A simple and efficient copper-catalyzed three-component reaction to synthesize (Z)-1,2-dihydro-2-iminoquinolines

Abstract

A operationally simple synthesis of (Z)-1,2-dihydro-2-iminoquinolines that proceeds under mild conditions is achieved by copper-catalyzed reaction of 1-(2-aminophenyl)ethan-1-ones, sulfonyl azides and terminal ynones. In particular, the reaction goes through a base-free CuAAC/ring-opening process to obtain the Z-configured products due to hydrogen bonding.

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Nitrogen-containing polyheterocycles are present in a wide variety of bioactive natural products¹ and biological molecules that may be good drug candidates.² Specifically, quinoline-based compounds represent a medicinally and pharmaceutically important class of heterocyclic motifs that are found as the core structural skeletons in a variety of potential candidates.³ 2-Aminoquinolines are found to be antagonists for the hormone 1-receptor (MCH1-R),⁴ as targets for JNK phosphorylation,⁵ as potent and selective neuronal nitric oxide synthase inhibitors,⁶ and as new inhibitors of protein kinase CK₂.⁷ Therefore, the development of novel methods for the synthesis of these quinoline derivatives is important in the field of synthetic organic and pharmaceutical chemistry.

In the past few years, utilizing the annulation reactions of Cu,⁸ Pd,⁹ Ni,¹⁰ Ag,¹¹ Ru,¹² and a few other catalysts^13–15 have provided attractive and valuable routes for the construction of 2-aminoquinolines. As an isomer of 2-aminoquinolines, the synthesis of 2-iminoquinoline skeletons has still rarely been investigated. To the best of our knowledge, only two examples of the nickel¹⁶ or copper-catalyzed¹⁷ cascade reaction have been developed, leading to 2-iminoquinolines. However, these two examples have been limited to the use of a base or obtained the E-configured products (Scheme 1a and b).

Scheme 1 Synthesis of 2-iminoquinolines.

Previous studies reported on the copper-catalyzed multicomponent reactions (MCRs) of sulfonyl azides and terminal alkynes with other components that generated N-heterocycles and related compounds (CuAAC/ring-opening reaction),^18,19 and have also been used in the synthesis of 2-aminoquinolines²⁰ and 2-iminoquinolines.¹⁷ However, the reaction was generally carried out under strong basic conditions. This limited the application of some substrates, such as terminal ynones, which would undergo self-condensation under the basic conditions.²¹ Thus, neutral or weak acidic conditions have been developed in our previous study, and the terminal ynones were successfully used in the CuAAC/ring-opening reaction to form highly active intermediate α-acyl-N-sulfonyl ketenimines.²² Herein, we report the base-free copper-catalyzed reaction of 1-(2-aminophenyl)ethan-1-ones, sulfonyl azides and terminal alkynes, leading to Z-configured 2-iminoquinolines (Scheme 1c).

Our investigations began with an examination of the synthesis of the parent and previously unreported system, N-(3-acetyl-4-methylquinolin-2(1H)-ylidene)-4-methylbenzene sulfonamide (4a), from 1-(2-aminophenyl)ethan-1-one (1a), but-3-yn-2-one (2a) and p-tosyl azide (3a). Initial screenings involved using CuI as a catalyst in a range of standard solvents. These screenings revealed that the desired conversion could be achieved in many solvents (Table 1, entries 1–9), with MeCN delivering product 4a in highest yield (96%). The other solvents gave comparable yields, such as DCE, toluene, THF and 1,4-dioxane, while DMSO and DMF gave the lowest yield of 4a at 20% and 46%, respectively. Thus, the optimal solvent was determined to be MeCN. Encouraged by this promising result, a variety of catalysts were screened. Among the copper catalysts used, most Cu-catalysts exhibited high catalytic reactivity in this reaction, whether it was Cu^I-catalysts or Cu^II-catalysts (Table 1, entries 10–14). Other catalysts, such as AgOAc, failed to produce the desired product (Table 1, entries 15). Lastly, the effect of temperature was evaluated. Screening results revealed that a reaction temperature above or below 80 °C decreased the reaction yield and produced side-products (Table 1, entries 16 and 17).

Table 1 Optimization of the catalytic conditions^a

Entry	Cat.	Solvent	Yield^b (%) 4a
a Reaction conditions: 1a (0.5 mmol), cat. (10 mol%) in the solvent (3 mL) was added 2a (1.5 equiv.) and 3a (1.5 equiv.) stirring at 80 °C for 4 h.b Isolated yields.c nd = not detected the target product.d The reaction temperature was 70 °C.e The temperature was 90 °C.
1	CuI	CHCl3	72
2	CuI	DCE	81
3	CuI	Toluene	79
4	CuI	MeCN	96
5	CuI	THF	85
6	CuI	1,4-Dioxane	94
7	CuI	DMSO	20
8	CuI	DMF	46
9	CuI	EtOH	40
10	CuCl	MeCN	88
11	CuBr	MeCN	84
12	CuBr2	MeCN	78
13	Cu(OAc)2	MeCN	80
14	Cu(OTf)2	MeCN	22
15	AgOAc	MeCN	nd^c
16	CuI	MeCN	90^d
17	CuI	MeCN	86^e

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With optimized reaction conditions for the formation of the “parent reaction” having been defined, the capacity of these to affect the coupling of a range of different substrates was investigated. As shown in Table 2, the electron effects of the substituents R¹ had slight influences for the substrates 1. For example, substrates bearing a 4-Me, 5-F, 4-Br and 4,5-(OMe)₂ group were examined, and 90–96% yields of 4a–4f were isolated. The substrates R² bearing the –Ph and 4-Br–C₆H₄ group also can obtain 4g–4h in good yield. Next, the scope and limitation of the substrate terminal ynones 2 were tested. When R³ was employed by the n-pentyl, isopropyl, –Ph, –OMe, –OEt and –O^t–Bu groups, it provided the corresponding iminoquinoline derivatives 4i–4n in good yields of 92–95%. It is noteworthy that the substrate sulfonyl azides also showed slight influences for the reaction. The R⁴ changed for aliphatic or aromatic substituents also can smoothly give the anticipated products (4o–4v) in excellent yields. From the above experimental results, this reaction is easy to operate and highly efficient.

Table 2 Substrate scopes^a

a Unless otherwise noted, the reaction conditions were as follows: 1 (0.5 mmol), CuI (10 mol%) in the MeCN (3 mL) was added 2 (1.5 equiv.), 3 (1.5 equiv.) with stirring at 80 °C for 4 h.b Gram-scale synthesis of compound 4a: magnify by 10 times.

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Except for 4m, none of the products 1,2-dihydro-2-iminoquinolines 4a–4v have been reported previously, which were subject to full spectroscopic characterization (see ESI for details†) and the derived data were in complete accordance with the assigned structures. Furthermore, 4a and 4s were confirmed by single-crystal X-ray analysis (Fig. 1). These analyses revealed that both incorporate Z-configured imine residues due to the hydrogen bonding (Fig. 1, the red dotted line). Thus, it has been assumed that all the other products formed during the course of this study possess the same geometry about the C=N bond.

Fig. 1 Single-crystal X-ray analysis of 4a (CCDC 2092343) and 4s (CCDC 2092351).

In order to further explain the effect of hydrogen bonding on the spatial structure of products, we synthesized N1 substituted product 4w through 1-(2-(methylamino)phenyl)ethan-1-one (1i), but-3-yn-2-one (2a) and p-tosyl azide (3a) under the standard condition. The single crystal analyses revealed that the product 4w gave the E-configured imine residues without the hydrogen bonding (Fig. 2).

Fig. 2 Single-crystal X-ray analysis of 4w (CCDC 2092350).

Products 4a–4v are all relatively stable species that survive chromatographic purification under conventional conditions. However, the 2-iminoquinolines skeletons were easy hydrolysis to 2-aminoquinolines. For example, upon treatment with 1.5 equivalents of 30% H₂SO₄ in water under reflux for 6 h, compound 4a is converted into 2-iminoquinolines product 5a of yield 98% (Scheme 2).

Scheme 2 Hydrolysis of 2-iminoquinolines.

A possible reaction pathway for the formation of N-(3-acetyl-4-methylquinolin-2(1H)-ylidene)-4-methylbenzenesulfonamide (4a) from precursors 1a, 2a and 3a is shown in Scheme 3. Thus, in keeping with earlier proposals,²² substrates 2a and 3a are expected to react in the presence of the copper(I) catalyst, so as to form the metallated triazole A that fragments with the accompanying loss of nitrogen to form a highly active intermediate, α-acyl-N-sulfonyl ketenimine B. Then, B is captured by 1a to generate the adduct C, which can transfer to the isomer D that undergoes aldol condensation to deliver the observed product 4a.

Scheme 3 Plausible reaction mechanism.

In summary, we have developed an operationally simple and effective means for preparing (Z)-1,2-dihydro-2-iminoquinolines from a mixture of the corresponding 1-(2-aminophenyl)ethan-1-ones, sulfonyl azides and terminal ynones through the base-free CuAAC/ring-opening process, and obtain the Z-configured products. This methodology is quite flexible and offers the capacity to generate forms of the title products that will be particularly useful in, for example, building more 2-iminoquinolines block facility.

Experimental

General

All melting points were determined on a Yanaco melting point apparatus and were uncorrected. IR spectra were recorded as KBr pellets on a Nicolet FT-IR 5DX spectrometer. All spectra of ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) were recorded on a Bruker AVANCE NEO 400 MHz spectrometer in DMSO-d₆ or CDCl₃ (otherwise as indicated), with TMS used as an internal reference and the J values are given in Hz. HRMS were obtained on a Thermo Scientific Q Exactive Focus Orbitrap LC-MS/MS spectrometer. All 1-(2-aminophenyl)ethan-1-ones (1a–1i, see ESI Section 1†) were prepared by purchase, terminal ynones (2a–2g, see ESI Section 1†) were prepared by purchase or literature methods,²³ and sulfonyl azides (3a–3i, see ESI Section 1†) were prepared by literature methods.²⁴

Preparation and characterizations of compounds 4a–4w and 5a

(Z)-N-(3-Acetyl-4-methylquinolin-2(1H)-ylidene)-4-methylbenzene sulfonamide (4a). To a solution of 1-(2-aminophenyl)ethanone (1a, 67.6 mg, 0.5 mmol), CuI (9.5 mg, 0.05 mmol) in MeCN (1.5 mL) was added. Then, the mixture but-3-yn-2-one (2a, 51.0 mg, 0.75 mmol), TsN₃ (3a, 147.8 mg, 0.75 mmol) in MeCN (1.5 mL) was added. After the reaction was stirred at 80 °C for 4 h and cooled to room temperature, the solvent was removed by evaporating in vacuum. The residue was purified by flash chromatography [silica gel, 20% EtOAc in petroleum ether (60–90 °C)] to give 170 mg (96%) of product 4a as a white solid, m.p. 195.5–196.8 °C. IR (KBr) ν 3462, 3267, 1705, 1615, 1592, 1366, 1138 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 11.93 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.40–7.36 (m, 2H), 7.23 (t, J = 8.0 Hz, 2H), 2.47 (s, 3H), 2.42 (s, 3H), 2.36 (s, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 201.7, 150.5, 145.1, 142.5, 139.7, 134.8, 132.4, 131.9, 129.1 (2C), 125.7 (2C), 125.1, 124.8, 121.1, 117.0, 31.3, 21.2, 15.5; HRMS (ESI) m/z calcd for C₁₉H₁₉N₂O₃S⁺ [M + H]⁺ 355.11108, found 355.11041.

The products 4b–4w were prepared by the similar procedure.

(Z)-N-(3-Acetyl-4,7-dimethylquinolin-2(1H)-ylidene)-4-methylbenzene sulfonamide (4b). 173 mg (94%), white solid, m.p. 233.8–234.4 °C. IR (KBr) ν 3450, 3240, 1701, 1609, 1520, 1350, 1134 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 11.90 (s, 1H), 7.80 (d, J = 6.8 Hz, 2H), 7.66 (d, J = 7.6 Hz, 1H), 7.26–7.17 (m, 4H), 2.47 (s, 6H), 2.40 (s, 3H), 2.36 (s, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 202.1, 150.8, 145.3, 143.3, 142.5, 139.9, 135.2, 131.6, 129.3 (2C), 126.5, 125.9 (2C), 125.0, 119.2, 117.0, 31.5, 21.6, 21.4, 15.6; HRMS (ESI) m/z calcd for C₂₀H₂₁N₂O₃S⁺ [M + H]⁺ 369.12674, found 369.12601.

(Z)-N-(3-Acetyl-6-fluoro-4-methylquinolin-2(1H)-ylidene)-4-methylbenzenesulfonamide (4c). 171 mg (92%), white solid, m.p. 184.1–186.4 °C. IR (KBr) ν 3240, 3190, 1709, 1609, 1416, 1350, 1130, 1072 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 12.02 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.45 (td, J = 9.2 Hz, 2.4 Hz, 2H), 7.38 (td, J = 8.8 Hz, 2.8 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 2.49 (s, 3H), 2.40 (s, 3H), 2.39 (s, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 202.6, 159.2 (d, J = 244.6 Hz), 150.5, 144.1 (d, J = 3.6 Hz), 142.8, 139.6, 133.6, 131.7, 129.3 (2C), 125.9 (2C), 122.4 (d, J = 8.4 Hz), 120.4 (d, J = 24.7 Hz), 119.1, 110.5 (d, J = 23.6 Hz), 31.4, 21.4, 15.8; HRMS (ESI) m/z calcd for C₁₉H₁₈FN₂O₃S⁺ [M + H]⁺ 373.10167, found 373.10077.

(Z)-N-(3-Acetyl-6-chloro-4-methylquinolin-2(1H)-ylidene)-4-methylbenzenesulfonamide (4d). 181 mg (93%), white solid, m.p. 204.2–205.9 °C. IR (KBr) ν 3466, 3198, 1709, 1617, 1589, 1531, 1350, 1134 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 11.90 (s, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 1.0 Hz, 1H), 7.47 (dd, J = 8.8 Hz, 1.0 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H), 2.39 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 201.4, 150.5, 143.8, 142.8, 139.5, 133.6, 132.1, 130.4, 129.3 (2C), 125.9 (2C), 124.6, 122.3, 118.7, 31.3, 21.4, 15.7; HRMS (ESI) m/z calcd for C₁₉H₁₈ClN₂O₃S⁺ [M + H]⁺ 389.07212, found 389.07147.

(Z)-N-(3-Acetyl-7-bromo-4-methylquinolin-2(1H)-ylidene)-4-methyl benzenesulfonamide (4e). 195 mg (90%), white solid, m.p. 261.2–263.7 °C. IR (KBr) ν 3401, 3252, 1618, 1524, 1346, 1138 cm⁻¹; {¹H} NMR (400 MHz, DMSO-d₆) δ 11.94 (s, 1H), 8.42 (s, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.62 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 2.35 (s, 6H), 2.31 (s, 3H), 2.31 (s, 3H); {¹³C} NMR (100 MHz, DMSO-d₆) δ 202.3, 150.1, 145.2, 143.0, 140.4, 137.0, 133.1, 130.0 (2C), 128.3, 127.9, 126.3 (2C), 125.6, 121.4, 120.6, 31.6, 21.5, 15.9; HRMS (ESI) m/z calcd for C₁₉H₁₈BrN₂O₃S⁺ [M + H]⁺ 433.02160, found 433.02118.

(Z)-N-(3-Acetyl-6,7-dimethoxy-4-methylquinolin-2(1H)-ylidene)-4-methylbenzenesulfonamide (4f). 191 mg (92%), white solid, m.p. 128.2–130.0 °C. IR (KBr) ν 3437, 3248, 1609, 1520, 1423, 1334, 1269 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 12.04 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.01 (s, 1H), 6.92 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 2.41 (s, 3H), 2.35 (s, 3H), 2.29 (s, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 202.3, 153.6, 149.9, 147.4, 144.8, 142.2, 140.2, 131.5, 129.9, 129.1 (2C), 125.6 (2C), 115.1, 104.6, 99.1, 56.4, 56.1, 31.5, 21.2, 15.9; HRMS (ESI) m/z calcd for C₂₁H₂₃N₂O₅S⁺ [M + H]⁺ 415.13221, found 415.13144.

(Z)-N-(3-Acetyl-4-phenylquinolin-2(1H)-ylidene)-4-methylbenzene sulfonamide (4g). 194 mg (93%), white solid, m.p. 228.9–229.4 °C. IR (KBr) ν 3421, 3252, 1713, 1623, 1362, 1284, 1134 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 12.12 (s, 1H), 7.86 (d, J = 6.8 Hz, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.48–7.44 (m, 4H), 7.28–7.26 (m, 6H), 2.39 (s, 3H), 2.19 (s, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 200.2, 150.8, 148.6, 142.8, 139.8, 135.6, 133.2, 132.1 (2C), 129.6, 129.3 (2C), 128.9 (2C), 128.6 (2C), 127.8, 126.4, 126.0, 124.8, 121.3, 116.9, 31.5, 21.5; HRMS (ESI) m/z calcd for C₂₄H₂₁N₂O₃S⁺ [M + H]⁺ 417.12674, found 417.12585.

(Z)-N-(3-Acetyl-4-(4-bromophenyl)quinolin-2(1H)-ylidene)-4-methyl benzenesulfonamide (4h). 238 mg (96%), white solid, m.p. 243.9–244.5 °C. IR (KBr) ν 3451, 3152, 1709, 1618, 1528, 1366, 1288, 1134 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 11.92 (s, 1H), 7.64 (d, J = 7.6 Hz, 2H), 7.45–7.40 (m, 3H), 7.25 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 7.2 Hz, 4H), 6.96 (d, J = 8.0 Hz, 2H), 2.19 (s, 3H), 2.01 (s, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 199.9, 150.6, 147.4, 142.8, 139.6, 135.6, 133.3, 132.3, 132.1, 131.9 (2C), 130.6 (2C), 129.3 (2C), 127.5, 126.0 (2C), 124.9, 123.8, 120.9, 117.0, 31.5, 21.4; HRMS (ESI) m/z calcd for C₂₄H₂₀BrN₂O₃S⁺ [M + H]⁺ 495.03725, found 495.03677.

(Z)-N-(3-Hexanoyl-4-methylquinolin-2(1H)-ylidene)-4-methylbenzene sulfonamide (4i). 194 mg (95%), white solid, m.p. 141.3–142.1 °C. IR (KBr) ν 3461, 3275, 1622, 1531, 1369, 1138, 1084 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 11.92 (s, 1H), 7.78 (t, J = 8.0 Hz, 3H), 7.60 (t, J = 7.6 Hz, 1H), 7.39–7.34 (m, 2H), 7.22 (d, J = 8.4 Hz, 2H), 2.70 (t, J = 7.2 Hz, 2H), 2.39 (s, 3H), 2.36 (s, 3H), 1.64–1.57 (m, 2H), 1.27–1.19 (m, 4H), 0.85 (t, J = 6.8 Hz, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 204.5, 150.8, 145.1, 142.6, 139.8, 135.0, 132.6, 131.9, 129.2 (2C), 125.9 (2C), 125.1, 124.8, 121.3, 117.2, 43.7, 31.1, 23.1, 22.4, 21.4, 15.7, 13.9; HRMS (ESI) m/z calcd for C₂₃H₂₇N₂O₃S⁺ [M + H]⁺ 411.17369, found 411.17322.

(Z)-N-(3-Isobutyryl-4-methylquinolin-2(1H)-ylidene)-4-methylbenzene sulfonamide (4j). 180 mg (94%), white solid, m.p. 155.9–156.7 °C. IR (KBr) ν 3263, 2970, 1701, 1624, 1531, 1369, 1281, 1138 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 11.93 (s, 1H), 7.79 (d, J = 8.0 Hz, 3H), 7.62 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 8.4 Hz, 2H), 7.23 (d, J = 9.3 Hz, 2H), 2.40 (s, 3H), 2.37 (s, 3H), 1.12 (s, 3H), 1.10 (s, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 208.5, 151.1, 145.9, 142.6, 139.8, 135.1, 132.2, 131.9, 129.3 (2C), 125.9 (2C), 125.2, 124.8, 121.4, 117.2, 41.1, 21.4, 17.9 (2C), 16.2; HRMS (ESI) m/z calcd for C₂₁H₂₃N₂O₃S⁺ [M + H]⁺ 383.14239, found 383.14163.

(Z)-N-(3-Benzoyl-4-methylquinolin-2(1H)-ylidene)-4-methylbenzene sulfonamide (4k). 196 mg (94%), white solid, m.p. 239.1–241.2 °C. IR (KBr) ν 3433, 3271, 1674, 1621, 1531, 1369, 1146 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 11.99 (s, 1H), 7.82–7.66 (m, 4H), 7.49–7.34 (m, 7H), 7.06 (s, 2H), 2.40 (s, 3H), 2.33 (s, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 194.0, 151.4, 146.9, 142.2, 139.8, 136.5, 135.5, 133.6, 132.1, 130.6, 129.1 (2C), 129.0 (2C), 128.7 (2C), 125.8 (2C), 125.1, 124.9, 121.4, 117.3, 21.4, 16.1; HRMS (ESI) m/z calcd for C₂₄H₂₁N₂O₃S⁺ [M + H]⁺ 417.12674, found 417.12601.

Methyl (Z)-4-methyl-2-(tosylimino)-1,2-dihydroquinoline-3-carboxylate (4l). 170 mg (92%), white solid, m.p. 190.1–192.0 °C. IR (KBr) ν 3360, 2959, 1748, 1622, 1592, 1369, 1138 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 11.87 (s, 1H), 7.82 (d, J = 6.4 Hz, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.36–7.29 (m, 2H), 7.21 (d, J = 8.0 Hz, 2H), 3.90 (s, 3H), 2.44 (s, 3H), 2.33 (s, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 165.8, 150.7, 146.4, 142.4, 140.0, 135.0, 132.2, 129.1 (2C), 126.1, 125.8, 125.0, 124.9 (2C), 120.6, 117.1, 52.7, 21.3, 16.4; HRMS (ESI) m/z calcd for C₁₉H₁₉N₂O₄S⁺ [M + H]⁺ 371.10600, found 371.10532.

Ethyl (Z)-4-methyl-2-(tosylimino)-1,2-dihydroquinoline-3-carboxylate (4m). 179 mg (93%), white solid, m.p. 144.5–146.4 °C (lit¹⁷ 146–147 °C). {¹H} NMR (400 MHz, CDCl₃) δ 11.84 (s, 1H), 7.78 (d, J = 7.6 Hz, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.53 (td, J = 8.0 Hz, 1.2 Hz, 1H), 7.32–7.26 (m, 2H), 7.15 (d, J = 8.4 Hz, 2H), 4.34–4.29 (m, 2H), 2.42 (s, 3H), 2.29 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 165.4, 150.7, 146.2, 142.5, 140.0, 135.2, 132.1, 129.1 (4C), 126.0, 125.1, 124.9, 120.9, 117.2, 61.9, 21.4, 16.4, 14.0.

Tert-butyl (Z)-4-methyl-2-(tosylimino)-1,2-dihydroquinoline-3-carboxylate (4n). 196 mg (95%), white solid, m.p. 134.8–136.6 °C. IR (KBr) ν 3460, 3283, 2978, 1732, 1624, 1582, 1285, 1146 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 11.80 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.32–7.25 (m, 2H), 7.19–7.16 (m, 2H), 2.43 (s, 3H), 2.30 (s, 3H), 1.45 (s, 9H); {¹³C} NMR (100 MHz, CDCl₃) δ 164.5, 150.9, 145.1, 142.4, 140.3, 135.2, 131.8, 129.1 (2C), 127.5, 126.0 (2C), 125.1, 124.7, 121.1, 117.1, 28.0 (3C), 21.4, 16.1; HRMS (ESI) m/z calcd for C₂₂H₂₅N₂O₄S⁺ [M + H]⁺ 413.15295, found 413.15222.

(Z)-N-(3-Acetyl-4-methylquinolin-2(1H)-ylidene)methane sulfonamide (4o). 134 mg (96%), white solid, m.p. 151.1–153.0 °C. IR (KBr) ν 3256, 3210, 1705, 1628, 1601, 1531, 1366, 1096 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 11.65 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.54 (td, J = 8.0 Hz, 1.2 Hz, 1H), 7.32 (td, J = 8.0 Hz, 0.8 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 2.99 (s, 3H), 2.48 (s, 3H), 2.37 (s, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 202.0, 150.7, 144.9, 134.9, 132.2, 131.8, 125.0, 124.7, 121.0, 117.1, 42.5, 31.3, 15.6; HRMS (ESI) m/z calcd for C₁₃H₁₅N₂O₃S⁺ [M + H]⁺ 277.06524, found 277.06476.

(Z)-N-(3-Acetyl-4-methylquinolin-2(1H)-ylidene)ethane sulfonamide (4p). 136 mg (93%), white solid, m.p. 155.4–156.7 °C. IR (KBr) ν 3485, 3256, 1709, 1671, 1605, 1273, 1096 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 11.69 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.53 (td, J = 7.2 Hz, 0.4 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 3.07–3.02 (m, 2H), 2.48 (s, 3H), 2.37 (s, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 201.9, 151.3, 144.6, 134.9, 132.2, 131.8, 125.0, 124.6, 120.9, 117.0, 49.0, 31.3, 15.5, 8.11; HRMS (ESI) m/z calcd for C₁₄H₁₇N₂O₃S⁺ [M + H]⁺ 293.09543, found 293.09485.

(Z)-N-(3-Acetyl-4-methylquinolin-2(1H)-ylidene)propane-1-sulfonamide (4q). 146 mg (95%), white solid, m.p. 121.6–123.3 °C. IR (KBr) ν 3280, 3206, 1710, 1631, 1596, 1377, 1261 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 11.70 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 3.02–2.98 (m, 2H), 2.48 (s, 3H), 2.37 (s, 3H), 1.84–1.74 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 202.0, 151.1, 144.6, 134.9, 132.3, 131.8, 125.0, 124.6, 120.9, 117.0, 56.4, 31.3, 17.2, 15.5, 12.8; HRMS (ESI) m/z calcd for C₁₅H₁₇N₂O₃S⁻ [M − H]⁻ 305.09653, found 305.09616.

(Z)-N-(3-Acetyl-4-methylquinolin-2(1H)-ylidene)butane-1-sulfonamide (4r). 147 mg (92%), white solid, m.p. 95.4–96.8 °C. IR (KBr) ν 3183, 2959, 1709, 1638, 1531, 1366, 1088 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 11.70 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 3.05–3.01 (m, 2H), 2.49 (s, 3H), 2.38 (s, 3H), 1.78–1.70 (m, 2H), 1.41–1.31 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 202.0, 151.2, 144.6, 135.0, 132.2, 131.8, 125.1, 124.6, 121.0, 117.1, 54.5, 31.4, 25.4, 21.3, 15.6, 13.4; HRMS (ESI) m/z calcd for C₁₆H₂₁N₂O₃S⁺ [M + H]⁺ 321.12674, found 321.12637.

(Z)-N-(3-Acetyl-4-methylquinolin-2(1H)-ylidene)-1-phenylmethane sulfonamide (4s). 159 mg (90%), white solid, m.p. 154.3–156.2 °C. IR (KBr) ν 3458, 3240, 1709, 1621, 1585, 1528, 1361, 1288 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 11.37 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.38 (d, J = 7.6 Hz, 2H), 7.32 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 7.6 Hz, 2H), 7.06–7.03 (m, 2H), 4.13 (s, 2H), 2.51 (s, 3H), 2.40 (s, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 202.0, 152.0, 144.7, 134.6, 132.1, 131.7, 130.9 (2C), 129.4, 128.2 (3C), 124.9, 124.7, 120.9, 116.9, 60.7, 31.5, 15.6; HRMS (ESI) m/z calcd for C₁₉H₁₉N₂O₃S⁺ [M + H]⁺ 355.11108, found 355.11072.

(Z)-N-(3-Acetyl-4-methylquinolin-2(1H)-ylidene)-4-chlorobenzene sulfonamide (4t). 178 mg (95%), white solid, m.p. 228.0–228.9 °C. IR (KBr) ν 3462, 3275, 1618, 1369, 1277, 1138, 1080 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 11.86 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.57 (td, J = 7.6 Hz, 0.8 Hz, 1H), 7.36–7.31 (m, 4H), 2.41 (s, 3H), 2.37 (s, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 201.8, 150.8, 145.6, 141.2, 138.2, 134.9, 132.5, 132.1, 128.9 (2C), 127.4 (2C), 125.2, 125.1, 121.4, 117.3, 31.5, 15.7; HRMS (ESI) m/z calcd for C₁₈H₁₆ClN₂O₃S⁺ [M + H]⁺ 375.05647, found 375.05569.

(Z)-N-(3-Acetyl-4-methylquinolin-2(1H)-ylidene)-4-bromobenzene sulfonamide (4u). 199 mg (95%), white solid, m.p. 247.2–248.5 °C. IR (KBr) ν 3421, 3275, 1705, 1630, 1531, 1372, 1142 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 11.87 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.58 (td, J = 4.0 Hz, 1.2 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.34 (t, J = 8.4 Hz, 2H), 2.41 (s, 3H), 2.38 (s, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 201.8, 150.8, 145.6, 141.8, 135.0, 132.6, 132.2, 131.9 (2C), 127.5 (2C), 126.8, 125.2, 125.1, 121.4, 117.4, 31.5, 15.8; HRMS (ESI) m/z calcd for C₁₈H₁₆BrN₂O₃S⁺ [M + H]⁺ 419.00595, found 419.00549.

(Z)-N-(3-Acetyl-4-methylquinolin-2(1H)-ylidene)-4-methoxy benzenesulfonamide (4v). 180 mg (97%), white solid, m.p. 190.6–191.5 °C. IR (KBr) ν 3414, 3352, 1709, 1628, 1535, 1366, 1254, 1134 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 11.93 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.0 Hz, 1H), 7.62 (td, J = 8.0 Hz, 0.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 9.2 Hz, 2H), 3.81 (s, 3H), 2.47 (s, 3H), 2.42 (s, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 202.0, 162.4, 150.6, 145.0, 135.1, 134.6, 132.7, 132.0, 128.0 (2C), 125.2, 124.8, 121.3, 117.2, 113.9 (2C), 55.5, 31.5, 15.7; HRMS (ESI) m/z calcd for C₁₉H₁₉N₂O₄S⁺ [M + H]⁺ 371.10600, found 371.10535.

(E)-N-(3-Acetyl-4-hydroxy-1,4-dimethyl-3,4-dihydroquinolin-2(1H)-ylidene)-4-methylbenzenesulfonamide (4w). 145 mg (75%), white solid, m.p. 211.1–211.5 °C. IR (KBr) ν 3448, 2974, 1713, 1535, 1273, 1142, 1084 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 7.88 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 7.6 Hz, 3H), 7.19 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 5.06 (s, 1H), 4.34 (s, 1H), 3.52 (s, 3H), 2.43 (s, 3H), 2.23 (s, 3H), 1.38 (s, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 205.1, 161.9, 143.0, 139.9, 136.5, 134.1, 129.4 (2C), 128.7, 126.6 (2C), 125.6, 124.1, 116.4, 71.5, 60.4, 33.6, 30.9, 28.1, 21.5; HRMS (ESI) m/z calcd for C₂₀H₂₃N₂O₄S⁺ [M + H]⁺ 387.13730, found 387.13651.

1-(2-Amino-4-methylquinolin-3-yl)ethanone (5a). A solution of N-(3-acetyl-4-methylquinolin-2(1H)-ylidene)-4-methylbenzene sulfon-amide (4a, 70.8 mg, 0.2 mmol) in 30% H₂SO₄ (3 mL) was refluxed for 6 h. Then, the pH of the mixture was adjusted to 9–10 with saturated K₂CO₃ after cooling to room temperature. The product was extracted with DCM, the aqueous layer was extracted with 3 × 20 mL DCM, and the organic phases were combined and dried with anhydrous MgSO₄. Then, the solvent was removed by evaporating in vacuum. The residue was purified by flash chromatography [silica gel, 30% EtOAc in petroleum ether (60–90 °C)] to give 39 mg (98%) of product 5a as a white solid, m.p. 154.0–154.5 °C. IR (KBr) ν 3448, 3125, 2924, 1690, 1663, 1601, 1420, 1223 cm⁻¹; {¹H} NMR (400 MHz, CDCl₃) δ 7.77 (d, J = 8.0 Hz, 1H), 7.58–7.50 (m, 2H), 7.24 (t, J = 7.2 Hz, 2H), 5.09 (s, 2H), 2.54 (s, 3H), 2.353 (s, 3H); {¹³C} NMR (100 MHz, CDCl₃) δ 206.3, 152.7, 147.2, 142.2, 130.7, 126.4, 124.0, 123.9, 123.3, 123.2, 32.6, 16.4; HRMS (ESI) m/z calcd for C₁₂H₁₃N₂O⁺ [M + H]⁺ 201.10224, found 201.10193.

All NMR spectra: please see ESI Section 3.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Financial support was provided by the Foundation and Applied Basic Research Fund project of Guangdong Province of China (2019A1515110918); Medical Scientific Research Foundation of Guangdong Province (A2021037 and A2020202); Discipline Construction Project of Guangdong Medical University (4SG21004G); Funds for PhD researchers of Guangdong Medical University in 2021; and the Science and technology program of Guangdong Province (2019B090905011).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2092343, 2092351 and 2092350. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1ra06330h

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