Mol Divers DOI 10.1007/s11030-015-9605-3

FULL-LENGTH PAPER

Iodine-catalyzed sp3 C–H bond activation by selenium dioxide: synthesis of diindolylmethanes and di(3-indolyl)selanides P. Seetham Naidu1 · Swarup Majumder1 · Pulak J. Bhuyan1

Received: 23 November 2014 / Accepted: 16 May 2015 © Springer International Publishing Switzerland 2015

Abstract An efficient reaction protocol was developed for the synthesis of several diindolylmethane derivatives via the sp3 C–H bond activation of aryl methyl ketones by SeO2 and indoles in the presence of catalytic amounts of I2 at 80 ◦ C using dioxane as solvent. Unexpectedly, an interesting class of di(3-indolyl)selenide compounds was isolated when the reaction was carried out at room temperature. Keywords C–H activation · Iodine · Indole · Diindolylmethanes · Selanides · Indolylselanides

Introduction Diindolylmethanes (DIMs) are an important class of naturally occurring compounds isolated from both terrestrial and marine origin which have long been used in folk medicine [1,2]. 3,3 -DIM is a metabolite of indole-3-methanol, an anticancer agent available in cruciferous vegetables [3,4], which shows potent anticancer activity against various forms of cancers, such as human prostate cancer [5] and breast cancer [6]. DIMs are used for the treatment of recurrent respiratory papillomatosis (RRP), and some are in Phase III clinical trials for cervical dysplasia [7]. Interestingly, it has been shown that DIMs act synergistically when combined with taxol in the induction of apoptosis in human breast Electronic supplementary material The online version of this article (doi:10.1007/s11030-015-9605-3) contains supplementary material, which is available to authorized users.

B 1

Pulak J. Bhuyan [email protected] Medicinal Chemistry Division, CSIR-North East Institute of Science & Technology, Jorhat 785006, Assam, India

cancer cells [8]. Selected biologically relevant DIMs are shown in Fig. 1 [9,10] in which 3,3 -DIM I is used for the treatment of RRP, vibridole II shows antibacterial activity, 4(di(1H-indol-3-yl)methyl)benzene-1,2-diol III acts as HIV-1 integrase inhibitor and bisindolylmaleimide IV is a potent inhibitor of PKC. Considering the biological importance of DIMs, the synthesis of the basic DIM molecular unit and its functionalization has received a lot of attention. DIMs are usually synthesized from the reaction of indoles with aldehydes or ketones in the presence of protic acids [11], Lewis acids [12–14], rare earth catalysts [15,16], and ionic liquids [17,18]. Very recently, Shiri et al. published a review article on DIMs [19]. Diarylselenides are recognized as an interesting class of compounds that exhibit diverse biological properties, such as anticancer and antioxidant activities [20,21]. They are also used as precursors in the synthesis of various selenonium salts, selenoxides, selenimines, and selenide dihalides of biological importance [22,23]. More interestingly, di(3indolyl)selenides possess cytotoxic activity against HT-1080 and MG-22A tumor cell lines [24]. The insertion of an aryl group to an sp3 carbon atom next to a carbonyl group is a strategy widely used for the synthesis of various bioactive natural products, drugs, and industrial materials [25–29]. Therefore, considerable efforts have been made in the last few years to obtain better methods for the insertion of aryl groups to sp3 carbons alpha to ketones [30–34]. Cross-dehydrogenative couplings and Csp3 –H bond couplings with aryl halide/aryl metal are the most used reaction protocols for the α-arylation of sp3 C–H bonds of ketones [35–39]. A recent investigation by Myrboh et al. resulted in an sp3 C–H bond diarylation using selenium dioxide in presence of BF3 -Et2 O [40]. In pursuing our interest in the design of new reactions for the synthesis of diverse heterocyclic compounds [41–43],

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Mol Divers

CH3

Table 1 Optimization studies for the synthesis of 3a

O

O

N H

N H

I

N H

N H

2

II

1a

OH OH O

N H

N H

H N

N H

N H

III

O

IV

Fig. 1 Diindolylmethanes of biological importance

particularly DIMs of biological significance [44], herein we report an efficient reaction protocol for the sp3 C–H bond activation of aryl methyl ketones by SeO2 in the presence of I2 as catalyst, to afford DIM derivatives 3 (Scheme 1). When the same reaction was performed at room temperature, it produced di(3-indolyl)selenides 4 without the involvement of aryl methyl ketones 2 in the reaction process (Scheme 3).

2a

SeO2 1,4-Dioxane 80 oC

We initiated our study with the reaction of indole 1a (2 equiv), phenyl methyl ketone 2a (1 equiv), and SeO2 (1 equiv) in presence BF3 -Et2 O following a reported method [40]. TLC showed that while the reactants were consumed several compounds were formed, even when the reaction was carried out at low temperature. Then, we screened a series of Lewis acids (Table 1, entries 2–7) and Brønsted acids (Table 1, entries 8–10) as catalysts for the reaction using dioxane as solvent. It was observed that the desired compound was not formed when the reaction was performed at room temperature. However, when the temperature was raised to 80 ◦ C, the reaction occurred in some cases giving very poor yield of the desired product 3a, and in other cases the desired product was not formed. The results are summarized in Table 1. To our delight, when the reaction was carried out in the

Temp ( ◦ C)

yield (%)a

Catalyst

Oxidizing intermediary

1

BF3

SeO2

80

NIP

2

AlCl3

SeO2

80

40

3

InCl3

SeO2

80

NR

4

ZnCl2

SeO2

80

30

5

FeCl3

SeO2

80

40

6

Sc(OTf)3

SeO2

80

30

7

Yb(OTf)3

SeO2

80

20

8

TFA

SeO2

80

NR

9

AcOH

SeO2

80

30

10

PTSA

SeO2

80

20

11

I2

SeO2

80

78

12

I2

SeO2

100

70

13



SeO2

25

NR

14



SeO2

80

NR

a Isolated

yield, NIP no isolable product, NR no reaction

O R2 + 1a-b

3a

Entry

Scheme 1 Synthesis of 2,2-bisindolyl-1-arylethanones 3

2

NH

N H

presence of catalytic amount of I2 (5 mol%) at 80 ◦ C, 2,2di(1H-indol-3-yl)-1-phenylethan-1-one 3a was obtained in very good yield (Table 1, entry 11). Increasing the temperature further to 100 ◦ C did not improve the reaction yield (Table 1, entry 12), and no reaction occurred in the absence of iodine (Table 1, entries 13–14). Overall, we observed that the reaction of 1a (2.0 mmol) with 2a (1.0 mmol) and SeO2 (1.0 mmol) in the presence of I2 (5 mol%) in dioxane (5 mL) and water (2 drops) at 80 ◦ C was the best condition to afford 3a in 78 % yield (Table 1, entry 11). It is important to note that the reaction was faster in presence of water than without it. The structure of the compound 3a was ascertained from the spectroscopic data, elemental analysis, and X-ray diffraction study (Fig. 2). The generality of our reaction was explored by utilizing various aryl methyl ketones with indole/N-methylindole (Table 2). It was observed that the electron-donating groups on the phenyl ring of aryl methyl ketones exhibited good reactivity (Table 2, products 3b–c and

Results and discussion

123

N H

+

Ph

N R1

O SeO2, I2 Dioxane

2a-h

Ar

80 oC

N R1

3a-p

N R1

Mol Divers Table 2 Scope of aryl methyl ketones and substituted indoles Ar O O SeO2, I2 + 2 N 1,4-Dioxane N N 2 1 80 oC R1 R 2 R1 R 3 1

Fig. 2 X-ray crystal structure of compound 3a (CCDC 956470)

3j–k) whereas electron-withdrawing groups slightly reduced the reactivity (Table 2, products 3d–f and 3l–n). A reasonable mechanism for the reaction is outlined in Scheme 2. The reaction occurred via the initial oxidation of aryl methyl ketone 2 with selenium dioxide to aldehyde [A ][45]. Then, a nucleophilic attack of the indole molecule 1 on the intermediate [A] in the presence of iodine and water produced the intermediate [B] by eliminating water. Subsequently, the second indole molecule attacks the intermediate [B] in the presence of iodine to give intermediate [C] which eliminates a proton to produce the product 3 (Scheme 2). As discussed earlier, the reaction of 1a, 2a and SeO2 in the presence of I2 did not afford the desired compound 3a at room temperature (25–30 ◦ C). However, it was observed that another compound was formed in the reaction process by complete consumption of indole 1a leaving the methyl phenyl ketone 2a intact (Scheme 3), and the compound was identified as di(3-indolyl)selenide 4a [24] from the spectroscopic data and elemental analysis. Then, we performed the reaction of indole 1a and selenium dioxide in presence of iodine as catalyst in dioxane at room temperature under stirring conditions (Scheme 4). As expected, we isolated the di(3-indolyl)selenide 4a in 75 % yield by a simple work-up procedure. The reaction was generalized by synthesizing the compounds 4a–f by utilizing various indoles 1 with selenium dioxide (Table 3). To confirm the structure of the product, an X-ray diffraction study of compound 4d was performed (Fig. 3). Indole with both electron-donating and electron-withdrawing groups exhibited almost same reactivity to afford the desired products in good yields (72–80 %, Table 3). The reaction did not occur in the absence of the catalyst, and so far we are not in a position to propose any mechanism for the formation of product 4.

En

R1

R2

Pd.

Time (h)

Yd. (%)

1

H

C6 H5

3a

3

78

2

H

4-CH3 C6 H4

3b

2

80

3

H

4-CH3 OC6 H4

3c

2

82

4

H

4-ClC6 H4

3d

2.5

70

5

H

4-BrC6 H4

3e

2.5

68

6

H

4-NO2 C6 H4

3f

2.5

67

7

H

2-Thiophenyl

3g

2

74

8

H

2-Naphthyl

3h

2

72

9

CH3

C6 H5

3i

3

84

10

CH3

4-CH3 C6 H4

3j

3

87

11

CH3

4-CH3 OC6 H4

3k

3

89

12

CH3

4-ClC6 H4

3l

3

75

13

CH3

4-BrC6 H4

3m

3

74

14

CH3

4-NO2 C6 H4

3n

3

76

15

CH3

2-Thiophenyl

3o

3

78

16

CH3

2-Naphthyl

3p

3

76

En. entry, Pd. product, Yd. yield

Conclusion In summary, we have developed an efficient method for the sp3 C–H bond activation of aryl methyl ketones by SeO2 in the presence of catalytic amounts of I2 for the production of DIMs from readily available aryl methyl ketones and indoles. Further, we have developed an efficient method for the synthesis of di(3-indolyl)selenides from the reaction of indoles and SeO2 in the presence of I2 as catalyst in dioxane at room temperature.

Experimental section General remarks All reagents and solvents were of reagent grade and used without drying. The IR spectra were recorded on a PerkinElmer system-2000 FTIR spectrometer. 1 H NMR and 13 C NMR spectra were recorded on a Bruker Avance-DPX 300 MHz and 75 MHz FT NMR in DMSO-d6 and CDCl3 using TMS as an internal standard. Chemical shifts were reported in ppm (δ units, s singlet, d doublet, t triplet, q quartet, m multiplet). LCMS were recorded on a Bruker Daltonics

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Mol Divers Scheme 2 Proposed mechanism for the formation of 3

O

O

O SeO2

2

R2

OH H2O OH

R2

R2

C O

H

H

[A] O

OH

N

O

Ar

N [B]

Scheme 3 Reaction of indole, acetophenone and SeO2 in the presence of I2 at room temperature

N R1

1

1

N R1

O

Ar H

[C]

N R1

+

N H

-H

N R1

R1

1,4-Dioxane r.t Table

3 Synthesis

N R1

N 3 R1 4

R4

Scheme 4 Synthesis of di(3-indolyl)selanides 4

ESQUIRE 3000 LC ESI ion trap mass spectrometer. Elemental analyses were performed on a Perkin–Elmer-2400 spectrometer. Analytical TLC and column chromatography were performed using E. Merck aluminum-backed silica gel plates coated with silica gel G and E. Merck silica gel (100– 200 mesh). Melting points (uncorrected) were determined on a Buchi B-540 apparatus.

N R1

1

R3

NH 4a

di(3-indolyl)selenides

R4

R3 R

3

N H

of

Se

SeO2, I2 1,4-Dioxane r.t

N R1

Se

2a R4

Ar

+

I2, SeO2

R4

R4

[B]

N

Ar

-H2O

O

1a

R3

O

N R1

R1 1

R1

[A]

Ar

+

I2

N R1

R2 O

O

CHO

SeO2, I2

R4

Se N R1

1,4-Dioxane r.t

4

R3 R3

4

N R1

En.

R1

R3

R4

Pd.

Time (h)

Yd. (%)

1

H

H

H

4a

4

75

2

H

H

5-Br

4b

5

72

3

H

H

6-Br

4c

5

80

4

CH3

H

H

4d

4

78

5

CH3

H

5-Br

4e

4

70

6

H

CH3

H

4f

5

74

En. entry, Pd. product, Yd. yield

General procedure for preparation of 3 In a typical experimental procedure, SeO2 (0.110 g, 1 mmol), dioxane (5 mL), and 2 drops of water were taken in a roundbottomed flask and heated for 15 min until complete SeO2 dissolution. To this solution, phenyl methyl ketone 2a (0.120 g, 1 mmol) and I2 (0.006 g, 5 mol%) were added, and the mixture was then heated at 80 ◦ C for 15 min. Then, indole 1a (0.234 g, 2 mmol) was added to the reaction mixture and heating was continued at 80 ◦ C for 2.5 h. After reaction completion (monitored by TLC), the reaction mixture

123

was evaporated to dryness under reduced pressure, water was added (10 mL) and the mixture extracted with—EtOAc (2×15 mL). The combined extracts were washed with 15mL of 10 % Na2 S2 O3 , dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 8:2 ratio of hexane:ethyl acetate as eluent to afford the compound 3a. Compounds 3b–p were synthesized using this procedure.

Mol Divers

113.9, 113.3, 111.8, 55.8, 41.2; IR (KBr, cm−1 ): 3408.1, 3378.5, 3049.5, 1666.7, 1595.6, 1456.0, 1418.2, 1338.7, 1225.9, 1091.1, 790.4, 697.3; MS (m/z): 381.5 [M+1]; Anal. Calcd. for C25 H20 N2 O2 : C, 78.93; H, 5.31; N, 7.36. Found: C, 79.03; H, 5.28; N, 7.33. 1-(4-Chlorophenyl)-2,2-di(1H-indol-3-yl)ethan-1-one (3d) White solid; Rf : 0.34; yield 0.268 g (70 %); mp 170–172 ◦ C; 1 H NMR (300 MHz, DMSO-d ) δ 10.88 (s, 2H, NH), 7.77 (d, 6 2H), 7.45–7.35 (m, 2H), 7.30–7.19 (m, 6H), 7.05 (t, 2H), 6.89 (t, 2H), 6.64 (s, 1H); 13 C NMR (75 MHz, DMSO-d6 ) δ 197.0, 137.5, 134.5, 130.2, 128.5, 127.7, 126.6, 121.9, 121.0, 118.8, 118.5, 112.4, 111.6, 41.8; IR (KBr, cm−1 ): 3405.2, 3380.8, 3054.5, 1680.8, 1592.5, 1456.3, 1420.7, 1340.2, 1220.4, 1091.6, 797.9, 746.7, 695.1; MS (m/z): 385.4 [M+1]; Anal. Calcd. For C24 H17 N2 OCl: C, 74.90; H, 4.46; N, 7.28. Found: C, 74.88; H, 4.49; N, 7.31.

Fig. 3 ORTEP representation of compound 4d (CCDC 956471)

2,2-Di(1H-indol-3-yl)-1-phenylethan-1-one (3a) Brown solid; Rf : 0.30; yield 0.273 g (78 %); mp 135– 137 ◦ C; 1 H NMR (300 MHz, DMSO-d6 ) δ 10.94 (s, 2H, NH), 8.19 (d, 2H), 7.58 (d, 3H), 7.50 (d, 2H), 7.36 (d, 2H), 7.19 (s, 2H), 7.06 (t, 2H), 6.95 (t, 2H), 6.67 (s, 1H); 13 C NMR (75 MHz, DMSO-d6 ) δ 198.7, 136.8, 136.7, 132.9, 128.7, 128.6, 127.2, 124.9, 119.1, 118.7, 112.8, 111.5, 41.8; IR (KBr, cm−1 ): 3397.1, 3380.1, 3058.1, 1678.6, 1592.9, 1458.2, 1420.2, 1340.2, 1220.8, 1087.9, 798.1, 742.8, 694.9; MS (m/z): 351.4 [M+1]; Anal. Calcd. for C24 H18 N2 O: C, 82.26; H, 5.18; N, 7.99. Found: C, 82.30; H, 5.21; N, 8.04. 2,2-Di(1H-indol-3-yl)-1-(p-tolyl)ethan-1-one (3b) Brown solid; Rf : 0.32; yield 0.291 g (80 %); mp 224– 226 ◦ C; 1 H NMR (300 MHz, DMSO-d6 ) δ 10.96 (d, 2H, NH), 8.09 (d, 2H), 7.56 (d, 2H), 7.35 (d, 2H), 7.28 (d, 2H), 7.17 (d, 2H), 7.06 (t, 2H), 6.98–6.90 (m, 2H), 6.62 (s, 1H), 2.32 (s, 3H); 13 C NMR (75 MHz, DMSO-d6 ) δ 197.9, 143.8, 136.8, 134.5, 129.1, 128.6, 126.9, 124.8, 121.4, 119.4, 118.9, 113.5, 111.9, 41.8, 21.5; IR (KBr, cm−1 ): 3400.4, 3375.3, 3055.7, 1676.9, 1600.4, 1457.5, 1420.8, 1340.1, 1220.5, 1093.2, 787.2, 694.4; MS (m/z): 365.4 [M+1]; Anal. Calcd. for C25 H20 N2 O: C, 82.40; H, 5.53; N, 7.69. Found: C, 82.44; H, 5.56; N, 7.72. 2,2-Di(1H-indol-3-yl)-1-(4-methoxyphenyl)-ethan-1-one (3c) ◦ C;

Brown solid; Rf : 0.31; yield 0.311 g (82 %); mp 221–223 1 H NMR (300 MHz, DMSO-d ) δ 10.91 (s, 2H, NH), 8.18 (d, 6

2H), 7.57 (d, 2H), 7.35 (d, 2H), 7.07–6.86 (m, 8H), 6.68 (s, 1H), 3.79 (s, 3H); 13 C NMR (75 MHz, DMSO-d6 ) δ 197.9, 162.8, 136.9, 130.8, 129.6, 127.3, 125.0, 119.9, 118.4, 117.5,

1-(4-Bromophenyl)-2,2-di(1H-indol-3-yl)ethan-1-one (3e) Brown solid; Rf : 0.32; yield 0.291 g (68 %); mp 144–146 ◦ C; 1 H NMR (300 MHz, DMSO-d ) δ 10.93 (s, 2H, NH), 8.19 (d, 6 2H), 7.56–7.32 (m, 6H), 7.18 (d, 2H), 7.06 (d, 2H), 6.97 (d, 2H), 6.65 (s, 1H); 13 C NMR (75 MHz, DMSO-d6 ) δ 197.0, 136.7, 134.9, 131.1, 129.9, 127.9, 126.8, 124.0, 121.2, 119.2, 118.7, 112.7, 111.5, 41.9; IR (KBr, cm−1 ): 3409.6, 3375.3, 3055.7, 1680.9, 1587.1, 1456.3, 1419.7, 1339.5, 1220.6, 1093.5, 796.6, 747.3, 694.8; MS (m/z): 430.7 [M+1]; Anal. Calcd. For C24 H17 N2 OBr: C, 67.14; H, 3.99; N, 6.53. Found: C, 67.18; H, 4.02; N, 6.48. 2,2-Di(1H-indol-3-yl)-1-(4-nitrophenyl)ethan-1-one (3f) Brown solid; Rf : 0.28; yield 0.264 g (67 %); mp 138– 140 ◦ C; 1 H NMR (300 MHz, DMSO-d6 ) δ 10.86 (s, 2H, NH), 7.75 (d, 2H), 7.44–7.26 (m, 8H), 7.22 (d, 2H), 6.89 (t, 2H), 6.74 (s, 1H); 13 C NMR (75 MHz, DMSO-d6 ) δ 197.9, 150.7, 141.6, 137.3, 129.7, 127.6, 126.9, 122.6, 122.5, 121.7, 119.5, 118.9, 112.3, 111.7, 41.9; IR (KBr, cm−1 ): 3404.8, 3365.3, 3056.5, 1680.1, 1601.4, 1457.6, 1421.3, 1341.6, 1219.1, 1097.6, 794.8, 695.4; MS (m/z): 396.3 [M+1]; Anal. Calcd. For C24 H17 N3 O3 : C, 72.92; H, 4.33; N, 10.63. Found: C, 72.95; H, 4.36; N, 10.66. 2,2-Di(1H-indol-3-yl)-1-(thiophen-2-yl)ethan-1-one (3g) Red solid; Rf : 0.37; yield 0.263 g (74 %); mp 147– 149 ◦ C; 1 H NMR (300 MHz, DMSO-d6 ) δ 10.86 (s, 2H, NH), 7.85 (t, 2H), 7.54–7.51 (q, 2H), 7.27 (d, 2H), 7.10 (d, 2H), 7.03–6.98 (m, 3H), 6.93 (d, 2H), 6.27 (s, 1H); 13 C

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Mol Divers

NMR (75 MHz, DMSO-d6 ) δ 191.1, 143.9, 138.2, 133.7, 132.4, 128.4, 127.1, 121.7, 119.1, 118.9, 112.7, 111.5, 42.8; IR (KBr, cm−1 ): 3400.2, 3379.1, 3057.6, 1675.5, 1593.7, 1453.8, 1415.7, 1340.2, 1220.8, 1090.1, 786.3, 696.8; MS (m/z): 357.5 [M+1]; Anal. Calcd. For C22 H16 N2 OS: C, 74.13; H, 4.52; N, 7.86. Found: C, 74.09; H, 4.56; N, 7.90.

2,2-Di(1H-indol-3-yl)-1-(naphthalen-2-yl)-ethan-1-one (3h) Brown solid; Rf : 0.39; yield 0.288 g (72 %); mp 205– 207 ◦ C; 1 H NMR (300 MHz, DMSO-d6 ) δ 10.86 (s, 2H, NH), 8.31 (d, 2H), 8.06 (d, 2H), 7.90 (d, 2H), 7.42 (d, 1H), 7.25–7.17 (q, 4H), 7.07 (t, 3H), 6.86–6.79 (q, 3H), 6.44 (s, 1H); 13 C NMR (75 MHz, DMSO-d6 ) δ 197.9, 136.8, 134.5, 130.8, 129.6, 129.1, 128.6, 127.3, 126.9, 125.0, 124.8, 121.0, 119.2, 118.5, 113.1, 111.8, 41.8; IR (KBr, cm−1 ): 3408.1, 3398.4, 3054.6, 1673.2, 1591.8, 1453.9, 1415.6, 1345.5, 1219.4, 1092.6, 783.0, 689.0; MS (m/z): 401.5 [M+1]; Anal. Calcd. For C28 H20 N2 O: C, 83.98; H, 5.03; N, 7.02. Found: C, 83.96; H, 5.06; N, 7.04.

1-(4-Methoxyphenyl)-2,2-bis(1-methyl-1H-indol-3yl)ethan-1-one (3k) Brown solid; Rf : 0.24; yield 0.363 g (89 %); mp 137– 139 ◦ C; 1 H NMR (300 MHz, CDCl3 ) δ 8.09 (d, 2H), 7.57 (d, 2H), 7.29–7.21 (m, 2H), 7.09 (d, 2H), 6.97–6.86 (m, 4H), 6.48 (S, 1H), 3.82 (s, 3H), 3.68 (s, 6H); 13 C NMR (75 MHz, CDCl3 ) δ 198.1, 164.6, 137.1, 130.7, 129.3, 128.1, 127.1, 121.0, 119.0, 118.6, 117.4, 112.1, 108.9, 55.7, 41.5, 32.8; IR (CDCl3 , cm−1 ): 3054.3, 2935.6, 1687.4, 1615.8, 1595.0, 1540.9, 1474.7, 1370.2, 1155,2, 1014.9, 981.3, 740.2, 688.9; MS (m/z): 409.6 [M+1]; Anal. Calcd. For C27 H24 N2 O2 : C, 79.39; H, 5.92; N, 6.86. Found: C, 79.42; H, 5.89; N, 6.83. 1-(4-Chlorophenyl)-2,2-bis(1-methyl-1H-indol- 3yl)ethan-1-one (3l)

2,2-Bis(1-methyl-1H-indol-3-yl)-1-phenylethan-1one (3i)

Brown solid; Rf : 0.24; yield 0.309 g (75 %); mp 150– 152 ◦ C; 1 H NMR (300 MHz, CDCl3 ) δ 7.93 (d, 2H), 7.40 (d, 2H), 7.26–7.16 (m, 5H), 7.09–7.01 (m, 3H), 6.83 (t, 2H), 6.44 (s, 1H), 3.67 (s, 6H); 13 C NMR (75 MHz, CDCl3 ) δ 197.5, 137.7, 137.2, 136.4, 129.1, 128.6, 127.6, 126.3, 121.9, 121.2, 119.8, 118.7, 117.0, 109.3, 41.7, 32.8; IR (CDCl3 , cm−1 ): 3056.2, 2933.8, 1686.3, 1615.0, 1593.8, 1541.1, 1473.9, 1370.2, 1152.6, 1012.4, 978.9, 740.5, 689.7; MS (m/z): 413.4 [M+1]; Anal. Calcd. For C26 H21 N2 OCl: C, 75.64; H, 5.13; N, 6.78. Found: C, 75.62; H, 5.15; N, 6.82.

Brown solid; Rf : 0.27; yield 0.317 g (84 %); mp 78–81 ◦ C; 1 H NMR (300 MHz, CDCl ) δ 8.11 (d, 2H), 7.57 (d, 2H), 7.50 3

1-(4-Bromophenyl)-2,2-bis(1-methyl-1H-indol-3yl)ethan-1-one (3m)

(d, 1H), 7.39 (t, 2H), 7.29–7.18 (m, 4H), 7.07 (t, 2H), 6.87 (s, 2H), 6.52 (s, 1H), 3.67 (s, 6H); 13 C NMR (75 MHz, CDCl3 ) δ 198.7, 137.3, 137.0, 132.9, 128.9, 128.7, 127.4, 121.9, 119.2, 119.1, 112.8, 109.5, 41.86, 32.8; IR (CDCl3 , cm−1 ): 3054.3, 2933.4, 1685.4, 1614.1, 1594.9, 1540.0, 1473.3, 1371.6, 1330.3, 1155.7, 1013.5, 979.5, 740.8, 689.0; MS (m/z): 379.1 [M+1]; Anal. Calcd. For C26 H22 N2 O: C, 82.51; H, 5.86; N, 7.40. Found: C, 82.54; H, 5.82; N, 7.38.

2,2-Bis(1-methyl-1H-indol-3-yl)-1-(p-tolyl)-ethan-1-one (3j) Brown solid; Rf : 0.26; yield 0.341 g (87 %); mp 136– 138 ◦ C; 1 H NMR (300 MHz, CDCl3 ) δ 8.03 (d, 2H), 7.57 (d, 2H), 7.29–7.17 (m, 6H), 7.07 (d, 2H), 6.87 (d, 2H), 6.50 (s, 1H), 3.68 (s, 6H), 2.38 (s, 3H); 13 C NMR (75 MHz, CDCl3 ) δ 198.3, 143.6, 137.3, 134.4, 130.2, 129.2, 128.9, 128.5, 127.1, 121.7, 119.1, 119.0, 113.0, 109.4, 41.5, 32.7, 21.6; IR (CDCl3 , cm−1 ): 3055.1, 2934.5, 1688.1, 1615.4, 1594.7, 1541.0, 1475.3, 1370.9, 1154.5, 1014.8, 980.2, 741.1, 689.3; MS (m/z): 393.5 [M+1]; Anal. Calcd. For C27 H24 N2 O: C, 82.62; H, 6.17; N, 7.14. Found: C, 82.65; H, 6.19; N, 7.17.

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Brown solid; Rf : 0.26; yield 0.338 g (74 %); mp 169–171 NMR (300 MHz, CDCl3 ) δ 7.96 (d, 2H), 7.83 (d, 2H), 7.65 (d, 2H), 7.31–7.15 (m, 6H), 7.01 (s, 1H), 6.83 (s, 1H), 6.38 (s, 1H), 3.69 (s, 6H); 13 C NMR (75 MHz, CDCl3 ) δ 197.4, 137.3, 135.6, 131.7, 128.8, 128.6, 126.3, 120.2, 119.7, 118.7, 112.0, 109.0, 42.0, 32.6; IR (CDCl3 , cm−1 ): 3054.7, 2934.3, 1687.1, 1615.8, 1594.5, 1540.9, 1474.2, 1371.5, 1152.4, 1014.0, 979.3, 740.7, 688.9; MS (m/z): 458.3 [M+1]; Anal. Calcd. For C26 H21 N2 OBr: C, 68.28; H, 4.63; N, 6.13. Found: C, 68.31; H, 4.60; N, 6.15. ◦ C; 1 H

2,2-Bis(1-methyl-1H-indol-3-yl)-1-(4-nitro-phenyl)ethan-1-one (3n) Brown solid; Rf : 0.28; yield 0.321 g (76 %); mp 155– 157 ◦ C; 1 H NMR (300 MHz, CDCl3 ) δ 8.62 (d, 1H), 8.32 (d, 2H), 8.18 (t, 2H), 7.61–7.52 (m, 6H), 7.38–7.34 (m, 2H), 7.25 (s, 1H), 6.67 (s, 1H), 3.88 (s, 6H); 13 C NMR (75 MHz, CDCl3 ) δ 197.9, 150.7, 143.3, 137.3, 131.2, 129.7, 128.8, 126.9, 123.8, 122.6, 119.5, 116.3, 111.7, 109.7, 42.8, 32.7; IR (CDCl3 , cm−1 ): 3054.3, 2935.5, 1687.6, 1614.8, 1595.1, 1540.8, 1475.5, 1371.9, 1153.2, 1014.0, 980.4, 740.0, 689.0;

Mol Divers

MS (m/z): 424.4 [M+1]; Anal. Calcd. For C26 H21 N3 O3 : C, 73.74; H, 5.00; N, 9.92. Found: C, 73.76; H, 4.98; N, 9.94. 2,2-Bis(1-methyl-1H-indol-3-yl)-1-(thiophen-2-yl)ethan-1-one (3o) Brown solid; Rf : 0.32; yield 0.299 g (78 %); mp 148–150 ◦ C; NMR (300 MHz, CDCl3 ) δ 7.92 (d, 1H), 7.61–7.56 (m, 3H), 7.29–7.18 (m, 4H), 7.10–7.04 (m, 3H), 6.95 (s, 2H), 6.34 (s, 1H), 3.69 (s, 6H); 13 C NMR (75 MHz, CDCl3 ) δ 191.6, 143.9, 137.2, 133.7, 132.4, 128.5, 128.2, 127.1, 121.7, 119.2, 119.0, 112.6, 109.4, 43.2, 32.8; IR (CDCl3 , cm−1 ): 3053.8, 2933.9, 1686.7, 1614.6, 1594.7, 1541.3, 1474.8, 1369.1, 1154.1, 1015.2, 979.8, 740.6, 690.8; MS (m/z): 385.2 [M+1]; Anal. Calcd. For C24 H20 N2 OS: C, 74.97; H, 5.24; N, 7.29. Found: C, 74.96; H, 5.28; N, 7.31. 1H

134.8, 131.2, 121.7, 120.1, 119.5, 111.4, 98.9; IR (KBr, cm−1 ): 3414.1, 3409.9, 3057.8, 1592.5, 1453.6, 1347.1, 1230.7, 741.1; MS (m/z): 312.7 [M+1]; Anal. Calcd. For C16 H12 N2 Se: C, 61.74; H, 3.89; N, 9.01. Found: C, 61.71; H, 3.92; N, 9.04.

Bis(5-bromo-1H-indol-3-yl)selane (4b) White solid; Rf : 0.69; yield 0.337 g (72 %); mp 192–194 ◦ C; 1 H NMR (300 MHz, DMSO-d ) δ 11.69 (s, 2H, NH), 7.73 (s, 6 1H), 7.67 (d, 1H), 7.46 (d, 2H), 7.36 (d, 1H), 7.18–7.02 (m, 3H); 13 C NMR (75 MHz, DMSO-d6 ) δ 136.3, 133.1, 131.0, 121.2, 120.1, 119.7, 111.2, 98.9; IR (KBr, cm−1 ): 3415.2, 3410.6, 3058.2, 1593.8, 1452.6, 1346.9, 1230.4, 742.3; MS (m/z): 470.2 [M+1]; Anal. Calcd. For C16 H10 N2 Br2 Se: C, 40.97; H, 2.15; N, 5.97. Found: C, 40.99; H, 2.11; N, 5.93.

2,2-Bis(1-methyl-1H-indol-3-yl)-1-(naphthalen-2-yl)ethan-1-one (3p) Bis(6-bromo-1H-indol-3-yl)selane (4c) Red solid; Rf : 0.34; yield 0.325 g (76 %); mp 107– 109 ◦ C; 1 H NMR (300 MHz, CDCl3 ) δ 8.75 (d, 2H), 8.08 (t, 2H), 7.99–7.79 (m, 6H), 7.63–7.53 (m, 6H), 7.25 (s, 1H), 6.57 (s, 1H), 3.66 (s, 6H); 13 C NMR (75 MHz, CDCl3 ) δ 198.7, 137.3, 133.7, 132.1, 129.7, 128.9, 128.6, 127.9, 126.0, 121.9, 121.2, 119.2, 118.7, 117.2, 112.9, 109.5, 41.9, 33.6; IR (CDCl3 , cm−1 ): 3054.4, 2935.6, 1688.2, 1614.5, 1593.8, 1540.3, 1474.9, 1368.4, 1154.9, 1014.8, 980.3, 741.4, 690.3; MS (m/z): 429.7 [M+1]; Anal. Calcd. For C30 H24 N2 O: C, 84.08; H, 5.65; N, 6.54. Found: C, 84.10; H, 5.68; N, 6.51.

White solid; Rf : 0.70; yield 0.375 g (80 %); mp 192– 194 ◦ C; 1 H NMR (300 MHz,DMSO-d6 ) δ 11.67 (s, 2H, NH), 8.34 (d, 2H), 7.90 (d, 1H), 7.40 (d, 1H), 7.28–7.16 (m, 4H); 13 C NMR (75 MHz, DMSO-d ) δ 136.2, 134.8, 131.1, 121.6, 6 120.1, 119.4, 111.2, 98.9; IR (KBr, cm−1 ): 3411.7, 3408.7, 3058.3, 1594.1, 1455.3, 1342.5, 1232.3, 741.0; MS (m/z): 470.2 [M+1]; Anal. Calcd. For C16 H10 N2 Br2 Se: C, 40.97; H, 2.15; N, 5.98. Found: C, 40.99; H, 2.11; N, 5.95.

General procedure for preparation of 4

Bis(1-methyl-1H-indol-3-yl)selane (4d)

A mixture of indole (0.234 g, 2 mmol), SeO2 (0.110 g, 1 mmol) in dioxane (5 mL) was taken in a round bottomed flask. To this mixture I2 (0.006 g, 5 mol%) was added and the reaction mixture was stirred at room temperature for 4 h. After completion (monitored by TLC), the solvent was evaporated under reduced pressure, water (10 mL) was added water to the mixture, and the mixture was extracted with EtOAc (2 × 15 mL). The combined extracts were washed with 15mL of 10 % Na2 S2 O3 , dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 9:1 ratio of hexane:ethyl acetate which afforded compound 4a. Compounds 4b–f were synthesized using this procedure.

White solid; Rf : 0.79; yield 0.264 g (78 %); mp 161– 163 ◦ C; 1 H NMR (300 MHz, CDCl3 ) δ 7.94 (d, 1H), 7.25– 7.18 (q, 4H), 7.10–7.02 (q, 2H), 6.83–6.76 (q, 3H), 3.67 (s, 6H); 13 C NMR (75 MHz, CDCl3 ) δ 137.1, 133.8, 130.3, 121.0, 120.2, 119.9, 109.4, 99.5, 32.8; IR (CDCl3, cm−1 ): 3056.4, 1592.2, 1451.6, 1352.9, 1235.8, 1117.0, 741.1; MS (m/z): 340.6 [M+1]; Anal. Calcd. For C18 H16 N2 Se: C, 63.72; H, 4.75; N, 8.26. Found: C, 63.74; H, 4.72; N, 8.29.

Bis(1H-indol-3-yl)selane (4a) White crystals; Rf : 0.71; yield 0.233 g (75 %); mp 209– 211 ◦ C; 1 H NMR (300 MHz, DMSO-d6 ) δ 11.60 (s, 2H, NH), 7.78–7.76 (q, 2H), 7.37 (t, 2H), 7.33–7.30 (q, 2H), 7.14–7.06 (m, 4H); 13 C NMR (75 MHz, DMSO-d6 ) δ 136.1,

Bis(5-bromo-1-methyl-1H-indol-3-yl)selane (4e) White solid; Rf : 0.75; yield 0.347 g (70 %); mp 173– 175 ◦ C; 1 H NMR (300 MHz, CDCl3 ) δ 7.74 (s, 1H), 7.65 (t, 2H), 7.46 (d, 1H), 7.36 (d, 1H), 7.20–7.02 (m, 3H), 3.78 (s, 6H); 13 C NMR (75 MHz, CDCl3 ) δ 137.2, 133.8, 130.3, 121.5, 120.4, 119.9, 109.3, 99.5, 32.8; IR (CDCl3 , cm−1 ): 3056.8, 1591.3, 1453.6, 1348.1, 1232.5, 1117.9, 740.6; MS (m/z): 498.3 [M+1]; Anal. Calcd. For C18 H14 N2 Br2 Se: C, 43.49; H, 2.84; N, 5.64. Found: C, 43.52; H, 2.88; N, 5.61.

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Mol Divers

Bis(2-methyl-1H-indol-3-yl)selane (4f) Light brown solid; Rf : 0.77; yield 0.250 g (74 %); mp 185– 187 ◦ C; 1 H NMR (300 MHz, DMSO-d6 ) δ 11.73 (s, 2H, NH), 7.56 (d, 2H), 7.38–7.21 (m, 3H), 7.14–6.92 (m, 3H), 2.35 (s, 6H); 13 C NMR (75 MHz, DMSO-d6 ) δ 143.6, 136.2, 131.09, 122.0, 120.5, 119.6, 111.6, 98.9, 13.4; IR (KBr, cm−1 ): 3414.9, 3409.5, 3058.4, 1590.6, 1454.8, 1345.4, 1233.0, 742.1; MS (m/z): 340.2 [M+1]; Anal. Calcd. For C18 H16 N2 Se: C, 63.72; H, 4.75; N, 8.26. Found: C, 63.74; H, 4.79; N, 8.22. Acknowledgments We thank the CSIR, New Delhi for financial assistance (CAAF-NE project). SM thanks the CSIR, New Delhi for the Senior Research Fellowship (SRF) grant and PSN thanks the UGC, New Delhi for the Senior Research Fellowship.

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Iodine-catalyzed [Formula: see text] C-H bond activation by selenium dioxide: synthesis of diindolylmethanes and di(3-indolyl)selanides.

An efficient reaction protocol was developed for the synthesis of several diindolylmethane derivatives via the [Formula: see text] C-H bond activation...
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