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 Na2H2EDTA2H2O 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 Na2H2EDTA2H2O 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 1:51:31:1 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 1:51:31:1 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.

N-ethyl-N’-tertbutyl-benzo[1,3]thiadiazepine 3

O N NH S N O2

White powder (90% yield); 1H-NMR (300 MHz, DMSO-d6) δ 1.00 (t, J = 7.11 Hz, 3H), δ 1.56 (s, 9H), δ 3.08-3.29 (m, 2H), δ 7.66-7.88 (m, 4H), δ 8.75 (t, J = 6.12 Hz, 1H); 13C-NMR (300 MHz, DMSO-d6) δ 13.1,

27.8, 38.2, 62.3, 123.6, 130.9, 132.4, 132.6, 132.7, 144.3, 155.4, 164.2 ; HRMS: Calculated for C14H18O3N3S [M+H]: 308.10744; measured: 308.10802.

6 N,N’-di-p-tolyl-benzo[1,3]thiadiazepine 4

O N NH S N O2

White powder (98% yield); 1H-NMR (300 MHz, DMSO-d6) δ 2.22 (s, 3H), δ 2.35 (s, 3H), δ 7.09-7.17 (m, 4H), δ 7.31-7.46 (m, 4H), δ 7.77-7.84 (m, 3H), δ 7.93-8.00 (m, 1H), δ 9.63 (s, 1H); 13C-NMR (300 MHz, DMSO-d6) δ 20.9, 21.2, 123.4, 123.8, 128.2, 129.7, 130.1, 130.6, 132.4, 133.1, 133.5, 134.5, 135.9, 136.7,

138.6, 142.5, 153.5, 166.6; HRMS: Calculated for C22H20N3O3S [M+H]: 406.12199; measured: 406.12195.

4-methyl-N-tosylbenzamide 5

O O2 S N H

White powder (90% yield); 1H-NMR (300 MHz, DMSO-d6) δ 2.32 (s, 3H), δ 2.36 (s, 3H), δ 7.26 (d, J = 8.16 Hz, 2H), δ 7.41 (d, J = 8.00 Hz, 2H), δ 7.74 (d, J = 7.80 Hz, 2H), δ 7.87 (d, J = 8.05 Hz, 2H), δ 12.36 (s, 1H); 13C-NMR (300 MHz, DMSO-d6) δ 12.5, 126.1, 128.2, 128.9, 129.1, 129.5, 129.9, 137.1, 144.1,

144.6, 165.4. HRMS: Calculated for C15H15O3N1S [M-H]: 288.06999; measured: 288.07024.

(E)-N-isopropyl-N-(N-isopropyl-N'-tosylcarbamimidoyl)-4-methylbenzamide 6

NH O O2 S N N

White powder (87% yield); 1H-NMR (300 MHz, DMSO-d6) δ 0.72-0.89 (m, 6H), δ 1.35 (d, J = 6.60 Hz 6H), δ 2.27 (s, 3H), δ 2.33 (s, 3H), δ 3.47-3.57 (m, 1H), δ 3.47-3.57 (m, 1H), δ 4.29-4.41 (m, 1H), δ 7.10 (d, J = 7.98 Hz, 2H), δ7.26 (d, J = 8.10 Hz, 2H), δ 7.46-7.53 (m, 4H), δ 8.59 (d, J = 8.43 Hz, 1H); 13C-NMR (300 MHz, DMSO-d6) δ 14.5, 20.5, 20.9, 21.2, 21.3, 21.7, 22.5, 23.7, 25.2, 31.4, 45.0, 51.1, 60.2, 125.8, 126.1, 128.1, 128.5, 128.7, 129.3, 129.5, 134.2, 140.6, 141.6, 142.0, 151.9, 168.9, 170.8. HRMS: Calculated for C22H29O3N3S [M+H]: 416.20024; measured: 416.20036.

(E)-N-cyclohexyl-N-(N- cyclohexyl -N'-tosylcarbamimidoyl)-4-methylbenzamide 7

7 NH O O2 S N N

Colorless crystals (67% yield); 1H-NMR (300 MHz, DMSO-d6) δ 0.92-1.80 (m, 20H), δ 2.29 (s, 3H) δ 2.35 (s, 3H), 3.29-3.33 (m, 1H), δ 4.02 (m, 1H), δ 7.10 (d, J = 8.02 Hz, 2H), δ 7.26 (d, J = 8.10 Hz, 2H), δ 7.43 (d, J = 7.96 Hz, 2H), δ 7.51 (d, J = 7.89 Hz, 2H), δ 7.88 (d, J = 8.52 Hz, 1H). 13C-NMR (300 MHz, DMSO- d6) δ 21.3, 21.4, 24.6, 25.4, 25.7, 26.1, 30.3, 31.0, 33.8, 52.1, 58.3, 125.7, 128.2, 128.6, 129.4, 134.1, 140.5,

141.6, 141.9, 151.4, 168.5. HRMS: Calculated for C28H37O3N3S [M+H]: 496.26284; measured: 496.26271.

N-cyclohexyl-carbamoyl-saccharin 8

O O N S HN O2

White powder (95% yield); 1H-NMR (300 MHz, DMSO-d6) δ 0.91-1.31 (m, 10H), δ 1.02-2.02 (m, 10H), δ 3.44-3.87 (m, 1H), ), δ 7.63-8.40 (m, 5H); 13C-NMR (300 MHz, DMSO-d6) δ 24.4, 25.3, 32.2, 49.2, 121.9,

124.9, 126.3, 133.4, 135.8, 137.5, 147.2, 159.6; HRMS: Calculated for C14H16O3N2SNa [M+Na]: 311.0723; measured: 311.0725.

N-butyl-carbamoyl-saccharin 9

O O N S HN O2

White powder (71% yield); 1H-NMR (300 MHz, DMSO-d6) δ 0.87 (s, 3H), δ 1.18-1.39 (m, 2H), δ 1.39- 1.56 (m, 2H), δ 3.12-3.27 (m, 2H), δ 7.91-8.41 (m, 5H); 13C-NMR (300 MHz, DMSO-d6) 13C-NMR (300 MHz, DMSO-d6) δ 14.0, 19.8, 31.4, 121.9, 124.8, 126.2, 135.9, 137.4, 137.6, 147.0, 159.4; HRMS:

Calculated for C12H14N2NaO4S [M+Na]: 305.0566; measured: 305.0566.

N-(2-chloroethyl)-carbamoyl-saccharin 10

8 O O N S HN O2 Cl

White powder (80% yield); 1H-NMR (300 MHz, DMSO-d6) δ 3.18 (t, J = 4.56Hz, 2H), δ 3.79 (t, J = 4.75Hz, 2H), δ 7.56-7.73 (m, 3H), δ 6.81 (m, 2H), δ 7.87-8.14 (m, 2H); 13C-NMR (300 MHz, DMSO-d6) δ 41.1,

41.9, 119.9, 123.3, 132.1, 132.6, 167.6. HRMS: Calculated for C10H10O4N2SCl [M+H]: 289.00443; measured: 289.00411.

N-phenyl-carbamoyl-saccharin 11

O O N S HN O2

White powder (99% conversion); 1H-NMR (300 MHz, DMSO-d6) δ 6.62-6.72 (m, 3H), δ 7.08-7.17 (m, 2H), δ 7.66-7.77 (m, 4H), δ 7.82-7.88 (s, 1H); 13C-NMR (300 MHz, DMSO-d6) δ 120.4, 121.8, 123.9, 129.8,

132.0, 133.4, 143.0, 165.3, 171.1. HRMS: Calculated for C15H11O4N2S [M+H]: 303.04340; measured: 303.04234.

N-methyl-saccharin

O

N CH3 S O2

White powder (98% yield); 1H-NMR (300 MHz, DMSO-d6) δ 3.15 (s, 3H), δ 7.94-8.12 (m, 3H), δ 8.28-8.33 (m, 1H); 13C-NMR (300 MHz, DMSO-d6) δ 23.3, 121.9, 125.4, 127.0, 135.6, 136.0, 137.1, 158.9.

9 Infrared Spectroscopy

N,N’-dicyclohexyl-benzo[1,3]thiadiazepine 1

O N NH S N O2

N,N’-diisopropyl-benzo[1,3]thiadiazepine 2

O N NH S N O2

10 N-ethyl-N’-tertbutyl-benzo[1,3]thiadiazepine 3

O N NH S N O2

N,N’-di-p-tolyl-benzo[1,3]thiadiazepine 4

O N NH S N O2

11 4-methyl-N-tosylbenzamide 5

O O2 S N H

(E)-N-isopropyl-N-(N-isopropyl-N'-tosylcarbamimidoyl)-4-methylbenzamide 6

NH O O2 S N N

12 (E)-N-cyclohexyl-N-(N-cyclohexyl-N'-tosylcarbamimidoyl)-4-methylbenzamide 7

NH O O2 S N N

N-cyclohexyl-carbamoyl-saccharin 8

O O N S HN O2

13 N-butyl-carbamoyl-saccharin 9

O O N S HN O2

N-(2-chloroethyl)-carbamoyl-saccharin 10

O O N S HN O2 Cl

14 N-phenyl-carbamoyl-saccharin 11

O O N S HN O2

15 1H and 13C NMR Spectroscopy

O N NH S N O2 1

Varian MERCURY 300Mz Solvent Peaks: d -DMSO at 2.48ppm 6 H O at 3.35 ppm 2 Ethyl Acetate at 1.17, 1.99, 4.03ppm. Hexane at 0.86, 1.25ppm

Varian MERCURY 300Mz Solvent Peaks: d -DMSO heptet at 39.97ppm 6 Ethyl acetate at 14.40, 20.68, 59.74, 170.31ppm Hexane at 13.88, 22.05, 30.95ppm

16 2D NMR: 1H-15N HMBC

2D NMR: 1H-13C HSQC

17 O N NH S N O2 2

Varian MERCURY 300Mz Solvent Peaks: d -DMSO at 2.48 ppm 6 H O at 3.35 ppm 2

Varian MERCURY 300Mz Solvent Peaks: d -DMSO heptet at 39.97ppm 6

18 O N NH S N O2 3

Varian MERCURY 300Mz Solvent Peaks: d -DMSO at 2.48ppm 6 H O at 3.3461ppm 2 Ethyl Acetate at 1.17, 1.99, 4.03ppm. Hexane at 0.86, 1.25ppm

Varian MERCURY 300Mz Solvent Peaks: d -DMSO heptet at 39.97ppm 6 Ethyl acetate at 14.40, 20.68, 59.74, 170.31ppm Hexane at 13.88, 22.05, 30.95 ppm

19 O N NH S N O2

4

Varian MERCURY 300Mz Solvent Peaks: d -DMSO at 2.48 ppm 6 H O at 3.3461ppm 2 Ethyl Acetate at 1.17, 1.99, 4.03ppm.

Varian MERCURY 300Mz Solvent Peaks: d -DMSO heptet at 39.97ppm 6 Ethyl acetate at 14.40, 20.68, 59.74, 170.31ppm

20 O O2 S N H 5

Varian MERCURY 300Mz Solvent Peaks: d -DMSO at 2.48 ppm 6 H O at 3.3461ppm 2

Varian MERCURY 300Mz Solvent Peaks: d -DMSO heptet at 39.97 ppm 6

21 NH O O2 S N N 6

Varian MERCURY 300Mz Solvent Peaks: d -DMSO at 2.48 ppm 6 H O at 3.3461ppm 2 Ethyl Acetate at 1.17, 1.99, 4.03ppm

Varian MERCURY 300Mz Solvent Peaks: d -DMSO heptet at 39.97ppm 6 Ethyl acetate at 14.40, 20.68, 59.74, 170.31ppm

22 NH O O2 S N N

7

Varian MERCURY 300Mz Solvent Peaks: d -DMSO at 2.48 ppm 6 H O at 3.35 ppm 2 Acetone at 1.93 ppm

Varian MERCURY 300Mz Solvent Peaks: d -DMSO heptet at 39.97 ppm 6 Ethyl acetate at 14.40, 20.68, 59.74, 170.31 ppm

23 O O N S HN O2 8

Varian MERCURY 300Mz Solvent Peaks: d -DMSO at 2.48 ppm 6 H O at 3.35 ppm 2

Varian MERCURY 300Mz Solvent Peaks: d -DMSO heptet at 39.97ppm 6

24 O O N S HN O2 9

Varian MERCURY 300Mz Solvent Peaks: d -DMSO at 2.48 ppm 6 H O at 3.35 ppm 2

Varian MERCURY 300Mz Solvent Peaks: d -DMSO heptet at 39.97ppm 6

25 O O N S HN O 2 Cl 10

Varian MERCURY 300Mz Solvent Peaks: d -DMSO at 2.48 ppm 6 H O at 3.35 ppm 2

Varian MERCURY 300Mz Solvent Peaks: d -DMSO heptet at 39.97ppm 6

26 O O N S HN O2 11

diphenylurea (DPU) signals

Varian MERCURY 300Mz Solvent Peaks: d -DMSO at 2.48 ppm 6 H O at 3.35 ppm 2

Based on NMR, there is 99% conversion, full consumption of the saccharin starting material (absence of saccharin peaks). However, there are significant N,N’-diphenylurea (DPU) peaks observed. Isolated yield for N-phenyl-carbamoyl-saccharin 10 was not obtained.

27 O

N CH3 S O2 12

Varian MERCURY 300Mz Solvent Peaks: d -DMSO at 2.48 ppm 6 H O at 3.35 ppm 2

Varian MERCURY 300Mz Solvent Peaks: d -DMSO heptet at 39.97 ppm 6

28 X-ray crystallographic data

Table S1. General and X-ray crystallographic data for all investigated carbodiimide insertion products

1 2 3 4 Molecular formula C20H27N3O3S C14H19N3O3S C14H19N3O3S C24H25N3O4S2 Mr 389.18 309.11 309.11 483.13 Crystal System Orthorombic Orthorhombic Monoclinic Orthorhombic Crystal colour Colorless Colorless Colorless Colorless Space group Pbca Pbca P21/c Pna21 Temperature (K) 100K 298K 100K 100K Unit cell dimensions (Å,°) a 12.474(6) 11.1910(9) 11.537(7) 26.324(2) b 11.835(5) 11.3302(9) 14.933(9) 14.6841(11) c 26.509(12) 25.142(2) 9.438(6) 5.8835(4) α 90 90 90 90 β 90 90 112.304(7) 90 γ 90 90 90 90 Volume (Å3) 3912.52 3188.0(4) 1504.35 2274.23 Z 8 8 4 4 −3 Dcalc (g cm ) 1.441 1.289 1.366 1.412 μ (mm−1) (abs coeff) 0.300 0.216 0.229 0.272 F(000) 1816 1312 656 1016 Refl. collected/independent 3464/ 2283 3959/ 2255 2686/ 1804 3896 / 3310 No. observed refl. [I>2σ(I)]* 35897 35978 13409 31390 No. restraints/No. parameters 0/ 244 6/ 223 0/194 1/ 302 R [all/gt] 0.0950/ 0.0517 0.0958/ 0.0439 0.0841/ 0.0550 0.0568 / 0.0403 wR [ref/gt] 0.1382/ 0.1148 0.1226/ 0.1008 0.1833/ 0.1630 0.0848 / 0.0789 Goodness-of-fit on F2 1.018 1.026 1.030 1.053 Largest diff. peak and hole (e Å−3) 0.297, -0.487 0.165, -0.300 0.249, -0.396 0.270, -0.350 2 2 2 2 2 2 2 2 1/2 *R = ∑||Fo|-|Fc||/∑Fo,w = 1/[σ (Fo )+(g1P) + g2P] where P = (Fo +2Fc )/3, S = Σ[w(Fo – Fc ) /(Nobs – Nparam)] .

6 7 Molecular formula C22H29N3O3S C28H37N3O3S Mr 415.19 495.26 Crystal System Monoclinic Monoclinic Crystal colour Colorless Colorless Space group P21/n P21 Temperature (K) 100K 100K Unit cell dimensions (Å,°) a 10.0595(10) 12.0370(3) b 20.175(2) 35.2714(10) c 11.1108(11) 12.5698(3) α 90 90 β 107.837(4) 96.9780(10) γ 90 90 Volume (Å3) 2146.55 5297.1(2) Z 4 8 −3 Dcalc (g cm ) 1.286 1.243 μ (mm−1) 0.179 1.351 F(000) 888 2128 Refl. collected/independent 4971/ 4458 20864/14988 No. observed refl. [I>2σ(I)]* 65819 20864 No. restraints/No. parameters 0/ 268 1/1270 R [all/gt] 0.0454/0.0373 0.1019/0.0637 wR [ref/gt] 0.1087/0.0993 0.1531/0.1357 Goodness-of-fit on F2 1.117 1.010 Largest diff. peak and hole (e Å−3) 0.365, -0.623 0.567, -0.424 2 2 2 2 2 2 2 2 1/2 *R = ∑||Fo|-|Fc||/∑Fo,w = 1/[σ (Fo )+(g1P) + g2P] where P = (Fo +2Fc )/3, S = Σ[w(Fo – Fc ) /(Nobs – Nparam)] .

29 Table S2. General and X-ray crystallographic data for the isocyanate coupling products 8, 10 and 11

8 10 11 Molecular formula C15H20N2O5S C10H9ClN2O4S C14H10N2O4S Mr 340.11 288.00 302.04 Crystal System Orthorhombic Monoclinic Monoclinic Crystal colour Colorless Colorless Colorless Space group P212121 P21/c P21/c Temperature (K) 100K 150K 100K Unit cell dimensions (Å,°) a 6.7492(7) 11.8316(16) 6.4988(6) b 7.2139(7) 14.0713(19) 15.6631(14) c 31.441(3) 7.0351(10) 12.8234(14) α 90 90 90 β 90 96.718(2) 100.670(4) γ 90 90 90 Volume (Å3) 1530.8(3) 1163.2 1282.74 Z 4 4 4 −3 Dcalc (g cm ) 1.477 1.649 1.669 μ (mm−1) 0.240 0.516 0.274 F(000) 720 592 660 Refl. collected/independent 60042 2137/ 1808 2262/ 1842 No. observed refl. [I>2σ(I)]* 8232/ 7166 11594 18893 No. restraints/No. parameters 0/211 0/ 163 0/190 R [all/gt] 0.0529/ 0.0405 0.0425/ 0.0341 0.0471/ 0.0338 wR [ref/gt] 0.1032 / 0.0983 0.0893/ 0.0839 0.0849/ 0.0796 Goodness-of-fit on F2 1.098 1.064 1.054 Largest diff. peak and hole (e Å−3) 0.503, -0.568 0.337, -0.366 0.213, -0.392 2 2 2 2 2 2 2 2 1/2 *R = ∑||Fo|-|Fc||/∑Fo,w = 1/[σ (Fo )+(g1P) + g2P] where P = (Fo +2Fc )/3, S = Σ[w(Fo – Fc ) /(Nobs – Nparam)] .

O N NH S N O2

Figure S1. Molecular structure visualized using ORTEP-3 with thermal ellipsoids at 50% probability of N,N’- dicyclohexyl-benzo[1,3]thiadiazepine 1 as determined by single-crystal X-ray diffraction (see Table S1).

30 O N NH S N O2 Figure S2. Molecular structure visualized using ORTEP-3 with thermal ellipsoids at 50% probability of N,N’- diisopropyl-benzo[1,3]thiadiazepine 2 as determined by single-crystal X-ray diffraction (see Table S1).

O N NH S N O2 Figure S3. Molecular structure visualized using ORTEP-3 with thermal ellipsoids at 50% probability of N-ethyl-N’- tertbutyl-benzo[1,3]thiadiazepine 3 as determined by single-crystal X-ray diffraction (see Table S1).

O N NH S N O2

Figure S4. Molecular structure visualized using ORTEP-3 with thermal ellipsoids at 50% probability of N,N’-di-p- tolyl-benzo[1,3]thiadiazepine 4 as determined by single-crystal X-ray diffraction (see Table S1).

31 NH O O2 S N N

Figure S4a. Molecular structure visualized using ORTEP-3 with thermal ellipsoids at 50% probability of (E)-N- isopropyl-N-(N-isopropyl-N'-tosylcarbamimidoyl)-4-methylbenzamide 6 as determined by single-crystal X-ray diffraction (see Table S1).

NH O O2 S N N

Figure S4b. Molecular structure visualized using ORTEP-3 with thermal ellipsoids at 50% probability of (E)-N- cyclohexyl-N-(N-cyclohexyl -N'-tosylcarbamimidoyl)-4-methylbenzamide 7 as determined by single-crystal X-ray diffraction (see Table S1).

O O N S HN O2

Figure S6. Molecular structure visualized using ORTEP-3 with thermal ellipsoids at 50% probability of N-cyclohexyl- carbamoyl-saccharin 8 as determined by single-crystal X-ray diffraction (see Table S1).

32 O O N S HN O2 Cl

Figure S7. Molecular structure visualized using ORTEP-3 with thermal ellipsoids at 50% probability of N-(2- chloroethyl)-carbamoyl-saccharin 10 as determined by single-crystal X-ray diffraction (see Table S1).

O O N S HN O2 Figure S8. Molecular structure visualized using ORTEP-3 with thermal ellipsoids at 50% probability of N-phenyl- carbamoyl-saccharin 11 as determined by single-crystal X-ray diffraction (see Table S1).

33 Figure S9. Comparison of 1H NMR spectra for the product of the reaction between saccharin and DCC obtained mechanochemically (blue) and from solution, following the procedure of Lerch and Moffatt (black)

Figure S10. Comparison of 2-D 15N HMBC NMR spectra for the product of the reaction between saccharin and DCC obtained mechanochemically (top) and from solution, following the procedure of Lerch and Moffatt (bottom)

34 Figure S11. Comparison of the PXRD pattern of the crude reaction mixture involving saccharin and DCC in presence of CuCl catalyst and CH3NO2 as the LAG liquid, to the PXRD pattern simulated for the crystal structure of 1.

35