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Sulfur-Phenolate Exchange As a Fluorine-Free Approach to S(VI) Exchange Chemistry on Sulfonyl Moieties

Alyssa F.J. van den Boom, Muthusamy Subramaniam and Han Zuilhof*

*Laboratory of Organic Chemistry, Wageningen University, Stippeneng 4, Wageningen 6708WE, The Netherlands, Email: Han.Zuilhofwur.nl

A. F. J. van den Boom, M. Subramaniam, H. Zuilhof, Org. Lett., 2022, 24, 8621-8626.

DOI: 10.1021/acs.orglett.2c03421


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Abstract

The nitrophenolate group in 4-nitrophenyl phenylmethanesulfonate can be exchanged for a wide range of (substituted) phenols and alkyl alcohols. Quantitative yields were reached within 10 min under ambient conditions and required only filtering through silica as workup.


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General procedure for the synthesis of products (for NMR screening)

In a typical exchange reaction, 5 mg of NaH (0.124 mmol, 1.2 equiv) and 0.113 mmol (1.1 equiv) of phenol/alcohol were dissolved in 0.9 mL of CD3CN, and the reaction was stirred for ~5 min to generate the phenolate. After this time, 30 mg (0.103 mmol, 1.0 equiv) of 4-nitrophenyl phenylmethanesulfonate was added, and stirring was continued. TLC (25% ethyl acetate in hexane) was used to monitor the progress of the reaction by the disappearance of the spot belonging to 4-nitrophenyl phenylmethanesulfonate. When this spot had fully disappeared, the reaction mixture was filtered into an NMR tube through a short silica plug, to remove the sodium nitrophenolate. The filtered reaction mixture was then directly analyzed using 1H NMR. No internal standard was needed in this case, as the sodium nitrophenolate was filtered off, and no other side products - except in the case of degradation - are formed during the reaction. As a result, the reaction mixture only contains the product and any remaining starting material, both of which provide well-separated signals in 1H NMR. The yield could therefore be determined by the disappearance of the signals belonging to 4-nitrophenol, with a simultaneous appearance of product signals. A reference spectrum of the reactant phenol was recorded in all cases, and successful binding was further confirmed by a change in chemical shift for the signals belonging to the added phenol upon attachment to the S(VI) hub. When the reaction was filtered prematurely - or when conversion was <100% - signals from an attached nitrophenol group were still visible (though with a lower integral value), and the product signals of the partially attached phenol had lower integrals than expected based on full conversion. When degradation took place, no product signals were observed, and signals from the starting material had shifted or disappeared.

Products for isolated yields and full characterization

Compounds for which the isolated yield was determined, and novel compounds that had to be characterized more extensively, were synthesized in the same way as described above for the NMR products, using nondeuterated acetonitrile as the solvent, on a scale of 150 mg (0.51 mmol) of 4-nitrophenyl phenylmethanesulfonate. After the reaction was completed, the solvent was evaporated, and the products were purified using flash column chromatography (silica gel) with 25%-40% ethyl acetate in hexane, depending on the polarity of the product. For highly polar products, 5% methanol in DCM was used as the mobile phase.


Sulfur-Phenolate Exchange as a Mild, Fast, and High-Yielding Method toward the Synthesis of Sulfonamides

A. F. J. van den Boom, H. Zuilhof, Org. Lett., 2023, 25, 788-793.


Key Words

sulfonates


ID: J54-Y2022