Abstract
Herein, we report a highly effective protocol for the cross-coupling of (hetero)aryl bromides with fluorinated alcohols using the commercially available precatalyst tBuBrettPhos Pd G3 and Cs2CO3 in toluene. This Pd-catalyzed coupling features a short reaction time, excellent functional group tolerance, and compatibility with electron-rich and -poor (hetero)arenes. The method provides access to 18F-labeled trifluoroethyl ethers by cross-coupling with [18F]trifluoroethanol.
Highlights
Fluorinated alkyl aryl ethers are encountered in medicinal chemistry and agrochemistry, due to the ability of fluorine to modulate molecular properties including lipophilicity and metabolic stability.[1]
Include Chan−Lam coupling of aryl boronic acids,[2,3] Williamson ether synthesis,[4] and transition metal mediated cross-coupling of aryl halides with fluorinated alcohols.[5−8] Copper mediated approaches include coupling of fluorinated alcohols with aryl iodides under copper catalysis reported by Bonnet-Delpon and co-workers[5] and reaction of aryl bromides with a copper(I) fluoroalkoxide complex reported by the Weng group.[8]
Shekhar and co-workers reported novel biaryl phosphorinane ligands for Pd-catalyzed C−O cross-coupling with electron-rich and heteroaryl halides, but these ligands are currently not commercially available.[9]
Summary
Fluorinated alkyl aryl ethers are encountered in medicinal chemistry and agrochemistry, due to the ability of fluorine to modulate molecular properties including lipophilicity and metabolic stability.[1]. We report the Pdcatalyzed C−O coupling of fluorinated alcohols using tBuBrettPhos Pd G3 with the mild base Cs2CO3 in toluene. Under conditions similar to those reported by Singh, using BrettPhos, Pd2(dba)[3], and Cs2CO3 in toluene, no coupled product was formed after 1 h (entry 1).[6] Switching the ligand to either XPhos or tBuXPhos resulted in no product formation (entries 2 and 3).[15,16] Using tBuBrettPhos as ligand, the coupled product was observed in 51% yield (entry 4).
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