| Palladium-catalyzed Buchwald-Hartwig(BH) amination reactions are among the most powerful synthetic methods for the construction of C-N bonds. It is generally thought that BH amination reactions proceed via the well-documented Pd(0)/Pd(II) catalytic cycle. First, the aryl halide undergoes an oxidative addition(OA) reaction at the activated Pd(0) site. Subsequently, deprotonation of the coordinated amine assisted by the base could afford an intermediate of transmetalation. Finally, a reductive elimination(RE) reaction of the yielded intermediate occurs to afford the cross-coupling product. The commonly proposed reaction mechanism for the NHC-Pd(II) catalyzed amination reaction is through a Pd(0)/Pd(II) catalytic cycle, started by the activation of Pd(II) to Pd(0). However, In some special reaction system, if the NHC-Pd(II) is inadequate to be reduced to a Pd(0) species, the Pd(0)/Pd(II) catalytic cycle could not be applied. Is there any other possible mechanism to drive the Buchwald-Hartwig amination reactions? Considered here is the Pd-PEPPSI-catalyzed aryl amination of chlorobenzene with aniline. We ruled out possible pathways of activation of original Pd(II) to Pd(0) from two aspects of experiments and theoretical calculation. A Pd(II)-involved σ-bond metathesis mechanism, which is not dependent on the Pd(0)/Pd(II) catalytic cycle, was proposed.First, some possible factors, such as 1,4-dioxane solvent, 3-chlorine pyridine ligand of the PEPPSI complex, and KOtBu, which might potentially reduce the Pd(II) to Pd(0) were ruled out experimentally. To rule out the potentially critical role of the 1,4-dioxane solvent in reducing the Pd(II) complex, amination reactions in which 1,4-dioxane was replaced by toluene or aniline, were carried out and proceeded with excellent yields of the desired product. To rule out the potentially critical role of the 3-chlorine pyridine ligand in reducing the Pd(II) complex, we synthesized another PEPPSI analog, 1h((IPr)Pd Cl2Ph-NH2), in which the labile ligand is replaced by aniline. 1h can also effectively promote the same reaction. The base, KOtBu, might play a reductive role in converting the Pd(II) precatalyst to the Pd(0) species. Therefore, we carried out the amination reaction replacing KOtBu with KOH, some desired product was also obtained.Aniline is most likely to function as a potential reducing agent in converting Pd(II) to the Pd(0) species. Thus, possible pathways involving aniline were computationally explored. Three anilido-containing Pd(II)-intermediates might be formed. RE of the three intermediates might not be feasible because of relatively high energy barrier. So it is difficult for aniline to reduce the Pd(II) to Pd(0) species. Moreover, the three intermediates might undergo four kinds of different mechanistic pathways, which are the Pd(II)/Pd(IV) mechanism, single electron transfer mechanism, halide atom transfer mechanism and a Pd(II)-involved σ-bond metathesis mechanism, to yield the cross-coupling product. Computational results suggest that the σ-bond metathesis mechanism pathway of anilido-containing Pd(II) intermediates has a lower energy barrier in leading to the C-N cross-coupling product and, therefore, is much more feasible to drive the BH amination reaction. Other proposed reaction pathways, such as Pd(II)/Pd(IV) mechanism, single electron transfer mechanism, and halide atom transfer mechanism, cannot compete with the σ-bond metathesis mechanism. In some special cases, if reactants/additives are inadequate to reduce a Pd(II) precatalyst, a Pd(II)-involved σ-bond metathesis mechanism might be feasible to drive the Buchwald-Hartwig amination reactions. Finally, the investigation of the substituent effect of the proposed σ-bond metathesis mechanism suggested that the chlorobenzenes with electron-withdrawing group at the para-position are more reactive to undergo the BH aminations. The unprecedented mechanism proposed herein is expected to stimulate further mechanistic studies of Buchwald-Hartwig amination reactions. |
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