Development of a continuous process for α-thio-β-chloroacrylamide synthesis with enhanced control of a cascade transformation

A continuous process strategy has been developed for the preparation of α-thio-β-chloroacrylamides, a class of highly versatile synthetic intermediates. Flow platforms to generate the α-chloroamide and α-thioamide precursors were successfully adopted, progressing from the previously employed batch chemistry, and in both instances afford a readily scalable methodology. The implementation of the key α-thio-β-chloroacrylamide casade as a continuous flow reaction on a multi-gram scale is described, while the tuneable nature of the cascade, facilitated by continuous processing, is highlighted by selective generation of established intermediates and byproducts.


General procedures
Solvents were distilled prior to use as follows: dichloromethane was distilled from phosphorus pentoxide, ethyl acetate was distilled from potassium carbonate, hexane was distilled prior to use. Organic phases were dried using anhydrous magnesium sulfate. All commercial reagents were used without further purification unless otherwise stated. 1 H (300 MHz) and 13 C (75.5 MHz) NMR spectra were recorded on a Bruker Avance 300 MHz NMR spectrometer. 1 H (400 MHz) and 13 C (100.6 MHz) NMR spectra were recorded on a Bruker Avance 400 MHz NMR spectrometer. All spectra were recorded at 300 K in deuterated chloroform (CDCl 3 ) unless otherwise stated, using tetramethylsilane (TMS) as internal standard. Chemical shifts (δ H and δ C ) are reported in parts per million (ppm) relative to TMS and coupling constants are expressed in hertz (Hz). Splitting patterns in 1 H spectra are designated as s (singlet), d (doublet), dd (doublet of doublets), ddd (doublet of doublet of doublets), t (triplet), q (quartet) and m (multiplet).
Infrared spectra were measured using a Perkin Elmer FTIR UATR2 spectrometer, or as potassium bromide discs (for solids) on a Perkin-Elmer Paragon 1000 FT-IR spectrometer.
Elemental analysis was carried out by Microanalysis Laboratory, National University of Ireland, Cork, using Perkin-Elmer 240 and Exeter Analytical CE440 elemental analysers.
Low resolution mass spectra (LRMS) were recorded on a Waters Quattro Micro triple quadrupole instrument in electrospray ionization (ESI) mode using 50% acetonitrile-water containing 0.1% formic acid as eluent. High resolution (precise) mass spectra (HRMS) were recorded on a Waters LCT Premier Tof LC-MS instrument in electrosprayionization mode using 50% acetonitrile-water containing 0.1% formic acid as eluent. Samples prepared for either LRMS or HRMS by employing acetonitrile as solvent. Melting points were obtained using a uni-melt Thomas Hoover Capillary melting point apparatus and are uncorrected.
HPLC was performed on an Agilent Technologies 1120 Compact LC system (Agilent Technologies, Santa Clara, CA, USA) on Agilent Chemstation (Rev. B.04.03[52]) software S4 for data acquisition. Chromatography was carried out using a YMC-Pack ODS-A reverse phase column (250 mm x 4.6 mm, 5 μm) with a flow rate of 0.8 mL/min. Samples were injected (5 μL) by the autosampler and were detected by UV absorbance at 250 nm and by a 385-ELSD evaporative light scattering detector (LC-ELSD) (Agilent Technologies, Santa Clara, CA, USA). Nitrogen (99.995%) was used as the evaporation gas at a flow rate of 1.6 L.min -1 . The ELSD was operated with the nebulizer and evaporator temperatures at 40°C.
Experimental details for previously reported compounds 1, 2, Z-3, 4 and 5 prepared using batch reactions [1], have been included in this document to allow convenient comparison with the corresponding continuous process.

Continuous flow setup
All continuous processes were performed using either a Vapourtec R-Series flow reactor or a Vapourtec E-Series flow reactor.
The R-Series flow reactor consists of four piston pumps and up to four temperature controlled tubular reactors. To prepare the reactor for operation, pumps were purged with the solvent to be used in the reaction prior to use. All reaction tubing, coils, inlets and connections were also purged thoroughly in a similar manner. with the solvent to be used in the reaction prior to use. All reaction tubing, coils, inlets and connections were also purged thoroughly in a similar manner.

HPLC conditions for reaction analysis
Due to the inherent complexity of the cascade process, the development of a robust HPLC method which would allow rapid quantitation of reaction products, intermediates and starting materials was considered to be highly advantageous for process optimization. A 40 min method employing isocratic 60:40 acetonitrile/water as the mobile phase gave resolution of the different reaction components (Table S3). The starting material 2, key intermediates 4 and 5 and final product Z-3 of the cascade could all be successfully identified by this method, using authentic isolated samples which were prepared in batch-in addition to the isomer E-3 and the overchlorination products 6 and 7. This method was used for optimization of the βchloroacrylamide cascade in flow (Tables 2-5). In the case of Tables 2, 4 and 5, the product ratio was determined by weighting the peak areas generated against the relative response factors of the compounds under investigation at 250 nm. a Determined using calibration curves. b As the compounds 5 and 6 could not be isolated, their relative response factors were estimated to give the same response as α-thioamide 2, based on a similar level of conjugation.

S7
A closely related 30 min method employing gradient 60:40-90:10 acetonitrile/water as mobile phase was used for analysis of the α-thioamide synthesis (Tables 1 and S5) affording resolution of the different reaction components (Table S5). The starting material 1, final product 2 and diphenyl disulfide could all be successfully identified by this method, using authentic isolated samples prepared in batch. In order to accommodate running consecutive samples the following gradient was employed:

Optimized continuous process
Scheme S1 A solution of 2-chloropropionyl chloride (65.4 g, 0.5 mol) in EtOAc (2.5 L) and a solution of p-toluidine (54.1 g, 0.5 mol) and diisopropylethylamine (65.3 g, 0.5 mol) in EtOAc (2.5 L) were prepared. The 2-chloropropionyl chloride solution was pumped (8 mL/min) into a T-S9 piece where it met the solution of p-toluidine and diisopropylethylamine (8 mL/min). The combined stream passed through two 10 mL reactor coils at 25 °C (2.5 min residence time).
After exiting the reactor, the solution was collected and worked up in two portions. Each portion was washed with a saturated solution of sodium bicarbonate (1 L), distilled water (1 L) and brine (1 L), dried, filtered and concentrated under reduced pressure. The resulting solid was recrystallised from dichloromethane/hexane to give the amide (91.7 g, 93%) as a white solid, which demonstrated identical spectroscopic properties to those previously reported. The crude product can also be purified by recrystallization from EtOAc/heptane with a similar recovery.

Original batch process
The title compound was prepared in a similar manner to that described

Continuous processmethanol as solvent
Due to the greater solubility of sodium chloride-a significant reaction by-product-in methanol compared to ethanol, methanol was investigated as a possible alternative solvent to ethanol with a view to enabling a flow process. A variety of temperature and reactant concentrations were examined (Table S6). As preparing sodium methoxide (from sodium metal and dry methanol) before each reaction is undesirable for large scale operation, alternative bases were also examined (Table S6). It is S11 also noteworthy, that commercial sodium methoxide performed poorly-compared to methoxide freshly prepared from sodium metal-due to problems with its solubility (entry 6, Table S6). Sodium carbonate was also found to give inferior results to those obtained with freshly prepared sodium methoxide (entry 7, Table S6). Use of 10 equivalents of sodium hydroxide, however, gave an acceptable yield of product, a reduced yield of diphenyl disulfide and no detected quantity of unreacted α-chloroamide 1 (entry 8, Table S6), the latter which had been a persistent impurity in all previous batches of 2. While employing 10 equivalents of sodium hydroxide resulted in higher levels of unisolated impurities in the reaction medium (entry 8, Table S6), the crude product was otherwise found to contain only diphenyl disulfide as an impurity.
General procedure Table 1 Thiophenol solution (in ethanol) was pumped (  the reaction was cooled in an ice bath and was quenched by addition of water (100 mL). The solid precipitate was isolated by suction filtration. This gave pure α-thioamide 2 (24.44 g, 88%) as a white solid which exhibited identical spectroscopic properties to those previously reported. S12
Following stirring at 90 °C for 3 hours, the reaction mixture was cooled to 0 °C. The succinimide by-product was removed by filtration and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel
The mixture was stirred for 10 min at room temperature then heated to 40 o C and stirred at this temperature for 17 h. Filtration and evaporation of the solvent from the filtrate under reduced pressure gave the crude product which by 1 H NMR analysis was found to contain at least 78% dichloride 5, along with a minor amount of α-thio-β-chloroacrylamide Z-3. The dichloride 5 was characterised from sample which was a mixture with Z-3; ν max /cm -1 Characteristic signals for the α-thio-β-chloroacrylamide Z-3 were also present.

N-(4-Methylphenyl)-3,3-dichloro-2-(phenylthio)propenamide (7)
N-Chlorosuccinimide ( Then the reaction mixture was cooled to 0 o C. The succinimide by-product was removed by filtration and the solvent was evaporated from the filtrate. The crude product was purified by successive attempts at column chromatography on silica gel using 1% ethyl acetate/hexane to S14 give the pure dichloroacrylamide 7 ( 0.043 g, 19.5 %) as a white solid; mp 128-130 o C; (Found C,56.75;H,3.99;N,4.00;S,9.16;Cl;20.63  Only 4 of 5 possible aromatic CH carbon signals were observed at 100.6 MHz. General procedure Table 2 α-Thioamide solution ( General procedure Table 3 A solution of α-thioamide 2 (50 or 400 mmol) in solvent A (2 mL) was prepared. A solution of NCS (100 or 800 mmol) in solvent B (2 mL) was also prepared. The reagent solutions were injected into flowing streams (0.2 mL/min each) of solvent A or B. After the reagent solutions combined, they were passed into a convection flow coil reactor (10 mL) heated to 120 °C for 25 min before passing through a back pressure regulator (100 psi) and exiting the reactor. A sample of the reactor output was collected and the solvent removed by evaporation under reduced pressure. The sample was subsequently dissolved in CDCl 3 and analysed by S15 1 H NMR spectroscopy. The relative molar proportions of α-thioamide 2, acrylamide 4, dichloride 5 and β-chloroacrylamides Z-3 and E-3 were measured based on the integrals of their characteristic signals.

Scheme S2
The α-thioamide solution was pumped (2.5 mL/min) into a T-piece where it met the solution of NCS (2.5 mL/min). The combined stream passed through a 10 mL reactor coil at 130 °C (2.0 min residence time). The reactor output was collected and the solvent removed under reduced pressure. The crude product was then dissolved in toluene, and resulting solution was S17 cooled to 0 °C and kept at this temperature for approximately 30 min, during which the succinimide byproduct precipitated and was removed by filtration. The filtrate was evaporated by reduced pressure and the resulting solid was analysed by 1 H NMR spectroscopy and found to contain a mixture of Z-3 and E-3 in a ratio of 89:11. The crude product was purified by recrystallization from EtOAc/heptane to give the desired product Z-3 as an off-white solid (19.28 g, 57%) which exhibited identical spectroscopic properties to those previously reported [1]. Concentration of the liquors gave crude material which was purified by wet flash chromatography using 1-5% EtOAc/hexane, affording an additional quantity of pure Z-3 (3.68 g, 11%).