Selective functionalization reactions of aromatic and heteroaromatic halides with carbon, oxygen, and nitrogen nucleophiles have attracted much attention in the last decades. In addition to typical metal-catalyzed coupling reactions, direct functionalization of aryl halides through the formation of Grignard reagents offer new ways for the efficient construction of biologically interesting carboand heterocycles. Recent elegant examples include the development of LiClmediated preparation of Grignard reagents by Knochel and co-workers. Inspired by their work and our interest in functionalization reactions of aryl halides, we have been fascinated in the direct synthesis of aryl fluoride compounds from aryl Grignard reagents. Although a large number of known pharmaceutical and agrochemical products contain fluorinated arenes (Scheme 1), which enhance solubility, bioavailability, and metabolic stability compared with non-fluorinated analogues, there is no convenient and general synthetic method available for their synthesis. Commonly known methods for the introduction of a fluorine atom to arenes require relatively harsh reaction conditions. Typical examples include the direct fluorination of arenes, the Balz–Schiemann reaction of aryldiazonium salts with HBF4, and the so-called Halex exchange reaction of activated aryl halides with metal fluorides. In addition, transition-metal-promoted fluorinations have been achieved through the use of electrophilic N!F reagents such as Selectfluor or N-fluoropyridinium salts. Unfortunately, in most of these reactions stoichiometric amounts of the transition metal must be used or specific directing groups on the substrate are required. Most recently, Buchwald and co-workers developed an elegant palladium-catalyzed fluorination of aryl triflates using AgF or CsF. Our initial investigations aimed at the fluorination of 4bromoanisole (1), which is a particularly challenging substrate for nucleophilic fluorination, to give 4-fluoroanisole (2 ; Table 1). In our model reaction we converted 1 into the corresponding aryl Grignard 3 mediated by LiCl, according to the procedure developed by Krasovskiy and Knochel. We Scheme 1. Selected examples of therapeutically important aryl fluoride compounds.
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Apr 1, 2013
Masaki Otani + 8
Open Access