One-Pot Synthesis of Highly Functionalized Bicyclic Imidazopyridinium

Dec 19, 2016 - Shi-Sheng Cui , Rong Huang , Da-Yun Luo , Sheng-Jiao Yan , Jun Lin. European Journal of Organic Chemistry 2017 2017 (24), 3442-3450 ...
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Research Article pubs.acs.org/journal/ascecg

One-Pot Synthesis of Highly Functionalized Bicyclic Imidazopyridinium Derivatives in Ethanol Liang Chen,† Rong Huang,† Xuan-Xuan Du, Sheng-Jiao Yan,* and Jun Lin* Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming 650091, P. R. China

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S Supporting Information *

ABSTRACT: A concise and eco-friendly route for the synthesis of highly functionalized bicyclic pyridinium derivatives (3) via a one-pot reaction of chromone-3-carboxaldehydes (1) and N-benzyl nitro ketene aminals (NBNKAs) (2) under reflux in ethanol media has been developed. The targeted compound was efficiently obtained by filtration without further post-treatment. In the one-pot two step reaction, CC and CN bonds were constructed, while at the same time one CO bond was cleaved. This protocol represents a valuable route to obtain highly functional bicyclic pyridinium derivatives in a concise, rapid, and practical manner. The reaction is particularly attractive due to features such as low cost, mild conditions, atom economy, high yield, using biocompatible solvent, and potential biological activity of the product. KEYWORDS: Environment friendly, Atom economy, Imidazopyridine, Pyridinium, Neonicotinoids

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fadrozole,28,29 olprinone,30 zolpidem,31,32 mosapramine,33 and minodronic acid34 (Figure 1). Another class of heterocyclic compounds is the neonicotinoid derivatives, which show insecticide activity. For example, imidacloprid (Figure 1) was introduced as an insecticide in the 1980s.35 In addition, the biological properties of neonicotinoids, i.e., insecticidal (Figure 1 6Cl-PMNI, IPPA08, Paichongding)36−41 and antibacterial,42 as well as their versatile binding modes, are based on special molecular features including an electron-withdrawing nitro group, flexible linkages, and hydroheterocyles or guanidine/amidine groups.43 N-Benzyl nitro ketene aminals (NBNKAs 2) (Scheme 1) belong to the heterocyclic ketene aminals (HKAs).44−51 NBNKAs are versatile building blocks that have been widely used to construct molecularly diverse heterocyclic compounds52−60 such as quinolones, pyridines,61 pyrroles, and spirooxindoles.62,63 On the basis of the biological activities of imidazopyridines and neonicotinoid derivatives, we have designed new molecules as target compounds that combine the skeletons of imidazopyr-

INTRODUCTION Vital manufactured products are produced by chemical processes that usually consume natural resources and generate large amounts of toxic waste.1−3 To eliminate these problems, the ideal chemical process should be green and sustainable.4−6 The American Environmental Protection Agency (EPA) has defined the green chemistry concept as “the design of chemical products and processes that reduce or eliminate the use or generation of hazardous substances”.7 In the green chemistry field, developing an environmentally friendly and efficient method to construct CC and CN bonds is of salient interest for the synthesis of N-containing heterocyclic compounds.8,9 Group-assisted purification (GAP)10,11 chemistry enables the synthesis of organic compounds without using traditional purification technologies including column chromatography and recrystallization. This technology has generated efforts toward searching for environmentally benign reagents and reactions to reduce the waste generated from silica and solvents, particularly toxic solvents. N-Containing heterocyclic compounds are widely encountered in contemporary medicinal chemistry,12−18 including a large number of commercialized synthetic and natural products.19−22 Among these compounds, imidazopyridines are present in various clinically approved drugs23−27 such as © 2016 American Chemical Society

Received: October 30, 2016 Revised: December 4, 2016 Published: December 19, 2016 1899

DOI: 10.1021/acssuschemeng.6b02622 ACS Sustainable Chem. Eng. 2017, 5, 1899−1905

Research Article

ACS Sustainable Chemistry & Engineering

Figure 1. Biologically active imidazopyridines and neonicotinoid insecticides and targeted compounds.

Scheme 1. General Strategy for the Synthesis of Target Compounds 3

mL) was refluxed for 8 h. The precipitate was filtered and washed with 2 mL of ethanol to afford NBNKAs 2. The structure of NBNKAs 2 was confirmed by 1H NMR, 13C NMR, and HRMS spectra.

idines and the neonicotinoid derivative 6Cl-PMNI, taking advantage of their excellent biological activities. The target compounds contain the pyridinium structure to increase water solubility, antibacterial activity,64,65 and surfactant capacity.66,67 We describe herein a one-pot strategy for the diastereoselective convergent synthesis of a series of bicyclic imidazopyridinium derivatives (3). To the best of our knowledge, the synthesis of the polycyclic pyrrole derivatives has not been reported by the reaction of chromone-3-carboxaldehyde68−70 (1) and N-benzyl nitro ketene aminals (NBNKAs) (2).

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EXPERIMENTAL SECTION

General Methods. Melting points were determined on a XT-4A melting point apparatus and are uncorrected. NMR spectra were recorded on a Bruker DRX500 (1H, 500 MHz; 13C, 125 MHz) and a Bruker DRX600 (1H, 600 MHz; 13C, 150 MHz) with DMSO-d6 as the solvent. The chemical shifts (δ’s) are expressed in parts per million relative to the residual deuterated solvent signal, and coupling constants (J) are given in hertz. IR spectra were recorded on a Thermo Nicolet Avatar 360 FT-IR apparatus using KBr pellets. HRMS (ESI) experiments were performed on an Agilent LC/MSD TOF instrument. All received reagents and solvents were used without further purification unless otherwise stated. The materials 1a−d were purchased from Aldrich Corporation Limited. NBNKAs 2 were prepared according to a procedure described in the literature.71 General Procedure for the Synthesis of Compounds 2. The solution of 4 (10 mmol of 4 dissolved in 10 mL of acetonitrile) was added dropwise to ethylene diamine (3.00 g, 50 mmol) with stirring in an ice bath. The mixture was warmed to room temperature and stirred overnight. Then, the solvent was removed under reduced pressure. Water was added to the residue, which was then extracted with dichloromethane. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford 5 which was used for the next step without additional purification. The mixture of 5 (5 mmol) and 1,1bis(methylthio)-2-nitroethylene (5 mmol) dissolved in ethanol (20

General Procedure for the Synthesis of Compounds 3. A 25 mL round-bottom flask was charged with chromone-3-carboxaldehyde 1 (1.1 mmol), EtOH (15 mL), and NBNKAs 2 (1 mmol), and the solution was stirred for 20 min at reflux until NBNKA 2 was completely consumed as indicated by TLC. Then, the mixture was cooled at room temperature, and a small amount of acid (1−5 drops HClO4 or HCl) was dropped into the solution until the pH was 2−4. Finally, the mixture was filtered to afford pure product 3. The characterization details for the partial representative compounds were shown below. 6-(2-Hydroxybenzoyl)-8-nitro-1-(4-nitrobenzyl)-2,3-dihydro-1Himidazo[1,2-a]pyridin-4-ium Perchlorate (3aa). Yellow solid, mp 236−238 °C. Rf = 0.38 (dichloromethane/ethanol 40:1). IR (KBr, νmax, cm−1): 3436, 1654, 1620, 1557, 1345, 1244, 1091, 624. 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 9.27 (s, 1H, ArH), 8.84 (s, 1H, ArH), 8.27 (d, J = 8.5 Hz, 2H, ArH), 7.78 (d, J = 8.5 Hz, 2H, ArH), 7.52− 7.55 (m, 1H, ArH), 7.48 (d, J = 7.5 Hz, 1H, ArH), 7.01−7.08 (m, 2H, ArH), 5.11 (s, 2H, CH2), 4.88 (t, J = 10.0 Hz, 2H, CH2), 4.22 (t, J = 9.8 Hz, 2H, CH2). 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 189.4, 156.9, 149.5, 147.6, 142.7, 142.3, 135.1, 132.4, 131.3, 128.8, 124.1, 124.1, 123.8, 123.0, 120.3, 117.6, 53.7, 52.5, 51.1. HRMS (ESI-TOF, [M − ClO4−]+): calcd for C21H17N4O6, 421.1143; found, 421.1143. 1900

DOI: 10.1021/acssuschemeng.6b02622 ACS Sustainable Chem. Eng. 2017, 5, 1899−1905

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ACS Sustainable Chemistry & Engineering Table 1. Optimization of the Reaction Conditionsa

entry

solvent

T (°C)

t (min)

yieldb(%)

1 2 3 4 5 6 7 8 9 10

EtOH EtOH EtOH MeOH DMF CH3CN 1,4-dioxane THF H2O H20

reflux rt MW (reflux)c reflux 110 reflux reflux reflux rt 70

20 120 20 10 30 30 30 30 120 30

94 75 92 85 54 51 47 68 45 64

a c

Reactions (entries 1−10) were carried out using 1a (1.1 mmol), 2a (1.0 mmol), and solvent (15 mL). bIsolated yield based on NBNKA 2a. Microwave power was 700 W.

1-(3,5-Difluorobenzyl)-6-(2-hydroxybenzoyl)-8-nitro-2,3-dihydro1H-imidazo[1,2-a]-pyridin-4-ium Perchlorate (3aj). Yellow solid, mp 220−221 °C. Rf = 0.36 (dichloromethane/ethanol 40:1). IR (KBr, νmax, cm−1): 3727, 3424, 1659, 1624, 1557, 1245, 1096, 623. 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 9.24 (s, 1H, ArH), 8.83 (d, J = 1.5 Hz, 1H, ArH), 7.52−7.55 (m, 1H, ArH), 7.47−7.49 (m, 1H, ArH), 7.27 (d, J = 6.5 Hz, 2H, ArH), 7.18−7.23 (m, 1H, ArH), 7.01−7.06 (m, 2H, ArH), 4.87 (t, J = 10.0 Hz, 2H, CH2), 4.83 (s, 2H, CH2), 4.21 (t, J = 9.8 Hz, 2H, CH2). 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 189.4, 163.0 (dd, 1JC−F = 244.4 Hz, 3JC−F = 13.1 Hz), 156.9, 149.3, 147.5, 142.5, 138.9 (t, 3JC−F = 9.4 Hz), 135.0, 132.4, 131.2, 123.7, 122.9, 120.3, 117.6, 110.9(m), 103.7 (t, 2JC−F = 25.6 Hz), 53.2, 52.4, 51.0. HRMS (ESI-TOF, [M − ClO4−]+): calcd for C21H16F2N3O4+, 412.1103; found, 412.1104. 1-Benzyl-6-(5-fluoro-2-hydroxybenzoyl)-8-nitro-2,3-dihydro-1Himidazo[1,2-a]pyridin-4-ium Perchlorate (3bf). Yellow solid, mp 159−160 °C. Rf = 0.36 (dichloromethane/ethanol 40:1). IR (KBr, νmax, cm−1): 3425, 1666, 1483, 1234, 1161, 1094, 792, 624. 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 9.19 (d, J = 1.0 Hz, 1H, ArH), 8.77 (d, J = 1.5 Hz, 1H, ArH), 7.33−7.44 (m, 6H, ArH), 7.22− 7.24 (m, 1H, ArH), 7.01−7.04 (m, 1H, ArH), 4.82 (t, J = 10.0 Hz, 2H, CH2), 4.77 (s, 2H, CH2), 4.18 (t, J = 10.0 Hz, 2H, CH2). 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 188.1, 155.7 (d, 1JC−F = 236.3 Hz), 153.0, 148.8, 147.8, 142.3, 133.5, 132.8, 132.4, 129.3, 128.6, 127.8, 124.3 (d, 3JC−F = 6.3 Hz), 122.2, 121.5 (d, 2JC−F = 23.8 Hz), 119.0 (d, 3 JC−F = 7.5 Hz), 116.5 (d, 2JC−F = 25.0 Hz), 53.8, 52.4, 50.9. HRMS (ESITOF, [M − ClO4−]+): calcd for C21H17FN3O4+, 394.1198; found, 394.1196. 1-Benzyl-6-(5-chloro-2-hydroxybenzoyl)-8-nitro-2,3-dihydro-1Himidazo[1,2-a] pyridin-4-ium Perchlorate (3cf). Yellow solid, mp 172−173 °C. Rf = 0.45 (dichloromethane/ethanol 40:1). IR (KBr, νmax, cm−1): 3436, 3079, 1657, 1548, 1469, 1305, 1089, 624. 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 9.18 (s, 1H, ArH), 8.75 (d, J = 1.0 Hz, 1H, ArH), 7.49−7.51 (m, 1H, ArH), 7.33−7.40 (m, 6H, ArH), 7.03 (d, J = 9.0 Hz, 2H, ArH), 4.80 (t, J = 10.0 Hz, 2H, CH2), 4.75 (s, 2H, CH2), 4.17 (t, J = 10.0 Hz, 2H, CH2). 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 188.0, 155.3, 148.8, 147.8, 142.2, 134.1, 133.5, 132.4, 129.9, 129.2, 128.6, 127.8, 125.4, 123.7, 122.1, 119.4, 53.7, 52.4, 50.9. HRMS (ESI-TOF, [M − ClO4−]+): calcd for C21H17ClN3O4+, 410.0902; found, 410.0901. 6-(2-Hydroxy-5-methylbenzoyl)-1-(4-methoxybenzyl)-8-nitro-2,3dihydro-1H-imi-dazo[1,2-a]pyridin-4-ium Perchlorate (3dh). Yellow solid, mp 207−208 °C. Rf = 0.42 (dichloromethane/ethanol 40:1). IR (KBr, νmax, cm−1): 3072, 1659, 1302, 1281, 1251, 1098, 625. 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 9.16 (s, 1H, ArH), 8.74 (d, J = 1.5 Hz, 1H, ArH), 7.31−7.35 (m, 3H, ArH), 7.24 (d, J = 1.0 Hz, 1H,

ArH), 6.93−6.95 (m, 3H, ArH), 4.80 (t, J = 9.8 Hz, 2H, CH2), 4.68 (s, 2H, CH2), 4.13 (t, J = 10.0 Hz, 2H, CH2), 3.75 (s, 3H, CH3), 2.25 (s, 3H, CH3). 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 189.4, 159.6, 154.7, 148.4, 147.5, 142.5, 135.7, 132.3, 130.9, 129.7, 129.1, 125.1, 123.4, 122.5, 117.5, 114.7, 55.6, 53.2, 52.0, 50.8, 20.3. HRMS (ESI-TOF, [M − ClO4−]+): calcd for C23H22N3O5+, 420.1554; found, 420.1554. 1-(4-Chlorobenzyl)-6-(5-fluoro-2-hydroxybenzoyl)-8-nitro-2,3-dihydro-1H-imidazo[1,2-a]pyridin-4-ium Chloride. (3be′). Yellow solid, mp 230−231 °C. Rf = 0.40 (dichloromethane/ethanol 40:1). IR (KBr, νmax, cm−1): 3437, 1649, 1556, 1428, 1318, 1230, 1161, 662. 1H NMR (600 MHz, DMSO-d6 + HCl) (δ, ppm): 9.23 (s, 1H, ArH), 8.77 (d, J = 1.6 Hz, 1H, ArH), 7.48 (d, J = 8.6 Hz, 2H, ArH), 7.45 (d, J = 8.6 Hz, 2H, ArH), 7.35 (m, 1H, ArH), 7.18−7.24 (m, 2H, ArH), 4.86 (t, J = 9.9 Hz, 2H, CH2), 4.78 (s, 2H, CH2), 4.18 (t, J = 9.9 Hz, 2H, CH2). 13C NMR (150 MHz, DMSO-d6 + HCl) (δ, ppm): 188.1, 155.7 (d, 1JC−F = 235.5 Hz), 153.1, 149.0, 147.7, 142.3, 133.1, 132.9, 132.4, 129.9, 129.1, 124.5 (d, 3JC−F = 6.0 Hz), 122.3, 121.3 (d, 2JC−F = 22.5 Hz), 119.3 (d, 3JC−F = 7.5 Hz), 116.3 (d, 2JC−F = 24.0 Hz), 53.3, 52.3, 51.0. HRMS (ESI-TOF, [M − Cl−]+): calcd for C21H16ClFN3O4+, 428.0808; found, 428.0807.

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RESULTS AND DISCUSSION Here, we established a one-pot two step protocol to synthesize a series of bicyclic imidazopyridinium derivatives. For assessment of the optimal reaction conditions for the synthesis of pyridinium 3aa, the reaction of chromone-3-carboxaldehyde (1a) with (E)1-(4-nitrobenzyl)-2-(nitromethylene)-imidazolidine (2a) was chosen as the model reaction. First, the reaction of 1a with 2a was carried out without catalysts. We investigated the effects of different solvents including EtOH, DMF, CH3CN, 1,4-dioxane, THF, and water at different temperatures (Table 1). The results demonstrate that the reaction proceeded in an aprotic solvent (CH3CN, 1,4-dioxane, or THF) or protic solvent (EtOH, MeOH or water) in 20−120 min. The polarity of the solvent (CH3CN, DMF, and 1,4-dioxane) affected the precipitation of the target products. The products partially dissolved in these solvents, resulting in low yields (Table 1, entries 4−6). Using water as the solvent, the reaction could not proceed completely since the raw materials were not effectively dissolved in water, so we obtained the level product in a lower yield. Among all the solvents, ethanol provided the best yield because its polar nature allowed for the dissolution of the raw materials. Ethanol increased precipitation of the product due to its low surface tension. Next, to study the effect of temperature 1901

DOI: 10.1021/acssuschemeng.6b02622 ACS Sustainable Chem. Eng. 2017, 5, 1899−1905

Research Article

ACS Sustainable Chemistry & Engineering Table 2. One-Pot Protocol for the Regioselective Synthesis of Compound 3a

entry

1 (R)

2 (Ar)

HX

3

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

1a (H) 1a (H) 1a (H) 1a (H) 1a (H) 1a (H) 1a (H) 1a (H) 1a (H) 1a (H) 1a (H) 1a (H) 1b (F) 1b (F) 1b (F) 1b (F) 1b (F) 1b (F) 1b (F) 1b (F) 1b (F) 1b (F) 1b (F) 1c (Cl) 1c (Cl) 1c (Cl) 1c (Cl) 1c (Cl) 1c (Cl) 1c (Cl) 1c (Cl) 1c (Cl) 1d (Me) 1d (Me) 1d (Me) 1b (F)

2a (4-NO2C6H4) 2b (4-CF3C6H4) 2c (4-CNC6H4) 2d (4-FC6H4) 2e (4-ClC6H4) 2f (C6H5) 2g (4-MeC6H4) 2h (4-MeOC6H4) 2i (3-FC6H4) 2j (3,5-difluorophenyl) 2k (6-chloropyridin-3-yl) 2l (2-chlorothiazol-5-yl) 2b (4-CF3C6H4) 2c (4-CNC6H4) 2d (4-FC6H4) 2e (4-ClC6H4) 2f (C6H5) 2g (4-MeC6H4) 2h (4-MeOC6H4) 2i (3-FC6H4) 2j (3,5-difluorophenyl) 2k (6-chloropyridin-3-yl) 2l (2-chlorothiazol-5-yl) 2b (4-CF3C6H4) 2d (4-FC6H4) 2f (C6H5) 2g (4-MeC6H4) 2h (4-MeOC6H4) 2i (3-FC6H4) 2j (3,5-difluorophenyl) 2k (6-chloropyridin-3-yl) 2l (2-chlorothiazol-5-yl) 2c (4-CNC6H4) 2h (4-MeOC6H4) 2k (6-chloropyridin-3-yl) 2e (4-ClC6H4)

HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HClO4 HCl

3aa 3ab 3ac 3ad 3ae 3af 3ag 3ah 3ai 3aj 3ak 3al 3bb 3bc 3bd 3be 3bf 3bg 3bh 3bi 3bj 3bk 3bl 3cb 3 cd 3cf 3cg 3ch 3ci 3cj 3ck 3cl 3dc 3dh 3dk 3be′

94 96 90 95 96 94 97 96 90 93 94 93 94 92 93 95 96 96 95 93 98 96 94 92 94 94 97 95 97 98 93 92 97 97 96 94

a All reactions were run under the following conditions: 1 (1.1 mmol) and 2 (1.0 mmol) were refluxed in the solvent EtOH (15 mL) for 20 min, and when the mixture cooled at room temperature, HClO4 or HCl was added to keep the pH of the solution at 2−4 and stirred for 10 min. bIsolated yield based on NBNKAs 2.

With the optimized conditions in hand, we explored the scope and limitation of the reaction involving various chromone-3carboxaldehydes (1a−d) with NBNKAs (2a−l) (Table 2, entries 1−36). Although the reaction was completely finished within 20 min in all cases, the different substituent groups (R = F, Cl, H, Me) at the C6 position of the chromone-3-carboxaldehyde 1 usually had a slight influence on the reaction rate. An electronwithdrawing group on chromone-3-carboxaldehyde 1 (F or Cl) accelerated the reaction by increasing the electrophilicity of the formyl group at the C3 position (Scheme 1). In cases where the reaction was complete, there were no great discrepancies in the reaction yields for different substituent groups (Table 2). After the reaction was complete, the mixture was filtered to obtain pure product 3.

on the reaction, room temperature and reflux were tested (Table 1, entries 1 vs 2). It was found that reflux temperature was necessary. Additionally, adding the acid was very important to the yield of the reaction. We found that the desirable product 3aa was not obtained when the acid was added in the initial stage of the reaction. The best time to add the acid was after the precipitate was formed, which provided an excellent yield (Table 1, entry 1). The pH value also influenced the yield, as the reaction proceeded smoothly only when pH = 2−4. Consequently, the optimal reaction conditions for the preparation of 3aa was refluxing the mixture of 1a and 2a in EtOH for about 20 min, then cooling the mixture at room temperature, and adding HClO4 or HCl to maintain the pH of solution at 2−4. 1902

DOI: 10.1021/acssuschemeng.6b02622 ACS Sustainable Chem. Eng. 2017, 5, 1899−1905

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ACS Sustainable Chemistry & Engineering

of compounds 3 as well as further exploring the capacity of compounds 3 as an ionic liquid.

The chemical structures of bicyclic pyridinium derivatives 3 were fully characterized by IR, 1H NMR, 13C NMR, and HRMS spectroscopy. To further verify the structure of the target products, 3bk was selected as a representative compound and was confirmed by X-ray diffraction analysis, as shown in Figure 2 (CCDC1512000).

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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/acssuschemeng.6b02622. Spectroscopic and analytical data as well asthe original copy of 1H and 13C NMR spectra of all new compounds (PDF) X-ray crystallographic data (CIF file) of compound 3bk (CCDC 1512000) (CIF)

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Figure 2. ORTEP diagram of 3bk; ellipsoids are drawn at the 30% probability level.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Phone and fax: +86 87165031633. *E-mail: [email protected]. ORCID

A proposed mechanism for the synthesis of bicyclic pyridinium derivatives 3 by the reaction of chromone-3-carboxaldehyde 1 with NBNKAs 2 is illustrated in Scheme 2. NBNKAs 2, with a strong electron-withdrawing nitro group at the α-position and two electron-donating diamino groups on the diaza-heterocycle of NBNKAs,72,73 can serve as a nucleophilic component to react with the electrophilic formyl group of chromone-3-carboxaldehyde 1. First, the carbonyl group of the chromone-3carboxaldehyde 1 and the diamino group of NBNKAs 2 can form intermolecular hydrogen bonding, which enhances the electrophilicity of the formyl group of 1. Int1 is formed via an aza-ene reaction accompanying the formone C−C bond. Thereafter, intramolecular aza-Michael addition of Int1 with the elimination of a water molecule or direct intramolecular allylic substitution gives Int2. Target product 3 is generated by opening the pyran ring of Int2 by perchloric acid hydrolysis, during which the lone pair electrons on the nitrogen atom migrate to form a quaternary ammonium.

Jun Lin: 0000-0002-2087-6013 Author Contributions †

L.C. and R.H. contributed equally to this paper.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Program for Changjiang Scholars and Innovative Research Team in University (IRT13095), the National Natural Science Foundation of China (U1202221, 21362042, 21262042, 21662042, 81160384, and 21162037), the Reserve Talent Foundation of Yunnan Province for Middle-Aged and Young Academic and Technical Leaders (2012HB001), Excellent Young Talents, Yunnan University (XT412003), Donglu Scholar of Yunnan University, and High-Level Talents Introduction Plan of Yunnan Province (C6143001).

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CONCLUSIONS To summarize, we report a new reaction for the efficient synthesis of two libraries of highly functionalized bicyclic imidazopyridinium derivatives via cyclization of chromone-3carboxaldehyde 1 and NBNKAs 2 in ethanol. This is a concise, rapid, and environmentally friendly approach to prepare imidazopyridinium derivatives without further post-treatment. The reaction has attractive features, including facile and mild conditions, atom economy, and operational simplicity. Moreover, this series of bicyclic imidazopyridiniums may provide potential biological activities for medical treatment. Our further investigations will aim at assessing the in vitro biological activities

REFERENCES

(1) Hunt, A. J.; Sin, E. H. K.; Marriott, R.; Clark, J. H. Generation, capture, and utilization of industrial carbon dioxide. ChemSusChem 2010, 3, 306−322. (2) Agana, B. A.; Reeve, D.; Orbell, J. D. An approach to industrial water conservation–a case study involving two large manufacturing companies based in Australia. J. Environ. Manage. 2013, 114, 445−460. (3) Singh, J.; Laurenti, R.; Sinha, R.; Frostell, B. Progress and challenges to the global waste management system. Waste Manage. Res. 2014, 32, 800−812. (4) Marr, P. C.; Marr, A. C. Ionic liquid gel materials: applications in green and sustainable chemistry. Green Chem. 2016, 18, 105−128.

Scheme 2. Mechanism Hypotheses for the Synthesis of Target Compounds 3

1903

DOI: 10.1021/acssuschemeng.6b02622 ACS Sustainable Chem. Eng. 2017, 5, 1899−1905

Research Article

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