Microwave-Assisted Domino Hydroformylation/Cyclization Reactions: Scope and Limitations

Abstract

Hydroformylation of alkenes can be carried out in short time and with low syngas pressure under microwave (MW) dielectric heating. Alkenes, carrying O-, N-, or C-nucleophilic fragments, can be designed for domino reactions, mainly cyclocondensations. Allyl and homoallyl alcohols are excellent substrates for cyclizative hydroformylation to lactols under MW heating. In the presence of NaOAc as an additional nucleophile, a domino reaction occurs giving 2-acetoxytetrahydrofurans, suitable to introduce a C-nucleophile on tetrahydrofuran rings through an oxocarbenium ion. The synthesis of the furanopiperidine substructure of cyclopamine is described as an application. With alkene amides, the domino process collapsed to a transient acyliminium ion that further cyclized with an additional C-nucleophile. To perform domino hydroformylation Pictet-Spengler or aza-Sakurai reactions, an autoclave under conventional heating is essential. Syntheses of (±)-epilupinine and of a homoberberine alkaloid are reported to illustrate each sequence. Although apparently more versatile, hydroformylation of alkenes using MW heating is sensitive to the nature of the nucleophiles present in the substrates, evidencing that the conventional heating process cannot be completely replaced by MW irradiation.

Key words

domino reaction - heterocycles - nucleophilic addition - cyclization - hemiacetals - Pictet-Spengler reaction

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http://www.cem.com/page163.html.

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http://www.anton-paar.com/001/en/60/262.

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In a 10 mL vial, the gas present under the reaction conditions is roughly 3 mmol for 1 mmol of substrate.