Notes: Synthesis of 2-Isopropyl-4-methoxyphenol

Zenker, Nicholas; Jorgensen, Eugéne C.

doi:10.1021/jo01091a610

Cited by 9 publications

(3 citation statements)

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“…Retrosynthetically, a Friedel–Crafts reaction between mequinol and an isopropyl cation would provide 2-isopropyl-4-methoxyphenol (Scheme ). Not surprisingly, this reaction was reported to afford a complex reaction profile and low yield due to an overalkylation side reaction of 3 . However, we were inspired by the simplicity of this proposal and quickly leveraged high-throughput experimentation (HTE) to evaluate this approach …”

Section: Results and Discussionmentioning

confidence: 99%

“…In most cases, overalkylation products dominated the product mixture. This observation is consistent with literature reports since phenol 3 is more electronically rich than mequinol, and product 3 would also react with the isopropyl cation to provide overalkylation products . In order to achieve a clean isopropylation of mequinol, it was thought that conditions not involving a classic isopropyl cation mechanism could provide better results.…”

Section: Results and Discussionmentioning

confidence: 99%

“…This observation is consistent with literature reports since phenol 3 is more electronically rich than mequinol, and product 3 would also react with the isopropyl cation to provide overalkylation products. 8 In order to achieve a clean isopropylation of mequinol, it was thought that conditions not involving a classic isopropyl cation mechanism could provide better results. We therefore tested transitionmetal catalysts, hoping that a C−H activation and hydroarylation would provide the desired phenol product.…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 2: Development of a Robust Process for Phenol Synthesis

Peng

Humphrey

Maloney

et al. 2020

Org. Process Res. Dev.

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Various synthetic routes to 2-isopropyl-4-methoxyphenol 3, the phenol core of Gefapixant citrate (MK-7264), are described, which provide better alternatives to the initial four-step supply route. These new routes include a coumarin fragmentation approach in flow, a rhenium-catalyzed isopropylation of mequinol, and a bromination/methoxylation of 2-isopropylphenol. After exploring several approaches, a robust two-step process for the preparation of 3 from the commodity starting material 2isopropylphenol was developed. The optimized route employs a highly regioselective bromination. After isolating the bromophenol DABCO cocrystal, a copper-catalyzed methoxylation delivers 3 in high yield. This route is successfully demonstrated at the plant scale with low process mass intensity and cost.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 2: Development of a Robust Process for Phenol Synthesis

Peng

Humphrey

Maloney

et al. 2020

Org. Process Res. Dev.

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Radikalische Alkylierung von Chinonen: Erzeugung von Radikalen in Redoxreaktionen

Jacobsen

Torssell

1972

Justus Liebigs Ann. Chem.

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Eingegangen am 2. Mai 1972 C-Radikale werden durch H-Abstraktion aus dem organischen Losungsmittel mit OH-Radikalen (Fentons Reagenz) erzeugt. In Anwesenheit von Chinonen werden die Radikale abgefangen, wobei alkylierte Chinone gebildet werden. Die Alkylierung verlauft in guten Ausbeuten, wenn die Radikale durch oxydative Decarboxylierung von Carbonsauren (mit Silberionen und Persulfat) erzeugt werden. Alkylation of Quinones with Radicals: Generation of Radicals in Redox ReactionsCarbon radicals are generated from organic solvents by H-abstraction with OH' (Fenton's reagent). They are scavenged by quinones whereby alkylated quinones are formed. The alkylation proceeds with good yields when the radicals are produced by oxidative decarboxylation of carboxylic acids (with silver ions and persulfate).Da der Nachweis von Radikalen in letzter Zeit durch die ESR-Spektroskopie erheblich erleichtert worden ist, war es naheliegend, diese spektroskopische Methode zur Untersuchung der synthetischen Verwendbarkeit radikalischer Reaktionen auszunutzen. So wurde z. B. mit der Nitroxidmethode nachgewiesen, daD bei der Zersetzung von Wasserstoffperoxid in Sulfoxiden Alkylradikale gebildet wurdenl), und zwar in so groBer Menge, daR die Reaktion mit Erfolg zur Alkylierung von Aromaten verwendet werden konnte 2.3).Die Bildung von Kohlenstoffradikalen aus verschiedenen Losungsmitteln als Folge der Wasserstoffabstraktion durch OH' ist sowohl mit der Flow-Methode4) als auch mit der Nitroxidmethodes) untersucht worden. Die Ergebnisse der beiden Methoden sind zum Teil verschieden, was auf die Sekundarreaktion der Primarradikale zuriickzufuhren ist6). Mit der Flow-Methode ist ein empfindlicherer Nachweis der verschiedenen *) Professor Georg Wittig zum 75. Geburtstag gewidmet.

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Pure Liquids: Extended References

Wohlfarth¹,

Wohlfarth²

Refractive Indices of Inorganic, Organometallic, and Organononmetallic Liquids, and Binary Liquid Mixtures

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Notes: Synthesis of 2-Isopropyl-4-methoxyphenol

Cited by 9 publications

References 0 publications

Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 2: Development of a Robust Process for Phenol Synthesis

Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 2: Development of a Robust Process for Phenol Synthesis

Radikalische Alkylierung von Chinonen: Erzeugung von Radikalen in Redoxreaktionen

Pure Liquids: Extended References

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