synthesis and catalytic functionalization of biologically active indoles

CDCl 3) d = 137.0, 134.7, 132.6, 128.9, 127.6, 127.0, 125.7, 124.9,
123.0, 121.0, 118.1, 110.7, 74.9, 52.8, 47.6, 46.7, 11.6, 8.9 ppm. MS
(CI, M + H + ): m/z (relative intensity): 405. HRMS (CI, M − H + )
calcd. for C 22H 26Cl 2N 2O: 403.1338; found: 403.1334.
2-Methyl-3-(2-N,N-diethylaminoethoxy)indole (10). To a deep
blue solution of Na (684 mg, 29.7 mmol) in NH 3 (ca. 20 mL) at
−78 ◦ C, a solution of compound 9b (1.0 g, 2.97 mmol) in dry
THF (10 mL) was added dropwise. The mixture was stirred at
−33 ◦ C for 2 h, quenched with NH 4Cl at −78 ◦ C, allowed to
warm to room temperature, and concentrated. The residue was
diluted with H 2O and extracted with CHCl 3 (3 × 20 mL). The
combined organic layers were dried over Na 2SO 4, filtered and the
solvents were removed in vacuo to give a yellow oil in 95% yield
(700 mg, 2.84 mmol). The crude material was used for the next
reaction.
1 H NMR (300 MHz, CDCl3): d = 7.72 (br s, 1H, NH), 7.54 (m,
1H), 7.09 (m, 1H), 7.11–7.01 (m, 2H), 4.14 (t, 2H, J = 6.6 Hz),
2.89 (t, 2H, J = 6.6 Hz), 2.66 (q, 4H, J = 7.2Hz),2.33(s,3H),
1.07 (t, 6H, J = 7.2 Hz) ppm. 13 C NMR (75 MHz, CDCl 3): d =
135.1, 132.7, 122.5, 121.9, 120.9, 118.9, 116.9, 110.6, 72.3, 52.6,
47.5, 11.6, 10.2 ppm. MS (EI, 70 eV): m/z (relative intensity): 246
(1) [M + ], 160 (1), 146 (11), 117 (5), 100 (100), 86 (40), 72 (11), 56
(7), 44 (18). HRMS (EI): calcd. for C 15H 22N 2O: 246.1987; found:
246.2006.
1-(N-Naphthalene-2-ylsulfonyl)-2-methyl-3-(2-N,N-diethylaminoethoxy)indole
(11). The above mentioned crude 10 (700 mg, 2.84
mmol) in dry THF (8 mL) was added dropwise to NaH (682 mg,
28.4 mmol, 65% content in a mineral oil suspension that was
washed with dry n-hexane three times before use) suspended in
dry THF (10 mL) at room temperature under argon, and then
the mixture was stirred for 10 min. A dry THF (3 mL) solution of
2-naphthalenesulfonylchloride (1.9 g, 8.5 mmol) was added to the
mixture, and the resulting solution was stirred at 50 ◦ Cfor2h.
The reaction was quenched by adding aq. Na 2CO 3 (20 mL) and
the mixture was extracted with CHCl 3 (3 × 20 mL). After drying
with Na 2SO 4, removal of the solvent and chromatography of the
crude material with CHCl 3–10% MeOH gave compound 11 as
brown oil in 24% yield (300 mg, 0.69 mmol).
1 H NMR (300 MHz, DMSO), 11 (oxalate): d = 9.53 (br, 2H),
8.70 (d, 1H, J = 2.2 Hz), 8.22 (d, 1H, J = 8.2Hz),8.18(d,1H,
J = 8.5Hz),8.04(d,1H,J = 8.8Hz),7.99(d,1H,J = 8.2 Hz),
7.75–7.66 (m, 2H), 7.65 (dd, 1H, J = 8.8 Hz, J = 2.0Hz),7.59(d,
1H, J = 7.9 Hz), 7.35 (m, 1H), 7.26 (t, 1H, J = 7.6 Hz), 4.28 (t,
2H, J = 5.4 Hz), 3.38 (t, 2H, J = 5.4Hz),3.13(q,4H,J = 7.3 Hz),
2.60 (s, 3H), 1.17 (t, 6H, J = 7.3 Hz) ppm. 13 CNMR(75MHz,
DMSO), 11 (oxalate): d = 164.4, 140.3, 134.9, 134.4, 133.8, 131.6,
130.2, 129.9, 129.8, 128.3, 128.2, 128.0, 124.9 (2), 124.1, 124.0,
120.9, 117.9, 114.7, 68.5, 50.9, 47.0, 11.4, 8.9 ppm. MS (EI, 70
eV): m/z (relative intensity): 436 (1) [M + ], 160 (1), 146 (11), 117
(5), 100 (100), 86 (40), 72 (11), 56 (7), 44 (18), 29 (6). HRMS (EI):
calcd. for C 25H 28N 2O 3S: 436.1815; found: 436.1808.
General procedure for the formation of the oxalate
The product oil was diluted in a small amount of dry ethanol.
After addition of oxalic acid in excess (1.1 equiv), the solution
was stored in a fridge. The formed precipitate was isolated. The
yield after the formation of the oxalate from the product oil for
compound 11 constituted 55%.
General procedure for the sulfonylation with n-butyl lithium
n-Butyl lithium (1.6 M in hexane, 1.33 mL, 2.1 mmol) was added
to a solution of the free indole 10 (2.03 mmol) in anhydrous THF
(5 mL) at −78 ◦ C during 20 min. After complete addition, the
mixture was stirred at −78 ◦ C for 10 min, and was thereafter
allowed to reach room temperature over 1 h. After cooling to
−78 ◦ C, a solution of sulfonyl chloride (2.3 mmol) in anhydrous
THF (3 mL) was added over 20 min at −78 ◦ C. The resulting
mixture was allowed to slowly reach room temperature over
3 days, was thereafter poured into water (20 mL) containing brine
(5 mL), and extracted with CHCl3 (3 × 30 mL). The combined
organic extracts were washed with water (50 mL) and dried over
MgSO4. After removal of the solvents in vacuo, the desired product
was isolated by column chromatography in CHCl3–MeOH as
brown oil. This isolated oil was used for the preparation of the
oxalate.
2-(Benzo[b]thiophen-3-ylsulfonyl)methyl-3-(2-N,N-diethylaminoethoxy)indole
(12a) (oxalate). Yield: 23% free indole, 70%
oxalate (from product oil). 1H NMR (300 MHz, DMSO): d =
11.02 (s, 1H), 9.82 (br, 2H), 8.55 (s, 1H), 8.17 (ddd, 1H, J =
8.0 Hz, J = 1.3 Hz, J = 0.8Hz),8.05(ddd,1H,J = 8.0 Hz,
J = 1.3 Hz, J = 0.8 Hz), 7.55–7.42 (m, 3H), 7.35 (dt, 1H, J =
8.0 Hz, J = 1.0Hz),7.11(ddd,1H,J = 8.0 Hz, J = 7.0 Hz, J =
1.0Hz),6.98(ddd,1H,J = 8.0 Hz, J = 7.0 Hz, J = 1.0 Hz), 4.88
(s, 2H), 4.04 (t, 2H, J = 5.3 Hz), 3.11–3.04 (m, 6H), 1.16 (t, 6H,
J = 7.2 Hz) ppm. 13C NMR (75 MHz, DMSO): d = 164.7, 140.2,
139.4, 137.4, 134.1, 134.0, 132.5, 125.8, 123.7, 122.8, 122.5, 119.3,
119.0, 117.8, 113.0, 112.2, 68.3, 52.8, 50.7, 47.0, 8.9 ppm. MS
(EI, 70 eV): m/z (relative intensity): 442 (28) [M + − oxalic acid],
245 (30), 181 (30), 145 (69), 134 (83), 100 (78), 86 (100), 72 (58),
64 (17), 56 (44), 44 (90). HRMS (EI): calcd. for C23H26N2O3S 2:
442.1379; found: 442.1384.
2-(5-Chloro-3-methylbenzo[b]thiophen-2-ylsulfonyl)-methyl-3-(2-
N,N-diethylaminoethoxy)indole (12b) (oxalate)
Yield: 20% free indole, 46% oxalate (from product oil). 1HNMR (300 MHz, DMSO): d = 11.00 (s, 1H), 8.14 (d, 1H, J = 8.7 Hz),
8.09 (d, 1H, J = 2.1Hz),7.64(dd,1H,J = 8.7 Hz, J = 2.1 Hz),
7.58 (d, 1H, J = 8.0Hz),7.35(d,1H,J = 8.0Hz),7.13(ddd,1H,
J = 8.0 Hz, J = 7.0 Hz, J = 1.2Hz),7.00(ddd,1H,J = 8.0 Hz,
J = 7.0 Hz, J = 1.1 Hz), 4.94 (s, 2H), 4.18 (t, 2H, J = 5.1 Hz),
3.27 (t, 2H, J = 5.1Hz),3.08(q,4H,J = 7.2Hz),2.38(s,3H),
1.15 (t, 6H, J = 7.2 Hz) ppm. 13C NMR (75 MHz, DMSO): d =
164.4, 140.8, 140.0, 138.5, 137.7, 135.6, 134.0, 130.8, 128.3, 125.2,
124.1, 122.7, 119.3, 119.1, 117.9, 112.8, 68.6, 53.9, 51.0, 47.1, 11.9,
9.0 ppm. MS (EI, 70 eV): m/z (relative intensity): 490 (1) [M + −
oxalic acid], 422 (2), 244 (6), 214 (4), 181 (100), 147 (29), 100 (63),
86 (20), 72 (10), 64 (16), 56 (16), 44 (9). HRMS (EI): calcd. for
C24H27ClN2O3S2: 490.1146; found: 490.1140.
2-(6-Chloroimidazo[2,1-b]thiazol-5-ylsulfonyl)methyl-3-(2-N,Ndiethylaminoethoxy)indole
(12c) (oxalate). Yield: 20% free
indole, 64% oxalate (from product oil). 1H NMR (300 MHz,
DMSO): d = 10.90 (s, 1H), 7.55 (d, 1H, J = 8.0Hz),7.47(d,1H,
J = 4.5Hz),7.39(d,1H,J = 4.5 Hz), 7.30 (d, 1H, J = 8.0 Hz),
1806 | Org. Biomol. Chem., 2008, 6, 1802–1807 This journal is © The Royal Society of Chemistry 2008