Chapter-8

Chapter-8

Synthesis of Bis(indolyl)methanes and Related Natural Products

8.1. Introduction Indoles and their derivatives possess various biological properties like antibacterial, cytotoxic, anti oxidative and insecticidal activities. Some indole derivatives are used as antibiotics in pharmaceutical industry.217 Biologically active indole alkaloids displaying great structural variety are ubiquitous in nature, particularly in marine environments. Bis(indolyl) alkanes have received considerable attention because of occurrence in bioactive metabolites of terrestrial and marine origin. The alkaloids obtained from marine organisms frequently posses novel frameworks while in other cases terrestrially related compounds clearly exist. Marine metabolites often possess complexities such as halogen substituents. Their synthesis, stereochemistry, structure elucidation, chemical modification and pharmacology have received a great deal of interdisciplinary attention from areas of research other than chemistry and include pharmacology, physiology and medicine. 3,3′-Diindolyl methane (DIM) is a major digestive product of indol-3-methanol, a potential anticancer component of cruciferous vegetables. 3,3’-diindolyl methane is potent activator of the immune response system in vivo. 3,3’-diindolyl methane exhibits potent anti proliferative and anti androgenic properties in androgen-dependent human prostate cancer cells.218 Recent biological studies show that 4-(di(1H-indol-3-yl)methyl)benzene-1,2-diol (1) worked as HIV-1 integrase inhibitor.

Vibrindole A (2) exhibits antibacterial activity and its metabolites of the marine bacterium Vibrio parahaemolyticus. Compound 3 has growth inhibitory activity on prostate cancer cells. Compound 4 was reported to act as a non-steroidal aromatage inhibitor against breast cancer.

Figure 8.1. Pharmacologically active compounds containing the indole and bisindole motif Dragmacidin 5 is a bis(indole) alkaloid isolated from a deep water marine sponge dragmacidin species and showed cytotoxicity against human colon, human lung and human mammary cancer cell lines in vitro.219 Hyrtiosin A and B is isolated from the Okinawan sponge. Hyrtios erecta exhibited cytotoxic activity and it is too active in vitro against human epidermoid carcinoma KB cells.220 Dragacidin D, Topsentin B1 and B2 (Figure 8.2) are bisindole alkaloids and exhibit anticancer activity. Coscinamide A, B and C (Figure 8.2) are isolated from the organic extract of coscinoderma show antiviral activity.221 Dragmacidin D and E (Figure 8.2) isolated from the Dragmacidin species work as enzyme inhibitors. Dragmacidin D was also shown to inhibit neutral nitric oxide synthase, which may prove to help in the treatment of Huntington’s, Parkinson’s and Alzheimer’s disease.222

Figure 8.2. Pharmacologically active compounds containing the indole and bisindole motif. Bis(indole) alkaloid Hyrtiosin B has been shown to pocess weak cytotoxic activity against human epidermoid KB cells in vitro.223 Marine sponge Topsentins and its analogs show antitumor, antiviral and anti-inflammatory activities.224 Few of indole derivatives are known their application in agrochemicals225 and material science.226 Recently Pedro Molina and co-workers227 have developed new probes, based on bis(indolyl)methane derivatives to sense Cu2+ ions among other transition metal ions. Hamacanthin B (Figure 8.3) is isolated from Hamacantha species and has been reputed to show significant antimicrobial activity against Canadiba albicans and Cryptococcus neoformans.

Figure 8.3. Hamacanthin B Owing to the various biological importances of bisindole derivatives, there are synthetic approaches available in the literature and some of these approaches are described below. 8.1.1. Review of synthetic approaches of bis(indolyl) methanes: a. Meshram et at.228 described use of silica-supported cupric fluoroborate (CuBF4)2 as a catalyst for the synthesis of bis(indolyl) methane derivatives (18). In this process a mixture of indole (16), aldehydes (17) and cupric fluoroborate was heated to 80 °C in dichloromethane. Final products were obtained after column purification.

Scheme 1. Reagents and conditions: (a) Cu(BF4)2.SiO2, DCM, 80 °C b. Heravi et al.229 used Niobium(V)chloride as a catalyst for the synthesis of bis(indolyl) methane derivatives. In this process, a mixture of indole (16), aldehydes (17) and Niobium(V)chloride was heated to 90 °C without solvent.

Scheme 2. Reagents and conditions: (a) NbCl5, 90 °C c. Depu Chen et al.230 reported lanthanide triflates as a catalyst for the bis(indolyl)methane derivatives synthesis. Mixture of indole (16), aldehydes (17) and lanthanide triflate was stirred at room temperature in ethanol/water mixture as solvent to obtained the bis(indolyl) methane derivatives (18).

Scheme 3. Reagents and conditions: (a) Ln(OTf)3, Ethanol, Water, 25-30 °C d. J.S.Yadav et al.231 evaluated Lithium per-chlorate as catalyst for the bis(indolyl)methane`s synthesis. In this process, a mixture of indole (16), aldehydes (17) and Lithium per-chlorate was stirred at room temperature in ethanol/water mixture as solvent.

Scheme 4. Reagents and conditions: (a) LiClO4, Acetonitrile, 25-30 °C e. M.B.Teimoun et al.232 reported synthesis of bis(indolyl)methane`s derivatives (18) via coupling of indole (16), aldehydes (17) in the presence of hexamethylenetetramine-bromine as a catalyst in water at 75 °C.

Scheme 5. Reagents and conditions: (a) HMTAB, Water, 75 °C f. T.Perumal et al.233 reported potassium hydrogen sulfate as a catalyst for the bis(indolyl)methane derivative synthesis. In this paper a mixture of indole (16), aldehydes (17) and potassium hydrogen sulfate was stirred at room temperature in methanol at ambient temperature.

Scheme 6. Reagents and conditions: (a) KHSO4, Methanol, 25-30 °C g. K. Tabatabaeian et al.234 used Ruthenium(III)chloride as catalyst for the synthesis of bis(indolyl) methane derivatives. In this process, a mixture of indole (16), aldehydes (17) and Ruthenium(V)chloride stirred at room temperature in methanol.

Scheme 7. Reagents and conditions: (a) Ru(III)Cl, Methanol, 25-30 °C

8.1.2. Limitation of reported synthetic approaches of bis(indolyl) methanes: Although a number of modified methods under improved conditions have been reported, many of them suffer from drawbacks such as that many Lewis acids are deactivated or

sometimes decomposed by nitrogen-containing reactants when the reaction is carried out in large scale. Even when the desired reactions proceed, more than stoichiometric amounts of Lewis acids are required because the acids are trapped by nitrogen. Moreover, after completion of the reaction, the excess Lewis acids are destroyed in the aqueous quench, liberating large amounts of harmful mixtures containing metal ions and organic wastes that are detrimental to our delicate eco-system. Further, the use of soluble metal catalysts in these systems often necessitates a tedious catalyst separation step. Consequently, there is a need for a greater catalytically efficient method for these transformations which might work under mild and more economical and environmentally benign conditions. Therefore, the ideal synthesis is shown to lead the product with good yields, environmentally compatible reagent, operational simplicity, reusability, economic viability and greater selectivity.

8.2. Results and discussion Owing to the ubiquitous nature of indole derivatives in organic compounds, there is a need for a greater catalytically efficient method for these transformations which might work under mild and more economical conditions. The ion exchange resins play a crucial role nowadays in the field of chemistry. Ion exchange resins are used as Bronsted or Lewis acid catalysts.235 The use of resin as a catalyst has significant practical advantages since it is inexpensive and non toxic. In particular, the chemistry of resin in organic synthesis has recently received increasing attention over its companion reagents owing to its stability in water and air actively utilized as a catalyst for various types of organic syntheses. In addition, the growing concern for the influence of the chemical reagents on the environment as well as on human body, recovery and reusability of the chemical reagents has attracted the attention of synthetic organic chemists. More importantly pharmaceutical industry has given more importance towards recovery and reuse of chemical reagents to reduce the cost of a product as well as the environmental burden.

Search for a new method for the construction of bis(indoloyl) methane derivatives allow us to develop a new protocol by using Indion Ina 225H as a catalyst. Based on the commercial availability, low toxicity and economic feasibility, we chose Indion Ina 225H as a catalyst. In recent years, Indion Ina 225H has received considerable attention as an inexpensive, easily available, recovered and reused for several times, which makes it useful and attractive for synthesis of these class of compounds for economic viability and greater selectivity. Indion Ina 225H resin236 is a macro reticular sulfonic acid based cation exchange resin which is inexpensive and commercially available with low cost. It appears as golden yellow beads. The matrix is styrene divinylbenzene copolymer. To the best of our knowledge there is no report of the use of Indion Ina 225H resin as a catalyst for these types of reactions. Optimization of reaction conditions and substrate studies To find out the best catalyst system for the conversion of indole to bis(indolyl)methanes in large scale synthesis we have screened various solid support resins such as Amberjet 1200H, Amberlite IR 120, Indion 130, Indion Ina 225H, Amberlyst 15, inorganic acids, sulfuric acid etc (Table 8.1). Reaction of indole (2 mmol) and benzaldehyde (1 mmol) was used as a model substrate. As seen from the Table 8.1, Indion Ina 225H catalyzes the reaction better than other catalyst except sulfuric acid, which is highly corrosive and hazardous and not acceptable for large scale synthesis.

Table 8.1. Screening of catalyst Entry

Catalysta

Time (hrs)

Yield (%)b

1

Indion Ina 225H

1

98

2

Indion 130

24

NR

3

Amberlyst-15

12

85

a

b

4

Dowex 50

24

traces

5

Amberjet 1200 H

24

NR

6

Amberlite IR 120

24

NR

7

H2SO4

2

90

8

p-TsOH

6

80

9

Sulfamic acid

12

78

100 mg of the catalyst was used.

Yields referred to the isolated yield. Next, we investigated the catalytic activity of Indion Ina 225H resin with different solvents and

the results are summarized in Table 8.2. While choosing the solvent we have preferably avoided the use of ICH class-1 solvents (benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethane and 1,1,1-trichloroethane) and ICH class–4 solvents (1,1-diethoxy propane, 1,1-dimethoxy propane, 2,2dimethoxy propane, Isooctane, isopropyl ether, methyl isopropyl ketone, methyltetrahyrofuran, petroleum ether etc) in the synthesis. Among the solvent examined, acetonitrile proved to be the most effective (Table 8.2, entry 9 & 10).

Scheme 8: Reagents and conditions: (a) Indion Ina 225H, Acetonitrile, 25-50 °C Table 8.2. Effect of solventa on the conversion of indole (16) and benzaldehyde (19) to bis(indolyl)methanes with different molar equivalence of Indion Ina 225H resin.a Entry

Solvent

Temperature (°C)

Yield %b

1

Methanol

Reflux

20

2

Ethanol

Reflux

25

3

i-PrOH

Reflux

20

4

H20

60

NR

5

THF

Reflux

35

6

Toluene

80

40

7

Dichloromethane

Reflux

20

8

2-Methyl THF

Reflux

18

9

Acetonitrile

50

98

10

Acetonitrile

RT

98

a

All reactions were carried out using 2:1 mol ratio of indole and benzaldehyde and 100mg of Indion Ina 225H resin. b

Isolated yield.

c

NR, no reaction.

To explore the generality and scope of this method, a wide variety of substituted indoles and aldehydes were reacted using Indion Ina 225H resin under optimized experimental (Scheme 9) conditions to afford the corresponding bis(indolyl)methane and the results are summarized in Table 8.3. The isolated products were characterized by spectral analyses. General scheme for synthesis of bis(indoloyl)methane derivatives from carbonyl compounds and indole derivatives is shown below.

Scheme 9: Reagents and conditions: (a) Indion Ina 225H, Acetonitrile, 25-50 °C

Table 8.3. Indion Ina 225 H catalyzed efficient synthesis of bis(indolyl)methanesa

Carbonyl

Productb

Temp (°C)

Time (hrs)

Yield (%)c

1

20

50

2.5

90

2

24

50

2.0

92

3

25

50

2.5

95

4

26

RT

3.4

95

5

27

50

2.1

95

6

28

50

2.3

95

7

29

RT

3.0

93

Entry

Indole derivative

compound

8

30

RT

2.5

95

9

31

RT

2.2

96

10

32

RT

2.3

95

11

33

RT

2.6

94

12

34

RT

2.4

95

13

35

RT

2.3

95

14

36

RT

2.6

95

15

37

RT

2.2

89

16

38

50

2.0

92

17

39

50

2.0

93

18

40

50

2.0

93

19

41

50

2.5

90

20

42

50

2.0

92

21

43

50

2.5

95

22

-

50

24

NRd

44

a

All reaction were carried out using 200 mg of Indion Ina 225H in acetonitrile.

b

All products were characterized by their spectroscopic and physical data and are agreement with the literature data. c

Yield refers to pure isolated products.

d

NR, no reaction.

The effect of electron deficiency and the nature of substituents on the aromatic ring of aldehyde showed some effect on this conversion. The chloro and nitro-substituted aryl aldehydes (Table 8.3, entry 5, 6, 7, 10 & 14) required longer reaction times to produce comparable yields than those of their simple electron-rich counterparts. Electron-rich aldehydes like 3,4-dimethoxybenzaldehyde (22b) and 4(trifluoromethyl)benzaldehyde (22i, Table 8.3, entry 2 & 11) reacted rapidly with indole (21a) and 5substituted indole to give excellent yields of the products. The reaction works equally good with the aliphatic aldehydes (Table 8.3, entry 16-18) and indoles in shorter reaction time with high yields. The reaction conditions are mild enough not to induce any isomerization for furfural (Table 8.3, entry 15) or damage to moieties such as methoxy, which often undergo cleavage in strongly acidic reaction media (Table 8.3, entry 2, 13). The chemo selectivity of the aldehydes and ketones was also verified and found that the resin is specific to aldehydes as shown in Table 8.3 entry 19-21. As seen from the Table 8.3 aetophenone (Table 8.3, entry 22) did not react at all with indole in presence of Indion Ina 225H resin under the reaction condition we studied. On the other hand, no side products were observed during the course of the reactions we studied. The products mentioned in Table 8.3 were isolated without any column purification. With the above successful results, we want to enhance the scope of the present methodology towards the synthesis of biologically active bis(indolyl) methanes, such as Vibrindole A (2), 4-(di(1Hindol-3-yl)methyl)benzene-1,2-diol (1) and Streptindole (45), for their broad range of pharmacological activity (Figure 8.1). Vibrindole A (2) is a metabolite of the marine bacterium Vibrio parahaemolyticus which exhibits antibacterial activity. In recent studies on cancer therapeutics, 4-(di(1H-indol-3yl)methyl)benzene-1,2-diol (1) served as a HIV-1 integrase inhibitor. Streptindole (45) is isolated from intestinal bacteria Streptococcus faecium IB37 and causes DNA lesions in Bacillus subtilis cells.

8.2.1. Scheme for synthesis of Vibrindole A (2)

Scheme 10: Reagents and conditions: (a) Indion Ina 225H, Acetonitrile, 50 °C Syntheis of the Vibrindole began by mixing a mixture of indole (16) (200 mmol) and acetaldehyde (46) (100 mmol) and Indion Ina 225H resin (50g with respect to aldehyde) in acetonitrile (500 ml) was stirred at 50 °C for two hours. The reaction progress was monitored by TLC. After complete conversion the heterogeneous mass was filtered and the resin was washed with acetonitrile. The solvent was removed in a rotary evaporator under reduced pressure. To the crude reaction mass heptanes (500 mL) was added and distill off the heptane in a rotary evaporator under reduced pressure to result off-white solid. To this solid again added 200 mL of heptanes and sired for 15-20 minutes at room temperature. The solid was filtered and dried in an oven in vacuum to afford the pure product. (Yield: 95%).

8.2.2. Scheme for synthesis of 4-(di(1H-indol-3-yl)methyl)benzene-1,2-diol (1)

Scheme 11: Reagents and conditions: (a) Indion Ina 225H, Acetonitrile, 50 °C Process followed for the preparation of 4-(di(1H-indol-3-yl)methyl)benzene-1,2-diol, a mixture of indole (16) (200 mmol) and 3,4-dihydroxy benzaldehyde (47) (100 mmol) and Indion Ina 225H resin (50g with respect to aldehyde) in acetonitrile (500 ml) was stirred at 50°C for two hours. The reaction progress was monitored by TLC. After complete conversion the heterogeneous mass was filtered and the resin was washed with acetonitrile. The solvent was removed in a rotary evaporator under reduced pressure. To the crude reaction mass heptanes (500 mL) was added and distill off the heptane in a rotary evaporator under reduced pressure to result off-white solid. To this solid again added 200 mL of heptanes and sired for 15-20 minutes at room temperature. The solid was filtered and dried in an oven in vacuum to afford the pure product. (Yield: 93%). 8.2.3. Synthetic scheme for Streptindole (45)

Scheme 12: Reagents and conditions: (a) Indion Ina 225H, Acetonitrile, 25-30 °C; (b) BH3.THF, THF, 5-10 °C; (c) FeF3, Acetonitrile, Acetic anhydride, 25 °C Reaction of indole (16) and ethyl glyoxylate (48) in presence of Indion Ina 225H resin in acetonitrile resulted ethyl di-1H-indol-3-ylacetate (49) which is then reduced to the corresponding alcohol (50) by BH3-THF complex in THF. Finally, the alcohol (50) is O-acetylated using FeF3 as a Lewis acid catalyst to afford streptindole (45) (Scheme 12). This acylation reaction is facilitated by the action of FeF3 as a useful reagent which can be recovered and reused for several runs. 8.2.4. Reaction mechanism

Figure 8.4. Proposed mechanism for the synthesis of bisindole derivatives.

A plausible mechanism indicates that the aldehyde and the resin formed I. This complex activates the carbonyl compound and then reacts with first molecule of indole to form the compound II. The compound II converts to a stable azafulvenium cation III. The azafulvenium cation III reacts with the second molecule of indole to form IV, which aromatizes further to from the desired product. 8.2.5. Reusability of catalyst After completion of the reaction the resin was filtered and washed with acetonitrile. The recovered resin was recycled for consecutive four times for the reaction to furnish the product with a little variation in yields (Table 8.4).

Table 8.4. Indion Ina 225H resin recyclability.a

a

Entry

Run

Yieldb

1

0

95

2

1

93

3

2

92

4

3

90

5

4

90

Reactions were performed with indole (2 mmol), aldehyde (1mmol) using 100 mg of Indion INA 225H

resin catalyst and 1 mL of acetonitrile as a solvent at room temperature for 1 h. b

Isolated yield.

Infrared Spectrum of the recovered Indion Ina 225H and fresh Indioan Ina 225H resin Infrared spectrum of the recovered (after 5th run) and fresh sample of Indion Ina 225H resin is shown in Figure 8.5. The FT-IR spectrum shows absorption at 3700-3400 cm-1 (-OH stretches). The presence of moisture is evident through the broadness of the peak around 3600 cm -1 due to the bending mode of the adsorbed water in the recovered sample of Indiaon Ina 225H resin sample (after 5th run). The sulfonic acids on the resin can be readily identified by the appearance of two strong bands at 1400 and 1210-1120 cm-1 due to the asymmetric and symmetric stretching vibrations of the S=O group respectively.

Indion Ina 225H

Recovered Indion Ina 225H resin (after 5th run)

Wave numbers (cm-1)

Figure 8.5. Infrared spectrum of Indion Ina 225H resin.

8.3. Nature of the products and product characterization

Numbers of compounds which were synthesized in the research program are stable at room temperature and could be handled safely and stored at ambient conditions. However, all other compounds were obtained as solids except 38, 39 and 40. All the compounds were obtained without column chromatography. All the synthesized products were well characterized by spectroscopic data (IR,

1

H NMR, 13C NMR, and mass) and HRMS data. A representative example of 1H NMR and 13C NMR of 1-(4-

(di(1H-indol-3-yl)methyl)phenyl)ethanone (41) are shown in Figure 8.18 and 8.19. When Indole 21a reacted with 4-acetyl benzaldehyde 22n in the presence of Indion Ina 225H resin as a catalyst in acetonitrile, peak appeared

in 1H NMR at ~ 5.92 (s, 1H) of compound 41 is prominent peak

corresponds to the bisindole formation. In 4-acetyl benzaldehyde 22n aldehydes is reacted with indole and not the ketone group. In

13

C NMR spectra, peak at ~ 40.19 is further supported for bisindole

formation. In IR peak at 3406 is N–H cm-1 stretching of indole and peak at 1669 is C=O cm-1 stretching of ketone. In mass data, molecular ion peak 365.10 (M+H), for compound (41) which is in agreement with the structure, is further confirmed by HRMS data C25H19N2O: 363.1497; found: 363.1483.

8.4. Conclusion In conclusion, we have developed a simple and efficient method for the synthesis of various bis(indoloyl) methane compounds. Our method is much superior to many of the available methods for a number of reasons. It is fast and efficient, employs a cheap and a column chromatography purification free methodology for the isolation of the compounds. The reactions are very clean and products were obtained in excellent to high yields without the formation of side products. We have demonstrated the utility of our methodology towards the synthesis of biologically active moiety such as Vibrindole A, 3,3′Diindolyl methane and Streptindole. The synthetic importance of the methodology demonstrated towards the multi gram quantities of naturally occurring bis(indoloyl) methane compounds, upon which we have recently embarked. Furthermore, the catalyst can be recovered conveniently and reused for several runs without loss of catalytic activity.

8.5. Experimental Section

In a typical experimental procedure, a mixture of indole (1a) (200 mmol) and benzaldehyde (2a) (100 mmol) and Indion Ina 225H resin (50g with respect to aldehyde) in acetonitrile (500 ml) was stirred at room temperature for an appropriate time (Table 3). After confirming the complete consumption of starting material by TLC, the heterogeneous mass was filtered and the resin was washed with acetonitrile. The solvent was removed in a rotary evaporator under reduced pressure. To the crude reaction mass heptanes (500 mL) was added and distill off the heptane in a rotary evaporator under reduced pressure to result off-white solid. To this solid again added 200 mL of heptanes and sired for 1520 minutes at room temperature. The solid was filtered and dried in an oven in vacuum to afford the pure product. (Yield: 90%).

3-((1H-indol-3-yl)(phenyl)methyl)-1H-indole (20) White solid; MP: 143-145 °C; IR (KBr): 3404, 3051, 1492, 1454, 1415, 1336, 1091, 1008, 744 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 10.78 (brs, 2H, NH), 7.32-7.36 (m, 4H), 7.24-7.28 (m, 4H), 7.14-7.18 (m, 1H), 7.00-7.04 (m, 2H), 6.85-6.87 (t, 2H, J = 6.8Hz), 6.81 (d, 2H, J = 2.0Hz), 5.82 (s, 1H, Ar-CH); 13C NMR (50 MHz, DMSO-d6): δ 144.80, 136.51, 128.21, 127.92, 126.56, 125.68, 123.45, 120.78, 119.02, 118.08, 118.00, 111.36, 39.69; MS (ES): m/z = 324.2 (M+H).

3-[(1H-indol-3-yl)(3,4-dimethoxyphenyl)methyl]-1H-indole (24). Red solid; MP: 193-195°C (Lit-195 °C); IR (KBr): 3414, 3055, 2960, 1593, 1506, 1460, 1340, 1228, 1134, 1022, 752 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 10.74 (brs, 2H, NH), 7.32 (d, 2H, J = 7.6 Hz), 7.27 (d, 2H, J = 7.6 Hz), 6.99 -7.04 (m, 3H), 6.87 (d, 2H, J = 7.2 Hz), 6.83 (s, 1H), 6.81 (d, 2H, J = 2.4 Hz), 5.75 (s, 1H, ArCH), 3.69 (s, 3H, -OCH3), 3.63 (s, 3H, -OCH3); 13C NMR (50 MHz, DMSO-d6): δ 148.34. 146.89, 137.47, 136.55, 126.63, 123.41, 120.78, 120.12, 119.13, 118.34, 118.06, 112.53, 111.50, 111.37, 55.41; MS (ES): m/z 382.16 (M-H); ESI-HRMS: m/z [M-H]+ calculated for C25H21N2O2: 381.1603; found 381.1607.

3,3'-(Biphenyl-4-ylmethylene)bis(1H-indole) (25) Bric red solid; MP: 233-236 °C; IR (KBr): 3419, 3037, 1550, 1487, 1454, 1415, 1336, 1215, 1093, 1006, 860, 763, 744; 1H NMR (400 MHz, DMSO-d6): δ 9.60 (brs, 2H, NH), 7.56 (d, 2H, J = 8.4Hz), 7.48 (d, 2H, J = 8.4Hz), 7.36-7.43 (m, 9H), 7.27-7.31 (t, 1H, J = 7.2Hz), 7.08-7.12 (t, 2H, J = 8.0Hz), 6.91-6.95 (t, 2H, J = 8.0Hz), 6.75 (s,2H), 5.90 (s, 1H, Ar-CH); MS (ES): m/z = 397.30 (M+H)

4-[di(1H-indol-3-yl)methyl]benzonitrile (26). Slight brown solid; MP: 209-210°C (208-210 °C); IR (KBr): 3446, 2924, 2227, 1604, 1498, 1456, 1415, 1336, 1093, 744 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 7.97 (brs, 2H, NH), 7.43 (d, 2H, J = 8.4 Hz), 7.36 (d, 2H, J = 8.4 Hz), 7.31 (d, 2H, J = 8.0 Hz), 7.20 (t, 2H, J = 6.8 Hz), 7.00-7.04 (m, 2H), 6.66 (s, 2H), 5.93 (s, 1H, Ar-CH); 13C NMR (75 MHz, DMSO-d6): δ 150.79, 136.50, 132.00, 129.22, 126.32, 123.71, 120.98, 118.97, 118.84, 118.30, 116.74, 111.48, 108.56; MS (ES): m/z = 346.2 (M-H); ESI-HRMS: m/z [M-H]+ calculated for C24H16N3: 346.1344; found 346.1331.

3-[(1H-indol-3-yl)(4-nitrophenyl)methyl]-1H-indole (27). Yellow solid; MP: 228-230 °C; IR (KBr): 3454, 2924, 1593, 1506, 1456, 1415, 1340, 1010, 746 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 9.10 (brs, 2H, NH), 8.08-8.12 (m, 2H), 7.51 (d, 2H, J = 8.8 Hz), 7.38 (d, 2H, J = 8.4 Hz), 7.28 (d, 2H, J = 8.2 Hz), 7.08-7.12 (m, 2H), 6.91-6.95 (m, 2H), 6.72 (d, 2H, J = 1.6 Hz), 5.98 (s, 1H, Ar-CH);

13

C NMR (75 MHz, DMSO-d6): δ 153.02, 145.68, 136.51, 129.35, 126.29, 123.77, 123.31,

121.01, 118.82, 118.34, 116.61, 111.50; MS (ES): m/z = 366.3 (M-H); ESI-HRMS: m/z [M-H]+ calculated for C23H16N3O2: 366.1243; found 366.1233.

3-[(1H-indol-3-yl)(3-nitrophenyl)methyl]-1H-indole (28). Brick red solid; MP: 96-99 °C; IR (KBr): 3412, 3055, 1523, 1456, 1348, 1093, 1010, 744 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.21 (t, 1H, J = 2.0 Hz), 8.06-8.08 (m, 1H), 7.98 (brs, 2H, NH), 7.68 (d, 2H, J = 7.2 Hz), 7.43 (d, 2H, J = 7.6 Hz), 7.34-7.39 (m, 4H), 7.17-7.21 (m, 2H), 7.00-7.04 (m, 2H,), 6.67 (d, 2H, J = 2.0 Hz), 5.99 (s, 1H);

13

C NMR (75 MHz, CDCl3): δ 148.36, 146.33, 136.66, 134.81, 129.05, 126.55, 123.66, 123.49,

122.19, 121.39, 119.44, 118.12, 111.27, 39.97; MS (ES): m/z = 366.6 (M-H); ESI-HRMS: m/z [M-H]+ calculated for C23H16N3O2: 366.1243; found 366.1231.

3-[(4-chlorophenyl)(1H-indol-3-yl)methyl]-1H-indole (29). Brownish red solid; MP: 98-101 °C; IR (KBr): 3414, 3052, 1487, 1454, 1089, 1012, 742 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.95 (brs, 2H, NH), 7.34 (d, 2H, J = 8.8 Hz), 7.20-7.25 (m, 4H), 7.20 (t, 2H, J = 8.4 Hz), 6.98-

7.00 (m, 2H), 6.64 (d, 2H, J = 1.6 Hz), 5.86 (s, 1H, Ar-CH); 13C NMR (75 MHz, DMSO-d6): δ 143.91, 136.52, 130.18, 130.01, 127.89, 126.40, 123.53, 120.87, 118.94, 118.18, 117.49, 111.42; MS (ES): m/z = 358.2 (M-H); ESI-HRMS: m/z [M-H]+ calculated for C23H16N2Cl: 355.1002; found 355.0988.

4-[(5-hydroxy-1H-indol-3-yl)(1H-indol-3-yl)methyl]benzonitrile (31) Brick red solid; MP: 212-215 °C; IR (KBr): 3406, 2227, 1604, 1581, 1487, 1456, 1184, 973, 800, 773 cm-1; 1

H NMR (400 MHz, DMSO-d6): δ 10.54 (brs, 2H, NH), 8.48 (s, 2H, OH), 7.72(d, 2H, J = 8.4 Hz), 7.48 (d, 2H,

J = 8.4 Hz), 7.13-7.15 (m, 2H), 6.69 (d, 2H, J = 2.0 Hz), 6.55-6.70 (m, 4H), 5.69 (s, 1H, Ar-CH); 13C NMR (75 MHz, DMSO-d6): δ 150.83, 150.02, 131.98, 131.10, 129.27, 127.05, 124.18, 119.06, 115.79, 111.79, 111.36, 108.49, 102.97; MS (ES): m/z = 378.3 (M-H); ESI-HRMS: m/z [M-H]+ calculated for C24H16N3O2: 378.1243; found 378.1227.

3-[(1H-indol-3-yl)(4-nitrophenyl)methyl]-1H-indol-5-ol (32)

Yellow solid; MP: 225-228 °C; IR (KBr): 3417, 2927, 1591, 1572, 1487, 1456, 1344, 1182, 937, 775 cm-1; 1

H NMR (400 MHz, DMSO-d6): δ 10.57 (brs, 2H, NH), 8.48 ((s, 2H, OH), 8.16 (d, 2H, J = 8.8 Hz), 7.56 (d,

2H, J = 8.8 Hz), 7.15 (d, 1H, J = 2.0 Hz), 7.13 (d,1H, J = 1.6 Hz), 6.72 (d, 2H, J = 2.4 Hz), 6.55-6.57 (m, 4H), 5.76 (s, 1H, Ar-CH);

13

C NMR (75 MHz, DMSO-d6): δ 153.08, 150.04, 145.66, 131.10, 129.39, 127.00,

124.21, 123.28, 115.64, 111.81, 111.37, 102.93; MS (ES): m/z = 398.2 (M-H); ESI-HRMS: m/z [M-H]+ calculated for C23H16N3O4: 398.1141; found: 398.1140.

3-[(4-(trifluoromethyl)phenyl)(1H-indol-3-yl)methyl]-1H-indol-5-ol (33) Brown solid; MP: 146-148 °C; IR (KBr): 3415, 2926, 1583, 1485, 1462, 1454, 1325, 1168, 1118, 1066, 1016, 937, 800, 667 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 10.52 (brs, 2H, NH), 8.47 (s, 2H, OH), 7.62 (d, 2H, J = 8.4 Hz), 7.50 (d, 2H, J = 8.4 Hz), 7.12 (d, 2H, J = 8.8 Hz), 6.69 (d, 2H, J = 2.0 Hz), 6.54-6.58 (m, 4H), 5.69 (s, 1H, Ar-CH);

13

C NMR (75 MHz, DMSO-d6): δ 149.99, 131.12, 128.96, 127.08, 124.84, 124.82,

124.13, 116.10, 111.77, 111.31, 102.98; MS (ES): m/z = 423.2 (M-H); ESI-HRMS: m/z [M-H]+ calculated for C25H18N2O4F3 (M-HCOO)+ 467.1219; found: 467.1236.

3-[(4-tert-butylphenyl)(1H-indol-3-yl)methyl]-1H-indol-5-ol (34) Pink solid; MP: 144-146 °C; IR (KBr): 3415, 2960, 1581, 1487, 1462, 1359, 1182, 937, 773 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 10.41 (brs, 2H, NH), 8.43 (s, 2H, OH), 7.28 (dd, 2H, J = 8.8 & 2.0 Hz), 7.22 (dd, 2H, J = 8.8 & 2.0 Hz), 7.10 (d, 2H, J = 8.8 Hz), 6.66 (d ,2H, J = 2.0 Hz), 6.61 (d, 2H, J = 2.0 Hz), 6.52-6.55 (m, 2H), 5.52 (s, 1H, Ar-CH), 1.25 (s, 9H); 13C NMR (75 MHz, DMSO-d6): δ 149.78, 147.62, 141.83, 131.07, 127.79, 127.26, 124.57, 123.84, 117.17, 111.57, 111.05, 103.14, 34.03, 31.24; MS (ES): m/z = 409.4 (MH); ESI-HRMS: m/z [M-H]+ calculated for C28H27N2O4 (M-HCOO)+ 455.1971; found: 455.1966.

4-[(1H-indol-3-yl)(5-methoxy-1H-indol-3-yl)methyl]benzonitrile (35) Pink solid; MP: 110-113 °C; IR (KBr): 3410, 2935, 2225, 1604, 1581, 1483, 1452, 1209, 1170, 1041, 925, 798 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 10.72 (brs, 2H, NH), 7.72 (d, 2H, J = 8.4 Hz), 7.54 (d, 2H, J = 8.0 Hz), 7.23 (d, 2H, J = 8.8 Hz), 6.86 (d, 2H, J = 2.0 Hz), 6.69-6.73 (m, 4H), 5.87 (s, 1H, Ar-CH), 3.60 (s, 6H, OCH3); 13C NMR (75 MHz, DMSO-d6): δ 152.74, 150.92, 131.99, 131.69, 129.22, 126.72, 124.43, 119.02, 116.38, 112.08, 110.70, 108.47, 101.18, 55.24; MS (ES): m/z = 406.3 (M-H); ESI-HRMS: m/z [M-H]+ calculated for C26H20N3O2: 406.1556; found: 406.1556.

3-[(1H-indol-3-yl)(3-nitrophenyl)methyl]-5-bromo-1H-indole (36) Light pink solid; MP: 122-115 °C; IR (KBr): 3427, 3052, 1523, 1456, 1415, 1348, 1211, 1097, 883, 794, 582 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 11.10 (brs, 2H, NH), 8.16 (s, 1H), 8.08 (dd, 1H, J = 7.2 & 1.6 Hz), 7.81 (d, 1H, J = 7.6 Hz), 7.61 (t, 1H, J = 7.6 Hz), 7.50 (d, 2H, J = 1.6 Hz), 7.35 (d, 2H, J = 8.0 Hz), 7.17 (dd, 2H, J = 8.4 & 2.0 Hz), 6.97 (dd, 4H, J = 8.4 & 2.0 Hz), 6.13 (s, 1H, Ar-CH); 13C NMR (75 MHz, DMSO-d6): δ 147.81, 146.68, 135.19, 134.84, 129.71, 128.07, 125.49, 123.64, 122.50, 121.22, 120.95, 116.58, 113.65, 111.08; MS (ES): m/z = 526.0 (M-H); ESI-HRMS: m/z [M-H]+ calculated for C23H14N3O2Br2: 521.9453; found: 521.9459.

3-[(furan-2-yl)(1H-indol-3-yl)methyl]-1H-indole (37) Off white solid; MP: 113-115 °C; IR (KBr): 3412, 3053, 1454, 1008, 783, 742 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 10.82 (brs, 2H, NH), 7.51 (d, 1H, J = 2.0 Hz), 7.39 (d, 2H, J = 8.0 Hz), 7.32 (d, 2H, J = 8.0 Hz), 7.00-7.04 (m, 4H), 6.86-6.90 (m, 2H), 6.35-6.36 (m,1H), 6.08 (d, 1H, J = 2.8 Hz), 5.88 (s, 1H, Ar-CH); 13C NMR (75 MHz, DMSO-d6): δ 157.50, 141.18, 136.32, 126.30, 123.17, 120.77, 118.94, 118.16, 115.65, 111.38, 110.11, 105.73, 33.55; MS (ES): m/z = 311.2 (M-H);

3-[1-(1H-indol-3-yl)butyl]-1H-indole (38) Light brown thick liquid; IR (KBr): 3408, 2926, 2850, 1614, 1454, 1095, 1012, 736 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 10.70 (brs, 2H, NH), 7.50 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J = 7.6 Hz), 7.10 (d, 2H, J = 2.0 Hz), 6.99-6.85 (m, 2H), 6.86-6.82 (m, 2H), 4.39 (t, 1H, J = 7.6 Hz), 2.20 (m, 2H), 1.30 (m, 2H), 0.91 (t, 3H, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3): δ 136.48, 127.11, 121.61, 121.34, 120.44, 119.59, 118.89, 111.01, 38.11, 33.64, 21.40, 14.21; MS (ES): m/z = 287.20 (M-H); ESI-HRMS: m/z [M-H]+ calculated for C20H19N2: 287.1548; found: 287.1553.

3-(1-(1H-indol-3-yl)octyl)-1H-indole (39) Light brown thick liquid; IR (KBr): 3415, 2926, 2852, 1618, 1456, 1417, 1336, 1093, 1010, 740, 582 cm-1; 1

H NMR (400 MHz, DMSO-d6): δ 10.70 (brs, 2H, NH), 7.47 (d, 2H, J = 8.0 Hz), 7.27 (d, 2H, J = 8.0 Hz), 7.19

(d, 2H, J = 2.0 Hz), 6.99-6.96 (m, 2H), 6.86-6.82 (m, 2H), 4.36 (t, 1H, J = 7.6 Hz), 2.16 (d, 2H, J = 6.4 Hz), 1.31 (m, 10H), 0.82 (t, 3H, J = 6.4 Hz);

13

C NMR (75 MHz, CDCl3): δ 136.50, 127.11, 121.61, 121.35,

120.47, 119.59, 118.90, 111.02, 35.87, 33.98, 31.91, 29.75, 29.29, 28.33, 22.66, 22.66; MS (ES): m/z = 343.4 (M-H);

3-[1-(1H-indol-3-yl)decyl]-1H-indole (40) Light brown thick liquid; IR (KBr): 3415, 2924, 2852, 1618, 1456, 1093, 1010, 740, 582 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 10.70 (brs, 2H, NH), 7.48 (d, 2H, J = 8.0 Hz), 7.28 (d, 2H, J = 8.0 Hz), 7.19 (d, 2H, J = 2.0 Hz), 6.96-7.0 (m, 2H), 6.82-6.86 (m, 2H), 4.36 (t, 1H, J = 7.6 Hz), 2.16 (d, 2H, J = 6.8 Hz), 1.30-1.19 (m, 12H), 0.84 (t, 3H, J = 6.8 Hz); 13C NMR (75 MHz, CDCl3): δ 136.55, 127.15, 121.63, 121.33, 120.55, 119.62, 118.91, 110.99, 35.87, 34.01, 31.90, 29.81, 29.65, 29.33, 28.34, 22.68, 14.12; MS (ES): m/z = 371.3 (MH).

1-(4-(di(1H-indol-3-yl)methyl)phenyl)ethanone (41)

Off white solid; MP: 96-98 °C; IR (KBr): 3406, 2923, 1669, 1603, 1456, 1271, 1093, 741 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 2H), 7.88-7.86 (d, 2H, J = 7.6 Hz), 7.49-7.47 (d, 2H, J = 8.4 Hz), 7.36-7.34 (d, 2H, J = 7.6 Hz), 7.28-7.26 (d, 2H, J = 8.4 Hz), 7.06-7.02 (t, 2H, J = 7.2 Hz), 6.88-6.84 (m, 4H), 5.92 (s, 1H), 2.53 (s, 3H);

13

C NMR (100 MHz, DMSO-d6): δ 198.32, 149.89, 136.61, 135.19, 128.87, 128.43,

126.76, 123.65, 121.98, 119.61, 119.26, 118.49, 111.17, 40.19, 26.54; MS (ES): m/z = 365.10 (M+H); ESIHRMS: m/z [M+H]+ calculated for C25H19N2O: 363.1497; found: 363.1483.

1-(4-(bis(5-hydroxy-1H-indol-3-yl)methyl)phenyl)ethanone (42). Off white solid; MP: 156-158 °C; IR (KBr): 3408, 2853, 1664, 1602, 1457, 1360, 1275, 1180, 938, 800, 603 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 10.53 (s, 2H), 8.49 (s, 2H), 7.88-7.86 (d, 2H, J = 8.0 Hz), 7.44-7.42 (d, 2H, J = 8.4 Hz), 7.14-7.12 (d, 2H, J = 8.0 Hz), 6.69-6.68 (d, 2H, J = 2.4 Hz), 6.57-6.56 (d, 2H, J = 3.2 Hz), 6.54-6.53 (d, 2H, J = 2.4 Hz), 5.66 (s, 1H), 2.53 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 194.47, 150.62, 150.01, 134.68, 131.17, 128.55, 128.18, 127.18, 124.15, 116.21, 111.79, 111.30, 103.09, 39.87, 26.64; MS (ES): m/z = 397.10 (M+H); ESI-HRMS: m/z [M+H]+ calculated for C25H21N2O3: 397.1552; found: 397.1546.

1-(4-(bis(5-bromo-1H-indol-3-yl)methyl)phenyl)ethanone (43). Light brown solid; MP: 105-107 °C; IR (KBr): 3419, 2923, 2853, 1669, 1603, 1457, 1270, 1095, 884, 793 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 2H), 8.49 (s, 2H), 7.90-7.88 (d, 2H, J = 8.4 Hz), 7.48-7.46 (d, 2H, J = 9.2 Hz), 7.45 (s, 2H), 7.35-7.33 (d, 2H, J = 8.4 Hz), 7.17-7.15 (dd, 2H, J = 2.0 & 8.4 Hz), 6.93-6.92 (d, 2H, J = 2.4 Hz), 5.98 (s, 1H), 2.50 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 198.38, 148.89, 135.50, 135.30, 128.73, 128.64, 128.37, 125.04, 124.84, 121.95, 117.87, 112.76, 112.71, 39.86, 26.62; MS (ES): m/z = 523.10 (M+H); ESI-HRMS: m/z [M+H]+ calculated for C25H17N2OBr: 518.9708; found: 518.9713.

3-(1-(1H-indol-3-yl)ethyl)-1H-indole (45). Off white solid; MP: 144-146 °C; IR (KBr): 3415, 2958, 1456, 1419, 1336, 1220, 1097, 1008, 817, 742, 582 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 10.70 (brs, 2H, NH), 7.44 (d, 2H, J = 7.6 Hz), 7.30 (d, 2H, J = 8.0 Hz), 7.12 (d, 2H, J = 2.0 Hz), 6.97-7.01 (m, 2H), 6.83-6.87 (m, 2H), 4.58 (q, 1H), 1.74 (d, 3H, J = 6.8 Hz); 13C NMR (75 MHz, DMSO-d6): δ 136.51, 126.40, 121.51, 120.55, 119.99, 118.98, 117.79, 111.25, 27.85, 21.88; MS (ES): m/z = 261.2 (M-H); ESI-HRMS: m/z [M-H]+ calculated for C18H15N2: 259.1235; found: 259.1240.

4-[di(1H-indol-3-yl)methyl]benzene-1,2-diol (46). Brick red solid; MP: 123-125 °C; IR (KBr): 3401, 3053, 1606, 1512, 1456, 1417, 1278, 1217, 1188, 1095, 744 cm-1; 1H NMR (400 MHz, DMSO-d6): δ 10.74 (brs, 2H, NH), 8.62 (brs, 2H, OH), 7.33 (d, 2H, J = 8.0 Hz), 7.26 (d, 2H, J = 8.0 Hz), 7.03-6.99 (m, 2H), 6.86-6.82 (m, 2H), 6.77 (d, 1H, J =1.6 Hz), 6.69 (s, 1H), 6.61 (s, 2H), 5.62 (s, 1H, Ar-CH); 13C NMR (75 MHz, DMSO-d6): δ 144.62, 143.10, 136.53, 135.93, 126.68, 123.31, 120.71, 119.19, 119.00, 118.66, 118.00, 115.79, 115.10, 111.33; MS (ES): m/z = 353.4 (M-H); ESI-HRMS: m/z [M-H]+ calculated for C23H17N2O2:353.1290; found: 353.1288.

Ethyl 2,2-di(1H-indol-3-yl)acetate (51): Brick red solid; MP: 123-125°C; IR (KBr): 3406, 2923, 1669, 1603, 1456, 1271, 1093, 741 cm-1; 1H NMR (400MHz, DMSO-d6): δ 10.93 (s, 2H), 7.53 (d, 2H, J = 8.0 Hz), 7.36 (d, 2H, J = 8.0 Hz), 7.21 (d, 2H, J = 2.4 Hz), 7.08-7.04 (t, 2H, J = 7.2 Hz), 6.96-6.92 (t, 2H, J = 8.4 Hz), 5.42 (s, 1H), 4.13-4.09 (m, 2H), 1.18 (t, 3H, J = 7.2 Hz);

13

C NMR (100MHz, DMSO-d6): δ 173.65, 136.29, 126.61, 123.39, 122.03, 119.48, 119.24,

113.49, 111.24, 61.13, 40.60, 14.20; MS (ES): m/z = 319.20 (M+H); ESI-HRMS: m/z [M+H]+ calculated for C20H19N2O2: 319.1447; found 319.1450.

2,2-di(1H-indol-3-yl)ethanol (52). 1

H NMR (400MHz, CDCl3): δ 8.04 (brs, 2H), 7.62 (d, 2H, J = 7.8 Hz), 7.41 (dd, 2H, J = 0.7 & 8.0 Hz), 7.01-

7.28 (m, 6H), 4.82 (t, 1H, J = 5.8 Hz), 4.31 (d, 2H, J = 5.8 Hz), δ 1.73 (brs, 1H); 13C NMR (100MHz, CDCl3): δ 173.90, 136.63, 126.91, 123.75, 122.23, 119.72, 119.56, 113.72, 111.64, 61.45, 40.92, 14.91; MS (ES): m/z = 277.20 (M+H);

2,2-di(1H-indol-3-yl)ethyl acetate (47-Streptindole). 1

H NMR (400MHz, CDCl3): δ 8.01 (brs, 2H), 7.64 (d, 2H, J = 7.3 Hz), 7.37 (d, 2H, J = 7.7 Hz), 7.01-7.31 (m,

6H), 4.97 (t, 1H, J = 7.0 Hz), 4.76 (d, 2H, J = 7.0 Hz), 2.03 (s, 3H); 13C NMR (100MHz, CDCl3): δ 171.51, 136.62, 127.24, 122.39, 122.20, 119.62, 116.60, 111.34, 67.57, 33.78, 21.32; MS (ES): m/z = 319.20 (M+H).

8.5. Spectral data of selected compounds (1H NMR and 13C NMR)

Figure 8.6. 1H NMR spectra of compound 24

Figure 8.7. 13C NMR spectra of compound 24

















