Remote C-H Bond Functionalizations. Группа авторов

olefination of phosphonates at room temperature using the 2‐cyanophenol template (Scheme 2.62) [54]. At elevated temperature, the reaction could be extended to meta‐C–H hydroxylation or acetoxylation by varying the acetoxylating agent PhI(OCOR)₂. Notably, sequential di‐meta‐olefination would afford tri‐alkenylated arenes that could be used in organic electronics as well as optoelectronics.

Scheme 2.62 meta‐C–H functionalizations of phosphonates.

      Source: Modified from Bera et al. [54].

Later in 2017, Maiti and coworkers achieved the meta‐C–H alkylation of benzylphosphonates by using a pyrimidine‐based template using allyl alcohols, leading to the formation of β‐aryl aldehydes and ketones (Scheme 2.63) [39]. Notably, the generality of this meta‐alkylation had been demonstrated in phenethylsulfonyl ester as well as phenethyl carbonyl scaffolds as discussed earlier. Moreover, meta‐C–H cyanation of benzylphosphonates was also achieved by using the same pyrimidine‐based template, albeit only two examples were disclosed [41].

Scheme 2.63 meta‐C–H alkylation of phosphonates.

      Source: Modified from Bag et al. [39].

Phosphonates are useful synthons in the synthetic chemistry, since they could be transformed readily to the versatile alkenyl product by well‐established Horner–Wadsworth–Emmons reactions. And due to the importance of deuterium‐labeled compounds for pharmaceutical industry and reaction mechanistic studies, efficient direct deuteration methods would be very valuable. Recently, Yu, Dai, and coworkers developed palladium‐catalyzed meta‐selective C–H deuteration of benzylphosphonates by using a pyridine‐based directing template (Scheme 2.64) [19]. Notably, this method could be generally used for other substrates such as benzylsulfonates and benzyl alcohols via the practical ester linkage.

Scheme 2.64 meta‐C–H deuteration of phosphonates.

      Source: Modified from Xu et al. [19].

2.3 Mechanistic Considerations

      The mechanisms of the aforementioned template assisted meta‐C–H activation reactions are still not exactly very clear at present. However, detailed mechanistic investigations through computational and experimental mechanistic studies have been performed by such as the groups of Houk, Yu, and Wu, and the Maiti group to gain some hints of the reaction mechanism.

The representative template assisted meta‐C–H activation is olefination via Pd(II)/Pd(0) process with the nitrile‐based directing template. Thus, a tentative catalytic cycle could be proposed for this reaction (Scheme 2.65). The catalytic process proceeds through five major steps: C–H activation, olefin binding and alkene migratory insertion, β‐hydride elimination, reductive elimination, and re‐oxidation of the Pd‐catalyst. Computational study using density functional theory elucidated that the C–H activation step, which proceeds via a concerted metalation–deprotonation (CMD) pathway, was the rate‐ and regioselectivity‐determining step [55]. However, unlike the presentation in Scheme 2.65, it was found that the C–H activation with the nitrile‐based directing template occurred via a Pd–Ag heterodimeric transition state (Scheme 2.66). Moreover, the nitrile directing template coordinated with Ag an end‐on fashion rather than the Pd metal center. The Pd was then linked with Ag by the bridging acetate ligand and delivered to the meta‐C

H bond in the transition state, resulting in the observed high meta‐selectivity. However, it is worth noting that not all the template assisted meta‐C–H olefination required the use of silver salt, such as the meta‐C–H olefination of benzoic acids by the Li group [28]. In addition, significant effects of distortions of the template were observed in the structural and distortion energy analysis of the transition states, which had help to devise the conformationally flexible directing template for benzoic acids by the groups of Houk and Yu in 2017 [29].

Scheme 2.65 Proposed catalytic cycle for meta‐C–H olefination.

Scheme 2.66 Proposed transition state through computational study.

Subsequently, Houk, Yu, Wu, and coworkers revealed the dual roles of the amino acid ligand in improving reactivity and selectivity through mass spectrometry (MS) and DFT calculations [56]. It was found that the amino acid ligand aced as both a dianionic ligand and a proton acceptor, leading to the stabilization of the monomeric Pd complexes and serving as the internal base for proton abstraction through a CMD pathway.

      Besides the MPAA ligand, the HFIP solvent is another key factor for most of the template assisted meta‐C–H activation reactions. Although the exact role of HFIP is unknown at present, Maiti and coworkers proposed that the solvent HFIP could act as a coordinating ligand in the early stage of the reaction to promote the reaction through experimental and computational investigation [40,54]. Moreover, they also found that the hydrogen‐bonding between HFIP and the pyrimidine‐based template was vital to decrease the basicity of the pyrimidine group and increase the π‐acidity of the Pd center based on nuclear magnetic resonance (NMR) studies [51].

2.4 Conclusion

Since 2012, the directing template approach has promoted a range of meta‐selective C–H activation reactions with several classes of substrate. Three major classes of directing templates have been engineered by recognition of the geometry and distance between the directing atom and the target meta‐C

H bonds. The number of transformation types also increases gradually since the first discovery of meta‐C–H olefination. Despite the advances, the directing template strategy still suffers from several limitations. First, the transformation type is still limited, such as amination, fluorination, and alkynylation are not feasible at present. Thus, new protocols with possible new templates are needed. Second, it is not step‐economic to link the template with the substrate with a covalent bond. Although breakthroughs in using catalytic amount of templates have been disclosed, these protocols were limited to special substrates and suffer from limitations such as high metal catalyst loadings and high molecular weights. Therefore, the discovery of more efficient