Rapid Asymmetric Transfer Hydroformylation (ATHF) of Disubstituted Alkenes Using Paraformaldehyde as a Syngas Surrogate

As an alternative to conventional asymmetric hydroformylation (AHF), asymmetric transfer hydroformylation (ATHF) by using formaldehyde as a surrogate for syngas is reported. A catalyst derived from commercially available [Rh(acac)(CO)2] (acac=acetylacetonate) and 1,2-bis[(2S,5S)-2,5-diphenylphospholano]ethane(1,5-cyclooctadiene) (Ph-BPE) stands out in terms of both activity and enantioselectivity. Remarkably, not only are high selectivities achievable, the reactions are very simple to perform, and higher enantioselectivity (up to 96 % ee) and/or turnover frequencies than those achievable by using the same catalyst (or other leading catalysts) can be obtained by using typical conditions for AHF.


Synthesis of cis-alkenes. General methods
Preparation of (Z)-methyl-4-(4-methoxystyryl)benzoate. Method A A 50 mL two-necked round-bottom flask was charged with 4-(4-methoxyphenylethynyl)benzoic acid methyl ester (407 mg, 1.35 mmol), Lindlar's catalyst (162.5 mg, 0.077 mmol, 5 mol%), quinoline (59.4 mg, 0.46 mmol, 30 mol%) and anhydrous toluene (11.5 mL) under a N 2 atmosphere. The flask was the purged with H 2 using a H 2 filled balloon before being stirred at room temperature for 3 hours under a positive pressure of H 2 (H 2 filled balloon). The reaction mixture was then filtered through celite to remove the catalyst. The celite was washed with diethyl ether. The combined organic layer were extracted using water and then brine before drying over Na 2 SO 4 , filtering and concentrating in vacuo. The crude product was purified via column chromatography (SiO 2 , hexane: ethyl acetate 9:1) to remove the quinoline before triturating with methanol (30 mL) to remove any unreacted starting material to afford (Z)methyl-4-(4-methoxystyryl)benzoate as a yellow oil (81 %). 1

Method B
A modification of a known procedure was followed. 5 A Schlenk tube was charged with the diarylalkyne, 1,2-bis(3-methoxyphenyl)ethyne, (1 equiv, 2.94 mmol, 0.7 g) under a N 2 atmosphere. THF was added (10 mL) and the Schlenk was cooled down to -78 ºC. Ti(O i Pr) 4 (1.1 equiv, 3.24 mmol, 0.96 mL) was added and then n-BuLi (2.2 equiv, 6.47 mmol, 1.6 M in hexanes, 4.04 mL) was added dropwise. The resulting solution was left to reach room temperature for 15 min, warmed to 50 ºC and left for 1 hour. The reaction was quenched by adding saturated aqueous NH 4 Cl solution (5 mL) and diluted with ether (10 mL). The resulting mixture was stirred at room temperature for 10 minutes and then separated. The aqueous solution was extracted with Et 2 O (3 x 15 mL). The organic phases were combined and dried over magnesium sulfate. After removal of the solvent under reduced pressure, the resulting crude product was purified by flash chromatography on silica gel to give pure cis-olefin.

General procedure for reduction of aldehyde products to alcohols
The crude reaction mixture was diluted with EtOH (3 ml). NaBH 4 (111 mg, 3 mmol) was added and the reaction mixture was stirred at room temperature under a N 2 atmosphere for 3 h. The contents of the vial were then transferred to a round bottom flask and the solvents partially removed under vacuum. The reaction mixture was then diluted with dichloromethane (5 ml), quenched with dilute HCl (1M) until it reached acidic pH, and transferred to a separation funnel. The organic layer was separated and the aqueous layer extracted 3 times with dichloromethane (3 x 10 ml). The combined organic layers were dried over anhydrous MgSO 4 and the solvent was removed with a rotary evaporator to give the crude mixture, which was purified by chromatography on SiO 2 with unoptimised methods. In all cases, this primarily yielded samples of pure alcohols. a Reaction carried out in Argonaut using 0.4 mol% |Rh(acac)(CO)2] and x mol % ligand that was preactivated at 10 bar syngas, 50 o C, 40 minutes in 2 ml toluene, prior to the addition of substrate in 3 ml toluene. % conversion determined by NMR on crude sample with no side products detected. b e.e. determined after reduction of the crude reaction mixtures to alcohols using NaBH4 and using chiral HPLC.

Asymmetric hydroformylation of acenaphthylene (18) using a low pressure autoclave
The reactions was run using a Parr 50 mL stainless steel autoclave equipped with a pressure gage, gas inlet, safety valve and injection port equipped with rubber septum. [Rh(acac)(CO 2 )] (0.5 mol%) and (S,S)-PhBPE (0.75 mol%) were placed into a glass vial. A stirring bar was added and the vial was sealed with a crimp cap and put under inert atmosphere. Two needles were pierced into the vial and this was introduced into the autoclave, which had been previously purged with three vacuum/argon cycles. Toluene (3 mL), an internal standard (1 drop of cyclooctane) and acenaphthylene (126 mg, 0.832 mmol) were added using a syringe.
The autoclave was then purged three times with CO/H 2 (1:1), pressurised to 5 bar and immersed into an oil bath preheated to the desired temperature (60 °C). After the desired reaction time (17 h), the autoclave was cooled down to room temperature, the pressure slowly released and opened. A small sample was taken and analysed by 1 H NMR to calculate the conversion of the resulting aldehyde (59% conversion of alkene, 56 % conversion to aldehyde). The aldehyde was reduced to the corresponding alcohol in order to measure the corresponding enantiomeric excess (17 % ee). solution was mixed and a small sample taken for a t 0 NMR. The solution was then added to the microwave vial and heated to the desired temperature in a preheated oil bath. After the desired reaction time, the autoclave was cooled to room temperature and the pressure was released. A small sample was taken and analysed by 1 H NMR to calculate the conversion of the resulting aldehydes. Products were reduced using the general procedure to the corresponding alcohols.

Cyclopentanecarboxylic acid
The aldehyde was oxidised by a modification of a literature procedure. 14 The reaction crude from the ATHF of cyclopentene (1.664 mmol) was diluted with tBuOH (3 ml) and TEMPO (10 mol%, 26 mg, 0.1664 mmol) was added to the mixture. In a separate flask NaH 2 PO 4 (2 equiv., 0.400 g, 3.33 mmol) was dissolved in water (9 mL), to this solution was added NaClO 2 (2 equiv., 0.301 g, 3.33 mmol) and the mixture was stirred until a clear solution formed. This   (