Electronic Supplementary Material (ESI) for ChemComm. This journal is © The Royal Society of Chemistry 2016 Supplementary Information Carbodiimide insertion into sulfonylimides: one-step route to azepine derivatives by a two-atom saccharin ring expansion Davin Tan, Tomislav Friščić* McGill University, Department of Chemistry and FRQNT Centre for Green Chemistry and Catalysis, 801 Sherbrooke St., H3A 0B8 Montréal, Québec, Canada. Content...................................................................................................................................................... 1 Experimental Section............................................................................................................................... 2 Spectroscopic Data…………………........................................................................................................6 o Infrared Spectroscopy..………..................................................................................................10 o 1H and 13C NMR Spectroscopy…...............................................................................................15 X-ray crystallographic data ………......................................................................................................29 1 Experimental Section: Solution syntheses were performed either in a 20 mL reaction vial (1 mmol scale reactions) or a 50 mL one- neck round bottom flask with a small magnetic stirrer bar (gram scale reactions). Mechanochemical reactions were carried out in a Retsch MM400 mill at a frequency of 30 Hz using a 10 mL stainless steel milling jar and a single ball made of the same material (10 mm diameter, 4 grams weight). Selected gram-scale mechanochemical reactions were conducted using a stainless steel jar of 25 mL volume and two balls of 10 mm diameter. All 1H and 13C NMR spectra were recorded on a Varian MERCURY plus-300 (300 MHz) with chemical shifts (δ) given in parts per million (ppm). The molecular weights of the pure products were determined using high-resolution mass spectrometry (HR-MS). The FTIR-ATR spectra were collected using a Fourier Transform-Infrared Attenuated Total Reflection PerkinElmer UATR Two spectrometer in the range 400 cm-1 to 4000 cm-1. Powder X-ray diffraction data was obtained on a Bruker D2 Phaser diffractometer equipped with a CuKα source. Mechanochemical Synthesis For compounds 1-4, 8-11: O R R N N C NH N S N R O R O2 10 mol % CuCl benzo[1,2,4]thiadiazepines NH S 30Hz, 2hr, LAG O O2 R-NCO O Saccharin N S HN R O2 saccharyl-urea adduct Conventional reaction scale: a mixture of 0.50 mmol of saccharin, 0.50 mmol of respective carbodiimide or isocyanate (1 equiv) and 0.025-0.050 mmol (5-10% mol) of CuCl were milled, using nitromethane or acetone as the grinding liquid (=0.25 mL mg-1), in a 10 mL stainless steel jar using a single stainless steel ball of 10 mm diameter (4 grams weight) at a frequency of 30 Hz for 2 hrs. After milling, 3 mL deionized water and 20-40 mg of Na2H2EDTA2H2O were added to the crude mixture and milled for additional 10 minutes at a frequency of 25 Hz. The product was separated by vacuum filtration, washed with deionized water and dried. For gram scale reaction: a mixture of 5 mmol of saccharin, 5 mmol of respective carbodiimide (1 equiv), 0.25-0.50 mmol (5-10% mol) of CuCl and acetone as the grinding liquid (=0.25 mL mg-1) was milled in a 25 mL stainless steel milling jar with two 10 mm diameter stainless steel balls, at a frequency of 30 Hz for 2 hrs. After milling, 15 mL of deionized water and 200-400 mg of Na2H2EDTA2H2O were added to the crude mixture, milled for additional 10 minutes at a frequency of 25 Hz. The product was then filtered over vacuum, washed with deionized water and dried. 2 Solution synthesis For compounds 1-4: Conventional reaction scale: 1 mmol of saccharin, 1 mmol of respective carbodiimide (1 equiv), were placed in a 20 mL vial containing a stirring bar and 10 mL of solvent (acetone, ethyl acetate, or acetonitrile). The solution mixtures were then heated at reflux for 2 hours, solvent was removed in vacuo and the product was purified by flash column chromatography using a 1:2 mixture of ethyl acetate to hexane. For gram scale reaction: a mixture of 5 mmol of saccharin and 5 mmol of respective carbodiimide (1 equiv), were placed in a 50 mL round bottom flask with 25 mL of acetone as the solvent. The reaction was then stirred overnight (14-16 hours) under reflux. The solvent was then removed in vacuo and extracted using ethyl acetate and aqueous solution of Na2H2EDTA. The combined organic layers were dried using MgSO4 and the desired product was purified using silica column chromatography (ethyl acetate and hexane in a 1:1 ratio). Specifically for compound 4, purification using column chromatography was performed using a gradient elution of 1:51:31:1 ethyl acetate to hexane ratio. Synthesis of N-methylsaccharin: O O o - + DMF, 110 C N Na + CH3I N CH3 S overnight stir S O2 O2 12, 98% yield N-methylsaccharin was synthesized using a modified protocol by Fernández-Tomé et al.1 A solution of 10 mmol hydrated sodium saccharinate and 10 mmol iodomethane (1 equivalent) in 100 mL of N,N- dimethylformamide was heated to 110 oC and left to stir overnight in a 250 mL round bottom flask. Then, the reaction mixture was allowed to cool to ambient temperature, and poured into a beaker containing 100 mL of deionized water. The resulting white precipitate was filtered, washed with water, and recrystallized using a mixture of ethanol and water (2:1 ratio). Synthesis of 4-methyl-N-tosylbenzamide 5: O O2 O2 S COOH S NH2 + EDC coupling N H DMAP, DCM overnight stir, r.t. 5, 90% yield A solution mixture of 10 mmol 4-tolylsulfonamide, 10 mmol 4-methylbenzoic acid (1 equivalent), 11 mmol 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (1.1 equivalents), 10 mmol 4-dimethylamino-pyridine (1 equivalent) in 150 mL of dichloromethane was stirred overnight at room temperature in a 250 mL round bottom flask. The reaction mixture was then extracted exhaustively with 5M sulfuric acid and the organic layer collected was removed in vacuo. The desired 4-methyl-N-tosylbenzamide product was purified via flash column chromatography using silica and ethyl acetate as the eluting solvent. Synthesis of compound 6: 3 O NH O O2 O2 S S N + DIC 20mol% CuCl N N H CH3CN reflux, 4hr 6, 99% conversion, 87% isolated yield A solution of 2 mmol 4-methyl-N-tosylbenzamide, 2 mmol DIC and 20 mol% CuCl catalyst in 25 mL acetonitrile was refluxed overnight (14-16 hours) in a 50 mL round bottom flask. The reaction is monitored using thin layer chromatography 1:1 ethyl acetate to hexane as mobile phase (Rf value of product is 0.6 on neutral alumina or 0.1 on silica). After the reaction is complete, the solvent is removed in vacuo and the catalyst is removed by extraction using ethyl acetate and aqueous EDTA solution. The desired product is purified by flash column chromatography using neutral alumina with ethyl acetate and hexane in a 1:3 ratio as the eluting solvent, followed by another column chromatography on silica using a gradient elution of ethyl acetate and hexane in 1:51:31:1 ratio. Synthesis of compound 7: O O NH O 2 O2 S S N + DCC 20mol% CuCl N N H CH3CN reflux, 4hr 7, 93% conversion, 67% isolated yield A solution of 2 mmol 4-methyl-N-tosylbenzamide and 2 mmol DCC and 20 mol% CuCl catalyst in 25 mL acetonitrile was refluxed overnight (14-16 hours) in a 50 mL round bottom flask. The solvent was removed in vacuo and the catalyst is removed by extraction using ethyl acetate and aqueous EDTA solution. Based on crude 1H NMR, the reaction conversion was 93% and the product was obtained in 67% isolated yield after recrystallization from acetone.s 4 Control mechanochemical reactions: outcomes and conditions O N LAG, (1) N-K+/Na+ + C no catalyst No Reaction, S based on TLC, IR & NMR N 30Hz, 2hr O2 O N LAG, indicates CuCl catalyst is required (2) + C no catalyst no reaction, NH based on TLC, IR & NMR under milling S N 30Hz, 2hr conditions O2 O LAG, + Cy NCO no catalyst no reaction, (3) NH based on TLC, IR & NMR S 30Hz, 2hr O2 O N LAG, 20 mol% CuCl no reaction, (4) N CH + C 3 based on TLC, IR S N 30Hz, 2hr & NMR O2 O LAG, 20 mol% CuCl no reaction, (5) NH based on TLC S 30Hz, 2hr O2 O LAG, O2 S 20 mol% CuCl no reaction, N based on TLC (6) H 30Hz, 2hr All control reactions were conducted mechanochemically using a 10 mL stainless steel jar with one 10 mm diameter stainless steel ball (weight 4 grams). 5 Spectroscopic Data N,N’-dicyclohexyl-benzo[1,3]thiadiazepine 1 O N NH S N O2 White powder (95% yield); 1H-NMR (300 MHz, DMSO-d6) δ 0.98-1.86 (m, 20H), δ 3.54 (m, 1H), δ 4.12 (m, 1H), δ 7.67-7.81 (m, 4H) δ 8.23 (d, J = 7.26Hz, 1H); 13C-NMR (300 MHz, DMSO-d6) δ 24.8, 25.3, 25.6, 26.1, 52.7, 60.8, 123.4, 130.7, 131.8, 132.4, 132.8, 143.9, 153.9, 165.8; HRMS: Calculated for C20H27N3O3S [M+H]: 388.17004; measured: 388.17065. N,N’-diisopropyl-benzo[1,3]thiadiazepine 2 O N NH S N O2 White powder (91% yield); 1H-NMR (300 MHz, DMSO-d6) δ 0.96-1.11 (m, 6H), δ 1.14 (d, J = 6.20 Hz 6H), δ 3.80-3.92 (m, 1H), δ 4.40-4.50 (m, 1H), δ 7.68-7.96 (m, 4H) δ 8.12 (d, J = 7.26Hz, 1H) ; 13C-NMR (300 MHz, DMSO-d6) δ 21.4, 23.7, 41.1, 45.7, 53.4, 123.5, 130.7, 132.0, 132.5, 133.1, 143.9, 154.2, 165.8; HRMS: Calculated for C14H20N3O3S [M+H]: 310.1220; measured: 310.1219.