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Synthesis 2020; 52(12): 1833-1840
DOI: 10.1055/s-0039-1691740
paper
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 2,4-Diarylquinoline Derivatives via Chloranil-Promoted Oxidative Annulation and One-Pot Reaction

Dongping Cheng∗
a   College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
,
Xianhang Yan
a   College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
,
Jing Shen
a   College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
,
Yueqi Pu
a   College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
,
Xiaoliang Xu∗
b   College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, P. R. of China   Email: chengdp@zjut.edu.cn
,
Jizhong Yan∗
a   College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
› Author Affiliations

The authors are grateful to the Natural Science Foundation of China (21602197) and the Natural Science Foundation of Zhejiang Province (LY18B020018).
Further Information

Publication History

Received: 24 December 2019

Accepted after revision: 06 February 2020

Publication Date:
24 February 2020 (online)

 
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Abstract

An oxidative annulation for the synthesis of 2,4-diarylquinolines from o-allylanilines is disclosed that uses recyclable reagent Chloranil­ as the oxidant. The corresponding products are obtained in moderate to excellent yields. Furthermore, a one-pot access to 2,4-di­aryl­quinolines from easily available anilines and 1,3-diarylpropenes is described as a highly atom-efficient protocol that involves oxidative coupling, rearrangement, and oxidative annulation.


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Key words

oxidative annulation - one-pot reaction - chloranil - 2,4-di­arylqunoline

The quinoline nucleus is an important structure unit that exists widely in natural products and pharmaceuticals such as antibacterial,[1] antimalarial,[2] antioxidant,[3] anti-inflammatory­,[4] and insecticidal agents.[5] Quinolines are also applied as crucial ligands in the synthesis of phosphorescent materials, fluorsensors, and asymmetric catalysts.[6] Given their outstanding characteristics, various quinoline derivatives containing different substituents at specific positions have been designed and synthesized.[7] Among them, 2,4-diarylquinolines have been proven to be especially important because of their potential biological activities, as shown in Figure [1].[3] [8] As a result, a large number of synthetic protocols have been developed for the preparation of 2,4-diarylquinolines.[9]

Zoom Image
Figure 1 Bioactive 2,4-diarylquinoline skeleton

The traditional routes for synthesizing 2,4-diarylquinolines include the Combes reaction of anilines and 1,3-di­aryl-1,3-diketones,[10] the Friedländer reaction of 2-aminobenzophenone and acetophenones/benzylalcohols,[11] the Povarov reaction of anilines, arylaldehydes, and arylacetyl­enes/arylethylenes,[12] and the transition-metal- or acid-catalyzed­ cyclization of N-benzylanilines and arylacetyl­enes/arylethylenes.[13] However, these methods usually suffer­ from the drawbacks of prolonged reaction time and undesired self-condensation of the starting materials. Recently, a strategy based on the cyclization of o-functionalized anilines has emerged as an efficient alternative for constructing 2,4-diarylquinolines.[14] For example, the Ghorai­ group developed the KOtBu-mediated oxidative cycloisomerization of o-cinnamylanilines with DMSO as an oxidant (Scheme [1, a]).[15] The Alabugin group reported the DDQ/FeCl3-mediated intramolecular oxidative amination of o-substituted anilines (Scheme [1, b]).[16] Considering the importance of 2,4-diarylquinolines, it is still desirable to develop new, concise and efficient routes for the preparation of such structures under mild conditions. Recently, our group has explored the use of metal-free tandem annulations for constructing heterocycles with potential biological activities.[17] With our ongoing interest in this research area, herein, we disclose an oxidative annulation for the synthesis of 2,4-diarylquinolines from o-allylanilines mediated by Chloranil. Quinones as good oxidants have been widely applied in organic synthesis.[18] Although Chloranil is a cheap and recyclable reagent, an extensive review of the literature revealed that the application of Chloranil in oxidative coupling/annulation reactions is not common.[19] Based on our previous report,[20] a one-pot access to 2,4-diarylquinolines from easily available anilines and 1,3-diarylpropenes is also developed in this paper. The approach affords a highly atom-efficient protocol, with the loss of only six hydrogen atoms, which involves oxidative coupling, rearrangement, and oxidative annulation.

Zoom Image
Scheme 1 Previous and present strategies via oxidative annulation

Considering the similarity of o-allylaniline 1a to Alabugin’s substrate, the standard reaction conditions of Alabugin’s method were tried (Table [1], entry 1).[16] That is, the cyclization of 1a was performed in CH3CN at 80 °C in the presence of DDQ/FeCl3. Unfortunately, the desired product 2,4-diphenylquinoline could be isolated in only 39% yield. To optimize the reaction conditions, other quinones such as benzoquinone (BQ, E red = –0.50 V vs. SCE) and Chloranil (CA, E red = 0.01 V vs. SCE) were used instead of DDQ (E red = 0.51 V vs. SCE) (entries 2 and 3).[21] The reaction did not proceed when benzoquinone was used as an oxidant. It was found that FeCl­3 did not promote the reaction and the product was obtained in 66% yield only in the presence of Chloranil (entries 3 and 4). Encouraged by the result, several solvents, such as 1,4-dioxane, CH3NO2, 1,2-ClCH2CH2Cl (DCE), DMSO, and DMF were screened (entries 6–10). The reaction was found to proceed in all the examined solvents, but DCE was optimal. Decreasing the temperature to 60 °C reduced the yield (entry 11). Furthermore, the amount of Chloranil was examined and the results indicated that 2.1 equivalents Chloranil­ was best suited for the reaction (entries 12–14). After the reaction, the tetrachlorohydroquinone formed could be recycled to Chloranil by aerobic oxidation (see the Supporting Information for recyclability experiments).[22] The reaction proceeded well and the product was obtained in 88% yield when recycled Chloranil was used.

Table 1 Screening of the Optimal Conditionsa

Entry

Oxidant

Solvent

Temp (°C)

Yield (%)b

 1c

DDQ/FeCl3

CH3CN

80

39

 2c

BQ/FeCl3

CH3CN

80

–

 3c

Chloranil/FeCl3

CH3CN

80

60

 4

Chloranil

CH3CN

80

66

 5

DDQ

CH3CN

80

48

 6

Chloranil

1,4-dioxane

80

73

 7

Chloranil

CH3NO2

80

76

 8

Chloranil

DCE

80

88

 9

Chloranil

DMSO

80

41

10

Chloranil

DMF

80

64

11

Chloranil

DCE

60

76

12d

Chloranil

DCE

80

93

13e

Chloranil

DCE

80

81

14f

Chloranil

DCE

80

82

15

Chloranilg

DCE

80

88

a Reaction conditions: 1a (0.2 mmol), oxidant (2.2 equiv), solvent (3 mL), 2 h.

b Isolated yield.

c FeCl3 (20 mol%).

d Chloranil (2.1 equiv).

e Chloranil (2.0 equiv).

f Chloranil (2.3 equiv).

g Recycled Chloranil was used.

With the optimized conditions in hand, o-allylanilines with different substituents on the aniline moiety were first investigated. Aniline moieties containing electron-donating or electron-withdrawing substituents were good candidates for the reaction and afforded the corresponding products 2b–i in 68–93% yields (Table [2], entries 2–9). Notably, o-allylaniline, with a nitro group on the aniline moiety, reacted smoothly and provided the product 2f in 76% yield (entry 6). The desired products 2g–h were obtained in 86–93% yield when the ortho-position of the aniline moiety was substituted with a methyl or methoxyl group, regardless of their steric hindrance effect (entries 7 and 8). Secondly, various symmetrical 1′,3′-diarylallyl groups of o-allylanilines were examined (entries 10–16). The products were obtained­ in 90–91% yields when methyl group was attached­ at the para- and meta- position of 1′,3′-diarylallyls (entries 10 and 11). Only 61% yield was obtained when a methyl group was attached to the ortho-position, likely due to its steric bulk (entry 12). The yields were slightly lower when the para- and meta-position of 1′,3′-diarylallyls contained electron-withdrawing substituents such as F, Cl, or Br (entries 13–16). Finally, isomerized o-allylanilines with an unsymmetrical 1′,3′-diarylallyl group were examined, giving the isomerized products with excellent yields (entries 17 and 18).

Table 2 Substrate Scopea

Entry

R1

R2

R3

Ar1

Ar2

Product

Yield (%)b

 1

CH3

H

H

C6H5

C6H5

2a

93

 2

CH3O

H

H

C6H5

C6H5

2b

80

 3

F

H

H

C6H5

C6H5

2c

88

 4

Cl

H

H

C6H5

C6H5

2d

76

 5

Br

H

H

C6H5

C6H5

2e

90

 6

NO2

H

H

C6H5

C6H5

2f

76

 7

CH3

H

CH3

C6H5

C6H5

2g

86

 8

CH3O

H

CH3O

C6H5

C6H5

2h

93

 9

CH3O

CH3O

H

C6H5

C6H5

2i

68

10

CH3

H

H

4-CH3C6H4

4-CH3C6H4

2j

90

11

CH3

H

H

3-CH3C6H4

3-CH3C6H4

2k

91

12

CH3

H

H

2-CH3C6H4

2-CH3C6H4

2l

61

13

CH3

H

H

4-FC6H4

4-FC6H4

2m

80

14

CH3

H

H

4-ClC6H4

4-ClC6H4

2n

56

15

CH3

H

H

4-BrC6H4

4-BrC6H4

2o

50

16

CH3

H

H

3-ClC6H4

3-ClC6H4

2p

70

17

CH3

H

H

C6H5

4-ClC6H4

2q

95

18

CH3

H

H

C6H5

4-CH3C6H4

2r

90

a Reaction conditions: 1 (0.5 mmol), Chloranil (1.05 mmol), DCE (3 mL), 80 °C, 1–2 h.

b Isolated yield.

In 2012, our group reported the DDQ-mediated oxidative coupling of anilines and 1,3-diarylpropenes, which provided an efficient and convenient method for preparing N-allylanilines.[20] To obtain o-allylaniline 1a, the rearrangement of the coupling product N-allylaniline 5a was tried. Lewis acid Cu(OTf)2 (5 mol%) was subsequently added to the reaction mixture after the oxidative coupling of 4-methylaniline 3a and 1,3-diphenylpropene 4a (Scheme [2]). To our delight, the desired 2-allylaniline 1a was isolated in 60% yield when the reaction was stirred at 80 °C for 1 h. Screening other Lewis acids such as FeCl3, FeCl3·6H2O, CuCl2­, CuCl, CuBr, and FeSO4 indicated that FeCl3 was the best catalyst.

Zoom Image
Scheme 2 The conversion of N-allylaniline 5a into o-allylaniline 1a

Table 3 One-Pot Synthesis of 2,4-Diarylquinolinesa

Entry

Ar

R

Product

Yield (%)b

 1

C6H5

4-CH3

2a

77c

 2

C6H5

4-CH3

2a

87

 3

C6H5

4-CH3O

2b

61

 4

C6H5

4-F

2c

74

 5

C6H5

4-Cl

2d

65

 6

C6H5

4-Br

2e

70

 7

C6H5

2,4-(CH3)2

2g

89

 8

4-CH3C6H4

4-CH3

2j

67

 9

3-CH3C6H4

4-CH3

2k

66

10

2-CH3C6H4

4-CH3

2l

36

11

4-FC6H4

4-CH3

2m

67

a Reaction conditions: 3 (0.55 mmol), 4 (0.5 mmol), DDQ (0.55 mmol), DCE (3 mL), r.t., 10 min; FeCl3 (0.025 mmol), 80 °C, 1 h; Chloranil (1.05 mmol), 80 °C, 1–2 h.

b Isolated yield.

c 1,4-Dioxane (3 mL) as solvent.

Based on the above experiments, a one-pot cascade approach to 2,4-diarylquinolines from easily available anilines and 1,3-diarylpropenes was explored (Table [3]). The tandem reaction of 4-methylaniline 3a and 1,3-diphenylpropene 4a was carried out in 1,4-dioxane, which gave the final product 2,4-diphenylquinoline in 77% yield (entry 1). Examining a selection of solvents revealed that the yield could be increased­ to 87% when DCE was used (entry 2). Several corresponding­ products 2 were obtained from anilines 4 and symmetrical 1,3-arylpropenes 3 in moderate to good yields (entries 3–11).

Further, gram-scale oxidative annulation of 1a under similar reaction conditions provided the desired product 2a in good yield (80% isolated yield) (Scheme [3]).

Zoom Image
Scheme 3 Gram-scale synthesis
Zoom Image
Scheme 4 Control experiments
Zoom Image
Scheme 5 Proposed mechanism

To establish the mechanism of reaction, a series of control experiments were conducted (Scheme [4]). The desired product 2a was obtained in good yield when 2.1 equivalents of radical scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), butylated hydroxytoluene (BHT), or 1,1-diphenylethene (DPE) was added to the reaction mixture, which indicated that a radical process was disfavored in the oxidative annulation. Based on our previous work and on the above results, a plausible mechanism is proposed in Scheme [5]. Firstly, 4-methylaniline 3a reacts with 1,3-diphenylpropene 4a in the presence of DDQ to give 5a, which then rearranges to give o-allylaniline 1a. The latter reacts with Chloranil to afford the ion pair II via charge-transfer complex I and subsequent hydride transfer.[23] Finally, attack of the amino group on the allylic cation occurs, followed by oxidative dehydro-aromatization to generate the product 2a.

In summary, an efficient method for the synthesis of 2,4-diarylquinolines from o-allylanilines that uses recyclable Chloranil as the oxidant has been developed. The corresponding products are obtained in moderate to excellent yields. Additionally, a one-pot protocol is extended to the synthesis of 2,4-diarylquinolines from easily available anilines and 1,3-diarylpropenes through a three-step tandem reaction, which involves oxidative coupling, rearrangement, and oxidative annulation.

Column chromatography was carried out on silica gel (200–300 mesh). 1H NMR spectra were recorded with a 500 MHz spectrometer (Bruker AVANCE III 500MHz NMR spectrometer) or 600 MHz spectrometer (Bruker Ascend™ 600MHz superconducting NMR spectrometer). 13C NMR spectra were recorded with a 125 MHz spectrometer (Bruker AVANCE III 500MHz NMR spectrometer) or 150 MHz spectrometer (Bruker AscendTM 600MHz superconducting NMR spectrometer). Chemical shifts are reported in parts per million (δ) relative to the internal standard TMS (0 ppm) for CDCl3 or DMSO. The coupling constants, J, are reported in hertz (Hz). High-resolution mass spectra (HRMS) were recorded with a ESI-TOF (Agilent 6210 TOF LC/MS). Melting points were measured with a SGW X-4. The reagents were purchased from commercial chemical reagent companies and used without further purification unless otherwise stated. o-Allyl­aniline 1 was prepared according to reported procedures.[24]


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Synthesis of 2 through Oxidative Annulation; General Procedure

In a 10 mL round-bottomed flask o-allylaniline 1 (0.5 mmol) was dissolved in DCE (3 mL), then Chloranil (1.05 mmol, 0.2582 g) was added. The reaction mixture was stirred at 80 °C for 2 h. After the reaction, chloroform (10 mL) was added and the organic layer was washed with 2 N NaOH solution to remove tetrachlorohydroquinone completely, then with brine, dried over Na2SO4, and filtered. The solution was concentrated to dryness under reduced pressure and the crude product was purified by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc (10:1–80:1) as eluent to give the pure product 2.


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Synthesis of 2 through One-Pot Reaction; General Procedure

A solution of 1,3-diarylpropene 4 (0.5 mmol) and DDQ (0.55 mmol, 0.1249 g) in DCE (3 mL) was stirred at r.t. for 5 minutes. Aniline 3 (0.55 mmol) was added and the solution was stirred for 10 minutes, then FeCl3 (0.025 mmol, 0.0041 g) was added and the reaction mixture was stirred at 80 °C for 1 h. Finally, Chloranil (1.05 mmol, 0.2582 g) was added and the mixture was stirred at 80 °C for another 2 h. After completion of the reaction, the solution was concentrated under reduced pressure and the product was purified by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc­ (10:1–60:1) as eluent to give the pure product 2.

For the recyclability of Chloranil and its use in the one-pot synthesis of 2,4-diarylquinones, see the Supporting Information.


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6-Methyl-2,4-diphenylquinoline (2a)

Reaction time: 1 h; purification by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc (15:1) as eluent.

Yield: 0.1374 g (93%); yellow solid; mp 127–129 °C (lit.[25] 130–131 °C).

1H NMR (500 MHz, CDCl3): δ = 8.23–8.18 (m, 3 H), 7.82 (s, 1 H), 7.69 (s, 1 H), 7.61–7.53 (m, 8 H), 7.50–7.47 (m, 1 H), 2.51 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 156.0, 148.5, 147.4, 139.8, 138.7, 136.2, 131.7, 129.9, 129.5, 129.1, 128.8, 128.6, 128.3, 127.5, 125.7, 124.4, 119.4, 21.8.

HRMS (ESI): m/z [M + H]+ calcd for C22H18N: 296.1434; found: 296.1435.


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6-Methoxy-2,4-diphenylquinoline (2b)

Reaction time: 2 h; purification by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc (10:1) as eluent.

Yield: 0.1246 g (80%); yellow solid; mp 296–298 °C.

1H NMR (500 MHz, CDCl3): δ = 8.20–8.18 (m, 3 H), 7.80 (s, 1 H), 7.62–7.52 (m, 7 H), 7.48–7.45 (m, 1 H), 7.43 (dd, J = 9.2, 2.8 Hz, 1 H), 7.22 (d, J = 2.8 Hz, 1 H), 3.82 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 157.8, 154.6, 147.8, 144.9, 139.7, 138.8, 131.6, 129.4, 129.0, 128.8, 128.7, 128.4, 127.3, 126.7, 121.8, 119.7, 103.7, 55.5.

HRMS (ESI): m/z [M + H]+ calcd for C22H18NO: 312.1383; found: 312.1378.


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6-Fluoro-2,4-diphenylquinoline (2c)

Reaction time: 2 h; purification by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc (40:1) as eluent.

Yield: 0.1317 g (88%); light-yellow solid; mp 98–100 °C.

1H NMR (500 MHz, CDCl3): δ = 8.27 (dd, J = 9.1, 5.6 Hz, 1 H), 8.21–8.20 (m, 2 H), 7.86 (s, 1 H), 7.60–7.48 (m, 10 H).

13C NMR (126 MHz, CDCl3): δ = 161.8 (d, J = 245.8 Hz), 156.3 (d, J = 2.7 Hz), 148.8, 148.7, 145.9, 139.3, 138.0, 132.5 (d, J = 9.0 Hz), 129.43, 129.36, 128.9, 128.8, 128.7, 127.5, 126.5 (d, J = 9.6 Hz), 119.9, 119.7 (d, J = 25.6 Hz), 109.1 (d, J = 23.0 Hz).

HRMS (ESI): m/z [M + H]+ calcd for C21H15FN: 300.1183; found: 300.1174.


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6-Chloro-2,4-diphenylquinoline (2d)

Reaction time: 2 h; purification by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc (60:1) as eluent.

Yield: 0.1200 g (76%); white solid; mp 97–99 °C (lit.[15] 92–95 °C).

1H NMR (500 MHz, CDCl3): δ = 8.22–8.19 (m, 3 H), 7.89 (d, J = 2.1 Hz, 1 H), 7.86 (s, 1 H), 7.69 (dd, J = 9.0, 2.2 Hz, 1 H), 7.61–7.54 (m, 7 H), 7.51–7.48 (m, 1 H).

13C NMR (126 MHz, CDCl3): δ = 157.0, 148.5, 147.2, 139.2, 137.8, 132.2, 131.7, 130.5, 129.6, 129.4, 128.9, 128.8, 128.7, 127.5, 126.5, 124.5, 120.0.

HRMS (ESI): m/z [M + H]+ calcd for C21H15ClN: 316.0888; found: 316.0885.


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6-Bromo-2,4-diphenylquinoline (2e)

Reaction time: 2 h; purification by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc (60:1) as eluent.

Yield: 0.1621 g (90%); pale-yellow solid; mp 150–152 °C (lit.[26] 152–154 °C).

1H NMR (500 MHz, CDCl3): δ = 8.21 (d, J = 8.2 Hz, 2 H), 8.14 (d, J = 8.9 Hz, 1 H), 8.06 (d, J = 1.8 Hz, 1 H), 7.85 (s, 1 H), 7.82 (dd, J = 9.0, 2.1 Hz, 1 H), 7.61–7.53 (m, 7 H), 7.51–7.48 (m, 1 H).

13C NMR (126 MHz, CDCl3): δ = 157.2, 148.5, 147.4, 139.1, 137.7, 133.1, 131.8, 129.7, 129.5, 128.9, 128.84, 128.75, 127.8, 127.6, 127.0, 120.5, 120.0.

HRMS (ESI): m/z [M + H]+ calcd for C21H15BrN: 360.0382; found: 360.0379.


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6-Nitro-2,4-diphenylquinoline (2f)

Reaction time: 2 h; purification by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc (10:1) as eluent.

Yield: 0.1240 g (76%); white solid; mp 204–206 °C (lit.[15] 197–200 °C).

1H NMR (500 MHz, DMSO-d 6): δ = 8.71 (d, J = 2.4 Hz, 1 H), 8.53 (dd, J = 9.2, 2.5 Hz, 1 H), 8.44–8.42 (m, 2 H), 8.36 (d, J = 9.2 Hz, 1 H), 8.29 (s, 1 H), 7.76–7.59 (m, 8 H).

HRMS (ESI): m/z [M + H]+ calcd for C21H15N2O2: 327.1128; found: 327.1141.


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6,8-Dimethyl-2,4-diphenylquinoline (2g)

Reaction time: 2 h; purification by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc (40:1) as eluent.

Yield: 0.1330 g (86%); white solid; mp 124–126 °C.

1H NMR (500 MHz, CDCl3): δ = 8.35–8.33 (m, 2 H), 7.86 (s, 1 H), 7.60–7.55 (m, 8 H), 7.51–7.49 (m, 2 H), 2.99 (s, 3 H), 2.48 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 154.0, 148.6, 146.3, 139.9, 139.2, 137.6, 135.7, 131.9, 129.6, 129.1, 128.7, 128.5, 128.1, 127.4, 125.7, 122.3, 118.7, 21.8, 18.3.

HRMS (ESI): m/z [M + H]+ calcd for C23H20N: 310.159; found: 310.1582.


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6,8-Dimethoxy-2,4-diphenylquinoline (2h)

Reaction time: 2 h; purification by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc (15:1) as eluent.

Yield: 0.1588 g (93%); white solid; mp 147–149 °C (lit.[25] 145–148 °C).

1H NMR (500 MHz, CDCl3): δ = 8.16–8.15 (m, 2 H), 7.69 (s, 1 H), 7.62–7.55 (m, 5 H), 7.54–7.51 (m, 3 H), 7.46–7.43 (m, 1 H), 7.19 (s, 1 H), 4.10 (s, 3 H), 3.87 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 155.1, 152.5, 149.8, 147.5, 146.0, 139.9, 139.0, 129.3, 128.9, 128.8, 128.7, 128.3, 127.3, 121.1, 117.9, 108.7, 103.4, 56.2, 55.9.

HRMS (ESI): m/z [M + H]+ calcd for C23H20NO2: 342.1489; found: 342.1489.


#

6,7-Dimethoxy-2,4-diphenylquinoline (2i)

Reaction time: 2 h; purification by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc (20:1) as eluent.

Yield: 0.1161 g (68%); white solid; mp 164–165 °C (lit.[15] 160–162 °C).

1H NMR (500 MHz, CDCl3): δ = 8.21–8.20 (m, 2 H), 7.81 (s, 1 H), 7.60–7.55 (m, 4 H), 7.53–7.49 (m, 3 H), 7.44–7.41 (m, 1 H), 6.77 (s, 2 H), 4.11 (s, 3 H), 3.79 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 158.1, 156.8, 153.4, 147.8, 139.8, 139.1, 137.4, 129.3, 128.8, 128.7, 128.6, 128.3, 127.5, 127.4, 120.4, 101.2, 95.3, 56.3, 55.4.

HRMS (ESI): m/z [M + H]+ calcd for C23H20NO2: 342.1489; found: 342.1486.


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6-Methyl-2,4-di-p-tolylquinoline (2j)

Reaction time: 2 h; purification by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc (30:1) as eluent.

Yield: 0.1455 g (90%); light-yellow solid; mp 105–107 °C (lit.[25] 105–106 °C).

1H NMR (500 MHz, CDCl3): δ = 8.17 (d, J = 8.6 Hz, 1 H), 8.13 (d, J = 8.2 Hz, 2 H), 7.79 (s, 1 H), 7.71 (s, 1 H), 7.58 (dd, J = 8.6, 1.8 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 2 H), 7.40 (d, J = 7.8 Hz, 2 H), 7.36 (d, J = 8.0 Hz, 2 H), 2.51 (2 s, 2 × CH3, 6 H), 2.47 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 156.0, 148.4, 147.4, 139.1, 138.1, 137.0, 135.9, 135.8, 131.6, 129.8, 129.51, 129.46, 129.26, 127.33, 125.7, 124.4, 119.2, 21.8, 21.3.

HRMS (ESI): m/z [M + H]+ calcd for C24H22N: 324.1747; found: 324.1757.


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6-Methyl-2,4-di-m-tolylquinoline (2k)

Reaction time: 2 h; purification by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc (40:1) as eluent.

Yield: 0.1472 g (91%); light-yellow solid; mp 93–95 °C.

1H NMR (500 MHz, CDCl3): δ = 8.21 (d, J = 10.0 Hz, 1 H), 8.09 (s, 1 H), 8.01 (d, J = 7.8 Hz, 1 H), 7.82 (s, 1 H), 7.72 (s, 1 H), 7.61 (dd, J = 8.6, 1.9 Hz, 1 H), 7.50–7.36 (m, 5 H), 7.31 (d, J = 5.0 Hz, 1 H), 2.52 (2 s, 3 × CH3, 9 H).

13C NMR (126 MHz, CDCl3): δ = 156.2, 148.7, 147.2, 139.6, 138.6, 138.5, 138.4, 136.2, 131.8, 130.2, 120.0, 129.7, 129.0, 128.7, 128.4, 128.2, 126.7, 125.8, 124.7, 124.5, 119.5, 21.8, 21.6, 21.5.

HRMS (ESI): m/z [M + H]+ calcd for C24H22N: 324.1747; found: 324.1751.


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6-Methyl-2,4-di-o-tolylquinoline (2l)

Reaction time: 2 h; purification by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc (20:1) as eluent.

Yield: 0.0986 g (61%); light-yellow oil.

1H NMR (500 MHz, CDCl3): δ = 8.17 (d, J = 8.6 Hz, 1 H), 7.61–7.58 (m, 2 H), 7.43–7.41 (m, 3 H), 7.36–7.30 (m, 6 H), 2.48 (2 s, 2 × CH3, 6 H), 2.15 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 158.8, 147.7, 146.7, 140.7, 137.9, 136.4, 136.1, 136.0, 131.8, 130.8, 130.2, 129.8, 129.7, 129.6, 128.4, 128.3, 126.0, 125.79, 125.76, 124.5, 122.8, 21.7, 20.4, 20.1.

HRMS (ESI): m/z [M + H]+ calcd for C24H22N: 324.1747; found: 324.1736.


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2,4-Bis(4-fluorophenyl)-6-methylquinoline (2m)

Reaction time: 2 h; purification by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc (60:1) as eluent.

Yield: 0.1325 g (80%); white solid; mp 138–140 °C.

1H NMR (500 MHz, CDCl3): δ = 8.20–8.14 (m, 3 H), 7.70 (s, 1 H), 7.62 (s, 1 H), 7.58 (dd, J = 8.6, 1.8 Hz, 1 H), 7.54–7.52 (m, 2 H), 7.29–7.25 (m, 2 H), 7.22–7.18 (m, 2 H), 2.50 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 164.7, 163.8, 162.7, 161.9, 154.8, 147.5, 147.3, 136.5, 135.69, 135.66, 134.44, 134.42, 131.9, 131.2, 131.1, 129.8, 129.3, 129.2, 125.6, 124.1, 118.9, 115.74, 115.70, 115.6, 115.5, 21.8.

HRMS (ESI): m/z [M + H]+ calcd for C22H16F2N: 332.1245; found: 332.1249.


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2,4-Bis(4-chlorophenyl)-6-methylquinoline (2n)

Reaction time: 5 h; purification by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc (80:1) as eluent.

Yield: 0.1020 g (56%); white solid; mp 183–184 °C (lit.[15] 182–185 °C).

1H NMR (500 MHz, CDCl3): δ = 8.16–8.12 (m, 3 H), 7.70 (s, 1 H), 7.60 (d, J = 7.0 Hz, 2 H), 7.55 (d, J = 8.4 Hz, 2 H), 7.49 (d, J = 8.4 Hz, 4 H), 2.50 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 154.6, 147.5, 147.2, 137.8, 136.9, 136.8, 135.5, 134.6, 132.2, 130.8, 129.8, 129.0, 128.9, 128.7, 125.5, 124.1, 118.8, 21.9.

HRMS (ESI): m/z [M + H]+ calcd. for C22H16Cl2N: 364.0654; found: 364.0643.


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2,4-Bis(4-bromophenyl)-6-methylquinoline (2o)

Reaction time: 2 h; purification by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc (80:1) as eluent.

Yield: 0.1133 g (50%); yellow solid; mp 182–184 °C (lit.[15] 188–190 °C).

1H NMR (500 MHz, CDCl3): δ = 8.15 (d, J = 8.4 Hz, 1 H), 8.08–8.06 (m, 2 H), 7.73–7.70 (m, 3 H), 7.67–7.64 (m, 2 H), 7.61–7.59 (m, 2 H), 7.45–7.42 (m, 2 H), 2.50 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 154.7, 147.6, 147.3, 138.3, 137.3, 136.9, 132.2, 132.0, 131.9, 131.1, 129.8, 129.0, 125.5, 124.1, 123.9, 122.8, 118.7, 21.9.

HRMS (ESI): m/z [M + H]+ calcd for C22H16Br2N: 451.9644; found: 451.9651.


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2,4-Bis(3-chlorophenyl)-6-methylquinoline (2p)

Reaction time: 2 h; purification by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc (40:1) as eluent.

Yield: 0.1275 g (70%); white solid; mp 124–125 °C.

1H NMR (500 MHz, CDCl3): δ = 8.22 (d, J = 1.9 Hz, 1 H), 8.16 (d, J = 8.4 Hz, 1 H), 8.07–8.05 (m, 1 H), 7.72 (s, 1 H), 7.62–7.43 (m, 8 H), 2.51 (s, 3 H).

13C NMR (126 MHz, CDCl3): δ = 154.3, 140.7, 140.2, 137.2, 135.0, 134.7, 132.3, 130.1, 129.9, 129.5, 129.3, 128.6, 127.8, 127.6, 125.61, 125.55, 124.1, 119.0, 21.9.

HRMS (ESI): m/z [M + H]+ calcd for C22H16Cl2N: 364.0654; found: 364.0661.


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Mixture of 4-(4-Chlorophenyl)-6-methyl-2-phenylquinoline and 2-(4-Chlorophenyl)-6-methyl-4-phenylquinoline as 3:4 (2q)

Reaction time: 1 h; purification by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc (80:1) as eluent.

Yield: 0.1567 g (95%); white solid.

1H NMR (500 MHz, CDCl3): δ = 8.20–8.18 (m, 1 H), 8.16–8.14 (m, 3/7×5 H), 7.75 (d, J = 4.2 Hz, 1 H), 7.67 (s, 1 H), 7.60–7.48 (m, 5+4/7×5 H), 2.50 (s, 3/7×3 H), 2.50 (s, 4/7×3 H).

13C NMR (126 MHz, CDCl3): δ = 156.0, 154.6, 148.7, 147.3, 139.5, 138.5, 138.1, 137.0, 136.6, 135.4, 134.5, 131.98, 131.96, 130.9, 129.9, 129.8, 129.5, 129.3, 129.0, 128.87, 128.85, 128.7, 128.6, 128.4, 127.5, 125.8, 125.5, 124.4, 124.1, 119.3, 119.0, 21.8.

HRMS (ESI): m/z [M + H]+ calcd for C22H17ClN: 330.1044; found: 330.1054.


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Mixture of 6-Methyl-4-phenyl-2-(p-tolyl)quinoline and 6-Methyl-2-phenyl-4-(p-tolyl)quinoline as 3:1 (2r)

Reaction time: 2 h; purification by column chromatography on silica gel (200–300 mesh) with petroleum ether and EtOAc (25:1) as eluent.

Yield: 0.1392 g (90%); white solid.

1H NMR (500 MHz, CDCl3): δ = 8.24–8.19 (m, 1+3/4×2 H), 8.14 (d, J = 8.2 Hz, 1/4×2 H), 7.81 (d, 1 H), 7.74 (s, 3/4×1 H), 7.69 (s, 1/4×1 H), 7.61–7.55 (m, 4 H), 7.51–7.49 (m, 2 H), 7.40 (d, J = 7.9 Hz, 3/4×2 H), 7.37 (d, J = 8.0 Hz, 1/4×2 H), 2.53–2.47 (m, 6 H).

13C NMR (126 MHz, CDCl3): δ = 156.0, 148.5, 147.4, 139.8, 139.2, 138.7, 138.2, 136.9, 136.1, 136.0, 135.7, 131.7, 129.8, 129.7, 129.52, 129.49, 129.4, 129.3, 129.1, 128.8, 128.5, 128.2, 127.5, 127.3, 125.8, 125.6, 124.44, 124.35, 119.3, 119.2, 21.8, 21.3.

HRMS (ESI): m/z [M + H]+ calcd for C23H20N: 310.159; found: 310.1577.


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Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0039-1691740.
  • Supporting Information


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Figure 1 Bioactive 2,4-diarylquinoline skeleton
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Scheme 1 Previous and present strategies via oxidative annulation
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Scheme 2 The conversion of N-allylaniline 5a into o-allylaniline 1a
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Scheme 3 Gram-scale synthesis
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Scheme 4 Control experiments
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Scheme 5 Proposed mechanism