Continuous Flow Production of Thermally Unstable Intermediates in a Microreactor with Inline IR-Analysis: Controlled Vilsmeier–Haack Formylation of Electron-Rich Arenes

Abstract

The Vilsmeier–Haack formylation of aromatic compounds is a well-established process in organic synthesis, largely driven by the fact that the resulting aldehydes are generally useful intermediates for the synthesis of fine chemicals and pharmaceutical products. Industrial-scale production, however, is often hampered by laborious procedures requiring the use of hazardous chemicals to produce the highly reactive intermediates. In order to circumvent these issues, a flow chemistry approach was developed. This article describes the design and semiautomated optimization of the Vilsmeier–Haack formylation in continuous flow and subsequent scale-up to preparative volumes in an intrinsically safe manner.

Development of methodologies for reactions involving gases as reagents: microwave heating and conventionally-heated continuous-flow processing as examples

“…As such, they have proven valuable for performing chemistry that would traditionally be difficult to conduct in batch. For example, processes that are highly exothermic, require the use of highly reactive reagents, require very high temperatures or pressures, or generate unstable intermediates [17]. Additionally, reactions developed using a bench-sized flow unit, could feasibly be transferred to large-scale production either by using a larger flow reactor or by running multiple, smaller flow reactors in parallel.…”

The continuous flow synthesis of 2,4,5-trifluorobenzoic acid via sequential Grignard exchange and carboxylation reactions using microreactors

“…Another notable feature is the ease of scalability from bench experiment to large-scale production, either by running the flow-reactor for an extended time or by numbering the parallel microreactors, which is quite important from the viewpoint of industry production. In addition, the incorporation of real time monitoring with intelligent feedback loops into a microflow system, also offers considerable possibilities to develop fully automated processes [33][34][35].…”

Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions

“…To this end, a wide range of companies now produce equipment for both micro- and mesofluidic flow chemistry [1–2]. Some of the advantages of these devices are increased experimental safety, easy scale-up and thorough mixing of reagents [3–7]. It is not surprising, therefore, that a wide range of synthetic chemistry transformations have been reported using this equipment [8–9].…”

“…This opens the avenue for fast, reliable assay in comparison with the traditional approach in which performance is evaluated based on offline product analysis. When interfaced with microreactors, inline analysis has taken significant strides in recent years [7,10]. Spectroscopic tools such as infrared [11–15], UV–visible [16–18], NMR [19–20], Raman [21–25], and mass spectrometry [26–27] have all been interfaced with success.…”