[1546-79-8] · C5H3F3N2O · N-Trifluoroacetylimidazole · (MW 164.10)
(dehydration; protection; acylation)
Physical Data: mp 136-137 °C; bp 45-46 °C/14 mmHg.
Solubility: sol most common solvents, e.g. ether, THF.
Analysis of Reagent Purity: commercial material is 98+% pure.
Preparative Methods: N,N´-Carbonyldiimidazole (20.5 g) is dissolved in 100 ml of dry THF and treated dropwise with 28.8 g of Trifluoroacetic Acid in 80 mL of dry THF. The resulting solution is cooled for several hours. Removal of the solvent and distillation of the filtrate gives 14.4 g of material. Alternatively, Imidazole (25.8 g) in 120 mL of dried THF is treated dropwise, with cooling, with 39.9 g of Trifluoroacetic Anhydride in 50 mL of dried THF. Filtration, removal of solvent, and distillation gives 24.8 g of product.1
Purification: by distillation.
Handling, Storage, and Precautions: store under nitrogen, carefully excluding water. Irritant; moisture sensitive; keep cold; flammable.
The protection of various amino acids has been achieved using this reagent with p-Nitrophenol to form the p-nitrophenyl esters;2 yields are 50-80%. The method seems less satisfactory than currently available techniques, e.g. the 1,3-Dicyclohexylcarbodiimide method, but may be of use in some specific cases where other methods give low yields, e.g. preparation of p-nitrophenyl N-benzyloxycarbonyl-b-benzyl-L-aspartate. The formation of simple alkyl and aryl esters by this method proceeds better at higher temperatures. At room temperature, a dramatic increase in yield may be achieved by adding a catalytic amount of alkoxide base. However, neither higher temperature nor alkoxide base increases the yield in the amino acid protection sequence mentioned above.
When 1 mol of N-trifluoroacetylimidazole is treated with 2 mol of carboxylic acid in THF, a mixed anhydride and the pure anhydride are formed in an equilibrium reaction. The sparingly soluble salt of trifluoroacetylimidazole precipitates out of the solution, driving the reaction to completion (Scheme 1). Thus on standing for 5 h the pure anhydride is obtained in high yield, usually in excess of 80%.3
Reaction of trifluoroacetylimidazole with an equimolar amount of amine in THF or ether, evaporation of solvent followed by washing with water gives the corresponding trifluoroacetamide in good yields (80%).1
N-Trifluoroacetylimidazole converts aldoximes to nitriles4 under mild and practically neutral conditions. The reaction is carried out by heating the aldoximes with N-trifluoroacetylimidazole in ether or THF under reflux for 2-3.5 h. A wide range of aldoximes are dehydrated, e.g. aliphatic, aromatic, and alkenic. The reaction also tolerates halogen and nitro functional groups. The dehydration of aldoximes is generally considered to be a base-promoted bimolecular mechanism.5
N-Trifluoroacetylimidazole is a powerful acetylating agent for alcohols and amines. If the imidazole is used together with a strong Brønsted acid the nitrogen is protonated to form an imidazolium ion, increasing the electrophilicity of the acyl group. Thus it was found that N-trifluoroacetylimidazole in conjuction with trifluoroacetic acid could acylate aromatic hydrocarbons to give ketones6 in good yield (70-90%).
The use of other acyl imidazoles was also investigated, e.g. PhCO, p-NO2C6H4CO, and p-ClC6H4CO imidazoles, and the yields for acyl transfer here too are good (80-95%) except for the p-nitrophenyl acyl group which was transferred with a yield of only 16%.
Imidazoles of aliphatic carboxylic or aromatic carboxylic acids containing electron-donating groups gave 2-acylfluorenes in especially high yields. A mechanism is given, as well as a discussion of the Hammett plots for the corresponding reactions.
The reagent is used for the preparation of volatile trifluoroacetyl derivatives of amines, alcohols, etc. for GLC purposes which are sensitive to electron-capture detection.7
Sean Bew, Susan Champion & Gemma Perkins
University of Bristol, UK