Bargellini reaction

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Bargellini reaction
Named after Guido Bargellini
Reaction type Coupling reaction

The Bargellini reaction is a

phenol derivative in chemistry texts at the time. However, Bargellini demonstrated that a carboxylic acid
derivative was actually the correct structure.

Later,

ketones (particularly acetone) and either β-amino alcohols or diamines.[3]

History

Guido Bargellini was a disciple of

Fischer esterification reaction. Bargellini did his post-doctoral lab research in Fischer's laboratory. He spent most of his career as a chemist at the University of Rome
.

His interest in

coumarins, a recently isolated compound at the time, led Bargellini to experiment with multi-component reactions (MCRs) between phenols, chloroform, and acetone in a solution of a sodium hydroxide. He discovered the structure given to the compound produced a carboxylic acid instead of a phenol as previously thought. In 1894, Link, a German chemist, had published the reaction in Chemisches Zentralblatt and patented it. However, he wrote the product was either a ketone or a phenol, specifically he claimed it was a "hydrpxyphenyl hydroxyisopropyl keton" or "hydroxyisobutyrylphenol."[4] When Bargellini conducted the same experiment and began testing the product, the chemical properties could not be from a ketone or a phenol. Instead, he was certain it was a carboxylic acid, specifically an "α-phenoxyisobutyric acid." Link himself experimented with reactions in 1900 that proved his original claim was erroneous, yet it was never changed. Since Bargellini correctly identified the product, its structure and properties, then published his results in the Gazzetta Chimica Italiana
, the reaction was named after him.

However, the importance of the reaction in organic synthesis and later the pharmaceutical industry has made it important historically. Since the reaction is relatively easy to perform—the reagents being readily available—many other almost identical reactions were named in the decades after. This discovery led the way for new transformation reaction, the presently-established Bargellini-type reactions, that has been of great importance, specifically in the

Jocic–Reeve reaction and the Corey–Link reaction
. The Jocic–Reeve and Corey–Link reactions are almost always featured together with the Bargellini reaction in a MCR. The reaction itself has been modified several times to increase efficiency or produce a modified product.

The adaptability of the reaction is one of its greatest aspects. No decade has gone by without an important addition or twist of the reaction taking place. In the author's own words, "The first phase in the reaction is probably the formation of

α-hydroxyisobutyric acid, which, with the phenol, gives α-phenoxyisobutyric acid. The chloroform may also be replaced by bromoform, bromal, chloral, or carbon tetrachloride or tetrabromide." Most textbooks describe the reaction as a way to make morpholinones or piperazinones
, but it use extend much farther than that.

One hundred years later, the Bargellini reaction itself was used for the condensation of coumarins, an ironic twist to the history of the reaction since this was Bargellini's primary compound of interest and his own named reaction produced it.[5]

Reactions and reaction mechanisms

The original Bargellini reaction (1906):

Bargellinis Original 1906 rxn small

Reaction mechanism for original Bargellini reaction (1906):

Original Bargellini Rxn 1906 Mechanism

Present-day Bargellini reaction used for synthesis of hindered morpholinones or piperazinones from ketones (primarily acetone) and 2-amino-2-methylpropan-1-ol (β-amino alcohols) OR 1,2-diaminopropanes (diamines). The solvent used is

amino alcohols
, as shown in the two possible scenarios below:

Two types of Bargellini reactions

Reaction mechanism for Bargellini reaction:

General reaction mechanism for Bargellini reaction

The reaction mechanism proceeds when a sterically accessible ketone, usually acetone, is added to a solution of chloroform (trichloromethane) under strong basic conditions, creating a trichloromethide anion by deprotonation. This forms the corresponding trichloromethyl carbinol or -alkoxide, in a similar way to the Grignard reaction.[6]

This trihalogenated product is subject to addition via a base-induced intramolecular etherification gem-dichloro epoxy. The amine can attack the oxirane due to formation of tertiary carbocation in a nucleophilic substitution SN1 concerted elimination of one atom of chlorine. The nucleophilic intermediate is highly reactive and regioselective at the α-carbon, resulting in the formation of a α-substituted carboxylic acid chloride.

The final step occurs by nucleophilic acyl substitution and solvolysis, where the amino or hydroxyl group attacks the acid chloride forming the corresponding heterocycle.[7] The end product is a carboxylic acid derivative (primarily lactones and amides).

References

  1. PMID 24008246
    .
  2. ^ Bargellini, Guido (June 4, 1906). "Azione del cloroformio e idrato sodico sui fenoli in soluzione nell'acetone" [Action of chloroform and sodium hydroxide on phenols in acetone solution]. Gazzetta Chimica Italiana.
  3. PMID 33494521
    .
  4. doi:10.1039/ca9069000617
    .
  5. doi:10.1016/j.tetlet.2005.10.045
    .
  6. S2CID 93616494
    .
  7. ^ Timothy S. Snowden: Recent applications of gem-dichloroepoxide intermediates in synthesis. In: ARKIVOC. 2, 2012, S. 24–40

External links

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