Copper(II)-catalyzed remote sulfonylation of aminoquinolines with sodium sulfinates via radical coupling

Abstract

The efficient remote sulfonylation of N-(quinolin-8-yl)benzamide derivatives at the C5 position has been well developed. The reaction generates environmentally benign byproducts by utilizing stable and safe sodium sulfinates as sulfide sources. A series of N-(5-(phenylsulfonyl)quinolin-8-yl)benzamide derivatives were successfully obtained in moderate to high yields. In particular, they are less unpleasantly odorous and more environmentally friendly than previous means.

---

Introduction

Organosulfones have been proven to be a valuable building block in medicinal chemistry. It appears widely in medicinally active compounds, such as anti-HIV,¹ antibacterial,² antihyperglycemic,³ 5-HT₆ receptor (5-HT₆R) antagonists,⁴ D₂ receptor⁵ antagonists and anticancer drugs.⁶ Many representative examples of drugs and bioactive thioethers with quinoline or naphthyl scaffolds that are used as drug candidates for various diseases are shown in (Fig. 1).

Fig. 1 Aromatic sulfones used as drugs or drug candidates.

Several methods for the synthesis of aryl sulfones have been reported. The common approaches to prepare aryl sulfones include the oxidation of sulfoxides and sulfides⁷ or the sulfonylation of arenes via Friedel–Crafts sulfonylation in the presence of strong acids.⁸ It is disappointing that these methods are tedious and have low conversion. In recent years, many more efficient routes such as decarboxylative and C–H activation cross-coupling have been developed. For example, Rahul et al. reported an iodine-catalyzed decarboxylative coupling reaction to synthesize vinyl sulfones utilizing cinnamic acids and arylsulfonyl hydrazides.⁹ Many groups have developed the C–H bond activation of C(sp²)–H or C(sp)–H bonds with sulfonyl chlorides,¹⁰ sulfonyl hydrazides¹¹ diaryl disulfides¹² and sulfinic acids¹³ to synthesize organosulfones. But the sulfide sources are reported to have many properties such as toxicity, unpleasant odours and instability. Furthermore, many undesired byproducts are also produced. Thus, sodium sulfinates have attracted much attention because they provide a way to attain the desirable requirement of atom economy and relative safety. Chen’s¹⁴ group reported an efficient metal-free sulfonylated five-membered hetero-cyclic compound with sodium sulfinates. Next, our group¹⁵ independently reported aryl halides and sodium sulfinates which can also be used as coupling reagents catalyzed by copper to synthesize sulfone derivatives. Similarly, Xu et al. have developed a highly efficient method to synthesize vinyl sulfones reacting with cinnamic acids and sodium sulfinates¹⁶via a decarboxylative reaction with transition-metal-free. Furthermore, Tang and Xiao reported a C–H activation coupling method of oxime acetates¹⁷ or indoles¹⁸ with sodium sulfinates to synthesize sulfone derivatives.

Recently, more and more effort has been made to develop many techniques to control the reaction selectivity assistance of a directing group. Such as azobenzene,¹⁹ phenylpyridine²⁰ working as a directing group in direct sulfonylation via C–H functionalization with sulfonyl chlorides has been reported, which can provide a shortcut for ortho-aryl sulfones. However, Saidi²¹ and co-workers found that only meta-aryl sulfones were obtained when ruthenium was used as the catalyst in this reaction. Encouragingly, two publications from Wei and Wu’s group highlighted the discovery of the selective remote C–H sulfonylation at the C5–H position of 8-aminoquinoline with arylsulfonyl chlorides via copper catalysis (Fig. 2).²² But Liu and Rao reported that they only obtained ortho C–H bond sulfonylation of benzoic acid when using sodium sulfinates as sulfide sources.²³ In recent years, many efforts of our group have been expended on developing C–S bond formation.^15a,19a,24 Besides these contributions, we focused our efforts on how to build C–S bonds utilizing sodium sulfinates as sulfide sources via C–H functionalization. Among them, a catalyst-controlled selectivity in C–S bond formation in the synthesis of C2- and C3-sulfanylindoles was reported.²⁵ Herein, we report a simple and an environmental-friend procedure for the synthesis of N-(5-(phenylsulfonyl)quinolin-8-yl)benzamide and its derivatives via copper-catalyzed direct cross-coupling of the N-(quinolin-8-yl)benzamide derivatives with sodium sulfinates.

Fig. 2 Selective sulfonylation of 8-aminoquinoline.

Results and discussion

Initially, N-(quinolin-8-yl)benzamide (1a) and sodium 4-tolylsulfinate (2a) were used as the standard substrates under different conditions (Table 1).

Table 1 Reaction optimization^a

Entry	Catalyst [mol%]	Oxidant [equiv.]	Additive [equiv.]	Solvent	Yield^b [%]
a Reaction conditions: 1a (0.2 mmol), 2a (2.0 eq.), catalyst (15 mol%), oxidant (2.0 eq.), additive (2.0 eq.), solvent (2.0 mL), under air, 60 °C, 12 h. b Isolated yields. c Without catalyst. d Without oxidant. e Without additive. f The reaction was carried out at room temperature. g The reaction was carried out at 90 °C. TBHP = tert-butyl hydroperoxide. DTBP = di-tert-butyl peroxide. TBPB = tert-butyl perbenzoate.
1	Pd(OAc)2	TBHP	Na2CO3	CH3CN	0
2	FeSO4·7H2O	TBHP	Na2CO3	CH3CN	0
3	CuI	TBHP	Na2CO3	CH3CN	55
4	Cu(NO3)2	TBHP	Na2CO3	CH3CN	20(0)^c
5	Cu(OAc)2	TBHP	Na2CO3	CH3CN	60
6	Cu(OAc)2	TBHP	Na2CO3	DMF	15
7	Cu(OAc)2	TBHP	Na2CO3	THF	45
8	Cu(OAc)2	TBHP	Na2CO3	Acetone	65(0)^d
9	Cu(OAc)2	H2O2	Na2CO3	Acetone	15
10	Cu(OAc)2	DTBP	Na2CO3	Acetone	55
11	Cu(OAc)2	K2S2O8	Na2CO3	Acetone	30
12	Cu(OAc)2	TBPB	Na2CO3	Acetone	83(30)^e
13	Cu(OAc)2	TBPB	Cs2CO3	Acetone	45
14	Cu(OAc)2	TBPB	K2CO3	Acetone	42
15	Cu(OAc)2	TBPB	KHCO3	Acetone	37
16^f	Cu(OAc)2	TBPB	Na2CO3	Acetone	15
17^g	Cu(OAc)2	TBPB	Na2CO3	Acetone	80

---

To our delight, C₅-thioetherification did not take place in the presence of Pd(OAc)₂ or FeSO₄·7H₂O (15 mol%) in CH₃CN under air for 12 h (entry 1–2, Table 1). But the product can be isolated with a copper catalyst and the desired product was acquired in a 60% yield when Cu(OAc)₂ was used as the catalyst (entry 3–5, Table 1). Also, without catalyst, no product was isolated at all (entry 4^c, Table 1). Solvents such as DMF, THF, and acetone were screened, and acetone was found to be superior to the others (entries 6–8). Subsequently, various oxidants involving TBHP, H₂O₂, DTBP, K₂S₂O₈ and TBPB were tested for this reaction, among which TBPB gave the best results (entries 8–12, Table 1). In addition, the reaction did not occur at all without oxidant. Na₂CO₃ was superior to other bases, such as Na₂CO₃, CsCO₃, K₂CO₃ and KHCO₃ (entries 12–15, Table 1). Subsequently, the temperature also played an important role in the reaction, the yield is 15% at room temperature and 80% at 90 °C (entries 16–17, Table 1). According to our optimal conditions, we then investigated the substrate scope of this transformation (Table 2).

Table 2 Substrate scope of the copper(II)-catalyzed direct sulfonylation of N-(quinolin-8-yl)benzamide derivatives with sodium sulfinates^a,b

a Reaction conditions: 1 (0.2 mmol), 2a (2.0 eq.), Cu(OAc)₂ (15 mol%), TBPB (2.0 eq.), Na₂CO₃ (2.0 eq.), acetone (2.0 mL), under air, 60 °C, 12 h. b Isolated yields. TBPB = tert-butyl perbenzoate.

---

A series of sodium sulfinates were allowed to react with N-(quinolin-8-yl)benzamide (1a), affording the corresponding N-(5-(phenylsulfonyl)quinolin-8-yl)benzamide in moderate to good yields. It was found that sodium sulfinates containing an electron-donating group such as sodium p-tolylsulfinate or sodium benzenesulfinate gave good yields (Table 2, see compounds 3a, 3b). However, sodium p-trifluoromethylsulfinate, sodium p-fluorosulfinate, and sodium p-bromosulfinate with electron-withdrawing group afforded a lower yield (Table 2, see compounds 3c, 3d, and 3e). Meanwhile, the bulkier group on the phenyl ring of sodium sulfinate impedes the reaction, as exemplified by 3f and 3g. Additionally, heterocyclic-derived sodium sulfinates also have a lower yield (Table 2, see compounds 3h, 3j, and 3k). Unfortunately, no product was delivered when using sodium propane-2-sulfinate as a reactant (Table 2, see compounds 3r). Thus, 4-methyl-N-(quinolin-8-yl)benzamide, 2-methyl-N-(quinolin-8-yl)benzamide, 4-methoxy-N-(quinolin-8-yl)benzamide, 4-bromo-N-(quinolin-8-yl)benzamide, 4-cyano-N-(quinolin-8-yl)benzamide, N-(quinolin-8-yl)furan-2-carboxamide, and N-(quinolin-8-yl) cyclopropanecarboxamide were subjected to the reaction with various diaryl disulfides under the standard reaction conditions to yield the corresponding quinolone products in moderate yields (Table 2, see compounds 3i–3q). Also, many other examples based on different substituted quinoline rings have been tested, the yield is 53% for 3s and 72% for 3t but is trace for 3u (Table 2, see compounds 3s–3u). Subsequently, we also investigated the reaction mechanism; many experiments were conducted (Table 3).

Table 3 Mechanistic studies^a

Entry	R–H	ArSO2R	Yield^b [%]
a Reaction conditions: R–H (0.2 mmol), 2a (2.0 eq.), Cu(OAc)2 (15 mol%), TBPB (2.0 eq.), Na2CO3 (2.0 eq.), acetone (2.0 mL), under air, 60 °C, 12 h. b Isolated yields. c Addition of TEMPO (3.0 eq.). d Addition of BHT (3.0 eq.). e Without Cu(OAc)2, without Na2CO3. TBPB = tert-butyl perbenzoate. TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxy. BHT = butylated hydroxytoluene.
1			0
2			0
3			0
4			Trace^c
5			Trace^d
6			25^e

---

There are no sulfonylated products when N-(naphthalen-1-yl)benzamide 4, N-methyl-N-(quinolin-8-yl)benzamide 5 and quinolin-8-yl benzoate 6 react with 2a (entry 1–3, Table 3). In addition, when some radical scavengers such as TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) or BHT (butylated hydroxytoluene) were used in this sulfonylation reaction, this reaction was inhibited, and a trace of 3a was detected (entry 4–5, Table 3). But (2-tosylethene-1,1-diyl)dibenzene 7 was observed in the reaction of 1,1-diphenylethylene with 2a (entry 6, Table 3). After this, we also investigated the reactions of alternative 8-substituents and amides at other positions. And find that 8-aminoquinoline, 6-aminoquinoline or N-(quinolin-6-yl)benzamide lead to no reaction under our reaction conditions.

Referring to the literature,^{10a,13a,13b,16,18,24d,26} this experiment may undergo a free radical mechanism, and a plausible mechanism of this radical coupling reaction is described in Scheme 1. Initially, Cu(OAc)₂ reacts with aminoquinoline amide 1 to produce a chelated complex (A) which is promoted using Na₂CO₃. Then, TBPB turns sodium sulfinate into the sulfonyl free radical which reacts with complex (A) to generate intermediate (B) via a single-electron-transfer (SET) process. The intermediate (B) reacts with Cu(OAc)₂ to produce intermediate (C) and release CuOAc. Meanwhile, Cu(OAc)₂ is regenerated through oxidation. And intermediate (D) has been produced through a proton transfer (PT) process. Finally, intermediate (D) delivers the target product 3 and releases Cu(OAc)₂ which can work for the next catalytic cycle.

Scheme 1 Proposed mechanism with the copper catalyst.

Conclusions

We presented an regioselective C–H sulfonylation reaction of N-(quinolin-8-yl)benzamide derivatives for the synthesis of a variety of aminoquinolines-derived sulfones. Furthermore, sodium sulfinates work as the sulfonylation agents and Cu(OAc)₂ works as the catalyst, and they are all commercially available and inexpensive. Importantly, this protocol may provide an environmental-friendly and appealing alternative to the existing approaches to construct functionalized aminoquinoline derivatives, which are utilized as the key intermediates in the synthesis of drug candidates.

Experimental section

General information

All reactions were run under argon in Schlenk tubes using vacuum lines. CH₃CN, DMF, THF and acetone, were of analytical grade and were not distilled before use. ¹H NMR, ¹³C NMR spectra were recorded in CDCl₃ and DMSO using a 500 MHz spectrometer with shifts referenced to SiMe₄ (δ = 0). IR spectra were recorded on an FTIR spectrophotometer. Melting points were determined by using a local hot-stage melting point apparatus and are uncorrected. Elemental analyses were carried out on a CHN analyzer. Mass spectra were recorded using an LC-MS and HRMS (ESI-TOF analyzer) equipment.

General procedure for the synthesis of N-(5-tosylquinolin-8-yl)benzamide (3a). A mixture of 1a (49.6 mg, 0.2 mmol), 2a (71.2 mg, 2.0 eq.), Cu(OAc)₂ (5.4 mg, 15%) and Na₂CO₃ (42.4 mg, 2.0 eq.) in acetone (2.0 mL) was stirred at 60 °C under an air atmosphere for 12.0 h. Then the mixture was cooled to room temperature and poured into water (12 mL). The mixture was extracted with EtOAc (5 mL × 3) and the combined organic layer was washed with brine (10 mL), dried with Na₂SO₄, and the solvent was removed under reduced pressure. Product 3a was purified via flash column chromatography using PE/AcOEt as an eluent.

N-[5-(Toluene-4-sulfonyl)-quinolin-8-yl]-benzamide (3a)^24a. Obtained as a white solid in 83% yield; mp 182–183 °C. ¹H NMR (500 MHz, CDCl₃) δ 10.97 (s, 1H), 9.10 (dd, J = 8.8, 1.6 Hz, 1H), 9.05 (d, J = 8.4 Hz, 1H), 8.88 (dd, J = 4.2, 1.6 Hz, 1H), 8.56 (d, J = 8.5 Hz, 1H), 8.11–8.05 (m, 2H), 7.89–7.82 (m, 2H), 7.68–7.50 (m, 4H), 7.28 (d, J = 8.7 Hz, 2H), 2.37 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 165.70, 148.72, 144.16, 139.94, 139.12, 138.50, 134.41, 133.65, 132.44, 132.08, 129.92, 129.48, 128.97, 127.44, 127.32, 124.35, 123.32, 114.35, 21.52.

N-(5-(Phenylsulfonyl)quinolin-8-yl)benzamide (3b)^24a. Obtained as a white solid in 85% yield; mp 176–177 °C. ¹H NMR (500 MHz, CDCl₃) δ 10.97 (s, 1H), 9.06 (dd, J = 16.1, 8.5 Hz, 2H), 8.87 (s, 1H), 8.57 (d, J = 8.3 Hz, 1H), 8.06 (d, J = 7.3 Hz, 2H), 7.96 (d, J = 7.5 Hz, 2H), 7.52 (dd, J = 39.9, 7.2 Hz, 7H). ¹³C NMR (126 MHz, CDCl₃) δ 165.69, 148.79, 142.08, 140.13, 138.51, 134.36, 133.51, 133.14, 132.46, 132.35, 129.29, 128.98, 128.97, 127.42, 127.21, 124.38, 123.40, 114.28.

N-(5-((4-(Trifluoromethyl)phenyl)sulfonyl)quinolin-8-yl)benzamide (3c)^24a. Obtained as a white solid in 70% yield; mp 202–203 °C. ¹H NMR (500 MHz, CDCl₃) δ 11.00 (s, 1H), 9.09 (d, J = 8.4 Hz, 1H), 9.04 (dd, J = 8.8, 1.6 Hz, 1H), 8.91 (dd, J = 4.2, 1.6 Hz, 1H), 8.62 (d, J = 8.5 Hz, 1H), 8.08 (ddd, J = 5.7, 4.7, 3.0 Hz, 4H), 7.74 (d, J = 8.4 Hz, 2H), 7.63–7.56 (m, 4H). ¹³C NMR (126 MHz, CDCl₃) δ 165.74, 148.98, 145.58, 140.69, 138.45, 134.93 (q, J = 33.0 Hz), 134.18, 133.12, 133.04, 132.59, 129.02, 127.71, 127.63, 127.43, 126.48 (q, J = 3.6 Hz), 124.36, 123.98 (q, J = 271.4 Hz), 123.71, 114.29.

N-[5-(4-Bromo-benzenesulfonyl)-quinolin-8-yl]-benzamide (3d)^24a. Obtained as a white solid in 70% yield; mp 210–211 °C. ¹H NMR (500 MHz, CDCl₃) δ 11.00 (s, 1H), 9.09–9.04 (m, 2H), 8.91 (dd, J = 4.2, 1.6 Hz, 1H), 8.58 (d, J = 8.4 Hz, 1H), 8.14–8.06 (m, 2H), 7.86–7.81 (m, 2H), 7.64–7.62 (m, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 165.67, 148.88, 141.14, 140.39, 138.48, 134.28, 133.26, 132.59, 132.56, 132.50, 128.98, 128.72, 128.37, 128.34, 127.42, 124.28, 123.53, 114.27.

N-[5-(4-Fluoro-benzenesulfonyl)-quinolin-8-yl]-benzamide (3e)^24b. Obtained as a white solid in 75% yield; mp 207–208 °C. ¹H NMR (500 MHz, CDCl₃) δ 10.98 (s, 1H), 9.05 (d, J = 8.5 Hz, 2H), 8.90 (d, J = 2.7 Hz, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 7.2 Hz, 2H), 7.98 (dd, J = 8.9, 5.0 Hz, 2H), 7.64–7.55 (m, 4H), 7.16 (t, J = 8.6 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 165.74, 165.32 (d, J = 254.5 Hz), 148.88, 140.26, 138.49, 138.06, 134.26, 133.29, 132.54, 132.39, 130.05 (d, J = 9.5 Hz), 129.01, 128.71, 127.43, 124.23, 123.52, 116.64 (d, J = 22.5 Hz), 114.27.

N-(5-(Mesitylsulfonyl)quinolin-8-yl)benzamide (3f). Obtained as a white solid in 40% yield; mp 184–186 °C ¹H NMR (500 MHz, CDCl₃) δ 10.94 (s, 1H), 8.92 (d, J = 8.4 Hz, 1H), 8.86 (d, J = 4.2 Hz, 1H), 8.82 (d, J = 8.7 Hz, 1H), 8.05 (d, J = 8.0 Hz, 3H), 7.58 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 7.8 Hz, 3H), 6.95 (s, 2H), 2.56 (s, 6H), 2.29 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 165.70, 148.81, 143.59, 140.03, 139.05, 138.45, 134.46, 134.30, 133.32, 132.45, 132.38, 132.08, 129.36, 128.95, 127.40, 124.05, 123.11, 113.79, 22.81, 21.05.

N-(5-(Naphthalen-2-ylsulfonyl)quinolin-8-yl)benzamide (3g)^24a. Obtained as a white solid in 73% yield; mp 168–169 °C ¹H NMR (500 MHz, CDCl₃) δ 10.93 (s, 1H), 9.13 (dd, J = 8.7, 1.3 Hz, 1H), 9.05 (d, J = 8.4 Hz, 1H), 8.82 (dd, J = 4.2, 1.3 Hz, 1H), 8.66–8.58 (m, 2H), 8.08–8.01 (m, 2H), 7.94 (s, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.83–7.77 (m, 2H), 7.62–7.49 (m, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 165.64, 148.79, 140.14, 138.91, 138.46, 134.94, 134.31, 133.47, 132.45, 132.42, 132.13, 129.67, 129.37, 129.19, 128.96, 128.49, 127.93, 127.71, 127.41, 124.36, 123.43, 122.31, 114.26.

N-(5-(Thiophen-2-ylsulfonyl)quinolin-8-yl)benzamide (3h)^24b. Obtained as a white solid in 72% yield; mp 180–181 °C. ¹H NMR (500 MHz, CDCl₃) δ 10.98 (s, 1H), 9.24 (d, J = 7.2 Hz, 1H), 9.02 (d, J = 8.4 Hz, 1H), 8.90 (d, J = 2.6 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 7.1 Hz, 2H), 7.73 (d, J = 2.5 Hz, 1H), 7.64 (dd, J = 8.7, 4.2 Hz, 1H), 7.58 (dd, J = 18.8, 8.2 Hz, 4H), 7.04 (dd, J = 4.9, 3.9 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 164.67, 147.85, 142.86, 139.22, 137.44, 133.34, 132.53, 132.44, 132.04, 131.46, 130.95, 128.84, 127.97, 126.68, 126.41, 123.25, 122.44, 113.33.

N-(5-((4-Bromophenyl)sulfonyl)quinolin-8-yl)-4-methyl-benzamide (3i). Obtained as a white solid in 73% yield; mp 172–173 °C. ¹H NMR (500 MHz, CDCl₃) δ 10.94 (s, 1H), 9.03 (t, J = 8.6 Hz, 2H), 8.88 (d, J = 2.7 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 8.7 Hz, 3H), 7.35 (d, J = 8.0 Hz, 2H), 2.45 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 165.65, 148.85, 143.22, 141.15, 140.52, 138.46, 133.22, 132.59, 131.44, 129.65, 129.36, 128.71, 128.32, 128.12, 127.45, 124.27, 123.52, 114.16, 77.32, 77.06, 76.81, 21.59. HRMS (ESI+): calculated for C₂₃H₁₇BrN₂O₃S, [M + H]⁺ 481.0216, found 481.0226.

Methyl-3-((8-(4-methylbenzamido)quinolin-5-yl)sulfonyl) thiophene-2-carboxylate (3j). Obtained as a white solid in 48% yield; mp 184–185 °C. ¹H NMR (500 MHz, CDCl₃) δ 10.99 (s, 1H), 9.09 (d, J = 8.5 Hz, 1H), 8.90 (d, J = 7.3 Hz, 2H), 8.69 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 5.2 Hz, 1H), 7.60 (d, J = 5.2 Hz, 1H), 7.57 (d, J = 4.1 Hz, 1H), 7.37 (d, J = 7.9 Hz, 2H), 3.79 (s, 3H), 2.47 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 165.66, 159.19, 148.54, 144.94, 143.15, 140.23, 138.15, 134.88, 134.08, 133.08, 131.54, 131.02, 130.13, 129.65, 127.91, 127.45, 124.48, 123.31, 113.60, 52.90, 21.62. HRMS (ESI+): calculated for C₂₃H₁₈N₂O₅S₂, [M + H]⁺ 467.0730, found 467.0735.

N-(5-((3,5-Dimethylisoxazol-4-yl)sulfonyl)quinolin-8-yl)-2-methylbenzamide (3k). Obtained as a white solid in 43% yield; mp 153–154 °C. ¹H NMR (500 MHz, CDCl₃) δ 10.51 (s, 1H), 9.06 (d, J = 8.4 Hz, 1H), 8.92 (d, J = 8.7 Hz, 1H), 8.87 (d, J = 4.2 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.62 (dd, J = 8.7, 4.2 Hz, 1H), 7.44 (t, J = 6.9 Hz, 1H), 7.35 (t, J = 7.8 Hz, 2H), 2.79 (s, 3H), 2.61 (s, 3H), 2.25 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 173.40, 168.38, 157.51, 149.04, 140.62, 138.25, 137.16, 135.52, 132.49, 132.14, 131.70, 131.03, 128.79, 127.28, 126.20, 124.19, 123.55, 117.81, 113.74, 20.28, 12.99, 10.82. HRMS (ESI+): calculated for C₂₂H₁₉N₃O₄S, [M + H]⁺ 422.1169, found 422.1178.

4-Methyl-N-(5-tosylquinolin-8-yl)benzamide (3l). Obtained as a white solid in 80% yield; mp 187–189 °C. ¹H NMR (500 MHz, CDCl₃) δ 10.92 (s, 1H), 9.08 (d, J = 7.4 Hz, 1H), 9.02 (d, J = 8.4 Hz, 1H), 8.86 (d, J = 2.8 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.3 Hz, 2H), 7.57 (dd, J = 8.7, 4.2 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 5.7 Hz, 2H), 2.45 (s, 3H), 2.36 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 165.66, 148.69, 144.11, 143.11, 140.09, 139.15, 138.53, 133.56, 132.11, 131.60, 129.89, 129.63, 129.23, 127.45, 127.30, 124.33, 123.27, 114.19, 21.58, 21.51.

4-Methoxy-N-(5-tosylquinolin-8-yl)benzamide (3m)^24a. Obtained as a white solid in 85% yield; mp 178–179 °C. ¹H NMR (500 MHz, CDCl₃) δ 10.88 (s, 1H), 9.06 (d, J = 7.3 Hz, 1H), 9.00 (d, J = 8.4 Hz, 1H), 8.85 (d, J = 2.8 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 8.3 Hz, 2H), 7.56 (dd, J = 8.7, 4.2 Hz, 1H), 7.26 (d, J = 8.2 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H), 2.35 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 165.64, 159.17, 148.52, 144.92, 143.13, 140.22, 138.14, 134.87, 134.07, 133.06, 131.53, 131.00, 130.12, 129.63, 127.43, 124.46, 123.29, 113.59, 52.88, 21.60.

4-Bromo-N-(5-tosylquinolin-8-yl)benzamide (3n)^24a. Obtained as a white solid in 68% yield; mp 214–215 °C. ¹H NMR (500 MHz, CDCl₃) δ 10.93 (s, 1H), 9.08 (dd, J = 8.7, 1.6 Hz, 1H), 9.03 (d, J = 8.5 Hz, 1H), 8.86 (dd, J = 4.3, 1.6 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 7.98–7.93 (m, 2H), 7.85–7.81 (m, 2H), 7.57 (dd, J = 8.7, 4.2 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.26 (d, J = 5.7 Hz, 2H), 2.36 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 165.67, 148.69, 144.12, 143.12, 140.09, 139.16, 138.53, 133.57, 132.12, 131.61, 129.90, 129.64, 129.24, 127.46, 127.31, 124.34, 123.28, 114.20, 21.59.

4-Cyano-N-(5-tosylquinolin-8-yl)benzamide (3o). Obtained as a white solid in 71% yield; mp 170–171 °C. ¹H NMR (500 MHz, CDCl₃) δ 10.99 (s, 1H), 9.09 (d, J = 8.9 Hz, 1H), 8.99 (d, J = 8.7 Hz, 1H), 8.89 (d, J = 6.8 Hz, 1H), 8.55 (d, J = 8.6 Hz, 1H), 8.17 (d, J = 8.6 Hz, 2H), 7.85 (dd, J = 13.5, 7.9 Hz, 5H), 7.30 (d, J = 9.7 Hz, 3H), 2.37 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 163.73, 148.94, 144.32, 139.13, 138.76, 138.35, 138.10, 133.67, 132.79, 131.78, 130.28, 129.95, 128.07, 127.33, 124.22, 123.52, 117.86, 115.91, 114.57, 77.30, 77.05, 76.79, 21.55. HRMS (ESI+): calculated for C₂₄H₁₇N₃O₃S, [M + H]⁺ 428.1064, found 428.1074.

N-(5-Tosylquinolin-8-yl)furan-2-carboxamide (3p). Obtained as a white solid in 59% yield; mp 193–195 °C. ¹H NMR (500 MHz, CDCl₃) δ 10.99 (s, 1H), 9.08 (dd, J = 8.7, 1.4 Hz, 1H), 8.98 (d, J = 8.4 Hz, 1H), 8.90 (dd, J = 4.1, 1.4 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.65 (s, 1H), 7.58 (dd, J = 8.7, 4.1 Hz, 1H), 7.35 (dd, J = 3.8, 2.6 Hz, 1H), 7.31–7.25 (m, 2H), 6.62 (dd, J = 3.4, 1.7 Hz, 1H), 2.37 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 156.45, 148.83, 147.76, 145.05, 144.16, 139.59, 139.03, 138.36, 133.43, 131.89, 129.90, 127.31, 124.29, 123.33, 116.17, 114.28, 112.72, 21.51.

N-(5-Tosylquinolin-8-yl)cyclopropanecarboxamide (3q). Obtained as a white solid in 71% yield; mp 211–213 °C. ¹H NMR (500 MHz, CDCl₃) δ 10.25 (s, 1H), 9.03 (dd, J = 8.7, 1.6 Hz, 1H), 8.85–8.80 (m, 2H), 8.48 (d, J = 8.4 Hz, 1H), 7.83–7.79 (m, 2H), 7.54 (dd, J = 8.7, 4.2 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 2.35 (s, 3H), 1.85–1.79 (m, 1H), 1.17 (dd, J = 4.5, 3.0 Hz, 2H), 0.96 (dd, J = 7.8, 3.1 Hz, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 172.85, 148.54, 144.10, 139.94, 139.02, 137.88, 133.36, 132.05, 130.02, 129.87, 128.73, 128.22, 127.22, 124.21, 123.24, 113.98, 21.53, 16.45, 8.84. HRMS (ESI+): calculated for C₂₀H₁₈N₂O₃S, [M + H]⁺ 367.1111, found 367.1118.

N-(2-Methyl-5-tosylquinolin-8-yl)benzamide (3s)^22b. Obtained as a yellow solid in 53% yield; mp 200–201 °C. ¹H NMR (500 MHz, CDCl₃) δ 11.03 (s, 1H), 9.01 (d, J = 8.0 Hz, 1H), 8.94 (d, J = 10.0 Hz, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 10.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.57 (m, 3H), 7.44 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 4.0 Hz, 2H), 2.76 (s, 3H), 2.36 (s, 3H).

N-(6-Methoxy-5-tosylquinolin-8-yl)benzamide (3t)^22b. Obtained as a yellow solid in 72% yield; mp 188–189 °C. ¹H NMR (500 MHz, CDCl₃) δ 11.11 (s, 1H), 9.54 (dd, J = 9.0, 2.0 Hz, 1H), 8.80 (s, 1H), 8.75 (dd, J = 4.0, 1.6 Hz, 1H), 8.04 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.62 (m, 2H), 7.55 (t, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 3.87 (s, 3H), 2.40 (s, 3H).

1-(2,2-Diphenyl-ethenesulfonyl)-4-methyl-benzene (7)^9b. Obtained as a white solid in 25% yield; mp 93–94 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.45 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 4.3 Hz, 4H), 7.17 (d, J = 7.2 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 7.0 Hz, 2H), 6.98 (s, 1H), 2.34 (s, 3H).

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 21376058, 21302171), Zhejiang Provincial Natural Science Foundation of China (No. LZ13B020001) and Science Technology Plan of Zhejiang Province (No. 2014C31153), Science Technology Plan of Shandong Provincial (No. 2012GSF11812).

Notes and references

1. (a) G. L. Regina, A. Coluccia, A. Brancale, F. Piscitelli, V. Gatti, G. Maga, A. Samuele, C. Pannecouque, D. Schols, J. Balzarini, E. Novellino and R. Silvestri, J. Med. Chem., 2011, 54, 1587–1598; (b) V. Famiglini, G. L. Regina, A. Coluccia, S. Pelliccia, A. Brancale, G. Maga, E. Crespan, R. Badia, E. R. Muńoz, J. Esté, R. Ferretti, R. Cirilli, C. Zamperini, M. Botta, D. Schols, V. Limongelli, B. Agostino, E. Novellino and R. Silvestri, J. Med. Chem., 2014, 57, 9945–9957.
2. H. Rosen, R. Hajdu, L. Silver, H. Kropp, K. Dorso, J. Kohler, J. G. Sundelof, J. Huber, G. G. Hammond, J. J. Jackson, C. J. Gill, R. Thompson, B. A. Pelak, J. H. Epstein-Toney, G. Lankas, R. R. Wilkening, K. J. Wildonger, T. A. Blizzard, F. P. DiNinno, R. W. Ratcliffe, J. V. Heck, J. W. Kozarich and M. L. Hammond, Science, 1999, 283, 703–706.
3. A. Kenichi, S. Naotaka, T. Takayuki, I. Takahiro, M. Toshiaki, T. Keiji, X. Feng and Y. Naoki, WO 2009041475, April 2, 2009.
4. (a) A. V. Ivachtchenko, E. S. Golovina, M. G. Kadieva, V. M. Kysil, O. D. Mitkin, S. E. Tkachenko and I. M. Okun, J. Med. Chem., 2011, 54, 8161–8173; (b) N. Upton, T. T. Chuang, A. J. Hunter and D. J. Virley, Curr. Opin. Pharmacol., 2011, 11, 94–100; (c) J. Colomb, G. Becker, S. Fieux, L. Zimmer and T. Billard, J. Med. Chem., 2014, 57, 3884–3890.
5. C. F. Sturino, G. O’Neill, N. Lachance, M. Boyd, C. Berthelette, M. Labelle, L. Li, B. Roy, J. Scheigetz, N. Tsou, Y. Aubin, K. P. Bateman, N. Chauret, S. H. Day, J. F. Lévesque, C. Seto, J. H. Silva, L. A. Trimble, M. C. Carriere, D. Denis, G. Greig, S. Kargman, S. Lamontagne, M. C. Mathieu, N. Sawyer, D. Slipetz, W. M. Abraham, T. Jones, M. M. Auliffe, H. Piechuta, D. A. N. Griffith, Z. Y. Wang, R. Zamboni, R. N. Young and K. M. Metters, J. Med. Chem., 2007, 50, 794–806.
6. A. Kamal, G. Ramakrishna, V. L. Nayak, P. Raju, A. V. S. Rao, A. Viswanath, M. V. P. S. Vishnuvardhan, S. Ramakrishna and G. Srinivas, Bioorg. Med. Chem., 2012, 20, 789–800.
7. (a) W. G. Trankle and M. E. Kopach, Org. Process Res. Dev., 2007, 11, 913–917; (b) J. T. Reeves, Z. L. Tan, D. C. Reeves, J. J. Song, Z. S. Han, Y. B. Xu, W. J. Tang, B. S. Yang, H. Razavi, C. Harcken, D. Kuzmich, P. E. Mahaney, H. W. Lee, C. A. Busacca and C. H. Senanayake, Org. Process Res. Dev., 2014, 18, 904–911; (c) N. Fukuda and T. Ikemoto, J. Org. Chem., 2010, 75, 4629–4631; (d) K. Bahrami, M. M. Khodaei and M. S. Arabi, J. Org. Chem., 2010, 75, 6208–6213; (e) A. Rezaeifard, M. Jafarpour, A. Naeimi and R. Haddad, Green Chem., 2012, 14, 3386–3394.
8. (a) A. Gopalsamy, M. X. Shi, B. Stauffer, R. Bahat, J. Billiad, H. P. D. Leon, L. S. Wehr, A. Mangine, R. Moran, G. Krishnamurthy and P. Bodine, J. Med. Chem., 2008, 51, 7670–7672; (b) S. F. Barbuceanu, G. Saramet, G. L. Almajan, C. Draghici, F. Barbuceanu and G. Bancescu, Eur. J. Med. Chem., 2012, 49, 417–423; (c) B. M. Graybill, J. Org. Chem., 1967, 32, 2931–2933.
9. (a) R. Singh, B. K. Allam, N. Singh, K. Kumari, S. K. Singh and K. N. Singh, Org. Lett., 2015, 17, 2656–2659; (b) S. Mao, Y.-R. Gao, X.-Q. Zhu, D.-D. Guo and Y.-Q. Wang, Org. Lett., 2015, 17, 1692–1695.
10. (a) X. G. Liu, X. H. Chen and J. T. Mohr, Org. Lett., 2015, 17, 3572–3575; (b) F. Hu and X. Y. Lei, ChemCatChem, 2015, 7, 1539–1542.
11. X. W. Li, Y. L. Xu, W. Q. Wu, C. Jiang, C. R. Qi and H. F. Jiang, Chem.–Eur. J., 2014, 20, 7911–7915.
12. C. Lin, D. Y. Li, B. J. Wang, J. Z. Yao and Y. H. Zhang, Org. Lett., 2015, 17, 1328–1331.
13. (a) T. Shen, Y. Z. Yuan, S. Song and N. Jiao, Chem. Commun., 2014, 50, 4115–4118; (b) Q. Q. Lu, J. Zhang, G. L. Zhao, Y. Qi, H. M. Wang and A. W. Lei, J. Am. Chem. Soc., 2013, 135, 11481–11484; (c) Q. Q. Lu, J. Zhang, F. L. Wei, Y. Qi, H. M. Wang, Z. L. Liu and A. W. Lei, Angew. Chem., Int. Ed., 2013, 52, 7156–7159.
14. S. Liang, R. Y. Zhang, L. Y. Xi, S. Y. Chen and X. Q. Yu, J. Org. Chem., 2013, 78, 11874–11880.
15. (a) C. Shen, J. Xu, W. B. Yu and P. F. Zhang, Green Chem., 2014, 16, 3007–3012; (b) M. Yang, H. Y. Shen, Y. Y. Li, C. Shen and P. F. Zhang, RSC Adv., 2014, 4, 26295–26300.
16. Y. L. Xu, X. D. Tang, W. G. Hu, W. Q. Wu and H. F. Jiang, Green Chem., 2014, 16, 3720–3723.
17. X. D. Tang, L. B. Huang, Y. L. Xu, J. D. Yang, W. Q. Wu and H. F. Jiang, Angew. Chem., Int. Ed., 2014, 53, 4205–4208.
18. F. H. Xiao, H. Chen, H. Xie, S. Q. Chen, L. Yang and G. J. Deng, Org. Lett., 2014, 16, 50–53.
19. (a) C. C. Xia, Z. J. Wei, C. Shen, J. Xu, Y. Yang, W. K. Su and P. F. Zhang, RSC Adv., 2015, 5, 52588–52594; (b) D. Zhang, X. L. Cui, Q. Q. Zhang and Y. J. Wu, J. Org. Chem., 2015, 80, 1517–1522.
20. X. D. Zhao, E. Dimitrijević and V. M. Dong, J. Am. Chem. Soc., 2009, 131, 3466–3467.
21. O. Saidi, J. Marafie, A. E. W. Ledger, P. M. Liu, M. F. Mahon, G. Kociok-Köhn, M. K. Whittlesey and C. G. Frost, J. Am. Chem. Soc., 2011, 133, 19298–19301.
22. (a) H. W. Liang, K. Jiang, W. Ding, Y. Yuan, L. Shuai, Y. C. Chen and Y. Wei, Chem. Commun., 2015, 51, 16928–16931; (b) H. Qiao, S. Sun, F. Yang, Y. Zhu, W. Zhu, Y. Dong, Y. Wu, X. Kong, L. Jiang and Y. Wu, Org. Lett., 2015, 17, 6086–6089.
23. (a) J. D. Liu, L. Yu, S. B. Zhuang, Q. W. Gui, X. Chen, W. D. Wang and Z. Tan, Chem. Commun., 2015, 51, 6418–6421; (b) W. H. Rao and B. F. Shi, Org. Lett., 2015, 17, 2784–2787.
24. (a) S. Ranjit, R. Lee, D. Heryadi, C. Shen, J. E. Wu, P. F. Zhang, K. W. Huang and X. G. Liu, J. Org. Chem., 2011, 76, 8999–9007; (b) C. Shen, H. J. Xia, H. Yan, X. Z. Chen, S. Ranjit, X. J. Xie, D. Tan, R. Lee, Y. M. Yang, B. G. Xing, K. W. Huang, P. F. Zhang and X. G. Liu, Chem. Sci., 2012, 3, 2388–2393; (c) C. Shen, P. F. Zhang, Q. Sun, S. Q. Bai, T. S. A. Hor and X. G. Liu, Chem. Soc. Rev., 2015, 44, 291–314; (d) J. Xu, C. Shen, X. L. Zhu, P. F. Zhang, M. J. Ajitha, K. W. Huang, Z. F. An and X. G. Liu, Chem.–Asian J., 2016, 11, 882–892.
25. Y. Yang, W. M. Li, C. C. Xia, B. B. Ying, C. Shen and P. F. Zhang, ChemCatChem, 2016, 8, 304–307.
26. A. M. Suess, M. Z. Ertem, C. J. Cramer and S. S. Stahl, J. Am. Chem. Soc., 2013, 135, 9797–9804.

---

Footnote

† Electronic supplementary information (ESI) available: ¹H NMR spectra, ¹³C NMR spectrum, GC/MS profile, HRMS profile. See DOI: 10.1039/c6ra04013f

---