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Original article
13 (
1
); 120-133
doi:
10.1016/j.arabjc.2017.02.007

Hypervalent iodine(III) catalyzed rapid and efficient access to benzimidazoles, benzothiazoles and quinoxalines: Biological evaluation of some new benzimidazole-imidazo[1,2-a]pyridine conjugates

, , , , , , ,
a Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India
b Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
c Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India

⁎Corresponding author at: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India.

Received: , Accepted: ,
© The Author(s) 2017
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

Abstract

A rapid, simple and highly efficient method for the synthesis of a variety of 2-aryl-benzimidazoles, 2-aryl-benzothiazoles and quinoxalines has been developed using Koser’s reagent [PhI(OH)OTs] as catalyst. The present work highlights the potential of Koser's reagent ([PhI(OH)OTs]) for the synthesis of benzimidazoles, benzothiazoles and quinoxalines, etc. Short reaction time, high yields, importantly low catalyst loading, broad substrate scope and scalability are the salient features of this methodology. Particularly, this method has been employed successfully to synthesize highly structured indole-benzimidazole and quinoxaline-6-carboxamide derivatives as well as biologically important benzimidazole-imidazo[1,2-a]pyridine conjugates in moderate to good yields. These remarkable features make the present methodology a valid contribution to the existing precedents for the synthesis of benzimidazoles, etc. In the MTT assay, benzimidazole-imidazo[1,2-a]pyridine conjugates 3s, 3t and 3v were found to be active on MCF-7 (IC50 values of 5.10 ± 0.10, 8.23 ± 0.02, and 10.75 ± 0.03 µM, respectively) and MDA-MB-231 cell lines (IC50 values of 10.83 ± 0.13, 7.68 ± 0.05, and 7.87 ± 0.24 µM, respectively). Flow-cytometry analysis revealed that the treatment of MCF-7 cells with compound 3s showed moderate effect on the progression of G0/G1 phase of the cell cycle.

Keywords

Koser’s reagent
Benzimidazoles
Benzothiazoles
Quinoxalines
Imidazo[1,2-a]pyridine
1

1 Introduction

Benzimidazoles are useful intermediates to develop molecules of biological interest. Benzimidazole is considered as a privileged structure for drug design because many drugs such as albendazole (anthelmintic), omeprazole (antiulcer) and telmisartan (antihypertensive) possess benzimidazole as a core template (Yadav and Ganguly, 2015) (Fig. 1). The presence of benzimidazole nucleus in various therapeutic agents such as antimicrobial (Sharma et al., 2009), antiviral (Yun-Fei et al., 2006; Banie et al., 2007), anticancer (Chen et al., 2010), antihypertensive (Yagupolskii and Fedyuk, 2000; Kaur et al., 2008), antifungal (Goker et al., 2002) and antidiabetics (Deshpande et al., 1970), has made it an indispensable anchor for the development of new therapeutic agents. Benzimidazole derivatives exhibit anticancer activity by acting on a variety of targets such as Aurora kinase (Zhong et al., 2009), Poly(ADP-ribose) Polymerase-1 (PARP-1) (White et al., 2000; Penning et al., 2008, 2009) and phosphoinositide 3-kinase delta (PI3Kδ) (Murray et al., 2012). NU-1085, A-620223 (Underhill et al., 2011) and veliparib (ABT-888) (Wagner, 2015) are the few examples for benzimidazole based PARP-1 inhibitors (Fig. 1). Owing to such a wide range of biological activities, there is a considerable interest in the synthesis and biological evaluation of novel benzimidazole derivatives.

Structures of some benzimidazole drugs and drug molecules.
Figure 1 Structures of some benzimidazole drugs and drug molecules.

Several attempts have been made from time to time to develop an effective and inexpensive method for the synthesis of benzimidazole derivatives. There are three common protocols for the synthesis of 2-substituted benzimidazoles. The first one is the Phillips-Ladenburg reaction based on the interaction of diaminobenzenes with carboxylic acids (Ladenburg, 1875; Ladenburg, 1877; Phillips, 1928a; Phillips, 1928b; and Phillips, 1929), and the second one is the Weidenhagen reaction based on the interaction of ortho-phenylenediamine with aldehydes (Weidenhagen, 1936). The harsh temperature conditions, sometimes up to 250 to 300 °C, and low yields limit the use of these reactions in their classical form. Actually, all the currently available methods of the synthesis of benzimidazoles are a modification of the Phillips-Ladenburg and Weidenhagen reactions. Various reagents such as Pb(OAc)4 (Stephens and Bower, 1949), β-cyclodextrin (Katla et al., 2015), MnO2 (Bhatnagar and George, 1968), FeF3 (Kumar et al., 2012), TMSCl (Wan et al., 2009), benzofuroxan (Patzold et al., 1992), ZnO nanoparticles (Sharma et al., 2015), DDQ (Eynde et al., 1995), MnFe2O4 nanomaterial (Brahmachari et al., 2013), perchloric acid adsorbed on silica-gel (HClO4–SiO2) (D. Kumar et al., 2013; V. Kumar et al., 2013), oxone (Beaulieu et al., 2003), NH4VO3 (Jadhav et al., 2009), ZrO2-supported-β-cyclodextrin (ZrO2-β-CD) nanoparticles (Girish and Shashikanth, 2015), DMP (Kumar et al., 2009), sodium dodecylsulfate (SDS) (Kattimani et al., 2015), FeBr2 (Gopalaiah and Chandrudu, 2015), AgNO3 (Rustagi et al., 2011), ionic liquids such as imidazolium trifluoroacetate (Majumdar et al., 2015), prolinium nitrate (Rostamizadeh et al., 2009) and [pmim]BF4 (Saha et al., 2009) have been employed for this conversion. There are also reports on the use of cerric ammonium nitrate-H2O2 (Bahrami et al., 2008) and iodobenzenediacetate (IBD) (Du and Wang, 2007) for the synthesis of benzimidazoles. The third one is the acid-catalyzed rearrangement of quinoxalinone derivatives to 2-heteroaryl-substituted benzimidazoles by the reaction of N-, C-nucleophiles (Mamedov hetrocycle rearrangement) (Hassner and Namboothiri, 2012; Mamedov, 2016a; Mamedov, 2016b). However, some of the earlier methods based on Phillips-Ladenburg Weidenhagen reactions have drawbacks such as the use of expensive catalyst, harsh reaction conditions, longer reaction time, generation of toxic by-products and laborious workup procedures as to Mamedov rearrangement it requires a specially synthesized starting compounds. Hence, the development of a simple, rapid and cost-effective protocol is desirable.

During recent years, organohypervalent iodine compounds have emerged as environmentally friendly and efficient reagents for organic reactions involving oxidative transformations (Zhdankin, 2013). Among the hypervalent iodine reagents, Koser’s reagent is an important example of acid activated iodosyl benzene (PhIO.TsOH) because of its reactivity. Particularly, the potential of Koser’s reagent [PhI(OH)OTs] has been well explored for the oxidative functionalization of arenes, alkenes and alkynes (Koser, 2001), oxidative rearrangement of aryl alkenes (Justik and Koser, 2004), oxidative ring expansion of alkylidenebenzocycloalkenes (Justik and Koser, 2005) and α-tosyloxylation of ketones (Shang et al., 2007). Based on this knowledge and in continuation of our efforts toward the development of novel synthetic methodologies, we herein present a rapid, simple and efficient protocol for the synthesis of benzimidazoles, benzothiazoles and quinoxalines through a hypervalent (III) iodine catalyzed oxidation.

On the other hand, imidazo[1,2-a]pyridine and its derivatives exhibit a broad range of biological activities such as antitumor (Rupert et al., 2003; Badaway and Kappe, 1995; Lee et al., 2013), antibacterial (Rival et al., 1992), antifungal (Rival et al., 1991), antiviral (Hamdouchi et al., 1999; Lhassani et al., 1999) and antiprotozoal (Fisher and Lusi, 1972) activities. Several marketed drugs such as necopidem and saripidem (act as an anxiolytic agent), olprinone (the drug for acute heart failure) (Mizushige et al., 2002) and GSK812397 (used in the treatment of HIV infection) (Gudmundsson and Boggs, 2006) contain imidazo[1,2-a]pyridine moiety as core nucleus (Fig. 2). Recently, our research group also reported imidazopyridine-benzimidazole conjugates as promising tubulin inhibitors with G2/M cell cycle arrest and apoptosis inducing ability (Kamal et al., 2015).

Structures of some biologically active imidazo[1,2-a]pyridine derivatives.
Figure 2 Structures of some biologically active imidazo[1,2-a]pyridine derivatives.

2

2 Experimental

2.1

2.1 Synthesis

2.1.1

2.1.1 Materials and methods

All the starting materials were obtained from commercially available suppliers and were used without further purification with the exception of benzaldehyde and 2-furaldehyde which were distilled prior to use. Koser’s reagent was prepared in the laboratory according to the procedure available in the literature (Eleanor et al., 2010). The reactions were monitored by thin layer chromatography (TLC), using MERCK pre-coated silica gel 60-F254 aluminum plates. Visualization of spots on TLC plates was done by UV light. Melting point was checked using Stuart® SMP30 melting point apparatus and is uncorrected. NMR spectra were recorded on Bruker Avance 500 MHz spectrometer using tetramethyl silane (TMS) as the internal standard at 27 °C, with compound concentration of 5 mg for 1H NMR and 15 mg for 13C NMR and are reported in parts per million (ppm) downfield from TMS. Spin multiplicities are reported as s (singlet), brs (broad singlet), d (doublet), dd (double doublet), t (triplet) and m (multiplet). Coupling constant (J) values are reported in hertz (Hz). HRMS were determined with Agilent QTOF mass spectrometer 6540 series instrument and were performed in the ESI techniques at 70 eV. Column chromatography was performed using silica gel 60–120 mesh. Overall, by applying this method forty compounds were prepared out of which twelve compounds were new and structurally diverse.

2.1.2

2.1.2 General procedure for the synthesis of benzimidazole and benzothiazole derivatives (3a–z and 4a–f)

To a solution of o-phenylenediamine or 2-aminothiophenol (1) (1 mmol) in 1,4-dioxane (5 mL) under O2 atmosphere was added aldehyde (2) (1 mmol), followed by freshly prepared Koser’s reagent [PhI(OH)OTs] (1 mol%). The reaction mixture was allowed to stir at room temperature for the required time. In case of benzimidazole-indole and benzimidazole-imidazo[1,2-a]pyridine conjugates the reaction was carried out at 80 °C for the required time. After completion of the reaction as indicated by TLC analysis, the reaction mixture was concentrated to remove the solvent. It was extracted with ethyl acetate (3 × 10 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product (3a–z and 4a–f) was recrystallized from ethanol or purified by column chromatography (Silica gel, 60–120 mesh, 9:1 hexane/ethyl acetate).

2.1.3

2.1.3 General procedure for the synthesis of quinoxaline derivatives (6a–h)

To a magnetically stirred solution of o-phenylenediamine (1) (1 mmol) and benzil (5) (1 mmol) in 1,4-dioxane (5 mL) under O2 atmosphere was added freshly prepared Koser’s reagent [PhI(OH)OTs] (1 mol%) at room temperature. After completion of the reaction, as indicated by TLC analysis, the reaction mixture was concentrated to remove 1,4-dioxane. In case of quinoxaline-6-carboxamide derivatives, the reaction was carried out at 80 °C for the required time. After completion of the reaction as indicated by TLC analysis, the reaction mixture was concentrated to remove the solvent. It was extracted with ethyl acetate (3 × 10 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product (6a–h) was recrystallized from ethanol or purified by column chromatography (Silica gel, 60–120 mesh, 9:1 hexane/ethyl acetate).

2.1.4

2.1.4 HPLC data of compounds 3s, 3t and 3v

To check the purity of the most active benzimidazole-imidazo[1,2-a]pyridine conjugates (3s, 3t and 3v), HPLC analysis was performed. The results indicated >98.5% of purity for all the tested compounds.

2.1.5

2.1.5 Spectral data of synthesized compounds

IUPAC names for 5(6)-substituted benzimidazoles were assigned based on the reports available in the literature (Ozturk et al., 2003; Kucukbay et al., 2010; Sireci et al., 2010).

2.1.5.1
2.1.5.1 2-Phenyl-1H-benzo[d]imidazole (3a)

Yellow crystalline solid, 94% yield (90% yield by Kim et al., 2011), mp: 294–295 °C (292–294 °C by Kim et al., 2011); 1H NMR (500 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.19 (d, J = 7.2 Hz, 2H), 7.86 (d, J = 7.3 Hz, 1H), 7.60–7.38 (m, 4H), 7.31–7.08 (m, 2H); 13C NMR (125 MHz, DMSO-d6) δ 151.7, 144.2, 135.4, 130.6, 130.3, 129.4, 126.9, 123.0, 122.1, 119.3, 111.8; HRMS (ESI-TOF): m/z calculated for C13H11N2 [M+H]+ 195.0917, found 195.0930.

2.1.5.2
2.1.5.2 2-p-tolyl-1H-benzo[d]imidazole (3b)

Yellow solid, 89% yield (78% yield by Kim et al., 2011), mp: 276–277 °C (275–277 °C by Kim et al., 2011); 1H NMR (500 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.07 (d, J = 8.1 Hz, 2H), 7.74–7.45 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.19 (dd, J = 5.7, 2.7 Hz, 2H), 2.39 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 151.8, 144.2, 140.0, 135.4, 129.9, 127.9, 126.8, 122.7, 122.0, 119.1, 111.6, 21.4; HRMS (ESI-TOF): m/z calculated for C14H13N2 [M+H]+ 209.1073, found 209.1081.

2.1.5.3
2.1.5.3 2-(4-Methoxyphenyl)-1H-benzo[d]imidazole (3c)

Light yellow solid, 93% yield (82% yield by Kim et al., 2011), mp: 225–226 °C (222–225 °C by Kim et al., 2011); 1H NMR (500 MHz, DMSO-d6) δ 12.90 (s, 1H), 7.80–7.73 (m, 2H), 7.72–7.50 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.24 (dd, J = 24.9, 3.4 Hz, 2H), 7.10–7.03 (m, 1H), 3.87 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 160.1, 151.5, 131.9, 130.5, 119.2, 116.3, 111.8, 55.7; HRMS (ESI-TOF): m/z calculated for C14H13N2O [M+H]+ 225.1022, found 225.1017.

2.1.5.4
2.1.5.4 2-(3,4-Dimethoxyphenyl)-1H-benzo[d]imidazole (3d)

Off-white solid, 91% yield (59% yield by Mahesh et al., 2015), mp: 183–184 °C (181–182 °C by Mahesh et al., 2015); 1H NMR (500 MHz, DMSO-d6) δ 12.76 (s, 1H), 7.78 (d, J = 1.9 Hz, 1H), 7.75 (dd, J = 8.3, 1.9 Hz, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.27–7.08 (m, 3H), 3.89 (s, 3H), 3.84 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 151.9, 150.7, 149.3, 144.3, 135.4, 123.2, 122.5, 121.9, 119.7, 118.9, 112.3, 111.4, 110.2, 56.1, 56.0; HRMS (ESI-TOF): m/z calculated for C15H15N2O2 [M+H]+ 255.1128, found 255.1130.

2.1.5.5
2.1.5.5 2-(3,4,5-Trimethoxyphenyl)-1H-benzo[d]imidazole (3e)

White solid, 93% yield (64% yield by Chaturvedi et al., 2013), mp: 257–258 °C (260–262 °C by Chaturvedi et al., 2013); 1H NMR (500 MHz, DMSO-d6) δ 12.85 (s, 1H), 7.75–7.50 (m, 4H), 7.21 (s, 2H), 3.91 (s, 6H), 3.75 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 153.7, 153.5, 153.4, 151.6, 139.3, 125.9, 104.2, 60.5, 56.3; HRMS (ESI-TOF): m/z calculated for C16H17N2O3 [M+H]+ 285.1234, found 285.1247.

2.1.5.6
2.1.5.6 2-(3-Fluorophenyl)-1H-benzo[d]imidazole (3f)

Light yellow solid, 81% yield (90% yield by Qiu et al., 2015), mp: 258–259 °C (255–257 °C by Qiu et al., 2015); 1H NMR (500 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.97 (d, J = 10.2 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.62 (dd, J = 14.6, 7.1 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.35 (t, J = 8.5 Hz, 1H), 7.29–7.15 (m, 2H); 13C NMR (125 MHz, DMSO-d6) δ 163.9, 161.9, 150.4 (J = 3 Hz), 144.1, 135.4, 132.9 (J = 8.4 Hz), 131.6 (J = 8.4 Hz), 123.4, 122.9 (J = 2.7 Hz), 122.3, 119.5, 117.0 (J = 21.1 Hz), 113.4 (J = 23.6 Hz), 111.9; HRMS (ESI-TOF): m/z calculated for C13H10FN2 [M+H]+ 213.0823, found 213.0838.

2.1.5.7
2.1.5.7 2-(4-Fluorophenyl)-1H-benzo[d]imidazole (3g)

Light yellow solid, 83% yield (64% yield by Mahesh et al., 2015), mp: 240–241 °C (240–241 °C by Mahesh et al., 2015); 1H NMR (500 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.29–8.17 (m, 2H), 7.67 (d, J = 7.3 Hz, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.41 (t, J = 8.3 Hz, 2H), 7.29–7.11 (m, 2H); 13C NMR (125 MHz, DMSO-d6) δ 164.5, 162.5, 150.8, 144.2, 135.5, 129.2 (J = 8.6 Hz), 127.2 (J = 2.9 Hz), 122.6 (J = 95.7 Hz), 119.3, 116.4 (J = 21.9 Hz), 111.7; HRMS (ESI-TOF): m/z calculated for C13H9FN2 [M+H]+ 213.0823, found 213.0831.

2.1.5.8
2.1.5.8 2-(3-Nitrophenyl)-1H-benzo[d]imidazole (3h)

Light yellow solid, 81% yield (83% yield by Qiu et al., 2015), mp: 280–281 °C (200–202 °C by Qiu et al., 2015); 1H NMR (500 MHz, DMSO-d6) δ 13.31 (s, 1H), 9.03 (s, 1H), 8.62 (d, J = 7.6 Hz, 1H), 8.34 (d, J = 7.8 Hz, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.82–7.45 (m, 2H), 7.35–7.11 (m, 2H); 13C NMR (125 MHz, DMSO-d6) δ 149.5, 148.8, 144.0, 135.5, 132.9, 132.2, 131.1, 124.7, 123.7, 122.6, 121.3, 119.7, 112.1; HRMS (ESI-TOF): m/z calculated for C13H10N3O2 [M+H]+ 240.0768, found 240.0769.

2.1.5.9
2.1.5.9 2-(4-(Trifluoromethyl)phenyl)-1H-benzo[d]imidazole (3i)

White solid, 91% yield (76% yield by Nguyen et al., 2015), mp: 265–266 °C (263–265 °C by Nguyen et al., 2015); 1H NMR (500 MHz, DMSO-d6) δ 13.18 (s, 1H), 8.39 (d, J = 7.9 Hz, 2H), 7.94 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.26 (dt, J = 21.6 Hz, 7.2 Hz, 2H); 13C NMR (125 MHz, DMSO-d6) δ 150.1, 144.2, 135.5, 134.4, 130.1, 127.5, 126.4, 125.6, 123.6, 123.5, 122.5, 119.7, 112.1; HRMS (ESI-TOF): m/z calculated for C14H10F3N2 [M+H]+ 263.0791, found 263.0810.

2.1.5.10
2.1.5.10 2-(Furan-2-yl)-1H-benzo[d]imidazole (3j)

Reddish brown solid, 74% yield (72% yield by Kim et al., 2011), mp: 285–286 °C (285–287 °C by Kim et al., 2011); 1H NMR (500 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.74 (d, J = 4.2 Hz, 1H), 8.34 (d, J = 7.9 Hz, 1H), 8.01 (dd, J = 11.0, 4.3 Hz, 1H), 7.63–7.16 (m, 4H); 13C NMR (125 MHz, DMSO-d6) δ 146.0, 145.1, 144.1, 122.7, 112.7, 110.9; HRMS (ESI-TOF): m/z calculated for C11H9N2O [M+H]+ 185.0709, found 185.0736.

2.1.5.11
2.1.5.11 2-(Pyridin-2-yl)-1H-benzo[d]imidazole (3k)

Off-white solid, 72% yield (94% yield by Wade et al., 2015), mp: 220–221 °C (218–220 °C by Wade et al., 2015); 1H NMR (500 MHz, DMSO-d6) δ 12.96 (bs, 1H), 7.95 (d, J = 0.9 Hz, 1H), 7.61–7.52 (m, 2H), 7.30–7.15 (m, 4H), 6.74 (dd, J = 3.3, 1.7 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 151.1, 149.8, 148.9, 144.3, 138.0, 135.3, 125.2, 123.6, 122.3, 121.8, 119.7, 112.5; HRMS (ESI-TOF): m/z calculated for C12H10N3 [M+H]+ 196.0869, found 196.0876.

2.1.5.12
2.1.5.12 2-(1H-pyrrol-2-yl)-1H-benzo[d]imidazole (3l)

Off-white solid, 70% yield (90% yield by D. Kumar et al., 2013; V. Kumar et al., 2013), mp: 271–272 °C (268–270 °C by D. Kumar et al., 2013; V. Kumar et al., 2013); 1H NMR (500 MHz, DMSO-d6) δ 12.47 (s, 1H), 11.78 (s, 1H), 7.58–7.42 (m, 2H), 7.23–7.06 (m, 2H), 6.93 (d, J s = 1.3 Hz, 1H), 6.86–6.82 (m, 1H), 6.20 (dd, J = 5.2, 2.7 Hz, 1H); HRMS (ESI-TOF): m/z calculated for C11H10N3 [M+H]+ 184.0869, found 184.0872.

2.1.5.13
2.1.5.13 2-(Naphthalen-1-yl)-1H-benzo[d]imidazole (3m)

Off-white solid, 74% yield (83% yield by Yu and Lu, 2014), mp: 218–219 °C (216–218 °C by Yu and Lu, 2014); 1H NMR (500 MHz, DMSO-d6) δ 12.94 (s, 1H), 9.12 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 8.04 (dd, J = 14.6, 7.5 Hz, 2H), 7.79 (d, J = 7.6 Hz, 1H), 7.74–7.57 (m, 4H), 7.33–7.21 (m, 2H); 13C NMR (125 MHz, DMSO-d6) δ 156.6, 153.1, 141.0, 140.6, 140.2, 129.5, 129.4, 128.7, 127.9, 127.1, 122.0, 121.6, 120.8, 119.2; HRMS (ESI-TOF): m/z calculated for C17H13N2 [M+H]+ 245.1073, found 245.1077.

2.1.5.14
2.1.5.14 2-(1-Benzyl-1H-indol-3-yl)-1H-benzo[d]imidazole (3n)

Yellow solid, 75% yield mp: 218–220 °C; 1H NMR (500 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.63–8.44 (m, 1H), 8.22 (s, 1H), 7.67–7.57 (m, 2H), 7.46 (d, J = 5.7 Hz, 1H), 7.41–7.19 (m, 7H), 7.15 (dd, J = 7.0, 1.8 Hz, 2H), 5.55 (s, 2H); 13C NMR (125 MHz, DMSO-d6) δ 149.4, 138.0, 136.9, 129.7, 129.1, 128.1, 127.7, 126.1, 122.9, 122.1, 121.1, 111.1, 106.9, 49.9; HRMS (ESI-TOF): m/z calculated for C22H18N3 [M+H]+ 324.1495, found 324.1504.

2.1.5.15
2.1.5.15 2-(1-(3,4,5-Trimethoxybenzyl)-1H-indol-3-yl)-1H-benzo[d]imidazole (3o)

Yellow solid, 69% yield mp: 275–276 °C; 1H NMR (500 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.53 (d, J = 7.5 Hz, 1H), 8.19 (s, 1H), 7.73–7.35 (m, 3H), 7.32–7.19 (m, 2H), 7.17–7.12 (m, 2H), 6.72 (s, 2H), 5.43 (s, 2H), 3.72 (s, 6H), 3.63 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 153.5, 149.4, 137.5, 137.0, 133.2, 129.4, 126.2, 122.8, 122.4, 122.1, 121.6, 121.4, 121.0, 111.0, 106.9, 105.7, 61.1, 56.2, 50.1; HRMS (ESI-TOF): m/z calculated for C25H24N3O3 [M+H]+ 414.1812, found 414.1823.

2.1.5.16
2.1.5.16 5(6)-Chloro-2-(4-methoxyphenyl)-1H-benzo[d]imidazole (3p)

Yellow solid, 70% yield (93% yield by D. Kumar et al., 2013; V. Kumar et al., 2013), mp: 175–176 °C (174–175 °C by D. Kumar et al., 2013; V. Kumar et al., 2013); 1H NMR (500 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.11 (d, J = 8.8 Hz, 2H), 7.65–7.52 (m, 2H), 7.22 (d, J = 8.5, 2.0 Hz, 1H), 7.12 (d, J = 8.9 Hz, 2H), 3.84 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 161.1, 153.2, 131.0, 128.6, 127.9, 126.5, 122.5, 122.4, 114.9, 114.7, 114.6, 55.8; HRMS (ESI-TOF): m/z calculated for C14H12ClN2O [M+H]+ 259.0633, found 259.0633.

2.1.5.17
2.1.5.17 5(6)-Methyl-2-p-tolyl-1H-benzo[d]imidazole (3q)

Yellow solid, 78% yield (79% yield by Mahesh et al., 2015), mp: 164–165 °C (163–164 °C by Mahesh et al., 2015); 1H NMR (500 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.04 (d, J = 7.8 Hz, 2H), 7.61–7.23 (m, 4H), 7.01 (d, J = 7.8 Hz, 1H), 2.41 (s, 3H), 2.38 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 151.3, 139.8, 135.6, 129.9, 128.0, 126.7, 124.2, 123.6, 118.8, 111.3, 21.4; HRMS (ESI-TOF): m/z calculated for C15H15N2 [M+H]+ 223.1230, found 223.1231.

2.1.5.18
2.1.5.18 2-(3,4,5-Trimethoxyphenyl)-1H-benzo[d]imidazole-5(6)-carboxylic acid (3r)

Light Yellow solid, 61% yield mp: 280–281 °C; 1H NMR (500 MHz, DMSO-d6) δ 13.17 (s, 1H), 12.75 (s, 1H), 8.25–7.76 (m, 3H), 7.54 (s, 2H), 3.92 (s, 6H), 3.75 (s, 3H); HRMS (ESI-TOF): m/z calculated for C17H17N2O5 [M+H]+ 329.1132, found 329.1136.

2.1.5.19
2.1.5.19 2-(3-Phenylimidazo[1,2-a]pyridin-2-yl)-1H-benzo[d]imidazole (3s)

Off-white solid, 67% yield mp: 144–145 °C; 1H NMR (500 MHz, DMSO-d6) δ 12.91 (s, 1H), 8.21 (d, J = 6.9 Hz, 1H), 7.76–7.71 (m, 2H), 7.70–7.36 (m, 7H), 7.17 (t, J = 7.4 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 7.01–6.96 (m, 1H); 13C NMR (125 MHz, DMSO-d6) δ 147.9, 144.6, 144.4, 134.8, 133.6, 131.4, 129.3, 129.1, 128.6, 126.7, 124.7, 123.9, 122.7, 121.7, 119.3, 117.4, 113.9, 111.8; HRMS (ESI-TOF): m/z calculated for C20H15N4 [M+H]+ 311.1291, found 311.1294.

2.1.5.20
2.1.5.20 5(6)-Methyl-2-(3-phenylimidazo[1,2-a]pyridin-2-yl)-1H-benzo[d]imidazole (3t)

Light yellow solid, 62% yield mp: 124–126 °C; 1H NMR (500 MHz, DMSO-d6) δ 12.78 (s, 1H), 8.21 (t, J = 6.6 Hz, 1H), 7.73 (t, J = 7.2 Hz, 3H), 7.60 (t, J = 7.5 Hz, 2H), 7.55 (d, J = 7.3 Hz, 1H), 7.44–7.40 (m, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.28 (d, J = 3.5 Hz, 1H), 7.02–6.90 (m, 2H), 2.40 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 147.8, 147.4, 144.6, 142.5, 135.0, 133.7, 131.9, 131.4, 129.2, 129.1, 128.6, 126.6, 124.7, 124.1, 123.6, 123.3, 118.8, 117.4, 113.9, 111.6, 21.8; HRMS (ESI-TOF): m/z calculated for C21H17N4 [M+H]+ 325.1448, found 325.1447.

2.1.5.21
2.1.5.21 5(6)-Chloro-2-(3-phenylimidazo[1,2-a]pyridin-2-yl)-1H-benzo[d]imidazole (3u)

Light yellow solid, 65% yield mp: 164–165 °C; 1H NMR (500 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.32–8.09 (m, 1H), 7.78–7.10 (m, 10H), 7.04–6.93 (m, 1H); 13C NMR (125 MHz, DMSO-d6) δ 144.5, 132.8, 132.5, 131.9, 129.2, 126.7, 124.8, 122.7, 122.0, 120.5, 120.3, 118.6, 117.4, 114.6, 113.9, 113.0, 111.4; HRMS (ESI-TOF): m/z calculated for C20H14ClN4 [M+H]+ 345.0902, found 345.0905.

2.1.5.22
2.1.5.22 5(6)-Fluoro-2-(3-phenylimidazo[1,2-a]pyridin-2-yl)-1H-benzo[d]imidazole (3v)

Light yellow solid, 64% yield mp: 171–172 °C; 1H NMR (500 MHz, DMSO-d6) δ 13.03 (s, 1H), 8.20 (t, J = 5.8 Hz, 1H), 7.73 (d, J = 8.2 Hz, 3H), 7.61 (t, J = 7.3 Hz, 2H), 7.56 (d, J = 6.9 Hz, 1H), 7.52–7.40 (m, 2H), 7.32–7.20 (m, 1H), 7.07–6.91 (m, 2H); 13C NMR (125 MHz, DMSO-d6) δ 160.1, 159.6, 158.2, 157.8, 149.7, 148.9, 144.8, 144.7 (J = 17.3 Hz), 141.1, 135.0, 134.9, 133.2 (J = 6.6 Hz), 131.5, 131.3 (J = 2.7 Hz), 129.4, 129.1, 128.5, 126.8 (J = 7.0 Hz), 124.7, 124.1, 123.8, 120.2 (J = 10.2 Hz), 117.5, 114.0, 112.3 (J = 10.5 Hz), 110.7 (J = 25.8 Hz), 109.9 (J = 24.9 Hz), 104.7 (J = 23.7 Hz), 98.0 (J = 26.9 Hz); HRMS (ESI-TOF): m/z calculated for C20H14FN4 [M+H]+ 329.1197, found 329.1201.

2.1.5.23
2.1.5.23 2-(3-(4-Methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-1H-benzo[d]imidazole (3w)

Light yellow solid, 68% yield mp: 185–186 °C; 1H NMR (500 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.18 (d, J = 6.9 Hz, 1H), 7.71 (d, J = 9.1 Hz, 1H), 7.68–7.60 (m, 3H), 7.59–7.52 (m, 1H), 7.51–7.46 (m, 2H), 7.48–7.38 (m, 1H), 7.19–7.14 (m, 2H), 3.85 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 160.0, 148.1, 144.4, 132.8, 131.9, 129.2, 126.7, 126.5, 124.7, 123.9, 120.6, 117.4, 114.6, 113.7, 55.7; HRMS (ESI-TOF): m/z calculated for C21H17N4O [M+H]+ 341.1397, found 341.1400.

2.1.5.24
2.1.5.24 2-(3-(4-Methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-5(6)-methyl-1H-benzo[d]imidazole (3x)

Light yellow solid, 66% yield mp: 158–160 °C; 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J = 6.9 Hz, 1H), 7.70–7.64 (m, 2H), 7.61 (d, J = 8.7, 2.1 Hz, 2H), 7.58–7.51 (m, 1H), 7.50–7.42 (m, 2H), 7.33 (s, 1H), 7.07 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.81 (ddd, J = 6.9 Hz, 1.0 Hz, 1H), 3.89 (s, 3H), 2.44 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.3, 146.9, 144.6, 132.9, 132.7, 132.1, 132.0, 131.9, 128.5, 128.4, 125.9, 124.1, 123.9, 119.7, 117.4, 114.6, 113.0, 55.3, 21.6; HRMS (ESI-TOF): m/z calculated for C22H19N4O [M+H]+ 355.1553, found 355.1555.

2.1.5.25
2.1.5.25 5(6)-Chloro-2-(3-(4-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-1H-benzo[d]imidazole (3y)

Light yellow solid, 65% yield mp: 197–198 °C; 1H NMR (500 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.18 (d, J = 6.8 Hz, 1H), 7.72 (d, J = 11.0 Hz, 1H), 7.67–7.45 (m, 5H), 7.44–7.39 (m, 1H), 7.20–7.12 (m, 2H), 6.99 (d, J = 6.6 Hz, 1H), 3.88 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 160.1, 145.3, 144.5, 143.3, 132.7, 132.5, 131.9, 129.2, 126.7, 124.8, 122.7, 122.0, 120.5, 120.3, 118.6, 117.4, 114.6, 113.9, 113.0, 111.4, 55.7; HRMS (ESI-TOF): m/z calculated for C21H16ClN4O [M+H]+ 375.1007, found 375.1008.

2.1.5.26
2.1.5.26 5(6)-Fluoro-2-(3-(4-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-1H-benzo[d]imidazole (3z)

Light yellow solid, 66% yield mp: 210–212 °C; 1H NMR (500 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.18 (d, J = 6.8 Hz, 1H), 7.71 (d, J = 9.1 Hz, 1H), 7.64 (ddd, J = 10.5, 4.1 Hz, 2H), 7.61–7.45 (m, 3H), 7.45–7.39 (m, 1H), 7.129–7.12 (m, 2H), 6.99 (t, J = 6.7 Hz, 1H), 3.88 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 160.0, 148.0, 144.4, 133.0, 132.7, 132.5, 131.9 (J = 9.8 Hz), 129.2 (J = 11.9 Hz), 126.6, 124.7, 120.6, 120.4, 118.1, 117.4, 114.9, 114.6, 113.8, 55.7; HRMS (ESI-TOF): m/z calculated for C21H16FN4O [M+H]+ 359.1303, found 359.1306.

2.1.5.27
2.1.5.27 2-(4-Methoxyphenyl)benzo[d]thiazole (4a)

Yellow crystalline solid, 84% yield (46% yield by Gao et al., 2014), mp: 124–125 °C (123–125 °C by Gao et al., 2014); 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J = 8.7 Hz, 3H), 7.88 (d, J = 8.0 Hz, 1H), 7.51–7.45 (m, 1H), 7.40–7.34 (m, 1H), 7.01 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.9, 162.0, 154.0, 134.7, 132.0, 129.9, 129.1, 126.2, 124.8, 122.7, 121.5, 114.4, 114.3, 55.4; HRMS (ESI-TOF): m/z calculated for C14H12NOS [M+H]+ 242.0634, found 242.0630.

2.1.5.28
2.1.5.28 2-(3,4-Dimethoxyphenyl)benzo[d]thiazole (4b)

Yellow crystalline solid, 88% yield (55% yield by Gao et al., 2014), mp: 131–132 °C (130–131 °C by Gao et al., 2014); 1H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.61 (dd, J = 8.3, 2.0 Hz, 1H), 7.51–7.44 (m, 1H), 7.40–7.32 (m, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.05 (m, 3H), 3.98 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 168.2, 154.2, 151.9, 149.6, 135.1, 126.8, 126.5, 125.2, 123.0, 121.8, 121.4, 111.3, 110.0, 56.4, 56.3; HRMS (ESI-TOF): m/z calculated for C15H14NO2S [M+H]+ 272.0740, found 272.0724.

2.1.5.29
2.1.5.29 2-(3,4,5-Trimethoxyphenyl)benzo[d]thiazole (4c)

Yellow crystalline solid, 90% yield (95% yield by Bardajee et al., 2016), mp: 145–146 °C (146–148 °C by Bardajee et al., 2016); 1H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.55–7.50 (m, 1H), 7.44–7.39 (m, 1H), 7.37 (s, 2H), 4.02 (s, 6H), 3.95 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 168.1, 154.2, 153.9, 141.0, 135.2, 129.2, 126.7, 125.4, 123.3, 121.8, 105.1, 61.3, 56.6; HRMS (ESI-TOF): m/z calculated for C16H16NO3S [M+H]+ 302.0845, found 302.0850.

2.1.5.30
2.1.5.30 4-(Benzo[d]thiazol-2-yl)benzonitrile (4d)

White solid, 85% yield (70% yield by Gao et al., 2014), mp: 166–167 °C (165–167 °C by Gao et al., 2014); 1H NMR (500 MHz, CDCl3) δ 8.22 (d, J = 8.2 Hz, 2H), 8.13 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.55 (dd, J = 7.7, 1.9 Hz, 1H), 7.46 (dd, J = 7.6, 1.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 165.3, 154.0, 137.4, 135.3, 132.7, 127.9, 126.8, 126.1, 123.8, 121.8, 118.3, 114.1; HRMS (ESI-TOF): m/z calculated for C14H8N2S [M+H]+ 237.0481, found 237.0481.

2.1.5.31
2.1.5.31 2-(4-Fluorophenyl)benzo[d]thiazole (4e)

White solid, 87% yield (40% yield by Gao et al., 2014), mp: 102–104 °C (98–100 °C by Gao et al., 2014); 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.1 Hz, 3H), 8.12 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H); HRMS (ESI): m/z calculated for C13H9FNS [M+H]+ 230.0440, found 230.0445.

2.1.5.32
2.1.5.32 2-(3-Nitrophenyl)benzo[d]thiazole (4f)

Light yellow solid, 80% yield (96% yield by Wade et al., 2015), mp: 185–186 °C (182–184 °C by Wade et al., 2015); 1H NMR (500 MHz, CDCl3) δ 8.94 (s, 1H), 8.43 (d, J = 7.7 Hz, 1H), 8.34 (d, J = 8.1 Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.70 (dd, J = 8.0, 1.5 Hz, 1H), 7.55 (dd, J = 7.6, 1.4 Hz, 1H), 7.46 (dd, J = 7.5, 1.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 165.2, 154.2, 149.1, 135.6, 135.5, 133.3, 130.4, 127.1, 126.3, 125.5, 124.0, 122.6, 122.1; HRMS (ESI-TOF): m/z calculated for C13H9N2O2S [M+H]+ 257.0379, found 257.0382.

2.1.5.33
2.1.5.33 2,3-Diphenylquinoxaline (6a)

Off-white solid, 92% yield (>99% yield by Cai et al., 2008), mp: 128–130 °C (128–129 °C by Cai et al., 2008); 1H NMR (500 MHz, CDCl3) δ 8.34–8.23 (m, 2H), 7.88–7.78 (m, 2H), 7.62–7.47 (m, 4H), 7.45–7.30 (m, 6H); 13C NMR (125 MHz, CDCl3 + DMSO-d6) δ 152.9, 140.6, 138.5, 129.6, 129.5, 129.3, 128.7, 128.6, 128.4, 127.8; HRMS (ESI-TOF): m/z calculated for C20H15N2 [M+H]+ 283.1230, found 283.1232.

2.1.5.34
2.1.5.34 6-Methyl-2,3-diphenylquinoxaline (6b)

Light yellow solid, 90% yield (>99% yield by Cai et al., 2008), mp: 117–118 °C (112–114 °C by Cai et al., 2008); 1H NMR (500 MHz, DMSO-d6) δ 8.05 (d, J = 8.5 Hz, 1H), 7.94 (s, 1H), 7.72 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 7.51–7.42 (m, 4H), 7.43–7.32 (m, 6H), 2.59 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 153.3, 152.5, 141.0, 139.3, 133.0, 130.1, 129.1, 128.8, 128.5, 127.9, 21.8; HRMS (ESI-TOF): m/z calculated for C21H17N2 [M+H]+ 297.1386, found 297.1392.

2.1.5.35
2.1.5.35 2,3-Diphenylquinoxaline-6-carboxylic acid (6c)

Brown solid, 85% yield (97% yield by Heravi et al., 2007), mp: 274–276 °C (272 °C by Heravi et al., 2007); 1H NMR (500 MHz, DMSO-d6) δ 13.51 (s, 1H), 8.65 (s, 1H), 8.30 (dd, J = 8.5, 1.5 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 7.3 Hz, 4H), 7.45–7.33 (m, 6H); 13C NMR (125 MHz, DMSO-d6) δ 167.0, 155.2, 154.6, 142.8, 140.1, 138.8, 132.5, 131.1, 130.2, 130.0, 129.7, 129.6, 129.5, 128.5; HRMS (ESI-TOF): m/z calculated for C21H15N2O2 [M+H]+ 327.1128, found 327.1134.

2.1.5.36
2.1.5.36 6-Chloro-2,3-diphenylquinoxaline (6d)

White solid, 89% yield (94% yield by Cai et al., 2008), mp: 123–124 °C (124–126 °C by Cai et al., 2008); 1H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 2.3 Hz, 1H), 8.03 (d, J = 8.9 Hz, 1H), 7.64 (dd, J = 8.9, 2.3 Hz, 1H), 7.45–7.41 (m, 4H), 7.31–7.23 (m, 6H); HRMS (ESI-TOF): m/z calculated for C20H14ClN2 [M+H]+ 317.0846, found 317.0848.

2.1.5.37
2.1.5.37 6-Nitro-2,3-diphenylquinoxaline (6e)

Light yellow solid, 84% yield (90% yield by Cai et al., 2008), mp: 184–186 °C (188–190 °C by Cai et al., 2008); 1H NMR (500 MHz, DMSO-d6) δ 8.96 (d, J = 2.4 Hz, 1H), 8.59 (dd, J = 9.1, 2.6 Hz, 1H), 8.40 (d, J = 9.1 Hz, 1H), 7.58–7.50 (m, 4H), 7.45–7.35 (m, 6H); 13C NMR (125 MHz, DMSO-d6) δ 156.5, 155.8, 148.1, 143.4, 139.7, 138.4, 131.2, 130.2, 130.0, 129.8, 128.6, 125.3, 124.0; HRMS (ESI-TOF): m/z calculated for C20H14N3O2 [M+H]+ 328.1081, found 328.1082.

2.1.5.38
2.1.5.38 6-Chloro-7-fluoro-2,3-diphenylquinoxaline (6f)

White solid, 80% yield (82% yield by Patel et al., 2016), mp: 118–119 °C (110–112 °C by Patel et al., 2016); 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.55–7.46 (m, 4H), 7.43–7.31 (m, 6H); HRMS (ESI-TOF): m/z calculated for C20H13ClFN2 [M+H]+ 335.0746, found 335.0750.

2.1.5.39
2.1.5.39 2,3-Diphenyl-N-(pyridin-2-yl)quinoxaline-6-carboxamide (6g)

Light yellow solid, 77% yield mp: 208–209 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.85 (d, J = 1.9 Hz, 1H), 8.46–8.43 (m, 1H), 8.40 (dd, J = 8.7, 2.0 Hz, 1H), 8.27 (d, J = 1.7 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.94–7.85 (m, 1H), 7.52 (dd, J = 6.8, 1.3 Hz, 4H), 7.46–7.36 (m, 6H), 7.22 (ddd, J = 7.3, 4.9, 0.9 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 165.6, 154.9, 154.4, 152.5, 148.5, 142.3, 140.1, 138.9, 138.6, 135.7, 130.2, 129.6, 129.4, 129.3, 128.5, 120.5, 115.4; HRMS (ESI-TOF): m/z calculated for C26H19N4O [M+H]+ 403.1553, found 403.1568.

2.1.5.40
2.1.5.40 N-(1H-indol-4-yl)-2,3-diphenylquinoxaline-6-carboxamide (6h)

Yellow solid, 81% yield mp: 128–129 °C; 1H NMR (500 MHz, DMSO-d6) δ 11.19 (s, 1H), 10.52 (s, 1H), 8.88 (s, 1H), 8.42 (dd, J = 8.7, 1.5 Hz, 1H), 8.29 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 7.7 Hz, 4H), 7.48–7.37 (m, 7H), 7.36–7.33 (m, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 6.68 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 164.9, 154.7, 154.4, 142.1, 140.2, 139.0, 137.3, 136.7, 130.5, 130.2, 129.8, 129.5, 129.3, 128.9, 128.6, 124.9, 122.7, 121.3, 113.9, 109.2, 100.5; HRMS (ESI-TOF): m/z calculated for C29H21N4O [M+H]+ 441.1710, found 441.1713.

2.2

2.2 Biological assays

2.2.1

2.2.1 Cell cultures, maintenance and evaluation of antiproliferative activity

The synthesized test compounds were evaluated for their in vitro anticancer activity using MTT assay. All the cell lines used in this study were purchased from the American Type Culture Collection (ATCC, United States). MDA-MB-231 derived from human breast adenocarcinoma cells (ATCC No. HTB-26), MCF-7 derived from human breast adenocarcinoma cells (ATCC No HTB-22), HeLa derived from human cervical cancer cells (ATCC No. CCL-2), and A549 derived from human lung cancer cells (ATCC No. CCL-185) were seeded in 96-well plates at a density of 1 × 104 cells/well in their respective media containing 10% fetal bovine serum (GIBCO-Invitrogen) in a humidified incubator (Eppendorf CO2 incubator, Galaxy 170S model), under a 5% CO2 atmosphere at 37 °C. After 24 h of incubation cells were treated with compounds to be tested at four different concentrations (0.1, 1, 10 and 25 μM) in triplicates and nocodazole was used as positive control. After 48 h of incubation, 10 μL of MTT reagent (5 mg/mL) was added to each well and plates were incubated at 37 °C for 4 h in CO2 incubator. After incubation supernatant was carefully removed from each well and formazan crystals were dissolved in 100 μL of DMSO. Absorbance was recorded at 540 nm using a multimode plate reader (Infinite® M200Pro, Tecan, Switzerland) and percentage viability was calculated for test wells relative to control wells. Effect of each compound was analyzed by generating dose response curve as a plot of the percentage surviving cells versus compound concentration and expressed in terms of IC50, a value defined as the drug concentration required to inhibit the growth of cancer cells by 50%. IC50 values were indicated as means ± SD of three independent experiments.

2.2.2

2.2.2 Flow-cytometry analysis

To determine the effect of compound 3s on the cell cycle, cells were seeded in 12-well plates at a density of 1 × 105 cells/mL and allowed to attach for 24 h. After incubation, cells were treated with desired concentrations of compound 3s and incubated for 48 h. Then the cells were collected, washed and fixed in 70% ethanol in PBS at −20 °C. After leaving overnight, the fixed cells were pelleted and stained with Propidium Iodide (25 µg/mL)) in the presence of RNase A (40 µg/mL) containing 0.1% Triton X-100 for 30 min at 37 °C in dark, and about 10,000 events were analyzed on a flow cytometry (FACS verse, Becton Dickinson, US).

3

3 Results and discussion

3.1

3.1 Synthesis

Preliminary studies were carried out to optimize the reaction between o-phenylenediamine (1a) and benzaldehyde (2a) to give 2-phenylbenzimidazole (3a) in the presence of Koser’s reagent [PhI(OH)OTs] (Scheme 1). The proposed reaction between 1a and 2a did certainly occur in the presence of Koser’s reagent in ethanol to render the product 3a in 68% yield (entry 1, Table 1) when performed at room temperature for 1 h. To determine the ideal solvent for this reaction, several solvent systems such as ACN, DMF, MeOH, THF, H2O and 1,4-dioxane were screened. The desired product 3a was obtained in all the tested solvents (entries 2–7); however, the highest yield was observed in 1,4-dioxane, and it was selected as the suitable solvent to proceed further. To improve the yield, the same reaction was performed in 1,4-dioxane under O2 atmosphere. Gratifyingly, the reaction proceeded rapidly within 5 min and afforded the desired product in 94% yield (entry 8) whereas the reaction under N2 atmosphere furnished very poor yield after 5 h (entry 14). However, the O2 atmosphere dramatically promoted the PhI(OH)OTs-catalyzed synthesis of benzimidazoles in high yield with a shortened reaction time indicating that O2 is essential for the regeneration of catalytic PhI(OH)OTs. Lowering the concentration of catalyst, from 10 mol% (entry 8, Table 1) to 5 or 2.5 or 1 mol%, (entries 9, 10 and 11, Table 1) did not adversely affect the yield (94%, 93% and 94% respectively). However, when the amount of catalyst was further decreased to 0.5 or 0.25 mol%, the yields were found to be (81% and 56%, respectively, entries 12 and 13, Table 1) significantly lower. Hence, 1 mol% of the catalyst in 1,4-dioxane was considered optimal. A control experiment in the absence of Koser’s reagent resulted in <20% yield (entries 15, Table 1) which proves the emphasis on the importance of the catalyst.

Synthesis of 2-phenylbenzimidazole.
Scheme 1 Synthesis of 2-phenylbenzimidazole.
Table 1 Optimization of reaction conditions for the synthesis of 3a.a
Entry Solvent Atmosphere PhI(OH)OTs (mol%) Time Yield (%)b
1 EtOH Air 10 1 h 68
2 CH3CN Air 10 1 h 67
3 DMF Air 10 1 h 71
4 MeOH Air 10 1 h 65
5 THF Air 10 1 h 62
6 H2O Air 10 1 h 40
7 1,4-Dioxane Air 10 1 h 84
8 1,4-Dioxane O2 10 5 min 94
9 1,4-Dioxane O2 5 5 min 94
10 1,4-Dioxane O2 2.5 5 min 93
11 1,4-Dioxane O2 1 5 min 94
12 1,4-Dioxane O2 0.5 15 min 81
13 1,4-Dioxane O2 0.25 15 min 56
14 1,4-Dioxane N2 1 5 h 41
15 1,4-Dioxane O2 Nil 8 h <20
a Reaction conditions: 1a (1 mmol), 2a (1 mmol), rt.
b Isolated yield.

Under the optimized reaction conditions, o-phenylenediamine (1a) and a variety of benzaldehydes reacted efficiently to give the corresponding products (3a–i) in very good to excellent yields (Scheme 2a). The reaction proceeded smoothly with most of the benzaldehydes studied, regardless of them bearing electron-neutral (phenyl), donating (4-methyl, 4-methoxy, 3,4-dimethoxy and 3,4,5-trimethoxy benzaldehydes) or withdrawing groups (3-fluoro, 4-fluoro, 3-nitro and 4-trifluoromethyl benzaldehydes) as substituents (Table 2, entries 1–9). Also we studied the scope of heteroaryl aldehydes, such as furan-2-carboxaldehyde, pyrrole-2-carboxaldehyde, pyridine-2-carboxaldehyde, and bicyclic aryl aldehyde such as 1-naphthaldehyde. Most reacted well with o-phenylenediamine except pyrrole-2-carboxaldehyde and generated the corresponding products (3j–k, 3m) in good yields as tabulated in Table 2 (entries 10–13). Pyrrole-2-carboxaldehyde could not react with o-phenylenediamine efficiently at room temperature and therefore the reaction was carried out at 80 °C and the desired product (3l) was obtained in good yield after 15 min. The present protocol was also applied for the synthesis of indole-benzimidazole conjugates. Gratifyingly, the reaction between o-PDA and N-substituted indole-3-carboxaldehyde at 80 °C furnished the target molecules (3n–o) in moderate to good yields (Table 2, entries 14–15). We further surveyed this method onto substituted o-PDAs and the corresponding benzimidazoles (3p–r) were obtained in moderate to good yields (Table 2, entries 16–18). The reactivity of 4-methyl-o-phenylenediamine, however, was found to be more than that of 4-chloro-o-phenylenediamine and 3,4-diaminobenzoic acid.

(a) Synthesis of 2-substituted benzimidazoles/benzothiazoles. (b) Synthesis of benzimidazole-imidazo[1,2-a]pyridine conjugates.
Scheme 2 (a) Synthesis of 2-substituted benzimidazoles/benzothiazoles. (b) Synthesis of benzimidazole-imidazo[1,2-a]pyridine conjugates.
Table 2 Synthesis of benzimidazoles/benzothiazoles from o-phenylenediamines/2-aminothiophenol and a variety of aldehydes.a
Product R1 X R Yieldb (%) R1 X R Product Yieldb (%)
3ad H NH 94 CH3 NH 3q 78
3b H NH 89 COOH NH 3rc 61
3c H NH 93 H NH 3sc 67
3d H NH 91 CH3 NH 3tc 62
3e H NH 93 Cl NH 3uc 65
3f H NH 81 F NH 3vc 64
3g H NH 83 H NH 3wc 68
3h H NH 81 CH3 NH 3xc 66
3i H NH 91 Cl NH 3yc 65
3j H NH 74 F NH 3zc 66
3k H NH 72 H S 4a 84
3lc H NH 70 H S 4b 88
3m H NH 74 H S 4c 90
3nc H NH 75 H S 4d 85
3oc H NH 69 H S 4e 87
3p Cl NH 70 H S 4f 80
a Reaction conditions: 1 (1 mmol), 2 (1 mmol), PhI(OH)OTs (1 mol%), 1,4-dioxane (5 mL), rt.
b Isolated yield.
c Reaction was carried out at 80 °C for 15 min.
d Reaction performed on a 5g scale.

Also, we extended this method for the synthesis of benzimidazole-imidazo[1,2-a]pyridine conjugates (Scheme 2b). When we carried out the reaction between o-phenylenediamines and imidazo[1,2-a]pyridine-2-carbaldehyde under the optimized reaction conditions, the desired product was not obtained at room temperature. But they could react effectively at 80 °C and provide moderate yields of the products (3s–z). Thus, the synthesized molecules (3s–z) are positional isomers of previous imidazopyridine-benzimidazole conjugates which were reported by our research group (Kamal et al., 2015), and we became interested to study the effect of positional isomerism on biological activity. The results from MTT assay and cell cycle analysis are discussed in biological evaluation section. These encouraging results with benzimidazoles, captivated us to explore this method for the synthesis of benzothiazoles (4a–f). A variety of aldehydes reacted effectively with 2-aminothiophenol in the presence of Koser’s reagent to provide the corresponding products in very good yields.

Furthermore, we studied the scope of this protocol for the synthesis of quinoxalines (6a–h) (Scheme 3). A variety of o-PDAs reacted well with benzil in the presence of Koser’s reagent to provide the respective products (6a–f) in very good to excellent yields as shown in Table 3 (entries 1–6). Also, 3,4-diaminobenzamides reacted efficiently with benzil to produce respective quinoxaline-6-carboxamide derivatives (6g–h) in good to very good yields. Overall, by applying this method forty compounds have been prepared out of which twelve compounds were new and structurally diverse. All the known synthesized compounds were confirmed by comparing their physical properties and spectral data with the reported literature values (Kim et al., 2011; Mahesh et al., 2015; Chaturvedi et al., 2013; Qiu et al., 2015; Nguyen et al., 2015; D. Kumar et al., 2013; V. Kumar et al., 2013; Wade et al., 2015; Yu and Lu, 2014; Gao et al., 2014; Bardajee et al., 2016; Cai et al., 2008; Heravi et al., 2007; Patel et al., 2016).

Synthesis of quinoxalines.
Scheme 3 Synthesis of quinoxalines.
Table 3 Synthesis of quinoxalines from o-phenylenediamines and benzil.a
Entry R1 R2 Product Yieldb (%)
1 H H 6a 92
2 CH3 H 6b 90
3 COOH H 6c 85
4 Cl H 6d 89
5 NO2 H 6e 84
6 Cl F 6f 80
7 H 6gc 77
8 H 6hc 81
a Reaction conditions: 1 (1 mmol), 5 (1 mmol), PhI(OH)OTs (1 mol%), 1,4-dioxane (5 mL), rt.
b Isolated yield.
c Reaction was carried out at 80 °C for 15 min.

To test the scalability of the reaction, a 5 g scale synthesis of 3a was performed using 5 g of o-phenylenediamine, 4.91 g of benzaldehyde and 1 mol% of Koser’s reagent at room temperature in 1,4-dioxane and the desired product 3a was obtained in 93% yield, that was noticed comparable to the yield obtained in entry 1, Table 2.

3.2

3.2 Plausible reaction mechanism

Mechanistically, a probable pathway for the formation of benzimidazoles involves 2 steps namely condensation and oxidation as outlined in Fig. 3. o-Phenylenediamine and benzaldehyde condense to form Schiff’s base 6, with which the Koser’s reagent reacts to form a cyclic adduct 7 through the participation of intramolecular o-amino group. The cyclic adduct gets dehydrogenated to eliminate H2O, which further liberates PhI and TsOH and affords 2-phenylbenzimidole. The eliminated PhI and TsOH probably enter the catalytic cycle under O2 atmosphere to generate reactive iodine(III) PhI(OH)OTs and complete the catalytic cycle.

Plausible reaction mechanism.
Figure 3 Plausible reaction mechanism.

3.3

3.3 Evaluation of cytotoxicity by MTT assay

All the benzimidazole-imidazo[1,2-a]pyridine conjugates (3s–z) synthesized were evaluated for their antiproliferative activity against a panel of four cancer cell lines, viz., MDA-MB-231 (breast carcinoma), MCF-7 (breast carcinoma), HeLa (cervical carcinoma), and A549 (lung carcinoma) by employing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The selection of these molecules for MTT assay was based on the previous report by our group (Kamal et al., 2015) in which positional isomers of these molecules were studied. As our target was to study the effect of positional isomerism on antiproliferative activity, these conjugates were tested. Along with these molecules (3s–z), compounds 3n–o (benzimidazole-indole conjugates) and 6g–h (quinoxaline-6-carboxamide derivatives) which were newly synthesized compounds, were also evaluated by MTT assay. Concentration response course analysis was performed to determine the concentration of a compound required to arrest the growth of cancer cells by 50% (IC50). Nocodazole was used as a reference standard, and the results are summarized in Table 4. Among the compounds screened, conjugates 3s, 3t and 3v were found to be active on MCF-7 (IC50 values of 5.10 ± 0.10, 8.23 ± 0.02, and 10.75 ± 0.03 µM respectively) and MDA-MB-231 cell lines (IC50 values of 10.83 ± 0.13, 7.68 ± 0.05, and 7.87 ± 0.24 µM respectively) while 3n–o and 6g–h were found to be inactive on the cell lines studied, even at 30 µM concentration. In general, benzimidazole-imidazo[1,2-a]pyridine conjugates (3s–z) synthesized by the present method were found to be comparatively more active than their positional isomers reported previously by our group (Kamal et al., 2015). Overall, the results demonstrate that most of the compounds showed moderate cytotoxicity on all the tested cell lines and compounds 3s, 3t and 3v could emerge as potential leads for the development of new anticancer agents. Based on the cytotoxic activity, the most active compound 3s was taken up for further mechanistic study which is flow-cytometry analysis.

Table 4 IC50 valuesa (in µM) for compounds 3s–z, 3n–o and 6g–h on selected human cancer cell lines.
Compound MDA-MB-231b MCF-7b HeLac A549d
3s 10.83 ± 0.13 5.10 ± 0.10 8.22 ± 0.05 16.9 ± 0.02
3t 7.68 ± 0.05 8.23 ± 0.02 22.16 ± 0.05 10.5 ± 0.01
3u 11.03 ± 0.25 14.03 ± 0.01 12.76 ± 0.03 12.7 ± 0.02
3v 7.87 ± 0.24 10.75 ± 0.03 16.02 ± 0.02 18.02 ± 0.05
3w 9.96 ± 0.25 16.58 ± 0.02 17.78 ± 0.05 19.71 ± 0.01
3x 10.75 ± 0.17 22.16 ± 0.06 17.22 ± 0.03 20.16 ± 0.07
3y 11.62 ± 0.11 14.30 ± 0.14 14.83 ± 0.06 18.16 ± 0.03
3z 12.99 ± 0.23 24.57 ± 0.16 13.69 ± 0.04 26.16 ± 0.15
3n >30 >30 >30 >30
3o >30 >30 >30 >30
6g >30 >30 >30 >30
6h >30 >30 >30 >30
Nocodazole 0.13 ± 0.01 0.12 ± 0.02 3.2 ± 0.20 0.16 ± 0.01
a 50% inhibitory concentration after 48 h of drug treatment and mean ± SD of three individual experiments performed in triplicate.
b Human breast cancer cell line.
c Human cervical cancer cell line.
d Human lung cancer cell line.

3.4

3.4 Flow-cytometry analysis

Commonly cytotoxic agents alter the regulation of the cell cycle and result in the arrest of cell division in various phases, thereby preventing the growth and proliferation of cancer cells. To understand whether the inhibition of growth of MCF-7 cells on account of cell cycle arrest, cell cycle distribution of MCF-7 cells was determined by flow-cytometry analysis. These cells were treated with compound 3s at concentration of 2.5 and 5 µM for 48 h, and stained with propidium iodide, which was analyzed further using flow cytometry. The results from Fig. 4 demonstrate that the control cells exposed to DMSO showed 74.9% cells in G0/G1 phase, while compound 3s treatment at concentration of 2.5 and 5 μM increased G0/G1 population to 78.7 and 82.3% respectively in 48 h. These findings indicate that the treatment of MCF-7 cells with compound 3s showed moderate effect on the progression of G0/G1 phase of the cell cycle.

Flow-cytometry analysis in MCF-7 - breast cancer cell line: (1) Control, (2) 3s (2.5 µM) and (3) 3s (5 µM).
Figure 4 Flow-cytometry analysis in MCF-7 - breast cancer cell line: (1) Control, (2) 3s (2.5 µM) and (3) 3s (5 µM).

4

4 Conclusion

Herein, we report a rapid, simple and highly efficient method for the synthesis of a variety of 2-aryl-benzimidazoles, 2-aryl-benzothiazoles and quinoxalines using Koser’s reagent [PhI(OH)OTs] as catalyst. The salient features of this method include short reaction time, operationally simple procedure, high yields, low catalyst loading and scalability. Additionally, the protocol is amenable to heterocyclic aldehydes such as furan, pyrrole, pyridine and indole aldehydes. Also, this method is efficient for the synthesis of benzimidazole-imidazo[1,2-a]pyridine conjugates as well as highly structured quinoxaline-6-carboxamide derivatives. Benzimidazole-imidazo[1,2-a]pyridine conjugates 3s, 3t and 3v exhibited significant antiproliferative activity against MCF-7 and MDA-MB-231 cell lines. The results from flow-cytometry analysis revealed that the treatment of MCF-7 cells with compound 3s showed moderate effect on the progression of G0/G1 phase of the cell cycle.

Acknowledgments

Authors are grateful to DoP, Ministry of Chemicals and Fertilizers, Govt. of India, New Delhi, for the award of NIPER Fellowship.

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Appendix A

Supplementary material

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.arabjc.2017.02.007.

Appendix A

Supplementary material

Supplementary data 1

Supplementary data 1


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