Advances in the Continuous Flow Synthesis of 3- and 4-Membered Ring Systems.

Small carbo- and heterocyclic ring systems have experienced a significant increase in importance in recent years due to their relevance in modern pharmaceuticals, as building blocks for designer materials or as synthetic intermediates. This necessitated the development of new synthetic methods for the preparation of these strained ring systems focusing on effectiveness and scalability. The high ring strain of these entities as well as the use of high-energy reagents and intermediates has often challenged their synthesis. Continuous flow approaches have thus emerged as highly effective means to safely and reliably access these strained scaffolds. In this short review, key developments in this field are summarised showcasing the power of continuous flow approaches for accessing 3- and 4-membered ring systems via thermal, photo- and electrochemical processes.

[3+2]-Cycloaddition Reactions of gem-Difluorocyclopropenes with Azomethine Ylides - Access to Novel Fluorinated Scaffolds.

The introduction of fluorinated moieties into drugs as well as the increase of their overall three-dimensionality have become key strategies amongst medicinal chemists to generate sets of compounds with favorable drug-like properties. However, the introduction of fluorinated cyclopropane ring systems which combines both strategies is not widely exploited to date. This paper reports synthetic strategies exploiting the reactivity of gem-difluorocyclopropenes in dipolar cycloaddition reactions with azomethine ylides to afford sets of new fluorine-containing 3-azabicyclo[3.1.0]hexanes. In addition, the unexpected formation of complex trifluorinated scaffolds arising from proline esters and gem-difluorocyclopropenes is highlighted along with computational studies to elucidate the underlying mechanism. This study presents new avenues towards pharmaceutically relevant fluorinated 3-azabicyclo[3.1.0]hexanes that are accessible via robust and short synthetic sequences.

Synthesis of Modified Poly(vinyl Alcohol)s and Their Degradation Using an Enzymatic Cascade.

Poly(vinyl alcohol) (PVA) is a water-soluble synthetic vinyl polymer with remarkable physical properties including thermostability and viscosity. Its biodegradability, however, is low even though a large amount of PVA is released into the environment. Established physical-chemical degradation methods for PVA have several disadvantages such as high price, low efficiency, and secondary pollution. Biodegradation of PVA by microorganisms is slow and frequently involves pyrroloquinoline quinone (PQQ)-dependent enzymes, making it expensive due to the costly cofactor and hence unattractive for industrial applications. In this study, we present a modified PVA film with improved properties as well as a PQQ-independent novel enzymatic cascade for the degradation of modified and unmodified PVA. The cascade consists of four steps catalyzed by three enzymes with in situ cofactor recycling technology making this cascade suitable for industrial applications.

Continuous Flow Technology as an Enabler for Innovative Transformations Exploiting Carbenes, Nitrenes, and Benzynes.

Miniaturization offered by microreactors provides for superb reaction control as well as excellent heat and mass transfer. By performing chemical reactions in microreactors or tubular systems under continuous flow conditions, increased safety can be harnessed which allows exploitation of these technologies for the generation and immediate consumption of high-energy intermediates. This Synopsis demonstrates the use of flow technology to effectively exploit benzynes, carbenes, and nitrenes in synthetic chemistry programs.

Flow synthesis of oxadiazoles coupled with sequential in-line extraction and chromatography.

An efficient continuous flow process is reported for the synthesis of various 1,3,4-oxadiazoles via an iodine-mediated oxidative cyclisation approach. This entails the use of a heated packed-bed reactor filled with solid K2CO3 as a base. Using DMSO as solvent, this flow method generates the target heterocycles within short residence times of 10 minutes and in yields up to 93%. Scale-up of this flow process was achieved (34 mmol/h) and featured an integrated quenching and extraction step. Lastly, the use of an automated in-line chromatography system was exploited to realise a powerful flow platform for the generation of the heterocyclic targets.

A continuous flow synthesis of [1.1.1]propellane and bicyclo[1.1.1]pentane derivatives.

A continuous flow process to generate [1.1.1]propellane on demand is presented rendering solutions of [1.1.1]propellane that can directly be derivatised into various bicyclo[1.1.1]pentane (BCP) species. This was realised in throughputs up to 8.5 mmol h-1 providing an attractive and straightforward access to gram quantities of selected BCP building blocks. Lastly, a continuous photochemical transformation of [1.1.1]propellane into valuable BCPs bearing mixed ester/acyl chloride moieties was developed.

Development of a Telescoped Flow Process for the Safe and Effective Generation of Propargylic Amines.

Propargylic amines are important multifunctional building blocks that are frequently exploited in the synthesis of privileged heterocyclic entities. Herein we report on a novel flow process that achieves the safe and effective on-demand synthesis of propargylic amines in a telescoped manner. This process minimizes exposure to hazardous azide intermediates and renders a streamlined route into these building blocks. The value of this approach is demonstrated by the rapid generation of a small selection of drug-like thiazolines that result from a high-yielding reaction cascade between propargylic amines with different aryl isothiocyanates.