Bargellini Reaction


I recently had the opportunity to put into practice the early 20th century work of the Italian chemist Bargellini, when I had to synthesise α-heterocyclic amino carboxylic acids.

The Bargellini reaction typically involves the addition of trichloromethide to a non hindered ketone resulting in a trichloromethyl carbinol. This rapidly forms a gem-dichloroepoxide. Phenols can add to this gem-dichloroepoxide to give α-phenoxyisobutyric acids.

I followed the work of Butcher and Hurst (Tetrahedron Letters 50, 2009, 2497–2500), which extended the range of novel nucleophiles that can add to the gem-dichloroepoxide intermediate with substituted anilines and amino heterocycles.

Using Boc-protected piperidinone, analogues were made using poorly nucleophilic amino heterocycles. Butcher found that weak, sterically hindered nucleophiles still gave products in useful yields, with the nucleophilic atom not restricted to being a substituent on an aromatic ring (pyrazole).

Kam 04-01-2015 Picture 1

Reaction mechanism for the original Bargellini reaction:Kam 04-01-2015 Picture 2

(Phenoxide can be substituted for other nucleophiles such as anilines/amino heterocycles etc)

In summary, the Bargellini reaction offers a way to introduce varying points of diversity, exploring chemical space in a one pot atom efficient approach.

Blog written by Kamlesh Bala

References: 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.)”. Gazzeta chimica Italiana.

Aromatic amines as nucleophiles in the Bargellini reaction; Ken J. Butcher, Jenny Hurst , Tetrahedron Letters 50 (2009) 2497–2500

 

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