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Synfacts 2025; 21(07): 738
DOI: 10.1055/a-2601-4708
Innovative Drug Discovery and Development

Large-Scale Synthesis of Rawal’s Diene

Contributor(s):
Dirk H. Trauner
,
Ana V. Serna Moyeda
Shamrai OI, Iermolenko IA, Ostapchuk EN, Leha DO, Zarudnitskii EV, Ryabukhin SV *, Volochnyuk DM *. Enamine Ltd, Kyiv, Institute of Organic Chemistry, National Academy of Sciences of Ukraine, and Taras Shevchenko National University of Kyiv, Ukraine
Shackles Off: A Kilo Scale Synthesis of Rawal’s Diene.

Org. Process Res. Dev. 2025;
DOI: 10.1021/acs.oprd.5c00039
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Keywords

Rawal’s diene - pyranones - kilogram-scale

Significance

Although Rawal’s diene is more reactive than Danishefsky’s diene, its large-scale use has been limited due to its instability and scalability issues. The team led by Ryabukhin and Volochnyuk (from Enamine Ltd) have developed a kilogram-scale procedure for the synthesis of Rawal’s diene. They used this diene in [4 + 2] cycloadditions to prepare multigram quantities of 2-alkyl-2,3-dihydro-4H-pyran-4-ones, which are building blocks that are crucial to the pharmaceutical industry.


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Comment

In the optimized procedure, acetylacetaldehyde dimethyl acetal is treated with aqueous dimethylamine, yielding the corresponding enaminone 1. After deprotonation with NaHMDS, enolate 2 is trapped with TBSCl to make Rawal’s diene. The yield decreased upon scale-up, which was primarily attributed to hydrolysis and oxidation upon exposure to air during the filtration. Its quality and stability was studied by NMR. The authors found that Rawal’s diene can be stored at room temperature for 14 days under argon, but for longer times, storage at 4 °C is recommended.


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Publication History

Article published online:
23 June 2025

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