Methanolysis of amides under high-temperature and high-pressure conditions with a continuous tubular reactor

Zou, Pengcheng; Wang, Kai

doi:10.1016/j.cjche.2022.10.009

Cited by 2 publications

(2 citation statements)

References 40 publications

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“…However, SH conditions could compensate for the lack of reactivity and help bring completion back within a few minutes (Figure 14a), as demonstrated by Fukuyama et al in the sulfonic acid-catalyzed protection aldehydes, 45 by Zhang, Zou and co-workers in the Pinnick oxidation of aldehydes, 46 or by Wang et al in the acylation and methanolysis of amides under flow conditions. 47,48 In a study published in 2023, we reported SH conditions to overcome the sluggish nature of benzylideneacetone toward sterically hindered 4-hydroxycoumarin for preparing essential pharmaceutical warfarin (Figure 14b). 49 The gold standard reaction to produce racemic warfarin is notoriously slow.…”

Section: ■ Scope Of Reactionsmentioning

confidence: 99%

“…In conjunction with weak nucleophiles, the forecast for reaction completion within a reasonable time frame is rather dull. However, SH conditions could compensate for the lack of reactivity and help bring completion back within a few minutes (Figure a), as demonstrated by Fukuyama et al in the sulfonic acid-catalyzed protection aldehydes, by Zhang, Zou and co-workers in the Pinnick oxidation of aldehydes, or by Wang et al in the acylation and methanolysis of amides under flow conditions. , …”

Section: Scope Of Reactionsmentioning

confidence: 99%

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New Opportunities for Organic Synthesis with Superheated Flow Chemistry

Bianchi,

Monbaliu

2024

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS: Flow chemistry has brought a fresh breeze with great promises for chemical manufacturing, yet critical deterrents persist. To remain economically viable at production scales, flow processes demand quick reactions, which are actually not that common. Superheated flow technology stands out as a promising alternative poised to confront modern chemistry challenges. While continuous micro-and mesofluidic reactors offer uniform heating and rapid cooling across different scales, operating above solvent boiling points (i.e., operating under superheated conditions) significantly enhances reaction rates. Despite the energy costs associated with high temperatures, superheated flow chemistry aligns with sustainability goals by improving productivity (process intensification), offering solvent flexibility, and enhancing safety. However, navigating the unconventional chemical space of superheated flow chemistry can be cumbersome, particularly for neophytes. Expanding the temperature/pressure process window beyond the conventional boiling point under the atmospheric pressure limit vastly increases the optimization space. When associated with conventional trial-and-error approaches, this can become exceedingly wasteful, resource-intensive, and discouraging. Over the years, flow chemists have developed various tools to mitigate these challenges, with an increased reliance on statistical models, artificial intelligence, and experimental (kinetics, preliminary test reactions under microwave irradiation) or theoretical (quantum mechanics) a priori knowledge. Yet, the rationale for using superheated conditions has been slow to emerge, despite the growing emphasis on predictive methodologies. To fill this gap, this Account provides a concise yet comprehensive overview of superheated flow chemistry. Key concepts are illustrated with examples from our laboratory's research, as well as other relevant examples from the literature. These examples have been thoroughly studied to answer the main questions Why? At what cost? How? For what? The answers we provide will encourage educated and widespread adoption. The discussion begins with a demonstration of the various advantages arising from superheated flow chemistry. Different reactor alternatives suitable for high temperatures and pressures are then presented. Next, a clear workflow toward strategic adoption of superheated conditions is resorted either using Design of Experiments (DoE), microwave test chemistry, kinetics data, or Quantum Mechanics (QM). We provide rationalization for chemistries that are well suited for superheated conditions (e.g., additions to carbonyl functions, aromatic substitutions, as well as C−Y [Y = N, O, S, C, Br, Cl] heterolytic cleavages). Lastly, we bring the reader to a rational decision analysis toward superheated flow conditions. We believe this Account will become a reference guide for exploring extended chemical spaces, accelerating organic synthesis, and advancing molecular sciences.

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