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CuH-Catalyzed Regio- and Enantioselective Hydrocarboxylation of Allenes: Toward Carboxylic Acids with Acyclic Quaternary Centers

Sheng Feng and Stephen L. Buchwald*

*Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States, Email: sbuchwalmit.edu

S. Feng, S. L. Buchwald, J. Am. Chem. Soc., 2021, 143, 4935-4941.

DOI: 10.1021/jacs.1c01880


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Abstract

An enantioselective CuH-catalyzed hydrocarboxylation of allenes with a commercially available fluoroformate provides enantioenriched α-quaternary and tertiary carboxylic acid derivatives in good yields with exclusive branched regioselectivity. A broad range of heterocycles and functional groups on the allenes were tolerated.

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proposed mechanism



General Procedures for CuH-Catalyzed Hydrocarboxylation Reactions

An oven-dried screw-cap reaction tube (Fisherbrand, 13*100 mm, part no. 1495935C) containing a magnetic stir bar was charged with Cu(OAc)2 (5.4 mg, 0.030 mmol) and (R)-DTBM-SEGPHOS (38.9 mg, 0.033 mmol). The reaction tube was loosely capped with a septum-containing cap (cap: Thermo Scientific C4015-66; Septum: Thermo Scientific C4015-60), and then transferred into a nitrogen-filled glovebox. The cap was removed and anhydrous THF (0.60 mL) was added to the tube via a 1 mL syringe. The tube was capped and the mixture was stirred for 15 min at room temperature. Next, the cap was removed and dimethoxymethylsilane (DMMS) (0.22 mL, 1.8 mmol) was added in one portion via a 1 mL syringe. The tube was recapped, and the mixture was stirred for another 10 min at room temperature to prepare an orange-colored CuH stock solution. A separate oven-dried screw-cap reaction tube (Fisherbrand, 20*125 mm, part no. 1495937A) containing a magnetic stir bar was loosely capped with a septum-containing cap (cap: Kimble Chase Open Top S/T Closure catalog no. 73804-18400; Septum: Thermo Scientific B7995-18), and then transferred into the glovebox. The cap was removed, and allene (0.60 mmol, 1.2 equiv) and 1-adamantyl fluoroformate (0.50 mmol, 99 mg, 1.0 equiv. Note: Weighed out as a solid. Low melting point ~30 C. Hold the bottle using an iron clamp to prevent melting the solids) were added. Anhydrous THF (0.50 mL) was added to the reaction tube via a 1 mL syringe while rinsing the walls of the tube. Next, the CuH stock solution (0.68 mL) was added via a 1 mL syringe to the reaction tube in one portion. The reaction tube was capped and removed from the glovebox. The reaction mixture was allowed to stir at the temperature and time as indicated for each substrate.

After the reaction mixture had stirred for the amount of time as indicated for each substrate, the reaction mixture was allowed to warm (or cool) to room temperature (if applicable), and the cap of the reaction tube was removed. While the reaction mixture was stirred at room temperature, sat. NH4F in MeOH (10 mL) was slowly added to quench the reaction mixture (Caution: gas evolution observed). The mixture was stirred with the tube uncapped at room temperature for 30 min, then the mixture was transferred to a 100 mL round bottom flask. The tube was rinsed with EtOAc, and the mixture was concentrated in vacuo with the aid of a rotary evaporator. The residue was dissolved in EtOAc (1 mL), then filtered through a short plug of basic activated alumina (~2.5 g) eluting with EtOAc (~10 mL). The resulting solution was collected in a 20 mL scintillation vial, and then concentrated in vacuo with the aid of a rotary evaporator. The residue was immediately purified by silica gel column chromatography (~30 g silica gel, diameter of the column ~2 cm, length of the packed column ~18 cm) to give the products as esters.


Key Words

Hydrocarboxylations, CuH, Silanes


ID: J48-Y2021