Catalytic Oxidative Deamination by Water with H2 Liberation

Selective oxidative deamination has long been considered to be an important but challenging transformation, although it is a common critical process in the metabolism of bioactive amino compounds. Most of the synthetic methods developed so far rely on the use of stoichiometric amounts of strong and toxic oxidants. Here we present a green and efficient method for oxidative deamination, using water as the oxidant, catalyzed by a ruthenium pincer complex. This unprecedented reaction protocol liberates hydrogen gas and avoids the use of sacrificial oxidants. A wide variety of primary amines are selectively transformed to carboxylates or ketones in good to high yields. It is noteworthy that mechanistic experiments and DFT calculations indicate that in addition to serving as the oxidant, water also plays an important role in assisting the hydrogen liberation steps involved in amine dehydrogenation.

Butyric acid (2a): 5 A 50 mL thick-glass pressure tube, equipped with a stirring bar, was charged with complex [Ru]-2 (3.0 mg, 0.0050 mmol), NaOH (40.0 mg, 1.0 mmol), n-butylamine (49 μL,0.50 mmol), 2.0 mL of dioxane, and 2.0 mL of water. The tube was sealed, and the reaction mixture was stirred and heated at 150 o C (silicon oil bath temperature, solvent reflux). After 48 h, the reaction mixture was cooled down to room temperature. Saturated brine (5.0 mL) was then added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 5.0 mL). The aqueous phase was then acidified with 4 M HCl (3.0 mL) and extracted with ethyl acetate (3 × 5.0 mL). The combined organic extracts from the acidified aqueous phase were dried over Na2SO4 and all volatiles were removed under vacuum. The product was obtained as a yellow oil in 95% yield (41.7 mg). 1  Determination of H2 and NH3 generated during the reaction: After cooling the reaction mixture to room temperature, the headspace was analyzed by GC with a TCD detector, using N2 as the carrier gas. As shown in Figure S1, only H2 was detected by GC while no other gases were present in detectable amounts. In a parallel experiment, the evolved gas was quantified by displacing water in an inverted graduated cylinder filled with water. About 24 mL of gas were collected, amounting to 98% yield based on full conversion of n-butylamine to butyrate. The reaction mixture was then acidified with 4 M HCl (3.0 mL). As shown in Figure S2, NH4 + was detected as a characteristic triplet at 7.10 ppm in the 1 H NMR spectrum of the reaction mixture. Following similar procedures and analytical methods, H2 and NH4 + were also detected upon the oxidative deamination of other amines and amides. Benzoic acid (2i): 5 A 50 mL thick-glass pressure tube, equipped with a stirring bar, was charged with complex [Ru]-2 (3.0 mg, 0.0050 mmol), NaOH (40.0 mg, 1.0 mmol), benzylamine (55 μL, 0.50 mmol), 2.0 mL of dioxane, and 2.0 mL of water. The tube was sealed, and the reaction mixture was stirred and heated at 150 o C (silicon oil bath temperature, solvent reflux). After 48 h, the reaction mixture was cooled down to room temperature and the generated gas was carefully released in a hood. Saturated brine (5.0 mL) was then added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 5.0 mL). The aqueous phase was then acidified with 4 M HCl (3.0 mL) and extracted with ethyl acetate (3 × 5.0 mL). The combined organic extracts from the acidified aqueous phase were dried over Na2SO4 and all volatiles were removed under vacuum. The product was obtained as a pale-yellow solid in 98% yield (59.7 mg). 1 6. In two control experiments, excess Hg (230 mg) or NEt3 (70 μL) was added at the beginning of the reaction. Following the same reaction procedure as described above, the product, benzoic acid, was isolated in 97% yield in both cases (59.0 and 59.4 mg, respectively). 5 A 50 mL thick-glass pressure tube, equipped with a stirring bar, was charged with complex [Ru]-2 (3.0 mg, 0.0050 mmol), NaOH (40.0 mg, 1.0 mmol), 4methoxylbenzylamine (49 μL, 0.50 mmol), 2.0 mL of dioxane, and 2.0 mL of water. The tube was sealed, and the reaction mixture was stirred and heated at 150 o C (silicon oil bath temperature, solvent reflux). After 48 h, the reaction mixture was cooled down to room temperature and the generated gas was carefully released in a hood. Saturated brine (5.0 mL) was then added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 5.0 mL). The aqueous phase was then acidified with 4 M HCl (3.0 mL) and extracted with ethyl acetate (3 × 5.0 mL). The combined organic extracts from the acidified aqueous phase were dried over Na2SO4 and all volatiles were removed under vacuum. The product was obtained as a pale-yellow solid in 95% yield (72.1 mg). 1  temperature, solvent reflux). After 48 h, the reaction mixture was cooled down to room temperature and the generated gas was carefully released in a hood. Saturated brine (5.0 mL) was then added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 5.0 mL). The aqueous phase was then acidified with 4 M HCl (3.0 mL) and extracted with ethyl acetate (3 × 5.0 mL). The combined organic extracts from the acidified aqueous phase were dried over Na2SO4 and all volatiles were removed under vacuum. The product was obtained as a pale-yellow solid in 87% yield (82.6 mg). 1  The tube was sealed, and the reaction mixture was stirred and heated at 150 o C (silicon oil bath temperature, solvent reflux). After 48 h, the reaction mixture was cooled down to room temperature and the generated gas was carefully released in a hood. Saturated brine (5.0 mL) was then added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 5.0 mL). The aqueous phase was then acidified with 4 M HCl (3.0 mL) and extracted with ethyl acetate (3 × 5.0 mL). The combined organic extracts from the acidified aqueous phase were dried over Na2SO4 and all volatiles were removed under vacuum. The product was obtained as a yellow solid in 93% yield (71.7 mg). 1  dioxane, and 0.50 mL of water. The tube was sealed, and the reaction mixture was stirred and heated at 150 o C (silicon oil bath temperature, solvent reflux). After 48 h, the reaction mixture was cooled down to room temperature and the generated gas was carefully released in a hood. Water (4.0 mL) was then added to the reaction mixture and ethyl acetate (3 × 4.0 mL) was used to extract the organic compounds. The combined organic extracts were analyzed by GC (FID detector), using mesitylene as an internal standard (94% yield).

4-Methoxybenzoic acid (2j):
Pentan-3-one (3x): 11 50 mL thick-glass pressure tube, equipped with a stirring bar, was charged with complex [Ru]-2 (3.0 mg, 0.0050 mmol), 3-aminopentane (58 μL, 0.50 mmol), 2.0 mL of dioxane, and 0.50 mL of water. The tube was sealed, and the reaction mixture was stirred and heated at 150 o C (silicon oil bath temperature, solvent reflux). After 48 h, the reaction mixture was cooled down to room temperature and the generated gas was carefully released in a hood. Water (4.0 mL) was then added to the reaction mixture and ethyl acetate (3 × 4.0 mL) was used to extract the organic compounds. The combined organic extracts were analyzed by GC (FID detector), using mesitylene as an internal standard (74% yield).
Cyclopentanone (3y): 12 A 50 mL thick-glass pressure tube, equipped with a stirring bar, was charged with complex [Ru]-2 (3.0 mg, 0.0050 mmol), cyclopentanamine (49 μL, 0.50 mmol), 2.0 mL of dioxane, and 0.50 mL of water. The tube was sealed, and the reaction mixture was stirred and heated at 150 o C (silicon oil bath temperature, solvent reflux). After 48 h, the reaction mixture was cooled down to room temperature and the generated gas was carefully released in a hood. Water (4.0 mL) was then added to the reaction mixture and ethyl acetate (3 × 4.0 mL) was used to extract the organic compounds. The combined organic extracts were analyzed by GC (FID detector), using mesitylene as an internal standard (84% yield).
Cyclohexanone (3z): 12 A 50 mL thick-glass pressure tube, equipped with a stirring bar, was charged with complex [Ru]-2 (3.0 mg, 0.0050 mmol), cyclohexanamine (57 μL, 0.50 mmol), 2.0 mL of dioxane, and 0.50 mL of water. The tube was sealed, and the reaction mixture was stirred and heated at 150 o C (silicon oil bath temperature, solvent reflux). After 48 h, the reaction mixture was cooled down to room temperature and the generated gas was carefully released in a hood. Water (4.0 mL) was then added to the reaction mixture and ethyl acetate (3 × 4.0 mL) was used to extract the organic compounds. The combined organic extracts were analyzed by GC (FID detector), using mesitylene as an internal standard (81% yield).

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O O S15 Cycloheptanone (3aa): 12 A 50 mL thick-glass pressure tube, equipped with a stirring bar, was charged with complex [Ru]-2 (3.0 mg, 0.0050 mmol), cycloheptanamine (64 μL, 0.50 mmol), 2.0 mL of dioxane, and 0.50 mL of water. The tube was sealed, and the reaction mixture was stirred and heated at 150 o C (silicon oil bath temperature, solvent reflux). After 48 h, the reaction mixture was cooled down to room temperature and the generated gas was carefully released in a hood. Water (4.0 mL) was then added to the reaction mixture and ethyl acetate (3 × 4.0 mL) was used to extract the organic compounds. The combined organic extracts were analyzed by GC (FID detector), using mesitylene as an internal standard (90% yield).
Cyclooctanone (3ab): 12 A 50 mL thick-glass pressure tube, equipped with a stirring bar, was charged with complex [Ru]-2 (3.0 mg, 0.0050 mmol), cyclooctanamine (68 μL, 0.50 mmol), 2.0 mL of dioxane, and 0.50 mL of water. The tube was sealed, and the reaction mixture was stirred and heated at 150 o C (silicon oil bath temperature, solvent reflux). After 48 h, the reaction mixture was cooled down to room temperature and the generated gas was carefully released in a hood. Water (4.0 mL) was then added to the reaction mixture and ethyl acetate (3 × 4.0 mL) was used to extract the organic compounds. The combined organic extracts were analyzed by GC (FID detector), using mesitylene as an internal standard (73% yield).
Acetophenone (3ac): 13 A 50 mL thick-glass pressure tube, equipped with a stirring bar, was charged with complex [Ru]-2 (3.0 mg, 0.0050 mmol), 1-phenylethylamine (64 μL, 0.50 mmol), 2.0 mL of dioxane, and 0.50 mL of water. The tube was sealed, and the reaction mixture was stirred and heated at 150 o C (silicon oil bath temperature, solvent reflux). After 48 h, the reaction mixture was cooled down to room temperature and the generated gas was carefully released in a hood. Water (4.0 mL) was then added to the reaction mixture and ethyl acetate (3 × 4.0 mL) was used to extract the organic compounds. The combined organic extracts were analyzed by GC (FID detector), using mesitylene as an internal standard (86% yield). was cooled down to room temperature and the generated gas was carefully released in a hood. Water (4.0 mL) was then added to the reaction mixture and ethyl acetate (3 × 4.0 mL) was used to extract the organic compounds. The combined organic extracts were analyzed by GC (FID detector), using mesitylene as an internal standard (98% yield).
1-(Naphthalen-1-yl)ethan-1-one (3ae): 13 A 50 mL thick-glass pressure tube, equipped with a stirring bar, was charged with complex [Ru]-2 (3.0 mg, 0.0050 mmol), 1-(1-naphthyl)ethylamine (40 μL, 0.25 mmol), 2.0 mL of dioxane, and 0.50 mL of water. The tube was sealed, and the reaction mixture was stirred and heated at 150 o C (silicon oil bath temperature, solvent reflux). After 48 h, the reaction mixture was cooled down to room temperature and the generated gas was carefully released in a hood. Water (4.0 mL) was then added to the reaction mixture and ethyl acetate (3 × 4.0 mL) was used to extract the organic compounds. The combined organic extracts were analyzed by GC (FID detector), using mesitylene as an internal standard (59% yield).

Procedures for mechanistic experiments
Catalytic deamination of benzylamine in the absence of base: A 50 mL thick-glass pressure tube, equipped with a stirring bar, was charged with complex [Ru]-2 or [Ru]-3 (0.0050 mmol), benzylamine (55 μL, 0.50 mmol), 2.0 mL of dioxane, and 2.0 mL of water. The tube was sealed, and the reaction mixture was stirred and heated at 150 o C (silicon oil bath temperature, solvent reflux). After 48 h, the reaction mixture was cooled down to room temperature. Saturated brine (5.0 mL) was then added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 5.0 mL). The combined organic extracts were analyzed by GC (FID detector) using mesitylene as an internal standard to determine the yields of benzyl alcohol and N-benzylidenebenzylamine. In the next step, the aqueous phase was acidified with 4 M HCl (3.0 mL) and extracted with ethyl acetate (3 × 5.0 mL). The combined organic extracts from the acidified aqueous phase were also analyzed by GC (FID detector) using mesitylene as an internal standard to determine the yield of benzoic acid. The tube was sealed, and the reaction mixture was stirred and heated at 150 o C (silicon oil bath temperature, solvent reflux). After 48 h, the reaction mixture was cooled to room temperature.

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Saturated brine (5.0 mL) was then added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 5.0 mL). The combined organic extracts were analyzed by GC (FID detector) using mesitylene as an internal standard to determine the yields of benzyl alcohol and Nbenzylidenebenzylamine. In the next step, the aqueous phase was acidified with 4 M HCl (3.0 mL) and extracted with ethyl acetate (3 × 5.0 mL). The combined organic extracts from the acidified aqueous phase were also analyzed by GC (FID detector) using mesitylene as an internal standard to determine the yield of benzoic acid. The reaction results with the bases including NEt3, Na2CO3, K3PO4 and NaOH are shown in Table S1.

Table S1. Effect of Different Bases on the Catalytic Oxidative Deamination of Benzylamine
Catalytic oxidation of benzyl alcohol by water: A 50 mL thick-glass pressure tube, equipped with a stirring bar, was charged with complex [Ru]-3 (2.9 mg, 0.0050 mmol), NaOH (40.0 mg, 1.0 mmol), benzyl alcohol (52 μL, 0.50 mmol), 2.0 mL of dioxane, and 2.0 mL of water. The tube was sealed, and the reaction mixture was stirred and heated at 150 o C (silicon oil bath temperature, solvent reflux). After 48 h, the reaction mixture was cooled down to room temperature and the generated gas was carefully released in a hood. Saturated brine (5.0 mL) was then added to the reaction mixture and the mixture was extracted with ethyl acetate (3 × 5.0 mL). The aqueous phase was then acidified with 4 M HCl (3.0 mL) and extracted with ethyl acetate (3 × 5.0 mL). The combined organic extracts from the acidified aqueous phase were dried over Na2SO4 and all volatiles were removed under vacuum. The product, benzoic acid, was obtained as a pale-yellow solid in 99% yield (60.7 mg).

Catalytic oxidative deamination of N-benzylidenebenzylamine by water:
A 50 mL thick-glass pressure tube, equipped with a stirring bar, was charged with complex [Ru]-3 (2.9 mg, 0.0050 mmol), NaOH (40.0 mg, 1.0 mmol), N-benzylidenebenzylamine (47 μL, 0.25 mmol), 2.0 mL of dioxane, and 2.0 mL of water. The tube was sealed, and the reaction mixture was stirred and heated at 150 o C (silicon oil bath temperature, solvent reflux). After 48 h, the reaction mixture was cooled down to room temperature and the generated gas was carefully released in a hood. Saturated brine (5.0 mL) was then added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 5.0 mL). The aqueous phase was then acidified with 4 M HCl (3.0 mL) and extracted with ethyl acetate (3 × 5.0 mL). The combined organic extracts from the acidified aqueous phase were dried over Na2SO4 and all volatiles were removed under vacuum. The product, benzoic acid, was obtained as a pale-yellow solid in 96% yield (58.5 mg).

Catalytic oxidation of benzaldehyde by water:
A 50 mL thick-glass pressure tube, equipped with a stirring bar, was charged with complex [Ru]-3 (2.9 mg, 0.0050 mmol), NaOH (40.0 mg, 1.0 mmol), benzaldehyde (51 μL, 0.50 mmol), 2.0 mL of dioxane, and 2.0 mL of water. The tube was sealed, and the reaction mixture was stirred and heated at 150 o C (silicon oil bath temperature, solvent reflux). After 48 h, the reaction mixture was cooled down to room temperature and the generated gas was carefully released in a hood. Saturated brine (5.0 mL) was then added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 5.0 mL). The aqueous phase was then acidified with 4 M HCl (3.0 mL) and extracted with ethyl acetate (3 × 5.0 mL). The combined organic extracts from the acidified aqueous phase were dried over Na2SO4 and all volatiles were removed under vacuum. The product, benzoic acid, was obtained as a pale-yellow solid in 99% yield (60.7 mg).

Determination of the kinetic profile of benzylamine dehydrogenation:
A series of 50 mL thickglass pressure tubes, equipped with a stirring bar, was charged with complex [Ru]-3 (2.9 mg, 0.0050 mmol), benzylamine (55 μL, 0.50 mmol), water (18 μL, 0.50 mmol), and 2.0 mL of dioxane. An additional series of pressure tubes was set up as described above, but in the absence of water. All tubes were sealed, and the reaction mixtures were then stirred and heated at 150 o C (silicon oil bath temperature, solvent reflux). The tubes were removed from the heating bath at different designated time intervals, i.e., after 3, 6, 12, 18 and 24 h. After cooling to room temperature, the reaction mixtures were then subjected to GC analysis, using biphenyl as the internal standard.

Crystallographic analysis of [Ru]-5
Crystals of [Ru]-5 were grown from a saturated pentane solution at -30 °C. Diffraction data for one of these crystals were collected at 100 K with Cu Kα radiation (λ = 1.54184 Å), on a Rigaku XtaLab Pro diffractometer, equipped with microfocus and a Dectris Pilatus 200K detector. The structure was solved by direct methods using SHELXT. 15 Data were refined as Full-matrix least-squares refinement based on F 2 with SHELXL 16 and OLEX2 17 . 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.
Crystallographic data and refinement parameters are summarized in Table S2.

Computational details
All geometries were optimized using Truhlar's M06-L functional, 18 the triple-ξ def2-TZVP basis set 19 and W06 density fitting to increase computational efficiency, 20 as well as Grimme's D3(0) empirical dispersion correction. 21 To take the influence of the solvent into account, optimizations were performed with the integral equation Free energy values (Gº) were then corrected to account for changes in standard states (Gº→Gº'). 28 Specifically, all species were corrected for the condensed phase (1 atm to 1M at 423.15K), with the exception of H2 (maintained at 1 atm standard state) and water (1 atm to 27.75M at 423.15K). [29][30][31] Optimizations and frequency calculations were done using the Gaussian 16 software suite in the C.01 revision. 32