New phosphine-diamine and phosphine-amino-alcohol tridentate ligands for ruthenium catalysed enantioselective hydrogenation of ketones and a concise lactone synthesis enabled by asymmetric reduction of cyano-ketones

Enantioselective hydrogenation of ketones is a key reaction in organic chemistry. In the past, we have attempted to deal with some unsolved challenges in this arena by introducing chiral tridentate phosphine-diamine/Ru catalysts. New catalysts and new applications are presented here, including the synthesis of phosphine-amino-alcohol P,N,OH ligands derived from (R,S)-1-amino-2-indanol, (S,S)-1-amino-2-indanol and a new chiral P,N,N ligand derived from (R,R)-1,2-diphenylethylenediamine. Ruthenium pre-catalysts of type [RuCl2(L)(DMSO)] were isolated and then examined in the hydrogenation of ketones. While the new P,N,OH ligand based catalysts are poor, the new P,N,N system gives up to 98% e.e. on substrates that do not react at all with most catalysts. A preliminary attempt at realising a new delta lactone synthesis by organocatalytic Michael addition between acetophenone and acrylonitrile, followed by asymmetric hydrogenation of the nitrile functionalised ketone is challenging in part due to the Michael addition chemistry, but also since Noyori pressure hydrogenation catalysts gave massively reduced reactivity relative to their performance for other acetophenone derivatives. The Ru phosphine-diamine system allowed quantitative conversion and around 50% e.e. The product can be converted into a delta lactone by treatment with KOH with complete retention of enantiomeric excess. This approach potentially offers access to this class of chiral molecules in three steps from the extremely cheap building blocks acrylonitrile and methyl-ketones; we encourage researchers to improve on our efforts in this potentially useful but currently flawed process.

Prostar operated by Galaxie workstation PC software. Catalysts 3 and 4 were prepared according to our published procedures 2a, b General Reagents

Dichlorotetrakis(dimethyl sulfoxide) ruthenium (II)
Prepared by modification of a literature procedure. 1 Ruthenium trichloride trihydrate (0.86 g, 4.13 mmol) was refluxed in dimethyl sulfoxide (5 mL) for 5 min under nitrogen. The volume was then reduced to half in vacuo and acetone added prompting formation of a yellow solid. The precipitate was filtered off, washed with acetone and dried in vacuo. Recrystallisation from dimethyl sulfoxide yielded complex (0.87 g, 44 %) as yellow crystals, mp 190 o C (lit. 1 193 o C).

General procedure for synthesis of the tridentate PNO ligands
To a solution of the corresponding 1-amino-2-indanol (0.298 g, 2.00 mmol) in ethanol (6 ml), a solution of 2-(diphenylphosphino)benzaldehyde (0.290 g, 1.00 mmol) in ethanol (6 mL) was added under a N 2 atmosphere. The resulting yellow solution was stirred at room temperature for 3 hours and then sodium borohydride (0.302g, 8 mmol) was added. The reaction mixture was stirred for a further 16 hours and then the solvent was removed under vacuum. The resulting residue was dissolved in dichloromethane (20 mL) and quenched with a saturated solution of ammonium chloride (10 mL). After extraction of the aqueous phase with dichloromethane (1 x 10 mL) under a N 2 atmosphere, the combined organic phases were dried using magnesium sulphate anhydrous and the solvent was then removed under vacuunm to afford the desired product as a pale yellow solid. The ligand can also be further purified by chromatography on silica gel using a mixture of diethy ether and hexane 4:1 as eluent.

General procedure for synthesis of PNO Ru complexes
[RuCl 2 (DMSO) 4 ] (183 mg, 0.38 mmol) was placed in a microwave tube under a N 2 atmosphere. The coorresponding PNO ligand (0.38 mmol) was then added via syringe as a solution in THF (5 mL). The reaction mixture was then heated using microwave radiation at 120 ˚C for 15 min. The solvent from the resulting orange solution was then partially removed under vacuum to a volume of approximately 1 mL and then hexane (3 mL) was added to obtain the desired complex as an orange-brown precipitate. The complex can also be further purified by chromatography on silica gel using a mixture of dichloromethane and acetone 1:1 as eluent.  The DPEN-derived ligand (R,R)-7 was prepared in the same manner as the ligand precursor of complex 3. 2 NMR analysis (EtOH, C 6 D 6 ) of the reaction mixture before treatment with sodium borohydride showed two species at -8.1 (Imine) and -15.8 ppm in a 1.3:1 ratio. After treatment with sodium borohydride for 16h and work-up, the 31 P NMR spectrum showed the presence of several species at δ P (DCM, C 6 D 6 ) = -9.

Hydrogenation Using [RuCl 2 (P^N^X)L] Catalysts
A solution of substrate (ca 1 mmol), catalyst and potassium tert-butoxide (1 M solution in 2methyl-2-propanol) in degassed isopropanol (3 mL) was prepared in a microwave vial under an atmosphere of nitrogen. The microwave tube was then placed inside a steel autoclave with two syringe needles piercing the lid of the vial. The autoclave was then sealed and flushed three times with hydrogen before being charged with hydrogen to the required pressure. The reactions were stirred at the same speed for the desired times at the required temperature using a stainless steel heating jacket connected to a thermocouple and heater. After the desired time passed, the autoclave was opened and the reaction mixture concentrated in vacuo. The conversion of substrate to product was calculated by 1 H NMR spectroscopy (In these experiments only starting material and product were observed, so an internal standard was generally not used). The products were isolated by column chromatography, or simple filtration through a 3 cm pad of silica with ether eluent, or short-path distillation and characterised by comparison of NMR, IR, MS, optical rotation and where appropriate melting point data, with authentic samples. The enantiopurity of the product (where applicable) was determined using high performance liquid chromatography with the chiral stationary phase noted for each product.

Racemic Reduction with Sodium Borohydride
All alcohols produced were also reduced with sodium borohydride on a small scale to develop the HPLC method. To a solution of the substrate (1 equivalent) in absolute ethanol was added powdered sodium borohydride (3 equivalents) in small portions to avoid vigorous reaction and the mixture stirred. The reaction was monitored by thin layer chromatography and upon completion quenched with 10 % hydrochloric acid solution. The mixture was then extracted with dichloromethane and washed with water and brine before drying with magnesium sulfate, filtration and concentration in vacuo yielded the product. The TLC, HPLC and NMR data is in agreement with the products from the hydrogenation reactions.

O O O
Furan (20 mmol, 1.36g) was placed in a two necked flask under a nitrogen atmosphere. Hexane (10 mL) and BuLi (62.5 mmol, 39 mL, 1.6 M solution in hexane) were added and the reaction mixture heated at 70 °C in an oil bath for 1.5 h. After that time, the flask was taken out of the oil bath and pivalonitrile (50 mmol, 4.15 g) was added. The reaction mixture was stirred for 1.5 h and the quenched with HCl 1M (20 ml). After extraction of the aqueous phase with diethtl ether (3 x 30 mL), the combined organic phases were dried using magnesium sulphate anhydrous and the solvent was then removed under vacuunm. The ketone was purified by chromatography on silica gel using a mixture of diethy ether and hexane 1:5 as eluent to give the product as a pale yellow solid (0.78 g, 3.3 mmol, 16%). 1  Prepared following the procedure of Wessig. 4 To a solution of 1-phenylprop-2-ene-1-one (0.841 g, 6.40 mmol) and ethyl cyanoacetate (0.677 mL, 6.40 mmol) in tetrahydrofuran wass added potassium carbonate (0.089 g, 6.50 mmol) and 18-crown-6 (0.142 mL, 0.66 mmol) and the mixture stirred for 2 h. After this period, water was added and the mixture diluted with diethyl ether. The organic component was separated, washed with further water, dried over magnesium sulfate, filtered, and concentrated in vacuo giving product that was deemed pure enough for direct use in the next step. In a similar procedure to that reported by Campbell, 5 acrylonitrile (2.62 mL, 0.04 mol) was added dropwise with stirring to a solution of isobutyrophenone (6.00 mL, 0.04 mol) in dioxane (10 mL) containing 30 % solution of potassium hydroxide in methanol (0.5 mL). This solution was heated at 50 o C for 24 h. After this time, the mixture was poured into water and the oil separated. Column chromatography of this oil on silica (Hexane:EtOAc 9:1) yielded the title compound as a colourless oil (1.71 g, 21 %). δ H (CDCl 3  Data are in agreement with the literature for the racemic compound that has been reported before. 15