Synthesis of 2-trifluoromethylquinolines via copper-mediated intramolecular oxidative cyclization of N-(2-alkenylaryl) enamines

Abstract

A general and efficient copper-mediated intramolecular oxidative cyclization of N-(2-alkenylaryl) enamines for the synthesis of 2-trifluoromethylquinolines has been developed. The targeted heterocycle is a privileged structure in many natural compounds and drugs with a broad range of biological activities.

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Introduction

Quinolines represent an important class of biologically active natural products which have been widely employed as privileged structures for developing pharmaceutically important molecules.¹ In particular, trifluoromethylated quinolines are particularly attractive because introducing fluorine atoms into an organic substrate usually plays a pivotal role in its physical, chemical, and biological properties.² For instance, mefloquine (Fig. 1), a 2-trifluoromethylquinoline-containing skeleton, is a well-known antimalarial drug.³ Compound A (Fig. 1) has very good antibacterial and antituberculosis activities.⁴ Compound B (Fig. 1) was reported as an intermittent preventative treatment (IPT) against plasmodium falciparum.⁵ Due to the importance of these heterocycles, efficient synthetic methods to 2-trifluoromethylated quinolines have already emerged.⁶ Uneyama and co-workers reported a route to 2-trifluoromethylated quinolines via Rh(I)-catalyzed coupling cyclization of N-aryl trifluoroacetimidoyl chlorides with alkynes (Scheme 1, eqn (1)).^6d Adapa and co-workers also reported the Friedlander synthesis of functionalized quinolines catalyzed by neodymium(III) nitrate hexahydrate (Scheme 1, eqn (2)).^6f Wu and Gong described a method to 3,4-disubstituted 2-trifluoromethylquinolines by a palladium-catalyzed tandem Sonogashira-alkyne carbocyclization of β-trifluoromethyl β-enaminoketones with arynes (Scheme 1, eqn (3)).^6k Recently, we also reported the synthesis of 2-trifloromethyl-quinoline derivatives via palladium-catalyzed intermolecular oxidative cyclization of N-arylenamines or N-(ortho-iodo)aryl enamines and isocyanides (Scheme 1, eqn (4)).^6n,o However, efficient synthetic methods for securing 2-trifluoromethylated quinolines remains of vital importance because there are still some shortcomings, such as harsh reaction conditions and the use of expensive catalysts. Therefore, the development of a new practical process for the synthesis of 2-trifluoromethylated quinolines under mild conditions is desirable.

Fig. 1 Representative examples of 4-alkyl-2-trifluoromethylquinoline.

Scheme 1 Synthesis of 2-trifluoromethylquinolines.

Recently, copper-catalyzed aerobic oxidative C–H functionalization has been widely used in organic synthesis because of the low-cost and low toxicity of copper catalysts and good functional group tolerance in the substrates.⁷ Many N-heterocyclic compounds have been efficiently synthesized through this method. For example, Ge and co-workers recently developed the copper-catalyzed aerobic intramolecular dehydrogenative cyclization reaction of N,N-disubstituted hydrazones through sequential C_sp³–H oxidation, cyclization, and aromatization processes leading to the formation of cinnolines^8a and pyrazole dervatives.^8b Fu and coworkers also reported the copper-catalyzed aerobic oxidative C–H functionalization for one-pot synthesis of imidazo/benzoimidazoquinazolinones,^9a acridones,^9b imidazopyridines,^9c and some other N-heterocycles.^9d In our continued efforts toward the development of transition-metal-catalyzed synthetic methods to effectively construct fluorine-containing heterocyales,¹⁰ herein we report a general and efficient copper-catalyzed domino intramolecular oxidative cyclization of N-(2-alkenylaryl) enamines for the synthesis of 2-trifluoromethyl substituted quinolines.

Results and discussion

We initiated the reaction of N-(2-alkenylaryl) enamines 1a catalyzed by CuI in the presence of DBU in air at 60 °C. Surprisingly, three cyclization products 2a, 3a, and 4a were obtained (Table 1, entry 1). Subsequently, a series of other bases (such as, Cs₂CO₃, K₃PO₄, KF, NaHCO₃, piperidine, and Et₃N) were evaluated, wherein Et₃N displayed the best selectivity and high catalytic activity, and the product 2a was isolated in 60% yield as unitary product (Table 1, entry 7). No reaction was observed in the absent of base, which indicated that the cyclization reaction was promoted firstly by base (Table 1, entry 8). Encouraged by these results, other solvents such as DMAc, DMSO, DCE, CH₃CN, and NMP were examined. It is noteworthy that the product of 2a was obtained in 68% yield in DMAc, while 3a was produced as the only product in moderate yields in DCE, CH₃CN, and NMP. The control reactions showed that the cyclization reaction took place smoothly in the absence of copper catalyst in air, N₂, and O₂, affording 4a as major product (Table 1, entries 14–16). The similar results were obtained when oxone or TBHP was used as oxidant (Table 1, entries 17 and 18). When the copper species was changed from CuI to CuCl₂, the yield of 2a was increased to 80%. However, no better results were observed when the transformation was catalyzed by other Lewis acids such as AlCl₃, AgOTf, and FeCl₃ (Table 1, entries 21–23). When 1a was treated with CuCl₂ (10 mol%) in the presence of Et₃N (4.0 equiv.) in DMAc at 60 °C under an O₂ atmosphere, 2a was isolated in 78% yield combining with 7% yield of 3a (Table 1, entry 24). Finally, the yields of 2a decreased obviously when the amount of base or reaction temperature was changed (data not shown in Table 1).

Table 1 Optimization of reaction conditions^a

Entry	Cat.	Base	Solvent	Yield^b (%) (2a/3a/4a)
a Reaction conditions: 1a (0.2 mmol), cat. (10 mol%), base (4.0 equiv.), solvent (2 mL), 60 °C, in air.b Isolated yields based on N-(2-alkenylaryl) enamines 1a, and the ratio of 2a/3a/4a was determined by ^1H NMR.
1	CuI	DBU	DMF	43 (11/68/21)
2	CuI	Cs2CO3	DMF	50 (0/100/0)
3	CuI	K3PO4	DMF	55 (33/67/0)
4	CuI	KF	DMF	70 (29/0/71)
5	CuI	NaHCO3	DMF	60 (33/67/0)
6	CuI	Piperidine	DMF	70 (0/85/15)
7	CuI	Et3N	DMF	60 (100/0/0)
8	CuI	—	DMF	0
9	CuI	Et3N	DMAc	68 (100/0/0)
10	CuI	Et3N	DMSO	55 (9/91/0)
11	CuI	Et3N	DCE	68 (0/100/0)
12	CuI	Et3N	CH3CN	52 (0/100/0)
13	CuI	Et3N	NMP	53 (0/100/0)
14	—	Et3N	DMAc	55 (9/0/91)
15	-(In N2)	Et3N	DMAc	68 (10/0/90)
16	-(In O2)	Et3N	DMAc	66 (7/0/93)
17	Oxone	Et3N	DMAc	59 (8/0/92)
18	TBHP	Et3N	DMAc	63 (9/0/91)
19	Cu(OAc)2	Et3N	DMAc	63 (100/0/0)
20	CuCl2	Et3N	DMAc	80 (100/0/0)
21	AlCl3	Et3N	DMAc	79 (16/0/84)
22	AgOTf	Et3N	DMAc	63 (16/0/84)
23	FeCl3	Et3N	DMAc	50 (32/0/68)
24	CuCl2/O2	Et3N	DMAc	85 (90/10/0)

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With this promising result in hand, we next investigated the substrate scope of this oxidative cyclization under the optimized conditions [CuCl₂ (10 mol%), Et₃N (4.0 equiv.), DMAc, at 60 °C in air] (Table 2). A wide range of N-(2-alkenylaryl)enamines 1 were transformed into the corresponding quinolines 2. tert-Butyl, ethyl, and methyl acrylate-derived substrates 1b–d were successfully converted directly into the quinoline products 2b–d in good yields (Table 2, entries 2–4). The catalyst system could tolerate various useful functional groups, including electron-donating or -withdrawing substituent such as methyl, chlorine, bromine, fluorine, trifluoromethoxy, nitro, and so on, leading to corresponding desired products in good to excellent yields (Table 2, entries 5–13). For example, when substrate 1i with a bromine substituent was employed in the reaction, the targeted product 2i was obtained in 73% yield keeping the C–Br bond intact (Table 2, entry 9). Unfortunately, only complex mixtures were observed when substrate 1h with a methoxy substituent was used, maybe due to its high activity (Table 2, entry 8). To our delight, substrate 1n with acrylonitrile also reacted smoothly under the standard conditions providing the product 2n in 76% yield. Interesting, when substrates containing tri-substituted alkenyl or styryl substituent were carried out under the optimized conditions, the same cyclization product 3a was obtained in moderate to good yields (Table 2, entries 15–18).

Table 2 CuCl₂-catalyzed synthesis of 2-trifluoromethylquinolines

Entry	Substrate 1	Product	Yield^a (%)
a Isolated yields based on N-(2-alkenylaryl)enamines 1.
1			80
2			86
3			77
4			71
5			85
6			81
7			95
8			—
9			73
10			80
11			73
12			74
13			81
14			76
15			72
16			44
17			47
18			56

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As mentioned above, under the conditions of CuI (10 mol%), Et₃N (4.0 equiv.), DCE, at 60 °C in air (Table 1, entry 11), the cyclization of substrate 1a afforded the quinoline product 3a in 68% yield. Tri-substituted butyl acrylate-derived substrates 1s–v with electron-donating or -withdrawing groups were found to be reactive under these conditions, leading to the corresponding products 3b–e in acceptable yields (44–68%) (Table 3, entries 1–4).

Table 3 CuCl₂-catalyzed synthesis of 2-trifluoromethylquinolines

Entry	Substrate 1	Product 3	Yield^a (%)
a Isolated yields based on N-(2-alkenylaryl) enamines 1s–v.
1			68
2			55
3			57
4			44

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In order to elucidate the mechanism of oxidative cyclization to form product 3, some control experiments were implemented. The oxidation of product 4a under air carried out smoothly, affording the product 2a in excellent yield (Scheme 2, eqn (1)). Based on the above mentioned conditions (Table 1, entry 11), 2.0 equiv. radical scavenger, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), was added in the reaction (Scheme 2, eqn (2)). As expected, no desired product 3a was detected, which indicated that this reaction might be involved a radical intermediate. Then, we tried the reactions of 4a under the different conditions (Table 1, entries 20 and 11), and the corresponding products 2a and 3a were obtained in good yields, respectively (Scheme 3, eqn (3)). Such control experiments confirm that compound 4a maybe the key intermediate. On the basis of previous work¹¹ and our control experiments, a plausible mechanism is proposed in Scheme 2. First, 3,4-dihydroquinoline derivatives 4 would be formed via base-promoted cyclization of 1, which underwent copper-catalyzed oxidation using air as oxidant to give 4-alkyl substituted 2-trifluoromethylquinolines 2 or 3 depending on the substrates and reaction conditions. Firstly, radical intermediate A and hydroperoxyl radical (·OOH) are generated from 4 and O₂ catalyzed by copper salt in the presence of Et₃N as base. Subsequently, hydroperoxide B would be produced by the combination of the two radicals (radical A and ·OOH), which underwent decomposition to provide the radical C and hydroxide radical (·OH). Then, radical D and carbonyl compound E¹² would be formed by the single electron transfer of radical C and C–C bond cleavage. Finally, the desired product quinoline 3 is afforded by the deprotonation of radical D.

Scheme 2 Control experiments.

Scheme 3 Proposed catalytic cycle.

Conclusion

In summary, we described the CuCl₂/air-mediated oxidative cyclization of N-(2-alkenylaryl) enamines in the presence of organic base (Et₃N), which provides a novel and efficient route to 2-(trifluoromethyl)quinoline derivatives with good functional group tolerance. Adjusting the reaction conditions, we could selectively synthesize with or without 4-alkyl substituted 2-(trifluoromethyl)quinoline derivatives in moderate to excellent yields.

Experimental section

General procedure for copper-catalyze intramolecular oxidative cyclization of N-(2-alkenylaryl)enamines (1a–r)

To a 25 mL tube containing a magnetic stir bar, was added N-(2-alkenylaryl) enamine 1 (0.2 mmol), CuCl₂ (10 mol%), and DMAc (2 mL). The resulting mixture was stirred at 60 °C in air for overnight (monitored by TLC). After being cooling to room temperature, evaporation of the solvent under reduced pressure followed purification by silica gel chromatography using petroleum ether/ethyl acetate (10 : 1) as eluent to provide the desired products 2 or 3a.

Ethyl 4-(2-butoxy-2-oxoethyl)-2-(trifluoromethyl)quinoline-3-carboxylate (2a). Isolated (R_f = 0.5, EtOAc–petroleum ether = 1 : 10) as a yellow solid (61.3 mg, 80% yield), mp: 62–64 °C. ¹H NMR (400 MHz, CDCl₃) δ 0.77 (t, J = 7.4 Hz, 3H), 1.13–1.22 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H), 1.43–1.50 (m, 2H), 4.02 (t, J = 6.6 Hz, 2H), 4.16 (s, 2H), 4.41 (q, J = 7.2 Hz, 2H), 7.69 (t, J = 7.6 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.5, 13.8, 18.9, 30.4, 35.1, 62.6, 65.5, 121.2 (q, ¹J_C–F = 275.1 Hz), 124.2, 125.2, 127.4, 129.7, 130.8, 131.4, 140.8, 143.7 (q, ²J_C–F = 34.1 Hz), 146.3, 166.1, 168.8; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₁F₃NO₄: 384.1417, found: 384.1411.

Ethyl 4-(2-(tert-butoxy)-2-oxoethyl)-2-(trifluoromethyl)quinoline-3-carboxylate (2b). Isolated (R_f = 0.5, EtOAc–petroleum ether = 1 : 10) as a yellow solid (66.0 mg, 86% yield), mp: 70–72 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.29 (s, 9H), 1.33 (t, J = 7.2 Hz, 3H), 4.05 (s, 2H), 4.39 (q, J = 7.2 Hz, 2H), 7.64 (t, J = 8.0 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9, 27.8, 36.4, 62.5, 82.3, 121.2 (q, ¹J_C–F = 274.6 Hz), 124.3, 125.2, 127.6, 129.6, 130.8, 131.3, 141.3, 143.5 (q, ²J_C–F = 33.8 Hz), 146.4, 166.2, 167.8; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₉H₂₀F₃NNaO₄: 406.1237, found: 406.1275.

Ethyl 4-(2-ethoxy-2-oxoethyl)-2-(trifluoromethyl)quinoline-3-carboxylate (2c). Isolated (R_f = 0.5, EtOAc–petroleum ether = 1 : 10) as a yellow solid (55.2 mg, 77% yield), mp: 62–64 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.21 (t, J = 7.2 Hz, 3H), 1.42 (t, J = 7.2 Hz, 3H), 4.16 (q, J = 7.2 Hz, 2H), 4.23 (s, 2H), 4.49 (q, J = 7.2 Hz, 2H), 7.76 (t, J = 7.6 Hz, 1H), 7.87 (t, J = 7.6 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9, 14.0, 35.2, 61.7, 62.7, 121.2 (q, ¹J_C–F = 275.0 Hz), 124.2, 125.2, 127.5, 129.8, 130.9, 131.4, 140.74, 143.9 (q, ²J_C–F = 34.2 Hz), 146.4, 166.1, 168.7; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₁₆F₃NNaO₄: 378.0924, found: 378.0888.

Ethyl 4-(2-methoxy-2-oxoethyl)-2-(trifluoromethyl)quinoline-3-carboxylate (2d). Isolated (R_f = 0.5, EtOAc–petroleum ether = 1 : 10) as a yellow solid (48.4 mg, 71% yield), mp: 82–84 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.42 (t, J = 7.2 Hz, 3H), 3.70 (s, 3H), 4.24 (s, 2H), 4.48 (q, J = 7.2 Hz, 2H), 7.77 (t, J = 7.6 Hz, 1H), 7.88 (t, J = 7.6 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.8, 34.9, 52.6, 62.7, 121.2 (q, ¹J_C–F = 274.7 Hz), 124.2, 125.3, 127.5, 129.9, 131.0, 131.5, 140.5, 143.9 (q, ²J_C–F = 34.1 Hz), 146.5, 166.1, 169.2; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₁₄F₃NNaO₄: 364.0767, found: 364.0730.

Ethyl 4-(2-butoxy-2-oxoethyl)-6-methyl-2-(trifluoromethyl)quinoline-3-carboxylate (2e). Isolated (R_f = 0.5, EtOAc–petroleum ether = 1 : 10) as a yellow solid (67.5 mg, 85% yield), mp: 74–76 °C; ¹H NMR (400 MHz, CDCl₃) δ 0.85 (t, J = 7.2 Hz, 3H), 1.21–1.30 (m, 2H), 1.41 (t, J = 7.0 Hz, 3H), 1.51–1.58 (m, 2H), 2.59 (s, 3H), 4.10 (t, J = 6.6 Hz, 2H), 4.19 (s, 2H), 4.47 (q, J = 7.2 Hz, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.82 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.5, 13.8, 18.9, 22.2, 30.4, 35.1, 62.6, 65.4, 121.3 (q, ¹J_C–F = 274.3 Hz), 123.0, 125.2, 127.5, 130.5, 133.7, 139.8, 140.3, 142.9 (q, ²J_C–F = 34.1 Hz) 145.0, 166.3, 168.9; HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₄F₃NO₄: 398.1574, found: 398.1577.

Ethyl 4-(2-(tert-butoxy)-2-oxoethyl)-6-methyl-2-(trifluoromethyl)quinoline-3-carboxylate (2f). Isolated (R_f = 0.5, EtOAc–petroleum ether = 1 : 10) as a yellow solid (64.3 mg, 81% yield), mp: 68–70 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.40 (s, 9H), 1.41 (t, J = 7.2 Hz, 3H), 2.60 (s, 3H), 4.11 (s, 3H), 4.02 (s, 2H), 4.48 (q, J = 7.2 Hz, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.83 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9, 22.2, 27.9, 36.4, 62.5, 82.2, 121.3 (q, ¹J_C–F = 273.5 Hz), 123.2, 125.2, 127.6, 130.5, 133.6, 140.1, 140.3, 142.9 (q, ²J_C–F = 34.3 Hz), 145.0, 166.4, 168.0; HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₃F₃NO₄: 398.1574, found: 398.1566.

Ethyl 4-(2-methoxy-2-oxoethyl)-6-methyl-2-(trifluoromethyl)quinoline-3-carboxylate (2g). Isolated (R_f = 0.5, EtOAc–petroleum ether = 1 : 10) as a yellow solid (67.4 mg, 95% yield), mp: 127–129 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.41 (t, J = 7.0 Hz, 3H), 2.60 (s, 3H), 3.70 (s, 3H), 4.20 (s, 2H), 4.41 (q, J = 7.2 Hz, 2H), 7.68 (d, J = 8.2 Hz, 1H), 7.80 (s, 1H), 8.11 (d, J = 8.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.8, 22.2, 34.8, 52.6, 62.6, 121.3 (q, ¹J_C–F = 274.3 Hz), 125.4, 127.5, 130.6, 133.8, 139.6, 140.4, 142.9 (q, ²J_C–F = 34.0 Hz), 145.1, 166.3, 169.3; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₁₆F₃NNaO₄: 378.0924, found: 378.0920.

Ethyl 6-bromo-4-(2-butoxy-2-oxoethyl)-2-(trifluoromethyl)quinoline-3-carboxylate (2i). Isolated (R_f = 0.5, EtOAc–petroleum ether = 1 : 10) as a white solid (67.5 mg, 73% yield), mp: 84–86 °C; ¹H NMR (400 MHz, CDCl₃) δ 0.87 (t, J = 8.0 Hz, 3H), 1.23–1.31 (m, 2H), 1.42 (t, J = 7.2, 3H), 1.53–1.60 (m, 2H), 4.12 (t, J = 6.6 Hz, 2H), 4.17 (s, 2H), 4.48 (q, J = 7.2 Hz, 2H), 7.92 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 8.25 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 12.5, 12.8, 18.0, 29.4, 34.2, 61.8, 64.7, 120.0 (q, ¹J_C–F = 274.2 Hz), 123.5, 125.1, 125.8, 127.7, 131.4, 134.0, 138.9, 143.2 (q, ²J_C–F = 35.1 Hz), 144.0, 166.7, 167.3; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₀BrF₃NO₄: 462.0522, found: 462.0526.

Ethyl 4-(2-butoxy-2-oxoethyl)-6-chloro-2-(trifluoromethyl)quinoline-3-carboxylate (2j). Isolated (R_f = 0.5, EtOAc–petroleum ether = 1 : 10) as a yellow solid (66.7 mg, 80% yield), mp: 86–84 °C; ¹H NMR (400 MHz, CDCl₃) δ 0.78 (t, J = 7.2 Hz, 3H), 1.17–1.23 (m, 2H), 1.33 (t, J = 7.0 Hz, 2H), 1.47–1.50 (m, 2H), 4.04 (t, J = 6.4 Hz, 3H), 4.08 (s, 2H), 4.41 (q, J = 7.0 Hz, 2H), 7.71 (d, J = 8.8 Hz, 1H), 7.99 (s, 1H), 8.09 (d, J = 8.8 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.6, 13.9, 19.0, 30.4, 35.2, 62.9, 65.7, 121.0 (q, ¹J_C–F = 274.2 Hz), 123.4, 126.0, 128.3, 132.4, 132.5, 136.2, 140.0, 144.09 (q, ²J_C–F = 33.4 Hz), 144.8, 165.8, 168.4; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₀ClF₃NO₄: 418.1027, found: 418.1028.

Ethyl 4-(2-butoxy-2-oxoethyl)-6-fluoro-2-(trifluoromethyl)quinoline-3-carboxylate (2k). Isolated (R_f = 0.5, EtOAc–petroleum ether = 1 : 10) as a white solid (58.5 mg, 73% yield), mp: 77–79 °C; ¹H NMR (400 MHz, CDCl₃) δ 0.77 (t, J = 7.4 Hz, 3H), 1.14–1.23 (m, 2H), 1.33 (t, J = 7.2 Hz, 3H), 1.46–1.51 (m, 2H), 4.02 (t, J = 6.8 Hz, 2H), 4.40 (q, J = 7.2 Hz, 2H), 7.53–7.57 (m, 1H), 7.61 (d, J = 7.2 Hz, 1H), 8.16 (dd, J = 5.6, 9.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.4, 13.8, 18.9, 30.4, 35.3, 62.8, 65.6, 108.2 (d, ²J_C–F = 23.0 Hz), 121.1 (q, ¹J_C–F = 274.7 Hz), 121.9 (d, ²J_C–F = 25.8 Hz), 125.9, 128.8 (d, ³J_C–F = 10.1 Hz), 133.7 (d, ³J_C–F = 9.5 Hz), 140.2, 143.3 (q, ²J_C–F = 35.1 Hz), 143.5, 162.5 (d, ¹J_C–F = 252.0 Hz), 165.8, 168.4; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₀F₄NO₄: 402.1323, found: 402.1334.

Ethyl 4-(2-butoxy-2-oxoethyl)-6-(trifluoromethoxy)-2-(trifluoromethyl)quinoline-3-carboxylate (2l). Isolated (R_f = 0.5, EtOAc–petroleum ether = 1 : 10) as a white solid (69.1 mg, 74% yield), mp: 74–76 °C; ¹H NMR (400 MHz, CDCl₃) δ 0.86 (t, J = 7.4 Hz, 3H), 1.21–1.31 (m, 2H), 1.42 (t, J = 8.0 Hz, 3H), 1.52–1.59 (m, 2H), 4.11 (t, J = 8.0 Hz, 2H), 4.19 (s, 2H), 4.49 (q, J = 7.2 Hz, 2H), 7.73 (d, J = 9.2 Hz, 1H), 7.91 (s, 1H), 8.31 (d, J = 9.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.3, 13.7, 18.8, 30.4, 35.3, 62.8, 65.7, 114.7, 120.4 (q, ¹J_C–F = 258.0 Hz), 120.9 (q, ¹J_C–F = 274.7 Hz), 125.2, 126.2, 128.2, 133.3, 140.8, 144.4 (q, ²J_C–F = 34.7 Hz), 144.6, 149.4, 165.6, 168.2; HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₀F₆NO₅: 468.1240, found: 468.1234.

Ethyl 4-(2-butoxy-2-oxoethyl)-6-nitro-2-(trifluoromethyl)quinoline-3-carboxylate (2m). Isolated (R_f = 0.5, EtOAc–petroleum ether = 1 : 10) as a white solid (69.3 mg, 81% yield), mp: 80–82 °C; ¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J = 7.2 Hz, 3H), 1.26–1.33 (m, 2H), 1.44 (t, J = 7.0 Hz, 3H), 1.58–1.63 (m, 2H), 4.14 (t, J = 6.4 Hz, 2H), 4.30 (s, 2H), 4.51 (q, J = 7.2 Hz, 2H), 8.42 (d, J = 8.8 Hz, 1H), 8.63 (d, J = 7.2 Hz, 1H), 9.07 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.5, 13.8, 19.0, 30.4, 35.3, 63.1, 66.0, 120.7 (q, ¹J_C–F = 275.3 Hz), 121.3, 124.7, 126.9, 127.1, 133.0, 143.4, 147.1 (q, ²J_C–F = 35.1 Hz), 147.5, 148.3, 165.1, 168.0; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₀F₃N₂O₆: 429.1268, found: 429.1278.

Ethyl 4-(cyanomethyl)-2-(trifluoromethyl)quinoline-3-carboxylate (2n). Isolated (R_f = 0.5, EtOAc–petroleum ether = 1 : 10) as a yellow solid (46.8 mg, 76% yield), mp: 117–119 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.46 (t, J = 7.2 Hz, 3H), 4.24 (s, 2H), 4.53 (q, J = 7.2 Hz, 2H), 7.90 (t, J = 8.4 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 8.2 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.8, 17.8, 63.4, 115.1, 120.9 (q, ¹J_C–F = 274.4 Hz), 123.2, 125.1, 126.0, 130.8, 131.5, 132.2, 136.2, 144.07 (q, ²J_C–F = 34.6 Hz), 146.5, 165.5; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₁₁F₃N₂NaO₂: 331.0665, found: 331.0666.

Ethyl 4-(1-methoxy-1-oxopropan-2-yl)-2-(trifluoromethyl)quinoline-3-carboxylate (3a). Isolated (R_f = 0.5, EtOAc–petroleum ether = 1 : 10) as a white solid, mp: 64–66 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.43 (t, J = 7.2 Hz, 3H), 4.46 (q, J = 7.2 Hz, 2H), 7.76 (t, J = 7.2 Hz, 1H), 7.91 (t, J = 7.8 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.69 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9, 62.5, 121.1 (q, ¹J_C–F = 274.5 Hz), 124.1, 127.5, 128.2, 129.5, 130.1, 132.3, 140.1, 144.7 (q, ²J_C–F = 34.9 Hz), 146.9, 165.5; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₁F₃NO₄: 270.0736, found: 270.0755.

General procedure for copper-catalyze intramolecular oxidative cyclization of N-(2-alkenylaryl) enamines (1s–v)

To a 25 mL tube containing a magnetic stir bar, was added N-(2-alkenylaryl)enamine 1 (0.2 mmol), CuI (10 mol%), and DCE (2 mL). The resulting mixture was stirred at 60 °C in air for overnight (monitored by TLC). After being cooling to room temperature, evaporation of the solvent under reduced pressure followed purification by silica gel chromatography using petroleum ether/ethyl acetate (10 : 1) as eluent to provide the desired products 3b–e.

Ethyl 6-methyl-2-(trifluoromethyl)quinoline-3-carboxylate (3b). Isolated (R_f = 0.5, EtOAc–petroleum ether = 1 : 10) as a white solid (38.5 mg, 68% yield), mp: 49–50 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.44 (t, J = 6.6 Hz, 3H), 2.59 (s, 3H), 4.47 (q, J = 6.8 Hz, 2H), 7.70 (s, 1H), 7.72 (t, J = 8.4 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.57 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 14.0, 21.8, 62.4, 121.3 (q, ¹J_C–F = 273.9 Hz), 124.0, 126.9, 127.5, 129.7, 134.8, 139.3, 140.1, 143.8 (q, ²J_C–F = 34.5 Hz), 145.5, 165.7; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₁₂F₃NNaO₂: 306.0712; found: 306.0719.

Ethyl 6-fluoro-2-(trifluoromethyl)quinoline-3-carboxylate (3c). Isolated (R_f = 0.5, EtOAc–petroleum ether = 1 : 10) as a white solid (29.8 mg, 52% yield), mp: 78–79 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.44 (t, J = 7.2 Hz, 3H), 4.48 (q, J = 7.2 Hz, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 8.4 Hz, 1H), 8.27 (dd, J = 5.2, 9.2 Hz, 1H), 8.63 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9, 62.7, 111.3 (d, ²J_C–F = 22.1 Hz), 121.0 (q, ¹J_C–F = 273.8 Hz), 122.9 (d, ²J_C–F = 25.9 Hz), 124.9, 128.5 (d, ³J_C–F = 10.7 Hz), 132.9 (d, ³J_C–F = 9.4 Hz), 139.3, 144.0, 144.1 (q, ²J_C–F = 35.9 Hz), 162.1 (d, ¹J_C–F = 252.3 Hz), 165.3; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₉F₄NNaO₂: 310.0462; found: 310.0471.

Ethyl 6-chloro-2-(trifluoromethyl)quinoline-3-carboxylate (3d). Isolated (R_f = 0.5, EtOAc–petroleum ether = 1 : 10) as a white solid (34.5 mg, 57% yield), mp: 81–82 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.45 (t, J = 7.0 Hz, 3H), 4.48 (q, J = 7.2 Hz, 2H), 7.84 (d, J = 9. 2 Hz, 2H), 7.95 (s, 1H), 8.19 (d, J = 9.2 Hz, 1H), 8.60 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9, 62.7, 121.0 (q, ¹J_C–F = 272.9 Hz), 125.0, 126.7, 128.1, 131.7, 133.4, 135.7, 139.0, 144.9 (q, ²J_C–F = 35.2 Hz), 145.2, 165.2; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₉ClF₃NNaO₂: 326.0166; found: 326.0191.

Ethyl 6-(trifluoromethoxy)-2-(trifluoromethyl)quinoline-3-carboxylate (3e). Isolated (R_f = 0.5, EtOAc–petroleum ether = 1 : 10) as a white solid (46.6 mg, 66% yield), mp: 76–77 °C; ¹H NMR (400 MHz, CDCl₃) δ 1.45 (t, J = 7.0 Hz, 3H), 4.49 (q, J = 7.2 Hz, 2H), 7.75 (d, J = 8.8 Hz, 1H), 7.79 (s, 1H), 8.31 (d, J = 9.2 Hz, 1H), 8.70 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9, 62.7, 117.4, 120.4 (q, ¹J_C–F = 258.0 Hz), 120.9 (q, ¹J_C–F = 274.2 Hz), 125.2, 126.3, 127.9, 132.6, 139.8, 145.0, 145.2 (q, ²J_C–F = 35.5 Hz), 149.1, 165.1; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₉F₆NNaO₃: 376.0739, found: 376.0769.

Ethyl 4-(2-butoxy-2-oxoethyl)-2-(trifluoromethyl)-3,4-dihydroquinoline-3-carboxylate (4a). Isolated (R_f = 0.5, EtOAc–petroleum ether = 1 : 10) as a yellow solid, mp: 68–70 °C; ¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J = 7.2 Hz, 3H), 1.23–1.33 (m, 5H), 1.48–1.55 (m, 2H), 2.47 (dd, J = 8.8, 14.4 Hz, 2H), 2.61 (dd, J = 8.8, 14.4 Hz, 2H), 3.98 (t, J = 6.8 Hz, 3H), 4.25 (q, J = 7.2 Hz, 2H), 4.45–4.48 (m, 1H), 6.86 (d, J = 7.6 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 7.14–7.20 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 13.6, 13.9, 19.0, 30.5, 35.8, 41.8, 60.9, 64.4, 102.6, 115.2, 121.9 (q, ¹J_C–F = 274.0 Hz), 122.9, 124.5, 127.7, 128.5, 135.4 (q, ²J_C–F = 33.7 Hz), 135.6, 164.8, 171.2; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₃F₃NO₄: 386.1574, found: 386.1579.

Acknowledgements

Financial Supported from National Natural Science Foundation of China (21262016), China Postdoctoral Science foundation (2013M531556, 2014T70617), and Natural Science Foundation of Jiangxi Province of China (20133ACB20008) is gratefully acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra09741c

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