Brønsted acid-catalyzed metal- and solvent-free quinoline synthesis from N-alkyl anilines and alkynes or alkenes

Abstract

Brønsted acid-catalyzed cyclization reactions of N-alkyl anilines with alkynes or alkenes in the presence of oxygen gas as an oxidant under metal- and solvent-free conditions are described. Various quinoline derivatives are obtained in satisfactory to excellent yields. Different groups, such as methyl, fluoro, chloro, bromo, methoxy, and ester linked on benzene rings, are tolerated under optimized reaction conditions.

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Introduction

Quinoline motifs have attracted considerable interest due to their potent applications¹ in photoelectric materials² and pharmaceuticals,³ including antimalarial, antibacterial, antileishmanial, anti-inflammatory, and insecticidal agents.⁴ Many methods have been established for the conversion of anilines to various substituted quinolines in the presence of different reaction partners since the late 1800s. Various classical name reactions are identified for quinoline synthesis; these reactions include Skraup, Doebner–von Miller, Combes, Conrad–Limpach, Povarov, Friedländer, and Pfitzinger reactions (Scheme 1a).⁵ These methods either use adverse conditions, such as high temperature of approximately 200 °C, or hazardous reagents in stoichiometric amounts, which adversely affect the environment-friendly chemistry and atom economy. Moreover, some methods rely on reagents for quinoline synthesis that needs additional steps.

Scheme 1 Various approaches for the synthesis of quinolines.

Recently, transition metal-catalyzed coupling reactions have been used as potent tools for the synthesis of heterocyclic compounds, especially quinolines.⁶ Fe, Cu, In, Bi, Pd, and Ag salts have been used as catalysts for quinoline synthesis. Furthermore, a transition-metal-catalyzed quinoline synthesis uses N-alkyl anilines and arylacetylenes or arylethylenes through direct cross-dehydrogenative coupling (CDC) of a C–H bond to construct a new C–C bond (Scheme 1b).⁷ Given its high atom economy and environment-friendly nature, the CDC reaction has frequently been used to construct quinoline motifs. Liu⁸ and Mancheño⁹ groups independently reported the iron-catalyzed synthesis of quinolines using either N-benzylanilines or N-aryl glycine esters and arylacetylenes or arylethylenes as reaction partners in the presence of di-tertiary-butyl peroxide or TEMPO oxoammonium salt as an oxidant in a stoichiometric amount through the direct CDC method. Liu and coworkers recently reported about the copper-catalyzed synthesis of quinolines via the CDC reaction of N-aryl glycine esters with olefins in the presence of either K₂S₂O₈ (in stoichiometric amount) or N-hydroxyphthalimide combined with O₂ as oxidants.¹⁰ Jia and Wang revealed that the CDC reaction of N-aryl glycine esters with olefins or arylacetylenes for the synthesis of quinolines can be promoted in the presence of catalytic InCl₃ and tris(4-bromophenyl)ammonium hexachloroantimonate (TBPA˙⁺) using O₂ as the terminal oxidant.¹¹ Quinoline synthesis via transition-metal-catalyzed CDC reaction commonly requires the use of costly inorganic or organic oxidants. Notably, Jia and coworkers recently succeeded on the metal-free CDC reaction of N-benzylanilines with arylethylenes for quinoline synthesis in the presence of catalytic radical cation salt, namely, TBPA˙⁺ using O₂ as the oxidant.¹²

Although these existing methods can provide easy access to quinoline derivatives, the development of remarkably efficient, environment-friendly, and economic organic synthetic process is still desirable. In the course of our research on the development of efficient methods for heterocyclic synthesis,¹³ we found that quinolines can readily be obtained from the Brønsted acid-catalyzed metal- and solvent-free CDC reaction of N-alkyl anilines with arylacetylenes or arylethylenes using O₂ as the oxidant (Scheme 1c). The results are reported in this paper.

Results and discussion

The cyclization of N-benzyl aniline (1a) with phenylacetylene (2a) was selected as a model reaction to optimize the reaction conditions. The results are shown in Table 1. Brønsted acid catalysts, including trifluoroacetic acid (TFA), p-toluene sulfonic acid (PTSA), methanesulfonic acid, benzoic acid (BzOH), sulphuric acid (H₂SO₄) and trifluoromethanesulfonic acid (TfOH), were initially screened in 1,2-dichloroethane (DCE) in air at 120 °C for 15 h. A relatively high yield (57%) of quinoline 3a was obtained when TfOH was used as the catalyst (entry 6 vs. entries 1–5). The solvent was subsequently screened, but the 3a yield could not be improved (entry 6 vs. entries 7–10).

Table 1 Optimization of reaction conditions^a

Entry	Acid cat.	Solvent	O2	Time (h)	Yield^b (%)
a Reaction conditions: N-Benzyl aniline (1a, 0.2 mmol, 36.7 mg), phenylacetylene (2a, 1.0 mmol, 102.1 mg), Brønsted acid (15 mol%), and solvent (2.0 mL), 120 °C. b Isolated yield. c No reaction; the starting materials were recovered. d The reaction occurred at 110 °C. e The reaction was performed in the presence of 10 mol% TfOH.
1	TFA	DCE	O2 in air	15	48
2	PTSA	DCE	O2 in air	15	45
3	CH3SO3H	DCE	O2 in air	15	40
4	BzOH	DCE	O2 in air	15	NR^c
5	H2SO4	DCE	O2 in air	15	Trace
6	TfOH	DCE	O2 in air	15	57
7	TfOH	Toluene	O2 in air	15	43
8	TfOH	1,4-Dioxane	O2 in air	15	54
9	TfOH	DMF	O2 in air	15	43
10	TfOH	CH3CN	O2 in air	15	NR^c
11	TfOH	DCE	O2 balloon	15	62
12	TfOH	None	O2 balloon	15	77
13	TfOH	None	O2 balloon	24	83
14	TfOH	None	O2 balloon	24	76^d
15	TfOH	None	O2 balloon	24	71^e
16	TfOH	None	N2	24	NR^c
17	none	None	O2 balloon	24	NR^c

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Additionally, an increased 3a yield (62%) was observed when the model reaction was performed under a pure oxygen atmosphere (O₂ balloon) in DCE for 15 h (entry 11 vs. entry 6). The further increased yield was observed under solvent-free conditions (entry 12, 77%). The highest 3a yield was finally obtained when the model reaction was carried out for a prolonged time (entry 13, 24 h, 83%). The 3a yield decreased with the reduced reaction temperature and acid catalyst loading (entries 14 and 15). No reaction was observed in the absence of oxygen gas or an acid catalyst (entries 16 and 17). Therefore, we performed the subsequent reactions of the N-alkyl anilines with arylacetylenes or arylethylenes in the presence of TfOH as a catalyst at 120 °C under solvent-free conditions for 24 h. During optimization, starting materials were recovered along with the product in case of low yield (Table 1).

On the basis of the optimized reaction conditions, we explored the scope and limitation of this type of cyclization reaction. The results are summarized in Scheme 2. Initially, alkyne 2a was used as a reaction partner to investigate the scope of N-alkyl anilines. As described in Table 1, the desired product 3a was obtained in 83% yield. The reactions of N-(4-fluorobenzyl)-2-methylaniline (1b) and N-benzyl-4-methylaniline (1c) proceeded well to produce the corresponding quinoline products 3b and 3c in good yields (84% and 81%, respectively). Good to excellent yields were obtained in the reactions of N-benzyl-4-methylanilines 1d–1k bearing a substituent (F, Br, Me, NO₂, or Cl) on the ortho-, meta-, or para-position of the benzyl group (1d–1k, 80%–90%). The reactions of N-(3,4-dichlorobenzyl)-4-methylaniline (1l), 4-methyl-N-(naphthalen-1-ylmethyl)aniline (1m), N-((5-bromothiophen-2-yl)methyl)-4-methylaniline (1n), and ethyl 2-(p-tolylamino)acetate (1o) also proceeded well and produced quinoline products 3l–3o in 78%–92% yields. Moreover, the reaction of N-benzylanilines 1p–1r having substituents (Cl, Br, and MeO) at the para-position of the aniline ring also produced the corresponding quinoline products 3p–3r in 81%–85% yields. Afterward, the reactions of N-benzyl-4-methylaniline (1c) with various arylacetylenes 2b–2k were examined to explore the scope of alkyne substrates. Quinolines 3s–3β were obtained in 68%–86% yields. These results indicated that different groups, such as methyl, fluoro, chloro, bromo, methoxy, nitro, and ester linked on benzene rings, were tolerated under the optimized reaction conditions. The notably maintained Br and Cl atoms in the structures of products should make the products considerably useful in organic transformation.

Scheme 2 Synthesis of quinolines from N-alkyl anilines and alkynes. Reaction conditions: N-Alkyl aniline (1, 0.2 mmol), alkyne (2, 1.0 mmol), and TfOH (2.7 μL, 0.03 mmol, 15 mol%) at 120 °C for 24 h under an O₂ atmosphere. All yields are of isolated materials.

We found that arylethylenes, instead of arylacetylenes, can be used for quinoline synthesis under the optimized reaction conditions. The results are summarized in Scheme 3. Similar good results were obtained, as shown in Scheme 2. Quinoline products 3a–3y and 3α–3δ were obtained in satisfactory to good yields (61%–89%).

Scheme 3 Synthesis of quinolines from N-alkyl anilines and alkenes. Reaction conditions: N-Substituted arylamine (1, 0.2 mmol), alkene (4, 1.0 mmol), and TfOH (2.7 μL, 0.03 mmol, 15 mol%) at 120 °C for 24 h under an O₂ atmosphere. All yields are of isolated materials.

Control experiments were conducted to gain insights into the mechanism of this type of cyclization reaction (Scheme 4). An imine-N-oxide 5 (59%) was obtained when the N-benzyl aniline substrate 1a was treated solely under the optimized reaction conditions (eqn (1)). Subsequently, imine-N-oxide 5 was used as a starting material to react with phenylacetylene under the standard conditions; 87% of quinoline 3a was obtained (eqn (2)). The quinoline 3a was also obtained in good yield (81%) when the imine-N-oxide 5 was treated with phenylacetylene under an N₂ atmosphere (eqn (3)). These results suggested that the current cyclization reaction might involve an imine-N-oxide intermediate.

Scheme 4 Control experiments.

On the basis of our experimental outcomes and previous reports,^8,14 a plausible catalytic cycle is proposed to account for the present Brønsted acid-catalyzed cyclization reaction (Scheme 5). N-Benzylaniline substrate 1a was oxidized in the presence of O₂ and an acid to produce imine-N-oxide 5. The imine-N-oxide 5 subsequently underwent the Diels–Alder-type cyclization reaction in the presence of phenylacetylene or styrene as a dienophile under heating conditions to generate an imine-N-oxide intermediate A. The intermediate A abstracted a proton from TfOH to form intermediate B, which underwent rearomatization reaction to produce intermediate C. Protonation of N-OH in intermediate C occurred to generate intermediate D. Dehydration and aromatization of intermediate D finally occurred to yield quinoline product 3a (generated from phenylacetylene) or an intermediate E (generated from styrene) and regenerated acid catalyst TfOH. The intermediate E subsequently underwent dehydrogenation reaction in the presence of O₂ gas under heating conditions to generate the target product 3a.

Scheme 5 Proposed mechanism.

Conclusions

A convenient and efficient method for quinoline synthesis was developed using simple and readily available N-alkyl anilines and arylacetylenes or arylethylenes as the starting materials. The Brønsted acid-catalyzed metal- and solvent-free cyclization proceeded well under an O₂ atmosphere to furnish quinolines in satisfactory to excellent yields. The widespread availability of the starting materials, cheap and environment-friendly oxidants, and experimental simplicity make the present methodology considerably useful in organic synthesis.

Experimental

General information

The reactions were performed in clean, oven-dried reactors fitted with air-tight stoppers. All the chemicals were used without further purification. The solvents were used after drying according to the given procedure. ¹H and ¹³C NMR spectra were obtained with a Bruker Avance II-400 spectrometer (400 MHz for 1H, 100 MHz for ¹³C) or a Varian Inova-500 spectrometer (500 MHz for 1H, 125 MHz for ¹³C); CDCl₃ and TMS were used as the solvent and internal standard, respectively. The chemical shifts are reported in ppm downfield (δ) from TMS and the coupling constants J are given in Hz. The peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. High-resolution mass spectra were recorded on either a Q-TOF mass spectrometer or a GC-TOF mass spectrometer. TLC was used with SiO₂ (silica gel 60 F254, Merck) as a stationary phase. Spots were viewed under UV light. Flash column chromatography was performed with SiO₂ (80 mesh) as a stationary phase.

General procedure for the synthesis of quinolines 3

N-Substituted arylamines 1a–1r (0.20 mmol), phenylacetylene 2a (110 μL, 1 mmol, 5 equiv.), or styrenes (115 μL, 1 mmol, 5 equiv.) were added to a clean, oven-dried reactor and stirred for 1 min. Trifluoromethanesulfonic acid (2.7 μL, 0.03 mmol, 15 mol%) was then added. Oxygen was purged directly from the cylinder such that the environment was completely saturated with it for 24 h at 120 °C. Afterward, the reaction mixture was purified by flash column chromatography on silica gel (eluent: petroleum ether/DCM = 8 : 2) to yield quinoline 3.

Procedure for synthesis of imine-oxide 5

1a was added into a 100 mL oven-dried round bottom flask (366.4 mg, 2.0 mmol). Trifluoromethanesulfonic acid (27.0 μL, 0.3 mmol) was also added to the above flask after heating, until 1a was melted. Oxygen was purged directly from the cylinder at 120 °C for 24 h. The acid catalyst and water generated were evaporated on a rotary evaporator. The crude mixture was dissolved in a diethyl ether : DCM mixture (9.5 : 0.5), washed two times with K₂CO₃ solution and subsequently with distilled water, and dried over anhydrous Na₂SO₄. The solvent was evaporated, which resulted in a yellow feathery solid. This solid was washed with ice-cold diethyl ether, which yielded white crystals of the title compound.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (No. 21372035, 21573032, and 21602026) for their financial support. This work was also supported by the China Postdoctoral Science Foundation (No. 2016 M590226).

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 1448399. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7gc03175k

‡ These authors contributed equally to this work.

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