be easily installed and cleaved. With high levels of D‐incorporation at the meta‐positions, this approach is potentially useful since deuterium‐labeled compounds are important for mechanistic and metabolic studies.
Scheme 2.59 meta‐C–H deuteration of alcohols.
Source: Modified from Xu et al. [19].
2.2.7 Silane Derivatives
In 2016, Maiti and coworkers reported the Pd‐catalyzed meta‐C–H olefination of synthetically versatile benzyl silanes using a nitrile‐based template (Scheme 2.60) [53]. Sequential olefinations through performing selective mono‐olefination and bis‐olefination were also demonstrated for synthesizing valuable 2,5‐ or 3,5‐hetero divinylbenzene derivatives. Notably, the templated could be easily installed, and meta‐olefinated toluene, benzaldehyde, and benzyl alcohols could be afforded while removing the silyl group with the template.
Scheme 2.60 meta‐C–H olefination of benzyl silanes.
Source: Modified from Patra et al. [53].
Subsequently in 2017, Maiti and coworkers also developed a pyrimidine‐based template assisted meta‐C–H cyanation of benzyl silanes using copper(I) cyanide as the cyanating agent (Scheme 2.61a) [41]. The meta‐cyano products are synthetically useful building blocks for preparing complex natural products as well as many drug molecules, and direct meta‐C–H cyanation of benzyl silane and converting the silyl group to hydroxy group could be applied to the preparation of antidepressant drug citalopram (Scheme 2.61b). It is worth mentioning that meta‐C–H allylation was also feasible with this template for benzyl silanes, although only limited examples were disclosed.
Scheme 2.61 (a) meta‐C–H cyanation of benzyl silanes. (b) Application of meta‐C–H cyanation of benzyl silanes.
Source: (a) Modified from Bag et al. [41].
2.2.8 Phosphonate Derivatives
In 2016, Bera, Maiti, and coworker achieved the first Pd(II)‐catalyzed meta‐C–H 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
