Brønsted Acidic Ionic Liquid-Promoted Amidation of Quinoline N

Research Article Cite This: ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX

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Brønsted Acidic Ionic Liquid-Promoted Amidation of Quinoline N‑Oxides with Nitriles Long-Yong Xie,† Sha Peng,† Ling-Hui Lu,‡ Jue Hu,† Wen-Hu Bao,† Fei Zeng,† Zilong Tang,§ Xinhua Xu,‡ and Wei-Min He*,†,‡ †

Hunan Provincial Engineering Research Center for Ginkgo Biloba, Hunan University of Science and Engineering, Yongzhou 425100, China ‡ State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, China § Key Laboratory of Theoretical Organic Chemistry and Functional Molecule of Ministry of Education, Hunan University of Science and Technology, Xiangtan 411201, China S Supporting Information *

ABSTRACT: An economic and eco-friendly straightforward synthesis of highly diversified N-acylated 2-aminoquinolines is successfully achieved via Brønsted acidic ionic liquid-promoted amidation of quinoline N-oxides with nitriles. The advantage of this present process is highlighted by its easily accessible starting materials, excellent functional group tolerance, 100% atom economy, operational simplicity, and clean reaction profile.

KEYWORDS: Ionic liquid, Quinoline N-oxide, Nitrile, Amidation reaction, Atom economy

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Scheme 1. Synthesis of N-Acylated 2-Aminoquinolines

INTRODUCTION Organic compounds containing N-acylamide(s) are versatile components of pharmaceuticals, agrochemicals, and organic functional materials.1,2 Among the aromatic compounds with amide linkages, N-acylated 2-aminoquinolines are very common structural motifs and are found in a number of biologically active molecules.3−7 Therefore, considerable efforts have been devoted in recent years to their preparation. The traditional synthetic strategies for N-acylated 2-aminoquinolines are based on acylation of 2-aminoquinolines8 or coupling of amides with 2-haloquinolines.9 However, the limited scope of 2-amino-/haloquinolines, low atom economy, and harsh reaction conditions often suppress the application of these methods. In contrast, the direct preparation of N-acylated 2aminoquinolines from N-activated quinolines via C−H bond activation represents an attractive alternative. In 1994, Kiselyov and Strekowski reported one example of sequential Nfluorination and amidation of quinoline10,11 through Nfluoroquinolinium intermediate in acetonitrile at ultralow temperature by using fluorine gas (F2) as a fluorinating reagent (Scheme 1a).12 However, the high toxicity, corrosivity, and explosivity of F2 severely restrict its application. In 2005, Kiselyov employed the N-fluoroquinolinium as reaction substrate to construct 2-amidoquinoline, but only one example (N-(quinolin-2-yl)acetamide) was presented in low yield (Scheme 1b).13 To overcome the above-mentioned disadvantages, N-fluoroquinolinium salts have been replaced with abundant and easily accessible quinoline N-oxides.14−26 In 2006, Couturier’s group first reported the amidation of quinoline N-oxides with carbonyl isocyanate (Scheme 1c), © XXXX American Chemical Society

which was conducted by using stoichiometric amounts of harmful oxalyl chloride in harsh reaction conditions.27 A trifluoroacetic anhydride (Tf2O)-promoted amidation of quinoline N-oxides with secondary amides in the presence of superstoichiometric amounts of 2-fluoropyridine as the base Received: March 26, 2018

A

DOI: 10.1021/acssuschemeng.8b01358 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX

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ACS Sustainable Chemistry & Engineering

1a and 2a (10 equiv) with 1-butanesulfonic acid-3-methylimidazolium tosylate (BAIL-1, 1.1 equiv) as the promoter at 120 °C for 8 h, the desired N-(8-methylquinolin-2-yl)acetamide 3aa was obtained in 95% 1H NMR yield (Table 1, entry 1). Encouraged by this result, various ionic liquids were further investigated. As expected, the nature of the ionic liquid exerted a pivotal role on the reaction efficiency, because related acidic ionic liquid other than BAIL-1 resulted in relatively lower yields (entries 2 and 3), and no reaction was observed when employing neutral ionic liquids (entries 4 and 5). When other Brønsted acids (such as H2SO4, MsOH, and TfOH) were used instead of BAIL-1, markedly inferior results were observed (entries 6−8). No reaction was observed when employing trifluoroacetic acid (TFA) or HOAc as the promoter (entries 9 and 10). To our delight, the desired 3aa was provided in excellent yield by using only 8 equiv of MeCN, which was employed with >200 equiv in the previous reports (entry 11).12,13 Further decreasing the amount of MeCN resulted in a slight lowering of 3aa (entry 12). Elevating the reaction temperature was not beneficial (entry 13), while reducing the temperature from 120 to 100 °C decreased the yield of 3aa (entry 14). It was noted that only a trace amount of 3aa was generated when performing the reaction at 80 °C (entry 15). Taken together, these results suggested that the amidation reaction might have a thermodynamic control of reaction. Decreasing the loading of BAIL-1 to 0.8 equiv leads to a slightly lower yield of 3aa (entry 16). Without BAIL-1 but under otherwise optimized reaction conditions, no reaction occurred (entry 17). After getting the satisfactory reaction conditions (Table 1, entry 11) in hand, the scope of the reaction was examined with respect to both nitriles and quinoline N-oxides (Table 2). Pleasingly, the aliphatic nitriles with various chain lengths and isomeric structures smoothly underwent the amidation, giving the desired products (3aa−3aj). Importantly, a variety of functional groups, such as alkyl (3aa−3ad), methoxyethyl (3ae), phenethyl (3af), chloroethyl (3ag), cinnamyl (3ah), and cycloalkyl (3ai−3aj), were all well-tolerated. The phenyl ring of benzonitrile can be modified by sterically hindered, electronrich or electron-poor substitute groups, delivering the corresponding products in good to excellent yields (3ak− 3at). The heterocyclic aromatic and polycyclic nitriles afforded the corresponding amide with good to excellent yields (3au− 3ax). Next, the scope of this amidation with respect to quinoline N-oxides was investigated. Quinoline N-oxides with a broad range of functional groups are tolerated, including alkyl (3ca−3ga), methoxy (3ha and 3ia), halide (3ja−3oa), and ester (3pa) substituents at different positions of quinolones. No reaction occurred when 2-methylquinoline N-oxide and 3methylquinoline N-oxide were used as the substrates. Benzo[h]quinoline N-oxide (1q) was determined to be a suitable reaction partner for this transformation. However, only a trace amount of amidation products were detected when isoquinoline N-oxide and pyridine N-oxide were utilized as the substrates. Once the scope of this amidation reaction was achieved, it was important to investigate the practical applicability of this green reaction. Conducting the amidation of 8-methylquinoline N-oxide 1a (10 mmol) under standard reaction conditions provided the desired N-(8-methylquinolin-2-yl)acetamide 3aa in 84% yield (Scheme 2a). Because silica gel chromatography purification is inevitably required for traditional amidation of quinolone to remove the promoters, additives, bases, and side

was developed by Medley and Movassaghi in 2009 (Scheme 1d).28 Although these strategies have remarkably expanded the scope of amidation of quinoline N-oxides, from a practical and eco-friendly point of view both protocols are obviously in violation of the first (prevention), second (atom economy), and seventh (use of renewable feedstocks) principles of green chemistry.29 Therefore, it is imperative to develop an economic, practical, and environmentally benign protocol to prepare diversified N-acylated 2-aminoquinolines. On the other hand, Brønsted acid (sulfuric acid, hydrochloric acid, etc.) promoted reaction is among the most important processes both in academic laboratories and chemical industries, but it has the disadvantage of requiring postreaction neutralization, resulting in high cost and environmental issues.30 With its high thermal stability, adjustable acidity, easy recyclability, and reusable properties, the Brønsted acidic ionic liquid (BAIL)-promoted reaction has drawn considerable industrial and academic interest.31−49 These reactions are usually solvent-free, because a mixture composed of BAIL, substrate, and product plays the role of solvent and the BAIL promoter can be easily recycled. However, to our knowledge, there exists no example of BAIL-promoted functionalization of quinoline N-oxides. On the basis of our continued pursuit of utilization of quinoline N-oxides50−53 and sustainable chemistry,54−56 herein we disclose a new strategy to access various N-acylated 2-aminoquinolines via BAIL-promoted amidation of quinoline N-oxides with nitriles (Scheme 1e).

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RESULTS AND DISCUSSION At the start of our investigations, 8-methylquinoline N-oxide (1a) and acetonitrile (2a) were selected as the model substrates to screen the reaction conditions (Table 1). After treatment of Table 1. Optimization of Reaction Conditionsa

entry

equiv of 2a

promoter

conditions

yieldb

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16c 17

10 10 10 10 10 10 10 10 10 10 8 7 8 8 8 8 8

BAIL-1 BAIL-2 BAIL-3 IL-1 [Emim][OTf] H2SO4 MsOH TfOH TFA HOAc BAIL-1 BAIL-1 BAIL-1 BAIL-1 BAIL-1 BAIL-1

120 °C, 8 h 120 °C, 8 h 120 °C, 8 h 120 °C, 8 h 120 °C, 8 h 120 °C, 12 h 120 °C, 8 h 120 °C, 8 h 120 °C, 8 h 120 °C, 8 h 120 oC, 8 h 120 °C, 8 h 130 °C, 8 h 100 °C, 12 h 80 °C, 12 h 120 °C, 12 h 120 °C, 12 h

95% 84% 82% NR NR 68% 71% 60% NR NR 95% 86% 94% 50% 13% 77% NR

a Unless otherwise specified, the reactions were carried out in a pressure tube in the presence of 1a (0.1 mmol), 2a, and promoter (1.1 equiv). bEstimated by 1H NMR using diethyl phthalate as internal reference. cBAIL-1 (0.8 equiv) was used. [Emim][OTf] = 1-ethyl-3methylimidazolium trifluoromethanesulfonate. NR = no reaction.

B

DOI: 10.1021/acssuschemeng.8b01358 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX

Research Article

ACS Sustainable Chemistry & Engineering Table 2. Reaction Scopea,b

a

All reactions were carried out in a pressure tube in the presence of 1 (0.3 mmol), 2 (2.4 mmol), and BAIL-1 (0.33 mmol); isolated yields are reported. bThe amidation reactions of 1b−1q were conducted at 150 °C.

Scheme 2. Gram-Scale Synthesis and One-Pot Transformation

formations were carried out. The extractive crude product could smoothly perform deprotection (1b → 4a) in good yield (Scheme 2b). In addition, 4,7-dichloroquinoline efficiently underwent one-pot oxidation, amidation, and deprotection,

products that might prevent subsequent transformations, this present amidation reaction was eco-friendly and avoided using any additives or bases as well as producing any byproducts. To demonstrate such a special superiority, two classical transC

DOI: 10.1021/acssuschemeng.8b01358 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX

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oxygen atom of quinoline N-oxide 1 attacked the carbon of IM1 to form an intermediate IM-2, which underwent intramolecular cyclization, accomplishing intermediate IM-3. Finally, the heterolytic cleavage of N−O bond of IM-3 generated an intermediate IM-4, which restores the aromaticity via deprotonation, thus furnishing product 3. The overall amidation process involves C−H bond and N−O bond cleavage, new C−N and CO bond formation, and a proton-exchange process between BAIL-1 and quinoline Noxide.

yielding compound 4b, which could then be simply converted into clinical antiallergic active compound 4c (Scheme 2c).57 From the viewpoint of green and sustainable chemistry, the use of promoter would be beneficial with simple separation and reusing. Thus, the recyclability and reusability of BAIL-1 was investigated under the optimized conditions. After the end of each reaction cycle, the product undergoes extraction for the determination of yield by 1H NMR. Only 8-methylquinoline Noxide 1a and acetonitrile 2a were freshly added for the next run. The process could be repeated five times without an obvious influence in the reaction outcomes (Figure 1).

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CONCLUSIONS In this research, a facile and eco-friendly approach for the production of various N-acylated 2-aminoquinolines from quinoline N-oxides with nitriles was developed. Remarkable advantages of this process are as follows: (1) the amidation reaction occurs with 100% atom economy and excellent regioselectivity; (2) this protocol features high functional group compatibility and easily accessible starting materials; (3) both aliphatic and aromatic nitriles, as well as heteroaromatic nitriles, are suitable for this transformation; (4) gram-scale synthesis and one-pot sequential transformations were easily achieved; and (5) the ionic liquid is easily recovered and could be reused for at least five consecutive cycles. We believe that this simple and efficient process to produce N-acylated 2aminoquinolines has the potential for multiple applications, and more reactions synthesizing highly functionalized quinolines may be discovered using quinoline N-oxides as substrate and ionic liquids as the promoter.

Figure 1. Recycle studies. Conditions: 3 mmol of 1a, 24 mmol of MeCN, 3.3 mmol of BAIL-1, 120 °C. To the recycled BAIL-1, only 3 mmol of 1a and 24 mmol of MeCN were added, and the next cycle was carried out under the same reaction conditions.

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To gain some insights into the reaction mechanism, several control experiments were carried out. No reaction occurred between 8-methylquinoline and acetonitrile 2a under the standard conditions, which indicated that the N−O group played a crucial role in this amidation reaction (Scheme 3a). Treatment of 8-methylquinoline N-oxide 1a with benzamide could not produce the desired product, which ruled out the intermediacy of benzamide (Scheme 3b). When 2 equiv of H218O was added to the reaction mixture, no 18O-3aa was detected by MS (Scheme 3c), which suggested that the origin of the oxygen atom of N-acylated 2-aminoquinoline is from quinoline N-oxide. On the basis of the above-mentioned experiment results and previous related work,13,20 a potential mechanism was proposed (Scheme 4). First, the nitrile 2 was protonated by BAIL-1 to produce a cationic intermediate IM-1. Then, the nucleophilic

EXPERIMENTAL SECTION

General Information. Unless otherwise specified, all reagents and solvents were obtained from commercial suppliers and used without further purification. All reagents were weighed and handled in air at room temperature. 1H NMR spectra were recorded at 400 MHz and 13 C NMR spectra were recorded at 100 MHz by using a Bruker Avance 400 spectrometer. Chemical shifts were calibrated using residual undeuterated solvent as an internal reference (1H NMR: CDCl3 7.26 ppm, dimethylsulfoxide (DMSO) 2.50 ppm; 13C NMR: CDCl3 77.0 ppm, DMSO 40.0 ppm). The following abbreviations were used to describe peak splitting patterns when appropriate: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, brs = broad singlet. IR spectra were recorded on a Nicolet iS10 FT-IR spectrometer, and only major peaks were reported in cm−1. Mass spectra were performed on a spectrometer operating on ESI-TOF. General Procedure for the Synthesis of N-Acylated 2Aminoquinolines. In a pressure tube was consecutively placed

Scheme 3. Mechanism Research

D

DOI: 10.1021/acssuschemeng.8b01358 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX

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ACS Sustainable Chemistry & Engineering Scheme 4. Plausible Mechanism

quinoline N-oxide 1 (0.3 mmol), nitrile 2 (2.4 mmol), and BAIL-1 (0.12 g, 0.33 mmol); then the mixture was heated to 120 °C (for products 3ba−3qa, the reaction mixture was heated to 150 °C). The progress of the reaction was monitored by thin-layer chromatography (TLC). The reaction typically took 8−12 h. Upon completion, the reaction was cooled to room temperature; then water (5 mL) was added to the reaction mixture, it was extracted with EtOAc (10 mL × 3), and the organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to obtain pure Nacylated 2-aminoquinolines.

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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.8b01358. 1 H and 13C NMR spectra of compounds 2−4 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected]. ORCID

Wei-Min He: 0000-0002-9481-6697 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (nos. 21302048, 21273068, and 21545010), Scientific Research Hunan Provincial Education Department (no. 15C0464), Science and Technology Innovative Research Team in Higher Educational Institutions of Hunan Province (2012-318), and the Construct Program of the Key Discipline in Hunan Province.

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DOI: 10.1021/acssuschemeng.8b01358 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX