The Jocic Reaction enables access to α-substituted carboxylic acids by the reaction of trichloromethylcarbinols with various nucleophiles in the presence of aqueous sodium hydroxide.
Mechanism of the Jocic Reaction
The mechanism as described by Snowden (Org. Lett., 2006, 8, 5881. DOI) includes the formation of a gem-dichlorooxirane intermediate. As the reaction only proceeds in protic solvents, Snowden postulates an SN1-type mechanism in the formation of the epoxide, where substantial bond breakage between chlorine and carbon facilitates the intramolecular attack:
In the next step, the reaction of the epoxide with either a strong nucleophile, or with hydroxide in the absence of an additional nucleophile, provides the α-substituted carboxylic acid (or acid derivative):
The ring opening of the epoxide follows a clear SN2 pathway including Walden inversion. Thus, the Jocic Reaction enables the synthesis of enantiomerically-enriched products with stereochemistry that is related to the configuration of the starting material. For example E.J. Corey (see recent literature) described a pathway to chiral α-amino acids using the Corey-Bakshi-Shibata Reduction of trichloromethyl ketones, followed by the Jocic Reaction of the intermediate chiral trichloromethylcarbinols with sodium azide and palladium-catalyzed hydrogenation to yield the amino acid:
A review by Wilkinson (Synthesis 1971, 131. DOI) describes the use of the Jocic Reaction, especially with tethered nucleophiles for the synthesis of heterocycles.