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Electrophilic addition: do you know your cyclopropanation from your hydrozirconation?

April 12, 2019


Electrophilic addition reactions are a bit like the coming together of the leading characters in a romantic comedy. On the one hand, a substrate possessing an electron-rich carbon–carbon double or triple bond. On the other, an electron-deficient electrophile that can’t wait to form new bonds of its own. Despite their differences, they’re a perfect match: the reaction resulting in the addition of the electrophile across the carbon–carbon bond.

Electrophilic addition reactions come in all shapes and sizes, with many playing a key role in the synthesis of natural products and industrially significant chemicals. Among the earliest electrophilic addition reactions to be identified was the Prilezhaev reaction, named after the Russian chemist Nikolai Alexandrovich Prilezhaev who, in 1909, was the first to oxidize alkenes to oxiranes using peroxycarboxylic acids. Today, peroxycarboxylic acids such as meta-chloroperoxybenzoic acid (mCPBA) are commonly used to prepare epoxides, which are vital for the manufacture of epoxy resin adhesives.

Since the Prilezhaev reaction was discovered, a wide range of electrophilic addition reactions have been developed. Read on for four of our favorites.

1.Simmons–Smith cyclopropanation

In 1958, chemists Howard E. Simmons Jr. and Ronald D. Smith stereospecifically converted a series of unfunctionalized alkenes into cyclopropanes using diiodomethane and a zinc–copper couple. This important transformation has since become known as the Simmons–Smith cyclopropanation, and is widely used in natural product synthesis. Notably, the Simmons–Smith cyclopropanation reaction was employed in the total synthesis of the antimitotic agent (+)-curacin A, where it was used to generate the cyclopropane ring.

While a zinc–copper couple is often used for this reaction, a zinc–silver couple can deliver improved yields and shorter reaction times. A variant of this reaction known as the Furukawa modification, which uses diethylzinc with diiodomethane, also gives excellent results. Another variant, the Molander modification, describes the use of iodo- or chloromethyl samarium iodide for the cyclopropanation of allylic alcohols in the presence of other olefins.

2.Schwartz hydrozirconation

Although zirconocene hydrochloride was first prepared in 1970 by Helmut Weigold and Peter C. Wailes, for many years the reagent’s synthetic potential remained untapped. This changed in 1974, when Jeffrey Schwartz and Donald W. Hart reacted organozirconium intermediates with a series of electrophiles including hydrochloric acid, bromine and acid chlorides to produce the respective alkanes, bromoalkanes and ketones. Zirconocene hydrochloride has subsequently come to be known as Schwartz’s reagent, and its reaction with multiple bond-containing substrates is called the Schwartz hydrozirconation.

Schwartz’s reagent can be prepared by reducing zirconocene dichloride with lithium aluminum hydride, however many chemists choose to source the compound from commercial suppliers. The reagent has been used in the total synthesis of several important macrolides possessing antibiotic and antifungal properties.

3.Noyori asymmetric hydrogenation

In 1980, Japanese chemist Ryōji Noyori reported that alpha-(acylamino)acrylic acids and esters could undergo asymmetric hydrogenation to generate the corresponding amino acid products in the presence of catalytic amounts of rhodium complexed with 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (or BINAP for short). Subsequent research efforts revealed that the asymmetric hydrogenation of functionalized olefins could be accomplished using BINAP-Ru(II) dicarboxylate complexes. Oligomeric halogen-containing BINAP-Ru(II) complexes were particularly effective at catalyzing the asymmetric hydrogenation of functionalized ketones. The reduction of functionalized olefins and ketones using BINAP-Ru(II) and hydrogen gas has since become known as the Noyori asymmetric hydrogenation, with Noyori’s efforts in this field contributing to his awarding of the Nobel Prize in Chemistry in 2001.

The Noyori asymmetric hydrogenation has been used in many total syntheses, including the preparation of the anti-inflammatory drug naproxen and the antibiotic levofloxacin.

4.Shi asymmetric epoxidation

For many years, chemists had tried in vain to develop an efficient non-metal catalyst for asymmetric epoxidation reactions. However, the poor electrophilicity of the catalytic ketone and instability of the dioxirane intermediate proved to be highly problematic. In 1996, Yian Shi’s discovery of a ketone catalyst derived from fructose marked a major milestone in epoxidation chemistry. When used to treat alkenes in the presence of potassium peroxymonosulfate (commonly known as oxone), Shi’s catalyst demonstrated excellent enantioselectivity, and the reaction has come to be known as the Shi asymmetric epoxidation.

The Shi epoxidation is thought to proceed through a dioxirane intermediate, generated from the reaction between oxone and the catalyst. The reaction has featured prominently in a number of total synthesis campaigns, not least that of glabrescol, an important steroid precursor.

Other electrophilic addition reactions

The named transformations highlighted here aren’t the only electrophilic addition reactions available to synthetic chemists. Other notable examples include the Jacobsen–Katsuki epoxidation, Sharpless asymmetric epoxidation, Brown hydroboration reaction, and Davis’ oxaziridine oxidation. To find out more, visit our dedicated electrophilic addition reactions page.


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