A novel exchange method to access sulfated molecules

Organosulfates and sulfamates are important classes of bioactive molecules but due to their polar nature, they are both difficult to prepare and purify. We report an operationally simple, double ion-exchange method to access organosulfates and sulfamates. Inspired by the novel sulfating reagent, TriButylSulfoAmmonium Betaine (TBSAB), we developed a 3-step procedure using tributylamine as the novel solubilising partner coupled to commercially available sulfating agents. Hence, in response to an increasing demand for complementary methods to synthesise organosulfates, we developed an alternative sulfation route based on an inexpensive, molecularly efficient and solubilising cation exchanging method using off-the-shelf reagents. The disclosed method is amenable to a range of differentially substituted benzyl alcohols, benzylamines and aniline and can also be performed at low temperature for sensitive substrates in good to excellent isolated yield.


S1. General Methods:
All reactions involving moisture sensitive reagents were carried out using standard Schlenk techniques, in a dry reaction vessel under argon. All solvents used under anhydrous conditions were decanted directly from an SPS dispensary or were stored over 4 Å molecular sieves 24 h prior to use.
Solvents used for workup procedures were of technical grade from Sigma-Aldrich, Honeywell, VWR or Fisher Scientific. Unless stated otherwise, solvents were removed by rotary evaporation under reduced pressure between 30-50 °C. All chemical reagents were used as received unless stated otherwise. Reactions were monitored by TLC analysis on Merck silica gel 60 F254 using UV light (254 nm) and/or potassium permanganate. 1 H, 13 C and 19 F NMR spectra were recorded either on a Bruker AVIII operating at 300 MHz for 1H and fitted with a 5 mm BBFO probe or on a Bruker AVANCE NEO operating at 400 MHz for 1H fitted with a 5 mm "smart"BBFO probe, respectively. Chemical shift data are reported in parts per million (ppm, δ scale) downfield from tetramethylsilane (TMS: δ 0.0) and referenced internally to the residual proton in the solvent. The deuterated solvents used for NMR analysis were: chloroform (CDCl3: δH 7.26, δC 77.2), dimethyl sulfoxide (d6-DMSO: δH 2.50, δC 39.5), and deuterium oxide (D2O: δH 4.79).Coupling constants are given in Hertz (Hz). All individual signals were assigned using 2D NMR spectroscopy ( 1 H-

Work-up procedure A:
The flask containing the tributylammonium salt was charged with EtOH (30 mL) and sodium 2-ethylhexanoate (5.0 eq. per sulfate group). The reaction mixture was stirred vigorously for 1 h at room temperature. The precipitate was collected by filtration, washed with EtOH (3 × 20 mL) and dried to a constant weight to afford the desired sulfate ester as its sodium salt.
Work-up procedure B: The flask containing the tributylammonium salt was charged with ethyl acetate (30 mL) and sodium 2-ethylhexanoate (5.0 eq. per sulfate group). The reaction mixture was stirred vigorously for 1 h at room temperature. The precipitate was collected by filtration, washed with ethyl acetate (3 × 20 mL) and dried to a constant weight to afford the desired sulfate ester as its sodium salt.
Work-up procedure C: The flask containing the tributylammonium salt was charged with MeCN (25 mL) and sodium iodide (5.0 eq. per sulfate group). The reaction mixture was stirred vigorously for 1 h at room temperature. The precipitate was removed by filtration, washed with MeCN (3 × 20 mL) and dried to a constant weight to afford the desired sulfate ester as its sodium salt.
General procedure 2. Synthetic procedure for the preparation of sodium benzylsulfamates using sulfur trioxide trimethylamine complex and tributylamine.
A flame dried 100 mL round bottom flask was charged with the appropriate amine (1.0 mmol) and trimethylamine.sulfur trioxide complex (TMST) (2.0 mmol) under argon. Anhydrous MeCN (2.0 mL) was added and the reaction mixture heated at 60 °C (monitored by TLC). After 30 min, tributylamine (2.0 mmol) was added to the reaction mixture and stirred for 30 min at 60 °C. The flask was cooled to room temperature and the solvent removed under reduced pressure to afford the desired sulfate ester as its tributylammonium salt.

Work-up procedure A:
The flask containing the tributylammonium salt was charged with EtOH (30 mL) and sodium 2-ethylhexanoate (1.5 eq. per sulfate group). The reaction mixture was stirred vigorously for 1h at room temperature. The precipitate was removed by filtration, washed with EtOH (3 × 20 mL) and dried to a constant weight to afford the desired sulfate ester as its sodium salt.

Work-up procedure B:
The flask containing the tributylammonium salt was charged with MeCN (25 mL) and sodium iodide (1.5 eq. per sulfate group). The reaction mixture was stirred vigorously for 1h at room temperature. The precipitate was removed by filtration, washed with MeCN (3 × 20 mL) and dried to a constant weight to afford the desired sulfate ester as its sodium salt.
A 25 mL flask was charged with the appropriate amine (1.0 mmol) and TMST (2.0 eq) under argon. Anhydrous MeCN was added (giving a concentration of 0.50 mol dm -3 to the limiting reagent), the reaction mixture was heated at 30 °C and monitored by TLC. After reaction completion the flask was cooled to room temperature and the solvent removed under reduced pressure. The reaction was quenched with EtOH (10 mL) and filtered. The solution was evaporated and extracted with H2O (10 mL) and ethyl acetate (4 x 40 mL). The organic layer was dried (MgSO4), filtered, and the solvent was removed in vacuo giving the desired trimethylammonium salt as an oil.
A 25 mL flask was charged with the appropriate amine (1.0 mmol) and tributylamine (2.0 eq) dissolved in anhydrous MeCN (giving a concentration of 0.50 mol dm -3 to the limiting reagent) under argon. After addition of TMST (2.0 eq), the reaction mixture was heated at 30 °C and monitored by TLC. After reaction completion the flask was cooled to room temperature and the solvent removed under reduced pressure. The reaction was quenched with EtOH (10 mL) and filtered. The solution was evaporated and extracted with H2O (10 mL) and ethyl acetate (4 x 40 mL). The organic layer was dried (MgSO4), filtered, and the solvent was removed in vacuo giving the desired tributylammonium salt as an oil.

S3. Compound characterization:
Tributylammonium benzyl sulfate (3a) [1] Following general procedure 4: benzyl alcohol (0.10 mL, 1.0 mmol) and tributylamine (0.47 mL, 2.0 mmol) were dissolved in anhydrous MeCN (2.0 mL). After addition of TMST (278 mg, 2.0 mmol) the reaction mixture was heated at 30 °C for 3 h. The crude compound was purified using silica gel chromatography (DCM-MeOH; 1:9) to yield the title compound as a yellow oil (138 mg, 37%). Data were consistent with the literature. [1] Sodium benzyl sulfate (4a) [1] Following the general procedure 1: benzyl alcohol (0.1 mL, 1.0 mmol) and sulfur trioxide pyridine complex (318 mg, 2.0 mmol) were dissolved in anhydrous MeCN (2.0 mL) and heated under reflux at 90 °C for 3 h. Tributylamine (0.4 mL, 2.0 mmol) was added to the mixture and stirred for 30 min. After the completion of reaction, the flask was cooled to room temperature and the solvent removed under reduced pressure. The crude product was purified using work up procedure A to yield the title compound as a bright white solid (196 mg, 93%). Data were consistent with the literature. [1] Sodium 2-methylbenzyl sulfate (4b) Following general procedure 1: 2-methylbenzyl alcohol (122 mg, 1.0 mmol) and sulfur trioxide pyridine complex (318 mg, 2.0 mmol) were dissolved in anhydrous MeCN (2.0 mL) and heated under reflux at 90 °C for 3 h. Tributylamine (0.4 mL, 2.0 mmol) was added to the mixture and stirred for 30 min. After the completion of the reaction, the flask was cooled to room temperature and the solvent removed under reduced pressure. The crude product was purified using work up procedure B to yield the title compound as a bright white solid (216 mg, 96%).  Sodium 3-methylbenzyl sulfate (4c)

M.P. 200-202 °C
Following general procedure 1: 3-methylbenzyl alcohol (0.12 mL, 1.0 mmol) and sulfur trioxide pyridine complex (318 mg, 2.0 mmol) were dissolved in anhydrous MeCN (2.0 mL) and heated under reflux at 90 °C for 3 h. Tributylamine (0.4 mL, mmol) was added to the mixture and stirred for 30 min. After the completion of the reaction, the flask was cooled to room temperature and the solvent removed under reduced pressure. The crude product was purified using work up procedure A to yield the title compound as a bright white solid (190 mg, 85%).    Sodium 2-chlorobenzyl sulfate (4e) [1] Following the general procedure 1: 2-chlorobenzyl alcohol (142.5 mg, 1.0 mmol) and sulfur trioxide pyridine complex (318 mg, 2.0 mmol) were dissolved in anhydrous MeCN (2.0 mL) and heated under reflux at 90 °C for 3 h. Tributylamine (0.4 mL, 2.0 mmol) was added to the mixture and stirred for 30 min. After the completion of the reaction, the flask was cooled to room temperature and the solvent removed under reduced pressure. The crude product was purified using work up procedure C to yield the title compound as a yellow solid (180 mg, 73%).

M. P. 172-174 °C
M.P. 239-241°C (lit. [1]  Data were consistent with the literature. [1] Sodium 3-chlorobenzyl sulfate (4f) Following general procedure 1: 3-chlorobenzyl alcohol (0.11 mL, 1.0 mmol) and sulfur trioxide pyridine complex (318 mg, 2.0 mmol) were dissolved in anhydrous MeCN (2.0 mL) and heated under reflux at 90 °C for 3 h. Tributylamine (0.4 mL, 2.0 mmol) was added to the mixture and stirred for 30 min. After the completion of the reaction, the flask was cooled to room temperature and the solvent removed under reduced pressure. The crude product was purified using work up procedure A to yield the title compound as a bright white solid (201 mg, 82%). Sodium 4-chlorobenzyl sulfate (4g) [1] Following general procedure 1: 4-chlorobenzyl alcohol (142.5 mg, 1.0 mmol) and sulfur trioxide pyridine complex (318 mg, 2.0 mmol) were dissolved in anhydrous MeCN (2.0 mL) and heated under reflux at 90 °C for 3 h. Tributylamine (0.4 mL, 2.0 mmol) was added to the mixture and stirred for 30 min. After the completion of the reaction, the flask was cooled to room temperature and the solvent removed under reduced pressure. The crude product was purified using work up procedure C to yield the title compound as a bright white solid (220 mg, 90%).
M.P. 227-229 °C (lit. [1]  Data were consistent with the literature. [1] Sodium3-(trifluoromethyl) benzyl sulfate (4h) Following general procedure 1: 3-(trifluoromethyl) benzyl alcohol (0.13 mL, 1.0 mmol) and sulfur trioxide pyridine complex (318 mg, 2.0 mmol) were dissolved in anhydrous MeCN (2.0 mL) and heated under reflux at 90 °C for 3 h. Tributylamine (0.4 mL, 2.0 mmol) was added to the mixture and stirred for 30 min. After the completion of the reaction, the flask was cooled to room temperature and the solvent removed under reduced pressure. The crude product was purified using work up procedure C to yield the title compound as a white solid (274 mg, 98%).

M.P. 224-226 °C
IR νmax cm -1 3109w, 1470w, 1452w, 1329w, 1250w, 1203m, 1069m  Sodium 4-methoxybenzyl sulfate (4i) [1] Following general procedure 1: 4-methoxybenzyl alcohol (0.12 mL, 1.0 mmol) and sulfur trioxide pyridine complex (318 mg, 2.0 mmol) were dissolved in anhydrous MeCN (2.0 mL) and heated under reflux at 90 °C for 3 h. Tributylamine (0.4 mL, 2.0 mmol) was added to the mixture and stirred for 30 min. After the completion of the reaction, the flask was cooled to room temperature and the solvent removed under reduced pressure. The crude product was purified using work up procedure C to yield the title compound as a bright white solid (170 mg, 70%).  Sodium 2-nitrobenzyl sulfate (4j) [1] Following general procedure 1: 2-nitrobenzyl alcohol (153 mg, 1.0 mmol) and sulfur trioxide pyridine complex (318 mg, 2.0 mmol) were dissolved in anhydrous MeCN (2.0 mL) and heated under reflux at 90 °C for 3 h. Tributylamine (0.4 mL, 2.0 mmol) was added to the mixture and stirred for 30 min. After the completion of the reaction, the flask was cooled to room temperature and the solvent removed under reduced pressure. The crude product was purified using work up procedure C to yield the title compound as a yellow solid (166 mg, 65%).  Data were consistent with the literature. [1] Sodium 4-nitrobenzyl sulfate (4k) [1] Following the general procedure 1: 4-nitrobenzyl alcohol (153 mg, 1.0 mmol) and sulfur trioxide pyridine complex (318.3 mg, 2.0 mmol) were dissolved in anhydrous MeCN (2.0 mL) and heated under reflux at 90 °C for 3 h. Tributylamine (0.4 mL, 2.0 mmol) was added to the mixture and stirred for 0.5 h. After the completion of the reaction, the flask was cooled to room temperature and the solvent removed under reduced pressure. The crude product was purified using work up procedure C to yield the title compound as a white solid (167 mg, 66%).  Data were consistent with the literature. [1] Trimethylammonium benzyl sulfamate (6a) [2] Following general procedure 3: benzyl amine (0.109 mL, 1.0 mmol) and TMST (278.3 mg, 2.0 mmol) were dissolved in anhydrous MeCN (2.0 mL) and the reaction mixture was heated at 30 °C for 3 h. After purification the title compound was afforded as a clear oil (122 mg, 50%). -1 3444w, 3033w, 2928w, 1453w, 1157w Data were consistent with the literature. [2] Tributylammonium benzyl sulfamate (7a) [2] Following general procedure 4: benzyl amine (0.109 mL, 1.0 mmol) and tributylamine (0.47 mL, 2.0 mmol) were dissolved in anhydrous MeCN (2.0 mL). After addition of TMST (278.3 mg, 2.0 mmol) the reaction mixture was heated at 30 °C for 3 h. The title compound was obtained as a clear oil (317 mg, 84%) after purification.
Sodium benzyl sulfamate (8a) [1] Following the general procedure 2: Benzylamine (0.1 mL, 1.0 mmol) and sulfur trioxide trimethylamine complex (278 mg, 2.0 mmol) were dissolved in anhydrous MeCN (2.0 mL) and heated under reflux at 60 °C for 30 mins. Tributylamine (0.4 mL, 2.0 mmol) was added to the mixture and stirred for 30 mins. After the completion of the reaction, the flask was cooled to room temperature and the solvent removed under reduced pressure. The crude compound was purified using work up procedure B to yield the title compound as a white solid (208 mg, 99%). Data were consistent with the literature. [1] Sodium (3-methylbenzyl) sulfamate (8b) Following the general procedure 2: 3-methylbenzylamine (0.12 mL, 1.0 mmol) and sulfur trioxide trimethylamine complex (278 mg, 2.0 mmol) were dissolved in anhydrous MeCN (2.0 mL) and heated under reflux at 60 °C for 30 mins. Tributylamine (0.4 mL, 2.0 mmol) was added to the mixture and stirred for 30 mins. After the completion of the reaction, the flask was cooled to room temperature and the solvent removed under reduced pressure. The crude compound was purified using work up procedure A to yield the title compound as a white solid (209 mg, 94%).
M.P. 223-225 °C (lit. [2]  Data were consistent with the literature. [2] Preparation of Sodium (4-chlorobenzyl) sulfamate (8e) [2] Following the general procedure 2: 4-chlorobenzylamine (0.12 mL, 1.0 mmol) and sulfur trioxide trimethylamine complex (278 mg, 2.0 mmol) were dissolved in anhydrous MeCN (2.0 mL) and heated under reflux at 60 °C for 30 mins. Tributylamine (0.4 mL, 2.0 mmol) was added to the mixture and stirred for 30 mins. After the completion of the reaction, the flask was cooled to room temperature and the solvent removed under reduced pressure. The crude compound was purified using work up procedure A to yield the title compound as a white solid (240 mg, 98%).
M.P. 234-236 °C (lit. [2]  Data were consistent with the literature. [2] Sodium (3-methoxybenzyl) sulfamate (8f) [2] Following the general procedure 2: 3-methoxybenzylamine (0.13 mL, 1.0 mmol) and sulfur trioxide trimethylamine complex (278 mg, 2.0 mmol) were dissolved in anhydrous MeCN (2.0 mL) and heated under reflux at 60 °C for 30 mins. Tributylamine (0.4 mL, 2.0 mmol) was added to the mixture and stirred for 30 mins. After the completion of the reaction, the flask was cooled to room temperature and the solvent removed under reduced pressure. The crude compound was purified using work up procedure A to yield the title compound as a white solid (224 mg, 93 %).
M.P. 219-221 °C (lit. [2] 218-220 °C)  Data were consistent with the literature. [2] Sodium (4-metheoxybenzyl) sulfamate (8g) [2] Following the general procedure 2: 4-methoxybenzylamine (0.13 mL, 1.0 mmol) and sulfur trioxide trimethylamine complex (278 mg, 2.0 mmol) were dissolved in anhydrous MeCN (2.0 mL) and heated under reflux at 60 °C for 30 mins. Tributylamine (0.4 mL, 2.0 mmol) was added to the mixture and stirred for 30 mins. After the completion of the reaction, the flask was cooled to room temperature and the solvent removed under reduced pressure. The crude compound was purified using work up procedure A to yield the title compound as a white solid (238 mg, 99%).