The Journal of Organic Chemistry
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7.6 Hz), 7.19−7.15 (m, 1H), 6.61−6.53 (m, 2H), 4.56 (s, 1H), 3.43 (t,
2H, J = 6.4 Hz), 2.88 (s, 3H), 2.56 (t, 2H, J = 6.8 Hz), 1.87−1.80 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 149.7, 131.8, 129.3, 115.9,
108.7, 107.6, 93.6, 78.1, 50.2, 30.1, 27.9, 16.9; IR (neat): 3416, 2931,
2098(s), 1601, 1575, 1510, 1461, 1449, 1426, 1320, 1287, 1256, 1168,
747; MS (ESI, m/z) 237 (M + Na+); HRESIMS Calcd for
[C12H14N4Na]+ (M + Na+) 237.1111, found 237.1112.
N-((4-Chlorophenyl)ethynyl)-4-methyl-N-phenylbenzenesulfon-
1
amide (2b). Pale yellow oil (248.1 mg, 65%): H NMR (400 MHz,
CDCl3) δ 7.61 (d, 2H, J = 7.6 Hz), 7.45−7.21 (m, 11H), 2.43 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 145.1, 138.7, 133.9, 132.9, 132.6,
129.5, 129.1, 128.6, 128.3, 128.2, 126.2, 121.1, 83.9, 69.5, 21.6; IR
(neat): 2923, 2236, 1593, 1487, 1374, 1186, 1174, 1089, 1013, 689,
657; MS (ESI, m/z) 404 (M + Na+); HRESIMS Calcd for
[C21H16ClNNaO2S]+ (M + Na+) 404.0482, found 404.0484.
General Procedure of the Synthesis of Highly Function-
alized Indole Derivatives from o-Alkynyl Anilines and
Ynamides. Ynamide 2 (0.36 mmol), 2-bromopyridine N-oxide
(104.4 mg, 0.60 mmol), and IPrAuNTf2 (13.5 mg, 0.015 mmol)
were added in this order to a suspension of o-alkynyl aniline 1 (0.30
mmol) in H2O (3.0 mL) at room temperature. The reaction mixture
was stirred at 80 °C, and the progress of the reaction was monitored
by TLC. The reaction typically took 3 h. Upon completion, the
reaction was diluted with DCM (30 mL) and washed with H2O (2 ×
15 mL). The resulting solution was extracted again with DCM (30
mL), and the combined organic layers were dried with MgSO4. The
mixture was then concentrated, and the residue was purified by
chromatography on silica gel (eluent: hexanes/ethyl acetate) to afford
the desired product 3.
2-(5-(2-(Methylamino)phenyl)pent-4-ynyl)isoindoline-1,3-dione
1
(1d). White solid (mp 75−77 °C, 229.3 mg, 72%): H NMR (500
MHz, CDCl3) δ 7.81 (dd, 2H, J = 2.4 Hz, J = 4.4 Hz), 7.67 (dd, 2H, J
= 2.4 Hz, J = 4.0 Hz), 7.23−7.13 (m, 2H), 6.56−6.52 (m, 2H), 4.91 (s,
1H), 3.90 (t, 2H, J = 5.6 Hz), 2.93 (s, 3H), 2.53 (t, 2H, J = 5.6 Hz),
2.04−1.99 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 168.5, 150.1,
133.9, 132.1, 131.8, 129.2, 123.2, 115.7, 108.7, 107.8, 93.9, 78.2, 37.0,
30.2, 27.5, 17.3; IR (neat): 3402, 2920, 2244, 1771, 1709(s), 1600,
1508, 1395, 1371, 1171, 748, 719; MS (ESI, m/z) 341 (M + Na+);
HRESIMS Calcd for [C20H18N2NaO2]+ (M + Na+) 341.1260, found
341.1263.
5-(2-(Methylamino)phenyl)pent-4-ynyl Pivalate (1e). White solid
(mp 80−82 °C, 167.8 mg, 58%): 1H NMR (400 MHz, CDCl3) δ 7.23
(dd, 1H, J = 1.6 Hz, J = 8.0 Hz), 7.19−7.15 (m, 1H), 6.60−6.53 (m,
2H), 4.66 (s, 1H), 4.24 (t, 2H, J = 6.4 Hz), 2.88 (d, 3H, J = 5.2 Hz),
2.57 (t, 2H, J = 7.2 Hz), 1.98−1.92 (m, 2H), 1.48 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 153.5, 149.8, 131.8, 129.2, 115.9, 108.7, 107.8,
93.8, 81.9, 77.9, 65.4, 30.1, 28.0, 27.7, 16.2; IR (neat): 3416, 2982,
2099, 1739(s), 1601, 1575, 1511, 1461, 1394, 1368, 1321, 1277, 1255,
1166, 1106, 747; MS (ESI, m/z) 312 (M + Na+); HRESIMS Calcd for
[C17H23NNaO3]+ (M + Na+) 312.1570, found 312.1581.
5-(2-(Methylamino)phenyl)pent-4-ynyl Acetate (1f). Pale yellow
oil (141.0 mg, 61%): 1H NMR (400 MHz, CDCl3) δ 7.24 (dd, 1H, J =
1.6 Hz, J = 7.6 Hz), 7.20−7.16 (m, 1H), 6.62−6.55 (m, 2H), 4.63 (s,
1H), 4.25 (t, 2H, J = 6.0 Hz), 2.89 (s, 3H), 2.57 (t, 2H, J = 7.2 Hz),
2.07 (s, 3H), 1.98−1.89 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
177.0, 149.8, 131.9, 129.3, 116.0, 108.8, 107.9, 94.0, 77.9, 63.0, 30.2,
28.0, 20.9, 16.4; IR (neat): 2920, 2239, 1737, 1702, 1591, 1488, 1470,
1365, 1241, 1173, 1150, 1087, 746, 695, 579, 562; MS (ESI, m/z) 254
(M + Na+); HRESIMS Calcd for [C14H17NNaO2]+ (M + Na+)
254.1151, found 254.1154.
5-Chloro-2-(hex-1-yn-1-yl)-N-methylaniline (1g). Pale yellow oil
(168.3 mg, 76%): 1H NMR (400 MHz, CDCl3) δ 7.07 (d, 1H, J = 8.0
Hz), 6.55 (dd, 1H, J = 2.0 Hz, J = 8.0 Hz), 6.50 (d, 1H, J = 2.0 Hz),
4.65 (s, 1H), 2.85 (d, 3H, J = 4.8 Hz), 2.44 (t, 2H, J = 6.8 Hz), 1.63−
1.54 (m, 2H), 1.51−1.42 (m, 2H), 0.94 (t, 2H, J = 7.2 Hz); 13C NMR
(100 MHz, CDCl3) δ 150.5, 134.9, 132.6, 116.0, 108.8, 106.9, 96.7,
76.2, 31.0, 30.1, 22.0, 19.3, 13.6; IR (neat): 2957, 2930, 2870, 1596,
1568, 1509, 1446, 1427, 1409, 1286, 1159, 1088, 884, 831, 794; MS
(ESI, m/z) 244 (M + Na+); HRESIMS Calcd for [C13H16ClNNa]+ (M
+ Na+) 244.0863, found 244.0861.
2-(2-Hexyl-1-methyl-1H-indol-3-yl)-N,2-diphenyl-N-tosyl-
1
acetamide (3a). Pale yellow oil (121.5 mg, 70%): H NMR (400
MHz, CDCl3) δ 7.87 (d, 2H, J = 8.4 Hz), 7.40 (t, 1H, J = 7.6 Hz),
7.30−7.04 (m, 12H), 7.02−6.84 (m, 2H), 6.77 (t, 1H, J = 7.2 Hz),
4.94 (s, 1H), 3.55 (s, 3H), 2.47 (s, 3H), 2.15−2.06 (m, 1H), 1.85−
1.73 (m, 1H), 1.10−1.03 (m, 2H), 1.02−0.88 (m, 6H), 0.77 (t, 3H, J =
7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 172.2, 144.6, 139.6, 139.0,
136.5, 136.2, 136.1, 130.4, 129.6, 129.5, 129.2, 129.0, 128.8, 128.2,
127.1, 126.8, 120.6, 119.5, 119.2, 108.5, 106.2, 49.4, 31.3, 29.6, 29.1,
29.0, 24.2, 22.3, 21.7, 13.9; IR (neat): 2955, 2927, 2858, 2253, 2099,
1701(s), 1600, 1488, 1470, 1452, 1365, 1187, 1173, 1150, 1088, 912,
742, 695, 562; MS (ESI, m/z) 601 (M + Na+); HRESIMS Calcd for
[C36H38N2NaO3S]+ (M + Na+) 601.2495, found 601.2498.
2-(2-(3-Chloropropyl)-1-methyl-1H-indol-3-yl)-N,2-diphenyl-N-
tosylacetamide (3b). White solid (mp 169−171 °C, 109.6 mg, 64%):
1H NMR (400 MHz, CDCl3) δ 7.87 (d, 2H, J = 8.4 Hz), 7.42 (t, 1H, J
= 7.2 Hz), 7.32−7.10 (m, 9H), 7.03−6.98 (m, 3H), 6.95−6.82 (m,
2H), 6.80 (t, 1H, J = 5.2 Hz), 4.99 (s, 1H), 3.59 (s, 3H), 3.22−3.12
(m, 2H), 2.47 (s, 3H), 2.41−2.33 (m, 1H), 2.10−2.02 (m, 1H), 1.48−
1.32 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 172.1, 144.7, 138.8,
137.8, 136.5, 136.1, 136.0, 130.4, 129.8, 129.5, 129.2, 129.1, 128.7,
128.3, 127.1, 127.0, 121.1, 119.7, 118.9, 108.7, 106.9, 49.1, 44.3, 31.6,
29.6, 21.7, 21.5; IR (neat): 2926, 2090, 1703(s), 1597, 1487, 1470,
1451, 1365, 1172, 1149, 1087, 695, 562; MS (ESI, m/z) 593 (M +
Na+); HRESIMS Calcd for [C33H31ClN2NaO3S]+ (M + Na+)
593.1636, found 593.1641.
2-(2-(3-Azidopropyl)-1-methyl-1H-indol-3-yl)-N,2-diphenyl-N-
1
2-(Hex-1-yn-1-yl)-N,4-dimethylaniline (1h). Pale yellow oil (124.9
tosylacetamide (3c). Pale yellow oil (86.7 mg, 50%): H NMR (400
1
mg, 62%): H NMR (400 MHz, CDCl3) δ 7.07 (d, 1H, J = 2.0 Hz),
MHz, CDCl3) δ 7.87 (d, 2H, J = 8.0 Hz), 7.42 (t, 1H, J = 7.2 Hz),
7.31−7.11 (m, 9H), 7.05−7.00 (m, 3H), 6.96−6.85 (m, 2H), 6.81 (t,
1H, J = 7.6 Hz), 4.98 (s, 1H), 3.58 (s, 3H), 2.94−2.86 (m, 2H), 2.47
(s, 3H), 2.33−2.21 (m, 1H), 2.02−1.92 (m, 1H), 1.29−1.74 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 172.1, 144.7, 138.8, 137.8, 136.5,
6.98 (dd, 1H, J = 2.4 Hz, J = 8.0 Hz), 6.49 (d, 1H, J = 8.4 Hz), 4.41 (s,
1H), 2.86 (s, 3H), 2.45 (t, 2H, J = 6.8 Hz), 2.19 (s, 3H), 1.64−1.55
(m, 2H), 1.53−1.43 (m, 2H), 0.95 (t, 2H, J = 7.2 Hz); 13C NMR (100
MHz, CDCl3) δ 147.7, 132.3, 129.8, 125.2, 109.0, 108.4, 95.7, 77.1,
31.1, 30.6, 22.1, 20.2, 19.4, 13.7; IR (neat): 2956, 2926, 2859, 2813,
1613, 1580, 1518, 1464, 1315, 1279, 1168, 882, 803; MS (ESI, m/z)
224 (M + Na+); HRESIMS Calcd for [C14H19NNa]+ (M + Na+)
224.1410, found 224.1416.
Representative Synthetic Procedures for the Preparation of
Ynamides 2. Alkynyl bromides (1.2 mmol) and DMEDA (0.2 mmol,
17.6 mg) were added to a stirred solution of amides (1.0 mmol),
K2CO3 (2.0 mmol, 276.4 mg), FeCl3·6H2O (0.1 mmol, 27.0 mg), and
toluene (5 mL) under air, and the resulting mixture was stirred at 100
°C for 12 h. The suspension was filtered, and the residue was washed
with diethyl ether (3 × 15 mL). The purification of products was
achieved by flash chromatography (eluent: hexanes/ethyl acetate) to
afford the desired products 2.
136.1, 136.0, 130.4, 129.8, 129.7, 129.5, 129.2, 129.1, 128.7, 128.3,
127.0, 121.1, 119.7, 118.9, 108.7, 106.9, 50.6, 49.1, 29.6, 28.1, 21.7,
21.3; IR (neat): 2920, 2096(s), 1702(s), 1476, 1363, 1276, 1172, 1149,
1087, 912, 747, 695, 562; MS (ESI, m/z) 600 (M + Na+); HRESIMS
Calcd for [C33H31N5NaO3S]+ (M + Na+) 600.2040, found 600.2042.
2-(2-(3-(1,3-Dioxoisoindolin-2-yl)propyl)-1-methyl-1H-indol-3-yl)-
N,2-diphenyl-N-tosylacetamide (3d). Pale yellow oil (114.5 mg,
56%): 1H NMR (400 MHz, CDCl3) δ 7.88−7.85 (m, 4H), 7.77−7.23
(m, 2H), 7.37−7.32 (m, 1H), 7.27−7.19 (m, 5H), 7.14−7.11 (m, 4H),
7.05−6.98 (m, 3H), 6.95−6.82 (m, 2H), 6.80−6.76 (m, 1H), 4.90 (s,
1H), 3.55 (s, 3H), 3.38 (t, 2H, J = 7.2 Hz), 2.46 (s, 3H), 2.23−2.13
(m, 1H), 1.94−1.86 (m, 1H), 1.38−1.22 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 172.0, 168.0, 144.6, 138.7, 137.7, 136.5, 136.2, 136.1,
134.0, 132.0, 130.4, 129.7, 129.5, 129.2, 129.1, 128.6, 128.3, 127.0,
126.9, 123.2, 120.9, 119.6, 119.0, 49.2, 37.4, 29.6, 27.6, 21.8, 21.7; IR
The data of the ynamides 2a and 2c−2e were reported in our
previous work.5
D
dx.doi.org/10.1021/jo501872h | J. Org. Chem. XXXX, XXX, XXX−XXX