Dynamic Hydroxyl–Yne Reaction with Phenols

Dynamic Covalent Chemistry (DCvC) has gained increasing importance in supramolecular chemistry and materials science. Herein we prove the dynamic nature of the exchange between phenols and vinyl ethers. Exchange is fast at room temperature and under mild conditions. The equilibrium constants and the electronic effect of the phenol substituents were calculated. This novel incorporation to the DCvC toolbox could be quite useful, and as a proof it was used for the synthesis of a responsive molecular cage.


Materials and methods.
All reagents from commercial suppliers were used without further purification. All solvents were freshly distilled before use from appropriate drying agents. All other reagents were recrystallized or distilled when necessary. Analytical TLCs were performed with silica gel 60 F254 plates.
Visualization was accomplished by UV light or vanillin with acetic and sulfuric acid in ethanol with heating. Column chromatography was carried out using silica gel 60 (230-400 mesh ASTM). 1 H NMR spectra were recorded at 500 MHz and 400MHz, 13 C NMR spectra were recorded at 126 MHz and 100 MHz. Chemical shifts were reported in units (ppm) by assigning TMS resonance in the 1 H NMR spectrum as 0.00 ppm (deuterated chloroform, 7.26 ppm; acetonitrile-d3 1.94 ppm; DMSO-d6 2.50 ppm). Data were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q=quartet, dd = double doublet, ddd = double double doublet, m =multiplet and br = broad), coupling constant (J values) in Hz and integration. Chemical shifts for 13 C NMR spectra were recorded in ppm from tetramethylsilane using the central peak of CDCl3 (77.14 ppm) as the internal standard. High resolution mass spectra (HRMS) was measured by ESI method with an Agilent LC-Q-TOF-MS 6520 spectrometer.

General procedure for the synthesis of vinyl ether derivatives
To a solution of the appropriated phenol (1.0 mmol, 1 equiv.) in CH2Cl2 (10 mL) were added DABCO (1,4-Diazabicyclo[2.2.2]octane) (0.1 mmol, 0.1 equiv.) and methyl propiolate (1.1 mmol, 1.1 equiv.) dropwise. The reaction mixture was stirred at room temperature for 1 hour. Then, the solvent was removed under vacuum and the crude was purified by silica gel flash column chromatography using an elution of ethyl acetate/hexane to afford the desired product.
Characterization and spectral data.

General procedure
To a solution of the corresponding phenols (0.081 mmol of each one, 1 equiv.), and the corresponding activated alkyne (0.081 mmol, 1 equiv.) in DMSO-d6 as a deuterated solvent (0.5 mL) was added Cs2CO3 (0.163 mmol, 2 equiv.). The reaction mixture was monitored by 1 H NMR at 25°C until thermodynamic equilibrium was reached. The last spectrum was selected for the calculation of the equilibrium constants. NMR spectra was processed and analyzed using Bruker Topspin 4.1 and MNova software. Peak areas were calculated by integration and/or using linefitting to a Lorentz-Gauss functions using routines incorporated in the previously mentioned software.
DMSO-d6 (400 MHz Due to overlappings in the NMR spectrum, we took the ratio between 1-prop and 5-prop and we assumed the ratio between 1 and 5 was exactly the inverse.

CD3CN (400 MHz)
1h 4h S20 The reaction mixture was left for 45 days, and no major decomposition was observed.

General procedure
To a solution of the corresponding vinyl ether derivative (0.20 mmol, 1 equiv.) and phenol (0.20 mmol, 1 equiv.) in DMSO-d6 as a deuterated solvent (0.6 mL) was added the base DMAP or Cs2CO3 (0.40 mmol, 2 equiv.). The reaction mixture was monitored by 1 H NMR at 90°C in case of using DMAP and at 25ºC in case of using Cs2CO3.

Reaction with ketones and primary amides.
We carried out exchange reactions with phenyl ethynyl ketone (keto) and with the propiolamide of the p-anisidine. In both cases, although reactions seem to reach equilibrium, 1 H NMR of the crude reaction mixtures over time shows decomposition of the vinyl ethers initially formed.
Therefore a proper quantification is not possible.