HETEROCYCLES

Paper | Regular issue | Vol. 83, No. 8, 2011, pp. 1757-1769
Received, 26th March, 2011, Accepted, 23rd May, 2011, Published online, 27th May, 2011.
DOI: 10.3987/COM-11-12220

■ A Facile Synthesis of Symmetrical and Unsymmetrical Bis(indolyl)acetamides Mediated by Protic Acid

Hai Shang, Fei-Yue Hao, Li Pan, Hong Chen,* and Mao-Sheng Cheng*

The Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China

Abstract

We report the preparation of symmetrical bis(indolyl)acetamides using the dimerization of 2-hydroxy-(2-indolyl)acetamides and unsymmetrical bis(indolyl)acetamides via electrophilic substitution of indoles with 2-hydroxy-(2-indolyl)acetamides. Both conversions were mediated by protic acid in THF at room temperature.

INTRODUCTION
Bis(indolyl)alkanes are one of the most important classes of bioactive compounds.1 Therefore, improved syntheses of both symmetrical and unsymmetrical bis(indolyl)alkanes have been developed.2 Generally, symmetrical bis(indolyl)alkanes are obtained from the condensation of indoles with aldehydes or ketones in the presence of protic or Lewis acids.3 Recently, several unsymmetrical bis(indolyl)alkanes have been synthesized using ClSiMe3 catalysis,4,5 TLC-grade silica gel under microwave irradiation,6 and ceric ammonium nitrate (CAN) under ultrasonic irradiation.7 However, there is no report on the biological activity of bis(indolyl)acetamides and synthesis of bis(indolyl)acetamides has only rarely been reported.8 Owing to the similar structures of bis(indolyl)alkanes and bis(indolyl)acetamides (two indole or substituted indole units in a molecule), we consider that to develop a facile method for the preparation of bis(indolyl)acetamides and to investigate their biological activity are of some significance. Herein, we report a facile preparation of symmetrical bis(indolyl)acetamides using the dimerization of 2-hydroxy-(2-indolyl)acetamides and unsymmetrical bis(indolyl)acetamides via electrophilic substitution of indoles with 2-hydroxy-(2-indolyl)acetamides.

RESULTS AND DISCUSSION
Our research began with the observation that the dimerization of 2-hydroxy-(2-indolyl)acetamide 1a mediated by HBr in THF afforded symmetrical bis(indolyl)acetamide 2a (Table 1, Entry 2). First, we investigated the effects of a variety of protic and Lewis acids on this reaction using 1a as a model compound. The reaction was very sluggish when concentrated HCl was used as a mediate agent; 1a still remained after 72 h (as monitored by TLC). Reactions mediated by AlCl3, BF3⋅Et2O and TsOH gave low to moderate yields, while no reaction occurred when acetic acid was used as a mediate agent. Surprisingly, H2SO4 promoted the reaction in moderate yield in only 10 min, while HNO3 required long reaction time but provided a better yield. Next, we investigated the solvent effects on the H2SO4-mediated reaction. A trace amount of 2a was obtained in CH2Cl2, while no desired product was given in MeNO2. The reaction proceeded slowly to give 2a in 15.4% yield with residual 1a in CS2. No bis(indolyl)acetamide 2a was obtained when MeOH and EtOH were used as the solvent, but etherification of 1a with the alcohols was observed (Table 1 and Scheme 1).

Based on the above results, we explored the scope of this dimerization using various 2-hydroxy-(2-indolyl)acetamides mediated by H2SO4 or HNO3 in THF. As is shown in Table 2, 2-hydroxy-(2-indolyl)acetamides, including those with bromo substituents on the indole ring, proved to be good substrates mediated by H2SO4 (Table 2, Entries 4 and 5). However, the H2SO4-mediated reactions of 2-hydroxy-(2-indolyl)acetamides with indole rings unsubstituted at the N-atom gave complex mixtures with no desired products (Table 2, Entries 3 and 6). HNO3 was able to mediate the reactions of 2-hydroxy-(2-indolyl)acetamides with indole rings unsubstituted at the N-atom but failed for those with bromo-substituted and N-substituted indole rings.

We speculated that symmetrical bis(indolyl)acetamides were obtained via an electrophilic substitution reaction. To provide support for our speculation and increase the diversity of bis(indolyl)acetamides, we attempted to synthesize unsymmetrical bis(indolyl)acetamides through electrophilic substitution reactions of indoles with 2-hydroxy-(2-indolyl)acetamides. Unsymmetrical bis(indolyl)acetamide 4a was obtained in 20.4% yield, together with the symmetrical bis(indolyl)acetamide 2a in 44.3% yield, when mediated by H2SO4 at room temperature using a 1:2 molar ratio of indole to 1a. However, when the molar ratio of indole and 1a was adjusted to 1:1, unsymmetrical bis(indolyl)acetamide 4a was obtained in 67.3% yield, with only a trace amount of symmetrical bis(indolyl)acetamide 2a. Based on this reaction, unsymmetrical bis(indolyl)acetamides 4a-4g were synthesized in moderate to excellent yields via the reaction of 2-hydroxy-(2-indolyl)acetamides with substituted indoles in a 1:1 molar ratio (Table 3 and Table 4). It was observed that the substitution reaction of the 3-methylindole occurred exclusively at the 2-position.

A reasonable mechanism for the above reactions is proposed in Scheme 2. First, azafulvenium salt 5 is generated by dehydroxylation.9 Dehydroxylation might be caused by the high sensitivity of 2-hydroxy-(2-indolyl)acetamide 1 to acid. Next, azafulvenium salt 5 undergoes further reaction with a second molecule of 2-hydroxy-(2-indolyl)acetamide or indole or substituted indoles to form symmetrical and unsymmetrical bis(indolyl)acetamides, respectively. The rearrangement of 2-hydroxy- (2-indolyl)acetamides with 3-methylindole, which results in the substitution at the 2-position of 3-methylindole, is worthy of note.10
In summary, we have demonstrated a facile synthesis of symmetrical bis(indolyl)acetamides via the dimerization of 2-hydroxy-(2-indolyl)acetamides and unsymmetrical bis(indolyl)acetamides via the electrophilic substitution of indoles with 2-hydroxy-(2-indolyl)acetamides mediated by protic acid at room temperature. Easy availability of the cheap reagent and mild reaction conditions of the present methodology make it a highly attractive protocol for synthesis of diverse and new bioactive symmetrical and unsymmetrical bis(indolyl)acetamides.

EXPERIMENTAL
All commercially available reagents and solvents were employed without further purification. Melting points were determined in a Büchi Melting Point B-540 apparatus and were uncorrected. Infrared spectra were recorded in a Bruker IFS-55 spectrophotometer. 1H NMR and 13C NMR spectra were recorded in Bruker ARX 300 MHz or 600 MHz, using TMS as the internal standard. Chemical shift values were reported in δ (ppm) and coupling constants in hertz. ESI mass spectra were performed using an Aiglent 1100. High resolution mass spectrometry (HRMS) were obtained using a Bruker MicroTOF QII Time of Flight mass spectrometer. Column chromatography was performed on silica gel H and analytical TLC data on silica gel HF254.
Starting Matericals
2-Hydroxy-(2-indolyl)acetamides were prepared by the reduction of substituted indol-3-yl-2-oxoacetamides with NaBH4 in methanolic THF at room temperature. The substituted indol-3-yl-2-oxoacetamides were prepared by reference 11.
General procedure for preparation of 2-hydroxy-(2-indolyl)acetamides 1a-1h
To a solution of corresponding indol-3-yl-2-oxoacetamide (4 mmol) in THF (10 mL) and MeOH (10 mL) cooled in an ice bath was added NaBH4 (2 mmol). Then the mixture was stirred at room temperature until TLC analysis showed that the starting material had been completely converted. The reaction was quenched at 0 °C with aqueous NH4Cl and extracted three times with CH2Cl2. After the organic layers were dried (Na2SO4), the solvents were concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel with PE-EtOAc.
2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-hydroxy-N-(pyridin-4-yl)acetamide (1a)
Yield 82.3%; white solid; mp 182.9-184.6 °C (PE-THF); IR 3425.7, 1664.3, 1583.3, 1497.2 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 5.36-5.43 (m, 3H), 6.29 (d, 1H, J = 4.6 Hz), 7.02 (t, 1H, J = 7.3 Hz), 7.10 (t, 1H, J = 7.1 Hz), 7.24 (d, 2H, J = 8.4 Hz), 7.38 (d, 2H, J = 8.4 Hz), 7.42 (d, 1H, J = 8.1 Hz), 7.52 (s, 1H), 7.74 (d, 1H, J = 6.8 Hz), 7.76 (d, 2H, J = 6.0 Hz), 8.41 (d, 2H, J = 6.0 Hz), 10.37 (s, 1H); ESI-MS m/z: 389.9 [M - H]-.
2-Hydroxy-2-(1-methyl-1H-indol-3-yl)-N-(pyridin-4-yl)acetamide (1b)
Yield 70.8%; white solid; mp 187.7-188.4 °C (PE-THF); IR 3374.6, 1691.2, 1598.0, 1528.2 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 3.76 (s, 3H), 5.38 (d, 1H, J = 4.5 Hz), 6.24 (d, 1H, J = 4.5 Hz), 7.03 (t, 1H, J = 7.7 Hz), 7.15 (t, 1H, J = 7.4 Hz), 7.35 (s, 1H), 7.40 (d, 1H, J = 8.2 Hz), 7.71-7.78 (m, 3H), 8.42 (d, 2H, J = 6.2 Hz), 10.35 (s, 1H); ESI-MS m/z: 280.1 [M - H]-.
2-Hydroxy-2-(1H-indol-3-yl)-N-(pyridin-4-yl)acetamide (1c)
Yield 43.8%; white solid; mp 180.5-182.3 °C (PE-THF); IR 3312.7, 3044.2, 1689.6, 1601.6, 1584.5, 1512.7 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 5.38 (d, 1H, J = 4.3 Hz), 6.22 (d, 1H, J = 4.4 Hz), 6.98 (t, 1H, J = 7.6 Hz), 7.08 (t, 1H, J = 7.2 Hz), 7.34-7.40 (m, 2H), 7.72 (d, 1H, J = 7.9 Hz), 7.76 (d, 2H, J = 6.1 Hz), 8.41 (d, 2H, J = 5.9 Hz), 10.34 (s, 1H), 11.05 (s, 1H); ESI-MS m/z: 266.0 [M - H]-.
2-[1-(4-Chlorobenzyl)-5-bromo-1H-indol-3-yl]-2-hydroxy-N-(pyridin-4-yl)acetamide (1d)
Yield 66.2%; pale yellow solid; mp 133.4-136.2 °C (PE-THF); IR 3351.5, 2852.0, 1690.1, 1583.2, 1510.4 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 5.39 (d, 1H, J = 4.6 Hz), 5.41 (s, 2H), 6.38 (d, 1H, J = 4.5 Hz), 7.19-7.27 (m, 3H), 7.38 (d, 2H, J = 8.3 Hz), 7.43 (d, 1H, J = 8.8 Hz), 7.58 (s, 1H), 7.75 (d, 2H, J = 5.6 Hz), 7.96 (d, 1H, J = 1.3 Hz), 8.43 (d, 2H, J = 5.3 Hz), 10.41 (s, 1H); ESI-MS m/z: 470.0 [M + H]+.
2-(5-Bromo-1-methyl-1H-indol-3-yl)-2-hydroxy-N-(pyridin-4-yl)acetamide (1e)
Yield 73.3%; white solid; mp 184.1-186.0 °C (PE-THF); IR 3326.7, 2859.5, 1697.2, 1602.9, 1585.3, 1511.1 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 3.76 (s, 3H), 5.37 (d, 1H, J = 4.2 Hz), 6.33 (d, 1H, J = 4.4 Hz), 7.26 (dd, 1H, J = 1.3, 8.7 Hz), 7.37-7.42 (m, 2H), 7.75 (d, 2H, J = 5.9 Hz), 7.95 (d, 1H, J = 1.2 Hz), 8.42 (d, 2H, J = 5.9 Hz), 10.38 (s, 1H); ESI-MS m/z: 360.0 [M + H]+.
2-(5-Bromo-1H-indol-3-yl)-2-hydroxy-N-(pyridin-4-yl)acetamide (1f)
Yield 83.1%; white solid; mp 198.3-199.9 °C (PE-THF); IR 3299.4, 1686.2, 1585.3, 1512.5 cm-1; 1H NMR (600 MHz, DMSO-d6) δ: 5.37 (d, 1H, J = 3.4 Hz), 6.28 (d, 1H, J = 3.4 Hz), 7.19 (dd, 1H, J = 1.7, 8.5 Hz), 7.34 (d, 1H, J = 8.5 Hz), 7.42 (d, 1H, J = 2.0 Hz), 7.75 (d, 2H, J = 5.8 Hz), 7.93 (s, 1H), 8.42 (d, 2H, J = 6.1 Hz), 10.36 (s, 1H), 11.25 (s, 1H); ESI-MS m/z: 346.0 [M + H]+.
2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-N-tert-butyl-2-hydroxyacetamide (1g)
Yield 90.8%; white solid; mp 168.4-170.3 °C (PE-THF); IR 3385.5, 3253.4, 2966.0, 1651.9, 1524.2 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 1.30 (s, 9H), 5.06 (d, 1H, J = 5.0 Hz), 5.38 (s, 2H), 5.85 (d, 1H, J = 5.0 Hz), 7.00 (t, 1H, J = 7.7 Hz), 7.09 (t, 1H, J = 7.4 Hz), 7.23 (d, 2H, J = 8.3 Hz), 7.32 (s, 1H), 7.34-7.44 (m, 4H), 7.67 (d, 1H, J = 7.7 Hz); ESI-MS m/z: 393.1 [M + Na]+.
2-Hydroxy-2-(2-methyl-1H-indol-3-yl)-N-(pyridin-4-yl)acetamide (1h)
Yield 51.8%; white solid; mp 214.0-214.9 °C (PE-THF); IR 3400.9, 3329.2, 3300.3, 3054.3, 1694.3, 1601.1, 1582.1, 1508.1 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 2.42 (s, 3H), 5.35 (d, 1H, J = 3.8 Hz), 6.13 (d, 1H, J = 3.8 Hz), 6.88 (t, 1H, J = 7.5 Hz), 6.97 (t, 1H, J = 7.4 Hz), 7.24 (d, 1H, J = 7.9 Hz), 7.57 (d, 1H, J = 7.7 Hz), 7.79 (d, 2H, J = 6.1 Hz), 8.41 (d, 2H, J = 6.0 Hz), 10.33 (s, 1H), 10.94 (s, 1H); ESI-MS: m/z 280.1 [M - H]-.
General procedure for preparation of compounds 2a, 2b, 2d, 2e, and 2g mediated by H2SO4
H2SO4 (1 mmol) was added dropwise to a solution of corresponding 2-hydroxy-(2-indolyl)acetamide (0.5 mmol) in THF (5 mL). Then the mixture was stirred at room temperature until TLC analysis showed that the starting material had been completely converted. Water (15 mL) was added and the resulting solution was alkalized to pH 9-10 with triethylamine. The reaction mixture was extracted with EtOAc, and the combined organic layers were washed successively with water and brine. After the organic layers were dried (Na2SO4), the solvents were concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel with EtOAc.
General procedure for preparation of compounds 2a-2c, 2f, and 2g mediated by HNO3
HNO3 (1 mmol) was added dropwise to a solution of corresponding 2-hydroxy-(2-indolyl)acetamide (0.5 mmol) in THF (5 mL). Then the mixture was stirred at room temperature until TLC analysis showed that the starting material had been completely converted. Water (15 mL) was added and the resulting solution was alkalized to pH 9-10 with triethylamine. The reaction mixture was extracted with EtOAc, and the combined organic layers were washed successively with water and brine. After the organic layers were dried (Na2SO4), the solvents were concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel with EtOAc.
2,2-Bis[1-(4-chlorobenzyl)-1H-indol-3-yl]-N-(pyridin-4-yl)acetamide (2a)
White solid; mp 234.9-235.5 °C (PE-EtOAc); IR 3318.9, 1674.0, 1591.1, 1511.0 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 5.40 (s, 4H), 5.61 (s, 1H), 6.98 (t, 2H, J = 7.5 Hz), 7.08 (t, 2H, J = 7.5 Hz), 7.16 (d, 4H, J = 8.4 Hz), 7.34 (d, 4H, J = 8.4 Hz), 7.37-7.40 (m, 4H), 7.57 (d, 2H, J = 7.8 Hz), 7.62 (d, 2H, J = 6.2 Hz), 8.42 (d, 2H, J = 6.0 Hz), 10.80 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ: 42.4, 48.7, 110.7, 113.4, 113.8, 119.4, 119.8, 122.0, 127.6, 128.1, 128.9, 129.3, 132.4, 136.6, 137.9, 146.4, 150.9, 172.4; ESI-HRMS: calcd for C37H29Cl2N4O, 615.1721; found, 615.1721 [M + H]+.
2,2-Bis(1-methyl-1H-indol-3-yl)-N-(pyridin-4-yl)acetamide (2b)
White solid; mp 239.1-239.7 °C (PE-EtOAc); IR 3327.5, 1675.2, 1589.5, 1510.0 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 3.74 (s, 6H), 5.58 (s, 1H), 7.00 (t, 2H, J = 7.5 Hz), 7.14 (t, 2H, J = 7.5 Hz), 7.19 (s, 2H), 7.40 (d, 2H, J = 8.2 Hz), 7.59 (d, 2H, J = 7.7 Hz), 7.61 (d, 2H, J = 5.4 Hz), 8.40 (d, 2H, J = 4.1 Hz), 10.74 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ: 32.3, 41.6, 109.7, 112.2, 113.2, 118.6, 118.8, 121.2, 126.8, 128.1, 136.7, 145.9, 150.4, 172.2; ESI-HRMS: calcd for C25H23N4O, 395.1866; found, 395.1863 [M + H]+.
2,2-Bis(1H-indol-3-yl)-N-(pyridin-4-yl)acetamide (2c)
White solid; mp 250.1-251.4 °C (PE-EtOAc); IR 3406.8, 1677.2, 1592.5, 1521.4 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 5.59 (s, 1H), 6.95 (t, 2H, J = 7.2 Hz), 7.06 (t, 2H, J = 7.1 Hz), 7.20 (d, 2H, J = 2.0 Hz), 7.36 (d, 2H, J = 8.0 Hz), 7.58 (d, 2H, J = 7.8 Hz), 7.62 (d, 2H, J = 5.6 Hz), 8.40 (d, 2H, J = 4.1 Hz), 10.76 (s, 1H), 10.95 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ: 42.0, 111.5, 113.0, 113.2, 118.4, 118.8, 121.0, 123.8, 126.5, 136.3, 146.0, 150.4, 172.3; ESI-HRMS: calcd for C23H19N4O, 367.1554; found, 367.1555 [M + H]+.
2,2-Bis[1-(4-chlorobenzyl)-5-bromo-1H-indol-3-yl]-N-(pyridin-4-yl)acetamide (2d)
White solid; mp 228.1-230.0 °C; IR 3383.6, 1664.4, 1589.8, 1508.1 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 5.43 (s, 4H), 5.56 (s, 1H), 7.17-7.21 (m, 6H), 7.34-7.41 (m, 6H), 7.59 (s, 2H), 7.62 (d, 2H, J = 5.9 Hz), 7.70 (d, 2H, J = 1.2 Hz), 8.44 (d, 2H, J = 5.2 Hz), 10.79 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ: 41.8, 48.3, 111.7, 112.1, 112.5, 113.4, 121.7, 124.0, 128.6, 128.8, 129.1, 132.0, 134.8, 137.0, 145.7, 150.4, 171.3; ESI-HRMS: calcd for C37H27Br2Cl2N4O, 770.9923; found, 770.9926 [M + H]+.
2,2-Bis(5-bromo-1-methyl-1H-indol-3-yl)-N-(pyridin-4-yl)acetamide (2e)
White solid; mp 274.3-275.9 °C (PE-EtOAc); IR 3442.3, 1708.1, 1593.5, 1509.3 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 3.76 (s, 6H), 5.54 (s, 1H), 7.26 (dd, 2H, J = 1.8, 8.7 Hz), 7.32 (s, 2H), 7.42 (d, 2H, J = 8.7 Hz), 7.59 (d, 2H, J = 5.9 Hz), 7.74 (d, 2H, J = 1.4 Hz), 8.43 (d, 2H, J = 5.7 Hz), 10.71 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ: 32.6, 41.1, 111.3, 111.5, 112.1, 113.3, 121.0, 123.7, 128.3, 129.8, 135.4, 145.7, 150.4, 172.6; ESI-HRMS: calcd for C25H21Br2N4O, 551.0077; found, 551.0075 [M + H]+.
2,2-Bis(5-bromo-1H-indol-3-yl)-N-(pyridin-4-yl)acetamide (2f)
White solid; mp 183.4-185.5 °C (PE-EtOAc); IR 3419.4, 1672.5, 1591.3, 1508.4 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 5.54 (s, 1H), 7.18 (dd, 2H, J = 1.7, 8.6 Hz), 7.36 (d, 2H, J = 8.4 Hz), 7.33 (d, 2H, J = 2.3 Hz), 7.61 (d, 2H, J = 6.2 Hz), 7.72 (d, 2H, J = 1.4 Hz), 8.43 (d, 2H, J = 6.0 Hz), 10.72 (s, 1H), 11.23 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ: 41.7, 111.2, 112.4, 113.3, 113.7, 121.1, 123.6, 125.6, 128.2,
135.0, 145.8, 150.4, 171.8; ESI-HRMS: calcd for C23H17Br2N4O, 522.9764; found, 522.9767 [M + H]+.
2,2-Bis[1-(4-chlorobenzyl)-1H-indol-3-yl]-N-tert-butylacetamide (2g)
White solid; mp 259.6-261.5 °C (PE-EtOAc); IR 3402.3, 3285.5, 1645.7, 1549.0, 1491.5, 1464.0 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 1.26 (s, 9H), 5.35 (s, 1H), 5.37 (s, 4H), 6.95 (t, 2H, J = 7.3 Hz), 7.06 (t, 2H, J = 7.3 Hz), 7.14 (d, 4H, J = 8.4 Hz), 7.22 (s, 2H), 7.34 (d, 4H, J = 8.4 Hz), 7.37 (d, 2H, J = 8.3 Hz), 7.55 (d, 2H, J = 7.8 Hz), 7.85 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 28.5, 41.1, 48.1, 50.1, 110.0, 114.5, 118.6, 119.5, 121.2, 127.2, 127.4, 128.4, 128.8, 131.8, 136.0, 137.6, 171.3; ESI-HRMS: calcd for C36H33Cl2N3ONa, 616.1893; found, 616.1890 [M + Na]+.
2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-methoxy-N-(pyridin-4-yl)acetamide (3a)
The same procedure with the preparation of compound 2a mediated by H2SO4 except using MeOH instead of THF as a solvent. White solid; mp 171.0-172.2 °C (MeOH); IR 3293.2, 1677.8, 1588.9, 1510.3 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 3.37 (s, 3H), 5.15 (s, 1H), 5.43 (s, 2H), 7.04 (t, 1H, J = 7.5 Hz), 7.13 (t, 1H, J = 7.2 Hz), 7.22 (d, 2H, J = 8.1 Hz), 7.38 (d, 2H, J = 8.2 Hz), 7.44 (d, 1H, J = 8.1 Hz), 7.59 (s, 1H), 7.69-7.76 (m, 3H), 8.43 (d, 2H, J = 5.2 Hz), 10.44 (s, 1H); ESI-MS m/z: 404.0 [M - H]-.
2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-ethoxy-N-(pyridin-4-yl)acetamide (3b)
The same procedure with the preparation of compound 2a mediated by H2SO4 except using MeOH instead of THF as a solvent. White solid; mp 163.4-165.0 °C (MeOH); IR 3282.6, 3033.4, 1678.2, 1586.0, 1510.4 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 1.21 (t, 3H, J = 7.0 Hz), 3.49-3.66 (m, 2H), 5.24 (s, 1H), 5.42 (s, 2H), 7.04 (t, 1H, J = 7.4 Hz), 7.12 (t, 1H, J = 7.6 Hz), 7.22 (d, 2H, J = 8.4 Hz), 7.37 (d, 2H, J = 8.4 Hz), 7.43 (d, 1H, J = 8.1 Hz), 7.55 (s, 1H), 7.70 (d, 2H, J = 6.2 Hz), 7.74 (d, 1H, J = 7.8 Hz), 8.43 (d, 2H, J = 5.8 Hz), 10.35 (s, 1H); ESI-MS m/z: 420.1 [M + H]+.
General procedure for preparation of compounds 4a-4g mediated by H2SO4
To a solution of corresponding 2-hydroxy-(2-indolyl)acetamide (0.5 mmol) and indole (0.5 mmol) in THF (5 mL), H2SO4 (1 mmol) was added dropwise. Then the mixture was stirred at room temperature until TLC analysis showed that the starting material had been completely converted. Water (15 mL) was added and the resulting solution was alkalized to pH 9-10 with triethylamine. The reaction mixture was extracted with EtOAc, and the combined organic layers were washed successively with water and brine. After the organic layers were dried (Na2SO4), the solvents were concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel with EtOAc.
General procedure for preparation of compounds 4a-4g mediated by HNO3
To a solution of corresponding 2-hydroxy-(2-indolyl)acetamide (0.5 mmol) and indole (0.5 mmol) in THF (5 mL), HNO3 (1 mmol) was added dropwise. Then the mixture was stirred at room temperature until TLC analysis showed that the starting material had been completely converted. Water (15 mL) was added and the resulting solution was alkalized to pH 9-10 with triethylamine. The reaction mixture was extracted with EtOAc, and the combined organic layers were washed successively with water and brine. After the organic layers were dried (Na2SO4), the solvents were concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel with EtOAc.
2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-(1H-indol-3-yl)-N-(pyridin-4-yl)acetamide (4a)
White solid; mp 154.4-156.0 °C (PE-EtOAc); IR 3414.4, 3318.9, 1681.6, 1589.7, 1510.5 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 5.40 (s, 2H), 5.61 (s, 1H), 6.93-7.01 (m, 2H), 7.04-7.11 (m, 2H), 7.18 (d, 2H, J = 8.4 Hz), 7.21 (d, 1H, J = 2.1 Hz), 7.33-7.40 (m, 5H), 7.57-7.60 (m, 2H), 7.62 (d, 2H, J = 6.4 Hz), 8.42 (d, 2H, J = 6.2 Hz), 10.77 (s, 1H), 10.97 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ: 42.0, 48.2, 110.2, 111.6, 112.8, 113.1, 113.3, 118.5, 118.9, 119.2, 121.1, 121.4, 123.8, 126.4, 127.2, 127.6, 128.5, 128.8, 131.9, 136.0, 136.3, 137.4, 145.9, 150.4, 172.1; ESI-HRMS: calcd for C30H24ClN4O, 491.1633; found, 491.1633 [M + H] +.
2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-(2-methyl-1H-indol-3-yl)-N-(pyridin-4-yl)acetamide (4b)
White solid; mp 240.1-241.2 °C (PE-EtOAc); IR 3401.1, 3243.7, 1671.3, 1589.5, 1508.5 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 2.42 (s, 3H), 5.40 (s, 2H), 5.54 (s, 1H), 6.84 (t, 1H, J = 7.7 Hz), 6.89-6.96 (m, 2H), 7.05 (t, 1H, J = 7.8 Hz), 7.15-7.23 (m, 3H), 7.28 (d, 1H, J = 7.8 Hz), 7.33-7.39 (m, 3H), 7.61 (d, 2H, J = 6.4 Hz), 7.64 (d, 1H, J = 8.7 Hz), 8.40 (d, 2H, J = 6.0 Hz), 10.61 (s, 1H), 10.88 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ: 12.0, 41.6, 48.1, 107.6, 110.2, 110.3, 113.1, 113.3, 118.1, 118.7, 118.8, 119.4, 119.9, 121.4, 127.3, 127.4, 127.7, 128.4, 128.8, 131.8, 133.0, 135.1, 136.1, 137.6, 146.0, 150.4, 172.0; ESI-HRMS: calcd for C31H26ClN4O, 505.1789; found, 505.1788 [M + H]+.
2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-(5-bromo-1H-indol-3-yl)-N-(pyridin-4-yl)acetamide (4c)
White solid; mp 175.5-177.0 °C (PE-EtOAc); IR 3407.6, 1673.0, 1592.3, 1508.1 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 5.41 (s, 2H), 5.57 (s, 1H), 6.97 (t, 1H, J = 7.1 Hz), 7.08 (t, 1H, J = 7.0 Hz), 7.14-7.21 (m, 3H), 7.32-7.42 (m, 6H), 7.53 (d, 1H, J = 7.8 Hz), 7.61 (d, 2H, J = 6.2 Hz), 7.75 (s, 1H), 8.42 (d, 2H, J = 6.2 Hz), 10.76 (s, 1H), 11.21 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 42.0, 48.2, 110.3, 111.2, 112.4, 112.7, 113.3, 113.7, 119.0, 119.1, 121.5, 121.6, 123.6, 125.6, 127.2, 127.6, 128.3, 128.6, 128.9, 131.9, 135.1, 136.1, 137.5, 145.9, 150.5, 171.9; ESI-HRMS: calcd for C30H23BrClN4O, 569.0738; found, 569.0732 [M + H]+.
2-(1H-Indol-3-yl)-2-(2-methyl-1H-indol-3-yl)-N-(pyridin-4-yl)acetamide (4d)
White solid; mp 186.4-188.4 °C (PE-EtOAc); IR 3401.8, 3302.1, 1670.0, 1592.7, 1510.2 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 2.41 (s, 3H), 5.52 (s, 1H), 6.83-6.97 (m, 3H), 7.04 (t, 1H, J = 7.8 Hz), 7.08 (d, 1H, J = 1.8 Hz), 7.22 (d, 1H, J = 7.9 Hz), 7.31 (d, 1H, J = 8.1 Hz), 7.34 (d, 1H, J = 8.1 Hz), 7.61 (d, 2H, J = 6.2 Hz), 7.67 (d, 1H, J = 7.8 Hz), 8.40 (d, 2H, J = 5.7 Hz), 10.57 (s, 1H), 10.86-10.87 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ: 12.0, 41.7, 107.9, 110.3, 111.5, 113.0, 113.3, 118.1, 118.3, 118.4, 119.4, 119.9, 121.0, 123.5, 126.7, 127.8, 133.0, 135.1, 136.3, 146.1, 150.3, 172.2; ESI-HRMS: calcd for C24H21N4O, 381.1710; found, 381.1709 [M + H]+.
2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-N-tert-butyl-2-(1H-indol-3-yl)acetamide (4e)
White solid; mp 188.0-189.7 °C (PE-EtOAc); IR 3400.2, 3286.1, 1655.0, 1547.3, 1491.7, 1455.8 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 1.26 (s, 9H), 5.33 (s, 1H), 5.37 (s, 2H), 6.92-6.98 (m, 2H), 7.00-7.08 (m, 3H), 7.15 (d, 2H, J = 8.4 Hz), 7.22 (s, 1H), 7.31-7.38 (m, 4H), 7.54 (d, 1H, J = 8.1 Hz), 7.57 (d, 1H, J = 8.0 Hz), 7.82 (s, 1H), 10.80 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ: 28.5, 41.1, 48.1, 50.1, 110.0, 111.4, 114.4, 114.8, 118.1, 118.6, 119.1, 119.4, 120.8, 121.2, 123.4, 126.8, 127.3, 127.5, 128.4, 128.8, 131.8, 136.0, 136.3, 137.6, 171.5; ESI-HRMS: calcd for C29H28ClN3ONa, 492.1813; found, 492.1815 [M + Na]+.
2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-2-(3-methyl-1H-indol-2-yl)-N-(pyridin-4-yl)acetamide (4f)
White solid; mp 171.4-171.8 °C (PE-EtOAc); IR 3429.5, 3056.4, 1695.1, 1591.7, 1508.4 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 2.36 (s, 3H), 5.41 (d, 2H, J = 1.9), 5.69 (s, 1H), 6.91-7.03 (m, 3H), 7.09 (t, 1H, J = 7.4 Hz), 7.24 (d, 2H, J = 8.4 Hz), 7.33-7.48 (m, 7H), 7.63 (d, 2H, J = 6.3 Hz), 8.45 (d, 2H, J = 6.2 Hz), 10.56 (s, 1H), 10.86 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ: 8.6, 41.8, 48.4, 106.3, 110.3, 111.3, 111.6, 113.4, 117.9, 118.1, 118.5, 119.2, 120.7, 121.7, 127.0, 127.6, 128.1, 128.5, 129.0, 131.6, 131.9, 135.7, 135.9, 137.2, 145.6, 150.5, 170.6; ESI-HRMS: calcd for C31H26ClN4O, 505.1789; found, 505.1787 [M + H]+.
2-[1-(4-Chlorobenzyl)-1H-indol-3-yl]-N-tert-butyl-2-(3-methyl-1H-indol-2-yl)acetamide (4g)
White solid; mp 221.5-222.7 °C (PE-EtOAc); IR 3419.2, 3289.8, 1641.3, 1549.4, 1490.3, 1460.3 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: 1.28 (s, 9H), 2.31 (s, 3H), 5.38 (d, 2H, J = 4.3 Hz), 5.43 (s, 1H), 6.68-7.01 (m, 3H), 7.06 (t, 1H, J = 7.7 Hz), 7.21 (d, 2H, J = 8.4 Hz), 7.30 (s, 1H), 7.32-7.40 (m, 5H), 7.48 (d, 1H, J = 7.8 Hz), 8.04 (d, 1H, J = 8.0 Hz), 10.32 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ: 8.5, 28.4, 40.8, 48.3, 50.4, 105.3, 110.1, 111.3, 113.4, 117.6, 117.9, 118.8, 118.9, 120.2, 121.4, 127.1, 127.2, 128.2, 128.4, 128.9, 131.9, 133.3, 135.5, 135.8, 137.3, 170.2; ESI-HRMS: calcd for C30H30ClN3ONa, 506.1970; found, 506.1967 [M + Na]+.

ACKNOWLEDGEMENTS
We thank the Great Program of Science Foundation of Tianjin (06YFJZJC02700) for financial support.

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