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Direct Functionalization Processes: A Journey from Palladium to Copper to Iron to Nickel to Metal-Free Coupling Reactions
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  • 作者:James J. Mousseau ; Andr茅 B. Charette
  • 刊名:Accounts of Chemical Research
  • 出版年:2013
  • 出版时间:February 19, 2013
  • 年:2013
  • 卷:46
  • 期:2
  • 页码:412-424
  • 全文大小:830K
  • 年卷期:v.46,no.2(February 19, 2013)
  • ISSN:1520-4898
文摘
The possibility of finding novel disconnections for the efficient synthesis of organic molecules has driven the interest in developing technologies to directly functionalize C鈥揌 bonds. The ubiquity of these bonds makes such transformations attractive, while also posing several challenges. The first, and perhaps most important, is the selective functionalization of one C鈥揌 bond over another. Another key problem is inducing reactivity at sites that have been historically unreactive and difficult to access without prior inefficient prefunctionalization.
Although remarkable advances have been made over the past decade toward solving these and other problems, several difficult tasks remain as researchers attempt to bring C鈥揌 functionalization reactions into common use. The functionalization of sp3 centers continues to be challenging relative to their sp and sp2 counterparts. Directing groups are often needed to increase the effective concentration of the catalyst at the targeted reaction site, forming thermodynamically stable coordination complexes. As such, the development of removable or convertible directing groups is desirable. Finally, the replacement of expensive rare earth reagents with less expensive and more sustainable catalysts or abandoning the use of catalysts entirely is essential for future practicality.
This Account describes our efforts toward solving some of these quandaries. We began our work in this area with the direct arylation of N-iminopyridinium ylides as a universal means to derivatize the germane six-membered heterocycle. We found that the Lewis basic benzoyl group of the pyridinium ylide could direct a palladium catalyst toward insertion at the 2-position of the pyridinium ring, forming a thermodynamically stable six-membered metallocycle. Subsequently we discovered the arylation of the benzylic site of 2-picolonium ylides. The same N-benzoyl group could direct a number of inexpensive copper salts to the 2-position of the pyridinium ylide, which led to the first description of a direct copper-catalyzed alkenylation onto an electron-deficient arene. This particular directing group offers two advantages: (1) it can be easily appended and removed to reveal the desired pyridine target, and (2) it can be incorporated in a cascade process in the preparation of pharmacologically relevant 2-pyrazolo[1,5-a]pyridines.
This work has solved some of the challenges in the direct arylation of nonheterocyclic arenes, including reversing the reactivity often observed with such transformations. Readily convertible directing groups were applied to facilitate the transformation. We also demonstrated that iron can promote intermolecular arylations effectively and that the omission of any metal still permits intramolecular arylation reactions. Lastly, we recently discovered a nickel-catalyzed intramolecular arylation of sp3 C鈥揌 bonds. Our mechanistic investigations of these processes have elucidated radical pathways, opening new avenues in future direct C鈥揌 functionalization reactions.

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