be easily attached to the benzyl alcohol substrates and readily cleaved in situ with tetrabutylammonium fluoride (TBAF) under mild conditions, making the approach synthetically practical. Using the MPAA ligand Ac‐Gly‐OH in the presence of HFIP, a range of benzyl alcohols were meta‐olefinated smoothly with all substitution patterns on the aromatic ring. Moreover, the template was applicable to both primary and secondary alcohols with equal efficacy.
Scheme 2.51 meta‐C–H olefination of benzyl alcohols.
Source: Modified from Lee et al. [48].
To expand the potential of achieving site selectivity in C–H activation via the recognition of distal and geometric relationship between existing chelating groups and C
Scheme 2.52 meta‐C–H olefination of benzyl and phenyl ethyl alcohols.
Source: Modified from Chu et al. [49].
Scheme 2.53 meta‐C–H iodination of benzyl and phenylethyl alcohols.
In 2017, Xu, Jin, and coworkers reported a Pd‐catalyzed remote meta‐C–H olefination of a wide range of arene‐tethered alcohols such as 2‐phenylethyl, 3‐phenylpropyl alcohols, and their long‐chain homologues (Scheme 2.54) [50]. This 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
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 (
