Triol-promoted activation of C–F bonds: Amination of benzylic fluorides under highly concentrated conditions mediated by 1,1,1-tris(hydroxymethyl)propane

Abstract

SummaryActivation of the C–F bond of benzylic fluorides was achieved using 1,1,1-tris(hydroxymethyl)propane (2) as a hydrogen bond-donating agent. Investigations demonstrated that hydrogen bond-donating solvents are promoting the activation and hydrogen bond-accepting ones are hindering it. However, the reaction is best run under highly concentrated conditions, where solvents cannot interfere with the interaction between the organofluorine compound and the triol. Various benzylic fluorides react with secondary amines or anilines to form benzylic amines in good yields.

Revised mechanistic explanation for the alcohol-promoted amination of benzylic fluorides under highly concentrated conditions: Computational and experimental evidence on a model substrate

“…At low activator loadings, the catalyst gets quickly ''poisoned'' by the fluorides and could therefore be unable to coordinate and activate the benzylic fluorine. 3 In conclusion, the nucleophilic substitution of a benzylic fluoride by morpholine promoted by alcohols has been studied Water was the only solvent that would enhance the reactivity of our substrate, as expected from our previous work [11,12]. However, competing experiments demonstrated that at 100 8C, water is a better activator than the triol itself and most of the observed conversion was due to water.…”

“…This can be seen by both the length of the H-bonds and the F-H-O angles ( Table 1). In contrast, the H-bonds in the dicoordinated transition structure (TS 2H-bonds ) are reminiscent of the length and angles observed for the strong H-bonds with water, described in the previous study [11]. The relative free energies of both transition structures show that the stronger 2 H-bonds found in TS 2H-bonds offer an overall better acceleration of the S N 2 process than the 3 weaker H-bonds of TS 3H-bonds .…”

“…As a follow-up, we hypothesized that if these three hydroxyl groups could be linked together in the form of a triol, activation of C-F bonds could be also possible. As such, we have later demonstrated that nucleophilic substitution of benzylic fluorides promoted by a triol was achievable on a range of benzylic fluorides and a variety of amine nucleophiles (Scheme 1B) [11]. Herein, we demonstrate that, as opposed to our initial hypothesis, only two OH of the triol, along with a single OH of a second triol, provide the hydrogen bonds needed for the activation.…”

“…At this point, conversion was measured by 1 H NMR by integrating the peaks corresponding to the starting material (d 5.42 ppm, d, 2H) and the desired product (d 3.53 ppm, s, 2H). The identity of 2 has already been unequivocally established in previous work [11,12]. For the catalytic reactions, the procedure is the same but the amount of promoter is 0.5 or 0.1 equiv.…”

“…Alcohols and 1,2-to 1,6-alkanediols were dried over 4 Å molecular sieves, then distilled prior to use. 4-(fluoromethyl)biphenyl (1) was synthesized according to a literature protocol [11].…”