Bargellini reaction

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The Bargellini reaction is a multicomponent reaction in organic chemistry named after Guido Bargellini (1879–1963) . It offers good atom economy and is related to the reactions named after Jocic (-Reeve) and Corey-Link.

Bargellini reported in 1906 the formation of 2-methyl-2-phenoxypropionic acid by the action of acetone on phenol in chloroform in the presence of sodium hydroxide :

Multi-component synthesis of 2-methyl-2-phenoxypropionic acid.
Overview reaction using the example of the reaction of a β-amino alcohol (X = O) or a diamine (X = NR) with acetone and chloroform in a basic medium. A substituted morpholinone or piperazinone is formed (bottom right).

By using aluminum oxide coated with potassium fluoride as a basic component, substrates sensitive to hydrolysis can be protected.

Reaction mechanism

A sterically accessible ketone adds trichloromethide - formed in situ by deprotonation from chloroform under basic conditions - and forms the corresponding trichloromethyl carbinol or alkoxide . This addition product is subject to base-induced intramolecular etherification to gem- dichloro epoxide . Nucleophiles substitute regioselectively at the α-carbon on this intermediate reactive compound , which leads to the formation of α-substituted carboxylic acid chlorides. Nucleophilic acyl substitution, including solvolysis , ultimately gives the carboxylic acid derivative.

Possible reaction mechanism of the Bargellini reaction.

application

One area of ​​application of this reaction is the preparation of carboxylic acid derivatives which are sterically hindered in the α-position.

Examples of drugs and active ingredients that are accessible via the Bargellini reaction are fenofibrate , carfentanyl and griseofulvin analogues.

Individual evidence

  1. ↑ Gianluca Papeo, Maurizio Pulici: Italian Chemists' Contributions to Named Reactions in Organic Synthesis: An Historical Perspective . In: Molecules . 18, No. 9, September 4, 2013, pp. 10870-10900. doi : 10.3390 / molecules180910870 .
  2. ↑ Organische-Chemie.ch: Jocic reaction
  3. ↑ Guido Bargellini : Azione del cloroformio e idrato sodico sui fenoli in soluzione nell'acetone. In: Gazz. Chim. Ital. 36, 1906, pp. 329-338.
  4. ↑ Md. Rumum Rohman, Bekington Myrboh: KF-alumina-mediated Bargellini reaction. In: Tetrahedron Letters . 51, No. 36, 2010, pp. 4772-4775, doi : 10.1016 / j.tetlet.2010.07.029 .
  5. ↑ Not all ketones react equally well. See Gerhard Korger: About the synthesis of grisanones- (3). In: Chemical Reports. 96, No. 1, 1963, pp. 10-37, doi : 10.1002 / cber.19630960103 .
  6. ↑ Timothy S. Snowden: Recent applications of gem-dichloroepoxide intermediates in synthesis. In: ARKIVOC. 2, 2012, pp. 24-40 ( PDF ).
  7. ^ Jie Jack Li: Name Reactions . 3rd edition, Springer, 2006, ISBN 3-540-30030-9 , pp. 24-25.
  8. ↑ Ken J. Butcher, Jenny Hurst: Aromatic amines as nucleophiles in the Bargellini reaction. In: Tetrahedron Letters. 50, No. 21, 2009, pp. 2497-2500, doi : 10.1016 / j.tetlet.2009.03.044 .
  9. ↑ Gerhard Korger: About the synthesis of grisanones- (3). In: Chemical Reports. 96, No. 1, 1963, pp. 10-37, doi : 10.1002 / cber.19630960103 .

further reading

  • Lauren Rebecca Cafiero: New synthetic applications of trichloromethyl carbinols in synthesis. 2009 (Dissertation, PDF ; 5.0 MB)
  • Timothy S. Snowden: Recent applications of gem-dichloroepoxide intermediates in synthesis. In: ARKIVOC. 2, 2012, pp. 24-40 ( PDF ).

Web links

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