Application: Using Chemyx Fusion 4000 and Fusion 6000 In Continuous Flow Sulfuryl Chloride-Based Reaction

General Information

All commercially available reagents and solvents were purchased from Sigma-Aldrich, TCI Chemicals, J. T. Baker, or MilliporeSigma and used as received. Thin-layer chromatography (TLC) and column chromatography were performed using silica gel 60 F254 plates (0.25 mm) and silica gel (pore size 60 Å, 70–230 mesh, 63–200 μm), respectively, from Sigma-Aldrich. 1H and 13C NMR spectra were acquired using a Bruker 600 MHz spectrometer. Chemical shifts for hydrogens and carbons are reported in parts per million downfield from tetramethylsilane or referenced to residual solvent. Data are represented as follows: chemical shift (multiplicity, coupling constant, integration). Multiplicities are denoted as follows: singlet (s), broad singlet (br. s), doublet (d), broad doublet (br. d), triplet (t), quadruplet (q), octet (oct), doublet of doublets (dd), doublet of triplets (dt), doublet of doublets of doublets (ddd), triplet of doublets (td), and multiplet (m). Coupling constants (J) are given in hertz.

NMR data were processed using the ACD Laboratories software, and the names of compounds were generated using the PerkinElmer ChemDraw Ultra v12.0.2 software package. Syringe pumps utilized to perform flow experiments were purchased from Chemyx (Fusion 4000 and Fusion 6000). For the scale-up, Vapourtec E-series peristaltic pumps were used. Perfluoroalkoxy tubing (1/16″ o.d., 0.030″ i.d. and 1/8″ o.d., 1/16″ i.d.), back-pressure regulators, connections, and fittings were purchased from Swagelok, Cole-Parmer, and IDEX Corporation.

Thiol 3 (4.00 g; 17.4 mmol) was loaded in a volumetric flask (10 mL), and DCM was added up to the level of the etched line (solution A). The same was done to prepare a solution of SO2Cl2 (3.2 mL; 38.2 mmol; 2.2 equiv) in DCM (solution B). The entire flow system was previously flushed with DCM and pressurized at 75 psi using a BPR. A shut-off valve was placed between the T-union and the reactor coil to maintain the system pressure and to enable switching from solvent to reagent solution and vice versa. Solutions A and B were transferred into 8 mL Harvard syringes with 2 mL of extra tubing to accommodate the 10 mL solutions. Both solutions were pumped with Chemyx syringe pumps at a flow rate of 0.168 mL/min through a 10 mL PFA coil reactor (1/16″ o.d. tubing, Vapourtec). When the two solutions were totally injected, fresh DCM was pumped at 0.336 mL/min (through the shut-off valve) to keep the reaction mixture moving forward at the same flow rate (see Figures S2 and S3). Compound 4 was not isolated. Data for the crude mixture: 1H NMR (600 MHz, CDCl3): δH 4.77 (dt, J1 = 10.8 Hz, J2 = 4.4 Hz, 1H), 3.88 (s, 2H), 2.00–2.06 (m, 1H), 1.89–1.97 (m, 1H), 1.67–1.73 (m, 2H), 1.34–1.55 (m, 2H), 0.99–1.12 (m, 2H), 0.84–0.94 (m, 7H), 0.77 (d, J = 7.0 Hz, 3H).

Continuous Flow Synthesis of 7 Using Vapourtec Peristaltic Pumps

Thiol 3 (8.00 g; 34.8 mmol) was loaded in a volumetric flask (20 mL), and toluene was added up to the level of the etched line (solution A). The same was done to prepare a solution of SO2Cl2 (6.24 mL; 76.4 mmol; 2.2 equiv) in toluene (solution B). Each solution was transferred to a 20 mL vial under a nitrogen atmosphere and then connected to the V-3 peristaltic pumps (Vapourtec E-Series flow system). The whole system was previously flushed with toluene and pressurized to 40 psi using a BPR. A 50 mL Harvard syringe was filled with vinyl acetate 5 (neat) and pumped using a Chemyx syringe pump. The two-step reaction was carried out at 25 °C. The crude mixture was neutralized with a saturated NaHCO3 solution before NMR analysis. The thiol 3 used in these reactions was not purified by chromatographic column with silica gel. The crude starting material was treated only with a basic wash to remove the PTSA. The same result was obtained using purified and nonpurified starting material. However, water traces in thiol 3 can quench part of the SO2Cl2. After the basic wash, efficient drying was required to control the addition of the optimized amount of SO2Cl2 (see Figure S6). Compound 7 was obtained as a white goop after extraction with a saturated aqueous solution of NaHCO3. The overall assay yield starting from thiol 3 was 98% (0.67 mol; 258.2 g considering 158 g scale-up condition in flow). A crystal of one isomer (7a) was obtained (see Figure S8). 1H NMR (600 MHz, CDCl3): δH 6.56 (dd, J1 = 8.3 Hz, J2 = 4.03 Hz, 1H), 4.75 (dt, J1 = 11.0 Hz, J2 = 4.4 Hz, 1H), 5.43 (s, 1H), 3.48 (dd, J1 = 14.7 Hz, J2 = 8.3 Hz, 1H), 3.37 (dd, J1 = 14.7 Hz, J2 = 4.0 Hz, 1H), 2.17 (s, 3H), 2.02–2.07 (m, 1H), 1.87–1.97 (m, 1H), 1.43–1.56 (m, 2H), 1.01–1.12 (m, 2H), 0.92 (dd, J1 = 14.0 Hz, J2 = 6.6 Hz, 6H), 0.84–0.94 (m, 1H), 0.77 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (150 MHz, CDCl3): δC 168.1, 165.5, 81.6, 77.6, 61.5, 47.0, 40.3, 37.4, 34.0, 31.4, 26.1, 23.3, 22.0, 20,7, 20.6, 16.1.

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Article By: Juliana M. de Souza,†‡ Mateo Berton,† David R. Snead,*† and D. Tyler McQuade*†

Published online 2020 May 13.

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