Functionalization of unactivated carbon–hydrogen (C–H) single bonds is an efficient strategy for rapid generation of complex molecules from simpler ones. However, it is difficult to achieve selectivity when multiple inequivalent C–H bonds are present in the target molecule. The usual approach is to use
-chelating directing groups, which lead to… σ
Figures at a glance
Figure 1: A template strategy for the activation of distal meta-C–H bonds (more than ten bonds away).
a, Remote meta-C–H activation is a challenge. I: ortho-directed C–H activation. DG, directing group. II, III and IV: Remote meta-C–H activation using an ‘end-on’ template. The dotted blue lines divide the arene template into four quadrants. The blue bonds in all figures highlight the targeted C–H bonds. b, Templates for toluenes and hydrocinnamic acids. c, Unprecedented positional selectivity in C–H activation, overriding electronic and steric biases, and ortho-directing effects.. d, Structurally related drug molecules (brand names in parentheses).
Figure 2: Template-directed meta-selective C–H olefination of toluene derivatives.
a, Arenes ( 8a– p) with a variety of substitution patterns undergo facile olefination. b, In the box, many election-deficient olefins and various di- and tri-substituted olefins were used. The isolated yield of the mono-olefinated product (and also the isolated yield of the di-olefinated product when applicable) is shown along with the selectivity. See Supplementary Information for experimental details. Selectivity of the mono- and di-olefinated products was determined by H NMR analysis and confirmed by one-dimensional selective NOESY experiments; the variance is estimated to be within 5%. OPiv, pivalate. 1
Figure 3: Template-directed meta-selective C–H olefination of hydrocinnamic acid derivatives.