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A Redox-Relay Heck Approach to Substituted Tetrahydrofurans

Tom J. M. Byrne, Megan E. Mylrea and James D. Cuthbertson*

*School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U.K., Email:

T. J. M. Byrne, M. E. Mylrea, J. D. Cuthbertson, Org. Lett., 2023, 25, 2361-2365.

DOI: 10.1021/acs.orglett.3c00769

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An operationally simple and efficient strategy for the synthesis of substituted tetrahydrofurans from readily available cis-butene-1,4-diol is based on a redox-relay Heck reaction, that generates cyclic hemiacetals. A subsequent reduction provides the corresponding 3-aryl tetrahydrofurans. Furthermore, the hemiacetals can also serve as precursors to a range of disubstituted tetrahydrofurans.

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General procedure A - Redox-Relay Heck Reaction:

To a microwave vial containing a mixture of NaHCO3 (2.00 equiv.), Pd(OAc)2 (0.02 equiv.), nBu4NCl (1.00 equiv.) and aryl iodide (1.00 equiv.) in MeCN (0.40 M) was added diol (1.20 equiv.) at r.t, the vial was capped, then the reaction was heated to 60 C in a heating block and stirred for 24 h. The reaction mixture was cooled to r.t and diluted with Et2O and water, then the aqueous phase was extracted with Et2O ( 3). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the hemiacetal which was immediately reduced using general procedure B.

Note: Use of Et2O in the work up is important to ensure effective removal of the tetrabutylammonium salt which was found to have a deleterious effect on the reduction step.

General procedure B - Reduction of Hemiacetals:

To a stirred solution of hemiacetal (1.00 equiv.) in DCM (0.20 M) at 0 C were added Et3SiH (1.10 equiv.) and BF3OEt2 (1.10 equiv.) dropwise over 2 min. The reaction was stirred at 0 C for 40 min then was quenched with sat. aq. NaHCO3. The reaction was diluted with DCM then the aqueous phase was separated and extracted with DCM ( 3). The combined organic layers were washed with 1M aq. HCl (except for acid sensitive compounds), brine, dried (MgSO4) and concentrated in vacuo to afford the crude product. The compounds are purified by flash column chromatography (SiO2, Cyclohexane : EtOAc).

Key Words

Heck reaction, tetrahydrofurans, triethylsilane

ID: J54-Y2023