Electron rich halo-substituted aromatics do not often undergo alkylation of amines only in presence of a base and without a catalyst. A set of strategies, however, already exist. Apparently, these strategies to easy the C-N bond formation, has been transported from the toolbox of catalytic C-C bond formation. The set includes Cu-mediated(Ullmann-type reactions)and Pd-catalyzed (Buchwald-Hartwig methods) as the main basic methodologies.
Lately, a very interesting Kumada Cross-Coupling between aryl-amines and aryl-halides has been published (Org.Lett. 2005, 7, 2209-2211). The use of EtMgBr activates the amine enhancing its reactivity and a simple and cheap Nickel triphenylphosphine based catalyst does the job. This paper opens the possibility to transmetallation with Zn, Sn and boron derivatives (Negishi, Stille and Suzuki couplings) which I’d guess are also possible and potentially very useful in particular cases.
On the other hand, Buchwald-Hartwig aminations showed a much better performance with secondary amines than the Ullmann-type coupling (Tetrahedron, 2006, 62, 9010-9016) in piperazine arylations. The role of the Pd catalyst, once more, is unclear, since there is no much difference using BINAP or the simpler and cheaper triphenylphosphine. The role of the base is key, but the role of the Cessium cation on the arylation of secondary amines under Pd catalytic conditions is also unclear to me.
In the aminoalcohols particular cases (J.Am.Chem.Soc., 2007, 129, 3490-3491), the N-arylation is preferred over O-arylation under Buchwald-Hartwig conditions. In the Ullmann-type reactions, however, C-O coupling can undergo preferently one way or another depending on the reaction conditions in this very interesting study.
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