46789-GB3
Scope and Mechanism of Aromatic Perfluoroalkylation by Iron Reagents
Trifluoromethyl arenes are commonly-used moieties in man-made biologically-active compounds. The trifluoromethyl groups are thought to increase stability in vivo and lipid solubility. Although longer perfluoroalkyl chains could further enhance the desirable qualities of trifluoromethyl substituents, they are less frequently incorporated into pharmaceuticals. We have made significant progress towards realizing an arene-limiting procedure for the perfluoroalkylation of aromatic compounds using dichloromethane solvent. This improved procedure has allowed us to isolate our desired products using column chromatography. We have found that aromatic compounds with ether, halide, alkyl, and ester functional groups are amenable to perfluoroalkylation under these conditions. We used our newly-discovered arene-limiting perfluoroalkylation conditions to prepare a perfluoroalkyl analogue of ibuprofen. We also attempted derivatize acetaminophen, but this was unsuccessful.
We tried to improve the modest yield and scope of arene perfluoroalkylation reactions using iron perfluoroalkyl reagents by exploring derivatives of these compounds. Rapid ligand exchange reactions of FeI(C4F9)(CO)4 with pyridine, bipyridine, and phenanthroline gave FeI(C4F9)(pyr)2(CO)2, FeI(C4F9)(bipy)(CO)2, and FeI(C4F9)(phen)(CO)2 respectively. FeI(C4F9)(CO)4 reacts more slowly with triphenylphosphine and bis(diphenylphophino)ethane to give FeI(C4F9)(PPh3)(CO)3 and FeI(C4F9)(dppe)(CO)2. All of these organometallic compounds have been isolated in pure form. FeI(C4F9)(CO)4 also reacts with methyl isocyanide (CNCH3) to give multiple compounds, most likely isomers of FeI(C4F9)(CNCH3)2(CO)2. When Tl+ was used to trap free I- in the ligand exchange reactions, complete loss of CO ligands was observed. In contrast to the parent FeI(C4F9)(CO)4, treatment of the substituted compounds with AgO2CCF3 in benzene gave little or no perfluorobutylbenzene.
We also began studying the mechanism of perfluoroalkylation. Treatment of a solution of FeI(C4F9)(CO)4 with one equiv of TlO2CCF3 or AgO2CCF3 in CH2Cl2 or THF gives a solution exhibiting the same pattern of IR bands as FeI(C4F9)(CO)4, but at slightly higher energy. We propose that this compound is Fe(O2CCF3)(C4F9)(CO)4. We have not yet been able to isolate this species, as it decomposes in solution over the course of approximately 1 h. We have attempted to trap this intermediate with PPh3, although we have not been completely successful as of yet.
