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Rearrangement reactions: why shifting bonds is so synthetically useful

March 5, 2019


Rearrangement reactions are among the most useful transformations in organic synthesis. Why? Well, these reactions do exactly what you might expect them to – rearrange the carbon skeleton of a molecule to produce a structural isomer of the original.

Most rearrangement reactions involve the relocation of a substituent between adjacent atoms, but some more adventurous rearrangements involve migrations over longer distances.

One of the earliest named rearrangement reactions is the Lossen rearrangement, in which O-acyl hydroxamic acids are converted to their corresponding isocyanates. Discovered in 1872 by German chemist Wilhelm Lossen, this reaction is still widely used today, due to the fact that the versatile isocyanate products generated by this transformation can be converted into a wide range of useful compounds, including amines, carbamates, ureas and amides.

Since the Lossen rearrangement was discovered, a whole host of other rearrangements have been developed – and some have proved particularly useful. We’ve taken a trip through rearrangement reaction history to pick our top five, and ‘rearranged’ them into a handy list for you!

1.Curtius rearrangement

First reported by German chemist Theodor Curtius in 1885, the Curtius rearrangement describes the thermal decomposition of an acyl azide to an isocyanate, with the loss of nitrogen. Although the uncatalyzed reaction requires high temperatures, catalysis using either protic or Lewis acids significantly lowers the temperature needed, enabling more delicate substrates to be used.

If the reaction is carried out in the presence of water, amines or alcohols, the isocyanate products can be converted to their corresponding amines, ureas and carbamates. Interestingly, it is also possible to induce the Curtius rearrangement with photochemical conditions, in a process known as the Harger reaction.

The Curtius rearrangement has been employed in the total synthesis of several notable natural products. Streptonigrone, an antitumor and antibacterial agent, and pancratistatin, a potent antitumor and antiviral compound, were both synthesized in campaigns involving the Curtius rearrangement.

2.Beckmann rearrangement

The mid-1880s were an exciting time for rearrangement reactions! After ‘courteously’ waiting for Curtius to report his discovery (or at least that’s what we think!), German chemist Ernst Otto Beckmann described another rearrangement just a year later. In 1886, he reported the conversion of aldoximes and ketoximes to their corresponding amides under acidic conditions. Since then, this reaction has come to be known as the Beckmann rearrangement.

The Beckmann rearrangement has developed a variety of synthetic uses and is still industrially important today. However, the reaction is not suitable for more sensitive substrates, as it is conducted under fairly harsh conditions – usually requiring temperatures over 130 °C and an excess of strong Brønsted acids such as sulfuric or acetic acid.

Perhaps the most common use of the Beckmann rearrangement is for the manufacture of caprolactam, a precursor that’s used in the synthesis of filaments and fibers such as nylon. In this process, cyclohexanone is converted to its oxime, which is then treated with acid to generate caprolactam by a Beckmann rearrangement.

3.Claisen rearrangement

The Claisen rearrangement is another reaction that has played a vital role in many total synthesis campaigns. Named after German chemist Rainer Ludwig Claisen, who reported the reaction in 1912, the transformation describes the thermal rearrangement of allyl vinyl ethers into their corresponding γ,δ-unsaturated carbonyl compounds.

The allyl vinyl ethers used in this reaction can be prepared in several ways – for example, they can be derived from the allylic alcohols via mercuric ion-catalyzed exchange with ethyl vinyl ether, or they can be produced by Wittig olefination of allyl formates and carbonyl compounds.

A more recent modification, the Johnson–Claisen rearrangement, has been used to synthesize a wide range of natural products and bioactive molecules. In this variation, an allylic alcohol is heated with trialkyl orthoacetate under mildly acidic conditions to produce a γ,δ-unsaturated ester.

4.Ferrier reaction

Another industrially useful rearrangement is the Ferrier reaction, which involves the Lewis acid-promoted rearrangement of unsaturated carbohydrates. Originally identified in 1914 by German chemist Emil Fischer, who described the allylic rearrangement of tri-O-acetyl-D-glucal to the corresponding 2,3-unsaturated hemiacetal, this reaction came into more widespread use in the 1960s when the British chemist Robert Ferrier recognized its enormous synthetic potential.

One Ferrier reaction just wasn’t enough, so Ferrier identified a second variant in 1979, widening the synthetic possibilities further. In this ‘Type II’ Ferrier reaction, exocyclic enol ethers can be converted to substituted cyclohexanones upon treatment with mercury (II) salts. The Type II reaction is particularly useful as the precursors are readily available from carbohydrates, and the Lewis acids used for the catalysis of this reaction can tolerate the presence of acid-sensitive functionalities.

The Ferrier reaction has been widely used in total synthesis. For example, a Type II Ferrier rearrangement was used in the stereoselective total synthesis of (+)-lycoricidine, an alkaloid with anti-cancer potential due to its antimitotic (cell-growth stopping) properties.

5.Hofmann rearrangement

The Hofmann rearrangement is closely related to our old friends the Lossen and Curtius rearrangements. In 1881, German chemist August Wilhelm Hofmann embarked on a series of experiments to determine the best conditions to convert acetamide into either methyl isocyanate or methylamine. Since then, the conversion of primary carboxamides to amines with one fewer carbon atom has come to be known as the Hofmann rearrangement.

Several modifications have since improved the reaction’s synthetic utility. For reactions of hydrophobic amines, methanolic sodium hypobromite can be used to provide the corresponding methylurethanes in high yields. A neutral electrochemically-induced Hofmann degradation has been developed that can tolerate acid- and base-sensitive substrates. Finally, to broaden the scope of the reaction for base-sensitive substrates, an oxidative rearrangement can be induced using hypervalent iodine reagents such as (diacetoxyiodo)benzene (or PIDA for short).

The Hofmann rearrangement is used for a range of important industrial applications, including the manufacture of diuretics such as furosemide. A modified version of this reaction was used in the total synthesis of the antifungal agent (+)-preussin.

Other rearrangement reactions

We’ve picked our top five here, but there are many more rearrangement reactions to choose from! Other well-known rearrangements include the Brook rearrangement, Carroll rearrangement, Ciamician–Dennstedt rearrangement, Cope rearrangement, Dimroth rearrangement, Favorskii rearrangement, Meisenheimer rearrangement, Overman rearrangement, Smiles rearrangement, Sommelet–Hauser rearrangement and Wittig rearrangement. To find out more, visit our dedicated rearrangement reactions page.



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