Ana Cukalovic

Microreactor Technology as an Efficient Tool for Multicomponent Reactions

Multicomponent reactions are an important tool in organic synthesis as they often allow the circumvention of multistep procedures by combining three or more molecules into one structure in a single step. An additional asset of the approach is the significant increase of the combinatorial possibilities, since a modification of the final product is easily accomplished by implementing minor changes in the reaction setup; this obviously allows considerable savings in time and resources. These advantages are of particular interest in pharmaceutical research for the construction of libraries. In order to increase the sustainability of chemical processes, the field is intensively explored, and novel reactions are frequently reported. Microreactor technology also offers a contemporary way of conducting chemical reactions in a more sustainable fashion due to the miniaturization and increased safety, and also in a technically improved manner due to intensified process efficiency. This relatively new technology is implemented in novel and improved applications and is getting more and more used in chemical research. The combination of the benefits from the two approaches clearly presents an attractive reaction design, and this chapter presents an overview of the reported examples in which the microreactor technology and the multicomponent approach are combined, usually with dramatically improved results compared to those previously reported.

Production of biobased HMF derivatives by reductive amination

5-(Hydroxymethyl)furfural (HMF) has recently attracted a significant amount of revived attention as a renewable building block for conversion to a wide range of useful derivatives. A simple procedure for the conversion of HMF to (5-alkyl- and 5-arylaminomethyl-furan-2-yl)methanol has now been developed. Reactions were conducted without the use of a catalyst and under very mild conditions. As a proof of concept, a small library of derivatives was produced from HMF and several aliphatic and aromatic amines in high yields and requiring only minimal purification. This route presents a novel way for the production of furan-based renewable building blocks.

Efficient and catalyst-free condensation of acid chlorides and alcohols using continuous flow

An efficient, catalyst-free continuous flow procedure for the condensation of acid chlorides and alcohols was developed. Different esters could be obtained using this protocol with excellent conversions starting from the corresponding acid chlorides and alcohols in very short reaction times (5–7 min). The reaction was performed solventless for liquid reagents but requires a solvent for solid reagents in order to prevent clogging of the microreactor. Since no catalyst is needed, the purification of the reaction mixture is very straightforward. Scale-up of the reaction to a microreactor with an internal volume of 13.8 ml makes it possible to produce 2.2 g min−1 of ester with an isolated yield of 98% and recuperation of the formed HCl.

User Friendly and Flexible Kiliani Reaction on Ketoses Using Microreaction Technology

The Kiliani reaction, i.e. the elongation of the carbon chain by means of cyanide addition to the carbonyl group of carbohydrate derivatives, is studied on lower C3-, C4- and C6-ketoses under continuous flow conditions. Depending on the process parameters, the corresponding cyanohydrins or α-hydroxycarboxylic acids are obtained. A simple on-line purification of the effluent is studied using cation exchange resins. Reactions provide high yields and selectivity within short residence times, emphasizing the assets of the continuous flow process versus the batch process.

Efficient Continuous-Flow Benzotriazole Activation and Coupling of Amino Acids

Despite extensive research into peptide synthesis, coupling of amino acids with weakly nucleophilic heterocyclic amines remains a challenge. The need for microwave technology to promote this coupling interferes with the scalability of the process. By applying the microwave-to-flow paradigm, a library of (α-aminoacyl)amino-substituted heterocycles was continuously produced at near quantitative conversions and the reaction was scaled up successfully. Various N-Cbz-protected amino acids were activated using BtH/SOCl2 under continuous-flow conditions with excellent yields. Their coupling with heterocyclic amines was accomplished in MeCN-NMP on a preparative scale. However, performing both steps in-line resulted in an inconvenient work-up. Therefore, a two-step approach was taken, isolating the intermediate Bt-activated amino acid via simple filtration. This allows for a solvent switch to DMSO for the coupling reaction which led to excellent conversions for a broad range of substrates.

A guide for the implementation of the REACH regulation: Small and Medium Enterprises (SME)

The novel REACH legislation (EC Regulation No 1907/2006) entered into force on June 1st 2007 with a phased implementation over the next 11 years. The “Registration, Evaluation, Authorisation and Restriction of Chemical substances (REACH)” regulation aims at the control of the production and the use of chemical substances, and their impacts on human health and the environment. The regulation demands greater responsibility from industry to provide complete and accurate information on the safety of the chemicals it produces or trades.