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. 2012 Feb 29;134(8):3683-6.
doi: 10.1021/ja2122156. Epub 2012 Feb 17.

Mechanistic studies on direct arylation of pyridine N-oxide: evidence for cooperative catalysis between two distinct palladium centers

Yichen Tan  1 , Fabiola Barrios-Landeros, John F Hartwig
Affiliations

Mechanistic studies on direct arylation of pyridine N-oxide: evidence for cooperative catalysis between two distinct palladium centers

Yichen Tan et al. J Am Chem Soc. .

Abstract

Direct arylations of pyridine N-oxide (PyO), a convenient method to prepare 2-arylpyridines, catalyzed by Pd(OAc)(2) and PtBu(3) have been proposed to occur by the generation of a PtBu(3)-ligated arylpalladium acetate complex, (PtBu(3))Pd(Ar)(OAc) (1), and the reaction of this complex with PyO. We provide strong evidence that 1 does not react directly with PyO. Instead, our data imply that the cyclometalated complex [Pd(OAc)(tBu(2)PCMe(2)CH(2))](2), which is generated from the decomposition of 1, reacts with PyO and serves as a catalyst for the reaction of PyO with 1. The reaction of PyO with 1 occurs with an induction period, and the reaction of 1 with excess PyO in the presence of [Pd(OAc)(tBu(2)PCMe(2)CH(2))](2) is zeroth-order in 1. Moreover, the rates of reactions of PyO with bromobenzene catalyzed by [Pd(OAc)(tBu(2)PCMe(2)CH(2))](2) and [Pd(PtBu(3))(2)] depend on the concentration of [Pd(OAc)(tBu(2)PCMe(2)CH(2))](2) but not on the concentration of [Pd(PtBu(3))(2)]. Finally, the reaction of 1 with a model heteroarylpalladium complex containing a cyclometalated phosphine, [(PEt(3))Pd(2-benzothienyl)(tBu(2)PCMe(2)CH(2))], rapidly formed the arylated heterocycle. Together, these data imply that the rate-determining C-H bond cleavage occurs between PyO and the cyclometalated [Pd(OAc)(tBu(2)PCMe(2)CH(2))](2) rather than between PyO and 1. In this case, the resulting heteroarylpalladium complex transfers the heteroaryl group to 1, and C-C bond-formation occurs from (PtBu(3))Pd(Ar)(2-pyridyl oxide). This mechanism proposed for the direct arylation of PyO constitutes an example of C-H bond functionalization in which C-H activation occurs at one metal center and the activated moiety undergoes functionalization after transfer to a second metal center.

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Figures

Figure 1
Figure 1
Decay of (PtBu3)Pd(Ar)(OAc) (1) in toluene at 60 °C in the presence of 20 equiv of pyridine N-oxide, 1.0 equiv of PtBu3 and 2.5 equiv of K2CO3 with no additive (black) or with 1 equiv of added complex 2 (blue).
Figure 2
Figure 2
Plots of rate versus [PyO] and [2]1/2 in toluene at 60 °C for the reaction of complex 1 with PyO.
Scheme 1
Scheme 1
Synthesis of (PtBu3)Pd(Ar)(OAc) (1) and Reaction of (1) with PyO under the previously reported conditions.a a Yield of arylated product determined by 19F NMR.
Scheme 2
Scheme 2
Two Possible Modes for C-H Bond Cleavage by Cyclometallated Palladium Acetate Complex.
Scheme 3
Scheme 3
Reaction of PyO with 1 Catalyzed by 2.
Scheme 4
Scheme 4
Reaction of Benzothienylpalladium Complex 4 and 5 with arylpalladium acetate complex 1.
Scheme 5
Scheme 5
Revised Mechanism for the Direct Arylation of PyO.
See this image and copyright information in PMC

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