chain-elongation reactions using microreactors for applications in complex molecule assembly

Diastereoselective chain-elongation reactions are important transformations for the assembly of complex molecular structures, such as those present in polyketide natural products. Here we report new methods for performing crotylation reactions and homopropargylation reactions by using newly developed low-temperature flow-chemistry technology. In-line purification protocols are described, as well as the application of the crotylation protocol in an automated multi-step sequence.     

Lead-oriented synthesis: a new opportunity for synthetic chemistry

The pharmaceutical industry remains solely reliant on synthetic chemistry methodology to prepare compounds for small-molecule drug discovery programmes. The importance of the physicochemical properties of these molecules in determining their success in drug development is now well understood but we present here data suggesting that much synthetic methodology is unintentionally predisposed to producing molecules with poorer drug-like properties. This bias may have ramifications to the early hit- and lead-finding phases of the drug discovery process when larger numbers of compounds from array techniques are prepared. To address this issue we describe for the first time the concept of lead-oriented synthesis and the opportunity for its adoption to increase the range and quality of molecules used to develop new medicines.     

Deciding whether to go with the flow: evaluating the merits of flow reactors for synthesis

The fine chemicals and pharmaceutical industries are transforming how their products are manufactured, where economically favorable, from traditional batchwise processes to continuous flow. This evolution is impacting synthetic chemistry on all scales-from the laboratory to full production. This Review discusses the relative merits of batch and micro flow reactors for performing synthetic chemistry in the laboratory.     

Synthesis of (+)-dumetorine and congeners by using flow chemistry technologies

An efficient total synthesis of the natural alkaloid (+)-dumetorine by using flow technology is described. The process entailed five separate steps starting from the enantiopure (S)-2-(piperidin-2-yl)ethanol 4 with 29% overall yield. Most of the reactions were carried out by exploiting solvent superheating and by using packed columns of immobilized reagents or scavengers to minimize handling. New protocols for performing classical reactions under continuous flow are disclosed: the ring-closing metathesis reaction with a novel polyethylene glycol-supported Hoveyda catalyst and the unprecedented flow deprotection/Eschweiler-Clarke methylation sequence. The new protocols developed for the synthesis of (+)-dumetorine were applied to the synthesis of its simplified natural congeners (-)-sedamine and (+)-sedridine.     

Reactions of Difunctional Electrophiles with Functionalized Aryllithium Compounds: Remarkable Chemoselectivity by Flash Chemistry

Flash chemistry using flow microreactors enables highly chemoselective reactions of difunctional electrophiles with functionalized aryllithium compounds by virtue of extremely fast micromixing. The approach serves as a powerful method for protecting‐group‐free synthesis using organolithium compounds and opens a new possibility in the synthesis of polyfunctional organic molecules.     

Microfabricated devices for fluid mixing and their application for chemical synthesis

Over the last few decades, the processes of miniaturization, integration, and automation have revolutionized the world of science and industry. Within a chemical reaction process the unit operations, mixing, heating, and cooling, can be regarded as key steps. In microreactors, enhanced heat and mass transport, due to small characteristic dimensions together with large surface to volume ratios, are expected to open up a whole range of new possibilities. Increase in reaction yield, reduction of reaction time as well as byproduct formation, inherent process safety, and even completely new process routes are some of the advantages associated with microTAS (micro Total Analysis Systems) or microSYNTAS (micro SYNthesis Total Analysis Systems). This article aims to describe the development of microfabricated devices for fluid mixing, so-called micromixers, and their application for chemical synthesis.     

Peripheral substitution of a near-IR-absorbing soluble phthalocyanine using "click" chemistry

A series of near-IR-absorbing soluble phthalocyanines (Pcs) with eight alkyne moieties as side chains of the chromophore have been synthesized. One of these Pcs has been used as a scaffold for functional group modification using alkyne-azide click chemistry with various azides. This led to a small library of Pcs with photo and thermal crosslinkable, dendritic, and hydrophilic moieties starting from a single Pc molecule. A patterned thin film was fabricated by photocrosslinking one of these Pc derivatives.     

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.