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

SuFEx chemistry has recently evolved as next-generation click chemistry. However, in most SuFEx syntheses, additional reagents/catalysts and carefully controlled conditions are still needed. Here, we aim to further generalize S(VI) exchange chemistry, using 4-nitrophenyl phenylmethanesulfonate as example, in which the nitrophenolate group is 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.


Synthetic procedures
Unless mentioned otherwise, all reactions were performed at room temperature under ambient atmosphere.

4-Nitrophenyl phenylmethanesulfonate 1
NaH (60% in oil, 293 mg, 7.34 mmol, 1.4 equiv) was added to 4-nitrophenol (948 mg, 6.82 mmol, 1.3 equiv) in 80 ml of dry tetrahydrofuran, and the solution was stirred for 5 min. Next, phenylmethanesulfonyl chloride (1.0 g, 5.25 mmol, 1.0 equiv) was added, and stirring was continued for 24 h. Then, the reaction mixture was diluted with 150 ml of DCM and transferred to a separatory funnel, where it was washed with water (3  150 ml). The organic phase was isolated, dried over sodium sulphate, and the solvent was evaporated. Next, the product was further purified by column chromatography (n-hex/EA) (using a Biotage ® system and SiliCycle ® precast silica columns (200−300 mesh or 300−400 mesh)) to yield compound 1 (1.37 g, 89%) as white crystals.
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 1 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 1 H 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 1 H 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 1. 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 (e.g. 7i), 5% methanol in DCM was used as the mobile phase.

Base screening
For the base screening, the same protocol was used as described above for BTMG, with a few adjustments: 0.117 mmol of the base mentioned in the left column of Table S1 was used instead of BTMG; compound 1 was added after 20 min instead of 10; and the exchange reaction after addition of 1 was run for 15 min, before the reaction mixture was filtered into an NMR tube for analysis.

Reaction with 4-cyanophenyl-or 4-chlorophenyl phenylmethanesulfonate
Reactions using either 4-cyanophenyl phenylmethanesulfonate or 4-chlorophenyl phenylmethanesulfonate as starting material (instead of 1) were performed in the same way as described in the general procedure, though CH3CN was used instead of CD3CN. After synthesis had been completed, the solvent was evaporated on a rotavapor, and the products were purified using flash column chromatography (silica gel, 30% ethyl acetate in hexane).

Reaction with 4-nitrophenyl 4-methylbenzenesulfonate
Reactions performed with 4-nitrophenyl 4-methylbenzenesulfonate instead of 1 as a starting material were performed as described in the general procedure, on a scale of 90 mg (0.307 mmol) 4-nitrophenyl 4methylbenzenesulfonate, and using CH3CN as the solvent. When full conversion was reached, the solvent was evaporated on a rotavapor, and the crude product was purified using flash column chromatography (silica gel, 30% ethyl acetate in hexane).

Hydrolytic stability
To test the hydrolytic stability of compound 1, 50 mg of 1 was added to 5 ml of a 20% solution of DMSO in water. As compound 1 does not dissolve in this solution, the resulting suspension was stirred vigorously on a stir plate. Degradation of 1 was followed by absorption measurements on a spectrophotometer. The increase in absorption arising from the nitrophenol degradation product was taken as a measure for the amount of degradation.

Polymer synthesis
Inside an argon-filled glovebox (MBRAUN's MB 20 G-LMF gas purifier with H2O and O2 values of <0.1 ppm), butane-1,4-disulfonyl dichloride (0.5 g, 1.96 mmol, 1 equiv) and disodium bis-phenolate (0.53 g, 1.96 mmol, 1 equiv) were added in a 5 ml screw-capped glass vial equipped with a magnetic stir bar. 1.25 mL of anhydrous N-methyl-2-pyrrolidone (Thermo Scientific 99.9+% Extra Dry over Molecular Sieve, AcroSeal®) was added, and the vial was taken out of the glovebox. The reaction mixture was heated to 120 °C using an oil bath, and stirred for 24 h, during which course the reaction mixture turned viscous.
Next, the reaction mixture was cooled, and 4 mL DMF was added to dissolve the crude polymer. The resulting solution was poured slowly into 30 mL of MeOH under constant stirring. After a precipitate formed, the stirring was continued for another 10 min. The formed precipitate was then allowed to sediment for 10 S6 min, after which the methanol layer was removed and a minimal amount of DMF was added to re-dissolve the precipitate. This precipitate, sediment, and re-dissolve cycle was repeated, for a total of 4 cycles.
Afterwards, the polymer was purified by dialysis (Sigma-Aldrich, Pur-A-Lyzer™ Mega 6000) in DMSO, and subsequently used for degradation experiments. The molecular weight Mn of polymer 8 was found to be 27 kDa (Đ = 1.54) with GPC measurement.

Degradation of polysulfonate 8
NaH (9.8 mg, 0.24 mmol, 10 equiv) was added to phenol (23 mg, 0.24 mmol, 10 equiv) in 1 ml of tetrahydrofuran, and the solution was stirred for 5 min. Next, polysulfonate 8 (10 mg, 1.0 equiv) was added, and the stirring was continued for 24 h at 80 °C in an oil bath. Then the mixture was diluted with DCM (3 mL) and water (3 mL), adjusted to pH ~ 5 with 0.05 M HCl. Then, the organic layer was washed with water (2 × 3 mL), dried over Na2SO4, and used for GPC and LC-MS analysis.
Plausible mechanism for the degradation of polymer 8:

Hydrolytic stability
To measure the degradation of 1, the optical absorption at 418 nm was followed, as at this wavelength 1 does not have any significant absorption ( Figure S1). The degree of degradation (in %) was calculated using a calibration curve of 4-nitrophenol in 20% DMSO in water. The results after 9 days of exposure to 20% DMSO in water show only minimal degradation (<0.09%, Figure S2). However, the actual degradation is even lower, as the absorption across the whole spectrum was increased for several time points, due to the turbidity of the sample. This can also be clearly seen in Figure S1 above for the spectra of e.g. 2d, 3d, and 9d. An NMR spectrum taken after 9 days of the exposed sample confirms no degradation has taken place.

Base screening
In the table below, conversion refers to the percentage of 1 that has reacted, while yield refers to the percentage of the desired product found in the reaction mixture. In cases where the conversion is higher than the yield, side reactions or degradation of 1 occurred.

3b-p. 4-Methylphenyl benzylsulfonate
Prepared according to the general procedure described above using p-cresol as the phenol. NMR yield:

3c. 4-Aminophenyl benzylsulfonate
Prepared according to the general procedure described above using 4-aminophenol as the phenol. brown solid. The secondary product that was formed during this reaction -where phenol 2c had attached to 1 via the -NH2 moiety -was separated from the desired product using column chromatography (silica gel,

7i. β-Estradiol, benzylsulfonyl ester
Prepared according to the general procedure described above, using 2 equiv of NaH, and using β-estradiol as the phenol. White solid.  LC Mass Spectra of the degraded polysulfonate 8