A Vilsmeier Chloroformylation by Continuous Flow Chemistry

Abstract

Chloroformylation reactions are versatile reactions that allow the introduction of a chlorine atom and an aldehyde group in enolizable ketones, employing the well-known Vilsmeier reagent. However, the use of this unstable reagent is usually associated with hazards, especially when it is used on an industrial scale. The present article describes the preparation and use of the Vilsmeier reagent under continuous flow conditions for the preparation of an important intermediate in the synthesis of cyanine dyes. In addition, the traditionally used dimethylformamide has been substituted with more desirable formamides, together with the removal of the halogenated solvent usually employed in the reaction. Consequently, the optimized conditions allow the continuous production of the target compound in a 79–81% isolated yield in a more environmentally friendly, fast, and secure manner.

Intensified Continuous Flow Synthesis and Workup of 1,5-Disubstituted Tetrazoles Enhanced by Real-Time Process Analytics

“…Work toward a synthetic process for model tetrazole substrate 1 began by examining the formation of its proposed imidoyl chloride intermediate ( 3 ), analogous to the Vilsmeier–Haack reagent, from amide 2 (Figure a) . Numerous combinations of solvents and chlorinating agents were trialed, yet acetonitrile with POCl 3 appeared by far to be the most suitable.…”

Continuous‐/Micro‐Flow Reactions Using Highly Electrophilic PCl3 and POCl3

“…[34] The schematic procedure for the continuous-flow synthesis of vildagliptin precursor 34 is featured in Figure 17. POCl In 2018, O'Brien et al reported the condensation of malonic acid (36) and DCC (37). [35] The schematic procedure for the continuous-flow synthesis of 38 appears in Figure 18.…”

“…In 2020, Stevens et al examined chloroformylation in a continuous-flow reactor. [36] The schematic procedure for the In 2021, Williams and Kappe et al synthesized tetrazole derivatives 43 from amide 42, TMSN 3 , and POCl 3 . [37] The TMSN 3 sometimes contains explosive impurities, and, therefore, it is suitable for continuous-flow synthesis.…”

“…In 2020, Stevens et al. examined chloroformylation in a continuous‐flow reactor [36] . The schematic procedure for the continuous‐flow synthesis of 1‐formyl‐3‐(hydroxymethylene) cyclohex‐1‐ene ( 41 ) is featured in Figure 19.…”

Continuous Flow-Facilitated CB2 Agonist Synthesis, Part 2: Cyclization, Chlorination, and Amination

“…Such hazardous chemistry can be safely handled in flow by precise stoichiometry and temperature control, while operating in smaller reactor volumes with shortened reaction times . The use of continuous flow technology to enable safe generation and consumption of this reagent has been demonstrated multiple times in recent years …”