Iridium-catalyzed allylic fluorination using fluorine-18 fluoride

Objectives We recently introduced an iridium-catalyzed allylic fluorination of trichloroacetimidate derivatives of activated alcohols which was high yielding and reached completion within 15 min at room temperature (1). We have demonstrated that high specific activity fluorine-18 Kryptofix/potassium fluoride complex could be used as the fluoride source in this reaction. Here, we describe our progress towards optimizing this process for use in the synthesis of fluorine-18 labeled allylic fluorides. We have identified experimental parameters which lead to irreproducibility, increased the decay corrected radiochemical yield, expanded the compounds labeled, and simplified the procedure.

Methods A plastic vial was charged with solid [IrOMeCOD]2 (COD = Cyclooctadiene, 7 mg). A solution of [18F]-KF Kryptofix [2,2,2] was added (prepared by the 18O(p,n) 18F reaction using >95% O-18 enriched water, 10 mCi in 0.1 mL THF). To this solution trichloroacetimidate (13 mg, in 0.1 mL THF) was added. The vial was shaken, and then kept at room temperature for 15 min. Then a sample was diluted with 0.5 mL acetonitrile and analyzed by HPLC, which confirmed the presence of the allylic fluoride as the only fluorinated product. The yield was confirmed by passage of the bulk reaction solution through short alumina columns.

Results Initially, the reaction was erratic with low yields but with a stoichiometric excess of catalyst over Kryptofix the results stabilized and the reaction became reliable and reproducible. After optimization of additional parameters, the decay corrected radiochemical yield of the allylic fluoride shown was determined to be 48% - 64% (average 57%, n = 5). Several other allylic fluorides were synthesized in comparable yields.

Conclusions The iridium catalyzed allylic fluorination reaction can be applied to a variety of substrates using standard fluorine-18 potassium fluoride solutions