Dehydrogenative ester synthesis from enol ethers and water with a ruthenium complex catalyzing two reactions in synergy

We report the dehydrogenative synthesis of esters from enol ethers using water as the formal oxidant, catalyzed by a newly developed ruthenium acridine-based PNP(Ph)-type complex. Mechanistic experiments and density functional theory (DFT) studies suggest that an inner-sphere stepwise coupled reaction pathway is operational instead of a more intuitive outer-sphere tandem hydration–dehydrogenation pathway.


General Information
All experiments were carried out under an inert atmosphere (with N2 or Ar) using standard Schlenk techniques. Complexes RuH(CO)Acr*PNP(i-Pr) (1), 1 RuHCl(CO)AcrPNP(i-Pr) (2), 2 RuH(CO)PNNBPy*(t-Bu)(3), 3 RuH(CO)P tBu NNH*(t-Bu) (4), 4,5 , RuH(CO)2Acr*PNP(i-Pr) (5) 6 were prepared according to the previously reported procedures. All catalysts were weighed inside a nitrogen filled glove box. The enol ethers were purchased from standard commercial sources (some of the substrates contained KOH or amine in 100 ppm amount as stabilizers). All solvents were purified according to standard procedures under an argon atmosphere, bubbled with argon, and stored over 4 Å molecular sieves. 1,3,5trimethylbenzene (mesitylene) was purchased from commercial sources and used as received. Deionized water was used for the reactions which was degassed by bubbling argon for 30 minutes prior to its use. NMR spectra were recorded at room temperature on a Bruker AMX-300, AMX-400 or AMX-500 spectrometers. Chemical shifts of the NMR spectra are reported relative to residual signals of CDCl3 ( 1 H NMR: δ = 7.26 ppm, 13 C NMR: δ = 77.16 ppm), benzene-d6 ( 1 H NMR: δ = 7.16 ppm, 13 C NMR: δ = 128.06 ppm), dicholoromethane-d2 ( 1 H NMR: δ = 5.32 ppm, 13 C NMR: δ = 54.00 ppm) or the internal standard mesitylene. 31 P{ 1 H} NMR chemical shifts are reported in ppm downfield from H3PO4 and referenced to an external 85% solution of phosphoric acid in D2O. GC-MS was carried out on HP 6890 (flame ionization detector and thermal conductivity detector) and HP 5973 (MS detector) instruments equipped with a 30 m column (Restek 5MS, 0.32 mm internal diameter) with a 5% phenylmethylsilicone coating (0.25 mm) and helium as carrier gas. GC was carried out on HP 6890 or Agilent 7890B Series GC System with N2 or Helium as carrier gas. IR spectra were recorded on a Nicolet FTIR spectrophotometer (KBr, thin Film).

Synthesis of the acridine complex 6
Procedure: Inside a N2 glove box, 25 mg of RuHCl(CO)Acr(Ph) complex (obtained in the previous step) was suspended in 5 mL THF. 1 eq of NaBEt3H (pre-dissolved in 3 mL THF) was then added to the solution dropwise over 5 minutes. The solution was allowed to stir for 5 mins at which the reaction solution turned from yellow to dark red. The stirring was then turned off, and the THF was removed in vacuo. The resulting solid was washed with diethyl ether (0.5 mLx3). Subsequently, the red solid was dissolved in 5 mL benzene and filtered through a short Celite® plug. The resulting filtrate was then frozen, and benzene was removed afterwards in vacuo to obtain complex 6 as red powder in 73% yield.    Data were collected on a Rigaku Synergy-S diffractometer dual source equipped with Dectris Pilatus R CdTe 300K detector and microfocus, with MoKa (l=0.71073 Å). The data were processed with CrysAlis PRO . Structure was solved by direct methods with SHELXT. 8 Data were refined as Full-matrix least-squares refinement based on F 2 with SHELXL 9 and OLEX2 10 . All non-hydrogen atoms were further refined with anisotropic displacement coefficients. Hydrogen atoms were assigned isotropic displacement coefficients, and their coordinates were allowed to ride on their respective carbons. Hydride was located in the electron density map. Crystallographic data and refinement parameters are summarized in Supplementary Table S1. S13 Table S1. Crystal data and structure refinement for complex 6 + C6H6

General procedure for the reactions
In a N2 glove box, the ruthenium catalyst (2.25 or 4.5 µmol) was dissolved in 2 mL of dry 1,4-dioxane. 0.3 mmol of enol ether was then added to the solution. The solution was transferred to a 25 mL Schlenk flask with a side arm and taken out of the box. The desired amount of water was then added to the solution under argon flow using Schlenk techniques. The flask was dipped into an oil bath preheated to the desired temperature. After suitable reaction time, the flask was cooled down to room temperature, opened, and a known amount of mesitylene was added to the solution as internal standard. Part of the reaction solution was then dried using MgSO4 and analyzed via GC-MS, GC and 1 H NMR.
The yields were calculated based on the peak integration ratios in the GC or 1 H NMR spectrum. For selected reactions, the accumulated gas volume in the headspace was measured and analyzed by GC. All the ester products synthesized in this study have been reported previously in the literature. All products were identified by comparison of the 1 H NMR spectra from literature or by GC-MS spectra with those of the commercially available compounds. The GC-MS retention times and observed m/z values are provided in Table S2.   Table S2. GC-MS data for esters using HP 6890 equipped with flame ionization and thermal conductivity detectors and HP 5973 (MS detector) instruments, equipped with a 30 m column (Restek 5MS, 0.32 mm internal diameter) with a 5% phenylmethylsilicone coating (0.25 mm) and helium as carrier gas with a flow-rate of 1 ml/min). The parameters are shown in Figure S13.     Figure S16a. GC of a blank air sample. The peak around 1 min is due to the presence of O2 gas. N2 was used as the carrier gas. Figure S16b. Typical GC of the headspace gas after reaction. The peak at 0.25 min is due to the presence of H2 gas. The negative peak at 0.9 min is for the Ar gas. N2 was used as the carrier gas. h, the flask was cooled down to room temperature, opened, and a known amount of mesitylene was added to the solution as internal standard. Part of the reaction solution was then dried using MgSO4 and analyzed via GC-MS, and 1 H NMR. Yields were calculated from the 1 H NMR spectra. 58% of ester yield was observed when H2O was used (conversion 67%), whereas 25% of deuterated ester was observed when D2O was used (conversion 34%).

Computational Studies
All geometries were optimized using Truhlar's M06-L functional, 11 the triple-ξ def2-TZVP basis set 12 and W06 density fitting to increase computational efficiency 13 as well as Grimme's D3(0) empirical dispersion correction. 14 To take the influence of the solvent into account optimizations were performed with the integral equation formalism variant (IEFPCM) with the SMD variation of Truhlar and co-workers, with 1,4-dioxane, except otherwise stated. Frequency calculations at this level of theory at 398.15 K were run in order to confirm stationary points and transition states, as well as to compute thermodynamic properties. Single point energies of the optimized structures were computed using the range-separated meta-GGA hybrid functional ωB97M-V of the Head-Gordon group 15 including dispersion correction, 16 together with the triple-ξ def2-TZVPP basis set 12 and the corresponding auxiliary basis sets, def2/J 13 and def2-TZVPP/C, 17 for RIJCOSX density fitting. The single point calculations include the same solvation (SMD) approach as described above in the optimizations. Gibbs free energies were computed by adding the free energy correction terms from the frequency calculations to the single point energies according to: Free energy values (G o ) were then corrected to account for changes in standard states For the structures of TS3 and 1a-mer, and, structures were optimized, and frequency corrections were obtained in the gas phase at 398.15 K due to encountered optimization difficulty in dioxane continuum. Single point energies were calculated with the solvation model (dioxane). The resulting obtained values of free energies are likely to be within ±3 kcal/mol of the previously stated method in eq 1, verified with other selected structures.

Alternate hydration mechanism without the involvement of ruthenium complex
We considered the possibility of a reaction pathway where the initial hydration happens spontaneously without the involvement of ruthenium complex to generate a hemiacetal, from which dehydrogenation happens catalyzed by the ruthenium complex. This pathway is unlikely as our experimental results (Table 1) show that in the absence of acridine catalyst, no significant hydration products are observed under the reaction conditions. The computational analysis reveals that the uncatalyzed water assisted hydration pathway has a high activation barrier of around ~51.8 kcal/mol (with 2 water molecules involved in the transition state) under our reaction conditions, corroborating the experimental observations. Figure S38. Uncatalyzed hydration pathway leading to the formation of a hemiacetal. The relevant transition state was found quite high in energy. Free energies (kcal/mol) were calculated at 398.15 K relative to ethyl vinyl ether+2*water and are calculated in a 1,4dioxane continuum (all solutes are 1 M except for H2O, which is at 6.17 M).

Discussion about the possibility of outer sphere pathway involving 6-mer
Another stepwise reaction mechanism involving a first step vinyl ether hydration catalyzed by [Ru], followed by subsequent [Ru] catalyzed dehydrogenation of the generated acetal was also considered. However, during our DFT calculations (with both complex 1 and 6), we were unable to find the relevant zwitter ionic species resulting from initial nucleophilic water attack onto [Ru] bound vinyl ether. All optimization attempts from more than a dozen starting points resulted in spontaneous loss of water from the structure. This hints at the fact that such a zwitter ionic structure minima most likely does not exist in the potential energy surface, or if it does, is relatively very high in energy with facile loss of water being favorable from the structure. Furthermore, the experimental fact that both P i Pr2 complex and the PPh2 complex display similar catalytic activities for ester formation suggest the absence of such a stepwise mechanism where the Lewis acidity of the metal center in expected to play a big role in the reaction rate. Figure S39. Stepwise Ru-catalyzed hydration-dehydrogenation pathway with complex 1/6.

Reaction energy profile for ethyl vinyl ether oxidation by water catalyzed by 1
The energy profiles for both inner-sphere and outer-sphere reaction pathways were calculated also for complex 1 and compared to the energy profile associated with complex 6. While a similar energy profile is observed, there are several differences worth mentioning. First, the fac isomer of complex 1 was energetically uphill by 12.0 kcal/mol with respect to the mer isomer, in contrast to the Ph complex 6 whose fac isomer is 5.6 kcal/mol uphill compared to the mer isomer. Second, the inner sphere H2 evolution was found less facile with complex 1 (28.6 kcal/mol) as compared to complex 6 (22.4 kcal/mol). Similar trend is also observed for the hydroxide insertion onto bound vinyl ether transition state (28.6 kcal/mol for complex 1, as compared to 17.2 kcal/mol for complex 1, with respect to their mer isomers). Thus, in case of complex 1, the initial H2 evolution is also the most energetically demanding step under the reaction conditions, along with the hydroxide insertion step. An overall activation barrier of 28.6 kcal/mol was calculated for the Ru-Acr(iPr) system, as compared to the 26.0 kcal/mol for the Acr(Ph) system. These values are close and are also in agreement with the fact that similar reactivities are observed with complex 1 and 6 for the dehydrogenative oxidative ester synthesis from enol ethers. Figure S40. Energy profile of the inner sphere coupled catalytic pathway from enol ether to ester formation catalyzed by 1. Free energies (kcal/mol) were calculated at 398.15 K relative to 1-mer+water+ethyl vinyl ether and are calculated in a 1,4-dioxane continuum (all solutes are 1 M except for H2 and H2O, which are at 1 atm and 6.17 M, respectively). Mass balance is ensured throughout. The CO and acridine based ligands are omitted for clarity.

Energies of water and vinyl ether coordinated intermediates
The energies of the complexes, generating from the coordination of the vinyl ether or water to the metal center, with both complex 1 ( i Pr system) and 6 (Ph system), are shown in the following table.