Reusable and highly enantioselective water-soluble Ru(II)-Amm-Pheox catalyst for intramolecular cyclopropanation of diazo compounds

A reusable and highly enantioselective catalyst for the intramolecular cyclopropanation of various diazo ester and Weinreb amide derivatives was developed. The reactions catalyzed by a water-soluble Ru(II)-Amm-Pheox catalyst proceeded smoothly at room temperature, affording the corresponding bicyclic cyclopropane ring-fused lactones and lactams in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee). After screening of various catalysts, the Ru(II)-Amm-Pheox complex having an ammonium group proved to be crucial for the intramolecular cyclopropanation reaction in a water/ether biphasic medium. The water-soluble catalyst could be reused at least six times with little loss in yield and enantioselectivity.


2-Cyclohexylideneethan-1-ol
NaH in oil (132 mg, 5.5 mmol, 1.1 equiv) was washed by hexane, and THF was added (5 mL) at 0 °C. To a mixture was added triethyl phosphonoacetate (1.0 mL, 5 mmol, 1 equiv) and cyclohexanone in THF (5 mL). The mixture was stirred at 0 °C to rt for 8 h. The reaction mixture was quenched with NH 4 Cl aq. (5 mL) and extracted with Et 2 O. The organic layer was dried over Na 2 SO 4 , and concentrated under reduced pressure to give ethyl 2cyclohexylideneacetate as a colorless oil (93% yield, 783.8 mg, 4.7 mmol). This product was used for next reaction without further purification.
A solution of LiAlH 4 (353.7 mg, 9.3 mmol, 2 equiv) in Et 2 O (5 mL) was added a solution of reactant (783.8 mg, 4.7 mmol, 1 equiv) in Et 2 O (5 mL) at 0 °C. The mixture was stirred at 0 °C to rt for 2 h. The reaction mixture was quenched with H 2 O and extracted with CH 2 Cl 2 .

Typical procedure for the synthesis of trans-allylic diazo-Weinreb amide derivatives 6
According to the Fukuyama method, O-methylhydroxylamine hydrochloride was added to a solution of trans-allylic bromide and K 2 CO 3 in CH 3 CN, the reaction mixture was stirred at room temperature until the reaction was completed. After the evaporation of the solvent, the residue was used for the next step without further purification. K 2 CO 3 and bromoacetyl bromide were added to the residue at 0 °C. The reaction mixture was stirred for 15 min and then the reaction was quenched with H 2 O and extracted with CH 2 Cl 2 . The organic layer was washed with brine and dried over Na 2 SO 4 . After the evaporation of the solvent, the residue was used for the next step without further purification. The resulting bromoacetate was dissolved in THF. N,N`ditosylhydrazine and DBU were added dropwise at 0 °C and the reaction was stirred for 10 min.
The reaction was quenched by the addition of saturated solution of NaHCO 3 and extracted with diethyl ether. The organic layer was washed with brine, dried over Na 2 SO 4 and evaporated to give crude trans-allylic diazo-Weinreb amide derivatives that were purified by column chromatography to give the desired products.

Analytical data for various trans-allylic diazo-Weinreb amide derivatives products
Data for compounds 1f−h were already reported. 5

Amm-Pheox as a catalyst 6
To a solution of Ru(II)-Amm-Pheox catalyst (0.003 mmol) in H 2 O (1.00 mL), a solution of diazo Weinreb amide (1 mmol) in ether (1.00 mL) was added at room temperature. The progress of the reaction was monitored by TLC. After the reaction was completed, the two layers were separated and the aqueous layer was washed 3 times with ether. The collected ether layers were evaporated and the residue was purified using column chromatography on silica gel (Hex/EtOAc = 10:1) to give the desired product. The enantiomeric excesses of products were determined by HPLC analysis. Spectral data of this compound were already reported. 5
Based on these results, we expected that the Ru(II)-Amm-Pheox has more high solubility in water than Ru(II)-Pheox.