Hydrogenation of unactivated enamines to tertiary amines: rhodium complexes of fluorinated phosphines give marked improvements in catalytic activity

Summary In the hydrogenation of sluggish unactivated enamine substrates, Rh complexes of electron-deficient phosphines are demonstrated to be far more reactive catalysts than those derived from triphenylphosphine. These operate at low catalyst loadings (down to 0.01 mol %) and are able to reduce tetrasubstituted enamines. The use of the sustainable and environmentally benign solvent (R)-limonene for the reaction is also reported with the amine isolated by acid extraction.


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was filtered and volatiles were removed in vacuo. Crude enamine was dissolved in toluene (150 mL), exctacted into aqueous HCl (1 M, 3 × 100 mL) and the combined acidic fractions were basified with aqueous NaOH (1 M) until pH 10-12. The enamine was then extracted into ethyl acetate (3 × 70 mL), the combined organic fractions were washed with water (50 mL) and brine (50 mL), dried over MgSO 4 and solvent was removed under reduced pressure.
The enamine was dried in vacuo for 2 hours to afford the desired product (2.848 g, 14.0 mmol, 42%) as a pale yellow liquid.
Due to high stability of this enamine, it was found that acid-base work-up is a suitable method of purifying enamines with tetrasubstituted double bond studied in this paper (another example is enamine 1c). 1  A hexane solution (90 mL) of cyclohexyl(phenyl)methanone (4.911 g, 26.1 mmol) and diethylamine (16.5 mL, 159 mmol) was cooled to 0 °C and TiCl 4 (1.6 mL, 14.6 mmol) was added dropwise and the resulting suspension was left to stir for further 30 minutes followed by stirring the reaction mixture at room temperature for further 24 hours. After this time, the flask was opened to air and water-saturated diethyl ether (16 mL) was added. The solution S5 was filtered and volatiles were removed in vacuo. Crude enamine was dissolved in toluene (120 mL), exctacted into aqueous HCl (1 M, 3 × 80 mL) and the combined acidic fractions were basified with aqueous NaOH (1 M) until pH 10-12. The enamine was then extracted into ethyl acetate (3 × 50 mL), the combined organic fractions were washed with water (40 mL) and brine (40 mL), dried over MgSO 4 and solvent was removed under reduced pressure.
The enamine was dried in vacuo for 2 hours to afford the desired product ( A hexane solution (120 mL) of propiophenone (5.0 mL, 37.6 mmol) and diethylamine (24.0 mL, 231 mmol) was cooled to 0 °C and TiCl 4 (2.3 mL, 21.0 mmol) was added dropwise and the resulting suspension was left to stir for further 30 minutes followed by stirring the reaction mixture at room temperature for further 24 hours. After this time, the flask was opened to air and water-saturated diethyl ether (23 mL) was added. The solution was filtered and volatiles were removed in vacuo. The product was purified by Kugelrohr distillation (oven T = 85 °C, 1.2 mbar) to afford the desired enamine (2.014 g, 10.6 mmol, 28%) as a pale yellow liquid.

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Since the compounds are present as a mixture (E/Z = 91:9), signals are given to them separately where possible. 1   The reaction was tested at 60 °C (selectivity towards 1j = 69%), 50 °C (selectivity towards 1j = 78%) and at 25 °C (selectivity towards 1j = 68%). Activation of catalyst before the reaction at 50 °C by literature procedure 4 did not make any difference towards selectivity / activity of the catalyst. Single enantiomer of the ligand was tested as well at 50 °C where the same selectivity as with mixture of diastereomers was achieved.
A high pressure autoclave with 4 vials was used. A vial was charged with the desired ligand time, the vial placed into the pre-purged autoclave, the autoclave was sealed, purged with hydrogen 3 times, pressurised with H 2 gas to the desired pressure, heated to 65 °C and left to stir for 16 hours. After this time, the autoclave was cooled to room temperature, the gas pressure was released and 1 H NMR of the crude reaction solution was acquired in order to calculate the conversion.
After catalytic hydrogenation of enamine (only in cases of full conversions to the amines), the solution was diluted with toluene (8 mL) and the amine was extracted with hydrochloric acid (1 M, 3 × 20 mL). Combined acid fractions were basified with aq. NaOH (1 M) until pH 12, and the amine was extracted with ethyl acetate (3 × 25 mL). Combined organic fractions S12 were washed with brine (30 mL), dried over MgSO 4 and solvent was removed under reduced pressure. The desired product was dried in vacuo for 50 minutes to afford the desired amine. The product is a pale-yellow oil (148 mg, 83.5 mmol, 83%). 1