2012, Yu and coworkers devised the first effective U‐shaped nitrile‐based directing template that was covalently linked to the toluene derivatives via a removable benzyl ether linkage (Scheme 2.3) [11]. Notably, the directing ability of the template was improved by installing two isobutyl templates at the α‐position adjacent to the linearly chelating nitrile template due to the Thorpe–Ingold effect. This directing template efficiently enabled the meta‐C–H olefination of a broad range of toluene derivatives using Pd(OPiv)2 as the catalyst and AgOPiv as the oxidant. It is worth mentioning that such remote C–H activation that possibly demanded a cyclophane‐like 11‐membered palladacycle was first ever disclosed. Remarkably, the intrinsic electronic and steric biases of the substrates were successfully overridden. Finally, the directing template was readily cleaved through hydrogenolysis with a Pd/C catalyst.
Scheme 2.3 meta‐C–H activation of toluene derivatives.
Source: Modified from Leow et al. [11].
2.2.2 Acid Derivatives
2.2.2.1 Hydrocinnamic Acid Derivatives
In Yu's seminal report, meta‐C–H olefination of hydrocinnamic acid derivatives was also achieved using an easily synthesized and recyclable 2,2′‐azanediyldibenzonitrile directing template, which is now available from Sigma–Aldrich as the Yu–Li auxiliary [11]. This template was attached to several hydrocinnamic acids via a readily cleavable amide linkage (Scheme 2.4). It is worth mentioning that hydrocinnamic acids are core motifs of many drug molecules such as Baclofen. Notably, it was discovered that the MPAA ligand Ac‐Gly‐OH from the simplest amino acid significantly improved the yield of the reaction and improved the selectivity as well with the optimal HFIP solvent that was crucial for the full conversion of the substrate. It was found in subsequent reports that this set of novel reaction conditions was also highly effective for many of the directing templated assisted meta‐C–H transformations. In this transformation, not only the intrinsic electronic biases of the substrate were overridden (9, 10), but also challenging steric hindrance was overcome by the template (11). Intriguingly, biaryl acid substrate that has the same length between the chelating nitrile group and the target meta‐C
Scheme 2.4 meta‐C–H olefination of hydrocinnamic acid derivatives.
In 2016, Maiti and coworkers disclosed a 2‐hydroxybenzonitrile template for mono meta‐selective olefination of hydrocinnamic acids via an ester linkage (Scheme 2.5a) [14]. Due to the less statistical availability of the coordinating nitrile group compared with the original 2,2′‐azanediyldibenzonitrile directing template, high mono‐/di‐selectivity could be obtained with this new template at lower reaction temperature using 1,2‐dichloroethane (DCE) as the major solvent and HFIP as the minor solvent. Notably, hetero‐di‐olefination product could be afforded with a second meta‐C–H olefination under similar reaction conditions using HFIP as the sole solvent (Scheme 2.5b).
Scheme 2.5 (a) 2‐hydroxybenzonitrile template assisted mono meta‐selective olefination of hydrocinnamic acids; (b) meta‐selective hetero‐di‐olefination of hydrocinnamic acids.
Source: (a) Modified from Modak et al. [14].
Most recently, Li and coworkers developed the first example of carboxy group assisted, remote meta‐selective C(sp2)–H activation with a PdII‐catalyst via potential κ2 coordination of the carboxyl, suppressing the ortho‐C–H activation via the κ1 coordination (Scheme 2.6a) [15]. Unlike the previous nitrogen‐based CN‐containing or heteroarene‐containing templates, this is the first oxygen‐based carboxyl‐containing template, whose coordination geometry could be considered as a pseudo‐linear coordination along the aryl–CO2M bond similar to the nitrile‐coordination geometry. Notably, hydrocinnamic acids could be meta‐olefinated in a remote selective fashion, leaving the C
Scheme 2.6 (a) Proposed remote‐selective C‐H activation via κ2 coordination of the carboxyl. (b) Remote‐selective meta‐C–H olefination of hydrocinnamic acids. (c) Improved site‐selectivity and reactivity with a modified carboxyl‐containing template.
Source: (a) Modified from Li et al. [15].
Besides Pd‐catalysts, Rh‐catalyst could also be used for olefination of hydrocinnamic acids. In 2017, Lu, Sun, Yu, and coworkers reported the first example of Rh(III)‐catalyzed, directing template assisted remote meta‐C–H olefination of hydrocinnamic acids via a postulated 12‐membered macrocyclic intermediate (Scheme 2.7a) [16]. The directing template bearing a single nitrile group was slightly different from Yu's seminal template. Moreover, molecular oxygen could be used as the terminal oxidant for this reaction. Subsequently, meta‐C–H alkenylation of hydrocinnamic acids was also realized using alkynes, which are significantly less reactive than the polarized and reactive acrylate (Scheme 2.7b) [17]. Notably, transition
