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Copper-Catalyzed Asymmetric Reductions of Aryl/Heteroaryl Ketones under Mild Aqueous Micellar Conditions

David M. Fialho, Elham Etemadi-Davan, Olivia C. Langner, Balaram S. Takale, Amol Gadakh, Ganesh Sambasivam and Bruce H. Lipshutz*

*Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, United States, Email: lipshutzchem.ucsb.edu

D. M. Fialho, E. Etemadi-Davan, O. C. Langner, B. S. Takale, A. Gadakh, G. Sambasivam, B. H. Lipshutz, Org. Lett., 2021, 23, 3283-3286.

DOI: 10.1021/acs.orglett.1c00746


Abstract

A copper-catalyzed (Cu(OAc)2ĚH2O/(R)-3,4,5-MeO-MeO-BIPHEP) reduction of aryl/heteroaryl ketones provides nonracemic secondary alcohols in very good yields with excellent ee values in an aqueous micellar medium in the presence of PMHS as inexpensive, innocuous, and convenient stoichiometric hydride source.

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Experimental

A stock solution of ligated Cu(II) was prepared as follows. To a 2-dram glass vial equipped with a stir bar, Cu(OAc)2ĚH2O (9.6 mg, 48 Ámol) was added. The vial was sealed with a rubber stopper and purged with argon. In an argon-filled glove box, (R)-3,4,5-MeO-MeO-BIPHEP (49.8 mg, 52.8 Ámol) was added. The sealed vial was removed from the glove box and attached to a Schlenk line. Under argon, degassed toluene (640 μL) was added and rapid stirring was applied. TPGS-750-M 2 wt % aqueous solution (8 mL) was then added, creating an emulsion. The emulsion was stirred rapidly for 1.5 h. The stock solution was administered by withdrawing from the rapidly stirring emulsion with a syringe. To an argon purged reaction vial containing a stir bar and substrate ketone, the appropriate amount of stock solution was added to give a ketone concentration of 0.2 M. The reaction emulsion was allowed to stir rapidly at rt for 15 min. Then, the reaction vial was placed in an ice bath (while maintaining stirring) and a syringe containing the total amount of PMHS (35 μL PMHS per 100 μmol ketone) was added portion-wise every 0.5 h through the rubber stopper. After final addition, the reaction vial was removed from the ice bath and stirred at rt overnight attached to a manifold under argon. (Note: when performed in this manner, the hydrogen generated from the reaction is allowed to escape, and no positive pressure accumulates.) After completion, the reaction vial was opened and quenched by addition of a saturated solution of NH4F in MeOH (4 mL) in an ice bath. The ice bath was then removed, and the reaction was stirred at rt for 2 h. The mixture was extracted in the reaction vial with EtOAc (3 Î 8 mL) and the pooled extracts were passed through a silica plug. The remaining aqueous mixture was then passed through the silica plug and eluted with EtOAc. The combined organic phases were dried over MgSO4, deposited onto silica, and purified by flash chromatography on silica to afford the targeted chiral alcohols. The product was analyzed with HPLC to determine the enantiomeric excess.


Key Words

reduction of carbonyl compounds, PMHS, green chemistry


ID: J54-Y2021