Selective Room-Temperature Hydrogenation of Amides to Amines and Alcohols Catalyzed by a Ruthenium Pincer Complex and Mechanistic Insight

We report a room-temperature protocol for the hydrogenation of various amides to produce amines and alcohols. Compared with most previous reports for this transformation, which use high temperatures (typically, 100–200 °C) and H2 pressures (10–100 bar), this system proceeds under extremely mild conditions (RT, 5–10 bar of H2). The hydrogenation is catalyzed by well-defined ruthenium-PNNH pincer complexes (0.5 mol %) with potential dual modes of metal–ligand cooperation. An unusual Ru-amidate complex was formed and crystallographically characterized. Mechanistic investigations indicate that the room-temperature hydrogenation proceeds predominantly via the Ru–N amido/amine metal–ligand cooperation.


General Information
All hydrogenation experiments were carried out under an inert atmosphere (with N2 or Ar) using standard Schlenk techniques. Complexes RuHCl(CO)P tBu NNtBuH (Ru-1), 1 RuHCl(CO)P tBu NNBnH (Ru-2), 1 RuHCl(CO)P Ph NNtBuH (Ru-3), 2 and RuHCl(CO)P tBu NNEt (Ru-4) 3 were prepared according to the previously reported procedure. All catalysts were weighed inside a nitrogen filled glove box. The amides were either purchased from standard commercial sources or prepared by roughly following a previously reported method (below). 4 All solvents were purified according to standard procedures under an argon atmosphere, sparged with argon, and stored over 4 Å molecular sieves. 1,3,5-trimethylbenzene (mesitylene) and potassium tert-butoxide were purchased from commercial sources and used as received.
NMR spectra were recorded at room temperature on a Bruker AMX-300. Caution: Reactions are associated with H2 gas. They should be carefully handled inside proper fume hoods without any flame, spark or static electricity sources nearby.

Standard procedure for amide synthesis
To a stirring aqueous solution of NaOH (3 g in 30 mL water), 30 mmol of the amine were added.
The resulting solution was stirred for 5 min, after which 25 mmol of the corresponding acid chloride was added dropwise. The resulting solution was stirred vigorously at room temperature for an hour, during which formation of solid precipitates (amide) was observed. Subsequently, cold water (~10 mL) was added to the solution and the solid was filtered via vacuum filtration.
The solid was then washed with cold water, dried, and recrystallized in ethyl acetate/hexane S3 solvent system. In case of a liquid amides, it was extracted from the aqueous solution with dichloromethane. The DCM solution was washed with water (twice), dried and the DCM was then removed under partial vacuum to afford the amide.
3. Standard procedure for amide hydrogenation (Table 1 and Figure S2. 1 H NMR spectrum of the reaction mixture after hydrogenation of benzanilide (Table 1, entry 5) in CDCl3. Figure S3. 1 H NMR spectrum of the crude reaction mixture after hydrogenation of N-(4fluorophenyl) benzamide (Table 2, entry 6) in CDCl3. S5 Figure S4. 1 H NMR spectrum of the crude reaction mixture after hydrogenation of N-(4chlorophenyl) formamide (  Figure S6. GC chromatogram of the crude reaction mixture after hydrogenation of benzanilide (Table 1, entry 5). Figure S7. GC chromatogram of the crude reaction mixture after hydrogenation of Nphenyloctanamide (  Figure S8. 1 H NMR spectrum of complex Ru-1B in C6D6.
As seen in Figure S14, the dihydride complex is not observed at all during the reaction. This is in stark contrast to complex Ru-4, where immediate formation of the dihydride complex was observed ( Figure S15, vide infra). This is possibly due to the high stability of Ru-1B provided by the H-bonding between the amidate and PNNH ligand. S13 Figure S15. Reactivity of complex Ru-PNN Et (Ru-4) with t-BuOK, amide and H2 at RT probed by 31 P{ 1 H} NMR.
Upon addition of 1 equiv. of t-BuOK, deprotonation of the P "arm" of complex Ru-4 to form the dearomatized complex took place (panel 2). Upon addition of benzanilide, a mixture of products was observed (panel 3). It should also be noted here that peaks observed in this case were broader, which may signify rapid exchanges happening in the solution. The peaks immediately converged to the dihydride complex in presence of 5 bar H2 (panel 4). The corresponding hydride peaks were observed at -4.29 ppm in the 1 H NMR spectra as a doublet (JH,P = 17.0 Hz). S14 Figure S16. Reactivity of Ru-1 with t-BuOK, N-acetylmorpholine and H2 at RT probed by 31 P{ 1 H} NMR. S15 Figure S17. Reactivity of Ru-3 with t-BuOK, amide and H2 as probed by 31 P NMR.
Note that in case of Ru-3, the doubly deprotonated dearomatized anionic complex's 31 P signal appears at a lower chemical shift (~58 ppm) than that of the parent hydrido-chloride complex (~67.5 ppm), as opposed to the complex Ru-1 bearing two t-Bu substituents on the P atom ( 31 P chemical shift 110 ppm for the parent hydrido-chloride and 124.5 ppm for the cationic complex, see Figure S8). This is likely due to the 1 H abstraction from the P arm of the ligand, as the presence of Ph groups on P renders the protons of P arm more acidic. On the other hand, for Ru-1, the cationic complex contains a double bond on the N arm as can be observed by X-ray crystal structure of the enamido complex Ru-1A. 1 S16

Deuterium labeling experiment with complex Ru-1B
Procedure: In a vial, 7.5 mg of complex Ru-1B was dissolved in 0.5 mL of toluene d-8. The solution was transferred to a high pressure NMR tube and the 1 H NMR of the solution was recorded. The spectra displayed four distinct aliphatic C-H peaks in the 2.7-4.5 ppm region corresponding to the four methylene protons of the P and N arms of the ligand. Similarly, the N-H proton and the Ru-H hydride peaks were also observed at 10.5 and -16.95 ppm, respectively.
Subsequently, 5 bars of D2 gas was introduced to the NMR tube. The tube was shaken and the 1 H spectrum was recorded immediately. Figure S18. 1 H NMR spectrum of Ru-1B in toluene-d8. S17 Figure S19. 1 H NMR spectra of Ru-1B in toluene-d8 in the presence of D2 (5 bar) after 1 min.
As observed from Figure S18 and S19, immediate suppression of the N-H proton and methylene proton of the P arm was observed. This is due to the equilibrium between the amidate complex