Iron chelators recent developments

Deferoxamine is the oldest of the chelation therapies, and is administered typically at 40mg/kg body weight, for 8-12 h, 4 days per week. However, some patients do not receive sufficient benefit from deferoxamine and develop cardiac iron overload and failure [S ]. More recently, orally bioavailable chelators, such as deferiprone and deferasirox, have become popular. However, the oral iron chelators have shown side effects that differ from those of deferoxamine. Deferiprone has proven to be more efficacious than deferasirox in several clinical trials, and is now routinely administered when deferoxamine treatment has failed. However, it is associated with agranulocytosis in about 1% of patients through an as yet undetermined mechanism and neutropenia more rarely. Deferiprone has been in use in Europe since 1999 but was not approved in the United States until 2011, due in part to a controversy over its safety [4 ]. 

Various methodologies for catalytic direct arylations via C—H bond activation employing transition metals other than palladium have been developed in recent years. In particular, rhodium- and ruthenium-based complexes have enabled the development of promising protocols for catalytic direct arylations. Whilst rhodium catalysts were found broadly applicable to the direct aryiation of both arenes, as well as heteroarenes, ruthenium-catalyzed chelation-assisted C—H bond function-ahzations could be used for the conversion of a variety of attractive organic electrophiles. In addition, inexpensive copper and iron salts have recently been shown as economically attractive alternatives to previously developed more expensive catalysts. Given the economically and environmentally benign features of selective C—H bond functionalizations, the development of further valuable protocols is expected in this rapidly evolving research area. 

In an effort to move away from precious metal catalysts, various reports in recent years have focused on the use of first-row metal catalysts for direct arylations [57-60]. As a representative example of these new developments, we illustrate in Scheme 23.15 the chelate-assisted ortho-C-H arylation of arenes with Fe catalysts [61]. With iron being cheap, nontoxic, and ubiquitous, this protocol is highly attractive for pharmaceutical syntheses. Using the catalyst precursor Fe(acac)j in conjunction with bidentate pyridine ligands, Zn-aryl reagents as aryl transfer reagents and 1,2-dichloroisobutane as the oxidant, excellent yields of the arylated product were obtained. An interesting feature of this reaction is the hydrolysis of the imine moiety after work-up. The reaction conditions tolerate additional functionalities such as cyanides, chlorides, triflates, tosylates, and thiophenes. 

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