Remote C-H Bond Functionalizations. Группа авторов

protocol would be potentially useful for late‐stage modification and post‐synthetic diversification of biologically active molecules for drug discovery. Density functional theory (DFT) computational studies were also performed to reveal that regioselectivity of this reaction resulted from both the C–N–Ag angles and gauche conformations of phenyl ether play.

Scheme 2.54 meta‐C–H olefination of distal arene‐tethered alcohols.

      Source: Modified from Zhang et al. [50].

Subsequently, by using a different pyrimidine‐based template that was used for meta‐C–H cyanation of phenyl ethyl alcohols [41], Jayarajan, Maiti, and coworkers achieved meta‐C–H functionalizations of conformationally flexible long‐chain arenes derived from alcohols (Scheme 2.55) [51]. The chain length could be up to 18 bonds between the target C

H bond and the chelating nitrogen atom of the directing template. Remarkably, this approach enabled diverse functionalizations include olefination, alkylation, cyanation, and acetoxylation. Moreover, the template could be readily cleaved by using ceric ammonium nitrate (CAN) under mild conditions (Scheme 2.56). It is worth noting that when perfluoroolefins were used, meta‐C–H olefination was also feasible for these alcohol derivatives with different linker length under similar reaction conditions [24].

Scheme 2.55 meta‐C–H functionalizations of arenes with different linker lengths.

      Source: Modified from Jayarajan et al. [51].

Scheme 2.56 Removal of the pyrimidine‐based template.

In 2019, Paton, Maiti, and coworkers developed the Palladium(II)‐catalyzed meta‐selective C–H allylation of alcohol derivatives using synthetically inert acyclic internal olefins as allylic surrogates, under the conditions discussed earlier for benzylsulfonyl esters (Scheme 2.57) [27]. Experimental and computational studies implied that the pyrimidine‐based directing group was crucial this meta‐selective C–H activation in determining the product selectivities. Notably, besides phenylethyl alcohols, alcohol derivatives with longer chain homologues could also be viable in this transformation.

Scheme 2.57 meta‐C–H allylation of alcohol derivatives.

      Source: Modified from Achar et al. [27].

Recently, Wang, Kong, and coworkers developed the palladium‐catalyzed meta‐olefination of arene‐tethered diols assisted by a pyrimidine‐based template (Scheme 2.58) [52]. It was demonstrated this method could be used for the facile synthesis of various diol‐based natural products such as coumarins. Moreover, removal of the template was easily realized by hydrolysis under acidic conditions.

Scheme 2.58 meta‐C–H olefination of arene‐tethered diols.

      Source: Modified from Fang et al. [52].

Finally, Yu, Dai, and coworkers also achieved meta‐C–H deuteration of benzyl and phenyl ethyl alcohols with a pyridine‐based template using easily available deuterium source such as deuterated acetic acid (Scheme 2.59) [19]. The template was linked to the substrate through a practical ester linkage that could 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