/ Recent applications of gem-dichloroepoxide intermediates in synthesis
. It involves a minimum of three discreet substitution reactions (intramolecular nucleophilic substitution to give reactive gem-dichloroepoxide intermediate 4, inter- or intramolecular nucleophilic substitution and chloride elimination to produce 5, and nucleophilic acyl substitution to afford 6) in a one-pot process. . The wide variety of heteroatom nucleophiles compatible with the necessary reaction conditions provides access to a broad range of .-substituted carboxylic acid derivatives in a multi-component reaction process. . The reactions are typically conducted in inexpensive aqueous or lower alcohol solvents (neat or with an organic co-solvent depending upon substrate solubility and nucleophile compatibility), and the by-products are H2O and NaCl under most conditions. . The tolerance of protic media offers operational simplicity relative to typical epoxide substitution reactions. . The gem-dichloroepoxide intermediates (4) are inherently reactive and do not require the addition of strong Lewis or Brönsted acids for substitutions to occur. Disubstituted trichloromethyl carbinols (2 where R1 or R2 = H) used in Jocic-Reeve reactions are prepared in high yields by aldehyde additions to trichloromethide, from treatment of carbanions with chloral, or by reduction of trichloromethyl ketones, among other approaches.6 Due to the poor nucleophilicity of trichloromethide, from both steric and electronic perspectives, the preparation of many tertiary trichloromethyl carbinols (2 where R1 and R2 = alkyl or aryl) by ketone additions to trichloromethide generally results in lower yields compared to additions by aldehydes. However, tertiary trichloromethyl carbinols more readily form gem-dichloroepoxides than their secondary counterparts (thereby allowing the Bargellini reaction to proceed without isolation of 2), and the resulting 2,2-disubstituted-1,1-dichloroepoxides (4 where R ≠ H) are more stable and less prone to side reactions than the kinetically reactive 2-monosubstituted species (4 where R1 or R2 = H).7 Synthetic applications involving gem-dichloroepoxide intermediates reported in publications during the past decade (2001-early 2011) are the focus of this review. More details related to each named reaction are supplied in each respective section. 2. Jocic (Jocic-Reeve) Reactions The Jocic reaction,1 or preferably the Jocic-Reeve reaction considering Wilkins Reeves’ seminal contributions to both the mechanistic understanding and development of applications of the original Jocic reaction,5,8,9 is a powerful method for the preparation of a variety of .-substituted carboxylic acid derivatives and heterocycles. The reaction proceeds through a gem- dichloroepoxide intermediate and was first disclosed by Zicojin Jocic in 1897. He reported a preparation of 2,2,2-trichloro-1-phenylethanol and its unexpected conversion to 2-chloro-2- phenylacetic acid in 22% yield upon treatment with aqueous KOH.1 Jocic’s publication appeared nine years prior to Bargellini’s,3b which also involved preparation of a product proceeding
Top of page Top of page