Environment-Friendly Protocol for the Chlorination of

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Article Cite This: ACS Omega 2018, 3, 3513−3521

Environment-Friendly Protocol for the Chlorination of Imidazoheterocycles by Chloramine‑T Amrita Dey, Mukta Singsardar, Rajib Sarkar, and Alakananda Hajra* Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India S Supporting Information *

ABSTRACT: An environment-friendly method for the chlorination of imidazoheterocycles has been developed using chloramineT, a novel chlorinating reagent. A bunch of C-3 chloro-substituted imidazo[1,2-a]pyridines with variety of functionalities have been synthesized in good yields under neat condition at room temperature within very short time. This chlorination process is also applicable to imidazo[2,1-b]thiazole scaffolds. The present methodology is relevant to gram-scale synthesis. The major advantages of this system such as wide applicability, easy availability of reactants, open-air and metal- and solvent-free reaction conditions, no need of work-up, and simple purification technique represent a green synthetic protocol.

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INTRODUCTION The imidazopyridine, a nitrogen-containing important heterocycle moiety, has a wide range of biological activities and is found in several marketed drugs.1,2 This scaffold is also successfully employed in the field of material science.3,4 As a consequence, different processes have been reported for the synthesis and functionalization of imidazopyridine derivatives.5−15 Many efficient methods of important functionalization and various synthetic strategies of imidazo[1,2-a]pyridines from readily available starting materials have been also developed by our group.16−27 Diverse substitutions at 3position of imidazo[1,2-a]pyridines induce different pharmaceutical properties. Therefore, the incorporation of functionality at the C-3 position, which will be susceptible for further functionalization, is highly desirable. Aromatic chlorides are an essential group of compounds that are widely used in organic synthesis as reaction intermediates in various coupling and substitution reactions for the preparation of natural products and medicinally active compounds.28,29 Relative stability of the carbon−chlorine bond makes the aryl chlorides useful structural motifs in pharmaceuticals, agrochemicals, and other biologically active compounds.30−36 In fact, halogenated imidazoheterocycles also belong to a class of vital building blocks and multipurpose synthons,37−39 which could be further converted to more complex organic molecules through cross-coupling reactions and by other substitution reactions.40−44 Conventionally, chlorination of aromatic compounds has occurred by aromatic electrophilic substitution,45,46 a directed ortho-lithiation−chlorination,47 or the Sandmeyer reaction of anilines.48 However, all of these common methods involve harsh conditions, long reaction time, and poor regioselectivity. Consequently, recent efforts have focused on the improvement of new chlorination methods.49−54 In addition, accessible scheme to furnish 3-halogen-substituted imidazo[1,2-a]pyridines has been rarely reported.55−57 Re© 2018 American Chemical Society

cently, Jiang et al. exposed a procedure to synthesize 2-halosubstituted imidazo[1,2-a]pyridines using copper catalyst employing haloalkynes as the source of halogen.58 Moreover, in modern times, organic synthesis has experienced a judicious change to a more sustainable progression that avoids the general use of toxic and hazardous solvents or reagents, vigorous reaction conditions, or expensive and problematical catalytic systems. From the viewpoint of Green Chemistry, development of an efficient solvent-free approach without using transition metal to prepare halogenated imidazo[1,2-a]pyridines from cheap and readily available starting materials is highly attractive. Based on the running practice emphasizing on Green Chemistry, it is believed that “the best solvent is no solvent”. The crucial advantages of solvent-free reactions are avoiding pollution, price economy, no need of work-up, easy purification, and incredible increase in the rate with less energy consumption.59 Herein, we report a operationally simple, low-cost, room-temperature chlorination reaction using chloramine-T in neat condition within very short time. Chloramine-T is found to be an exceptionally proficient chlorinating agent for the synthesis of 3-chloroimidazo[1,2-a]pyridines under solvent-free conditions and there is no need of column chromatography for the purification in most of the cases. No overchlorination is found, and a variety of functional groups are tolerated. This chlorination technique is carried out in open air. In short, we have revealed a highly efficient chlorinating reagent active to imidazoheterocycles in neat condition (Scheme 1). Received: November 23, 2017 Accepted: March 15, 2018 Published: March 26, 2018 3513

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(Table 1, entry 13). So, finally, the use of 1 equiv chloramine-T in neat condition in ambient air at room temperature was the optimum reaction condition for the reaction of 1a to afford 95% yield of the desired chlorinating product 2a within 5 min (Table 1, entry 8). Under optimized reaction condition, a variety of imidazo[1,2a]pyridines were treated under this standard condition to evaluate the scope and general applicability of the present methodology. At first, the effect of the substituent on the pyridine ring of imidazopyridine was studied and the results are summarized in Scheme 2. The imidazo[1,2-a]pyridines bearing

Scheme 1. Chlorination of Imidazopyridines

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RESULTS AND DISCUSSION Our investigation was started with 8-methyl-2-phenylimidazo[1,2-a]pyridine (1a) as the model substrate to optimize the reaction conditions employing 1 equiv of chloramine-T as a chlorinating reagent and the results are summarized in Table 1.

Scheme 2. Substrates Scope of the Imidazo[1,2-a]pyridinea

Table 1. Optimization of the Reaction Conditionsa

entry

chlorinating agent (1 equiv)

solvent

temp. (°C)

isolated yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13

chloramine-T chloramine-T chloramine-T chloramine-T chloramine-T chloramine-T chloramine-T chloramine-T chloramine-T chloramine-T chloramine-T chloramine-T NCS

DCE DMSO toluene EtOH PEG-400 DMF H2O neat neat neat neat neat neat

rt rt rt rt rt rt rt rt rt 60 rt rt rt

66 35 40 47 43 trace 68 95 95b,c 95 42d 50%e n.d.

a

Reaction conditions: 0.5 mmol of 1 and 1 equiv of chloramine-T in neat condition at room temperature for 5 min in open air.

different electron-donating and electron-withdrawing groups like 8-Me, 7-Me, 6-Cl, 6-Br, and 6-CN successfully reacted to give the desired products in excellent yields (2a−2e). 8-Methyl2-(p-tolyl)imidazo[1,2-a]pyridine produced the chlorinated product (2f) with 72% yield. The structure of 3-chloro-7-methyl-2-phenylimidazo[1,2a]pyridine (2b) was further confirmed by X-ray crystallography (Figure 1).61 Next, the effect of the substituents present at the aryl group on 2-position of the imidazo[1,2-a]pyridine moiety was checked (Scheme 3). Simple 2-phenylimidazopyridine as well as imidazopyridines having substitution on phenyl ring (4-Me and 4-OMe) efficiently reacted to provide the good yield of the desired products (3a−3c). Halogens are also well tolerated

a

Reaction conditions: 0.5 mmol of 1a and 1 equiv of chlorinating agent in 2 mL solvent at the mentioned temperature for 5 min in open air. bFor 6 h. cWith 0.05 mL H2O. dUnder moisture-free condition. e With 1 equiv p-toluenesulfonamide.

Initially, the desired 3-chloro-8-methyl-2-phenylimidazo[1,2a]pyridine (2a) was obtained in 66% yield when the reaction was carried out in 1,2-DCE in open air at room temperature within 5 min (Table 1, entry 1). Then, the reaction was performed in various organic solvents such as dimethyl sulfoxide (DMSO), toluene, ethanol, poly(ethylene glycol) (PEG), dimethylformamide (DMF), and aqueous medium (Table 1, entries 2−7). Pleasantly, a good yield of the desired product was observed using water as the reaction medium (Table 1, entry 7). Gratifyingly, the targeted product was obtained with maximum yield (95%) in solvent-free conditions (Table 1, entry 8). But no further improvement was observed when the reaction was carried out for long time and also in the presence of 0.05 mL water (Table 1, entry 9) and at 60 °C (Table 1, entry 10). However, lower yield was obtained under anhydrous condition (Table 1, entry 11). No further chlorination occurred at any other position on the use of excess chloramine-T. The use of p-toluenesulfonamide also decreased the yield (Table 1, entry 12). The use of Nchlorosuccinimide (NCS) as a chlorinating agent did not give the desired product under the present reaction conditions

Figure 1. X-ray crystal structure of 2b (thermal ellipsoids are drawn at 50% probability level). 3514

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give the chlorinated product in high yield (3h). The imidazo[1,2-a]pyridine with a naphthyl and 2-thiophenyl substituent at the C-2 position also successfully afforded the products (3i and 3j) without any difficulties. Simple imidazo[1,2-a]pyridine and 2-isobutylimidazo[1,2-a]pyridine performed very well in this present reaction process, providing 3k and 3l with 84 and 89% yield, respectively. Furthermore, the applicability of the present methodology on 2-arylbenzo[d]imidazo[2,1-b]thiazole derivatives was investigated (Scheme 4). We were delighted to install the chlorination in these moieties with good to excellent yields (61−91%). Benzo[d]imidazo[2,1-b]thiazoles with electron-donating −Me and −OMe substituents on the benzene ring afforded the corresponding C-3chlorinated benzo[d]imidazo[2,1-b]thiazoles 5b, 5c, and 5d with 67, 91, and 68% yield, respectively. Furthermore, C-4 substituent like −Cl on the phenyl ring at the 2-position of the benzo[d]imidazo[2,1-b]thiazole moiety efficiently reacted with chloramine-T to produce the respective C-3 chlorinated benzo[d]imidazo[2,1-b]thiazoles derivatives (5d and 5e). The reaction of 2-(3-nitrophenyl)benzo[d]imidazo[2,1-b]thiazole afforded the expected product in very good yield (5f, 78%). It was observed that the C-3 chlorinated benzo[d]imidazo[2,1-b]thiazoles 5a, 5b, and 5d were obtained along with the corresponding unreacted 2-arylbenzo[d]imidazo[2,1-b]thiazole derivatives under the optimized reaction conditions (Scheme 4). Next, to obtain higher yields of the chlorobenzo[d]imidazo[2,1-b]thiazoles, we further optimized the reaction conditions at high temperature. Here, we have observed that the use of 1.5 equiv chloramine-T at 80 °C temperature with 4 h reaction time is the optimized condition to get a significant high yield of all the desired products (Scheme 5). But, in any reaction, no higher levels of chlorination, oxidized compounds, dimeric, or higher oligomeric species were found to be isolated. Unfortunately, some moities such as 1-methyl-1H-imidazole, indole, phenol, aniline, and 4-anisaldehyde were unreactive under the present reaction conditions (Scheme 6).

Scheme 3. Synthesis of the 3-Chloroimidazo[1,2a]pyridinesa

a

Reaction conditions: 0.5 mmol of 1 and 1 equiv of chloramine-T in neat condition at room temperature for 5 min in open air.

under the present reaction protocol (3d−3f). Strong electronwithdrawing group like −NO2 in the phenyl ring also successfully gave the desired product with a good yield (3g, 76%). Notably, the marketed drug zolimidine reacted well to Scheme 4. Scope of the Benzo[d]imidazo[2,1-b]thiazolesa

a

Reaction conditions: 0.5 mmol of 4 and 1 equiv of chloramine-T in neat condition at room temperature for 5 min in open air. 3515

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ACS Omega Scheme 5. Scope of the Benzo[d]imidazo[2,1-b]thiazoles at 80 °Ca

a

Reaction conditions: 0.5 mmol of 4 and 1.5 equiv of chloramine-T in neat condition at 80 °C for 4 h in open air.

Scheme 6. Unreactive Moieties

Scheme 8. Synthetic Application of 3-Chloro-8-methyl-2phenylimidazo[1,2-a]pyridine

The gram-scale reaction of the present protocol was also executed in the usual laboratory setup using 8-methyl-2phenylimidazo[1,2-a]pyridine (1a) (Scheme 7). The 3-chloroScheme 7. Gram-Scale Reaction

To understand the possible reaction mechanism, we checked the reaction with 2,2,6,6-tetramethylpiperidine-1-oxyl and observed no effect in the formation of the desired product (Scheme 9). A plausible reaction mechanism has been outlined in Scheme 10 on the basis of the experiments and literature reports.60 The chloramine-T shows disproportionation reaction in the

8-methyl-2-phenylimidazo[1,2-a]pyridine was obtained without significant decrease in yield, which clearly indicated the practical applicability of the current methodology. We demonstrated the synthetic utility of our synthesized compounds in Scheme 8, in particular, for the selective functionalization of the C−Cl bond and the preparation of biologically active target moieties. 3-Chloro-8-methyl-2phenylimidazo[1,2-a]pyridine (2a) was found to be a good substrate for traditional Pd-catalyzed cross-coupling reactions affording 8-methyl-2,3-diphenylimidazo[1,2-a]pyridine (6a) in 70% yield (Scheme 8, eq A).54 More importantly, Cl in 2a could be easily replaced to construct the C−SCN bond in the presence of NaSCN furnishing 66% yield of 8-methyl-2-phenyl3-thiocyanatoimidazo[1,2-a]pyridine (6b) (Scheme 8, eq B),15 which belongs to an important synthetic intermediate for making biologically active molecules.

Scheme 9. Controlled Experimenta

a

Reaction conditions: 0.5 mmol of 1a and 1 equiv of chloramine-T in neat condition at room temperature for 5 min in open air.

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mixture was stirred at room temperature for 5 min in ambient air. After the completion of the reaction (TLC), the reaction mixture was extracted with ethyl acetate (EA, 10 mL) and the unwanted materials were filtered out. The crude residue was obtained after the evaporation of the filtrate in vacuum and was purified by either direct recrystallization from hot ethanol (3 mL) or column chromatography on a silica gel (60−120 mesh) using petroleum ether as the eluent to afford a pure product. 3-Chloro-8-methyl-2-phenylimidazo[1,2-a]pyridine (2a). White solid (95%, 115 mg), Rf = 0.45 (PE/EA = 7:3), mp 202−203 °C. 1H NMR (400 MHz, CDCl3): δ 8.16−8.13 (m, 2H), 7.95 (d, J = 6.4 Hz, 1H), 7.50−7.46 (m, 2H), 7.39−7.35 (m, 1H), 7.01−6.99 (m, 1H), 6.80 (t, J = 6.8 Hz, 1H), 2.65 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 144.1, 139.3, 132.9, 128.5, 128.1, 127.75, 127.70, 123.6, 120.5, 112.9, 105.9, 16.6; anal. calcd for C14H11ClN2: C, 69.28; H, 4.57; N, 11.54%; found: C, 69.45; H, 4.48; N, 11.39%. 3-Chloro-7-methyl-2-phenylimidazo[1,2-a]pyridine (2b). White solid (92%, 112 mg), Rf = 0.4 (PE/EA = 8:2), mp 130−132 °C. 1H NMR (400 MHz, CDCl3): δ 8.12−8.10 (m, 2H), 7.95 (d, J = 6.8 Hz, 1H), 7.48−7.45 (m, 2H), 7.38−7.34 (m, 2H), 6.73 (dd, J = 7.2, 1.6 Hz, 1H), 2.40 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 144.1, 139.4, 136.1, 132.7, 128.6, 128.1, 127.5, 121.9, 116.0, 115.6, 105.0, 21.4; anal. calcd for C14H11ClN2: C, 69.28; H, 4.57; N, 11.54%; found: C, 69.07; H, 4.64; N, 11.35%. 3,6-Dichloro-2-phenylimidazo[1,2-a]pyridine (2c).56 White solid (87%, 114 mg), Rf = 0.45 (PE/EA = 8:2), mp 155−156 °C (Lit. mp 158.5−161.3 °C). 1H NMR (400 MHz, CDCl3): δ 8.15−8.09 (m, 3H), 7.57 (d, J = 9.6 Hz, 1H), 7.50−7.46 (m, 2H), 7.41−7.37 (m, 1H), 7.20 (dd, J = 9.6, 2.0 Hz, 1H); 13 C{1H} NMR (100 MHz, CDCl3): δ 142.1, 140.9, 132.2, 128.7, 128.6, 127.5, 126.4, 121.6, 120.7, 118.1, 106.3. 6-Bromo-3-chloro-2-phenylimidazo[1,2-a]pyridine (2d).56 Black solid (86%, 132 mg), Rf = 0.4 (PE/EA = 7:3), mp 161− 162 °C (Lit. mp 164.9−166.3 °C). 1H NMR (400 MHz, CDCl3): δ 8.27−8.26 (m, 1H), 8.12−8.09 (m, 2H), 7.55 (d, J = 9.2 Hz, 1H), 7.50−7.47 (m, 2H), 7.42−7.37 (m, 1H), 7.32 (dd, J = 9.6, 1.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 142.1, 140.6, 132.0, 128.9, 128.78, 128.73, 127.6, 123.0, 118.3, 108.1, 106.1. 3-Chloro-2-phenylimidazo[1,2-a]pyridine-6-carbonitrile (2e).56 Yellow solid (84%, 106 mg), Rf = 0.45 (PE/EA = 6:4), mp 232−234 °C (Lit. mp 238.2−240.3 °C). 1H NMR (400 MHz, CDCl3): δ 8.53 (s, 1H), 8.13−8.11 (m, 2H), 7.70−7.68 (m, 1H), 7.52−7.48 (m, 2H), 7.44−7.40 (m, 1H), 7.34 (dd, J = 9.2, 1.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 142.9, 142.3, 141.8, 131.4, 129.2, 128.8, 127.7, 124.8, 118.7, 116.3, 107.3, 99.4. 3-Chloro-8-methyl-2-(p-tolyl)imidazo[1,2-a]pyridine (2f). Yellowish oil (72%, 92 mg), Rf = 0.6 (PE/EA = 6:4). 1H NMR (400 MHz, CDCl3): δ 8.04 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.01−6.98 (m, 1H), 6.80 (t, J = 7.2 Hz, 1H), 2.65 (s, 3H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 144.0, 139.5, 137.9, 130.0, 129.3, 127.65, 127.60, 123.5, 120.5, 112.8, 105.6, 21.4, 16.6; anal. calcd for C15H13ClN2: C, 70.18; H, 5.10; N, 10.91%; found: C, 70.30; H, 4.96; N, 11.11%. 3-Chloro-2-phenylimidazo[1,2-a]pyridine (3a).56 White solid (92%, 105 mg), Rf = 0.4 (PE/EA = 7:3), mp 120−121 °C (Lit. mp 122.0−123.3 °C). 1H NMR (400 MHz, CDCl3): δ 8.08−8.01 (m, 3H), 7.57−7.54 (m, 1H), 7.42−7.38 (m, 2H), 7.33−7.28 (m, 1H), 7.18−7.14 (m, 1H), 6.86−6.82 (m, 1H);

Scheme 10. Possible Reaction Pathway

presence of moisture to dichloro-sulfonamide or hypochlorous acid which are effective chlorinating agent and the free sulfonamide. Then, a rapid nucleophilic attack by imidazopyridine to Cl+ cation constructed the targeted product (2a).

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CONCLUSIONS In conclusion, we have successfully developed an environmentally benign, efficient, and regioselective methodology for the chlorination of imidazo[1,2-a]pyridines at room temperature. The proposed method accepts a broad substrate scope applicability and allows a wide range of functionality. This technique is also capable of chlorinating the benzo[d]imidazo[2,1-b]thiazoles. General applicability, easy accessibility of reagents, operational simplicity, clean reaction, easy purification technique, open-air and metal- and solvent-free, environmentfriendly reaction conditions, and high yields are the notable advantages of the present protocol. These features make this convenient practice to be a green synthetic strategy. We believe that this “green” path will gain a much more attention in organic synthesis and academic and industrial field as a powerful and economical route for the chlorination of imidazoheterocycles.

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EXPERIMENTAL SECTION General Information. 1H NMR spectra were determined on a 400 MHz spectrometer in CDCl3 solution. Chemical shifts are expressed in parts per million (δ) and are referenced to tetramethylsilane as an internal standard and the signals were reported as s (singlet), d (doublet), t (triplet), m (multiplet), dd (doublet of doublets), and coupling constants J were given in Hz. Proton-decoupled 13C{1H} NMR spectra were recorded at 100 MHz in CDCl3 solution. Chemical shifts are referenced to CDCl3 (δ = 7.26 for 1H and δ = 77.16 for 13C{1H} NMR) as internal standards. Thin-layer chromatography (TLC) was monitored with an aluminum backed silica gel 60 (HF254) plates (0.25 mm). Silica gel (60−120 mesh) was used for column chromatography. Petroleum ether (PE) refers to the fractional boiling in the range of 60−80 °C unless otherwise mentioned. All solvents were dried and distilled before use. Commercially available substrates were freshly distilled before the reaction. All reactions involving moisture-sensitive reactants were executed using oven-dried glassware. The X-ray singlecrystal data were collected using a Mo Kα (λ = 0.71073 Å) radiation with a charge coupled device area detector. General Experimental Procedure (for 2, 3, and 5). A 1 equiv of chloramine-T (114 mg) was mixed with 1 (4) (0.5 mmol) in an oven-dried reaction tube. Then, the reaction 3517

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ACS Omega C{1H} NMR (100 MHz, CDCl3): δ 143.8, 139.9, 132.6, 128.6, 128.3, 128.0, 127.6, 124.9, 124.0, 122.8, 117.7, 113.0, 105.8. 3-Chloro-2-(p-tolyl)imidazo[1,2-a]pyridine (3b).56 White solid (80%, 97 mg), Rf = 0.4 (PE/EA = 7:3), mp 124−126 °C (Lit. mp 129.2−131.3 °C). 1H NMR (400 MHz, CDCl3): δ 8.08−8.06 (m, 1H), 8.03 (d, J = 8.0 Hz, 2H), 7.61 (dd, J = 9.2, 0.8 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.23−7.19 (m, 1H), 6.91−6.87 (m, 1H), 2.40 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 143.7, 139.9, 138.2, 129.7, 129.3, 127.4, 124.8, 122.7, 117.6, 112.8, 105.4, 21.4. 3-Chloro-2-(4-methoxyphenyl)imidazo[1,2-a]pyridine (3c).56 Light yellow solid (93%, 120 mg), Rf = 0.4 (PE/EA = 6:4), mp 123−125 °C (Lit. mp 126.2−127.5 °C). 1H NMR (400 MHz, CDCl3): δ 8.09−8.04 (m, 3H), 7.62 (d, J = 9.2 Hz, 1H), 7.27−7.20 (m, 1H), 7.02−6.98 (m, 2H), 6.93−6.89 (m, 1H), 3.85 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.8, 143.7, 139.8, 129.7, 128.9, 126.5, 125.2, 124.8, 122.7, 117.5, 114.1, 112.9, 104.9, 55.4. 3-Chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine (3d).56 White solid (94%, 124 mg), Rf = 0.4 (PE/EA = 7:3), mp 157− 159 °C (Lit. mp 159.0−161.3 °C). 1H NMR (400 MHz, CDCl3): δ 8.09−8.05 (m, 3H), 7.61 (d, J = 9.2 Hz, 1H), 7.45− 7.41 (m, 2H), 7.27−7.22 (m, 1H), 6.95−6.91 (m, 1H); 13 C{1H} NMR (100 MHz, CDCl3): δ 143.8, 138.8, 134.2, 131.1, 128.8, 128.7, 125.2, 122.8, 117.7, 113.2, 105.6. 3-Chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridine (3e). White solid (83%, 102 mg), Rf = 0.4 (PE/EA = 8:2), mp 95−97 °C. 1H NMR (400 MHz, CDCl3): δ 8.18−8.09 (m, 3H), 7.63 (d, J = 9.2 Hz, 1H), 7.29−7.24 (m, 1H), 7.19−7.14 (m, 2H), 6.97−6.93 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 162.9 (JC−F = 246 Hz), 143.8, 139.1, 129.4 (JC−F = 9 Hz), 128.8 (JC−F = 2 Hz), 125.1, 122.8, 117.7, 115.6 (JC−F = 21 Hz), 113.1; anal. calcd for C13H8ClFN2: C, 63.30; H, 3.27; N, 11.36%; found: C, 63.55; H, 3.22; N, 11.21%. 3-Chloro-2-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine (3f). White solid (98%, 145 mg), Rf = 0.35 (PE/EA = 7:3), mp 125−126 °C. 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 8.0 Hz, 2H), 8.05−8.03 (m, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.60−7.58 (m, 1H), 7.24−7.20 (m, 1H), 6.91−6.88 (m, 1H); 13 C{1H} NMR (100 MHz, CDCl3): δ 143.9, 137.1 (JC−F = 210 Hz), 129.9 (q, JC−F = 64 Hz), 128.1 (JC−F = 49 Hz), 127.5, 125.6, 125.5 (q, JC−F = 8 Hz), 122.9, 122.8, 120.2, 117.8, 113.3, 106.6; anal. calcd for C14H8ClF3N2: C, 56.68; H, 2.72; N, 9.44%; found: C, 56.49; H, 2.83; N, 9.61%. 3-Chloro-2-(3-nitrophenyl)imidazo[1,2-a]pyridine (3g). Yellow solid (76%, 104 mg), Rf = 0.45 (PE/EA = 7:3), mp 190−192 °C. 1H NMR (400 MHz, CDCl3): δ 9.03 (t, J = 2.0 Hz, 1H), 8.50−8.48 (m, 1H), 8.23−8.20 (m, 1H), 8.16−8.13 (m, 1H), 7.67−7.62 (m, 2H), 7.33−7.29 (m, 1H), 7.01−6.97 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 148.7, 144.0, 137.5, 134.5, 133.2, 129.6, 126.6, 125.7, 123.0, 122.9, 122.2, 118.0, 113.6, 106.8; anal. calcd for C13H8ClN3O2: C, 57.05; H, 2.95; N, 15.35%; found: C, 56.88; H, 2.84; N, 15.53%. 3-Chloro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (3h). White solid (88%, 135 mg), Rf = 0.4 (PE/EA = 7:3), mp 175−176 °C. 1H NMR (400 MHz, CDCl3): δ 8.36− 8.33 (m, 2H), 8.13−8.11 (m, 1H), 8.03−8.00 (m, 2H), 7.64− 7.62 (m, 1H), 7.31−7.26 (m, 1H), 6.99−6.95 (m, 1H), 3.08 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 144.0, 139.6, 138.1, 137.7, 128.1, 127.9, 127.7, 125.8, 123.0, 118.0, 113.6, 107.2, 13

44.6; anal. calcd for C14H11ClN2O2S: C, 54.82; H, 3.61; N, 9.13%; found: C, 54.64; H, 3.53; N, 9.35%. 3-Chloro-2-(naphthalen-1-yl)imidazo[1,2-a]pyridine (3i). White solid (92%, 128 mg), Rf = 0.55 (PE/EA = 8:2), mp 171−173 °C. 1H NMR (400 MHz, CDCl3): δ 8.63 (s, 1H), 8.29 (dd, J = 8.8, 2.0 Hz, 1H), 8.09−8.07 (m, 1H), 7.97−7.93 (m, 2H), 7.86−7.83 (m, 1H), 7.67−7.64 (m, 1H), 7.52−7.46 (m, 2H), 7.26−7.20 (m, 1H), 6.91−6.87 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 143.8, 139.7, 133.5, 133.1, 130.0, 128.5, 128.2, 127.7, 126.8, 126.4, 126.3, 125.1, 125.0, 122.7, 117.6, 113.0, 106.0; anal. calcd for C17H11ClN2: C, 73.25; H, 3.98; N, 10.05%; found: C, 73.46; H, 3.85; N, 10.28%. 3-Chloro-2-(thiophen-2-yl)imidazo[1,2-a]pyridine (3j). Gummy solid (98%, 115 mg), Rf = 0.5 (PE/EA = 6:4). 1H NMR (400 MHz, CDCl3): δ 8.15 (d, J = 6.8 Hz, 1H), 7.90− 7.87 (m, 1H), 7.72−7.68 (m, 1H), 7.48 (dd, J = 5.2, 1.2 Hz, 1H), 7.35−7.30 (m, 1H), 7.25−7.23 (m, 1H), 7.03−6.99 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 143.8, 135.9, 135.6, 127.9, 126.1, 125.4, 125.2, 122.6, 117.5, 113.4, 113.1; anal. calcd for C11H7ClN2S: C, 56.29; H, 3.01; N, 11.94%; found: C, 56.47; H, 3.12; N, 11.75%. 3-Chloroimidazo[1,2-a]pyridine (3k). Gummy liquid (84%, 64 mg), Rf = 0.5 (PE/EA = 6:4). 1H NMR (400 MHz, CDCl3): δ 8.07−8.05 (m, 1H), 7.61−7.59 (m, 1H), 7.55 (s, 1H), 7.23− 7.19 (m, 1H), 6.94−6.90 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 144.6, 130.2, 124.4, 122.7, 118.2, 113.1, 109.7; anal. calcd for C7H5ClN2: C, 55.10; H, 3.30; N, 18.36%; found: C, 54.91; H, 3.38; N, 18.52%. 3-Chloro-2-isobutylimidazo[1,2-a]pyridine (3l). Gummy liquid (89%, 93 mg), Rf = 0.4 (PE/EA = 7:3). 1H NMR (400 MHz, CDCl3): δ 8.00−7.98 (m, 1H), 7.53 (dd, J = 9.2, 1.2 Hz, 1H), 7.18−7.14 (m, 1H), 6.88−6.84 (m, 1H), 2.65 (d, J = 7.2 Hz, 2H), 2.22−2.12 (m, 1H), 0.96 (d, J = 6.8 Hz, 6H); 13 C{1H} NMR (100 MHz, CDCl3): δ 143.5, 142.3, 128.6, 124.0, 122.5, 117.2, 112.5, 106.9, 36.3, 28.9, 22.6; anal. calcd for C11H13ClN2: C, 63.31; H, 6.28; N, 13.42%; found: C, 63.48; H, 6.22; N, 13.29%. 3-Chloro-2-phenylbenzo[d]imidazo[2,1-b]thiazole (5a). Yellow solid, (61%, 86 mg), Rf = 0.5 (PE/EA = 7:3), mp 179−181 °C. 1H NMR (400 MHz, CDCl3): δ 8.26 (d, J = 8.0 Hz, 1H), 8.04−8.02 (m, 2H), 7.71 (d, J = 7.6 Hz, 1H), 7.48− 7.44 (m, 3H), 7.40−7.33 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 146.3, 141.4, 132.7, 132.6, 130.2, 128.6, 127.9, 126.8, 126.2, 125.3, 124.3, 113.6, 108.6; anal. calcd for C15H9ClN2S: C, 63.27; H, 3.19; N, 9.84%; found C, 63.47; H, 3.07; N, 9.61%. 3-Chloro-7-methyl-2-phenylbenzo[d]imidazo[2,1-b]thiazole (5b). Yellow solid (67%, 100 mg), Rf = 0.35 (PE/EA = 7:3), mp 177−179 °C. 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 8.4 Hz, 1H), 8.03−8.01 (m, 2H), 7.49−7.43 (m, 3H), 7.36−7.31 (m, 1H), 7.25−7.23 (m, 1H), 2.46 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 146.1, 141.1, 135.5, 132.7, 130.6, 130.2, 128.6, 127.8, 127.2, 126.7, 124.4, 113.2, 108.4, 21.5; anal. calcd for C16H11ClN2S: C, 64.32; H, 3.71; N, 9.38%; found: C, 64.17; H, 3.77; N, 9.53%. 3-Chloro-6-methoxy-2-phenylbenzo[d]imidazo[2,1-b]thiazole (5c). White solid (91%, 143 mg), Rf = 0.5 (PE/EA = 8:2), mp 178−180 °C. 1H NMR (400 MHz, CDCl3): δ 8.11 (d, J = 8.8 Hz, 1H), 8.01 (dd, J = 8.4, 1.2 Hz, 2H), 7.47−7.42 (m, 2H), 7.35−7.31 (m, 1H), 7.19 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 9.2, 2.8 Hz, 1H), 3.86 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 157.4, 145.6, 140.8, 132.7, 131.5, 128.6, 127.7, 126.8, 126.7, 114.2, 113.3, 108.7, 108.3, 56.0; anal. calcd for 3518

DOI: 10.1021/acsomega.7b01844 ACS Omega 2018, 3, 3513−3521

Article

ACS Omega

8-Methyl-2-phenyl-3-thiocyanatoimidazo[1,2-a]pyridine (6b).25 White solid (66%, 88 mg), Rf = 0.4 (PE/EA = 8:2), mp 97−99 °C (Lit. mp 98−100 °C). 1H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 6.8 Hz, 1H), 8.09−8.06 (m, 2H), 7.57−7.53 (m, 2H), 7.51−7.47 (m, 1H), 7.27 (d, J = 6.0 Hz, 1H), 7.05 (t, J = 6.8 Hz, 1H), 2.72 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 152.7, 148.3, 132.3, 129.3, 129.0, 128.8, 128.6, 126.8, 122.2, 114.4, 108.4, 94.9, 16.8.

C16H11ClN2OS: C, 61.05; H, 3.52; N, 8.90%; found: C, 61.19; H, 3.60; N, 8.69%. 3-Chloro-2-(4-chlorophenyl)-7-methoxybenzo[d]imidazo[2,1-b]thiazole (5d). White solid (68%, 119 mg), Rf = 0.45 (PE/EA = 6:4), mp 215−217 °C. 1H NMR (400 MHz, CDCl3): δ 8.11 (d, J = 8.8 Hz, 1H), 7.97−7.94 (m, 2H), 7.42− 7.39 (m, 2H), 7.20 (d, J = 2.4 Hz, 1H), 7.00 (dd, J = 9.2, 2.4 Hz, 1H), 3.87 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 157.5, 145.7, 139.7, 133.5, 131.6, 131.2, 128.8, 127.9, 126.7, 114.2, 113.4, 108.7, 56.0; anal. calcd for C16H10Cl2N2OS: C, 55.03; H, 2.89; N, 8.02%; found: C, 55.21; H, 2.76; N, 8.24%. 3-Chloro-2-(4-chlorophenyl)benzo[d]imidazo[2,1-b]thiazole (5e). White solid (81%, 129 mg), Rf = 0.35 (PE/EA = 7:3), mp 162−164 °C. 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 8.4 Hz, 1H), 7.98−7.94 (m, 2H), 7.69 (dd, J = 8.0, 0.8 Hz, 1H), 7.47−7.34 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 146.4, 140.2, 133.6, 132.5, 131.1, 130.1, 128.8, 128.4, 127.9, 126.3, 125.4, 124.3, 113.6, 108.6; anal. calcd for C15H8Cl2N2S: C, 56.44; H, 2.53; N, 8.78%; found: C, 56.57; H, 2.50; N, 8.61%. 3-Chloro-2-(3-nitrophenyl)benzo[d]imidazo[2,1-b]thiazole (5f). Light yellow solid (78%, 129 mg), Rf = 0.40 (PE/EA = 8:2), mp 199−201 °C. 1H NMR (400 MHz, CDCl3): δ 8.94 (t, J = 2.0 Hz, 1H), 8.41−8.38 (m, 1H), 8.28 (d, J = 7.6 Hz, 1H), 8.20−8.17 (m, 1H), 7.74 (dd, J = 8.0, 0.8 Hz, 1H), 7.62 (t, J = 8.4 Hz, 1H), 7.53−7.48 (m, 1H), 7.44−7.40 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 152.2, 138.4, 134.4, 132.5, 132.3, 129.6, 126.5, 125.8, 124.5, 122.4, 121.7, 121.4, 115.2, 113.8, 108.7; anal. calcd for C15H8ClN3O2S: C, 54.64; H, 2.45; N, 12.74%; found: C, 54.48; H, 2.50; N, 12.85%. Typical Experimental Procedure (for 6a). To a solution of 3-chloro-8-methyl-2-phenylimidazo[1,2-a]pyridine (2a) (121 mg, 0.5 mmol) in 1,4-dioxane (3 mL) were added phenylboronic acid (91 mg, 0.75 mmol), potassium carbonate (207 mg, 1.5 mmol), and water (2 mL). The reaction mixture was degassed with argon for 5 min. Bis(triphenylphosphine)palladium(II) dichloride (35 mg, 0.05 mmol) was added and the reaction mixture was heated to 80 °C for 4 h. The reaction mixture was cooled to room temperature and the organic solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (15 mL), extracted with water (10 mL), and washed with brine (10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash column chromatography gave 8-methyl2,3-diphenylimidazo[1,2-a]pyridine (6a). 8-Methyl-2,3-diphenylimidazo[1,2-a]pyridine (6a). 16 Gummy solid (70%, 99 mg), Rf = 0.4 (PE/EA = 7:3), mp 97−99 °C (Lit. mp 98−100 °C). 1H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 6.8 Hz, 1H), 7.71−7.68 (m, 2H), 7.55−7.45 (m, 5H), 7.32−7.25 (m, 3H), 7.03−7.01 (m, 1H), 6.67 (t, J = 6.8 Hz, 1H), 2.73 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 145.3, 142.1, 134.5, 130.8, 130.3, 129.5, 128.8, 128.4, 128.3, 127.6, 127.4, 123.5, 121.6, 121.3, 112.4, 17.3. Typical Experimental Procedure (for 6b). A mixture of 3-chloro-8-methyl-2-phenylimidazo[1,2-a]pyridine (2a) (121 mg, 0.5 mmol) and NaSCN (81 mg, 1.0 mmol) was dissolved in EtOH (2 mL) at room temperature in an oven-dried reaction tube. The reaction mixture was refluxed for 12 h. TLC indicated the completion of the reaction. The mixture was concentrated under vacuum and the crude product was purified by column chromatography using petroleum ether/ethyl acetate as an eluent to give the product, 8-methyl-2-phenyl-3thiocyanatoimidazo[1,2-a]pyridine (6b).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.7b01844. Scanned copies of 1H and 13C{1H} NMR spectra of the synthesized compounds (PDF) Crystallographic data for compound 2b (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Alakananda Hajra: 0000-0001-6141-0343 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS A.H. acknowledges the financial support from SERB-DST, New Delhi (File No. EMR/2016/001643). A.D. thanks the CSIR for her fellowship, M.S. thanks UGC-New Delhi for NFHE, and R.S. thanks SERB-DST for NPDF.

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REFERENCES

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DOI: 10.1021/acsomega.7b01844 ACS Omega 2018, 3, 3513−3521

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DOI: 10.1021/acsomega.7b01844 ACS Omega 2018, 3, 3513−3521