Mechanistic Studies on Direct Arylation of Pyridine N-Oxide: Evidence for Cooperative Catalysis between Two Distinct Palladium Centers

Abstract

Direct arylations of pyridine N-oxide (PyO), a convenient method to prepare 2-arylpyridines, catalyzed by Pd(OAc)2 and PtBu3 have been proposed to occur by the generation of a PtBu3-ligated arylpalladium acetate complex (PtBu3)Pd(Ar)(OAc) and the reaction of this complex with PyO. We provide strong evidence that (PtBu3)Pd(Ar)(OAc) does not react directly with pyridine N-oxide. Instead, our data imply that the cyclometallated complex [Pd(OAc)(tBu2PCMe2CH2)]2, which is generated from the decomposition of (PtBu3)Pd(Ar)(OAc), reacts with PyO and serves as a catalyst for the reaction of PyO with (PtBu3)Pd(Ar)(OAc). The reaction of PyO with (PtBu3)Pd(Ar)(OAc) occurs with an induction period, and the reaction of (PtBu3)Pd(Ar)(OAc) with excess PyO in the presence of [Pd(OAc)(tBu2PCMe2CH2)]2 is zero-order in (PtBu3)Pd(Ar)(OAc). Moreover, the rates of reactions of PyO with bromobenzene catalyzed by [Pd(OAc)(tBu2PCMe2CH2)]2 and [Pd(PtBu3)2] depend on the concentration of [Pd(OAc)(tBu2PCMe2CH2)]2, but not on the concentration of [Pd(PtBu3)2]. Finally, the reaction of (PtBu3)Pd(Ar)(OAc) with the model heteroarylpalladium complex containing a cyclometallated phosphine [(PEt3)Pd(2-benzothienyl)(tBu2PCMe2CH2)] rapidly formed the arylated heterocycle. Together, these data imply that the rate-determining C-H bond cleavage occurs between PyO and the cyclometallated [Pd(OAc)(tBu2PCMe2CH2)]2, rather than between PyO and (PtBu3)Pd(Ar)(OAc). In this case, the resulting heteroarylpalladium complex transfers the heteroaryl group to (PtBu3)Pd(Ar)(OAc), and C-C bondformation occurs from (PtBu3)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.

Recent Progress in C—C Cross-Coupling Reaction of PyridineN-Oxides

“…Hartwig 等 [45] CuI 催化的吡啶-N-氧化物的直接芳基化反应历程 主要由 3 个部分组成 [47] ; 首先, 是吡啶-N-氧化物的金属 化, 当 C-H 的酸性较强的时候会增加反应的效率, 甚 至用 K 3 PO 4 就可以金属化. 其次, 金属化的底物和 CuI 在配体菲啰啉存在下发生金属的交换反应, 最后再和芳 基碘发生偶联反应.…”

Cross‐Coupling of Heteroarenes by CH Functionalization: Recent Progress towards Direct Arylation and Heteroarylation Reactions Involving Heteroarenes Containing One Heteroatom

“…(1-Ad)COOH-catalyst also proved applicable to the chemoselective and site selective C-2 arylation of 2-(1H-pyrrol-3-yl)-pyridine (195) displaying acidic NH functionality with 4-bromoanisole (Scheme 100). [135] Ackermann and Lygin also discovered that the protocol used for the site selective arylation of compounds 193a, b and 195 was not limited to pyrroles and that the most efficient catalysis in direct arylation of N-substituted indoles 196a, b with aryl chlorides could be achieved with (1-Ad) 2 P(O)H (Ad = adamantyl) as the preA C H T U N G T R E N N U N G liA C H T U N G T R E N N U N G gand instead of (1-Ad)COOH.…”

“…[194] However, in 2012, Hartwig and co-workers provided evidence that complex 295 does not interact directly with pyridine N-oxide. [195] Instead, the data of these authors allowed them to propose that cyclometalated complex 296 (Figure 40), which is generated by de- composition of 295, reacts with pyridine N-oxide and serves as catalyst for the arylation of this substrate. [195] Scheme 153 illustrates the mechanism proposed for the arylation of pyridine N-oxide, in which the cooperative catalysis between two distinct palladium centers is evidenced in two catalytic cycles.…”

“…[195] Instead, the data of these authors allowed them to propose that cyclometalated complex 296 (Figure 40), which is generated by de- composition of 295, reacts with pyridine N-oxide and serves as catalyst for the arylation of this substrate. [195] Scheme 153 illustrates the mechanism proposed for the arylation of pyridine N-oxide, in which the cooperative catalysis between two distinct palladium centers is evidenced in two catalytic cycles. [195] In the bottom cycle, monomeric complex 296 reacts with pyridine N-oxide to cleave the C À H bond producing complex A that contains the cyclometalated phosphane.…”

“…[195] Scheme 153 illustrates the mechanism proposed for the arylation of pyridine N-oxide, in which the cooperative catalysis between two distinct palladium centers is evidenced in two catalytic cycles. [195] In the bottom cycle, monomeric complex 296 reacts with pyridine N-oxide to cleave the C À H bond producing complex A that contains the cyclometalated phosphane. In the left cycle, complex C, formed by oxidative addition of L n Pd(0) with the aryl bromide, under- goes transmetalation with the cyclometalated intermediate A to form the heteroaryl Pd species B. Reductive elimination would then give the 2-arylpyridine N-oxide product.…”