5.2. General Procedure A for the Synthesis of N,N′-Disubstituted Symmetric Sulfamides (1a-d)These compounds were prepared as described in the literature [15]. The reaction was carried out by dropwise addition of a solution of sulfuryl chloride (1 equiv) in 20 mL of dichloromethane to a solution of the corresponding amine (4–6 equiv) in 50 mL of CH2CL2 at 0°C in darkness. Gas evolution was observed during the addition. The reaction mixture was warmed to room temperature (rt), stirred for 24 h, and monitored by TLC (SiO2). The crude was washed by HCl (2 N, 2 × 20 mL) water (2 × 30 mL) and dried over Na2SO4. The solution was filtered and then concentrated under reduced pressure to leave yellow solid as the crude product. Column chromatography (CH2Cl2, MeOH 95 : 5) afforded the N,N′-dialkyl sulfamide.
N,N′-Dipropylsulfamide (1a)This compound was prepared according to the general procedure A, using a solution of propylamine (6 equiv) in CH2Cl2 and SO2Cl2 (1 equiv) in CH2Cl2. Yield = 60% (was obtained as a white solid); Rf = 0.45 [SiO2, CH2Cl2/MeOH (95 : 5)]; Mp 64–65°C (described: 62–63°C). IR (KBr, ν cm−1): 3280 (NH), 1333 and 1150 (SO2). 1H NMR (CDCl3): 0.95 (t, J = 7.2 Hz, 6H, CH3), 1.57 (sext, J = J′ = 7.1 Hz, 4H, β-CH2), 2.99 (q, 4H, α-CH2), 4.27 (t broad, 2H, NH). 13C NMR (CDCl3): 11.26 (γ-C), 22.89 (β-C), 44.95 (α-C). LRMS (CI): 181 [M+H]+.
N,N′-Dibutylsulfamide (1b)Yield = 58% (was obtained as a white solid); Rf = 0.36 [(SiO2, CH2Cl2))]; Mp: 126–127°C (described 126.5°C). IR (KBr, ν cm−1): 3281 (NH), 1314 and 1145 (SO2). 1H NMR (CDCl3): 4.33 (t broad, 2H, NH), 3.04 (m, 4H, α-CH2), 1.54 (m, 4H, β-CH2), 1.38 (m, 4H, γ-CH2), 0.93 (t, J = 7.1 Hz, 6H, CH3). 13C NMR (CDCl3): 43.2 (α-C), 31.7 (β-C), 20.11 (γ-C), 13.88 (CH3). LRMS (CI): 209 [M+H]+.
N,N′-Di(2Methoxyethyl)Sulfamide (1c)Yield = 61% (was obtained as a viscous oil); Rf = 0.36 [SiO2, CH2Cl2/MeOH (95 : 5)]; IR (KBr, ν cm−1): 3279 (NH), 1316 and 1147 (SO2). 1H NMR (CDCl3): 3.22 (q, 4H, α-CH2), 3.36 (s, 6H, CH3), 3.52 (m, 4H, β-CH2), 5.28 (t, 2H, NH), 13C NMR (CDCl3): 42.67 (α-C), 58.57 (CH3), 70.93 (β-C). LRMS (CI): 213 [M+H]+.
N,N′-Dibenzylsulfamide (1d)Yield = 59% (was obtained as a white solid); Rf = 0.37 (SiO2, CH2Cl2); Mp: 182–184°C (described 180–182°C). IR (KBr, ν cm−1): 3270 (NH), 3034 (CH-Ar), 1350 and 1143 (SO2). 1H NMR (CDCl3): 4.17 (d, 4H, CH2), 4.37 (t broad, 2H, NH), 7.28–7.34 (m, 10H, Ar-H). LRMS (CI): 277 [M+H]+, 199, 91.
5.3. General Procedure B for the Synthesis of N-tert-Butyloxycarbonyl, N′-Alkyl Sulfamide: Carbamoylation-Sulfamoylation (2a-f)To a stirred solution of CSI (1 equiv, 10 mmol, 1.4153 g) in 20 mL of anhydrous dichloromethane at 0°C was added a solution of tert-butyl alcohol (1 equiv, 10 mmol, 0.7412 g) in 20 mL of dried CH2Cl2. After being stirred for 30 min, the resulting solution of N(Boc)-sulfamoyl chloride and triethylamine (TEA) in 20 mL dichloromethane was added dropwise to a solution of amine (1 equiv) or (diamine 0.5 equiv) in 20 mL of CH2Cl2. The reaction temperature did not rise above 5°C. The resulting reaction solution was allowed to warm up to rt over 3 h. The reaction mixture was diluted with dichloromethane and washed with 0.1 N HCl and brine. The organic layer was dried (Na2SO4) and concentrated in vacuo to give the crude product. Recrystallization from CH2Cl2 at low temperature afforded the expected compounds in 70–85% yield.
2a and 2b were prepared according to the general procedure B; see [29].
N,N′-Bis(tert-Butoxycarbonylsulfamoyl)-1,2-Diaminoethane (2c)This compound was prepared according to the general procedure B using a solution of 1,2-ethan diamine (0.5 equiv, 5 mmol, 0.6010 g) in CH2Cl2. Yield = 70% (was obtained as a white solid); Rf = 0.20 [SiO2, CH2Cl2-MeOH 95 : 5]; IR(KBr, ν cm−1): 3286 and 3311(NH); 1709 (C=O); 1346 and 1141 (SO2). 1H NMR (DMSO-d6): 10.90 (s, 2H, NHBoc); 7.65 (s, 2H, NH); 2.98 (s, 4H, CH2); 1.43 (s, 18H, tBu). HRMS ESI+: m/z: 441 [M+Na]+.
N,N′-Bis(tert-Butoxycarbonylsulfamoyl)-1,3-Diaminopropane (2d)This compound was prepared according to the general procedure B using a solution of 1,3-propandiamine (0.5 equiv, 5 mmol, 0.3706 g) in dichloromethane Yield = 70% (was obtained as a white solid); Rf = 0.25 [SiO2, CH2Cl2-MeOH 95 : 5]; Mp: 175–177°C. IR (KBr, ν cm−1): 3266 and 3212(NH); 1697 (C=O); 1348 and 1138 (SO2). 1H NMR (DMSO-d6): 10.79 (s, 2H, NHBoc); 7.52 (t, 2H, NH); 2.89 (q, 4H, CH2-N); 1.63 (m, 2H, CH2); 1.42 (s, 18H, tBu). HRMS. ESI+: m/z: 455 [M+Na]+, 887 [M*2+Na]+.
Compound (2e)This compound was prepared according to the general procedure B using a solution of L-cystine methyl ester dihydrochloride (0.5 equiv, 5 mmol, 1.7064 g) in CH2Cl2 and triethylamine (2 equiv, 20 mmol, 2.0238 g). Yield = 71% (was obtained as a white solid); Rf = 0.37 [SiO2, CH2Cl2-MeOH 95 : 5]; IR (KBr, ν cm−1): 3289 and 3240(NH); 1709 and 1748 (C=O); 1364 and 1139 (SO2). 1H NMR (DMSO-d6): 10.98 (s, 2H, NHBoc); 8.40 (d, 2H, NH); 4.22 (q, 2H, CH); 3.66 (s, 6H, CH3); 3.00 (d, 4H, CH2); 1.41 (s, 18H, tBu). HRMS ESI+: m/z: 659 [M+Na]+, 1275 [M*2+Na]+.
Dimethyl-5,5′-oxybis(2-(N-(tert-butoxycarbonyl)sulfamoylamino)pentanoate) (2f)This compound was prepared according to the general procedure B using a solution of 1,3-propan diamine (0.5 equiv, 5 mmol, 0.661 g). Yield = 73% (was obtained as a white solid); Rf = 0.49 [SiO2, CH2Cl2-MeOH 95 : 5]; Mp: 132–134°C. IR (KBr, ν cm−1): 3296 (NH); 1713 and 1738 (C=O); 1371 and 1143 (SO2). 1H NMR (CDCl3): 7.52 (s, 2H, NHBoc); 5.79 (t, 2H, NH); 3.57 (t, 4H, CH2–O); 3.20 (q, 4H, CH2–N); 1.84 (m, 4H, CH2); 1.49 (s, 18H, tBu). HRMS ESI+: m/z: 514 [M+Na]+, 1004 [M*2+Na]+.
5.4. General Procedure C for the Preparation of N(Boc), N′-Sufamoyl amino Acid Esters (2g-j)To a suspension of the amino acid ester hydrochloride (1 equiv, 10 mmol) was added triethylamine (1 equiv, 10 mmol, 1.0119 g) in 20 mL of dichloromethane. Simultaneously the tert-butyl chlorosulfonyl carbamate was prepared by addition of tert-butyl alcohol (1 equiv, 10 mmol, 0.7412 g) in 20 mL of CH2Cl2 to an ice-cooled solution containing CSI (1 equiv, 10 mmol, 1.4153 g) in 20 mL of dichloromethane. The obtained reagent solution was slowly added to the solution of amino acid ester hydrochloride in 30 mL of dichloromethane at the same time as of Et3N (1 equiv, 10 mmol, 1.0119 g). The reaction was monitored by TLC. The mixture was then diluted with CH2Cl2 (100 mL) and washed with 2 portions of 1 M HCl and water. The solution was then dried with Na2SO4 and concentrated in vacuum to give the crude product. Recrystallization from CH2Cl2 at low temperature or chromatography on silica gel (eluent: CH2Cl2/MeOH, 9 : 1) afforded the pure carboxyl sulfamide.
The synthesis of the compounds, starting from CSI, tert-butyl alcohol and methyl esters of amino acids (L-alanine 2j and L-phenylalanine 2 h) has been previously reported [9, 10].
Ethyl [N,(N′-tert-Butyloxycarbonyl)-sulfamoyl]-Acetate (2g) This compound was prepared according to the general procedure C using a solution of glycine ethyl ester hydrochloride (1 equiv, 10 mmol, 1.396 g). Yield = 72% (was obtained as a white solid); Rf = 0.60 [SiO2, CH2Cl2-MeOH 9 : 1]; Mp 122–123°C. IR (KBr, ν cm−1): 1352 and 1126 (SO2), 1735 and 1675 (C=O). 1H NMR (300 MHz, CDCl3): 1.5 (s, 9H, tBu), 1.30 (t, 3H, CH3), 3.96 (d, 2H, N-CH2), 4.24 (q, 2H, CH2), 5.63 (t, 1H, NH-CH2), 7.25 (s, 1H, NHBoc). HRMS ESI+: m/z: 306[M+Na]+.
Methyl [N,(N′-tert-Butyloxycarbonyl)-sulfamoyl]-2-phenyglycynate (2i)This compound was prepared according to the general procedure C using a solution of phenyl glycine methyl ester hydrochloride (1 equiv, 10 mmol, 2.0165 g). Yield = 76% (was obtained as a white solid); Rf = 0.70 [SiO2, CH2Cl2-MeOH 9 : 1]; Mp 144–146°C. IR (KBr, ν cm−1): 1362 and 1141 (SO2), 1735–1712 (C=O). 1H NMR (300 MHz, CDCl3): 1.44 (s, 9H, tBu), 3.74 (s, 3H, O-CH3), 5.27 (d, 1H, CH), 6.27 (d, 1H, NH), 7.36 (s, 5H, Ph), 7.44 (s, 1H, NHBoc). HRMS ESI+: m/z: 367 [M+Na]+.
5.5. General Procedure D for the Synthesis of Benzothiadiazepines (3a-e)To a stirring solution of [N-tert-butyloxycarbonyl, N′-alkyl]-sulfamide (1 equiv, 1 mmol) in CH3CN (50 mL) in a 100 mL round bottom flask was added K2CO3 (2.5 equiv, 2.5 mmol, 0.34552 g) and α,α′-dibromo-o-xylene (1 equiv, 1 mmol, 0.26396 g). The resulting mixture was stirred at reflux for 4 hours then cooled to room temperature. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in CH2Cl2, washed with 2 portions of HCl (1 M) and water and dried with Na2SO4, and the solvent was removed under reduced pressure to give the crude oil. Flash chromatography on silica gel CH2Cl2 to furnish the pure fused cyclic sulfamide in 70–85% yields the following.
1,5-dihydro-2-tert-butoxycarbonyl-4-benzylbenzo[d][1,2,7]thiadiazepine-3,3-dioxides (3a)This compound was prepared according to the general procedure D, using a solution of 2a (1 equiv, 1 mmol, 0.28635 g). Yield = 71% (was obtained as a viscous oil); Rf = 0.36 [SiO2, CH2Cl2]. IR (KBr, ν cm−1): 1389 and 1141 (SO2), 1732 (C=O). 1H NMR (300 MHz, CDCl3): 1.43 (s, 9H, tBu), 4.14 (s, 2H, CH2-N), 4.37 (s, 2H, CH2-N-Boc), 4.91 (s, 2H, CH2-Ph), 7.03–7.37 (m, 9H, H-Ar). HRMS ESI+: m/z: 799 [M*2+Na]+.
1,5-dihydro-2-tert-butoxycarbonyl-4-(cyclohexyl)benzo[d][1,2,7]thiadiazepine-3,3-dioxides (3b)This compound was prepared according to the general procedure D, using a solution of 2b (1 equiv, 1 mmol, 0.27837 g). Yield = 80% (was obtained as a white solid); Rf = 0.42 [SiO2, CH2Cl2]; Mp 96–98°C. IR (KBr, ν cm−1): 1376 and 1145 (SO2), 1726 (C=O). 1H NMR (300 MHz, CDCl3): 1.23–1.72 (m, 10H, Cyclohexyl); 1.41 (s, 9H, tBu), 3.94 (m, 1H, CH), 4.58 (s, 2H, CH2), 4.88 (s, 2H, CH2), 7.20–7.28 (m, 4H, H-Ar). HRMS ESI+: m/z: 784 [M*2+Na]+.
1,5-dihydro-2-tert-butoxycarbonyl-4-((ethoxycarbonyl)methyl)benzo[d][1,2,7]thiadiazepine-3,3-dioxides (3c)This compound was prepared according to the general procedure D, using a solution of 2 g (1 equiv, 1 mmol, 0.28231 g). Yield = 79% (was obtained as a white solid); Rf = 0.20 [SiO2, CH2Cl2]; Mp 91–92°C. IR (KBr, ν cm−1): 1382 and 1134 (SO2), 1729 and 1748 2(C=O). 1H NMR (300 MHz, CDCl3): 1.28 (t, 3H, CH3), 1.41 (s, 9H, tBu), 3.77 (s, 2H, CH2CO), 4.23 (q, 2H, CH2-O), 4.72 (s, 2H, CH2-N), 4.88 (s, 2H, CH2-N-Boc), 7.20–7.35 (m, 4H, H-Ar). HRMS ESI+: m/z: 407 [M+Na]+, 791[M*2+Na]+.
1,5-dihydro-2-tert-butoxycarbonyl-4-(benzyl(methoxycarbonyl)methyl)benzo[d][1,2,7]thiadiazepine-3,3-dioxides (3d)This compound was prepared according to the general procedure D, using a solution of 2 h (1 equiv, 1 mmol, 0.35841 g). Yield = 76% (was obtained as a viscous oil); Rf = 0.37 [SiO2, CH2Cl2]. IR (KBr, ν cm−1): 1368 and 1142 (SO2), 1735 and 1742 (C=O). 1H NMR (300 MHz, CDCl3): 1.40 (s, 9H, tBu), 3.25 (s, 3H, CH3–O), 5.01 (t, 1H, CH), 4.76 (d, 2H, CH2-Ph), 4.73 (s, 2H, CH2–N–Boc), 4.65 (s, 2H, CH2–N), 7.08–7.28 (m, 9H, Ar-H). HRMS ESI+: m/z: 483 [M+Na]+, 944[M*2+Na]+.
1,5-dihydro-2-tert-butoxycarbonyl-4-(phenyl(methoxycarbonyl)methyl)benzo[d][1,2,7]thiadiazepine-3,3-dioxides (3e)This compound was prepared according to the general procedure D, using a solution of 2i (1 equiv, 1 mmol, 0.34438 g). Yield = 66% (was obtained as a white solid); Rf = 0.38 [SiO2, CH2Cl2]; Mp: 90–92°C. IR (KBr, ν cm−1): 1314 and 1138 (SO2), 1732 and 1708 (C=O). 1H NMR (300 MHz, CDCl3): 1.43 (s, 9H, tBu), 3.66 (s, 3H, CH3-O), 5.96 (s, 1H, CH), 6.98–7.32 (m, 9H, H-Ar), 4.38–4.80 (dd, 2H, CHaHb-N), 4.85–5.05 (dd, 2H, CHaHb-N-Boc), 6.98–7.32 (m, 9 h, H-Ar). HRMS ESI+: m/z: 469 [M+Na]+, 915[M*2+Na]+.
5.6. General Procedure E for the Synthesis of Fused Benzothiadiazepines (4a-f)An acetonitrile solution (50 mL) containing N,N′-disubstituted symmetric sulfamide (2 equiv, 2 mmol), 2,3,4,5-tetrakis(bromomethyl)benzene (1 equiv, 1 mmol, 0.44980 g), and anhydrous K2CO3 (4.5 equiv, 4.5 mmol, 0.6219 g) was heated at reflux for 10 hours. The reaction was followed by TLC (CH2Cl2). On completion, the reaction mixture was cooled to room temperature, filtered, and after removal of the solvent under reduced pressure a solid was obtained. The solid was redissolved in dichloromethane (CH2Cl2), washed with 2 portions of HCl 1 M (2 × 20 mL) followed with water (2 × 30 mL), and dried with Na2SO4. The solution was filtered and concentrated under reduced pressure to leave a crude product. The residue was purified by chromatography on silica gel using CH2Cl2 to yield fused symmetric and asymmetric benzothiadiazepines
Compound (4a)This compound was prepared according to the general procedure E, using a solution of 1a (2 equiv, 2 mmol and 0.36054 g). Yield = 76% (was obtained as a white solid); Rf = 0.25 [SiO2, CH2Cl2]; Mp 264–266°C. IR (KBr, ν cm−1): 1339 and 1148 (SO2). 1H NMR (300 MHz, CDCl3): 0.90 (t, 12H, CH3), 1.58 (m, 8H, β-CH2), 2.91 (t, 8H, α-CH2), 4.46 (s, 8H, N-CH2-Ar), 7.15 (s, 2H, H-Ar). 13C NMR (CDCl3): 11.02 (γ-C), 21.08 (β-C), 48.90 (α-C), 50.03 (CH2), 132.50 and 136.85 (CAr). LRMS (CI): 487 [M+H]+; HRMS ESI+: m/z: 509 [M+Na]+.
Compound (4b)This compound was prepared according to the general procedure E, using a solution of 1b (2 equiv, 2 mmol and 0.41664 g). Yield = 79% (was obtained as a white solid); Rf = 0.29 [SiO2, CH2Cl2]; Mp 141–143°C. IR (KBr, ν cm−1): 1354 and 1149 (SO2). 1H NMR (300 MHz, CDCl3): 0.91 (t, 12H, CH3), 1.34 (m, 8H, γ-CH2), 1.52 (m, 8H, β-CH2), 2.94 (t, 8H, α-CH2), 4.46 (s, 8H, N-CH2), 7.16 (s, 2H, H-Ar). 13C NMR (CDCl3): 13.68 (δ-C), 19.58 (γ-C), 29.79 (β-C), 46.82 (α-C), 49.97 (CH2), 132.49 and136.85 (CAr). LRMS (CI): 543 [M+H]+; HRMS ESI+: m/z: 567 [M+Na]+.
Compound (4c)This compound was prepared according to the general procedure E, using a solution of 1d (2 equiv, 2 mmol and 0.5527 g). Yield = 75% (was obtained as a white solid); Rf = 0.46 [SiO2, CH2Cl2]; Mp 313–314°C. IR (KBr, ν cm−1): 1364 and 1157 (SO2). 1H NMR (300 MHz, CDCl3): 4.25 (s, 8H, CH2-Ph), 4.35 (s, 8H, N-CH2), 6.79 (s, 2H, H-Ar), 7.28–7.37 (m, 20H, Ph). HRMS ESI+: m/z: 701 [M+Na]+.
Compound (4d)This compound was prepared according to the general procedure E, using a solution of 2a (2 equiv, 2 mmol, 0.5727 g). Yield = 55% (was obtained as a white solid); Rf = 0.22 [SiO2, CH2Cl2]; Mp 160–162°C. IR (KBr, ν cm−1): 1392 and 1150 (SO2), 1715 (C=O). 1H NMR (300 MHz, CDCl3): 1.42 (s, 18H, tBu), 4.05 (s, 4H, CH2-N-Bn), 4.39 (s, 4H, CH2-N-Boc), 4.90 (s, 4H, CH2-Ph), 7.13 (s, 2H, H-Ar), 7.36–7.44 (m, 10H, Ph). HRMS ESI+: m/z: 721 [M+Na]+.
Compound (4d′)Yield = 15% (was obtained as a white solid); Rf = 0.25 [SiO2, CH2Cl2]; Mp 159–161°C. IR (KBr, ν cm−1): 1371 and 1155 (SO2), 1715 (C=O). 1H NMR (300 MHz, CDCl3): 1.45 (s, 18H, tBu), 4.17 (s, 4H, CH2-N-Bn), 4.40 (s, 4H, CH2-N-Boc), 4.90 (s, 4H, CH2-Ph), 6.75 (s,1H, H-Ar), 7.27 (s, 1H, H-Ar), 7.36–7.44 (m, 10H, Ph). HRMS ESI+: m/z: 721 [M+Na]+.
Compound (4f)This compound was prepared according to the general procedure E, using a solution of 2j (2 equiv, 2 mmol, 0.5646 g). Yield = 37% (was obtained as a white solid); Rf = 0.20 [SiO2, CH2Cl2]; Mp 169–171°C. IR (KBr, ν cm−1): 1368 and 1144 (SO2), 1732 and 1745 (C=O). 1H NMR (300 MHz, CDCl3): 1.44 (s, 18H, tBu), 1.34 (d, 6H, CH3), 3.53 (s, 6H, O-CH3), 4.65 (q, 2H, CH), 4.86 (s, 4H, N-CH2-Ar), 5.00 (s, 4H, CH2-N-Boc), 7.13 (s, 2H, H-Ar). HRMS ESI+: m/z: 713 [M+Na]+.
Compound (4f′)Yield = 34% (was obtained as a white solid); Rf = 0.24 [SiO2, CH2Cl2]; Mp 168–170°C. IR (KBr, ν cm−1): 1390 and 1144 (SO2), 1732 and 1750 (C=O). 1H NMR (300 MHz, CDCl3): 1.42 (s, 18H, tBu), 1.30 (d, 6H, CH3), 3.47 (s, 6H, O-CH3), 4.63 (q, 2H, CH), 4.84 (s, 4H, N-CH2-Ar), 4.96 (s, 4H, CH2-N-Boc), 7.00 (s, 1H, H-Ar), 7.24 (s, 1H, H-Ar). HRMS ESI+: m/z: 713 [M+Na]+.
Compound (4e)This compound was prepared according to the general procedure E, using a solution of 2 g (2 equiv, 2 mmol, 0.5646 g). Yield = 48% (was obtained as a white solid); Rf = 0.18 [SiO2, CH2Cl2]; Mp 181–183°C. IR (KBr, ν cm−1): 1380 and 1139 (SO2), 1723 and 1751 (C=O). 1H NMR (300 MHz, CDCl3): 1.40 (s, 18H, tBu), 1.29 (t, 6H, CH3), 3.75 (s, 4H, CH2CO), 4.22 (q, 4H, CH2CH3), 4.73 (s, 4H, CH2), 4.86 (s, 4H, CH2-N-Boc), 7.21 (s, 2H, H-Ar). HRMS ESI+: m/z: 713 [M+Na]+.
Compound (4e′)Yield = 24% (was obtained as a white solid); Rf = 0.22 [SiO2, CH2Cl2]; Mp 179–181°C. IR (KBr, ν cm−1): 1380 and 1139 (SO2), 1723 and 1755 (C=O). 1H NMR (300 MHz, CDCl3): 1.43 (s, 18H: tBu), 1.28 (t, 6H: CH3), 3.77 (s, 4H, CH2CO), 4.20 (q, 4H, CH2CH3), 4.71 (s, 4H, CH2), 4.90 (s, 4H, CH2-N-Boc), 7.05 (s, 1H, H-Ar), 7.32 (s, 1H, H-Ar). HRMS ESI+: m/z: 713 [M+Na]+.