Arkivoc 2018, v, 00-00
Badenock, J. C. et al.
CH2Cl2 (1 x 65 mL). The entire solution was filtered through Celite® to separate the emulsion that formed. The
aqueous layer was further extracted with CH2Cl2 (3 x 65 mL). The organic layers were combined, washed with
brine (1 x 100 mL), dried (Na2SO4), and concentrated in vacuo to give a dark yellow oil. The oil was purified by
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flash chromatography (2:1 hexanes: EtOAc) to give 9 as a pale yellow solid (6.76 g, 79%): H-NMR (CDCl3)
9.60 (s, 1H), 7.89-7.85 (m, 1H), 7.68 (d, 1H, J 2.8 Hz), 7.41-742 (m, 1H), 7.26-7.21 (m, 2H), 5.94 (s, 1H), 1.55 (s,
9H); 13C-NMR (CDCl3) 165.5, 136.7, 128.5, 124.3, 122.5, 121.3, 119.1, 113.0, 112.5, 51.5, 29.3; IR (film) 3399,
3231, 2964, 1627, 1538, 1449, 1231, 737 cm-1; MS m/z 216 (M+), 161, 144, 116, 89. An analytical sample was
obtained via iterative recrystallizations from Et2O: mp 188-190 °C. Anal. Calcd for C13H16N2O: C, 72.19; H, 7.46;
N, 12.95. Found: C, 72.14; H, 7.41; N, 12.87.
N-(tert-Butyl)-1-methyl-1H-indole-3-carboxamide (10). To a stirred suspension of NaOH (1.27 g, 31.8 mmol,
1.3 eq.) in EtOH (100 mL) was added amide 9 (5.28 g, 24.4 mmol, 1 eq.) neat. The solution was stirred for 2 h
at rt. The EtOH was removed under reduced pressure, and the residue was dissolved in acetone (100 mL). The
suspension was stirred for 15 min, treated with MeI (2 mL, 31.8 mmol, 1.3 eq.) and stirred overnight. The
yellow solution was filtered under gravity, and the filtrate was concentrated in vacuo to give a pale yellow oil.
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The oil was triturated repeatedly with Et2O to yield 5.19 g of 10 as a white solid (92%): H-NMR (CDCl3) 7.90
(m, 1H), 7.62 (s, 1H), 7.37-7.23 (m, 3H), 5.82 (s, 1H), 3.80 (s, 3H), 1.52 (s, 9H); 13C-NMR (CDCl3) 164.7, 137.3,
132.3, 125.2, 122.4, 121.3, 119.8, 112.2, 110.1, 51.4, 33.2, 29.3; IR (KBr) 3444, 3367, 3100, 2956, 1622, 1533,
1456, 1278, 1111, 744 cm-1; UV (95% EtOH) δmax 298 nm; MS m/z 230 (M+), 174, 158 (100%), 130, 103, 77, 42.
An analytical sample was obtained via iterative recrystallizations from Et2O: mp 200-201.5 °C. Anal. Calcd for
C14H18N2O: C, 73.01; H, 7.88; N, 12.16. Found: C, 72.92; H, 7.86; N, 12.08.
N-(tert-Butyl)-N,1-dimethyl-1H-indole-3-carboxamide (8), Method B. To a stirred suspension of KH (117 mg,
2.93 mmol, 1.2 eq.) in THF (10 mL) was added 18-crown-6 (775 mg, 2.93 mmol, 1.2 eq.) neat. The suspension
was stirred at 0 °C under nitrogen for 1 h, at which time was added amide 10 (561.3 mg, 2.44 mmol, 1 eq.) in
THF (34 mL) via an addition funnel. The solution was stirred at 0 °C for 1 h, treated with MeI (0.2 mL, 2.93
mmol, 1.2 eq.), and stirred overnight. The solution was poured onto ice H2O (100 mL) and stirred thoroughly.
The white solid that formed was collected by vacuum filtration and dried under vacuum to give the amide 8 as
a white solid (516 mg, 88%). The filtrate was extracted with CH2Cl2 (3 x 65 mL) and the organic extracts were
washed with brine (2 x 50 mL), dried (Na2SO4), and concentrated in vacuo to give a yellow oil. Trituration of
the oil with Et2O gave the desired amide 8 as a white solid (12.5 mg). Total yield of 8 was 88% (529 mg). Both
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solids were homologous by TLC and H-NMR; 1H-NMR (CDCl3) 7.68-7.71 (dd, 1H, J′ 1.4 Hz, J″ 7.3 Hz), 7.46 (s,
1H), 7.19-7.35 (m, 3H), 3.81 (s, 3H), 3.06 (s, 3H), 1.57 (s, 9H); 13C-NMR (CDCl3) 169.4, 136.8, 132.4, 126.1,
122.4, 121.2, 121.0, 114.4, 109.9, 56.4, 35.5, 33.4, 28.1; IR (KBr) 3458, 3113, 2975, 1627, 1533, 1474, 1363,
325, 1238, 1132, 1086 cm-1; UV max (95% EtOH) 218, 264, 290, 332, 348 nm. An analytical sample of 8 was
obtained via iterative recrystallizations from Et2O: mp 165-166 °C. Anal. Calcd for C15H20N2O: C, 73.74; H, 8.25;
N, 11.47. Found: C, 73.67; H, 8.30; N, 11.44.
2-Bromo-N-(tert-butyl)-N,1-dimethyl-1H-indole-3-carboxamide (11). To a stirred solution of the methylated
amide 8 (816 mg, 3.34 mmol, 1 eq.) in THF (40 mL) at -78 °C was added slowly t-BuLi (3.0 mL, 5.01 mmol, 1.7
M in hexanes, 1.5 eq.). The solution was stirred at –78 °C for 1 h, then warmed to rt over 30 min before
recooling to –78 °C. At this time the anion was treated with dried 1,2-dibromo-1,1,2,2-tetrachloroethane (1.63
g, 5.01 mmol, 1.5 eq.) in THF (20 mL). The solution warmed to rt overnight then poured onto ice H2O (100 mL)
and stirred for 2 h. No precipitate formed upon stirring. The aqueous layer was extracted with CH2Cl2 (4 x 50
mL). The organic layers were combined, washed with brine (1 x 100 mL), dried (Na2SO4), and concentrated in
vacuo to give a brown oil. Purification using flash column chromatography (2:1 hexanes: EtOAc) gave bromide
11 as a yellow solid (887 mg, 86%); 1H-NMR (CDCl3) 7.57-7.71 (dt, 1H, J′ 1.2 Hz, J″ 8.0 Hz), 7.14-7.34 (m, 3H),
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