II. Chapter 2. Electrosynthesis of Carbonyl-containing Heterocycles from Arylalkenes
2.5. Experimental data
2.5.3. Characterization of products
3-(methoxy(phenyl)methyl)isobenzofuran-1(3H)-one (2a)
General procedure (A), 3.5 h, 76% yield; General procedure (B), 4 h, 92% yield; White solid, inseparable mixture of diastereomers (1:0.6); m.p. 100 – 105 ℃; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.6 Hz, 0.6H), 7.75 (d, J = 7.5 Hz, 1H), 7.61 -7.56 (m, 1H), 7.52 -7.33 (m, 6.6H), 7.31 -7.27 (m, 2.2H), 7.20 -7.15 (m, 2H), 6.92 (d, J = 8.0 Hz, 1H), 5.67 (d, J = 6.1 Hz, 1H), 5.55 (d, J = 5.4 Hz, 0.6H), 4.55 – 4.45 (m, 1.6H), 3.36 (s, 3H), 3.32 (s, 1.8H); 13C NMR (100 MHz, CDCl3) δ 170.2, 170.0, 146.9, 146.1, 136.3, 135.3, 133.5, 133.3, 129.3, 129.2, 128.7, 128.5, 128.2, 128.0, 127.4, 126.7, 125.4, 125.2, 123.7, 123.6, 84.4, 83.8, 82.7, 82.1, 57.6, 57.3; HRMS (DART) calcd for C16H15O3+ 255.1016, observed 255.1013;
3-((4-chlorophenyl)(methoxy)methyl)isobenzofuran-1(3H)-one (2b)
General procedure (A), 3 h, 83% yield; General procedure (B), 3 h, 91% yield; White solid, inseparable mixture of diastereomers (2:1); m.p. 107 – 112 ℃; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.7 Hz, 0.5H), 7.73 (d, J = 7.6 Hz, 1H), 7.65 – 7.49 (m, 2H), 7.45 (t, J = 7.3 Hz, 1H), 7.40 – 7.32 (m, 1.5H), 7.30 – 7.18 (m, 4H), 7.08 (d, J = 7.4 Hz, 2H), 5.67 (d, J = 5.5 Hz, 1H), 5.51 (d, J = 5.6 Hz, 0.5H), 4.60 (d, J = 5.4 Hz, 1H), 4.43 (d, J = 5.4 Hz, 0.5H), 3.35 (s, 3H), 3.31 (s, 1.5H); 13C NMR (100 MHz, CDCl3) δ 170.0, 169.8, 146.7, 146.0, 134.9, 134.4, 134.4, 133.6, 133.5, 129.4, 129.4, 129.2, 128.8, 128.7, 128.4, 126.7, 126.5, 125.5, 125.4, 123.7, 123.5, 83.5, 83.2, 82.3, 81.4, 57.6, 57.4; HRMS (DART) calcd for C16H14ClO3+ 289.0626, observed 289.0622;
3-(methoxy(p-tolyl)methyl)isobenzofuran-1(3H)-one (2c)
General procedure (A), 3 h, 75% yield; General procedure (B), 3 h, 92% yield; White solid, inseparable mixture of diastereomers (1:0.4); m.p. 95 – 100 ℃; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.5 Hz, 0.4H), 7.75 (d, J = 7.4 Hz, 1H), 7.59 (t, J = 7.4 Hz, 0.4H), 7.54 – 7.46 (m, 1.4 H), 7.46 – 7.39 (m, 1H), 7.31 (d, J = 7.6 Hz, 0.4H), 7.24- 7.16 (m, 1.4H), 7.14 - 6.98 (m, 4.2H), 6.91 (d, J = 7.4 Hz, 1H), 5.65 (d, J = 6.1 Hz, 1H), 5.53 (d, J = 5.2 Hz, 0.4H), 4.50 – 4.41 (m, 1.4H), 3.33 (s, 3H), 3.30 (s, 1.2H), 2.36 (s, 1.2H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.2, 170.1, 146.9, 146.2, 138.5, 138.2, 133.4, 133.2, 132.2, 129.2, 129.1, 129.0, 128.0, 127.3, 126.7, 126.7, 125.3, 125.2, 123.8, 123.6, 84.3, 83.7, 82.8, 82.3, 57.5, 57.1, 21.2; HRMS (DART) calcd for C17H17O3+ 269.1172, observed 269.1169;
3-(methoxy(p-tolyl)methyl)isobenzofuran-1(3H)-one (2d)
General procedure (A), 3 h, 82% yield; General procedure (B), 3 h, 94% yield; Clear oil, inseparable mixture of diastereomers (2:1); 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.6 Hz, 0.5H), 7.77 (d, J = 7.4 Hz, 1H), 7.60 (t, J = 7.5 Hz, 0.5H), 7.54 – 7.38 (m, 3.5H), 7.35 – 7.26 (m, 3.5H), 7.12 (d, J = 7.4 Hz, 2H), 6.84 (d, J = 7.2 Hz, 1H), 5.64 (d, J = 6.1 Hz, 1H), 5.52 (d, J = 5.8 Hz, 0.5H), 4.47 – 4.40 (m, 1.5H), 3.33 (s, 3H), 3.31 (s, 1.5 H), 1.35 (s, 4.5 H), 1.30 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.3, 170.1, 151.8, 151.5, 147.1, 146.3, 133.5, 133.4, 133.2, 132.4, 129.2, 129.1, 127.7, 127.0, 126.7, 126.7, 125.4, 125.3, 125.2, 125.2, 123.8, 123.6, 84.3, 83.6, 82.8, 82.5, 57.5, 57.2, 34.6, 34.6, 31.3, 31.3; HRMS (DART) calcd for C20H23O3+ 311.1642, observed 311.1644;
3-(methoxy(4-methoxyphenyl)methyl)isobenzofuran-1(3H)-one (2e)
General procedure (B), 3 h, 70% yield; White solid, inseparable mixture of diastereomers (3:1); m.p.
97 – 102 ℃; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.7 Hz, 0.33H), 7.76 (d, J = 7.4 Hz, 1H), 7.60 (t, J = 7.5 Hz, 0.33H), 7.53 – 7.41 (m, 2.33H), 7.35 (d, J = 7.6 Hz, 0.33H), 7.24 (d, J = 8.8 Hz, 0.66H), 7.08 (d, J = 8.6 Hz, 2H), 6.95 – 6.88 (m, 1.66 H), 6.81 (d, J = 8.7 Hz, 2H), 5.65 (d, J = 6.6 Hz, 1H), 5.52 (d, J = 5.6 Hz, 0.3H), 4.47 – 4.40 (m, 1.3H), 3.82 (s, 1H), 3.79 (s, 3H), 3.33 (s, 3H), 3.30 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 170.2, 170.1, 159.8, 159.7, 147.0, 146.2, 133.5, 133.3, 129.3, 129.2, 129.2, 128.6, 128.1, 127.2, 126.7, 126.7, 125.4, 125.2, 123.8, 123.6, 113.9, 113.6, 84.0, 83.5, 82.8, 82.3, 57.3, 57.0, 55.2, 55; HRMS (DART) calcd for C17H17O4+ 285.1122, observed 285.1120;
3-((2-bromophenyl)(methoxy)methyl)isobenzofuran-1(3H)-one (2f)
General procedure (A), 3 h, 72% yield; General procedure (B), 3 h, 90% yield; White semi-solid, inseparable mixture of diastereomers (2:1); 1H NMR (400 MHz, CDCl3) δ 7.91 – 7.84 (m, 1.5H), 7.64 – 7.48 (m, 6H), 7.43 – 7.35 (m, 2H), 7.26 – 7.20 (m, 1H), 7.08 – 7.01 (m, 1.5H), 5.69 (d, J = 4.4 Hz, 0.5H), 5.64 (d, J = 4.3 Hz, 1H), 5.06 (d, J = 4.6 Hz, 0.5H), 5.02 (d, J = 4.3 Hz, 1H), 3.30 (s, 1.5H), 3.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.2, 170.2, 146.2, 146.1, 135.7, 135.5, 133.7, 133.2, 133.2, 132.7, 130.1, 130.1, 129.3, 129.3, 129.2, 128.9, 127.9, 127.6, 126.9, 125.5, 125.4, 124.1, 123.8, 123.6, 122.4, 82.2, 82.1, 81.8, 81.2, 58.0, 57.6; HRMS (DART) calcd for C16H13BrO3+ 333.0121, observed 333.0112;
3-((4-acetylphenyl)(methoxy)methyl)isobenzofuran-1(3H)-one (2g)
= 5.3 Hz, 1H), 5.56 (d, J = 5.5 Hz, 0.6H), 4.72 (d, J = 5.3 Hz, 1H), 4.53 (d, J = 5.6 Hz, 0.6H), 3.38 (s, 3H), 3.34 (s, 1.8H), 2.62 (s, 1.8H), 2.56 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.6, 169.9, 169.7, 146.6, 145.9, 141.7, 140.5, 137.3, 137.1, 133.7, 133.5, 129.5, 129.4, 128.5, 128.1, 127.7, 126.9, 126.6, 126.5, 125.6, 125.4, 123.6, 123.5, 83.7, 83.3, 82.2, 81.2, 57.8, 57.7, 26.6, 26.6; HRMS (DART) calcd for C18H17O4+ 297.1122, observed 297.1126;
3-(methoxy(4-(trifluoromethyl)phenyl)methyl)isobenzofuran-1(3H)-one (2h)
General procedure (B), 5.5 h, 41% yield; White semi-solid, inseparable mixture of diastereomers (1:1);
1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.8 Hz, 1H), 7.74 – 7.61 (m, 5H), 7.59 – 7.43 (m, 7H), 7.39 (d, J = 6.8 Hz, 1H), 7.27 – 7.34 (m, 2H), 5.71 (d, J = 4.0 Hz, 1H), 5.52 (d, J = 5.2 Hz, 1H), 4.74 (d, J = 4.6 Hz, 1H), 4.48 (d, J = 5.6 Hz, 1H), 3.38 (s, 3H), 3.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.9, 169.7, 146.7, 145.9, 140.7, 139.3, 133.8, 133.6, 129.6, 129.5, 129.4, 128.2, 127.9, 125.6, 125.5 (q, J = 3.4 Hz), 125.5, 125.1 (q, J = 3.7 Hz), 123.5, 83.7, 83.1, 82.1, 81.1, 57.8, 57.8; HRMS (DART) calcd for C17H14F3O3+ 323.0890, observed 323.0890;
3-(methoxydiphenylmethyl)isobenzofuran-1(3H)-one (2i)
General procedure (B), 3 h, 92% yield; White solid; m.p. 138 – 143 ℃; 1H NMR (400 MHz, CDCl3) δ 7.60 – 7.46 (m, 4H), 7.42 – 7.31 (m, 5H), 7.19 – 7.12 (m, 2H), 7.11 – 7.03 (m, 3H), 6.40 (s, 1H), 3.23 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.1, 147.1, 139.7, 138.1, 133.2, 129.1, 128.9, 128.5, 128.2, 128.1, 127.4, 127.2, 126.7, 124.9, 124.6, 84.8, 81.5, 52.5; HRMS (DART) calcd for C22H19O3+ 331.1329, observed 331.1328;
4'-methoxyspiro[cyclohexane-1,3'-isochroman]-1'-one (2j)
General procedure (B), 3 h, 88% yield; White solid; m.p. 60 – 65 ℃; 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 7.4 Hz, 1H), 4.07 (s, 1H), 3.33 (s, 3H), 2.09 (d, J = 13.5 Hz, 1H), 1.83 – 1.28 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 164.0, 137.1, 133.1, 130.4, 129.2, 128.1, 125.0, 83.8, 79.1, 57.4, 33.9, 31.2, 25.2, 21.4, 21.0; HRMS (DART) calcd for C15H19O3+ 247.1329, observed 247.1330;
4-methoxy-4-phenylisochroman-1-one (2k)
General procedure (A), 3 h, 44% yield; General procedure (B), 3 h, 60% yield; White semi-solid; 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 7.4 Hz, 1H), 7.64 – 7.52 (m, 2H), 7.46 – 7.34 (m, 5H), 7.23 (d, J = 7.5 Hz, 1H), 4.61 (d, J = 11.6 Hz, 1H), 4.52 (d, J = 11.9 Hz, 1H), 3.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.1, 139.5, 137.2, 133.1, 131.0, 129.5, 128.6, 128.4, 128.4, 127.6, 125.8, 75.3, 52.5; HRMS (DART) calcd for C16H15O3+ 255.1016, observed 255.1015;
3-(ethoxy(phenyl)methyl)isobenzofuran-1(3H)-one (2aa)
General procedure (A), 3 equiv. ethanol was used as a nucleophile, 3 h, 50% yield; General procedure (B), ethanol was used as a solvent, 6.5 h, 75% yield; White semi-solid, inseparable mixture of diastereomers (1:0.6); 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.6 Hz, 0.6H), 7.73 (d, J = 7.5 Hz, 1H), 7.60 (t, J = 7.5 Hz, 0.6H), 7.53 – 7.47 (m, 1.6H), 7.45 – 7.31 (m, 4.8H), 7.26 – 7.24 (m, 2.8H), 7.19 – 7.12 (m, 2H), 7.01 (d, J = 7.6 Hz, 1H), 5.68 (d, J = 6.0 Hz, 1H), 5.53 (d, J = 6.0 Hz, 0.6H), 4.65 (d, J = 6.1 Hz, 1H), 4.54 (d, J = 6.0 Hz, 0.6H), 3.58 – 3.36 (m, 3.2H), 1.23 (t, J = 7.0 Hz, 3H), 1.18 (t, J
129.2, 129.1, 128.5, 128.4, 128.4, 128.1, 127.9, 127.5, 127.3, 126.8, 125.4, 125.1, 123.8, 123.8, 82.7, 82.3, 82.1, 65.3, 64.9, 15.2, 15.1; HRMS (DART) calcd for C17H17O3+ 269.1173, observed 269.1171;
3-(hydroxy(phenyl)methyl)isobenzofuran-1(3H)-one (2ab)
6:4 water/acetone as a solvent (0.033 M), KPF6 as an electrolyte, graphite electrodes, 3 mA, under air, 3.5 h, 80% yield; White solid, inseparable mixture of diastereomers (1:0.6); 1H NMR (400 MHz, CDCl3) δ 7.90 – 7.81 (m, 1.6H), 7.55 – 7.48 (m, 3.2H), 7.42 – 7.34 (m, 8 H), 6.92 (d, J = 7.7 Hz, 0.6H), 6.69 – 6.67 (m, 1H), 5.67 (d, J = 4.4 Hz, 0.6H), 5.63 (d, J = 6.9 Hz, 1H), 5.25 (t, J = 4.2 Hz, 0.6H), 4.80 (dd, J
= 7.0, 2.7 Hz, 1H), 2.75 (br s, 1H), 2.33 (br s, 0.6H); 13C NMR (100 MHz, CDCl3) δ 170.4, 170.0, 145.9, 145.7, 138.0, 137.4, 133.6, 133.5, 129.5, 129.4, 129.1, 128.6, 128.6, 128.4, 127.7, 126.9, 126.5, 126.4, 125.6, 125.5, 123.6, 123.5, 84.1, 83.7, 76.4, 73.7; HRMS (DART) calcd for C15H13O3+ 241.0860, observed 241.0863;
(3-oxo-1,3-dihydroisobenzofuran-1-yl)(phenyl)methyl acetate (2ac)
General procedure (A), 3 equiv. acetic acid was used as a nucleophile, 3 h, 47% yield; General procedure (B), 9:1 AcOH/MeCN was used as a solvent, 4 h, 52% yield; White solid, inseparable mixture of diastereomers (2:1); m.p. 107 – 112 ℃; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.3 Hz, 1H), 7.79 (d, J = 7.6 Hz, 0.5H), 7.62 (t, J = 7.4 Hz, 0.5H), 7.56 – 7.46 (m, 3H), 7.40 – 7.32 (m, 5H), 7.29 – 7.27 (m, 1H), 7.25 – 7.19 (m, 1.5H), 6.84 (d, J = 6.7 Hz, 1H), 6.22 (d, J = 3.9 Hz, 0.5H), 6.02 (d, J = 6.2 Hz, 1H), 5.79 (d, J = 3.7 Hz, 0.5H), 5.74 (d, J = 6.2 Hz, 1H), 2.14 (s, 1.5H), 2.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.7, 169.7, 169.4, 145.5, 145.3, 134.9, 133.8, 133.7, 129.7, 129.6, 129.2, 128.8, 128.6, 128.3, 127.9, 127.2, 126.8, 125.7, 125.6, 123.2, 122.9, 81.3, 81.3, 75.6, 75.4, 20.9, 20.8; HRMS (DART) calcd for C17H15O4+ 283.0965, observed 283.0965;
(3-oxo-1,3-dihydroisobenzofuran-1-yl)(phenyl)methyl methanesulfonate (2ad)
General procedure (A), 3 equiv. methanesulfonic acid was used as a nucleophile, 3 h, 49% yield; White semi-solid, inseparable mixture of diastereomers (1:0.4); 1H NMR (400 MHz, CDCl3) δ 7.91 – 7.82 (m, 1.4H), 7.66 – 7.51 (m, 3.2H), 7.47 – 7.33 (m, 6.6H), 7.16 (d, J = 7.7 Hz, 0.4H), 6.85 (d, J = 7.9 Hz, 1H), 5.94 (d, J = 5.1 Hz, 0.4H), 5.86 – 5.77 (m, 1.4H), 5.70 (d, J = 6.6 Hz, 1H), 2.97 – 2.83 (m, 4.2H); 13C NMR (100 MHz, CDCl3) δ 169.4, 169.2, 144.5, 144.3, 134.1, 134.0, 133.1, 132.8, 130.2, 130.1, 130.1, 129.7, 129.0, 128.9, 128.0, 127.0, 126.7, 125.9, 125.8, 123.5, 123.4, 83.1, 82.0, 80.9, 80.7, 39.2; HRMS (DART) calcd for C16H15O5S+ 319.0635, observed 319.0630;
(3-oxo-1,3-dihydroisobenzofuran-1-yl)(phenyl)methyl 4-methylbenzenesulfonate (2ae)
General procedure (A), 3 equiv. p-toluenesulfonic acid was used as a nucleophile, 3 h, 44% yield; White solid, inseparable mixture of diastereomers (ratio uncertain); 1H NMR (400 MHz, CDCl3) δ 7.80 – 7.72 (m, 1H), 7.64 – 7.55 (m, 3H), 7.53 – 7.46 (m, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.23 – 7.15 (m, 5H), 7.14 – 7.08 (m, 2H), 5.79 – 5.68 (m, 2H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.2, 169.1, 144.9, 144.7, 144.5, 134.0, 133.8, 133.4, 133.3, 132.7, 132.6, 129.9, 129.8, 129.6, 129.6, 129.4, 129.1, 128.3, 128.3, 127.8, 127.7, 127.3, 126.7, 126.4, 125.8, 125.6, 123.5, 123.4, 82.2, 81.9, 81.0, 80.4, 21.6, 21.6;
HRMS (DART) calcd for C22H19O5S+ 395.0948, observed 395.0946;
3-(chloro(phenyl)methyl)isobenzofuran-1(3H)-one (2af)
inseparable mixture of diastereomers (4:1); 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 7.9 Hz, 0.25H), 7.65 – 7.52 (m, 2.5H), 7.44 – 7.31 (m, 7.5H), 5.87 – 5.81 (m, 1.25H), 5.23 (d, J
= 5.8 Hz, 1H), 5.19 (d, J = 6.0 Hz, 0.25H); 13C NMR (100 MHz, CDCl3) δ 169.3, 145.7, 145.6, 135.5, 135.5, 133.8, 133.8, 129.9, 129.9, 129.7, 129.3, 129.1, 128.6, 128.5, 128.3, 128.0, 126.8, 125.7, 125.7, 123.7, 123.3, 82.6, 82.3, 62.7, 62.5; HRMS (DART) calcd for C15H12ClO2+ 259.0521, observed 259.0522;
3-(azido(phenyl)methyl)isobenzofuran-1(3H)-one (2ag)
General procedure (A), 3 equiv. Bu4NN3 was used as a nucleophile, DCM was used instead of DCE, graphite cathode was used instead of Ni-foam cathode, 4 h, 47% yield; White solid, inseparable mixture of diastereomers (1:0.8); 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.4 Hz, 1H), 7.84 (d, J = 7.4 Hz, 0.8H), 7.62 – 7.47 (m, 3.6H), 7.46 – 7.33 (m, 7.2H), 7.32 – 7.27 (m, 1.8H), 7.12 (d, J = 7.5 Hz, 1H), 6.93 (d, J = 7.5 Hz, 0.8H), 5.67 – 5.61 (m, 1.8H), 5.04 (d, J = 5.0 Hz, 1H), 4.83 (d, J = 6.1 Hz, 0.8H);
13C NMR (100 MHz, CDCl3) δ 169.5, 169.4, 145.7, 145.6, 134.1, 133.8, 133.8, 133.7, 129.8, 129.4, 129.1, 129.0, 128.9, 128.2, 127.5, 126.7, 126.6, 125.7, 125.7, 123.5, 123.2, 81.8, 81.7, 67.9, 67.2;
HRMS (DART) calcd for C15H12N3O2+ 266.0925, observed 266.0929;
3-phenylisochroman-1-one (3a)
General procedure (C), 1.5 h, 57% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.7 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.52 – 7.32 (m, 6H), 7.29 (d, J = 7.5 Hz, 1H), 5.56 (dd, J = 12.0, 3.1 Hz, 1H), 3.34 (dd, J = 16.4, 12.0 Hz, 1H), 3.14 (dd, J = 16.4, 3.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 165.3, 138.9, 138.5, 133.9, 130.4, 128.6, 128.6, 127.8, 127.3, 126.1, 125.1, 79.9, 35.6; HRMS (DART) calcd for C15H13O2+ 225.0911, observed 225.0910;
3-(4-chlorophenyl)isochroman-1-one (3b)
General procedure (C), 1.5 h, 41% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 7.3 Hz, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.48 – 7.34 (m, 5H), 7.32 – 7.27 (m, 1H), 5.54 (d, J = 12.1 Hz, 1H), 3.30 (dd, J = 16.5, 12.1 Hz, 1H), 3.12 (d, J = 16.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 165.0, 138.6, 137.1, 134.5, 134.0, 130.5, 128.9, 128.0, 127.5, 127.3, 125.0, 79.1, 35.5; HRMS (DART) calcd for C15H12ClO2+ 259.0521, observed 259.0515;
3-(p-tolyl)isochroman-1-one (3c)
General procedure (C), 1 h, 68% yield; White semi-solid; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 7.4 Hz, 1H), 7.56 (t, J = 7.0 Hz, 1H), 7.42 (t, J = 7.4 Hz, 1H), 7.36 (d, J = 7.7 Hz, 2H), 7.28 (d, J = 7.4 Hz, 1H), 7.21 (d, J = 7.5 Hz, 2H), 5.51 (d, J = 11.9 Hz, 1H), 3.33 (dd, J = 16.1, 12.3 Hz, 1H), 3.10 (d, J
= 16.5 Hz, 1H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.4, 139.0, 138.4, 135.6, 133.8, 130.3, 129.3, 127.8, 127.3, 126.1, 125.1, 79.9, 35.5, 21.2; HRMS (DART) calcd for C16H15O2+ 239.1067, observed 239.1067;
3-(4-(tert-butyl)phenyl)isochroman-1-one (3d)
General procedure (C), 1.5 h, 63% yield; White solid; m.p. 92 – 97 ℃; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.46 – 7.38 (m, 5H), 7.28 (d, J = 7.6 Hz, 1H), 5.53 (d, J = 11.9 Hz, 1H), 3.36 (dd, J = 16.5, 12.0 Hz, 1H), 3.12 (d, J = 16.5 Hz, 1H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 165.3, 151.7, 139.0, 135.5, 133.8, 130.4, 127.8, 127.3, 125.9, 125.6, 125.2, 79.8, 35.4, 34.6, 31.3; HRMS (DART) calcd for C19H21O2+ 281.1537, observed 281.1536;
3-(4-methoxyphenyl)isochroman-1-one (3e)
General procedure (C), 1 h, 69% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 7.6 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.47 – 7.36 (m, 3H), 7.28 (d, J = 7.8 Hz, 1H), 6.93 (d, J = 8.5 Hz, 2H), 5.50 (d, J = 12.1 Hz, 1H), 3.82 (s, 3H), 3.34 (dd, J = 16.1, 12.5 Hz, 1H), 3.09 (d, J = 16.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 165.4, 159.8, 139.0, 133.8, 130.6, 130.3, 127.8, 127.6, 127.3, 125.1, 114.0, 79.8, 55.3, 35.4; HRMS (DART) calcd for C16H15O3+ 255.1016, observed 255.1016;
3,3-diphenylisochroman-1-one (3i)
General procedure (C), 1 h, 73% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.7 Hz, 1H), 7.52 – 7.38 (m, 5H), 7.34 – 7.15 (m, 8H), 3.80 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 165.0, 143.0, 138.1, 134.0, 130.1, 128.4, 127.6, 127.5, 127.4, 126.1, 125.6, 86.5, 39.0; HRMS (DART) calcd for C21H17O2+ 301.1224, observed 301.1219;
spiro[cyclohexane-1,3'-isochroman]-1'-one (3j)
General procedure (C), 1 h, 85% yield; Clear oil; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H), 7.21 (d, J = 7.4 Hz, 1H), 3.01 (s, 2H), 1.95 – 1.32 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 165.0, 137.7, 133.7, 129.9, 128.0, 127.3, 125.1, 81.8, 38.1, 36.0, 25.3, 21.6; HRMS (DART) calcd for C14H17O2+ 217.1224, observed 217.1225;
3-methyl-3-phenylisobenzofuran-1(3H)-one (3k)
General procedure (C), 1 h, 73% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.6 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.49 – 7.42 (m, 3H), 7.40 – 7.28 (m, 3H), 2.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.9, 154.2, 140.7, 134.3, 129.1, 128.7, 128.3, 125.8, 125.0, 122.0, 87.5, 27.3; HRMS (DART) calcd for C15H13O2+ 225.0911, observed 225.0915
3-(3-fluorophenyl)isochroman-1-one (3l)
General procedure (C), 1.5 h, 37% yield; White semi-solid; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.8 Hz, 1H), 7.62 – 7.53 (m, 1H), 7.49 – 7.27 (m, 4H), 7.24 – 7.17 (m, 1H), 7.09 – 7.01 (m, 1H), 5.56 (dd, J = 11.9, 3.1 Hz, 1H), 3.31 (dd, J = 16.3, 11.8 Hz, 1H), 3.15 (dd, J = 16.4, 3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 164.9, 162.9 (d, J = 246.7 Hz), 138.5, 134.0, 130.5, 130.3 (d, J = 8.2 Hz), 128.0, 127.3, 126.1, 125.0, 121.6 (d, J = 3.1 Hz), 115.5 (d, J = 22.1 Hz), 113.21 (d, J = 22.8 Hz), 79.0, 35.5;
3-benzyl-3-phenylisobenzofuran-1(3H)-one (3m)
General procedure (C), 1.5 h, 51% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 7.70 - 7.55 (m, 5H), 7.44 – 7.29 (m, 4H), 7.12 – 7.04 (m, 3H), 6.99 – 6.89 (m, 2H), 3.70 (d, J = 13.9 Hz, 1H), 3.59 (d, J = 13.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.4, 151.5, 140.2, 133.8, 133.7, 130.7, 129.0, 128.7, 128.3, 127.8, 126.9, 126.1, 125.6, 125.3, 122.8, 89.5, 46.4; HRMS (DART) calcd for C21H17O2+
301.1224, observed 301.1222;
3,4-diphenyl-1H-isochromen-1-one (3m')
General procedure (C), 1.5 h, 47% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 7.9 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.44 – 7.39 (m, 3H), 7.36 – 7.31 (m, 2H), 7.27 – 7.16 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 162.2, 150.9, 138.8, 134.6, 134.3, 132.9, 131.2, 129.5, 129.2, 129.0, 128.9, 128.1, 128.0, 127.8, 125.3, 120.4, 116.8; HRMS (DART) calcd for C21H15O2+ 299.1067, observed 299.1067;
3-benzyl-2-methylisoindolin-1-one (5a)
General procedure (D), 1.5 h, 92% yield; Pale yellow semi-solid; 1H NMR (400 MHz, CDCl3) δ 7.79 – 7.72 (m, 1H), 7.42 – 7.36 (m, 2H), 7.29 – 7.21 (m, 3H), 7.11 – 7.03 (m, 2H), 7.00 – 6.93 (m, 1H), 4.66 (dd, J = 7.6, 5.1 Hz, 1H), 3.37 (dd, J = 13.8, 5.0 Hz, 1H), 3.15 (s, 3H), 2.90 (dd, J = 13.8, 7.7 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 168.3, 144.6, 135.9, 132.3, 130.8, 129.4, 128.4, 128.1, 126.9, 123.4, 122.7, 62.6, 38.5, 28.0; HRMS (DART) calcd for C16H16NO+ 238.1227, observed 238.1223;
2-methyl-3-(4-methylbenzyl)isoindolin-1-one (5b)
General procedure (D), 0.6 mA instead of 2.0 mA, 8 h, 38% yield; Pale yellow semi-solid; 1H NMR (400 MHz, CDCl3) δ 7.79 – 7.72 (m, 1H), 7.44 – 7.35 (m, 2H), 7.05 (d, J = 7.4 Hz, 2H), 7.02 – 6.98 (m, 1H), 6.95 (d, J = 7.6 Hz, 2H), 4.64 (dd, J = 7.1, 4.3 Hz, 1H), 3.33 (dd, J = 13.8, 4.4 Hz, 1H), 3.14 (s, 3H), 2.87 (dd, J = 13.7, 7.6 Hz, 1H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.4, 144.8, 136.5, 132.8, 132.3, 130.8, 129.3, 129.1, 128.0, 123.4, 122.7, 62.8, 38.1, 28.0, 21.0; HRMS (DART) calcd for C17H18NO+ 252.1383, observed 252.1383;
3-(4-acetylbenzyl)-2-methylisoindolin-1-one (5c)
General procedure (D), 1 h, 72% yield; White semi-solid; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 7.5 Hz, 1H), 7.47 – 7.36 (m, 2H), 7.13 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 6.8 Hz, 1H), 4.72 (dd, J = 7.3, 4.6 Hz, 1H), 3.41 (dd, J = 13.9, 4.4 Hz, 1H), 3.16 (s, 3H), 3.05 (dd, J = 13.8, 7.1 Hz, 1H), 2.56 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.5, 168.3, 144.1, 141.3, 135.9, 132.3, 131.0, 129.6, 128.4, 128.3, 123.5, 122.5, 62.2, 38.2, 28.0, 26.5; HRMS (DART) calcd for C18H18NO2+
280.1333, observed 280.1338
3-(3-fluorobenzyl)-2-methylisoindolin-1-one (5d)
General procedure (D), 1 h, 66% yield; Pale yellow semi-solid; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 6.3 Hz, 1H), 7.47 - 7.37 (m, 2H), 7.21 (q, J = 6.8 Hz, 1H), 7.03 (d, J = 6.3 Hz, 1H), 6.92 (t, J = 8.7 Hz, 1H), 6.84 (d, J = 7.7 Hz, 1H), 6.76 (d, J = 9.9 Hz, 1H), 4.66 (t, J = 6.1 Hz, 1H), 3.35 (dd, J = 13.7, 3.5 Hz, 1H), 3.14 (s, 3H), 2.94 (dd, J = 13.6, 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.4, 162.7 (d, J = 246.5 Hz), 144.3, 138.3 (d, J = 7.3 Hz), 132.3, 131.0, 129.9 (d, J = 8.3 Hz), 128.3, 125.1 (d, J = 2.8 Hz), 123.5, 122.5, 116.3 (d, J = 21.3 Hz), 114.0 (d, J = 20.8 Hz); HRMS (DART) calcd for C16H15FNO+ 256.1133, observed 256.1130
3-(4-chlorobenzyl)-2-methylisoindolin-1-one (5e)
General procedure (D), 2.5 h, 42% yield; Pale yellow semi-solid; 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 6.8 Hz, 1H), 7.46 – 7.37 (m, 2H), 7.20 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 7.9 Hz, 1H), 6.96 (d, J = 8.0 Hz, 2H), 4.64 (dd, J = 7.4, 4.6 Hz, 1H), 3.33 (dd, J = 14.1, 4.0 Hz, 1H), 3.14 (s, 3H), 2.94 (dd, J = 13.8, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.4, 144.3, 134.1, 132.9, 132.3, 131.0, 130.7, 128.6, 128.3, 123.6, 122.5, 62.4, 37.6, 28.0; HRMS (DART) calcd for C16H15ClNO+ 272.0837, observed 272.0836
3-(2-bromobenzyl)-2-methylisoindolin-1-one (5f)
General procedure (D), 2.5 h, 40% yield; Clear oil; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.4 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.47 – 7.34 (m, 2H), 7.32 – 7.26 (m, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 7.3 Hz, 1H), 4.83 (dd, J = 8.9, 5.5 Hz, 1H), 3.56 (dd, J = 13.9, 5.0 Hz, 1H), 3.16 (s, 3H), 2.81 (dd, J = 13.4, 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.3, 144.8, 136.1,
133.2, 132.5, 132.2, 130.8, 129.0, 128.2, 127.5, 124.8, 123.5, 123.0, 60.7, 39.9, 28.2; HRMS (DART) calcd for C16H15BrNO+ 316.0332, observed 316.0327
2-methyl-3-(4-(trifluoromethyl)benzyl)isoindolin-1-one (5g)
General procedure (D), 0.5 h, 77% yield; White solid; m.p. 100 – 105 ℃; 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.0 Hz, 1H), 7.52 – 7.37 (m, 4H), 7.15 (d, J = 7.9 Hz, 2H), 7.05 (d, J = 7.1 Hz, 1H), 4.70 (t, J = 5.7 Hz, 1H), 3.41 (dd, J = 13.9, 4.4 Hz, 1H), 3.16 (s, 3H), 3.05 (dd, J = 14.1, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.3, 144.1, 139.8, 132.3, 131.1, 129.7, 129.3 (d, J = 32.5 Hz), 128.4, 125.3 (q, J = 3.7 Hz), 124.0 (q, J = 272.2 Hz), 123.6, 122.4, 62.2, 38.0, 28.0; HRMS (DART) calcd for C17H15F3NO+ 306.1101, observed 306.1099
4-((2-methyl-3-oxoisoindolin-1-yl)methyl)benzonitrile (5h)
General procedure (D), 0.5 h, 90% yield; White semi-solid; 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.0 Hz, 1H), 7.54 – 7.37 (m, 4H), 7.17 – 7.02 (m, 3H), 4.75 – 4.67 (m, 1H), 3.41 (d, J = 13.7 Hz, 1H), 3.17 (s, 3H), 3.11 (dd, J = 13.8, 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.3, 143.7, 141.1, 132.3, 132.0, 131.1, 130.2, 128.5, 123.7, 122.3, 118.5, 111.0, 61.9, 38.0, 28.0; HRMS (DART) calcd for C17H15N2O+ 263.1179, observed 263.1180
2-methyl-3-(4-nitrobenzyl)isoindolin-1-one (5i)
General procedure (D), 0.5 h, 92% yield; White solid; m.p. 105 – 110 ℃; 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 7.4 Hz, 1H), 7.50 – 7.37 (m, 2H), 7.16 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 7.4 Hz, 1H), 4.75 (dd, J = 6.7, 4.5 Hz, 1H), 3.46 (dd, J = 14.0, 4.4 Hz, 1H), 3.22 – 3.14 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 168.3, 147.0, 143.6, 143.1, 132.3, 131.2, 130.3, 128.6, 123.8, 123.5, 122.3, 61.9, 37.8, 28.1; HRMS (DART) calcd for C16H15N2O3+ 283.1078, observed 283.1074
3-benzhydryl-2-methylisoindolin-1-one (5j)
General procedure (D), 1 h, 92% yield; White solid; 1H NMR (400 MHz, CDCl3) δ 7.77 (dt, J = 7.5, 1.0 Hz, 1H), 7.41 – 7.19 (m, 10H), 6.95 – 6.90 (m, 2H), 6.45 (dq, J = 7.7, 0.9 Hz, 1H), 5.19 (d, J = 6.8 Hz, 1H), 4.58 (d, J = 6.8 Hz, 1H), 2.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.7, 143.7, 139.9, 138.2, 132.9, 130.6, 129.0, 128.7, 128.7, 128.5, 128.2, 127.4, 127.2, 123.4, 123.4, 65.8, 54.0, 28.9; HRMS (DART) calcd for C22H20NO+ 314.1540, observed 314.1539;
3-(2-methoxybenzyl)-2-methylisoindolin-1-one (5k)
General procedure (D), 0.5 h, 49% yield; Pale yellow semi-solid; 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.77 (m, 1H), 7.41 – 7.33 (m, 2H), 7.31 – 7.26 (m, 1H), 7.01 (dd, J = 7.3, 1.7 Hz, 1H), 6.93 – 6.86 (m,
3H), 4.74 (dd, J = 8.2, 5.3 Hz, 1H), 3.86 (s, 3H), 3.42 (dd, J = 13.3, 5.3 Hz, 1H), 3.13 (s, 3H), 2.72 (dd, J = 13.3, 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.4, 157.6, 145.6, 132.2, 131.6, 130.6, 128.5, 127.8, 125.1, 123.2, 122.9, 120.4, 110.3, 61.1, 55.2, 34.5, 28.0; HRMS (DART) calcd for C17H18NO2+
268.1333, observed 268.1333
3-(3-methoxybenzyl)-2-methylisoindolin-1-one (5l)
General procedure (D), 0.5 h, 83% yield; Pale yellow semi-solid; 1H NMR (400 MHz, CDCl3) δ 7.81 – 7.74 (m, 1H), 7.44 – 7.37 (m, 2H), 7.18 (t, J = 7.9 Hz, 1H), 7.04 – 7.00 (m, 1H), 6.77 (dd, J = 8.2, 2.5 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 6.59 (t, J = 2.1 Hz, 1H), 4.67 (dd, J = 7.7, 5.0 Hz, 1H), 3.73 (s, 3H), 3.34 (dd, J = 13.8, 5.0 Hz, 1H), 3.14 (s, 3H), 2.88 (dd, J = 13.8, 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.4, 159.6, 144.7, 137.5, 132.3, 130.8, 129.5, 128.1, 123.4, 122.7, 121.8, 115.1, 112.4, 62.6, 55.1, 38.6, 28.0; HRMS (DART) calcd for C17H18NO2+ 268.1333, observed 268.1336
3-(methoxy(4-methoxyphenyl)methyl)-N-methylisobenzofuran-1(3H)-imine (6a)
General procedure (B), 3.0 mA instead of 2.0 mA, 2.5 h, 58% yield; Pale yellow semi-solid, inseparable mixture of diastereomers (1:0.6); 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.2 Hz, 0.6H), 7.64 (d, J = 7.1 Hz, 1H), 7.46 – 7.27 (m, 9.8H), 7.20 – 7.15 (m, 2H), 6.68 (d, J = 7.8 Hz, 1H), 5.66 (d, J = 6.3 Hz, 1H), 5.56 (d, J = 5.3 Hz, 0.6H), 4.42 – 4.36 (m, 1.6H), 3.35 (s, 3H), 3.33 (s, 1.8H), 3.21 (s, 3H), 3.13 (s, 1.8H); 13C NMR (100 MHz, CDCl3) δ 160.0, 159.8, 143.6, 142.5, 136.6, 136.0, 131.4, 131.2, 130.7, 130.4, 128.8, 128.7, 128.6, 128.2, 128.2, 128.1, 128.1, 127.5, 123.2, 122.9, 122.8, 122.5, 85.3, 85.1, 84.7, 84.5, 57.5, 57.2, 34.3, 34.3; HRMS (DART) calcd for C17H18NO2+ 268.1333, observed 268.1332;
General procedure (B), 3.0 mA instead of 2.0 mA, 2 h, 86% yield; White solid, inseparable mixture of diastereomers (5:1); m.p. 90 – 95 ℃; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.8 Hz, 0.2H), 7.64 (d, J = 7.4 Hz, 1H), 7.47 – 7.27 (m, 2.6H), 7.19 (d, J = 7.8 Hz, 0.4H), 7.09 (d, J = 7.6 Hz, 2H), 6.88 – 6.79 (m, 2.4H), 6.68 (d, J = 7.2 Hz, 1H), 5.63 (d, J = 6.4 Hz, 1H), 5.55 (d, J = 4.5 Hz, 0.2H), 4.36 – 4.30 (m, 1.2H), 3.8 (s, 3.6H), 3.32 (s, 3H), 3.30 (s, 0.6H), 3.22 (s, 3H), 3.14 (s, 0.6H) ; 13C NMR (100 MHz, CDCl3) δ 160.0, 159.9, 159.8, 159.5, 143.7, 142.6, 131.4, 131.2, 130.7, 130.3, 129.3, 128.8, 128.7, 128.5, 128.0, 123.2, 122.8, 122.7, 122.5, 113.6, 84.9, 84.8, 84.7, 84.7, 57.2, 57.0, 55.2, 34.3, 34.3;
HRMS (DART) calcd for C18H20NO3+ 298.1438, observed 298.1444
3-((4-(tert-butyl)phenyl)(methoxy)methyl)isobenzofuran-1(3H)-imine (6c)
General procedure (B), 3.0 mA instead of 2.0 mA, 2 h, 73% yield; Pale yellow semi-solid, inseparable mixture of diastereomers (1:0.6); 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.6 Hz, 0.6H), 7.66 (d, J = 7.7 Hz, 1H), 7.46- 7.31 (m, 6.2H), 7.28 – 7.21 (m, 2H), 7.14 (d, J = 7.4 Hz, 2H), 6.56 (d, J = 7.6 Hz, 1H), 5.63 (d, J = 6.5 Hz, 1H), 5.52 (d, J = 5.6 Hz, 0.6H), 4.38 – 4.28 (m, 1.6H), 3.32 (s, 4.8H), 3.24 (s, 3H), 3.15 (s, 1.8H), 1.32 (s, 14.4H); 13C NMR (100 MHz, CDCl3) δ 160.1, 160.0, 151.7, 151.1, 143.8, 142.7, 133.8, 133.2, 131.4, 131.2, 130.7, 130.4, 128.8, 128.7, 127.8, 127.1, 125.1, 123.1, 123.1, 122.7, 122.5, 110.0, 85.2, 85.0, 84.9, 84.8, 57.6, 57.2, 34.4, 34.3, 31.3, 31.3; HRMS (DART) calcd for C21H26NO2+ 324.1959, observed 324.1963
1-(4-(methoxy(3-(methylimino)-1,3-dihydroisobenzofuran-1-yl)methyl)phenyl)ethan-1-one (6d)
General procedure (B), 3.0 mA instead of 2.0 mA, 2 h, 30% yield; Pale yellow semi-solid, inseparable mixture of diastereomers (1:0.8); 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.6 Hz, 1.6H), 7.83 (d, J = 7.0 Hz, 2H), 7.69 (d, J = 7.7 Hz, 1H ), 7.59 (d, J = 7.1 Hz, 0.8H), 7.49 – 7.32 (m, 6.6H), 7.25 – 7.21 (m, 1.6H), 7.05 (d, J = 7.0 Hz, 0.8H), 5.71 (d, J = 5.6 Hz, 1H), 5.57 (d, J = 5.5 Hz, 0.8H), 4.62 (d, J = 5.6 Hz, 1H), 4.42 (d, J = 5.4 Hz, 0.8H), 3.37 (s, 3H), 3.35 (s, 2.4H), 3.18 (s, 3H), 3.12 (s, 2.4H), 2.61 (s, 2.4H), 2.57 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.7, 197.7, 159.7, 159.6, 143.3, 142.2, 142.1, 141.3, 137.1, 131.3, 131.0, 130.7, 129.1, 129.0, 128.4, 128.2, 128.1, 128.0, 127.8, 123.1, 122.9, 122.8, 122.7, 110.0, 84.9, 84.3, 84.2, 83.6, 57.7, 57.7, 34.3, 26.6, 26.6; HRMS (DART) calcd for C19H20NO3+
310.1438, observed 310.1439
3-(methoxy(3-methoxyphenyl)methyl)-N-methylisobenzofuran-1(3H)-imine (6e)
General procedure (B), 3.0 mA instead of 2.0 mA, 2.5 h, 68% yield; Clear oil, inseparable mixture of diastereomers (2:1); 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.3 Hz, 0.5H), 7.67 (d, J = 6.5 Hz, 1H), 7.49 – 7.28 (m, 4H), 7.25 – 7.12 (m, 1.5H), 6.88 – 6.74 (m, 4H), 6.71 (s, 1H), 5.65 (d, J = 6.0 Hz, 1H), 5.55 (d, J = 5.2 Hz, 0.5H), 4.38 (d, J = 6.2 Hz, 1H), 4.35 (d, J = 5.5 Hz, 0.5H), 3.34 (s, 3H), 3.33 (s, 1.5H), 3.21 (s, 3H), 3.14 (s, 1.5H); 13C NMR (100 MHz, CDCl3) δ 159.6, 159.5, 143.6, 142.6, 138.3, 137.7, 131.3, 130.8, 130.5, 129.2, 129.1, 128.9, 128.8, 123.2, 122.9, 122.9, 122.7, 120.6, 119.9, 114.4, 114.0, 113.2, 112.7, 85.1, 85.0, 84.8, 84.6, 57.6, 57.3, 55.2, 55.2, 34.2; HRMS (DART) calcd for C18H20NO3+ 298.1443, observed 298.1433
3-((3-fluorophenyl)(methoxy)methyl)-N-methylisobenzofuran-1(3H)-imine (6f)
General procedure (B), 3.0 mA instead of 2.0 mA, 3 h, 44% yield; Clear oil, inseparable mixture of diastereomers (1:0.7); 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.5 Hz, 0.7H), 7.62 (d, J = 7.6 Hz, 1H), 7.49 – 7.16 (m, 5.1H), 7.07 – 6.90 (m, 4.8H), 6.87 (d, J = 9.8 Hz, 1H), 5.65 (d, J = 5.5 Hz, 1H), 5.53 (d, J = 5.2 Hz, 0.7H), 4.49 (d, J = 5.7 Hz, 1H), 4.34 (d, J = 5.4 Hz, 0.7H), 3.36 (s, 3H), 3.34 (s, 2.1H), 3.19 (s, 3H), 3.13 (s, 2.1H); 13C NMR (100 MHz, CDCl3) δ 162.9 (d, J = 246.1 Hz), 162.6 (d, J
= 246.5 Hz), 159.7, 159.6, 143.4, 142.3, 139.6, 139.5, 138.8, 138.7, 131.4, 131.1, 130.9, 130.6, 129.7 (d, J = 8.0 Hz), 129.5 (d, J = 8.1 Hz), 129.0, 128.9, 123.7 (d, J = 2.9 Hz), 123.3 (d, J = 2.8 Hz), 123.1, 122.9, 122.8, 122.7, 115.4 (d, J = 21.2 Hz), 115.2 (d, J = 21.2 Hz), 114.8 (d, J = 22.0 Hz), 114.4 (d, J = 21.9 Hz), 84.7, 84.4, 84.3, 83.8, 57.6, 57.5, 34.3, 34.3; HRMS (DART) calcd for C18H20NO3+ 286.1238, observed 286.1238
3-((4-chlorophenyl)(methoxy)methyl)-N-methylisobenzofuran-1(3H)-imine (6g)
General procedure (B), 3.0 mA instead of 2.0 mA, 2.5 h, 79% yield; Clear oil, inseparable mixture of diastereomers (1:0.6); 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.4 Hz, 0.6H), 7.61 (d, J = 7.9 Hz, 1H), 7.47 – 7.23 (m, 5.2H), 7.21 – 7.16 (m, 3H), 7.08 – 7.02 (m, 2H), 6.98 – 6.90 (m, 1H), 5.63 (d, J = 5.6 Hz, 1H), 5.50 (d, J = 5.4 Hz, 0.6H), 4.46 (d, J = 5.8 Hz, 1H), 4.30 (d, J = 5.5 Hz, 0.6H), 3.32 (s, 3H), 3.29 (s, 1.8H), 3.16 (s, 3H), 3.09 (s, 1.8H); 13C NMR (100 MHz, CDCl3) δ 159.9, 159.7, 143.5, 142.3, 135.2, 134.5, 134.3, 134.1, 131.3, 131.0, 130.9, 130.6, 129.2, 129.0, 128.9, 128.9, 128.4, 128.3, 123.1, 123.0, 122.8, 84.6, 84.5, 84.2, 83.9, 57.5, 57.4, 34.2; HRMS (DART) calcd for C17H17ClNO2+ 302.0942, observed 302.0945
3-((2-bromophenyl)(methoxy)methyl)-N-methylisobenzofuran-1(3H)-imine (6h)
General procedure (B), 3.0 mA instead of 2.0 mA, 2 h, 70% yield; Clear oil, inseparable mixture of diastereomers (1:0.6); 1H NMR (400 MHz, CDCl3) δ 7.80 – 7.69 (m, 1.6H), 7.61 – 7.47 (m, 3H), 7.43 – 7.37 (m, 4H), 7.31 (t, J = 7.4 Hz, 1H), 7.23 – 7.15 (m, 2.2H), 6.97 – 6.92 (m, 1H), 5.67 (d, J = 4.6 Hz, 1H), 5.59 (d, J = 5.7 Hz, 0.6H), 5.01 (d, J = 4.8 Hz, 1H), 4.91 (d, J = 5.6 Hz, 0.6H), 3.29 (s, 1.8H), 3.24 (s, 3H), 3.20 (s, 3H), 3.17 (s, 1.8H); 13C NMR (100 MHz, CDCl3) δ 160.1, 160.0, 143.3, 142.6, 136.6, 136.1, 132.8, 132.7, 131.6, 131.3, 130.8, 130.6, 129.8, 129.7, 129.3, 128.9, 128.8, 127.6, 127.5, 124.5, 124.3, 123.2, 122.9, 122.2, 84.1, 84.0, 83.0, 82.9, 57.7, 57.6, 34.3, 34.3; HRMS (DART) calcd for C17H17BrNO2+ 346.0437, observed 346.0436
Chapter 3.
Electrosynthesis of Heterocycles from Arylalkenes
3.1. Design of electrosynthesis for heterocycles
Scheme 3-1. Design of electrosynthesis of heterocycles with arylalkenes
Arylalkenes are easily prepared and commonly used substrates for the synthesis of heterocycles.
Unfortunately, conventional strategies mostly require chemical oxidants or transition metal catalysts to generate reactive intermediates. As described in Chapter 1, existing methods are powerful tools which are widely used by synthetic chemists but limitations exist such as low sustainability and cost-efficiency.
In this regard, electrosynthesis offers a great solution. We envisaged that single electron oxidation on the anodic surface might afford reactive radical cation intermediate and subsequent cyclization and deprotonation may furnish desired heteroarene product (Scheme 3-1).
3.2. Synthesis of benzofurans from 2-alkenylphenols
3.2.1. Reaction optimization of synthesis for benzofuran
We started our study by screening various electrolytes, solvents, additives and electrosynthesis conditions with 2-alkenylphenol 7a as a model substrate. After extensive investigations, the optimized reaction condition was obtained (Et4NOTs, 5 equiv. of sulfuric acid, 1.0 mA, and isobutyronitrile), which afforded 2-phenylbenzofuran 8a in 77% yield (Table 3-1). Choice of other electrodes, reaction solvent or electrolyte resulted in inferior yields and the reaction under air showed poor result (Entry 25).
The control experiment without electricity revealed that the electron transfer on the electrode surface is the key factor of the reaction (Entry 26).
Table 3-1. Optimization of electrosynthesis for benzofurana
Entry Additive Electrolyte Solvent l (mA) / t (h) Anode/Cathode Yieldb
1 - Et4NOTs i-PrCN 3 mA/2 h Graphite/Graphite trace
2 2 eq. 2,6-lutidine Et4NOTs i-PrCN 3 mA/2 h Graphite/Graphite n.d.
3 2 eq. TfOH Et4NOTs i-PrCN 3 mA/2 h Graphite/Graphite 62%
4 2 eq. TfOH Et4NOTs i-PrCN 3 mA/2 h Graphite/Fe 36%
5 2 eq. TfOH Et4NOTs i-PrCN 3 mA/2 h Graphite/Pt 44%
6 6 eq. TFA Et4NOTs i-PrCN 3 mA/2 h Graphite/Graphite 49%
7 6 eq. TFA Et4NOTs i-PrCN 0.6 mA/8 h Graphite/Graphite 66%
8 5 eq. TFA Et4NOTs i-PrCN 0.6 mA/8 h Graphite/Graphite 53%
9 5 eq. CSA Et4NOTs i-PrCN 0.6 mA/5.5 h Graphite/Graphite trace 10 5 eq. MsOH Et4NOTs i-PrCN 0.6 mA/5.5 h Graphite/Graphite trace 11 5 eq. H2SO4 Et4NOTs i-PrCN 0.6 mA/9 h Graphite/Graphite 61%
12 5 eq. H2SO4 Et4NOTs i-PrCN 1.0 mA/5 h Graphite/Graphite 77%
13 4 eq. H2SO4 Et4NOTs i-PrCN 1.0 mA/5 h Graphite/Graphite 52%
14 3 eq. TfOH Et4NOTs i-PrCN 1.0 mA/5 h Graphite/Graphite 62%
15 5 eq. H2SO4 Et4NOTs i-PrCN 1.0 mA/5 h Graphite/Fe 35%
16 5 eq. H2SO4 Et4NOTs MeCN 1.0 mA/5 h Graphite/Graphite 67%
17 5 eq. H2SO4 Et4NOTs DCM 1.0 mA/5 h Graphite/Graphite 20%
18 5 eq. H2SO4 Et4NOTs MeOH 1.0 mA/5 h Graphite/Graphite trace 19 5 eq. H2SO4 - i-PrCN 1.0 mA/5 h Graphite/Graphite 22%
20 5 eq. H2SO4 LiClO4 i-PrCN 1.0 mA/5 h Graphite/Graphite 17%
21 5 eq. H2SO4 Bu4NClO4 i-PrCN 1.0 mA/5 h Graphite/Graphite 16%
22 5 eq. H2SO4 Bu4NBF4 i-PrCN 1.0 mA/5 h Graphite/Graphite 30%
23 5 eq. H2SO4 Bu4NOAc i-PrCN 1.0 mA/5 h Graphite/Graphite trace 24 5 eq. H2SO4 Bu4NPF6 i-PrCN 1.0 mA/5 h Graphite/Graphite 12%
25c 5 eq. H2SO4 Et4NOTs i-PrCN 1.0 mA/5 h Graphite/Graphite 16%
26d 5 eq. H2SO4 Et4NOTs i-PrCN -- /5 h Graphite/Graphite n.d.
[a] Reaction conditions: Undivided cell, 7a (0.1 mmol), electrolyte (0.1 M), solvent (3 mL), room temperature, under N2.
[b] Isolated yields. [c] Under air. [d] no electric current.
3.2.2. Substrate scope of benzofurans
With the optimized conditions in hand, we investigated the scope with various 2-alkenylphenols 7 (Table 3-2). First, we examined the electronic effects on the R2 group and found out that electron-rich substrates are favored (8b ~ 8g). Likewise, a similar trend was observed with the R1 group (8i ~ 8k).
Substrates bearing nitro groups showed low yields (8n, 8o) and heterocycles such as thiophene could be installed with moderate yield (8p). Furthermore, halide groups such as F, Cl remained intact (8f, 8g).
Table 3-2. Substrate scope of benzofuransa
[a] Reaction conditions: alkene (0.10 mmol), sulfuric acid (5 equiv.) in i-PrCN (3.0 mL) under N2, room temperature, with Et4NOTs (0.1 M) as electrolyte, constant current = 1 mA. Isolated yields are given. [b] 4 equiv. H2SO4 was used. [c] 6 equiv.
H2SO4 was used. [d] 8 equiv. H2SO4 was used.
3.2.3. Mechanistic investigations and proposed mechanistic pathway
To gain understandings of the reaction mechanism, cyclic voltammetry analysis and control experiments were carried out (Figure 3-1). (E)-2-styrylphenol 7a was prone to oxidation showing oxidation potential of 1.18 V (vs SCE). In the presence of radical scavenger TEMPO or BHT, all reactions were inhibited (Figure 3-1b), indicating that the reaction is radical pathway.
It was interesting that the reaction of 7a was poorly compatible with electrolytes other than Et4NOTs (Table 3-1). Considering the previous report of indole synthesis with 2-alkenylanilines in the presence of modified Koser reagent through 2- or 3-arylsulfonated indoline intermediates,38 we envisaged that tosylate may aid the formation of benzofuran. In this regard, we carried out a series of control experiments (Scheme 3-2). While only 12% of 8a was produced from the reaction that used Bu4NPF6
as an electrolyte, adding a catalytic amount of Et4NOTs to the reaction of Bu4NPF6 electrolyte dramatically improved the yield to 62% (Scheme 3-2a). Although only a catalytic amount of tosylate is required for the reaction, the reaction was optimized with Et4NOTs as an electrolyte due to cost efficiencies, since Et4NOTs is much cheaper than Bu4NPF6. Next, a control experiment with (E)-stilbene 7aa as a substrate was carried out (Scheme 3-2b). As a result, 7ab was isolated in unoptimized yield of 23%, suggesting oxidized alkene radical cation can be trapped by tosylate. Next, the Koser reagent 7ac which was previously reported to transform alkenes to corresponding vic-bis(tosyloxy)alkanes39 and 2- alkenylaniline substrates to corresponding indoles38 was added to 7a under i-PrCN solvent (Scheme 3- 2c). As a result, 2-phenylbenzofuran 8a was obtained in unoptimized yield of 31%.
Scheme 3-2. Control experiments of electrosynthesis for benzofuran
Based on the results of control experiments, plausible reaction mechanisms are illustrated in Scheme 3-3. Cyclic voltammetry analysis suggested that 7a can lose an electron on the anodic surface to afford Int-7a. While Path A, which operates without tosylate, cannot be ruled out, we reason that Path B is more likely to be a major pathway. After the initial formation of Int-7a (Ep/2ox = 1.10 V vs SCE), the radical cation is trapped by tosylate. Oxidation of Int-7d affords Int-7e and sequentially Int-7f via cyclization, which undergoes elimination to afford benzofuran 8a.
Scheme 3-3. Proposed mechanistic pathway for the synthesis of benzofuran
3.3. Synthesis of indoles from 2-alkenylanilines
3.3.1. Reaction optimization of synthesis for indole
For the model substrate of 2-alkenylaniline, 9a was chosen. Screening was carried out with various solvents, electrolytes and electrosynthesis conditions with 9a (Table 3-3). As a result, the use of Bu4NPF6 as an electrolyte in acetonitrile solvent with 0.6 mA constant current mode afforded 2a in 77%
yield (Entry 5). Adding trifluoroacetic acid to the reaction slightly increased the yield (Entry 13). The control experiment without electric current demonstrated that electricity was essential for the reaction (Entry 17).
Table 3-3. Optimization of electrosynthesis for indolea
Entry Additive Electrolyte Solvent Current/Time Anode/Cathode Yieldb
1 - - MeCN 0.6 mA/8.5 h Graphite/Graphite trace
2 - Et4NOTs MeCN 0.6 mA/8.5 h Graphite/Graphite n.d.
3 - Bu4NBF4 MeCN 0.6 mA/8.5 h Graphite/Graphite 20%
4 - Bu4NClO4 MeCN 0.6 mA/8.5 h Graphite/Graphite 63%
5 - Bu4NPF6 MeCN 0.6 mA/8.5 h Graphite/Graphite 77%
6 - Bu4NPF6 i-PrCN 0.6 mA/8.5 h Graphite/Graphite 75%
7 - Bu4NPF6 DCM 0.6 mA/8.5 h Graphite/Graphite trace
8 - Bu4NPF6 MeOH 0.6 mA/8.5 h Graphite/Graphite trace
9 - Bu4NPF6 MeCN 1.0 mA/6.5 h Graphite/Graphite 36%
10 - Bu4NPF6 MeCN 0.6 mA/8.5 h Graphite/Fe 68%
11 - Bu4NPF6 MeCN 0.6 mA/8.5 h Graphite/Pt n.d.
12 4 eq. TFA Bu4NPF6 MeCN 0.6 mA/8.5 h Graphite/Graphite 87%
13 3 eq. TFA Bu4NPF6 MeCN 0.6 mA/8.5 h Graphite/Graphite 85%
14 2 eq. TFA Bu4NPF6 MeCN 0.6 mA/8.5 h Graphite/Graphite 80%
15 4 eq. TFA Bu4NPF6 i-PrCN 0.6 mA/8.5 h Graphite/Graphite 89%
16 4 eq. TFA Et4NOTs i-PrCN 0.6 mA/8.5 h Graphite/Graphite 74%
17c - Bu4NPF6 MeCN --/8.5 h Graphite/Graphite n.d.
[a] Reaction conditions: Undivided cell, 9a (0.1 mmol), electrolyte (0.1 M), solvent (3 mL), room temperature, under N2.
[b] Isolated yields. [c] No electric current.
3.3.2. Substrate scope of indoles
With optimized conditions in hand, the scope was investigated with 2-alkenylaniline derivatives 1 with different substituents (Table 3-4). First, we examined other N-protecting groups N-Ms (10b) and N-Boc (10c). It turned out that N-Ts (10a) was the optimal N-protecting group for this chemistry. Both electron-
donating group (10e) and withdrawing group (10f) were tolerated with satisfying yields. Furthermore, indole with C2-alkyl group was also examined. To our delight, satisfying yield of 65% was found from cyclohexyl bearing substrate (10g). It is worth mentioning that 2-alkenylaniline substrates bearing electron rich groups on the other side of the aniline moiety afforded the mixture of 2- and 3- substituted indoles (10h, 10h’, 10i, 10i’), which is the similar result with the previously reported method of Youn group.26 This result indicates the existence of carbocation intermediate and migratorial process in the course of reaction.40-42 Encouraged by these results, we further investigated the scope with tri- substituted alkenes. β,β-disubstituted 2-alkenylanilines afforded 2,3-disubstituted indoles (10j~10m) via 1,2-aryl migration, which was an expected result according to the previous reports.40-42
Table 3-4. Substrate scope of indolesa
[a] Reaction conditions: alkene (0.10 mmol) in MeCN (3.0 mL) under N, room temperature, with BuNPF (0.1 M) as
3.3.3. Mechanistic investigations and proposed mechanistic pathway
To shed light on the reaction mechanism, electrochemical measurements with cyclic voltammogram and control experiments were carried out (Figure 3-2). As a result, a strong oxidation peak was found, indicating 9a was prone to oxidation (1.49 V vs SCE). In the presence of radical scavenger TEMPO or BHT, all reactions were inhibited, which indicate the reactions involve radical intermediates.
Figure 3-2. Mechanistic investigations for the synthesis of indole
According to the results of mechanistic investigations, a plausible mechanism is described in Scheme 3-4. Single electron oxidation on the anodic surface affords radical cation Int-9a which subsequently goes through cyclization and deprotonation to Int-9b. Another anodic oxidation and deprotonation will afford indole product 10a.
Scheme 3-4. Proposed mechanistic pathway for the synthesis of indole