Reagents used
Reactions were monitored by thin layer chromatography (TLC), carried out on 0.2 mm silica gel 60 F254 (Merck) plates using UV light (254 and 366 nm) for detection and compounds were purified by column chromatography by using silica gel of 5–20 µm (Merck, 60–120 mesh). Column dimension 39 × 2 cm and elution volume used is about 200–400 ml for each product. Common reagent grade chemicals are either commercially available and were used without further purification or were prepared by standard literature procedures.
Characterization
The 1H spectra were recorded on a Bruker XL 300 spectrometer (300 MHz). Chemical shifts were reported in parts per million using tetramethylsilane as an internal standard and were given in δ units. The solvent for NMR spectra was DMSO-d
6
unless otherwise stated. Elemental analyses were performed on a Hosli CH-Analyzer and are within ±0.4 of the theoretical percentage. All reactions were monitored by thin layer chromatography, carried out on 0.2 mm silica gel 60 F254 (Merck) plates using UV light (254 and 366 nm) for detection. Common reagents grade chemicals are either commercially available and were used without further purification or prepared by standard literature procedures.
Synthesis of benzylamide derivatives 2(a–l)
The mixture of benzyl amine (0.268 g, 2.5 mmol), acid chloride (3.5 mmol) and triethylamine (0.695 ml, 5 mmol) in DMF (5 ml) was stirred at room temperature for 5–6 h (TLC Check, 40 % ethyl acetate/hexane). To the stirring solution KF (88 mg, 1.5 mmol) was added and the reaction mixture was stirred for 0.5 h. Sucrose (0.514 g, 1.5 mmol) was added and stirring was continued for next half an hour. Water (50 ml) was then added to the reaction mixture under stirring. The products 2a–e and 2g–l were isolated by filtration and product 2f was extracted in EtOAc (25 ml).
Cyclopentanecarboxylic acid benzylamide 2a: white crystalline solid; [M.p. 94 °C, lit. mp 94 °C (Sudrik et al. 2002); yield 498 mg, 98 %] Analysis: IR (KBr): 3354, 1654, 1601 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.26 (bs, 1H, NH), 7.19–7.33 (m, 5H, ArH), 4.24 (d, J = 6.0 Hz, 2H, CH2), 2.52–2.72 (m, 1H, CH), 1.45–1.80 (m, 8H, 4 × CH2).
N-Benzyl-2, 2-dimethyl-propionamide 2b: white crystalline solid; [M.p. 83 °C, lit. Mp 81–84 °C (Martínez-Asencio et al. 2011a), yield 474 mg, 99 %] Analysis: IR (KBr): 3358, 1660, 1610 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.04 (t, J = 5.5 Hz, 1H, NH), 7.17–7.33 (m, 5H, ArH), 4.25 (d, J = 6.0 Hz, 2H, CH2), 1.12 (s, 9H, 3 × CH3).
N-Benzyl-4-fluoro-benzamide 2c: white crystalline solid [M.p. 144 °C, lit. mp 143–144 °C (Mamat et al. 2011) yield 567 mg, 99 %] Analysis: IR (KBr): 3365, 1647, 1611 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 9.07 (t, J = 5.9 Hz, 1H, NH), 7.93–8.01 (m, 2H, ArH), 7.22–7.36 (m, 7H, ArH), 4.48 (d, J = 6.0 Hz, 2H, CH2). 13C NMR (300 MHz, DMSO-d
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) δ 43.1, 115.5, 115.8, 127.2, 127.7, 128.7, 130.3, 130.4, 131.2, 131.3, 140.0, 162.7, 165.6.
Cyclopropanecarboxylic acid benzylamide 2d: white crystalline solid [M.p. 140 °C, lit.mp 140–141 °C (Yang and Shi 2005) yield 412 mg, 94 %] Analysis: IR (KBr): 3370, 1665, 1605 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.54 (br. s., 1H, NH), 7.20–7.35 (m, 5H, ArH), 4.27 (d, J = 6.0 Hz, 2H, CH2), 1.55–1.64 (m, 1H, CH), 0.62–0.72 (m, 4H, 2 × CH2).
Cyclohexanecarboxylic acid benzylamide 2e: white crystalline solid [M.p. 108 °C, lit. mp 107–109 °C (Saito et al. 2008) yield 532 mg, 98 %] Analysis: IR (KBr): 3345, 1651, 1612 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.20 (br. s., 1H, NH), 7.18–7.33 (m, 5H, ArH), 4.23 (d, J = 5.7 Hz, 2H, CH2), 2.15 (s, 1H, CH), 1.57–1.75 (m, 5H, 5xCH), 1.10–1.42 (m, 5H, 5 × CH).
Pentanoic acid benzylamide 2f: white crystalline solid [M.p. 42 °C, lit.mp 41.1–41.8 °C (Dermer and King 1943); yield 464 mg, 97 %] Analysis: IR (KBr): 3352, 1654, 1603 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.28 (t, J = 5.5 Hz, 1H, NH), 7.19–7.33 (m, 5H, ArH), 4.24 (d, J = 6.0 Hz, 2H, CH2), 2.13 (t, J = 7.4 Hz, 2H, CH2), 1.41–1.55 (m, 2H, CH2), 1.26 (dq, J = 14.9,7.4 Hz, 2H, CH2), 0.78–0.89 (m, 3H, CH3).
Furan-2-carboxylic acid benzylamide 2g: white crystalline solid [M.p. 113 °C, lit. mp 111–113 °C (Gernigon et al. 2012); yield 498 mg, 99 %] Analysis: IR (KBr): 3370, 1657, 1604 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.92 (t, J = 5.9 Hz, 1H, NH), 7.77–7.85 (m, 1H, ArH), 7.20–7.35 (m, 5H, ArH), 7.13 (d, J = 3.4 Hz, 1H, ArH), 6.62 (dd, J = 3.4, 1.9 Hz, 1H, ArH), 4.42 (d, J = 6.0 Hz, 2H, CH2).
N-Benzyl-4-nitro-benzamide 2h: light yellow crystalline solid [M.p. 140 °C, lit. mp 139 °C (Bahrami et al. 2010); yield 590 mg, 92 %] Analysis: IR (KBr): 3365, 1667, 1617, 1545 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 9.39 (t, J = 6.0 Hz, 1H, NH), 8.31–8.36 (m, 2H, ArH), 8.10–8.15 (m, 2H, ArH), 7.23–7.37 (m, 5H, ArH), 4.52 (d, J = 6.0 Hz, 2H, CH2).
N-Benzyl-4-methoxy-benzamide 2i: white crystalline solid [M.p. 129 °C, lit. mp125 °C (Kokare et al. 2007), yield 597 mg, 99 %] Analysis: IR (KBr): 3345, 1649, 1601 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.89 (t, J = 6.0 Hz, 1H, NH), 7.84–7.91 (m, 2H, ArH), 7.20–7.34 (m, 5H, ArH), 6.97–7.04 (m, 2H, ArH), 4.46 (d, J = 6.0 Hz, 2H, CH2), 3.8 (s, 3H, OCH3).
N-Benzyl-2, 4-Dichloro-benzamide 2j: white crystalline solid [M.p. 125 °C, lit. mp 125 °C (Richard Cremlyna et al. 1989); yield 666 mg, 95 %] Analysis: IR (KBr): 3355, 1654, 1619 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 9.02 (s, 1H, NH), 7.69 (s, 1H, ArH), 7.49 (s, 2H, ArH), 7.22–7.37 (m, 5H, ArH), 4.44 (d, J = 6.0 Hz, 2H, CH2).
N-Benzyl-propionamide 2 k: white crystalline solid [M.p. 51 °C, lit. mp 49–51 °C (Lee et al. 1999); yield 396 mg, 97 %] Analysis: IR (KBr): 3349, 1657, 1608 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.25 (br. s., 1H, NH), 7.19–7.34 (m, 5H, ArH), 4.24 (d, J = 6.0 Hz, 2H, CH2), 2.13 (q, J = 7.6 Hz, 2H, CH2), 0.97–1.15 (m, 3H, CH3).
N-Benzyl-benzamide 2l: white crystalline solid [M.p. 104 °C, lit. mp 104–106 °C (Nowrouzi and Jonaghani 2012); yield 523 mg, 99 %] Analysis: IR (KBr): 3358, 1656, 1610 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 9.04 (t, J = 5.9 Hz, 1H, NH), 7.87–7.92 (m, 2H, ArH), 7.43–7.56 (m, 3H, ArH), 7.20–7.35 (m, 5H, ArH), 4.48 (d, J = 6.0 Hz, 2H, CH2). Calculated for C14H13NO (211.27): C, 79.59; H, 6.20; N, 6.63. Found: C, 79.57; H, 6.21; N, 6.62.
Synthesis of sulfonamides derivatives 3(a–h)
The mixture of benzylamine (0.268 g, 2.5 mmol), sulfonyl chloride (3.5 mmol) and triethylamine (0.695 ml, 5 mmol) in DMF (5 ml) was stirred at room temperature for 5–6 h (TLC Check, 40 % ethyl acetate/hexane). To the stirring solution KF (88 mg, 1.5 mmol) was added and the reaction mixture was stirred for 0.5 h. Sucrose (0.514 g, 1.5 mmol) was added and stirring was continued for next half an hour. Water (50 ml) was then added to the reaction mixture under stirring. The product was isolated by filtration and washed with 10 ml water.
N-Benzyl-benzenesulfonamide 3a: white crystalline solid [M.p. 90 °C, lit. mp 89–90 °C (José et al. 2011); yield 594 mg, 96 %] Analysis: IR (KBr): 3365, 1601, 1340 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 9.04 (bs. s 1H, NH), 7.87–7.92 (m, 2H, ArH), 7.43–7.56 (m, 3H, ArH), 7.20–7.35 (m, 5H, ArH), 4.48 (d, J = 6.0 Hz, 2H, CH2).
N-Benzyl-4-methyl-benzenesulfonamide 3b: white crystalline solid [M.p. 111 °C, lit. mp 111 °C (Gao et al. 2005); yield 647 mg, 99 %] Analysis: IR (KBr): 3361, 1615, 1338 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.22 (bs, 1H, NH), 7.69–7.94 (m, 2H, ArH), 7.33–7.52 (m, 2H, ArH), 7.19–7.32 (m, 5H, ArH), 4.00 (s, 2H, CH2), 1.90 (s, 3H, CH3).
N-Benzyl-4-fluoro-benzenesulfonamide 3c: white crystalline solid [M.p. 99 °C, lit. mp 96–98 °C (Ramunno et al. 2012), yield 644 mg, 97 %] Analysis: IR (KBr): 3355, 1611, 1338 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.22 (bs, 1H, NH), 7.69–7.94(m, 2H, ArH), 7.33–7.52 (m, 2H, ArH), 7.19–7.32 (m, 5H, ArH), 4.00 (s, 2H, CH2). 13C NMR (300 MHz, DMSO-d
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) δ: 46.6, 116.5, 116.8, 127.6, 128.1, 128.7, 129.9, 130.0, 137.6, 137.7, 137.9, 162.8, 166.1.
N-Benzyl-4-chloro-benzenesulfonamide 3d: white crystalline solid [M.p. 105 °C, lit. mp 104–106 °C (Ramunno et al. 2012) yield 690 mg, 98 %] Analysis: IR (KBr): 3365, 1614, 1335 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.25 (bs, 1H, NH), 7.75–7.98 (m, 2H, ArH), 7.38–7.54 (m, 2H, ArH), 7.19–7.32 (m, 5H, ArH), 4.02 (s, 2H, CH2).
N-Benzyl-4-trifluromethoxy-benzenesulfonamide 3e: white crystalline solid [M.p. 114 °C, lit. mp 114 °C (Shi et al. 2009); yield 779 mg, 94 %] Analysis: IR (KBr): 3348, 1603, 1341 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.44 (bs, 1H, NH), 7.76–8.01 (m, 4H, ArH), 7.11–7.28 (m, 5H, ArH), 4.04 (s, 2H, CH2).
N-Benzyl-4-methoxy-benzenesulfonamide 3f: white crystalline solid [M.p. 113 °C, lit. mp 112–113 °C (Martínez-Asencio et al. 2011b); yield 686 mg, 99 %] Analysis: IR (KBr): 3357, 1607, 1344 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.42 (bs, 1H, NH), 7.84–7.91 (m, 2H, ArH), 7.20–7.34 (m, 5H, ArH), 6.97–7.04 (m, 2H, ArH), 4.46 (d, J = 6.0 Hz, 2H, CH2), 3.95 (s, 3H, OCH3).
N-Benzyl-2, 4-dichloro-benzenesulfonamide 3g: white crystalline solid [M.p. 115 °C, yield 775 mg, 98 %] Analysis: Calculated for C13H11Cl2NO2S (316.21): C, 49.38; H, 3.51; N, 4.43. Found: C, 49.37; H, 3.52; N, 4.42. IR (KBr): 3358, 1605, 1342 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.56 (s, 1H, NH), 7.86 (d, J = 8.7 Hz, 1H, ArH), 7.67–7.76 (m, 1H, ArH), 7.44–7.60 (m, 1H, ArH), 7.12–7.26 (m, 5H, ArH), 4.09 (s, 2H, CH2).
N-Benzyl-3, 4-dichloro-benzenesulfonamide 3h: white crystalline solid [M.p. 112 °C; yield 767 mg, 97 %] Analysis: Calculated for C13H11Cl2NO2S (316.21): C, 49.38; H, 3.51; N, 4.43. Found: 49.40; H, 3.52; N, 4.42. IR (KBr): 3354, 1605, 1343 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.40 (bs, 1H, NH), 7.86 (d, J = 1.9 Hz, 1H, ArH), 7.80 (d, J = 8.7 Hz, 1H, ArH), 7.65–7.75 (m, 1H, ArH), 7.13–7.29 (m, 5H, ArH), 4.05 (s, 2H, CH2). 13C NMR (300 MHz, DMSO-d
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) δ: 46.7, 127.1, 127.7, 128.2, 128.6, 128.8, 131.9, 132.4, 135.7, 137.5, 141.7.
Synthesis of urea derivatives 4(a–i)
The mixture of benzylamine (0.268 g, 2.5 mmol), isocyanate (3.5 mmol) and triethylamine (0.695 ml, 5 mmol) in DMF (5 ml) was stirred at room temperature for 5–6 h (TLC Check, 50 % ethyl acetate/hexane). To the above stirring solution, KF (88 mg, 1.5 mmol) was added and the reaction mixture was stirred for 0.5 h. Sucrose (0.514 g, 1.5 mmol) was added and stirring was continued for next half an hour. Water (50 ml) was then added to the reaction mixture under stirring. The product was isolated by filtration and washed with 10 ml water.
1-Benzyl -3-(3-cyano-phenyl)-urea 4a: white crystalline solid [M.p. 176 °C; yield 616 mg, 98 %] Analysis: IR (KBr): 3454, 2202, 1640, 1602 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.94 (s, 1H, NH), 7.95 (t, J = 1.7 Hz,1H, NH), 7.60 (ddd, J = 8.1, 2.3, 1.3 Hz, 1H, ArH), 7.43 (t, J = 7.9 Hz, 1H, ArH), 7.19–7.39 (m, 6H, ArH), 6.81 (t, J = 5.9 Hz, 1H, ArH), 4.31 (d, J = 6.0 Hz, 2H, CH2). 13C NMR (300 MHz, DMSO-d
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) δ: 43.2, 111.9, 119.4, 120.6, 122.7, 125.0, 127.2, 127.6, 128.8, 130.5, 140.5, 141.8, 155.4.
1-Benzyl-3-naphthalen-1-yl-urea 4b: white crystalline solid [M.p. 203 °C; yield 684 mg, 99 %] Analysis: Calculated for C18H16N2O (276.34): C, 78.24; H, 5.84; N, 10.14. Found: C, 78.22; H, 5.85; N, 10.13. IR (KBr): 3374, 1638, 1605 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.64 (s, 1H, NH), 8.11 (d, J = 7.6 Hz, 1H, ArH), 8.05 (dd, J = 7.7, 0.9 Hz, 1H, ArH), 7.85–7.98 (m, 1H, ArH), 7.66 (s, 1H, ArH), 7.24–7.59 (m, 10H, ArH), 7.06 (t, J = 5.9 Hz, 1H, ArH), 4.39 (d, J = 5.7 Hz, 2H, CH2). 13C NMR (300 MHz, DMSO-d
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) δ: 46.7, 127.1, 127.7, 128.2, 128.6, 128.8, 131.9, 132.4, 135.7, 137.5, 141.7.
1-Benzyl-3-(4-fluoro-phenyl)-urea 4c: white crystalline solid [M.p. 179 °C; yield 592 mg, 97 %] Analysis: Calculated for C14H13FN2O (244.27): C, 68.84; H, 5.36; N, 11.47. Found: C, 68.83; H, 5.35; N, 11.46. IR (KBr): 3354, 1635, 1602 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.87 (s, 1H, NH), 8.2 (t, J = 5.9 Hz, 1H, NH), 7.93–8.01 (m, 2H, ArH), 7.15–7.25 (m, 5H, ArH), 7.25–7.36 (m, 2H, ArH), 4.48 (d, J = 6.0 Hz, 2H, CH2).
1-Benzyl-3-(2-trifluoromethyl-phenyl)-urea 4d: white crystalline solid [M.p. 168 °C; yield 721 mg, 98 %] Analysis: Calculated for C15H13F3N2O (294.28): C, 61.22; H, 4.45; N, 9.52. Found: C, 61.20; H, 4.44; N, 9.53. IR (KBr): 3370, 1645, 1601 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.72 (s, 1H, NH), 7.60–7.97 (m, 4H, ArH), 7.45 (t, J = 5.7 Hz, 1H, NH), 7.25–7.35 (m, 5H, ArH), 4.31 (d, J = 5.7 Hz, 2H).
1-Benzyl-3-(2-methoxy- phenyl)-urea 4e: white crystalline solid [M.p. 177 °C; yield 622 mg, 97 %] Analysis: Calculated for C15H16N2O2 (256.31): C, 70.29; H, 6.29; N, 10.93. Found: C, 70.31; H, 6.28; N, 10.94. IR (KBr): 3365, 1636, 1607 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.72 (s, 1H, NH),7.08–7.36 (m, 7H, ArH), 6.85–6.95 (m, 1H, ArH), 6.69 (bs, 1H, NH), 6.44–6.58 (m,1H, ArH), 4.29 (bs, 2H, CH2), 3.5 (s, 3H, OCH3).
1-Benzyl-3-phenyl-urea 4f: white crystalline solid [M.p. 194 °C; yield 560 mg, 99 %] Analysis: Calculated for C14H14N2O (226.28): C, 74.31; H, 6.24; N, 12.38. Found: C, 74.33; H, 6.25; N, 12.39. IR (KBr): 3364, 1643, 1602 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.60 (s, 1H, NH), 7.08–7.40 (m, 8H, ArH), 6.879 (ddd, J = 8.0, 2.0, 0.9 Hz, 1H, ArH), 6.63 (t, J = 6.0 Hz, 1H, NH), 6.47 (ddd, J = 8.3, 2.6, 0.9 Hz, 1H, ArH), 4.33(d, J = 6.0 Hz, 2H, CH2).
1-Benzyl-3-(4-cyano-phenyl)-urea 4g: white crystalline solid [M.p. 198 °C; yield 578 mg, 92 %] Analysis: Calculated for C15H13N3O (251.29): C, 71.70; H, 5.21; N, 16.72. Found: C, 71.73; H, 5.22; N, 16.71. IR (KBr): 3374, 2201, 1643, 1608 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1H, NH), 7.39–7.62(m, 1H, ArH), 7.19–7.36 (m, 5H, ArH), 7.32 (bs, 1H, NH), 6.96–7.11 (m, 1H, ArH), 6.62–6.78 (m, 2H), 4.29 (d, J = 6.0 Hz, 2H, CH2).
1-Benzyl-3-(4-trifluoromethoxy-phenyl) urea 4h: white crystalline solid [M.p. 192 °C; yield 730 mg, 94 %] Analysis: Calculated for C15H13F3N2O2 (310.28): C, 58.07; H, 4.22; N, 18.37. Found: C, 58.06; H, 4.21; N, 18.36. IR (KBr): 3374, 1644, 1610 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.80 (s, 1H, NH), 7.5 (d, J = 7.6 Hz, 2H, ArH), 7.18–7.22 (m, 2H, ArH), 7.22–7.36 (m, 5H, ArH), 6.69 (t, J = 6.0 Hz, 1H, NH), 4.30 (d, J = 6.0 Hz, 2H, CH2).
1-Benzyl-3-(2,5-Dimethoxy-phenyl) urea 4i: white crystalline solid [M.p. 179 °C; yield 709 mg, 99 %] Analysis: Calculated for C16H18N2O3 (286.33): C, 67.12; H, 6.34; N, 9.78. Found: C, 67.11; H, 6.33; N, 9.77. IR (KBr): 3374, 1638, 1601 cm−1; 1H NMR (300 MHz, DMSO-d
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) δ 8.03 (s, 1H, NH), 7.8–7.84 (m, 1H, ArH), 7.21–7.38 (m, 6H, ArH & NH), 6.83–6.91 (m, 1H, ArH), 6.38–6.50 (m, 1H, ArH), 4.28 (d, J = 5.7 Hz, 2H), 3.75 (s, 3H, OCH3), 3.65 (s, 3H, OCH3).