N-benzylbenzamide

Conditions: temp:23.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of benzylamine (75.0 g, 0.700 mol), THF (300 mL) and triethylamine (70.8 g, 134 g, 0.700 mol) was added dropwise benzoyl chloride (98.4 g, 0.700 mol) at 2° C. or lower, and the mixture was allowed to warm, and stirred at 12-35° C. for 3 hr. The progress of the reaction was confirmed by TLC (eluent: toluene/ethyl acetate (4:1)). To the reaction mixture was added water (165 mL) at 16° C. or lower, the mixture was extracted with ethyl acetate (60 mL), and the aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layers were washed successively with 5% aqueous citric acid solution (50 mL×2) and 20% brine (75 mL×3), and dried over magnesium sulfate (20 g). The silica gel (12 g) was added to the solution, and the mixture was filtered through silica gel. The filtrate was concentrated under reduced pressure at 40° C. until the beginning of the precipitation. To the concentrate (263 g) was added ethyl acetate (41.5 g), and the resulting solid was dissolved at 60° C. The solution was cooled over 2 hr to 20° C., and ethyl acetate (40 mL) was added thereto. Then, the mixture was cooled to 5° C., and the resulting crystals were collected by filtration, and washed with cold ethyl acetate (75 mL). The obtained crystals were dried under reduced pressure at 40° C. to give N-benzylbenzamide (116 g, yield 78.5%) as white crystals. to warm lower, the mixture was extracted with ethyl acetate (60 mL) the aqueous layer was extracted with ethyl acetate (150 mL) The combined organic layers were washed successively with 5% aqueous citric acid solution (50 mL×2) and 20% brine (75 mL×3) dried over magnesium sulfate (20 g) The silica gel (12 g) was added to the solution the mixture was filtered through silica gel The filtrate was concentrated under reduced pressure at 40° C. until the beginning of the precipitation To the concentrate (263 g) was added ethyl acetate (41.5 g) the resulting solid was dissolved at 60° C The solution was cooled over 2 hr to 20° C., and ethyl acetate (40 mL) was added Then, the mixture was cooled to 5° C. the resulting crystals were collected by filtration washed with cold ethyl acetate (75 mL) The obtained crystals were dried under reduced pressure at 40° C.

Conditions: temp:60.01; pressure:0.00; stir:

Procedure: Isolated by chromatography using deactivated silica gel and ethyl acetate and petroleum ether (10:1 to 1:1) as the eluent.

Conditions: temp:60.01; pressure:0.00; stir:

Procedure: Isolated by chromatography using deactivated silica gel and ethyl acetate and petroleum ether (10:1 to 1:1) as the eluent.

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-benzoyl-2,4-dimethoxybenzylamine (100 mg, 0.37 mmol) was dissolved in 1 ml 95% (v/v) trifluoroacetic acid (TFA) and stirred for 1 h at 20° C. TFA was removed by blowing with N2 and the residue suspended in methanol (1 ml). The reaction mixture was analyzed by TLC using CH2Cl2 /MeOH/AcOH (85:10:5) as eluent and the generated benzamide was determined quantitatively by HPLC using benzamide standard chromatograms. TFA was removed

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of benzylamine (0.125 mmol) in 5 mL of THF is added diisopropylethyl amine (0.15 mmol) and benzoylchloride (0.10 mmol). The reaction mixture is stirred at room temperature for 1 hour or until TLC analysis shows consumption of the benzoyl chloride. To this mixture is added perfluorsulfonic acid resin prepared in example 8 (3 g, 0.3 mmol/g loading) and the slurry is gently agitated for 1 hour. The slurry is filtered and the resin washed with dichloromethane. The combined filtrates are combined and the solvent removed under reduced pressure to afford N-benzylbenzamide as a solid. consumption of the benzoyl chloride To this mixture is added perfluorsulfonic acid resin prepared in example 8 (3 g, 0.3 mmol/g loading) the slurry is gently agitated for 1 hour The slurry is filtered the resin washed with dichloromethane the solvent removed under reduced pressure

Conditions: temp:23.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of benzylamine (75.0 g, 0.700 mol), THF (300 mL) and triethylamine (70.8 g, 134 g, 0.700 mol) was added dropwise benzoyl chloride (98.4 g, 0.700 mol) at 2° C. or lower, and the mixture was allowed to warm, and stirred at 12-35° C. for 3 hr. The progress of the reaction was confirmed by TLC (eluent: toluene/ethyl acetate (4:1)). To the reaction mixture was added water (165 mL) at 16° C. or lower, the mixture was extracted with ethyl acetate (60 mL), and the aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layers were washed successively with 5% aqueous citric acid solution (50 mL×2) and 20% brine (75 mL×3), and dried over magnesium sulfate (20 g). The silica gel (12 g) was added to the solution, and the mixture was filtered through silica gel. The filtrate was concentrated under reduced pressure at 40° C. until the beginning of the precipitation. To the concentrate (263 g) was added ethyl acetate (41.5 g), and the resulting solid was dissolved at 60° C. The solution was cooled over 2 hr to 20° C., and ethyl acetate (40 mL) was added thereto. Then, the mixture was cooled to 5° C., and the resulting crystals were collected by filtration, and washed with cold ethyl acetate (75 mL). The obtained crystals were dried under reduced pressure at 40° C. to give N-benzylbenzamide (116 g, yield 78.5%) as white crystals. to warm lower, the mixture was extracted with ethyl acetate (60 mL) the aqueous layer was extracted with ethyl acetate (150 mL) The combined organic layers were washed successively with 5% aqueous citric acid solution (50 mL×2) and 20% brine (75 mL×3) dried over magnesium sulfate (20 g) The silica gel (12 g) was added to the solution the mixture was filtered through silica gel The filtrate was concentrated under reduced pressure at 40° C. until the beginning of the precipitation To the concentrate (263 g) was added ethyl acetate (41.5 g) the resulting solid was dissolved at 60° C The solution was cooled over 2 hr to 20° C., and ethyl acetate (40 mL) was added Then, the mixture was cooled to 5° C. the resulting crystals were collected by filtration washed with cold ethyl acetate (75 mL) The obtained crystals were dried under reduced pressure at 40° C.

Conditions: temp:23.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of benzylamine (75.0 g, 0.700 mol), THF (300 mL) and triethylamine (70.8 g, 134 g, 0.700 mol) was added dropwise benzoyl chloride (98.4 g, 0.700 mol) at 2° C. or lower, and the mixture was allowed to warm, and stirred at 12-35° C. for 3 hr. The progress of the reaction was confirmed by TLC (eluent: toluene/ethyl acetate (4:1)). To the reaction mixture was added water (165 mL) at 16° C. or lower, the mixture was extracted with ethyl acetate (60 mL), and the aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layers were washed successively with 5% aqueous citric acid solution (50 mL×2) and 20% brine (75 mL×3), and dried over magnesium sulfate (20 g). The silica gel (12 g) was added to the solution, and the mixture was filtered through silica gel. The filtrate was concentrated under reduced pressure at 40° C. until the beginning of the precipitation. To the concentrate (263 g) was added ethyl acetate (41.5 g), and the resulting solid was dissolved at 60° C. The solution was cooled over 2 hr to 20° C., and ethyl acetate (40 mL) was added thereto. Then, the mixture was cooled to 5° C., and the resulting crystals were collected by filtration, and washed with cold ethyl acetate (75 mL). The obtained crystals were dried under reduced pressure at 40° C. to give N-benzylbenzamide (116 g, yield 78.5%) as white crystals. to warm lower, the mixture was extracted with ethyl acetate (60 mL) the aqueous layer was extracted with ethyl acetate (150 mL) The combined organic layers were washed successively with 5% aqueous citric acid solution (50 mL×2) and 20% brine (75 mL×3) dried over magnesium sulfate (20 g) The silica gel (12 g) was added to the solution the mixture was filtered through silica gel The filtrate was concentrated under reduced pressure at 40° C. until the beginning of the precipitation To the concentrate (263 g) was added ethyl acetate (41.5 g) the resulting solid was dissolved at 60° C The solution was cooled over 2 hr to 20° C., and ethyl acetate (40 mL) was added Then, the mixture was cooled to 5° C. the resulting crystals were collected by filtration washed with cold ethyl acetate (75 mL) The obtained crystals were dried under reduced pressure at 40° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The applicants have previously reported the dehydrogenative coupling of alcohols with amines to form amides, catalyzed by complex 1, with liberation of hydrogen gas (Gunanathan 2007). To explore whether it might be possible to reverse this reaction by the application of hydrogen pressure, complexes 1-4 were tested as catalysts for the hydrogenation of amides. Thus, upon treatment of N-benzyl-2-methoxyacetamide with dihydrogen (10 atm) at 110° C. (bath temperature) in dry THF for 48 h with a catalytic amount of 1 (1 mol %), 62.7% of 2-methoxyethanol and 62.0% of benzyl amine were obtained. Performing the reaction at 140° C. using 1,4-dioxane as solvent did not significantly improve the yield (alcohol yield 66.3%). It was significant that the reaction was selective and the corresponding secondary amine was not observed. Under the same conditions complex 2 was inactive. Remarkably, employing complex 3 (1 mol %) as catalyst, hydrogenation of N-benzyl-2-methoxyacetamide under identical conditions (THF, 110° C.) resulted in the selective formation of 89.2% 2-methoxyethanol and 89.6% benzyl amine (Table 1B, entry 1). Thus, the normally observed C—O hydrogenolysis did not take place at all. Of practical significance, the air-stable complex 4 (which is stable in air for at least two days in solution) in the presence of one equivalent (relative to Ru) of base also efficiently catalyzes the hydrogenation of amides to alcohols and amines, by generation of the catalyst 3 in situ. Thus, upon heating a THF solution of 4 (1 mol %) with KOtBu (1 mol %) and N-benzyl-2-methoxyacetamide (1 mmol) at 110° C. under H2 (10 atm) for 48 h, 80.2% of alcohol and 81.8% of amine were formed. No reaction took place in the absence of base. Hydrogenation of N-hexyl-2-methoxyacetamide catalyzed by 3 yielded 2-methoxy ethanol and hexyl amine in 90.7% and 90.3% yields, respectively (Table 1B, entry 2). N-hexyl-3-methyloxetane-3-carboxamide undergoes hydrogenation to the alcohol and amine without hydrogenolysis of the strained oxetane ring (Table 1B, entry 3). The heterocyclic amide, N-hexylfuran-2-carboxamide was hydrogenated to yield 68.8% of furfuryl alcohol and 68.1% of hexylamine (Table 1B, entry 4). The aromatic non-activated amide, N-benzylbenzamide is also hydrogenated to benzyl alcohol and benzyl amine (Table 1B, entry 5), but the yield is lower, probably because of steric reasons. Significantly, the aliphatic non-activated amides, N-ethylacetamide and N-methylpropionamide also underwent hydrogenation to yield the corresponding alcohols and amines (71% of ethanol and ethylamine for entry 6 and 68.4% of n-propanol and methylamine for entry 7). The product gaseous amines were analyzed by GC-MS spectrometry of the gas phase and not quantified. As expected, the activated amides, anilide derivatives, were converted into their corresponding alcohols and aniline in excellent yields (91-95%; Table 1B, entries 9-12) along with trace amounts of the secondary amines (detected by GC-MS) under similar conditions. The reaction is also effective for bis-amides. Thus, N,N′-(ethane-1,2-diyl)bis(2-methoxyacetamide) (0.5 mmol) was also hydrogenated using catalyst 3 under mild conditions (Table 1B, entry 13). Noteworthy, tent-amides also underwent hydrogenation almost quantitatively to yield alcohols and secondary amines in equivalent amounts (Table 1B, entries 14-16). Gratifyingly, heating a solution of N-formymorpholine (1 mmol) and complex 3 in THF at 110° C. yielded after 32 h 97.1% of methanol and 98.3% of morpholine; no decarbonylation of the formyl group took place (Table 1B, entry 17). These results highlight the substantial scope of the unprecedented, selective hydrogenation of amides catalyzed by 3, or by the air-stable 4 with an equivalent of base (which generates 3 in situ).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A catalytic amount of N-benzyl-benzamide (Aldrich) and dry THF (Aldrich) (20 mL) were put into a three neck flask (inert atmosphere). To the cooled solution (−60° C.), 2.0 M solution of LDA (Aldrich) (10 mmole) in heptane (5 mL) was added. Subsequently, a solution of tert-butyl acetate (Aldrich) (1.3 mL, 10 mmole) dissolved in dry THF (4 mL) was slowly added to the reaction mixture drop by drop and the stirring was continued for 50 minutes at the temperature of −60° C., whereat the colour of solution changed from red-brown to yellow. A solution obtained by dissolving methyl-6-fluorosalicylate (474 mg; 2.4 mmole) in dry THF (10 mL) was added slowly to the carbanion solution and the stirring was continued overnight, whereat the temperature of the reaction mixture reached room temperature. Ethyl acetate (50 mL) and a saturated solution of ammonium chloride (50 mL) were added to the mixture, the layers were separated and then the organic layer was washed with a saturated sodium chloride solution (2×50 mL) and dried with sodium sulfate. The solvent was removed by evaporation under reduced pressure. The remaining brown oily product was mixed with trifluoroacetic acid (3 mL) and the obtained mixture was stirred for 4 hours at room temperature and diluted by a hexane:ether (2:1) solvent mixture (30 mL). A light brown precipitate was precipitated, which by purification on a silica gel column (12 g) using the solvent system chloroform:methanol:acetic acid (60:10:1) yielded 54 mg (12.5%) of light brown amorphous 5-fluoro-4-hydroxycoumarin. was slowly added to the reaction mixture drop by drop A solution obtained the stirring was continued overnight, whereat the temperature of the reaction mixture reached room temperature the layers were separated the organic layer was washed with a saturated sodium chloride solution (2×50 mL) dried with sodium sulfate The solvent was removed by evaporation under reduced pressure The remaining brown oily product was mixed with trifluoroacetic acid (3 mL) diluted by a hexane:ether (2:1) solvent mixture (30 mL) A light brown precipitate was precipitated which by purification on a silica gel column (12 g)

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-benzoyl-2,4-dimethoxybenzylamine (100 mg, 0.37 mmol) was dissolved in 1 ml 95% (v/v) trifluoroacetic acid (TFA) and stirred for 1 h at 20° C. TFA was removed by blowing with N2 and the residue suspended in methanol (1 ml). The reaction mixture was analyzed by TLC using CH2Cl2 /MeOH/AcOH (85:10:5) as eluent and the generated benzamide was determined quantitatively by HPLC using benzamide standard chromatograms. TFA was removed

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of benzylamine (0.125 mmol) in 5 mL of THF is added diisopropylethyl amine (0.15 mmol) and benzoylchloride (0.10 mmol). The reaction mixture is stirred at room temperature for 1 hour or until TLC analysis shows consumption of the benzoyl chloride. To this mixture is added perfluorsulfonic acid resin prepared in example 8 (3 g, 0.3 mmol/g loading) and the slurry is gently agitated for 1 hour. The slurry is filtered and the resin washed with dichloromethane. The combined filtrates are combined and the solvent removed under reduced pressure to afford N-benzylbenzamide as a solid. consumption of the benzoyl chloride To this mixture is added perfluorsulfonic acid resin prepared in example 8 (3 g, 0.3 mmol/g loading) the slurry is gently agitated for 1 hour The slurry is filtered the resin washed with dichloromethane the solvent removed under reduced pressure