Journal of the Korean Chemical Society (대한화학회지)

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Intramolecular Oxa-Mannich Reaction of 1,3-Dihydro-2-benzofuran-1-ol for Efficient Synthesis of 1-Aminophthalan Derivatives

  • Kim, Heebum (Department of Chemistry, Kyonggi University) ;
  • Kim, Sung-Gon (Department of Chemistry, Kyonggi University)
  • Received : 2021.10.25
  • Accepted : 2021.11.17
  • Published : 2022.02.20
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Abstract

An efficient method for the synthesis of 1-aminophthalans has been developed. The intramolecular oxa-Mannich reaction of 1,3-dihydro-2-benzofuran-1-ols with p-toluenesulfonylamine in the presence of Cs2CO3 as a base, without using any catalyst, provided the desired 1-aminophthalans in moderate to good yields.

Keywords

INTRODUCTION

N,O-Acetals, which are important intermediates for various valuable synthetic transformations in organic synthesis,1,2 are found in natural products and bioactive compounds.3 In particular, cyclic N,O-acetals are common privileged structural motifs in many natural products and synthetic pharmaceutical compounds that show important biological activities, including antifungal, antiviral, and anticancer properties.4 Despite its prevalence and significance, the acyclic N,O-acetal has received little attention from organic chemists. Because of the inherent instability of N,O-acetals, the development of a suitable synthetic method is very difficult, and direct reactions of N,O-acetals are limited.5 Therefore, the development of an efficient strategy for constructing the N,O-acetal skeleton remains an active area of research in organic chemistry.

Recently, we reported the enantioselective synthesis of 1-substituted phthalans via the asymmetric catalytic oxa-Michael reaction of 1,3-dihydro-2-benzofuran-1-ols with triphenylphosphoranes using an organocatalyst (Scheme 1a).6 We were interested in further expanding the synthesis of 1-substituted phthalans from 1,3-dihydro-2-benzofuran-1-ols as starting materials. Thus, we focused our attention on the synthetic application of 1,3-dihydro-1-isobenzofuranamines (1-aminophthans) via the reaction of 1,3-dihydro-2-benzofuran-1-ols with amines (Scheme 1b).

Phthalans, which are referred to as 1,3-dihydrobenzofurans, are widespread in natural products and biologically active compounds. They exhibit a broad spectrum of pharmacological properties such as antibacterial, antidepressive, anti-inflammatory, and anti-influenza activities.7 Hence, much effort has been undertaken to develop synthetic routes to new phthalan-containing heterocyclic compounds.8 However, there are very few reports on the synthesis methods of 1-aminophthans.9 Herein we present a metal and catalyst free intramolecular oxa-Mannich reaction10 of 1,3-dihydro-2-benzofuran-1-ol with p-toluenesulfonylamine for the efficient synthesis of 1-aminophthalans.

JCGMDC_2022_v66n1_9_f0001.png 이미지

Scheme 1. Synthesis of 1-substituted phthalan derivatives.

EXPERIMENTAL

General Procedures

Organic solvents were distilled prior to use. Organic solutions were concentrated under reduced pressure using a rotary evaporator. Chromatographic purification of products was accomplished using forced-flow chromatography on ICN 60 32-64 mesh silica gel 63. Thin-layer chromatography (TLC) was performed on EM Reagents 0.25 mm silica gel 60-F plates. Developed chromatograms were visualized by fluorescence quenching and with anisaldehyde stain. 1H and 13C NMR spectra were recorded (400 MHz for 1H and 100 MHz for 13C), and were internally referenced to residual protio solvent signals. Data for 1H NMR are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant (Hz) and integration. Data for 13C NMR are reported in terms of chemical shift. IR spectra were recorded on an FT IR spectrometer and are reported in wave numbers. High-resolution mass spectroscopy (HRMS) was performed by electron impact (EI).

General procedure for the reaction of 1,3-dihydro-2-benzofuran-1-ols with amines

To a solution of 1,3-dihydro-2-benzofuran-1-ol 1 (0.2 mmol), Cs2CO3 (0.24 mmol) and molecular sieves 4Å (20 mg) in CH2Cl2 (2 mL) was added amine 2 (0.2 mmol) at room temperature. The reaction mixture was stirred at the same temperature until 1,3-dihydro-2-benzofuran-1-ol 1 was complete consumed, as determined by TLC. Then, the resulting mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The crude residue was purified by flash column chromatography with EtOAc/hexanes as eluent to afford desired product 3.

Benzyl (1,3-dihydroisobenzofuran-1-yl)carbamate (3ab). White solid; m.p. 112–115°C; 1H NMR (400 MHz, CDCl3) δ 7.60–7.49 (m, 1H), 7.36 (dd, J = 9.7, 6.2 Hz, 7H), 7.25 (s, 1H), 6.91–6.72 (m, 1H), 5.41 (s, 1H), 5.26–5.12 (m, 3H), 5.04 (d, J = 12.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 153.6, 140.0, 136.2, 134.1, 129.4, 128.7, 128.4, 128.1, 126.0, 122.8, 121.4, 71.9, 69.8, 67.3; IR (film) 3033, 3032, 2923, 2853, 1746, 1698, 1669, 1527, 1461, 1353, 1263, 1246, 1051, 1011 cm-1; HRMS (EI) m/z calcd for [M]+ C16H15NO3: 269.1052 Found: 269.1050.

N-(1,3-Dihydroisobenzofuran-1-yl)-4-methylbenzenesulfonamide (3ac). White solid; m.p. 169–171°C; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.3 Hz, 2H), 7.40–7.29 (m, 5H), 7.21 (d, J = 6.8 Hz, 1H), 6.56 (dd, J = 10.2, 1.8 Hz, 1H), 5.16 (d, J = 10.1 Hz, 1H), 5.00 (dd, J = 12.6, 2.3 Hz, 1H), 4.92 (d, J = 12.7 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.7, 139.4, 138.8, 136.7, 129.8, 129.6, 128.3, 127.4, 123.2, 121.3, 89.1, 72.1, 21.7; IR (film) 3354, 3259, 3063, 3032, 2921, 1597, 1525, 1501, 1450, 1386, 1299, 1153, 1096, 1005 cm-1; HRMS (EI) m/z calcd for [M]+ C15H15NO3S: 289.0773 Found: 289.0794.

4-Methyl-N-(5-methyl-1,3-dihydroisobenzofuran-1-yl)benzenesulfonamide (3bc). White solid; m.p. 159–161°C; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 7.01 (s, 1H), 6.51 (d, J = 10.1 Hz, 1H), 5.07 (d, J = 10.2 Hz, 1H), 4.95 (dd, J = 12.6, 2.5 Hz, 1H), 4.87 (d, J = 12.5 Hz, 1H), 2.44 (s, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.6, 139.8, 139.7, 138.8, 134.0, 129.7, 129.2, 127.3, 122.9, 121.7, 89.0, 72.0, 21.7, 21.5; IR (film) 3253, 2952, 2931, 2855, 1705, 1444, 1342, 1159, 1017 cm-1; HRMS (EI) m/z calcd for [M]+ C16H17-NO3S: 303.0929 Found: 303.0941.

4-Methyl-N-(6-methyl-1,3-dihydroisobenzofuran-1-yl)benzenesulfonamide (3cc). White solid; m.p. 140–142°C; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.19–7.12 (m, 2H), 7.08 (d, J = 7.7 Hz, 1H), 6.50 (s, 1H), 5.14 (s, 1H), 4.96 (dd, J = 12.4, 2.0 Hz, 1H), 4.87 (d, J = 12.3 Hz, 1H), 2.45 (s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.6, 138.8, 138.3, 137.0, 136.5, 130.6, 129.7, 127.4, 123.6, 121.0, 89.0, 72.1, 21.7, 21.3; IR (film) 3267, 2922, 2854, 1756, 1567, 1495, 1443, 1340, 1297, 1156, 1066, 1013 cm-1; HRMS (EI) m/z calcd for [M]+ C16H17NO3S: 303.0929 Found: 303.0922.

4-Methyl-N-(7-methyl-1,3-dihydroisobenzofuran-1-yl)benzenesulfonamide (3dc). White solid; m.p. 161–163°C; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 6.4 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.5 Hz, 1H), 6.58 (dd, J = 10.1, 2.3 Hz, 1H), 4.99 (d, J = 12.5 Hz, 2H), 4.88 (d, J = 12.8 Hz, 1H), 2.45 (s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.5, 139.4, 138.9, 134.8, 134.2, 129.9, 129.7, 129.5, 127.3, 118.5, 88.6, 72.2, 22.8, 21.7; IR (film) 3273, 2931, 2920, 2853, 1609, 1597, 1443, 1339, 1304, 1156, 1066, 1002 cm-1; HRMS (EI) m/z calcd for [M]+ C16H17NO3S: 303.0929 Found: 303.0933.

4-Methyl-N-(4-methyl-1,3-dihydroisobenzofuran-1-yl)benzenesulfonamide (3ec). White solid; m.p. 155–157°C; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 7.5 Hz, 1H), 7.14 (t, J = 6.7 Hz, 2H), 6.55 (d, J = 10.1 Hz, 1H), 5.12 (d, J = 10.3 Hz, 1H), 4.95 (dd, J = 12.7, 2.2 Hz, 1H), 4.87 (d, J = 12.6 Hz, 1H), 2.45 (s, 3H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.6, 138.8, 138.4, 136.4, 131.7, 130.3, 129.7, 128.6, 127.3, 120.4, 89.5, 71.7, 21.7, 18.5; IR (film) 3263, 2940, 2918, 2850, 1722, 1605, 1486, 1443, 1339, 1314, 1264, 1157, 1064, 1010 cm-1; HRMS (EI) m/z calcd for [M]+ C16H17NO3S: 303.0929 Found: 303.0899.

N-(5-Methoxy-1,3-dihydroisobenzofuran-1-yl)-4-methylbenzenesulfonamide (3fc). White solid; m.p. 172–174 °C; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.3 Hz, 2H), 7.40–7.28 (m, 3H), 7.25–7.23 (m, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 5.14 (d, J = 10.1 Hz, 1H), 4.90 (dd, J = 13.4, 2.3 Hz, 1H), 4.83 (d, J = 13.4 Hz, 1H), 3.92 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.1, 143.8, 142.1, 138.6, 134.2, 130.1, 129.8, 127.4, 122.8, 112.0, 89.8, 73.1, 56.9, 22.8; IR (film) 3239, 2955, 2921, 2852, 1612, 1463, 1439, 1377, 1288, 1262, 1158, 1135, 1067, 1020 cm-1; HRMS (EI) m/z calcd for [M]+ C16H17NO4S: 319.0878 Found: 319.0907.

N-(4-Methoxy-1,3-dihydroisobenzofuran-1-yl)-4-methylbenzenesulfonamide (3gc). White solid; m.p. 164–166 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.54 (dd, J = 10.2, 2.7 Hz, 1H), 5.14 (d, J = 10.2 Hz, 1H), 4.97 (dd, J = 12.9, 2.8 Hz, 1H), 4.89 (d, J = 12.9 Hz, 1H), 3.82 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.1, 143.6, 138.8, 138.6, 130.2, 129.7, 127.5, 127.3, 115.0, 110.7, 89.5, 70.7, 55.5, 21.7; IR (film) 3263, 2937, 2915, 2865, 1605, 1486, 1443, 1339, 1314, 1264, 1157, 1064, 1010 cm-1; HRMS (EI) m/z calcd for [M]+ C16H17NO4S: 319.0878 Found: 319.0880.

N-(5-Bromo-1,3-dihydroisobenzofuran-1-yl)-4-methylbenzenesulfonamide (3hc). White solid; m.p. 175–177 °C; 1H NMR (400 MHz, CDCl3) δ 7.91–7.81 (m, 2H), 7.50–7.43 (m, 1H), 7.36 (d, J = 0.7 Hz, 1H), 7.33 (dd, J = 8.5, 0.6 Hz, 2H), 7.22 (d, J = 8.1 Hz, 1H), 6.57–6.45 (m, 1H), 5.17 (d, J = 10.3 Hz, 1H), 4.96 (dd, J = 13.0, 2.3 Hz, 1H), 4.88 (d, J = 12.9 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.8, 141.7, 138.5, 135.8, 131.5, 129.8, 127.3, 124.7, 124.7, 123.8, 88.8, 71.5, 21.7; IR (film) 3245, 2925, 2921, 2867, 1441, 1342, 1323, 1159, 1056, 1013 cm-1; HRMS (EI) m/z calcd for [M]+ C15H14Br-NO3S: 366.9878 Found: 366.9887.

N-(6-Bromo-1,3-dihydroisobenzofuran-1-yl)-4-methylbenzenesulfonamide (3ic). White solid; m.p. 162–163°C; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.2 Hz, 2H), 7.48 (s, 1H), 7.43 (s, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 10.2 Hz, 1H), 5.20 (d, J = 10.1 Hz, 1H), 5.01–4.92 (m, 1H), 4.86 (d, J = 12.8 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.9, 139.0, 138.5, 138.4, 132.8, 129.8, 127.3, 126.5, 122.8, 121.9, 88.6, 71.9, 21.8; IR (film) 3255, 2931, 2928, 2877, 1554, 1507, 1443, 1340, 1009 cm-1; HRMS (EI) m/z calcd for [M]+ C15H14BrNO3S: 366.9878 Found: 366.9859.

N-(4-Bromo-1,3-dihydroisobenzofuran-1-yl)-4-methylbenzenesulfonamide (3jc). White solid; m.p. 171–173°C; 1H NMR (400 MHz, CDCl3) δ 7.91–7.81 (m, 2H), 7.48 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 16.9 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 6.62 (dd, J = 10.5, 2.3 Hz, 1H), 5.17 (d, J = 10.3 Hz, 1H), 4.93 (dd, J = 13.4, 2.6 Hz, 1H), 4.86 (d, J = 13.3 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.8, 140.1, 138.7, 138.5, 132.6, 130.3, 129.8, 127.4, 122.1, 116.0, 90.0, 73.1, 21.8; IR (film) 3263, 2929, 2915, 2850, 1450, 1341, 1315, 1159, 1077, 1014 cm-1; HRMS (EI) m/z calcd for [M]+ C15H14Br-NO3S: 366.9859 Found: 366.9887.

N-(6-Chloro-1,3-dihydroisobenzofuran-1-yl)-4-methylbenzenesulfonamide (3kc). White solid; m.p. 160–162 °C; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.3 Hz, 2H), 7.37–7.28 (m, 4H), 7.14 (d, J = 8.1 Hz, 1H), 6.50 (d, J = 8.6 Hz, 1H), 5.18 (d, J = 10.2 Hz, 1H), 4.98 (dd, J = 12.8, 2.4 Hz, 1H), 4.88 (d, J = 12.8 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.9, 138.7, 138.5, 137.8, 134.2, 123.0, 129.8, 127.3, 123.5, 122.5, 88.7, 71.8, 21.7; IR (film) 3244, 2915, 2925, 2845, 1442, 1342, 1324, 1160, 1061, 1013 cm-1; HRMS (EI) m/z calcd for [M]+ C15H14ClNO3S: 323.0383 Found: 323.0380.

N-(6-Fluoro-1,3-dihydroisobenzofuran-1-yl)-4-methylbenzenesulfonamide (3lc). White solid; m.p. 145–147°C; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.20–6.96 (m, 3H), 6.51 (s, 1H), 5.19 (s, 1H), 4.97 (d, J = 12.3 Hz, 1H), 4.88 (d, J = 12.4 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.0 (d, J1 = 246.6 Hz), 143.8, 138.9 (d, J3 = 8.6 Hz), 138.5, 134.7 (d, J4 = 2.3 Hz), 129.8, 127.3, 122.6 (d, J3 = 8.7 Hz), 117.2 (d, J2 = 23.3 Hz), 110.3 (d, J2 = 23.9 Hz), 88.8 (d, J4 = 2.8 Hz), 71.8, 21.7; IR (film) 3245, 2945, 2928, 2844, 1605, 1491, 1437, 1342, 1323, 1245, 1159, 1062, 1011 cm-1; HRMS (EI) m/z calcd for [M]+ C15H14FNO3S: 307.0678 Found: 307.0689.

4-Methyl-N-(6-(trifluoromethyl)-1,3-dihydroisobenzofuran-1-yl)benzenesulfonamide (3mc). White solid; m.p. 159–161°C; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 7.9 Hz, 1H), 7.55 (s, 1H), 7.34 (d, J = 8.1 Hz, 3H), 6.58 (d, J = 10.5 Hz, 1H), 5.21 (d, J = 10.3 Hz, 1H), 5.07 (d, J = 13.5 Hz, 1H), 4.97 (d, J = 13.3 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.0, 143.4, 142.0, 138.4, 137.6, 131.0, 129.9, 127.3, 126.9, 122.0, 120.6, 88.8, 71.9, 21.7; IR (film) 3248, 2930, 2935, 2848, 1452, 1435, 1328, 1283, 1215, 1158, 1122, 1086, 1057 cm-1; HRMS (EI) m/z calcd for [M]+ C16H14F3NO3S: 357.0646 Found: 357.0623.

4-Methyl-N-(6-nitro-1,3-dihydroisobenzofuran-1-yl)benzenesulfonamide (3nc). White solid; m.p. 190–192°C; 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 7.9 Hz, 1H), 8.10 (s, 1H), 7.82 (d, J = 7.8 Hz, 2H), 7.36 (dd, J = 20.1, 8.1 Hz, 3H), 6.59 (d, J = 8.7 Hz, 1H), 5.30 (s, 1H), 5.11 (d, J = 14.2 Hz, 1H), 5.01 (d, J = 14.1 Hz, 1H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 146.3, 144.2, 138.6, 138.3, 129.9, 127.3, 126.6, 125.3, 122.3, 119.1, 88.6, 71.8, 21.8; IR (film) 3304, 2952, 2915, 2865, 1555, 1524, 1337, 1321, 1158, 1016 cm-1; HRMS (EI) m/z calcd for [M]+ C15H14N2O5S: 334.0623 Found: 334.0618.

RESULTS AND DISCUSSION

Based on our previous intramolecular oxa-Michael reaction of 1,3-dihydro-2-benzofuran-1-ols with triphenylphosphoranes,6 we first evaluated the suitability of a protected amine for the oxa-Mannich reaction of 1,3-dihydro-2-benzofuran-1-ol to afford 1-aminophthan. Initially, we carried out the reaction of 1,3-dihydro-2-benzofuran-1-ol 1a with BocNH2 2a in the presence of CsCO3 as the base and 4 Å molecular sieves as the water scavenger (Table 1). When the reaction was conducted for 72 h in CH2Cl2 at room temperature, 1-aminophthan 3aa was obtained in only 11% yield (Table 1, entry 1). However, when using CbzNH2 2b, the yield increased to 41% (Table 1, entry 2). Moreover, when using TsNH2 2c, the reaction proceeded to completion in 24 h to afford 1-aminophthan 3ac in 45% yield (Table 1, entry 3). Next, Ph2PONH2 2d was also examined for this oxa-Mannich reaction, and a trace amount of 1-aminophthan 3ad was obtained (Table 1, entry 4). Ts-NH2 2c was identified as the best protected amine for this oxa-Mannich reaction. Next, bases and organic solvents were screened to further optimize the reaction conditions. The use of inorganic bases such as K2CO3 and Na2CO3 did not improve the results (Table 1, entries 5 and 6). Among the various solvents employed, CH2Cl2 was the ideal choice for this asymmetric reaction in terms of the reaction outcome (Table 1, entries 7−11).

Table 1. Optimization of reaction of 1a with 2.[a]

JCGMDC_2022_v66n1_9_t0001.png 이미지

[a]All reactions were carried out in solvent (0.2 M) with 1a (0.1 mmol), 2 (0.1 mmol), base (1.2 equiv) and molecular sieves 4Å (20 mg). [b]Isolated yield after chromatographic purification.

With the optimized conditions in hand, we then explored the substrate scope of 1,3-dihydro-2-benzofuran-1-ols for this intramolecular oxa-Mannich reaction (Table 2). The electronic nature and position of the substituents influenced the reaction yield. The reactions proceeded well with both electron-donating substituents such as Me (3cc) and electron-withdrawing substituents such as Br (3ic), Cl (3kc), F (3lc), CF3 (3mc), and NO2 (3nc) at the 6-position of the aromatic ring. While the reaction of 5-methyl-substituted benzofuranol 1b provided the desired product 3bc in a moderate yield (45%), 5-bromo substituted benzofuranol 1h gave low yield (24%). In the case of 4-substituted benzofuranols, the electron-donating methyl and methoxy groups gave different results; 4-methoxy-substituted benzofuranol 1g furnished 1-aminophthalan 3gc in a high yield (68%), but 4-methyl-substituted benzofuranol 1e gave a low product yield (20%). Most of the reactions did not proceed completely and the starting material remained, resulting in a moderate yield.

Table 2. Substrate scope of 1,3-dihydro-2-benzofuran-1-ol.[a,b]

JCGMDC_2022_v66n1_9_t0002.png 이미지

[a]All reactions were carried out in CH2Cl2 (0.2 M) with 1 (0.2 mmol), 2c (0.2 mmol), Cs2CO3 (1.2 equiv) and molecular sieves 4Å (20 mg). [b]Isolated yield after chromatographic purification 

Next, the asymmetric intramolecular oxa-Mannich reaction of 1,3-dihydro-2-benzofuran-1-ol with TsNH2 was attempted. (Scheme 2). Unfortunately, the asymmetric oxa-Mannich reaction of benzofuranol 1a11 with TsNH2 2c, in the presence of squaramide-based catalyst I in toluene, furnished 3ac in moderate yield but almost as a racemate. Similar results were obtained when using chiral phosphoric acid II as an organocatalyst.12

JCGMDC_2022_v66n1_9_f0002.png 이미지

Scheme 2. Organocatalytic asymmetric reaction of 1a with 2a. 

CONCLUSION

In summary, we developed a metal-free intramolecular oxa-Mannich reaction of 1,3-dihydro-2-benzofuran-1-ol with p-toluenesulfonylamine and obtained the desired 1-aminophthalan derivatives in moderate to good yields. Research on the asymmetric version of this intramolecular oxa-Mannich reaction is ongoing, and the results will be reported in due course.

Acknowledgments

This research was supported by Kyonggi University Research Grant 2020.

References

  1. Warriner, S. Category 4: Compounds with Two Carbon-Heteroatom Bonds in Science of Synthesis: Houben-Weyl Methods of Molecular Transformations; Georg Thieme Verlag: Stuttguart, 2007; Vol 30, p 7.
  2. (a) Sugiura, M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S. J. Am. Chem. Soc. 2001, 123, 12510. https://doi.org/10.1021/ja0170448
  3. (b) Liu, R.-C.; Huang, W.; Ma, J.-Y.; Wei, B.-G.; Lin, G.-Q. Tetrahedron Lett. 2009, 50, 4046. https://doi.org/10.1016/j.tetlet.2009.04.097
  4. (c) Liu, Y.-W.; Ma, R.-J.; Yan, J.-H.; Zhou, Z.; Wei, B.-G. Org. Biomol. Chem. 2018, 16, 771. https://doi.org/10.1039/C7OB02989F
  5. (d) Mao, Z.-Y.; Liu, Y.-W.; Han, P.; Dong, H.-Q.; Si, C.-M.; Wei, B.-G.; Lin, G.-Q. Org. Lett. 2018, 20, 1090. https://doi.org/10.1021/acs.orglett.7b04056
  6. (e) Han, P.; Mao, Z.-Y.; Si, C.-M.; Zhou, Z.; Wei, B.-G.; Lin, G.-Q. J. Org. Chem. 2009, 50, 4046.
  7. (a) Tanaka, J.-I.; Higa, T. Tetrahedron Lett. 1996, 37, 5535. https://doi.org/10.1016/0040-4039(96)01149-5
  8. (b) Pettit, G. R.; Xu, J.-P.; Chapuis, J.-C.; Pettit, R. K.; Tackett, L. P.; Doubek, D. L.; Hooper, J. N. A.; Schmidt, J. M. J. Med. Chem. 2004, 47, 1149. https://doi.org/10.1021/jm030207d
  9. (c) Cichewicz, R. H.; Valeriote, F. A.; Crews, P. Org. Lett. 2004, 6, 1951. https://doi.org/10.1021/ol049503q
  10. (a) Corey, E. J.; Czako, B.; Kurti, L. Molecules and Medicine; Wiley: Hoboken, 2007.
  11. (b) Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K. Comprehensive Heterocyclic Chemistry III; Elsevier: 2008; Vol. 4 and 8.
  12. (a) Kinderman, S. S.; Wekking, M. M. T.; van Maarseveen, J. H.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. J. Org. Chem. 2005, 70, 5519. https://doi.org/10.1021/jo050503t
  13. (b) Kim, H.; Rhee, Y. H. J. Am. Chem. Soc. 2012, 134, 4011. https://doi.org/10.1021/ja2116298
  14. (c) Nguyen, N. H.; Nguyen, Q. H.; Biswas, S.; Patil, D. V.; Shin, S. Org. Lett. 2019, 21, 9009. https://doi.org/10.1021/acs.orglett.9b03411
  15. (a) Son, E. C.; Kim, S. Y.; Kim, S.-G. J. Org. Chem. 2021, 86, 6826. https://doi.org/10.1021/acs.joc.1c00715
  16. (b) Son, E. C.; No, J.; Kim, S.-G. Bull. Korean Chem. Soc. 2021, doi.org/10.1002/bkcs.12402.
  17. (a) Waugh, J.; Goa, K. L. CNS Drugs 2003, 17, 343. https://doi.org/10.2165/00023210-200317050-00004
  18. (b) Kwon, Y.-J.; Sohn, M.-J.; Kim, C.-J.; Koshino, H.; Kim, W.-G. J. Nat. Prod. 2012, 75, 271. https://doi.org/10.1021/np200720v
  19. (c) Suzuki, M.; Honda, K.; Fukazawa, M.; Ozawa, K.; Hagita, H.; Kawai, T.; Takeda, M.; Yata, T.; Kawai, M.; Fukuzawa, T.; Kobayashi, T.; Sato, T.; Kawabe, Y.; Ikeda, S. J. Pharmacol. Exp. Ther. 2012, 341, 692. https://doi.org/10.1124/jpet.112.191593
  20. (d) Ariefta, N. R.; Azim, M.; Aboshi, T.; Koseki, T.; Taniguchi, Y.; Fujita, M.; Shiono, Y. Org. Lett. 2020, 22, 3161. https://doi.org/10.1021/acs.orglett.0c00925
  21. (a) Karmakar, R.; Pahari, P.; Mal, D. Chem. Rev. 2014, 114, 6213. https://doi.org/10.1021/cr400524q
  22. (b) Albano, G.; Aronica, L. A. Synthesis 2018, 50, 1209. https://doi.org/10.1055/s-0037-1609175
  23. (c) Ilya, E.; Kulikova, L.; Van der Eycken, E. V.; Voskressensky, L. Chemistry Open 2018, 7, 914.
  24. (a) Takedam Y.; Hayakawa, J.; Yano, K.; Minakata, S. Chem. Lett. 2012, 41, 1672. https://doi.org/10.1246/cl.2012.1672
  25. (b) Prier, C. K.; Zhang, R. K.; Buller, A. R.; Brinkmann-Chen, S.; Arnold, F. H. Nat. Chem. 2017, 9, 629. https://doi.org/10.1038/nchem.2783
  26. (c) Wang, L.; Agnew, D. W.; Yu, X.; Figueroa, J. S.; Cohen, S. M. Angew. Chem., Int. Ed. 2018, 57, 511. https://doi.org/10.1002/anie.201709420
  27. (a) Liu, Y.; Ao, J.; Paladhi, S.; Song, C. E.; Yan, H. J. Am. Chem. Soc. 2016, 138, 16486. https://doi.org/10.1021/jacs.6b10660
  28. (b) Li, T.-R.; Lu, L.-Q.; Wang, Y.-N.; Wang, B.-C.; Xiao, W.-J. Org. Lett. 2017, 19, 4098. https://doi.org/10.1021/acs.orglett.7b01903
  29. (c) Wang, Z.-H.; Zhang, Z.-Y.; You, Y.; Zhao, J.-Q.; Zhou, M.-Q.; Zhang, X.-M.; Xu, X.-Y.; Yuan, W.- C. Tetrahedron 2019, 75, 3456. https://doi.org/10.1016/j.tet.2019.04.073
  30. a) Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. Adv. Synth. Catal. 2015, 357, 253. https://doi.org/10.1002/adsc.201401003
  31. (b) Rouf. A.; Tanyeli, C. Curr. Org. Chem. 2016, 20, 2996. https://doi.org/10.2174/1385272820666160805113749
  32. (c) Zhao, B.-L.; Li, J.-H.; Du, A.-M. Chem. Rec. 2017, 17, 994. https://doi.org/10.1002/tcr.201600140
  33. (a) Mahlau, M.; List, B. Angew. Chem., Int. Ed. 2013, 52, 518. https://doi.org/10.1002/anie.201205343
  34. (b) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047. https://doi.org/10.1021/cr5001496
  35. (c) Merad, J.; Lalli, C.; Bernadat, G.; Maury, J.; Masson, G. Chem.-Eur. J. 2018, 24, 3925. https://doi.org/10.1002/chem.201703556