Ortfio-metallation

The palladium-catalyzed formation of diarylamines has been used in several contexts to form molecules of biological relevance. The ability to prepare haloarenes selectively by an ortfio-metalation-halogenation sequence allows the selective delivery of an amino group to a substituted aromatic structure. Snieckus has used directed metalation to form aryl halides that were subsequently allowed to react with anilines to form diarylamines (Eq. (34)) [209]. Frost and Mendonqa have reported an iterative strategy to prepare, by the palladium-catalyzed chemistry, amides and sulfonamides that may act as peptidomimetics. Diaryl-amine units were constructed using the DPPF-ligated palladium catalysts, and the products were then acylated or sulfonated with 4-bromobenzoyl or arylsulfonyl chlorides [210]. Le-miere has coupled primary arylamines with 4-chloro-3(2H)-pyridazinones to form compounds with possible analgesic and antiinflammatory properties. 

For a review on the directed ortfio-metallation reaction, see V. Snieckus, Pure Appl. Chem., 1990,62, 2047 G. Qudguiner, F. Marsais, V. Snieckus and J. Epsztajn, Adv. Heterocycl. Chem., 1991,52, 187. 

Substrate— Aromatic bromides or iodides (Ar-X) are rapidly converted to the corresponding aryllithium (Ar-Li) when treated with 1 molar equivalent of -BuLi or 2 molar equivalents of t-BuLi. However, some substrates may rearrange to a more thermodynamically stable aryllithium via abstraction of a proton from a more acidic site, and this can lead to the formation of unwanted impurities (Scheme 12.5, eq. 2). Similarly, proton abstraction from aryl bromide substrates that contain an ortfio-directing metalation group (DMG) may lead to impurities in the final product. ... 

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