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Room-temperature copper-catalyzed carbon-nitrogen coupling of aryl iodides and bromides promoted by organic ionic bases.

Transition-metal-catalyzed couplings provide important tools in modern organic synthesis. The bases commonly employed for these couplings are salts of alkaline or alkaline-earth metals (e.g. K3PO4, NaOtBu, and Cs2CO3). They are thought to facilitate the otherwise slow transmetalation (e.g. in Suzuki couplings), reductive elimination (e.g. in Heck couplings), or nucleophile deprotonation/coordination (e.g. in carbon–heteroatom couplings). At present, the choice of base remains empirical. Problems are often encountered for the couplings in less polar solvents where most inorganic bases are poorly soluble. To solve these problems we propose the use of organic ionic bases composed of organic cations and basic anions. These bases are well soluble in organic solvents. More importantly, they exhibit novel useful reactivities. Figure 1 shows the organic ionic bases synthesized in the present study. Most of them are new compounds. They were prepared mainly through the reaction between an equimolar quantity of tetraalkylammonium or -phosphonium hydroxide and the appropriate acid. To demonstrate the advantage of using organic ionic bases, we report novel room-temperature (RT) Cu-catalyzed C–N couplings promoted by these bases. Our work starts with the coupling of aryl iodides with amines. Recently Buchwald et al. reported the first protocol for this coupling at room temperature; other research groups have described related work. In the present study we have examined different organic ionic bases. We found that TMAP and TEAP do not mediate the coupling (Figure 2a) at room temperature (25 1 8C), although they are both well soluble. Significant yields (ca. 40–80%) are obtained when TBAP is used, indicating the importance of choosing a bulky cation. When the cation is fixed as NnBu4 , the yield varies dramatically with different anions. These observations reveal that solubility alone does not explain the utility of organic ionic bases. The best yield (95 %) is obtained with TBAA, which is a carboxylate base. Remarkably, the use of a very simple and cheap ligand (i.e. l-proline as opposed to 2-isobutyrylcyclohexanone in the previous protocol) is sufficient for the reaction to proceed in high yields at room temperature. Also, the current protocol is not sensitive to water (see Scheme 1, footnote [a]). Application of the optimized protocol to diverse aryl iodides (Scheme 1) was successful. Both electron-rich and electron-poor aryl iodides show high to excellent yields when coupled with aliphatic amines. Side products may arise from the reaction of the nucleophile with the tetraalkylammonium cation. However, GC–MS analysis of the reaction mixtures from the described coupling reactions shows no such side products (see the Supporting Information). To further minimize this potential problem, we examined the organic ionic bases having tetraalkylphosphonium as the cation; they are known to be much more stable than tetraalkylammonium salts. Remarkably, the phosphonium bases perform even much better than the ammonium bases. For the coupling of PhI with BnNH2 at room temperature, TBPE can drive the reaction to completion within approximately 30 min (Figure 2c) whereas TBAA requires roughly 24 h. Additional evidence for the extremely facile C–N coupling is the fact that TBPE can promote the amination of aryl iodides even at 0 8C in 5 h (Scheme 2). The unprecedented facility of the coupling implies that even aryl bromides may be activated at room temperature. Indeed TBPE promotes the coupling of PhBr with BnNH2 at room temperature (70 % yield). Further tests of other phosphonium bases show that TBPM gives the best result Figure 1. Structures of the organic ionic bases in this study.