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Original article
12 (
8
); 3836-3846
doi:
10.1016/j.arabjc.2016.02.002

Ultrasound assisted Mizoroki–Heck reaction catalyzed by Pd/C: Synthesis of 3-vinyl indoles as potential cytotoxic agents

, , , ,
a Department of Chemistry, K.L. University, Vaddeswaram, Guntur 522502, Andhra Pradesh, India
b Department of Chemistry and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be’er-Sheva 84105, Israel
c Department of Chemistry, Krishna University, Machilipatnam 521001, Andhra Pradesh, India
d Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500046, India

⁎Corresponding authors. Tel.: +91 40 6657 1500. vbrmandava@yahoo.com (M.V. Basaveswara Rao), manojitpal@rediffmail.com (Manojit Pal)

Received: , Accepted: ,
© The Author(s) 2016
Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

3-Vinyl indoles were synthesized via Pd/C–Cu catalyzed coupling between 3-iodo-1-methyl-1H-indole and terminal alkenes under ultrasound irradiation.

Abstract

The Pd/C–PPh3 catalyst system facilitated the C–C bond forming reaction between 3-iodo-1-methyl-1H-indole and various terminal alkenes under ultrasound irradiation. The present ultrasound assisted Mizoroki–Heck coupling afforded a number of 3-vinyl indole derivatives in good to acceptable yields. Two of these indole derivatives showed cytotoxic activities against breast cancer cell lines.

Keywords

Indole
Alkenes
Pd/C
Ultrasound
Cytotoxicity
1

1 Introduction

The indole ring is considered as one of the privileged frameworks in medicinal and pharmaceutical chemistry. For example, 3-substituted indole nucleus is prevalent in numerous natural products and is extremely important in medicinal chemistry (Sharma et al., 2010; Carbone et al., 2013a,b). Indeed, 3-vinyl indole derivatives have been used as precursors (Zheng et al., 2015; Zhang et al., 2014; Zheng et al., 2014) for several bioactive agents that include the total synthesis of (±)-aplicyanins A, B and E and related analogues several of which showed considerable cytotoxicity (Šíša et al., 2009). The (E)-6-fluoro-3-[2-(3-pyridyl)vinyl]-1H-indole (A, Fig. 1) has been identified as a novel inhibitor of tryptophan 2,3-dioxygenase (TDO) thereby potential anticancer immunomodulator (Salter et al., 1995). Similarly, (E)-3-(2-carboxy-2-phenylvinyl)-4,6-dichloro-1H-indole-2-carboxylic acid (B, Fig. 1) has been identified as a potent and selective antagonist of the glycine site of the N-methyl-d-aspartate (NMDA) receptor (Baron et al., 2005). Very recently, 3-vinyl indole derivatives (C, Fig. 1) have been reported as inhibitors of diacylglycerol acyltransferase-1 (Kim et al., 2015) and trans-indole-3-acrylamide derivatives have been reported as a new class of tubulin polymerization inhibitors (Baytas et al., 2014).

Examples of bioactive 3-vinyl indole derivatives.
Figure 1 Examples of bioactive 3-vinyl indole derivatives.

The 3-vinyl indole derivatives are generally prepared from the corresponding aldehydes by using Horner–Wadsworth–Emmons olefination or similar methods (Šíša et al., 2009; Su et al., 2014; Lopez-Alvarado et al., 2009; Sodeoka et al., 2003; Pindur et al., 1989, 1995; Pindur and Pfeuffer, 1989). While being effective these methods however involve the cumbersome preparation of required organo-phosphorus reagents and removal of phosphorus containing by-product from the desired product. The methodology based on Pd-catalyzed coupling of an aryl/vinyl halide with an alkene, popularly known as Mizoroki–Heck reaction (Mizoroki et al., 1971; Heck, 1982; Tsuji, 1995; Beccalli et al., 2010; Farina, 2004; Cabri and Candiani, 1999; Beccalli et al., 2006) has been extended (Harrington and Hegedus, 1984; Harrington et al., 1987; Gribble and Conway, 1992) for the preparation of 3-vinyl indole derivatives (Sala et al., 2006). The use of 3-iodoindoles possessing an electron withdrawing group on the indole nitrogen was found to be more effective than the corresponding 3-bromoindoles in these coupling reactions. The use of C–H activation strategy has been explored for the preparation of 3-vinyl indoles (Sala et al., 2006; Fujiwara et al., 1981; Itahara et al., 1983, 1984; Capito et al., 2005; Grimster et al., 2005; Yokoyama et al., 1995; Osanai et al., 1999; Djakovitch and Rouge, 2007, 2009; Chen et al., 2012; Huang et al., 2013). Very recently, an elegant Pd(II)-catalyzed triple successive oxidative Heck (Fujiwara–Moritani reaction) of indole has been reported (Verma et al., 2015). While the direct use of indole in place of expensive 3-haloindoles is the major advantage of these methodologies, the requirement of excess quantity of Pd-catalyst and/or oxidants, low conversion rate along with C-2 vs C-3 selectivity in addition to the use of sealed tube [or oxygen pressure (1 atmosphere) (Chen et al., 2012)] is the practical drawbacks in several cases. Notably, the aerobic dehydrogenative Heck reaction (DHR) of heterocycles with styrenes has been reported to be more efficient in the absence of metallic co-oxidants (Vasseur et al., 2013). Nevertheless, due to our continuing interest in bioactive indole derivatives (Pal et al., 2004a,b; Rao et al., 2011; Nakhi et al., 2011; Kumar et al., 2012; Gorja et al., 2013; Dulla et al., 2014) we required a more convenient and direct access to a library of 3-vinyl indoles for our in house pharmacological screen.

The use of Pd/C in Mizoroki–Heck reaction has been reported earlier (Hagiwara et al., 2001; Xie et al., 2004; Perosa et al., 2004; Köhler et al., 2002; Köhler et al., 2008). Being less expensive, stable, easy to handle and recyclable catalyst Pd/C has advantages over the other Pd-complexes or salts. Indeed, the combination of Pd/C with ionic liquid as a recyclable catalyst system for the Mizoroki–Heck coupling has been documented in the literature (Hagiwara et al., 2001; Perosa et al., 2004). Moreover, these reactions can be accelerated when performed under microwave irradiation (Perosa et al., 2004). The Mizoroki–Heck reaction (Deshmukh et al., 2001; Zhang et al., 2006; Palmisano et al., 2007; Garella et al., 2010; An et al., 2011; Yahiaoui et al., 2011) of iodobenzene with methyl acrylate has also been studied using Pd/C as a catalyst in the presence of ultrasound (Ambulgekar et al., 2005). Like microwave, ultrasound enhanced the reaction rate as expected and was found to be essential for the reaction to proceed at room temperature. While the effects of base, solvent and recyclability of catalyst were studied in the presence and absence of ultrasound, the application and scope of this ultrasound based methodology in organic synthesis has not been explored. Only one and simple example was studied in this case. It was therefore necessary to examine the utility of this strategy as a general and greener method for the C–C bond forming reaction. Herein we report Pd/C mediated Mizoroki–Heck coupling of 3-iodoindole (1) with various alkenes (2) under ultrasound irradiation leading to 3-vinyl indoles (3) (Scheme 1). Notably, preparation of this class of indole derivatives using ultrasound assisted Mizoroki–Heck reaction catalyzed by Pd/C is not known (Cacchi and Fabrizi, 2005; Broggini et al., 2012; Clique et al., 2003).

Synthesis of 3-vinyl indoles via ultrasound assisted Mizoroki–Heck reaction catalyzed by Pd/C.
Scheme 1 Synthesis of 3-vinyl indoles via ultrasound assisted Mizoroki–Heck reaction catalyzed by Pd/C.

2

2 Materials and methods

2.1

2.1 General methods

Unless stated otherwise, reactions were performed under nitrogen atmosphere using oven-dried glassware. Reactions were monitored by thin layer chromatography (TLC) on silica gel plates (60 F254), visualizing with ultraviolet light or iodine spray. Flash chromatography was performed on silica gel (230–400 mesh) using distilled hexane and ethyl acetate. 1H NMR and 13C NMR spectra were recorded in CDCl3 or DMSO-d6 solution by using 400 or 100 MHz spectrometers, respectively. Proton chemical shifts (δ) are relative to tetramethylsilane (TMS, δ = 0.00) as internal standard and expressed in ppm. Spin multiplicities are given as s (singlet), d (doublet), dd (doublet of doublet), td (triplet of doublet), t (triplet) and m (multiplet) as well as b (broad). Coupling constants (J) are given in hertz. MS spectra were obtained on a Agilent 6430 series Triple Quard LC-MS/MS spectrometer. Melting points (mp) were recorded by using Buchi B-540 melting point apparatus and are uncorrected. A laboratory ultrasonic bath SONOREX SUPER RK 510H model producing irradiation of 35 kHz was used for performing reactions under ultrasound irradiation.

2.2

2.2 Preparation 3-iodo-1-methyl-1H-indole (1) (Bocchi et al., 1982)

To a stirring solution of 1-methyl indole (2.0 mmol) in DMF (10 mL) was added a solution of iodine (2.05 mmol) in DMF (10 mL) dropwise at 25–30 °C. Stirring continued at the same temperature till completion of the reaction (indicated by TLC). Then the reaction mixture was poured into cold water (250 mL) containing sodium thiosulphate (10%). The solid separated was filtered, washed with cold water (10–15 °C), dried and recrystallized from 5% to 10% hexane/EtOAc (1 mL for 50 mg) to give the desired product in 90% yield; yellow solid; mp 56–58 °C; 1H NMR (400 MHz, CDCl3) δ 7.50 (dd, J = 8.0 and 0.7 Hz, 1H), 7.38–7.30 (m, 3H), 7.08 (s, 1H), 3.70 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 136.4, 132.4, 130.1, 122.4, 120.8, 120.0, 109.2, 54.5, 32.8.

2.3

2.3 General procedure for the preparation of 3-vinyl indoles (3) (Bocchi et al., 1982)

A mixture of substituted indole 1 (0.3 mmol, 1.0 equiv.), alkene 2 (0.36 mmol, 1.2 equiv.), 10% Pd/C (0.05 equiv.), PPh3 (0.10 equiv.), and Et3N (0.6 mmol, 2.0 equiv.) in DMF (5.0 mL) was stirred at 30 °C under ultrasound (using a laboratory ultrasonic bath SONOREX SUPER RK 510H model producing irradiation of 35 kHz) in the presence of nitrogen atmosphere. After completion of the reaction (indicated by TLC) the mixture was diluted with cold water (30 mL), and extracted with EtOAc (3 × 30 mL). The combined organic phases were collected, washed with cold brine solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using 2–5% hexane-EtOAc (TLC Rf ∼ 0.5) as eluant to give the desired product.

2.3.1

2.3.1 (E)-Butyl-3-(1-methyl-1H-indol-3-yl)acrylate (3a) (Chen et al., 2012)

Light yellow solid; 62–64 °C; IR (neat) ν: 3054, 1704, 1627 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.89–7.84 (m, 2H), 7.30–7.21 (m, 4H), 6.41 (d, J = 15.7 Hz, 1H), 4.20 (t, J = 6.2 Hz, 2H), 3.72 (s, 3H), 1.71–1.65 (m, 2H), 1.46–1.41 (m, 2H), 0.97 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 168.3, 137.8, 137.8, 133.0, 125.8, 122.7, 121.1, 120.4, 112.4, 112.0, 109.8, 63.8, 33.0, 30.8, 19.1, 13.6; HRMS (ESI) calcd for C16H19NO2Na [M+Na+]: 280.1308, found: 280.1310.

2.3.2

2.3.2 (E)-tert-Butyl 3-(1-methyl-1H-indol-3-yl)acrylate (3b) (Tao et al., 2014)

Yellow low melting solid; IR (neat) ν: 3057, 1705, 1625 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 15.6 Hz, 1H), 7.30–7.20 (m, 4H), 6.34 (d, J = 15.6 Hz, 1H), 3.73 (s, 3H), 1.54 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 167.6, 137.8, 136.8, 132.7, 126.0, 122.7, 121.0, 120.4, 114.4, 112.1, 109.8, 79.5, 33.0, 28.2; HRMS (ESI) calcd for C16H19NO2Na [M+Na+]: 280.1308, found: 280.1311.

2.3.3

2.3.3 (E)-Methyl-2-(1-methylindol-3-yl)acrylate (3c) (Pindur et al., 1989)

Light brown solid, mp 95–97 °C; IR (neat) ν: 3055, 1706, 1629 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.93–7.87 (m, 2H), 7.36–7.23 (m, 4H), 6.41 (d, J = 15.7 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.6, 138.1, 138.0, 133.0, 126.0, 122.8, 121.2, 120.4, 112.1, 112.0, 109.8, 51.2, 33.1; HRMS (ESI) Calcd for C13H13NO2 [M+]: 215.0946, found: 215.0949.

2.3.4

2.3.4 (E)-Ethyl-3-(1-methyl-1H-indol-3-yl)acrylate (3d) (Chen et al., 2012)

Yellow solid; mp 95–98 °C; IR (neat) ν: 3053, 1704, 1613 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.82–7.76 (m, 2H), 7.22–7.15 (m, 4H), 6.33–6.30 (d, J = 15.8 Hz, 1H), 4.19–4.14 (q, J = 6.6 Hz, 2H), 3.65 (s, 3H), 1.27–1.23 (t, J = 7.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.4, 138.0, 133.2, 126.0, 122.9, 121.3, 120.6, 112.5, 112.0, 109.9, 60.1, 33.1, 14.5; HRMS (ESI) Calcd for C14H15NO2 [M+]: 229.1103, found: 215.1109.

2.3.5

2.3.5 (E)-1-Methyl-3-styryl-1H-indole (3e) (Chen et al., 2012)

Off white solid; mp 96–98 °C; IR (neat) ν: 3052, 1632, 1514 cm−1; 1H NMR (400 MHz, CDCl3): 8.02 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 7.5 Hz, 2H), 7.41–7.22 (m, 8H), 7.12 (d, J = 16.3 Hz, 2H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 138.6, 137.6, 128.5, 128.4, 126.3, 126.0, 125.6, 124.6, 122.1, 121.5, 120.1, 120.0, 114.0, 109.5, 32.8; HRMS (ESI) calcd for C17H16N [M+H+]: 234.1277, found: 234.1273.

2.3.6

2.3.6 (E)-N,N-dimethyl-3-(1-methyl-1H-indol-3-yl)acrylamide (3f)

Pale yellow solid; mp 97–99 °C; IR (neat) ν: 3054, 1654, 1510 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.90–7.85 (m, 2H), 7.33–7.20 (m, 4H), 6.85 (d, J = 15.3 Hz, 1H), 3.76 (s, 3H), 3.15–3.10 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 167.8, 137.8, 135.7, 132.4, 126.0, 122.5, 120.7, 120.3, 112.5, 111.8, 109.8, 37.2, 35.8, 33.0; HRMS (ESI) calcd for C14H17N2O [M+H+]: 229.1335, found: 229.1332.

2.3.7

2.3.7 (E)-N,N-diethyl-3-(1-methyl-1H-indol-3-yl)acrylamide (3g) (Chen et al., 2012)

Light brown solid; mp 94–96 °C; IR (neat) ν: 3055, 1655, 1514 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 15.8 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.31–7.22 (m, 4H), 6.80 (d, J = 15.8 Hz, 1H), 3.73 (s, 3H), 3.50–3.48 (m, 4H), 1.28–1.18 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 166.8, 137.9, 135.6, 132.4, 126.0, 122.6, 120.8, 120.2, 112.6, 112.2, 109.9, 42.2, 41.0, 33.0, 15.0, 13.4; HRMS (ESI) calcd for C16H20N2O [M+Na+]: 279.1468. Found: 279.1465.

2.3.8

2.3.8 (E)-1-(1-methyl-1H-indol-3-yl)oct-1-en-3-one (3h)

Light brown low melting solid; IR (neat) ν: 3055, 2356, 1705, 1514 cm−1; 1H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 15.7 Hz, 1H), 7.31–7.22 (m, 4H), 6.74 (d, J = 15.7 Hz, 1H), 3.75 (s, 3H), 2.60 (t, J = 7.3 Hz, 2H), 1.70 (t, J = 7.3 Hz, 2H), 1.36–1.31 (m, 4H), 0.90 (t, J = 6.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 200.7, 138.0, 135.8, 133.6, 126.0, 123.0, 121.3, 121.2, 120.4, 112.0, 110.0, 40.7, 33.0, 31.5, 24.4, 22.4, 13.8; HRMS (ESI) calcd for C17H22NO [M+H+]: 256.1696, found: 256.1698.

2.3.9

2.3.9 (E)-4-(1-methyl-1H-indol-3-yl)but-3-en-2-one (3i) (Caballero et al., 2001)

Yellow low melting solid; IR (neat) ν: 3058, 2360, 1707, 1516, 1129 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.7 Hz, 1H), 7.75 (d, J = 16.0 Hz, 1H), 7.38–7.26 (m, 4H), 6.75 (d, J = 16.0 Hz, 1H), 3.81 (s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.4, 138.1, 137.0, 133.5, 126.0, 123.0, 122.3, 121.3, 120.5, 112.0, 110.0, 33.1, 27.2; HRMS (ESI) calcd for C13H14NO [M+H+] 200.1075, found: 200.1077.

2.3.10

2.3.10 (E)-3-(1-methyl-1H-indol-3-yl)-1-phenylprop-2-en-1-one (3j) (Order et al., 1945; Black et al., 1992)

Yellow solid; mp 96–98 °C; IR (neat) ν: 3089, 2365, 1741, 1516 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.10–8.01 (m, 4H), 7.58–7.46 (m, 5H), 7.38–7.30 (m, 3H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.6, 139.0, 138.5, 138.2, 134.5, 132.0, 128.4, 128.2, 126.0, 123.1, 121.5, 120.7, 117.0, 113.0, 110.1, 33.2; HRMS (ESI) calcd for C18H16NO [M+H+] 262.1232, found: 262.1228.

2.3.11

2.3.11 (E)-3-(1-methyl-1H-indol-3-yl)acrylonitrile (3k) (Chen et al., 2012; López et al., 2005)

Light brown solid; mp 92–94 °C; IR (neat) ν: 3052, 2145, 1515 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 15.9 Hz, 1H), 7.35–7.25 (m, 4H), 5.70 (d, J = 15.9 Hz, 1H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.5, 138.0, 133.1, 125.4, 123.4, 121.8, 120.2, 120.1, 111.8, 110.3, 89.3, 33.3; HRMS (ESI) calcd for C12H11N2 [M+H+] 183.0922, found: 183.0925.

2.4

2.4 Sulforhodamine B (SRB) assay

Cancer cells (around 5000 in number) were seeded in 96-well plates and incubated overnight. The optimum cell number to be seeded was determined by a growth curve analysis for the cell line. Compounds (dissolved in 100% DMSO to a stock concentration of 200 mM) were added to the adhered cells at a final concentration of 10 μM. After 72 h of treatment, the cells were washed with phosphate-buffered saline and ice-cold 10% trichloroacetic acid was added to the cells to precipitate the proteins. It was incubated for 1 h at 4 °C. The cells were then washed with water and air-dried. Cellular proteins were then stained using 0.4% SRB solution in 1% acetic acid for 30 min at room temperature (25 °C). The unbound dye was washed away by destaining with 1% acetic acid and bound dye was solubilized with 10 mM Tris solution (pH 10.5). Absorbance of solubilized dye was measured at a wavelength of 590 nm. Percentage growth was determined by the formula [ ( At - A 0 / Ac - A 0 ) ] × 100 where At = absorbance after 72 h of test compound treatment, A0 = absorbance at time 0, Ac = absorbance after 72 h without treatment.

The known cytotoxic agent, gemcitabine was used as a positive control in the assay.

3

3 Results and discussion

3.1

3.1 Chemistry

We began our study with the coupling reaction of 3-iodo-1-methyl-1H-indole (1), prepared according to a known procedure (Bocchi and Palla, 1982), with n-butyl acrylate (2a) under standard Mizoroki–Heck reaction conditions. The use of conventional palladium catalytic systems e.g. (PPh3)2PdCl2 or Pd(OAc)2–PPh3 did not afford the good yield of desired product 3a (entries 1–2, Table 1). The dehalogenated product 4 was also isolated as a side product (20–21% yield) in these cases. These reactions were carried out at 90 °C using Et3N as a base as well as solvent. The use of a high boiling solvent such as DMF though allowed the reaction to proceed at higher temperature no significant change in the yield of 3a and 4 was observed (entry 3, Table 1). The change of catalyst to 10%Pd/C–PPh3 and use of longer reaction time also did not change the ratio of 3a and 4 formed (entry 4, Table 1). Notably, a significant improvement in yield of 3a was observed when the reaction was performed under ultrasound irradiation (using a laboratory ultrasonic bath SONOREX SUPER RK 510H model producing irradiation of 35 kHz) instead of conventional heating (entry 5, Table 1). Indeed, the reaction proceeded at lower temperature (50 °C) and reached to the completion within 2 h as indicated by thin layer chromatography (TLC). A further decrease in reaction temperature to 30 °C did not affect the product yield (entry 6, Table 1). While the side reaction involving dehalogenation of 1 was not suppressed completely in these cases we were delighted to achieve the higher yield of 3a. To assess the role of catalyst, ligand and base in the present 3-alkenylation of indole the coupling reaction was performed in the absence of Pd/C (entry 7, Table 1), PPh3 (entry 8, Table 1) and K2CO3 in place of Et3N (entry 9, Table 1) separately. The reaction either did not proceed or afforded poor yield of 3a in these cases. All these observations clearly indicated the key role played by the Pd/C, PPh3 and Et3N in the present reaction whereas the use of ultrasound allowed a faster reaction at a lower temperature with improved yield of 3a. The change of solvent from DMF to EtOH was also examined when the dehalogenated product 4 was obtained as a major product. Overall, the condition of entry 6 appeared as the best for synthesizing 3a and was used for further study.

Table 1 Effect of reaction conditions on the coupling of 1 with 2a.a
Entry Catalyst Solvent/base Temp (°C)/time (h) % yieldb
3a 4
1. (PPh3)2PdCl2 Et3N 90/6 49 21
2. Pd(OAc)2–PPh3 Et3N 90/6 47 20
3. Pd(OAc)2–PPh3 DMF/Et3N 100/6 50 17
4. 10%Pd/C–PPh3 DMF/Et3N 100/12 43 27
5. 10%Pd/C–PPh3 DMF/Et3N 50/2 78c 11
6. 10%Pd/C–PPh3 DMF/Et3N 30/2 75c 10
7. PPh3 DMF/Et3N 30/12 0c,d 0
8. 10%Pd/C DMF/Et3N 30/12 Tracec,e 0
9. 10%Pd/C–PPh3 DMF/K2CO3 30/12 19c 0
10. 10%Pd/C–PPh3 EtOH/Et3N 30/12 10c 66
a All reactions were carried out using 1 (1 equiv.), alkene 2a (1.2 equiv.), a Pd-catalyst (0.05 equiv.), PPh3 (0.10 equiv.) where necessary and a base (2 equiv.) in a solvent (5.0 mL) (5 mL of Et3N was used as a base as well as solvent in case of entries 1 and 2) under nitrogen.
b Isolated yield.
c The reaction was carried out under ultrasound irradiation.
d The reaction was carried out without Pd/C.
e The reaction was carried out without PPh3.

A number of 3-vinyl indole derivatives (3a–i) were prepared using the optimized reaction conditions (Table 2). A variety of terminal alkenes (2a–i) generally bearing an electron withdrawing groups such as ester, amide, ketone, aryl and cyano moiety were employed in the present coupling reaction (entries 1–11, Table 2). The reaction proceeded well in all these cases affording the corresponding desired product in acceptable yields. Notably, terminal alkenes that do not possess an electron withdrawing group (entry 12, Table 2) or alkenes possessing substituent at both ends [e.g. (E)-ethyl but-2-enoate) (entry 13, Table 2) were found to be less reactive in the present coupling reaction. The use of acrolein was also not successful due to its quick polymerization under the condition studied. We also examined the use of 3-iodo-1-(phenylsulfonyl)-1H-indole in place of 3-iodo-1-methyl-1H-indole (1) that was treated with 2a under the optimized condition (entry 6, Table 1). However, the reaction afforded a mixture of product with poor yield of the desired indole derivative. Though a marginally better yield of desired product was obtained when 3-bromo-1-methyl-1H-indole was employed the reaction also afforded appreciable quantity of dehalogenated product (i.e. 1-methyl-1H-indole) as a by-product. Nevertheless, all the 3-vinyl indole derivatives (3a–i) synthesized were characterized by spectral data. The E-geometry of the double bond was confirmed by the coupling constant (J) of olefinic protons of all the compounds that were found to be ∼16 Hz. It is worthy to mention that 3-vinyl indole derivatives e.g. compound 3b have been used for the construction of benzo[a]carbazole-5-carboxylates via the Diels–Alder reaction (Tao et al., 2014). Thus the synthetic utility of 3-vinyl-indoles has been demonstrated via their uses in Diels–Alder chemistry as a route to carbazoles and related species (Pindur and Otto, 1992; Lambert and Porter, 1981; Pindur et al., 1992; Tan et al., 2011; Cowell et al., 2015; Gioia et al., 2008).

Table 2 Preparation of 3-vinyl indoles via ultrasound assisted Mizoroki–Heck reaction catalyzed by Pd/C.a
Entry Alkene (2); R= Time (h) Product (3) % yieldb
1. 2a; –CO2Bu 2 3a; 75
2. 2b; –CO2tBu 2 3b; 77
3. 2c; –CO2Me 3 3c; 71
4. 2d; –CO2Et 2.5 3d; 73
5. 2e; –Ph 2 3e; 70
6. 2f; –CONMe2 2.5 3f; 72
7. 2g; –CONEt2 2.5 3g; 73
8. 2h; –COC5H11 3 3h; 69
9. 2i; –COCH3 3 3i; 65
10. 2j; –COPh 2.5 3j; 75
11. 2k; –CN 2 3k; 78
12. 2l; –CH2OC2H5 – 0
13. 2m; (E)-ethyl but-2-enoate – 0
a All reactions were carried out using 1 (1 equiv.), alkene 2 (1.2 equiv.), 10%Pd/C (0.05 equiv.), PPh3 (0.10 equiv.) and Et3N (2 equiv.) in DMF (5.0 mL) at 30 °C under nitrogen.
b Isolated yield.

A plausible reaction mechanism for the present Pd/C-catalyzed coupling of 1 with 2 under ultrasound is presented in Scheme 2. The reaction involves in situ generation of an active palladium(0) species (Pal, 2009; Rambabu et al., 2013; Chen et al., 2007) via a Pd leaching process from the minor portion of the bound palladium (Pd/C) (Köhler et al., 2002) and then goes into the solution. The leached Pd then undergoes interaction with PPh3 to give a dissolved Pd(0)–PPh3 complex. Notably the generation of active species from supported Pd catalyst under Heck reaction conditions has been studied earlier (Reimann et al., 2011). Nevertheless, being the actual catalytic species this complex then participates in oxidative addition with 1 to give the organo-palladium(II) species E-1. Subsequent formation of a π-complex of E-1 with the alkene 2 (not shown) followed by syn addition of Pd-carbon bond of E-1 across the double bond of 2 affords E-2. A torsional strain relieving rotation around the C–C bond of E-2 gives E-3 which then undergoes a syn β-hydride elimination to give the product 3 and HPdIII species. The regeneration of Pd(0) via reductive elimination of Pd from HPdIII species completes the catalytic cycle which continues till the complete consumption of 1. Overall, the catalytic cycle appears to operate in solution instead of on the surface and re-precipitation of Pd occurs on the surface of the charcoal at the end of the reaction.

Probable mechanism of Pd/C-catalyzed coupling of 1 with alkene 2.
Scheme 2 Probable mechanism of Pd/C-catalyzed coupling of 1 with alkene 2.

The results of Table 1 clearly suggest that the Pd/C-catalyzed coupling reaction was facilitated when performed under ultrasound irradiation though it is not clear whether the ultrasound has effect on one or more steps as shown in Scheme 2. It is known that the presence of an electron donating group on the indole nitrogen generally is not favorable for coupling at C-3 perhaps due to the high electron density of the iodo group bearing carbon resulting in a slower oxidative addition of Pd(0) to 1 (Scheme 2). The ultrasound possibly provides a positive effect on this step with the force created due to the cavitational collapse. Indeed, the cavitational collapse creates drastic conditions inside the medium within an extremely short period of time, e.g. the temperature of 2000–5000 K and pressure up to 1800 atmosphere can be produced inside the collapsing cavity under sonic conditions (Suslick and Flannigan, 2008; Mason, 1997; Luche, 1998). Also, strong physical effects including shear forces, jets, and shock waves are caused by this collapse outside the bubble. Thus, it is possible that the oxidative addition step (along with several other steps) was particularly driven by the force created due to the cavitational collapse. It is also possible that the Pd leaching process thereby in situ generation of active Pd(0) species was accelerated by the ultrasound. Notably, the ultrasound may facilitate the generation of Pd(0) nanoparticles that may serve as a reservoir of “homogeneous” catalytic active species (Cassol et al., 2005). The role of Pd nanoparticles in Heck and other coupling reactions (e.g. Suzuki–Miyaura reaction) has been studied (Ellis et al., 2010; Baumann et al., 2014).

3.2

3.2 Pharmacology

Due to the known anticancer properties of various 3-substituted indole derivatives all the synthesized compounds were evaluated for their ability to inhibit the growth of cancer cells. These compounds were tested at 10 μM against three cancer cells e.g. A549 (lung), MCF-7 (breast) and TZM-BL (cervical) using the sulforhodamine B (SRB) assay (Rubinstein et al., 1990; Skehan et al., 1990) with gemcitabine (Chu and DeVita, 2007) as a reference compound. Except 3f and 3g all these compounds showed moderate to weak activities against the lung, breast and cervical cancer cells. However, the compounds 3f and 3g showed >75% inhibition against breast cancer (MCF-7) cells (comparable to gemcitabine’s ∼ 50% inhibition) (Fig. 2) though they were found to be less active against other two cancer cells. Moreover, these compounds did not show significant effect on normal HEK 293T cells (10–15% inhibition vs gemcitabine’s 25%) indicating their selectivity toward cancer cells. Notably, comparison of structural features of compounds 3f and 3g with other indicates that the presence of an amide (–CONMe2 or –CONEt2) moiety could be responsible for their cytotoxic activities against MCF-7 cells. A possible explanation for observed cytotoxic activities of 3f and 3g could be their potential inhibition of thymidilate synthase (TS), a key enzyme required for cellular growth (Rao et al., 1998). Like 5-fluorouracil, the enone moiety (of 3f and 3g) may facilitate the binding of TS enzyme (Papamichael, 1999; Kundu et al., 1993) through its sulfhydryl (–SH) moiety with compounds 3f and 3g in the presence of cofactor methylene tetrahydrofolate thereby generating the corresponding enzyme-drug-cofactor complexes (Fig. 3). However, the low or moderate activities shown by other compounds in spite of the presence of enone moiety were not clearly understood. The participation of amide nitrogen (i.e. a mild H-bond acceptor) of 3f and 3g in additional interactions with the TS enzyme or cofactor could be the other reason. It is also not clear why these two compounds showed low activities against other cancer (e.g. lung and cervical) cell lines. Nevertheless, the observed selectivity of compounds 3f and 3g toward breast cancer cells is interesting. Thus, the present study indicated that the indole ring possessing an acrylamide moiety at C-3 could be a potential template for the identification of new anticancer agents.

% Inhibition of breast adenocarcinoma cells (MCF-7) after 72 h of compound treatment.
Figure 2 % Inhibition of breast adenocarcinoma cells (MCF-7) after 72 h of compound treatment.
Possible interactions of compounds 3f and 3g with TS enzyme.
Figure 3 Possible interactions of compounds 3f and 3g with TS enzyme.

5

5 Conclusion

In conclusion, the Pd/C–PPh3 catalyst system has been found to be effective in facilitating the C–C bond forming reaction between 3-iodo-1-methyl-1H-indole and various terminal alkenes under ultrasound irradiation. A variety of terminal alkenes containing an ester, amide, ketone and aryl moiety were employed in this ultrasound assisted Mizoroki–Heck reaction. The reaction proceeded well in all these cases affording the corresponding 3-vinyl indole derivatives in good to acceptable yields. The advantages and drawbacks along with the reaction mechanism of this methodology are discussed. All indole derivatives synthesized were tested against three cancer cell lines including lung, breast and cervical cancer. Two of these indole derivatives showed cytotoxic activities against breast cancer cells. Overall, the Pd/C based methodology presented here could be useful for the quicker access to a library of compounds based on 3-vinyl indole framework of potential pharmacological interest.

Acknowledgment

The authors thank the management of Dr. Reddy’s Institute of Life Sciences, Hyderabad, India, for continuous support and encouragement.

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